Despite advances in understanding of BKV biology and the risk factors that predispose kidney transplant recipients to develop BKV-associated nephropathy, it continues to be one of the most challenging causes of allograft dysfunction. Screening and early diagnosis of viral replication and BKV-associated nephropathy are of paramount importance to allow effective management strategies before severe allograft damage ensues.
The characteristic histologic changes on biopsy include tubular damage with tubulitis and interstitial inflammatory infiltrate.
These characteristics are similar to allograft cellular rejection.
polyomavirus infections have been associated with diverse disease pattern which involve either cytopathic, inflammatory, immunological or oncogenic pathologies.
BKV infection has been implicated in late ureteral stenosis (>1 month posttransplantation) because BKV replication has been demonstrated in the urothelium of patients experiencing ureteral stenosis.
Hemorrhagic cystitis is a serious complication that occurs in 25% of recipients of hematopoietic stem cell transplants in children and young adults.
Cohen-Bucay A, Ramirez-Andrade SE, Gordon CE, Francis JM, Chitalia VC. Advances in BK Virus Complications in Organ Transplantation and Beyond. Kidney Med. 2020 Oct 11;2(6):771-786. doi: 10.1016/j.xkme.2020.06.015. PMID: 33319201; PMCID: PMC7729234.
Polyomavirus-associated Nephropathy
BK virus nephropathy ureteral stenosis hemorrhagic cystitis could be assosciated with urothelial malignancy Progressive multi focal leuciencephalopathy with JC virus can cause pneumonia
Polyoma viruses are a group of small non enveloped DNA virus which can cause diseases in animals namely simian monkey….
BK virus leads to
BK virus nephropathy, urethral stenosis, hemorrhagic cystitis..There are rare reports of BK virus causing pneumonia in lung transplant patient…there are many reports of BK virus associated with urothelial malignancies with increased incidence and less causal associations…
JC virus is another form of polyoma virus…It can cause progressive multifocal encephalopathy…more common in HIV patients
SV 40 is a simian tropic virus causing disease only in monkeys
The association of BKV with PVAN in renal transplant recipients emphasizes the role of allo-situation in addition to immunosuppression. Most likely, patient, organ and virus specific determinants interact in a complementary fashion and are subject to dose- and magnitude dependent modulators (e.g., immunosuppression). https://www.ncbi.nlm.nih.gov/books/NBK6388/
The commonly occurring diseases due to polyomaviruses post renal transplantation are; BK virus nephropathy then interstitial nephritis, Hemorrhagic cystitis, Ureteral stenosis, chronic allograft nephropathy.
It is to be noted that another type of polyomavirus rather than BK is JCV which affects mainly CNS and brain.
BKV-associated nephropathy begins with viruria or asymptomatic hematuria and ends with extensive irreversible injury and allograft failure.
Ureteric stenosis
The prevalence of ureteric stenosis is 2–6%
Hemorrhagic cystitis
grade I: microscopic hematuria grade II: macroscopic hematuria grade III: hematuria with clots grade IV: hematuria with clots, clot retention, and renal failure secondary to obstructive nephropathy
References:
1.Dall A, Hariharan S. BK virus nephritis after renal transplantation. Clin J Am Soc Nephrol 2008; 3(Suppl 2):S68–S75.
2.Van Aalderen MC, Heutinck KM, Huisman C, Ten Berge IJ. BK virus infection in transplant recipients: clinical manifestations, treatment options and the immune response. Neth J Med 2012; 70:172–183.
3.Bohl DL, Brennan DC. BK virus nephropathy and kidney transplantation. Clin J Am Soc Nephrol 2007; 2(Suppl 1)S36–S46.
4.Hariharan S. BK virus nephritis after renal transplantation. Kidney Int 2006; 69:655–662.
5.Tremolada S, Akan S, Otte J, Khalili K, Ferrante P, Chaudhury PR et al. Rare subtypes of BK virus are viable and frequently detected in renal transplant recipients with BK virus-associated nephropathy. Virology 2010; 404:312–318.
Human Polyomaviruses are non-enveloped DNA viruses that remain latent in the immunocompetent individuals after primary infection. Illnesses related to these viruses occur when they are immunocompromised (organ transplant recipients).
BKV, JCV and Merkel virus being the most known viruses of this group
The diseases caused by Polyomaviruses post kidney transplantation include:
o BK virus nephropathy. o Interstitial nephritis. o Haemorrhagic cystitis o Ureteral stenosis. o Chronic allograft nephropathy. References 1. Cohen-Bucay A, Ramirez-Andrade SE, Gordon CE, Francis JM, Chitalia VC. Advances in BK Virus Complications in Organ Transplantation and Beyond. Kidney medicine. 2020 Nov-Dec; 2(6):771-86. 2. KDIGO clinical practice guideline for the care of kidney transplant recipients. American journal of transplantation: official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2009 Nov; 9 Suppl 3:S1-155.
● The group most commonly affected by BKV is transplant recipients, including renal transplant and BMT recipients.
● Polyomavirus BKV causes disease of the genitourinary tract in association with hematological malignancies, congenital immunodeficiency, and Wiskott-Aldrich syndrome
● Also polyomavirus is significantly associated with some cancers in humans, including malignant mesothelioma, ependymomas, osteosarcoma, and non-Hodgkin lymphoma
Scenario 1:
Human polyomavirus diseases includes:
BK virus leads to BK nephropathy and BK viremia and hemorrhagic cystitis.
JC virus causes progressive multifocal leuko-encephalopathy that is a progressive demyelinating CNS disorder involving cerebral white matter.
Mercle cell polyoma virus (MpyV) causes Mercle cell carcinoma.
Simian vacualating virus 40(SV40) causes disease in rhesus monkey induced by polio vaccines.
BK virus screening after renal transplantation can reveal viruria and/or viremia.
Reference: Boothpur R, Brennan DC. Human polyoma viruses and disease with emphasis on clinical BK and JC. J Clin Virol. 2010 Apr;47(4):306-12. doi: 10.1016/j.jcv.2009.12.006. Epub 2010 Jan 8. PMID: 20060360; PMCID: PMC3774018.
In kidney transplant recipients, BK and possibly other polyoma viruses can cause Bk virus nephropathy and ureteral stenosis,whereas hemorrhagic cystitis is prevalent in hematopoietic stem cell transplantation (HSCT) patients and uncommon in kidney transplant.Rare cases of BK disseminated disease (tubulointerstital nephritis, desquamative pneumonitis, meningoencephalitis, and retinitis) have also been described.
Polyoma viruses are composed of 14 subclasses. Human Polyoma virus 1=BK virus can lead to BKV nephropathy and hemorrhagic cystitis. Human Polyoma Virus 2= JC virus can lead to PMLE (progressive multi-focal leuco-encephalopathy), Hodgkin’s lymphoma and nephropathy. Human Polyoma Virus 3= Karolinska institute Polyoma Virus of Unknown significance. Human Polyoma Virus 4= Washington University Polyoma Virus of unknown significance.
Human Polyoma Virus 5= Merkel Cell Polyoma Virus can lead to Merkel cell carcinoma which is an aggressive neuro-endocrine skin malignancy. Human Polyoma Virus 6: of unknown significance. Human Polyoma Virus 7: of unknown significance. Human Polyoma Virus 8= Trichodysplasia Spinulosa Polyoma Virus can lead to skin keratin spines and follicular papules. Human Polyoma Virus 9: of unknown significance. Human Polyoma Virus 10= MX MW Polyoma Virus of unknown significance. Simian virus – discovered as a contaminant of polio and adenovirus vaccines.
BK virus (BKV) is a polyomavirus that is able to cause renal dysfunction in transplanted grafts via BK virus-associated nephritis (BKVAN). This condition was mis-diagnosed in the past due to clinical and histopthological similarities with acute rejection. Due to the prevalence of the virus in the population, it is an important pathogen in this context, and so it is important to understand how this virus functions and its’ relationship with the pathogenesis of BKVN. Screening for BKV often reveals viruria and/or viremia, which then manifests as BKVN, which can be asymptomatic or result in clinical features namely renal dysfunction. The pathogenesis of BKV infection is still unclear and needs to be further investigated; nevertheless there are a variety of hypotheses that indicate that there are a host of factors that play important roles. Treatments for BKVAN include a reduction in immunosuppression, the use of antiviral therapy or the combination of both treatment options.
3.Butel JS, Lednicky JA. Cell and molecular biology of simian virus 40: implications for human infections and disease, J Natl Cancer Inst, 1999, vol. 91 (pg. 119–34)
4. Lednicky JA, Arrington AS, Stewart AR, et al. Natural isolates of simian virus 40 from immunocompromised monkeys display extensive genetic heterogeneity: new implications for polyomavirus disease, J Virol, 1998, vol. 72 (pg. 3980-90)
5.Lafon ME, Dutronc H, Dubois V, et al. JC virus remains latent in peripheral blood B lymphocytes but replicates actively in urine from AIDS patients, J Infect Dis, 1998, vol. 177 (pg. 1502-5)
6.Azzi A, De Santis R, Ciappi S, et al. Human polyomaviruses DNA detection in peripheral blood leukocytes from immunocompetent and immunocompromised individuals, J Neurovirol, 1996, vol. 2 (pg. 411-6)
Types of polyoma viruses: JCV · Nephropathy · PML(Progressive multifocal leukoencepgalopathy) rarely in renal transplant patients and it is associated with high levels of viral genome found in the cerebrospinal fluid. BK Virus (BKV) · Nephropathy (PVAN) · upper respiratory tract infections · pneumonia · hemorrhagic cystitis · interstitial kidney disease · ureter stenosis · meningitis · encephalitis · retinitis · colitis · vasculitis · can also cause a PML-like disease
Reference:
Delbue and Ferraresso, J Transplant Technol Res 2020
What are the diseases caused by BK virus in kidney transplantion?
1- Subclinical viruria 2- BKVN:
is classified into three stages according to pathological changes
– stage A : characterized by presence of cytopathic changes (25%) , minimal tubular atrophy and interstitial infiltrates or fibrosis (<10%) , and graft loss occurs in around 10%.
Stage B: more prominent tubular atrophy and interstitial infiltration and fibrosis up to 50 % , with higher incidence of graft loss (50%).
Stage C : advanced stage of tubular atrophy and interstitial fibrosis with graft loss in 85% 3-Ureteric structure . 4- Heamorragic cystitis 5- Genitourinary cancers : some reports link BKV with increased incidence of genitourinary and urolithial cancers.
Ref
Safa K, Heher E, Gilligan H, Williams W Jr, Tolkoff-Rubin N, Wojciechowski D. BK Virus After Kidney Transplantation: A Review of Screening and Treatment Strategies and a Summary of the Massachusetts General Hospital Experience. Clin Transpl. 2015;31:257-263. PMID: 28514587
What are the diseases caused by polyomaviruses in renal transplant recipients? BK virus
– BKV viraemia
– BKV viruria
– BKV nephropathy
– Graft loss(10- 80%)
– Cystitis (Haemorrhagic & non haemorrhagic)
– Ureteric stricture
BK Virus has seropositivity rate of over 75% in normal population. Primary infection is thought to occur in the respiratory tract. However, its now established that BK virus can be latent without any symptoms in urinary tract. In immunocompromised patients especially with renal transplant, BK virus can compromise kidney function and cause tubulointerstitial inflammatory response similar to acute rejection with variable prevalence of 1-10% and graft loss up to 80%.
In renal transplant recipients, Polyomavirus especially BK virus can cause nephropathy and ureteral stenosis. In addition to hemorrhagic cystitis which is prevalent in hematopoietic stem cell transplantation (HSCT) patients.
Lamarche, Caroline MD; Orio, Julie MSc; Collette, Suzon MD; Senécal, Lynne MD; Hébert, Marie-Josée MD; Renoult, Édith MD; Tibbles, Lee Anne MD; Delisle, Jean-Sébastien MD, PhD. BK Polyomavirus and the Transplanted Kidney: Immunopathology and Therapeutic Approaches. Transplantation 100(11):p 2276-2287, November 2016. | DOI: 10.1097/TP.0000000000001333
The clinical spectrum of BKV infections include BK viruria, BK viremia, BKVN, and, less commonly, ureteral stenosis. The highest prevalence of BK viruria and viremia occurs at 2 to 3 months, and 3 to 6 months, respectively.
Serum BK viral load of at least 10,000 copies/ml has been suggested to be predictive of BKVN. Tubulointerstitial nephritis Ureteral stenosis or stricture Hemorrhagic cystitis
Diseases caused by polyomaviruses in renal transplant recipients
It can cause:
Viuria:
This can occur in 50% cases in first year post transplant and mostly progresses to viremia.
Viremia:
It can occur in first six months the incidence in 10-30%. Subsequently it can be between 5-10%
Polyomavirus-associated nephropathy (PVAN):
It is an emerging disease in renal transplant patients with prevalence of 1-10% and graft loss up to 80%. BK virus (BKV) is the primary etiologic agent, but JC virus (JCV) and possibly simian virus SV40 may account for some cases.
· Hemorrhagic Cystitis
· Ureteric Stricture
· Malignancy
Early screening and surveillance for BKV nephropathy is cost effective and can improve graft survival
Scadden JR, Sharif A, Skordilis K, Borrows R. Polyoma virus nephropathy in kidney transplantation. World J Transplant. 2017 Dec 24;7(6):329-338
polyomavirus include many different types :
BK virus
JC virus
Tichodysplasia spinulosa polyomavirus
Merckel cell polyomavirus
Karolinska Instutute polyomavirus
Wisconsin University polyomavirus
The most common types that affect the humans especially the immune compromise include BK &JC virus.
Diseases caused by the BK virus are:
1.BK Nephropathy
2.Ureteric stenosis
3.Hepatitis
4.Pneumonitis
5.Retinitis
6.Hemorrhgic cystitis
7.Urogenital malignancies
8.Tubulointerstitial nephritis
9.meningoencephalitis
10.Lymphoma.
What are the diseases caused by polyomaviruses in renal transplant recipients? 1. Tubulo-interstitial nephritis 2. BKV associated Nephropathy and grfat loss 3. Ureteral Stenosis and Stricture – severe Hydronephrosis and grfat loss 4. Precipitate Acute Rejection, especially Ac ABMR. 5. Haemorrhagic Cystitis – more with HSCT 6. Malignancy – Merkel Cell Carcinoma – associated with Cervical CIN, Bladder Cancer and Renal Cancer (causal relation not proven) References: Gabriel M Daonovitch: Hand book of Kidney transplantation 6th Edn Scadden JR et al. Polyoma virus nephropathy in kidney transplantation. World J Transplant. 2017 Dec 24;7(6):329-338
BK polyomavirus (BKPyV) is the main cause of polyomavirus‐associated nephropathy (PyVAN) after kidney transplantation and PyV‐associated hemorrhagic cystitis (PyVHC) after allogeneic hematopoietic cell transplantation (HCT).
Both PyVAN and PyVHC are rarely seen in non‐kidney SOT.
JC polyomavirus (JCPyV) is the main cause of progressive multifocal leukoencephalopathy
In addition, isolated cases of encephalitis, pneumonitis, retinitis, colitis, capillary‐leak syndrome, hemophagocytic syndrome, and urothelial cancer have been described
Hirsch HH, Randhawa PS, AST Infectious Diseases Community of Practice. BK polyomavirus in solid organ transplantation—Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clinical transplantation. 2019 Sep;33(9):e13528.
What are the diseases caused by polyomaviruses in renal transplant recipients? Human polyomavirus could be the causative agent of many diseases. Its small nonenveloped DNA virus, there are four main types causing diseases. It almost infect >90% of population at 10 years of age. Post-renal transplant the prevalence is 1 to 10% and of graft loss up-to 80%, strong immunosuppression would be the main cause of BKV associated complication(lecture ). On staging it could present with viruria, viremia, and BKVAN. It remain dormant until a patient become immunocompromised. . The earliest appearance with symptoms of viruria in first year post transplantation is up-to 50%, . While viruria is around 10-30% with in first six month. . BKVAN usually occurs if persistant and progressive viremia with tabulitis and decrease in eGFR. . Hemorrhagic cystitis, . Ureteric stenosis, hydronephrosis, obstructive nephropathy. . Genitourinary malignancies.
polyomaviruses are belonging to virus family papovaviradiae, it is non-envelop dsDNA virus.
human polyoma virus types are BK, JC, KI, WU, and Merkle cell MC
BK, JC, KI, and WU are belonged to SV40 group
MC virus is belonged to MuPyV (mouse polyoma virus)
both SV40 and MuPyV are belonged to avian polyoma virus
diseases caused by the virus:
1- interstitial nephritis or BK viral nephropathy BKVN or polyoma virus associated nephropathy PVAN
2- JC virus cause progressive multifocal leukencephalopathy which is demyelinating disease of CNS
3-Merkel cell carcinoma is an aggressive neuro-endocrine skin cancer, originating from the mechano-receptor Merkel cell. It is noted to be more common in immunosuppressed states suggesting an infectious etiology
Diseases caused by polyomaviruses in renal transplant recipients
CytopathicPredominant polyomavirus replication
Causative prototype: PML1 by JCV in AIDS
Cytopathic – inflammatoryReplication plus inflammatory infiltrate
Causative prototype: PVAN 2 pattern B (interstitial nephritis) in renal transplantation
ImmunePredominant inflammatory
Causative prototype: PML by JCV in AIDS 3
Reconstitutingimmune response subsequent to replication
Causative prototype: following initiation of HAART 4 Hemorrhagic cystitis by BKV in stem cell transplantation
AutoimmunePathologic immune response triggered by previous replication Antigenic complexes – viral DNA: host cell histones – large T-antigen: host cell DNA – viral capsid: host cell DNA
Causative prototype: Systemic lupus by BKV?
TransformingUncoupling of cell proliferation from lytic replication
Causative prototype: Urothelial carcinoma by BKV Lymphoma by JCV, SV40?
======================================= Reference
HH Hirsch, CB Drachenberg, et al, Polyomavirus-associated nephropathy in renal transplantation: critical issues of screening and management, 2006;577:160-73.
Diseases caused by polyomaviruses in renal transplant recipients
It can cause _
· Viruria
This can occur in 50% cases in first year post transplant and mostly progresses to viremia.
· Viremia
in first six months the incidence in 10-30%. Subsequently it can be between 5-10%
· Polyomavirus-associated nephropathy (PVAN) – It is an emerging disease in renal transplant patients with prevalence of 1-10% and graft loss up to 80%. BK virus (BKV) is the primary etiologic agent, but JC virus (JCV) and possibly simian virus SV40 may account for some cases.
· Hemorrhagic Cystitis
· Ureteric Stricture
· Malignancy
Early screening and surveillance for BKV nephropathy is cost effective and can improve graft survival
Scadden JR, Sharif A, Skordilis K, Borrows R. Polyoma virus nephropathy in kidney transplantation. World J Transplant. 2017 Dec 24;7(6):329-338
Polyoma virus infection leads to following deceases in Kidney Transplant Recipient
1) Tubulointerstitial Nephritis and graft loss
2) Ureteral Stenosis
3) Hemorrhagic Cystitis in Bone marrow transplant recipient
Review BK Virus Nephropathy in Kidney Transplantation A State-of-the-Art Review Sam Kant 1,2,* , Alana Dasgupta 3, Serena Bagnasco 3 and Daniel C. Brennan 1,2
Polyomavirus-associated nephropathy is account 1-10% and associated with graft loss up to 80%. BK virus (BKV) is the primary etiologic agent, but JC virus (JCV) and possibly simian virus SV40 may account for some cases.
The main cause of BKV activation and disease is Intense immunosuppression and ABO incompatible and HLA-mismatches.
Also older age, male gender, seronegative recipient), and viral factors (genotype, serotype) may have a contributory role.
The gold standard to confirm diagnosis of PVAN is allograft biopsy. Screening for polyomavirus replication in the urine and in the plasma and presence of viruria (“decoy cells”), plasma viral load. Increasing BK viremia (>10,000 copies/mL) or urine VP-1 mRNA (>6.5×105 copies/ng total RNA) load defines “presumptive PVAN” for which an intervention of reducing immunosuppression should be considered even if the diagnosis could not be confirmed by allograft biopsy. The response to intervention should be monitored using plasma DNA or urine mRNA load.
The main disease of BKV is interstitial nephritis/ ureteric stricture and stenosis/hemorrhagic cystitis.
JC virus may lead to progressive multifocal leukoencephalopathy (PML), However in few cases shows JC nephropathy.
SV40 is a DNA virus which associated with tumor in animals especially monkeys.
Different studies indicate that SV40 can replicate productively in human cells, including spongioblasts, fetal neural cells, newborn kidney cells, and some tumor cell lines.
Human papilloma virus 6 is associated with skin cancer and merkle,s cell carcinoma.
Diseases caused by human polyoma viruses in renal transplant patients:
-BK Virus can cause cystitis ; either hemorrhagic or non-hemorrhagic, uterine stricture & stenosis and BK virus -associated nephropathy.
JC virus can cause progressive multifocal leukoencephalopathy; a demyelinating disorder with ataxia, hemiparesis, visual field deficits, and cognitive impairment.
Trichodysplasia spinulosa polyoma virus; characterized by viral replication within keratinocytes and hyperproliferation of the inner root sheath cell associated by alopecia ,facial skin lesions madarosis.
Human polyomavirus 6 can cause pruritic, hyperpigmented skin eruptions in patients with kidney and pancreas transplant.
Merkle cell virus causing Merkle cell carcinoma; a neuroendocrine skin neoplasia.
Polyomavirus infection in KTRs; Clinical Manifestations
Polyomaviruses (JC virus [JCV], BK virus [BKV], and simian virus 40 [SV40]) establish subclinical and persistent infections and share the capacity for reactivation from latency in their host under immunosuppression(1).BKV causes infection in the kidney and the urinary tract, and its activation causes a number of disorders, including:
1. The classic sequence of infections inKTRs is viruria, viremia, and BKVAN.
· The most common and earliest manifestation of BKV is viruria occurring in up to 50% of patients in the first year of transplantation.
· The presence of sustained viruria may progress to viremia, which is asymptomatic initially.
2. Skin infection: HPyV-7 was implicated in the development of pruritic, brown plaques on the trunk and extremities in patients receiving immunosuppressed therapy who also developed viremia(2).
3. BKVAN usually occurs after a period of sustained progressively worsening viremia.
a) The vast majority of BKVAN occurs within the first post-transplant year, with the first 2–6 months being periods of highest incidence.
b) Manifesting as a decline in renal function with or without urinary abnormalities..
4. BKV infection led to allograft failure in 36% of the affected patients(3).
5. Ureteral stenosis(4) and hemorrhagic cystitis(1): albeit rare in kidney transplant recipients and mostly seen in patients with hematopoietic stem cell transplants.
6. Urothelial malignancies in transplant recipients(5).
7. Merkel cell polyomavirus (MCV) was discovered in 2008 from Merkel cell carcinoma, a rare but aggressive form of skin cancer. MCV is suspected to cause the majority of cases of Merkel cell carcinoma(6).
8. PML, the best-known clinical syndrome caused by JCV(a member of polyomaviruses).Although PML is not common, it has been reported in both organ transplant and BMT recipients(7-8).
References 1. David R. Snydman, Eun Jeong Kwak, Regis A. Vilchez, Parmjeet Randhawa, Ron Shapiro, Janet S. Butel, Shimon Kusne, Pathogenesis and Management of Polyomavirus Infection in Transplant Recipients, Clinical Infectious Diseases, Volume 35, Issue 9, 1 November 2002, Pages 1081–1087, https://doi.org/10.1086/344060 2. Human Polyomavirus; From: Encyclopedia of Virology (Fourth Edition), 2021Skin InfectionsCarlos N. Prieto-Granada, … Martin C. MihmJr., in Diagnostic Pathology of Infectious Disease (Second Edition), 3. Randhawa PS, Finkelstein S, Scantlebury V, et al. Human polyoma virus-associated interstitial nephritis in the allograft kidney, Transplantation, 1999, vol. 67 (pg. 103-9). 4. Gardner SD, Field AM, Coleman DV, Hulme B. New human papovavirus (BK) isolated from urine after renal transplantation, Lancet, 1971, vol. 1 (pg. 1253-7). 5. Hernández-Gaytán CA, Rodríguez-Covarrubias F, Castillejos-Molina RA, Hernández-Porras A, Tobia I, Dubin JM, Autrán-Gómez AM. Urological Cancers and Kidney Transplantation: a Literature Review. Curr Urol Rep. 2021 Dec 16;22(12):62. doi: 10.1007/s11934-021-01078-2. PMID: 34913107. 6. Polyomaviruses Wang-Shick Ryu, in Molecular Virology of Human Pathogenic Viruses, 2017 7. Ouwens JP, Haaxma-Reiche H, van der Bij W, et al. Visual symptoms after lung transplantation: a case of progressive multifocal leukoencephalopathy, Transpl Infect Dis, 2000, vol. 2 (pg. 29-32). 8. Seong D, Bruner JM, Lee KH, et al. Progressive multifocal leukoencephalopathy after autologous bone marrow transplantation in a patient with chronic myelogenous leukemia, Clin Infect Dis, 1996, vol. 23 (pg. 402-3).
What are the diseases caused by polyomaviruses virus in kidney transplantion?
They are small nonenveloped DNA and they are 14 types, the commonest types are BKA, JC virus and simian virus 40
BK may cause:
-Subclinical viremia and viruria:
-BK virus nephropathy:
Classified into 3 stages:
*stage A: presence of cytopathy with minimal tubular atrophy and risk of graft loss around 10%
*Stage B: cytopathy with more prominent tubular atrophy and interstitial fibrosis with risk of graft loss around 50%
*Stage C: marked tubular atrophy and interstitial fibrosis with risk of graft loss 80%.
-Hemorrhagic cystitis
-Ureteric stricture
-Cancer
Ref
Safa K, Heher E, Gilligan H, Williams W Jr, Tolkoff-Rubin N, Wojciechowski D. BK Virus After Kidney Transplantation: A Review of Screening and Treatment Strategies and a Summary of the Massachusetts General Hospital Experience. Clin Transpl. 2015;31:257-263. PMID: 28514587
Screening for polyomavirus infections 1 year following transplantation appears to save money, improves survival, and improves quality of life in kidney transplant recipients. Germaine Wong, et al.)
Many thanks Prof Sharma Yes Prof Dawlat has asked this important question
The cost of kidney transplantation is determined by the need for lifetime immunosuppressive drug use, which increases as transplant recipients’ lifespans and allograft survivals improve.
Biologics are costly, but there is potential for better graft function, less graft immune injury episodes, and better adherence.
James A, Mannon RB. The Cost of Transplant Immunosuppressant Therapy: Is This Sustainable?. Curr Transplant Rep. 2015;2(2):113-121. doi:10.1007/s40472-015-0052-y
The early screening and regular serviellance policy for prevention of BKV nephropathy is cost effective and can impact the graft survival , qauntative BKV PCR is recommended for screening , serviellance , and monitroing for BKVviremia and BKVN .
While graft biopsy is indicated in case of persistant high viralload after 3 weeks from reduction of IS , high BKV PCR viral load with more than 5log is highly indicated of associated BKVN.
What is the therapeutic and economic value of surveillance policy in post-transplant cases to detect and manage early cases? (1)
– screening for polyomavirus infection following kidney transplantation is recommended by most clinical practice guidelines
– an analysis done by Wong et al revealed that routine screening for BKV using PCR was cost-saving, improved overall quality of life and improved survival compared with no screening
– this analysis supported screening for all kidney transplant
recipients for polyomavirus infections during the 1st year following transplantation since this is the period during which the net immunosuppression load is greatest
References
1. Wong G, Myint TM, Lee YJ, Craig JC, Axelrod D, Kiberd B. Economic Evaluation of Screening for Polyomavirus Infection in Kidney Transplant Recipients: A Cost-Utility Analysis. Transplantation direct. 2022 May;8(5):e1318. PubMed PMID: 35464876. Pubmed Central PMCID: PMC9018998. Epub 2022/04/26. eng.
This can be done in the first 1 yr post transplant during which we have peak immunosuppression, the results will facilitate quick response and possibly better outcomes post transplant. Unfortunately in my centre, lack of resources has ensured that this is hardly practised.
REF;
Wong et al;Economic evaluation of screening of polymyovirus in KTR; A cost utility analysis.
What are the diseases caused by polyomaviruses in renal transplant recipients?
Polyomaviruses (JC virus [JCV], BK virus [BKV], and simian virus 40 [SV40]) establish subclinical and persistent infections and share the capacity for reactivation from latency in their host under immunosuppression.
1-JCV establishes latency mainly in the kidney, and its reactivation results in the development of progressive multifocal leukoencephalopathy. This demyelinating disease of the CNS caused by polyomavirus JCV presents with rapidly progressive focal neurological deficits, which may include hemiparesis, paresthesia, visual field deficits, ataxia, and cognitive and behavioral changes.
2-BKV causes infection in the kidney and the urinary tract, and its activation causes a number of disorders, including ;
1- The classic sequence of infections in kidney transplant recipients is viruria, viremia, and BKVAN.
2-The most common and earliest manifestation of BKV is viruria occurring in up to 50% of patients in the first year of transplantation, with most cases not progressing to viremia .
3- Viremia is present in 10–30 percent of recipients in the first six months post- transplantation and in 5–10 percent of recipients thereafter .
4- BKVAN usually occurs after a period of sustained progressively worsening viremia, manifesting as a decline in renal function with or without urinary abnormalities. The vast majority of BKVAN occurs within the first post-transplant year given attenuated cellular immunity, with the first 2–6 months being periods of highest incidence .
5- Other manifestations of the BK virus include;
1- Ureteral stenosis .
2-hemorrhagic cystitis
Are rare in kidney transplant recipients and mostly seen in patients with hematopoietic stem cell transplants.
6-There are reports of a possible link between the BK virus and genitourinary (GU) malignancies, especially given its protracted infection in epithelia of the GU tract.
Reference ;
1-Update on the Management of BK Virus Infection Ahmed Saleh, 1,4,5 Mohamed Salah El Din Khedr,1 Abeer Ezzat, Anna Takou, 3 Ahmed Halawa4
2-Review BK Virus Nephropathy in Kidney Transplantation A State-of-the-Art Review Sam Kant 1,2,* , Alana Dasgupta 3, Serena Bagnasco 3 and Daniel C. Brennan 1,2
3-Khalili ,K Stoner, GL, Human polyomaviruses: molecular and clinical perspectives 2001 New York Wiley-Liss .
That is a well-structured reply. Even though you have numbered your contents, it is not easy to read. I wish you could type headings and sub-headings as underline or in bold.
☆ Polyomavirus infection: ▪︎Polyomaviruses are small, nonenveloped DNA viruses, which are widespread in nature.
▪︎In immunocompetent hosts, the viruses remain latent after primary infection. With few exceptions, illnesses associated with these viruses occur in times of immune compromise, especially in conditions that bring about T cell deficiency [1].
☆ Diseases caused by polyomaviruses in renal transplant recipients 1. Polyomaviruses associated nephropathy
▪︎Is an emerging disease in renal transplant patients with variable prevalence of 1-10% and graft loss up to 80%.
▪︎ BK virus (BKV) is the primary etiologic agent, but JC virus (JCV) and possibly simian virus SV40 may account for some cases.
▪︎ Intense immunosuppression is viewed as the most important risk factor [2]. ▪︎Recently, transplant nephropathy due to BKV infection has been increasingly recognized as the cause for renal allograft failure.
▪︎Quantitation of polyomavirus DNA in the blood, cerebrospinal fluid, and urine, identification of virus laden “decoy cells” in urine, and histopathologic demonstration of viral inclusions in the brain parenchyma and renal tubules are the applicable diagnostic methods.
2. Neoplasia:
▪︎Genomic sequences of polyomaviruses have been reported to be associated with various neoplastic disorders and autoimmune conditions. ▪︎There are reports that link BKPyV with metastatic bladder carcinoma in immunosuppressed transplant recipients.
3. Ureteral stenosis & haorrhagic cystitis ▪︎BK virus may cause ureteral stenosis and haorrhagic cystitis which is albeit rare. genitourinary malignancies. in kidney transplant recipients reactivation of the BK virus infection may end with graft dysfunction and failure by causing tubulointerstitial nephritis/ or ureteral obstruction (W4 paper 1)
Note: While various antiviral agents have been tried to treat polyomavirus-related illnesses, current management aims at the modification and/or improvement in the hosts’ immune status [4].
_________________________
References
[1] Polyomaviruses and human diseases Nasimul Ahsan et al. Adv Exp Med Biol. 2006. [2] Polyomavirus-associated Nephropathy in Renal Transplantation: Critical Issues of Screening and Management Hirsch HH, Drachenberg CB, Steiger J, et al. [4] Polyomaviruses and human diseases Nasimul Ahsan et al. Adv Exp Med Biol. 2006).
What are the diseases caused by polyomaviruses in renal transplant recipients?
Polyomaviruses are non-enveloped icosahedral double stranded DNA viruses belonging to the polyomaviridae family.
Currently 13 human polyomaviruses have been identified with the most common being: BKV, JCV and SV40.
BKV and JCV are ubiquitous in the general population, with the primary infection occurring between 1-6 years of age.
The primary infection is mainly asymptomatic then the virus remains latent in either the kidney, lymphatic tissue, brain and spleen.
Viral reactivation and replication occurs when the host immunity specifically the T cell immunity is compromised. In the transplant population this occurs within the first 3 months post-transplant though late reactivation can also occur.
Conditions include:
Asymptomatic viruriaThis is detected in 10-45% of renal transplant recipients.
Several of the polyomaviruses have been detected in the urine of transplant recipients, however the clinically significant is BK viruria for it has been associated with BKVAN.
BKVANThe histological findings include tubular atrophy, interstitial inflammation and fibrosis.
Persistent BKV viruria and viremia has been identified as important cause of progressive graft dysfunction and loss.
Though the JCV has been detected in patients with allograft nephropathy, it has not been independently associated as a cause of kidney disease.
Ureteral stenosisThis is due to the direct cytopathic effect of the virus on the uroepithelium leading to ulceration and inflammation with ensuing obstructive uropathy.
Hemorrhagic cystitisThis is the most common genitourinary manifestation of polyomavirus infection in BMT recipients.
BMT recipients shed both BKV and JCV in urine. However BKV viruria is associated with development of hemorrhagic cystitis, whereby 64% of recipients progress to hemorrhagic cystitis.
Though JCV is shed in the urine of BMT recipients no clinical syndromes have been attributed to it in this population.
Progressive multifocal leukoencephalopathy (PML)Clinical syndrome that presents with demyelination of the CNS caused by JCV.
Leading to a rapidly progressive focal neurological deficits that may include hemiparesis, paresthesia, ataxia, visual field defects ,cognitive and behaviour changes.
Was common in the HIV era prior to HAART, however with introduction of HAART its incidence in this group has reduced.
Though rare it has also been reported in SOT and BMT recipients.
Merkel cell carcinomaThe Merkel cell polyomavirus has been detected in Merkel cell carcinoma a neuroendocrine skin neoplasia.
Its DNA has also been detected in non-melanoma skin cancers like squamous cell and basal cell.
It has also been detected in upper and lower respiratory tract infections.
Trichodysplasia spinulosa (TS)This is a rare skin disease in immunocompromised hosts and is characterised by the development of facial follicular papules and keratotic protrusions (spicules or spines) with alopecia of the eyelashes and brows.
It is associated with TS polyomavirus.
SV40 is significantly associated with some malignanciesIncluding malignant mesothelioma, ependymomas, osteosarcoma, and non-Hodgkin lymphoma.
However there are very few published studies on the frequency of SV40 infections among transplant recipients.
References
Entry, infection, replication, and egress of human polyomaviruses: an update Soumen Bhattacharjeesoumenb123@rediffmail.com and Sutanuka Chattaraj
Pathogenesis and Management of Polyomavirus Infection in Transplant Recipients
David R. Snydman, Eun Jeong Kwak, Regis A. Vilchez, Parmjeet Randhawa, Ron Shapiro, Janet S. Butel, Shimon Kusne
What are the diseases caused by polyomaviruses virus in kidney transplantion?
There are 14 types of polyomaviruses , the commonest types associated with complications in kidney transplant patients are BKV, JC virus and simian virus 40 (SV40) BKV may cause:
1- Subclinical viruria:
diagnosed by presence of decoy cells in urine can progress to BKVN so reducing IS is required . 2- BKVN:
is classified into three stages according to pathological changes
– stage A : characterized by presence of cytopathic changes (25%) , minimal tubular atrophy and interstitial infiltrates or fibrosis (<10%) , and graft loss occurs in around 10%.
Stage B: more prominent tubular atrophy and interstitial infiltration and fibrosis up to 50 % , with higher incidence of graft loss (50%).
Stage C : advanced stage of tubular atrophy and interstitial fibrosis with graft loss in 85% 3-Ureteric structure . 4- Heamorragic cystitis 5- Genitourinary cancers : some reports link BKV with increased incidence of genitourinary and urolithial cancers.
B- JCV
associated with development of multifocal leucoencephalopathy.
Ref
Safa K, Heher E, Gilligan H, Williams W Jr, Tolkoff-Rubin N, Wojciechowski D. BK Virus After Kidney Transplantation: A Review of Screening and Treatment Strategies and a Summary of the Massachusetts General Hospital Experience. Clin Transpl. 2015;31:257-263. PMID: 28514587
Polyomaviruses are around 14 types; one of them is the BK virus which is mostly encountered in Renal transplant recipients. It can cause Nephritis/BK nephropathy and acute rejection. It was associated with ureteral stenosis. Although mostly seen when the immunosuppression is in peak but can occur late, so patients should be screened for BK at 1, 3, 6, 12, and 24 months.
Other Polyomaviruses are not encountered in renal transplantation
Hemorrhagic cystitis is rare in renal transplant patients but is mostly encountered in Hematopeitic transplant patients.
Polyomaviruses include sJC virus [JCV], BK virus [BKV], and simian virus 40 [SV40]
It can lead to Polyomavirus nephritis
BKV reactivation common to occur within the first 3 months post renal transplantation, but late reactivation can happen.
Reactivation and replication of polyomavirus BKV is more prevalent in seropositive recipients receiving grafts from seropositive donors .
BKV can lead to viruria , tubulointerstitial nephritis, that can reach to severe allograft dysfunction and graft loss. Ureteral stenosis is one of BKV infection consequences ,through the direct cytopathic effect on the ureteral epithelium which leads to obstructive uropathy.
Also tubular casts secondary to tubular necrosis can lead to obstruction. Fatal BKV-induced vasculopathy was detected in a renal transplant recipient with concomitant necrotizing endothelial injury. Haemorrhagic cystitis
Hemorrhagic cystitis is the more common in bone marrow transplantion recipients Progressive multifocal leukoencephalopathyPML.
CNS demyelinating disease caused by polyomavirus JCV presents with rapidly progressive focal neurological deficits in immunocompromised cases with disrupted cell mediated immunity Renourinary carcinoma
BKPyV infection association with malignant tumor is controversial .
BKPyV infection for a long time was suggested to increase the possibility of renourinary carcinoma in renal transplant recipients
Reference
-David R. Snydman, Eun Jeong Kwak, Regis A. Vilchez, Parmjeet Randhawa, Ron Shapiro, Janet S. Butel, Shimon Kusne, Pathogenesis and Management of Polyomavirus Infection in Transplant Recipients, Clinical Infectious Diseases, Volume 35, Issue 9, 1 November 2002, Pages 1081–1087.
-Maenosono, R., Okumi, M., Unagami, K. et al. Total nephroureterocystectomy and urethrectomy due to urothelial carcinoma associated with the BK polyomavirus infection after kidney transplantation: a case report with literature review. Ren Replace Ther 6, 52 (2020).
_polyoma viruses causing diseases in renal tranpslant recipients included:
1_ JC polyoma which causes progressive multifocal leukoencephalopathy.
2_ BK polyoma virus which can cause BKVN with pathological changed (cytopthaic changes، with inflammatory cell infiltrate in interstium followed by tubular atrophy and interstitial fibrosis), this eventually leads to graft loss in 10_80% if cases.
_ it also has been linked to be associated with increased agressiveness and invasion of urothelial carcinoma (association rather than causation).
3_ Merckle cell polyoma which can cause Merckle cell carcinoma (progressive skin cancer , appears in sun exposed areas with high risk of distant metastasis).
What are the diseases caused by polyomaviruses in renal transplant recipients?
-BK and JC virus are the associated human polyomavirus diseases.
-they cause latent kidney epithelium infection while reactivation can be occurred during immune suppression.
-BK virus can cause tubulointerstial nephritis and ureteral stenosis or stricture.
– seropositive are up 90% world-wide, while 20-60% in urine or blood of kidney transplant recipients.
-BK viruria and viremia developed BK virus associated nephropathy.
– can be presented by allograft function loss around 9 months post-transplant.
– definite diagnosis can be confirmed by kidney biopsy with immonchistochemistry staining.
– monitoring by DNA PCR than detection with urine specimen is more specific.
– management include immunosuppression reduction while close monitoring for rejection.
– protocols recommend either to reduce or stop MMF by about 50% with decrease dose of CNI if needed.
– studies suggested prevention of BKN by medical therapy ( fluroquinolones, cidofovir or leflunomide). References:-
handbook of kidney transplantation 6th edition Gabriel M. Danovith
What are the diseases caused by polyoma viruses in renal transplant recipients?
· Polyoma viruses are small(45nm diameter), non-enveloped ,double stranded DNA viruses belonging to the polyoma viridiae family. They were first discovered by Ludwig Gross in 1953 as murine leukemia viruses.
· They establish a state of non-replicative infection termed latency in urogenital epithelial cells with reactivation after intense immunosuppression .
· About 30 species of polyoma viruses have been identified in birds and mammals, including 13 in humans: BK, JC, KI, WU, Merkel cell polyoma virus, H6, H7, H9, H10, H12, STL, trichodysplasia spinulosa-associated polyomavirus, and NJ.
· In kidney transplant recipients, BK(primary etiologic agent) and possibly other polyoma viruses(JC virus and possibly simian virus (SV40), as BK polyoma virus genome shares about 72% nucleotide homology with JC virus and 70% with SV40 )can cause :
§ Polyoma virus-associated nephropathy (PVAN)with variable prevalence of 1-10% and graft loss up to 80%.
§ ureteral obstruction(stenosis and strictures)
· Hemorrhagic cystitis is prevalent in hematopoietic stem cell transplantation (HSCT) patients (affects 5-20% of hematopoietic stem cell transplant recipients).
· Rare cases of BK disseminated disease (tubule-interstital nephritis, desquamative pneumonitis, meningo-encephalitis, and retinitis) have also been described, especially in patients with acquired immune deficiency syndrome.
· References:
1. Lamarche C et al. BK Polyomavirus and the Transplanted Kidney: Immunopathology and Therapeutic Approaches. Transplantation, 2016;100: 2276–2287.
2. Moens U et al. ICTV Virus Taxonomy Profile: Polyoma viridae. The Journal of general virology. 2017 Jun;98(6):1159-60.
3. Handbook of kidney transplantation 6th edition.
Screening for polyomavirus infections 1 year following transplantation appears to save money, improves survival, and improves quality of life in kidney transplant recipients.(Germaine Wong, et al.)
Polyoma viral infection includes BKV and JC viral infection
Usually, affect the uroepithelial structures with reactivation after intense immunosuppression
Up to 90% of young adults are seropositive and can be reactivated during intense immunosuppression like post-kidney transplantation, donor seropositivity also another risk factor for reactivation, tacrolimus , MMF based maintenance IS protocol
What are the diseases caused by polyomaviruses in renal transplant recipients?
1. Tubulointerstitial nephritis,
2. Ureteral obstruction (stenosis, stricture)
3. BKV Nephropathy with proteinuria and interstitial inflammation
4. can trigger rejection and is associated with graft loss in the range between 10-80%
BKV viruria and BKV viremia, BKVN, Definitive diagnosis require a renal biopsy with
immunohistochemistry staining for the presence of polyomavirus. Monitoring for BK virus in the plasma by
DNA PCR is more specific for the diagnosis of BK nephropathy than is detection with urine specimens. References
1. Kidney transplant handbook 6th edition
2 Prof Ahmed Halawa lecture week 4
What are the diseases caused by polyomaviruses in renal transplant recipients?1- BK virus nephropathy.
2- Interstitial nephritis.
3- Ureteral stenosis.
4- Hemorrhagic cystitis
5-Chronic allograft nephropathy.
– Polyomaviruses were first discovered in the 1950s in rodent tissues as tumor-associated viruses. SV40 was later discovered in the 1960s in a monkey cell line. These two are associated with tumors in rodents.
– Two human polyomaviruses i.e., JC virus (JCV) and BK virus (BKV) were discovered thereafter in the 1970s. They are transmitted via respiration during infancy with ~40-90% of adults being persistently infected without any apparent clinical symptoms.
– JCV can rarely cause progressive multifocal leukoencephalopathy (PML) in immunocompetent people.
– MCV (Merkel cell polyomavirus) causes merkel cell carcinoma (MCC), a rare but aggressive form of skin cancer.
BKV-associated nephropathy (BKVAN)
– BK virus can get reactivated following kidney transplantation due to the immunosuppressive state.
– BK reactivation manifests as viruria (in 30-40% of patients), viremia (in 10-20% of patients) or BKVAN (in 1-10% of patients) (1)
– BKVAN manifests as acute or progressive graft dysfunction with decreasing GFR, hematuria (in 19% of patients), and proteinuria with protein excretion <1g/day (in 48% of patients) (4)
– BKVAN occurs mostly commonly during the first 2 years post-kidney transplantation (5)
– KDIGO recommends screening for BK viruria or viremia monthly for the first 3-6 months then every 3 months until the end of the 1st year post-kidney transplant (5)
o degree of immunosuppression (use of ATG, higher cumulative steroid doses, steroid pulses as rejection therapy, tacrolimus-based regimens [this is controversial])
o rejection episodes
o delayed graft function
o ABO-incompatible transplantation
o Higher degree of HLA antigen mismatch
Recipient factors e.g.,
o Age (<18 and >55)
o Male sex
o African American race
o Ureteral stent placement
o Decreased cellular immunity
Donor factors e.g.,
o Deceased donor
o DCD – donation after circulatory death
o BK seropositive donor (especially D+/ R-)
– Definitive diagnosis of BKKVAN requires a graft biopsy with histological characteristics of tubilitis and interstitial inflammatory infiltrates. These findings are similar to graft rejection, differentiating the two can be a challenge and to make matters worse, these two processes can co-exist.
– other supportive findings in BKVAN include immunohistochemistry (i.e., SV40) and intranuclear viral inclusions without a surrounding halo on light and electron microscopy
Ureteral stenosis
– BKV replication occurs in the urothelium and can cause late ureteral stenosis (>1month post kidney transplantation)
– ureteral BKV infection is characterized by marked inflammation and ulcerations resulting in ureteral stenosis (6)
– patients present with asymptomatic hydronephrosis and a declining eGFR
– ultrasound can be used to confirm the diagnosis
Hemorrhagic cystitis
– can present with pain, hematuria, urinary obstruction and is associated with decreasing eGFR (7)
– more common in hematopoietic stem cell transplant recipients
References
1. Cohen-Bucay A, Ramirez-Andrade SE, Gordon CE, Francis JM, Chitalia VC. Advances in BK Virus Complications in Organ Transplantation and Beyond. Kidney medicine. 2020 Nov-Dec;2(6):771-86. PubMed PMID: 33319201. Pubmed Central PMCID: PMC7729234. Epub 2020/12/16. eng.
2. Reploeg MD, Storch GA, Clifford DB. Bk virus: a clinical review. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2001 Jul 15;33(2):191-202. PubMed PMID: 11418879. Epub 2001/06/22. eng.
3. Moens U, Calvignac-Spencer S, Lauber C, Ramqvist T, Feltkamp MCW, Daugherty MD, et al. ICTV Virus Taxonomy Profile: Polyomaviridae. The Journal of general virology. 2017 Jun;98(6):1159-60. PubMed PMID: 28640744. Pubmed Central PMCID: PMC5656788. Epub 2017/06/24. eng.
4. Nickeleit V, Singh HK, Randhawa P, Drachenberg CB, Bhatnagar R, Bracamonte E, et al. The Banff Working Group Classification of Definitive Polyomavirus Nephropathy: Morphologic Definitions and Clinical Correlations. Journal of the American Society of Nephrology : JASN. 2018 Feb;29(2):680-93. PubMed PMID: 29279304. Pubmed Central PMCID: PMC5791071. Epub 2017/12/28. eng.
5. KDIGO clinical practice guideline for the care of kidney transplant recipients. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2009 Nov;9 Suppl 3:S1-155. PubMed PMID: 19845597. Epub 2009/10/23. eng.
6. Mylonakis E, Goes N, Rubin RH, Cosimi AB, Colvin RB, Fishman JA. BK virus in solid organ transplant recipients: an emerging syndrome. Transplantation. 2001 Nov 27;72(10):1587-92. PubMed PMID: 11726814. Epub 2001/12/01. eng.
7. Laskin BL, Denburg MR, Furth SL, Moatz T, Altrich M, Kleiboeker S, et al. The Natural History of BK Polyomavirus and the Host Immune Response After Stem Cell Transplantation. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2020 Dec 15;71(12):3044-54. PubMed PMID: 31851312. Pubmed Central PMCID: PMC7819507. Epub 2019/12/19. eng.
1-What are the diseases caused by polyomaviruses in renal transplant recipients? –Clinical syndromes that are causally linked with polyomavirus infection are best established for BKPyV, JCPyV, Merkel cell polyomavirus (MCPyV), and trichodysplasia spinulosa polyomavirus (TSPyV), and occur primarily in the setting of cellular immune deficiency. –BKPyV-associated nephropathy;. -BKPyV is the primary cause of polyomavirus-associated nephropathy in renal transplant recipients, -JCPyV is a rare cause of nephropathy in renal transplant recipients and may be due to primary infection. BKPyV-associated nephropathy in native kidneys is rare but has been described in nonkidney organ transplant recipients. -Hemorrhagic cystitis;. -Acute hemorrhagic cystitis following engraftment among hematopoietic cell transplant (HCT) recipients (particularly allogeneic HCT recipients) may be associated with BKPyV infection, -BKPyV-associated hemorrhagic cystitis (BKPyV-HC) is estimated to complicate 5 to 25 percent of allogeneic HCT and is typically characterized by postengraftment urinary frequency, dysuria, hematuria, urinary blood clots, and urinary obstruction that may last for several weeks, -BKPyV viruria is common post-transplant, affecting >50 percent of HCT recipients. -Progressive multifocal leukoencephalopathy; -JCPyV is the main causative agent of progressive multifocal leukoencephalopathy (PML), a demyelinating disorder that almost always occurs in the setting of immunocompromise, -PML has been reported most commonly in patients with advanced HIV (particularly before the availability of potent antiretroviral therapy), but it has also been reported in patients with hematologic malignancies and in patients receiving certain lymphocyte-targeted agents, –Trichodysplasia spinulosa;. -Trichodysplasia spinulosa (TS) polyomavirus (TSPyV) has been detected in lesions of TS, a rare skin disease in immunocompromised patients characterized by viral replication within keratinocytes and hyperproliferation of the inner root sheath cell. -The diagnosis is characterized by the development of keratin spines (“spicules”) and follicular papules that often involve the face and is confirmed by a skin biopsy with characteristic histology or detection of the polyomavirus (SV-40 immunostaining, electron microscopy visualization of 40 to 45 nm viral particles in cells of the inner root sheath or molecular methods). -Associations with malignancy -Merkel cell carcinoma; -MCPyV DNA or virions are commonly found on healthy skin. Although rare, the virus is implicated in the pathogenesis of Merkel cell carcinoma, an aggressive neuroendocrine malignancy that affects the skin) -Putative associations; -JCPyV and BKPyV have been associated with an array of malignancies but whether they play a causal role is uncertain. Viral DNA sequences and viral protein expression has been detected in some tumor involving the brain, prostate, bladder, urothelium, and other organs. -There is also a higher than expected incidence of bladder cancer in kidney transplant recipients treated for BKPyV-associated nephropathy. -Other disease associations –Disseminated BKPyV infection; -Widespread endothelial BKPyV infection in a kidney transplant recipient resulted in severe muscle weakness, anasarca, and a fatal myocardial infarction. -BKPyV viremia, dysuria, and hematuria in a postallogeneic stem cell transplant recipient progressed to deterioration of renal function, hypertension, seizure, pancreatitis, and respiratory failure. -Colonic ulcers were documented in a kidney transplant recipient with abdominal pain and known BKPyV infection of the kidney allograft with associated BK viremia. -Biopsy specimens of the ulcers showed viral inclusion bodies, and in situ hybridization for BKPyV was strongly positive. Reduction in the immunosuppressive regimen led to healing of the ulcers and a decrease in serum BKPyV DNA. Studies for other viruses, including cytomegalovirus, were negative. –Trichodysplasia spinulosa polyoma virus (TSPyV); -Found in respiratory samples of a child with acute lymphoblastic leukemia who had cough, fever, and coryza . TSPyV has been found in blood and urine samples of otherwise asymptomatic transplant recipients. –Karolinska Institute polyomavirus (KIPyV); -Detected in respiratory and fecal specimens in immune competent pediatric patients but its role in respiratory tract disease remains uncertain.
%DISEASES CAUSED BY POLYOMAVIRUSES IN RENAL TRANSPLANT RECIPIENTS.
PREVALENCE.
-By adulthood,~ 50-90% of adults have detectable antibodies to BKPyV,JCPyV,Merkel cell polyomavirus ,Karolinska Institute Polyomavirus and WUPyV.
TRANSMISSION.
-Person to person.
-Oral/ Resp transmission; BKPyV, JCPyV, KIPyV & WUPyV.
-Skin contact ;MCPyV,HPyV6,HPyV7 & TSPyV.
-Other routes; Fecal oral, sexual or perinatal transmission.
CLINICAL MANIFESTATION.
1.BKPyV associated nephropathy– occurs in SOT post renal transplant mostly. Manifests as gradual renal failure with asymptomatic acute or slow rise in creatinine that can progress to graft failure.
2.Hemorrhagic cystitis – Can occur in HCT recipients esp allogenic recipients (5-25%).Manifests as post surgery urinary frequency ,dysuria,hematuria,urinary blood clots and obstructive features.Tx is supportive with some studies reporting use of cidofovir/BKPyV specific cytotoxic T cell therapy.
3.PML -Caused by JCPyV in immunocompromised pts. Manifests as gradual onset focl neurological deficits with ataxia, visual impairment and cognitive impairment. Reported in HIV and patients with hematological malignancies after recent lymphocyte targeted agents like Natalizumab.
4.Trichodysplasia spinulosa – Caused by TS polyomavirus xtised by viral replication in keratinocytes. Manifest as follicular papules or spicules on face and have SV – 40 staining on histology.TX involves topical valganciclovir, cidofovir, leflunomide, retinoids or removal of spicules physically.
5.Merkel cell Ca – A neuroendocrine malignancy with predominant derm involvement causes by MCPyV.
6.Other associated malignancies – Brain, Prostate, Bladder and urothelial tumors.
7.Other diseases associations;
Disseminated BLPyV – spread to kidney, brain ,lung, bladder, GIT, cardiac areas can occur with varied organ dependant manifestations.
TSPyV -reported in resp samples of children with ALL who had URTI features.
KIPyV- Repoted in resp and fecal samples in non immunocompromised children.
WUPyV – has been reported in resp, CSF results of a pt who had encephalitis. No studies so far linking it to PML.
HPyV6 -Has been seen in pts with derm manifestations post transplant -pruritis, skin discoloration post kidney and pancreas transplant.
HPyV7 – In HIV, post heart and lung transplant has been linked tp pruritis and increased blood VL levels.
HPyV9 – Post transplant and HIV pts have had it detected in resp, urine and blood samples asymptomatically.
HPy10 – Reportings have been made in pts who have been followed up for warts with anal condylomata ,hypogammaglobulinemia, infection and myelokathesis(WHIM Syndrome).
HPyV11 & HPy12 – Occasionally causes diseases in healthy children.
HPyV13 – Occasionally causes vasculitis,myositis and retinal blindness.
REFERENCES;
1.Upto date- Overview and virology of JC Polyomavirus, BK Polyomavirus and other Polyomavirus infections.
2.Prof Halawa lecture on BK virus post transplant.
That is a well-structured reply. As much as I adore my academic brother Ahmed Halawa, writing that his lecture is a reference is not a complete reply in a scientific write-up.
WHAT ARE THE DISEASES CAUSED BY POLYOMAVIRUS IN RENAL TRANSPLANT RECIPIENTS
kidney transplant recipients receive immunosuppression for prolonged period of time. This makes these patients very susceptible for various viral infections which triggers neoplasms in these patients.
Polyomaviruses are one of the major group of viruses responsible for neoplasms, post kidney transplantation.
Following are the three viruses belonging to family of polyoma virus responsible for post kidney transplantation
JC virus
BK virus
SV40
Following are the diseases causes by the above viruses:
BK virus
Hematuria
Urethral stenosis
tubulointerstitial nephritis
Progressive graft loss
JC virus
PVAN
Progressive multifocal leucoencephalopathy
SV40 can also cause similar presentation in small percentage
Ref:
Mara Medeirosa, J.. Alberúa, G. R.. Garcíaa, Y.. Fuentesa, L.. Velasqueza. Polyoma virus in transplant recipients, Vol. 28. Issue. 2.April 2008, pages 123-238
Serena Delbue, Mariano Ferraresso, Luciana Ghio, Camilla Carloni, Silvia Carluccio, Mirco Belingheri, Alberto Edefonti, Pasquale Ferrante, “A Review on JC Virus Infection in Kidney Transplant Recipients”, Journal of Immunology Research, vol. 2013, Article ID 926391, 7 pages, 2013. https://doi.org/10.1155/2013/926391
Diseases caused by polyomavirus in renal transplant recipients Introduction:
Human polymaviruses are small non enveloped DNA viruses which are widespread in nature.
They remain latent in the immunocompetent individuals after primary infection.
Illnesses related to these viruses occur in times of immuonocompromise especially T- cell deficiency.
There are14 groups of HPV, with BKV, JCV and Merkel virus being the most known.
Diseases related to HPV in renal transplant recipients:
1.BKV: A.BKVN:
Occurs in 1- 8% of renal transplant recipients and leads to progressive graft dysfunction/ graft failure.
In almost all cases the polyoma virus associated nephropathy is due to BKV.
B . Ureteric stenosis
BKV can rarely cause ureteric stenosis which lead to obstruction.
It usually affects the distal part of ureter.
C. Assocaiton with malignacy:
BKV has been linked (but not yet proven as a direct casue or association) to a variety of cancer in humans such as bladder and prostate cancer.
Also to adenocarcinoma, brain tumors, neuroblastoma and osteosarcomas.
D: Hemorrhagic cystitis:
BKV related hemorrhagic cystitis usually occur in bone marrow transplant recipients
But can rarely occur in renal transplant recipients,usually in the first year Post-transplantion.
CMV,EBV are also implicated.
2. JCV: A : Nephropathy:
Only few cases has been attributed to JCV.
It usually has a non aggressive clinical course with a favorable outcome.
B: progressive mutifocal leukoencephalopathy:
It is rare after transplantation.
Case reports and case series in organ transplants recipients reports a spectrum of disese due to JCV including neuropathy,encephalopathy and meningitis.
A brain biopsy is needed for diagnosis.
But diagnosis is strongly suggested by the characteristic finding of white matter changes on MRI and detection of JCV PCR in CSF.
3. Merkle cell virus:
Discovered in Merkel cell carcinoma, which is a rare but aggressive skin cancer.
Among the 14 known HP viruses, it is the only virus clearly linked to human cancer.
References: 1. professorAhmed Halawal lecture about BKV in renal transplant recipients. 2. Jhon E. Bennet etal. Principle and practice of infectious disease 2020 3. Mareli Coetzer D, etal. Hemorrhagic cystitis in a renal transplant recipients.OHSU
4.Molecular Virogy of Human Pthogenic Viruses. 2017
5. Masahiro Shad, Encylopia of cancer 2019
6. Serena Delbuec etal. Areview of JCV virus Infection in kdney Transplant Recepient 2013
That is a well-structured reply. As much as I adore my academic brother Ahmed Halawa, writing that his lecture is a reference is not a complete reply in a scientific write-up.
Human Polyomaviruses are small, double stranded DNA viruses belonging to the polyomaviridiae family (1). A total of 14 humanpolyomaviruses have been reported, which include BK virus, JC virus, KI virus, WU virus, and Merkel Cell virus (2).
c.Polyoma virus associated urothelial cancer (PyVUC).
d.Ureteral stenosis.
2) JC Virus: It is associated with progressive multifocal leukoencephalopathy (PML). JC virus has been seen as a co-infectious agent in kidney transplant recipients with BK virus associated interstitial nephritis (3).
3) Merkel Cell virus: It is associated with Merkel Cell carcinoma, a neuro-endocrine skin malignancy.
4) TS virus: It is associated with Trichodysplasia spinulosa, a proliferative dedifferentiated skin disorder (2).
5) Human polyoma virus 7: It is associated with pruritic hyperproliferative keratinopathy (brownish, pruritic plaques on extremities and trunk).
6) SV40 virus: It has been identified in renal transplant recipients, but its importance is poorly defined (3,4).
BK virus, JC virus, and SV40 virus have been shown to be associated with mesothelioma, pediatric and adult brain tumors, osteosarcoma, and nonHodgkin lymphomas (5).
References:
Boothpur R, Brennan DC. Human polyoma viruses and disease with emphasis on clinical BK and JC. J Clin Virol. 2010 Apr;47(4):306-12. doi: 10.1016/j.jcv.2009.12.006. Epub 2010 Jan 8. PMID: 20060360; PMCID: PMC3774018.Wu Z, Graf FE, Hirsch HH. Antivirals against human polyomaviruses: Leaving no stone unturned. Rev Med Virol. 2021 Nov;31(6):e2220. doi: 10.1002/rmv.2220. Epub 2021 Mar 17. PMID: 33729628.Kwak EJ, Vilchez RA, Randhawa P, Shapiro R, Butel JS, Kusne S. Pathogenesis and management of polyomavirus infection in transplant recipients. Clin Infect Dis. 2002 Nov 1;35(9):1081-7. doi: 10.1086/344060. PMID: 12384842.Bohl DL, Brennan DC. BK virus nephropathy and kidney transplantation. Clin J Am Soc Nephrol. 2007 Jul;2 Suppl 1:S36-46. doi: 10.2215/CJN.00920207. PMID: 17699509.Ahsan N, Shah KV. Polyomaviruses and human diseases. Adv Exp Med Biol. 2006;577:1-18. doi: 10.1007/0-387-32957-9_1. PMID: 16626024.
Human polyomaviruses (HPyVs) are members of a genus of DNA viruses in the Polyomaviridae family. The most common polyomaviruses associated with infectious diseases are JC polyomavirus (JCPyV) and BK polyomavirus (BKPyV).
1-BKPyV-associated nephropathy
2 endothelial BKPyV infection in a kidney transplant recipient resulted in severe muscle weakness, anasarca, and a fatal myocardial infarction
3- Colonic ulcers were documented in a kidney transplant recipient with abdominal pain and known BKPyV infection of the kidney allograft with associated BK viremia
4- Progressive multifocal leukoencephalopathy — JCPyV is the main causative agent of progressive multifocal leukoencephalopathy (PML), a demyelinating disorder that almost always occurs in the setting of immunocompromise,
5- Trichodysplasia spinulosa — Trichodysplasia spinulosa (TS) polyomavirus (TSPyV) has been detected in lesions of TS, a rare skin disease in immunocompromised patients characterized by viral replication within keratinocytes and hyperproliferation of the inner root sheath cell The diagnosis is characterized by the development of keratin spines
6-Human polyomavirus 6 (HPyV6) has been reported in association with pruritic, hyperpigmented skin eruptions in two patients, one with a history of kidney and pancreas transplant and the other with no history of immune compromise
7-Merkel cell carcinoma — MCPyV DNA or virions are commonly found on healthy skin , an aggressive neuroendocrine malignancy that affects the skin.
8-JCPyV and BKPyV have been associated with an array of malignancies involving the brain, prostate, bladder, urothelium, and other organs.
There is also a higher than expected incidence of bladder cancer in kidney transplant recipients treated for BKPyV-associated nephropathy
What are the diseases caused by polyomaviruses in renal transplant recipients?
Introduction: Polyomaviridae family of the ungrouped DNA viruses, detected in vertebrate hosts including rodents, cattle, birds, monkeys, and primates. It affects almost 90% of population during life.
Polyomavirus related diseases are:
BKPyV-associated nephropathy-human polyomaviruses (HPyVs): post solid organ transplantation, mostly renal transplant, mostly asymptomatic, but can present with acute kidney injury or progressive elevation of creatinine.
Hemorrhagic cystitis -human polyomaviruses (HPyVs): 5-25% usually post bone marrow transplants, but rarely in solid organ transplants, can be asymptomatic, but may be with gross hematuria, blood clots may cause obstruction, frequency, and dysuria.
Progressive multifocal leukoencephalopathy–JC polyomavirus (JCPyV): is a demyelinating occurs in immunocompromised patients including untreated HIV, and presents with progressive focal neurologic deficits including ataxia, hemiparesis, visual field deficits, and cognitive impairment. It has also been reported in patients with hematologic malignancies and in patients receiving certain lymphocyte-targeted agents, such as natalizumab.
Trichodysplasia spinulosa- Trichodysplasia spinulosa polyomavirus/2010: characterized by the development of cutaneous keratin “spines” and follicular papules most commonly on the face, and is confirmed by a skin biopsy with characteristic histology or detection of the polyomavirus (SV-40 immunostaining).
Merkel cell carcinoma, an aggressive neuroendocrine malignancy of the skin– Merkel cell polyomavirus/2008: an aggressive neuroendocrine malignancy that affects the skin. Multiple independent clonal integration sites and the presence of functionally truncating alterations of the viral genome support its etiologic role.
Solid Malignancies: bladder cancer, tumor in the brain, prostate, bladder, urothelium, and other organs.
Karolinska Institute polyomavirus (KIPyV), Wisconsin University polyomavirus (WUPyV) : are respiratory viruses.
Human polyomavirus 6 (HPyV6) has been reported in association with pruritic, hyperpigmented skin eruptions.
Human polyomavirus 7 (HPyV7) has been associated with a pruritic rash and viremia.
Human polyomavirus 10 (HPyV10)- WHIM SYNDROME
Human polyomavirus 11 and 12 (HPyV11 and HPyV12) have been found in stool samples of immune competent children with and without diarrhea.
Human polyomavirus 13 (HPyV13) has been detected in a muscle biopsy from a single pancreas recipient with vasculitis, myositis, and retinal blindness
Human polyomavirus 14 (HPyV14) has been isolated from skin swabs, eyebrow hairs, and oral gargles
Hodgkin’s lymphoma– JC polyomavirus (JCPyV).
References: UpToDtae-overview and virology of JC polyomavirus, BK polyomavirus, and other polyomavirus infections.
What are the diseases caused by polyomaviruses in renal transplant recipients?
Human polyomaviruses:
1. BK
2. JC
3. KI
4. WU
5. Merckle cell
The two viruses that can cause significant diseases in humans are BK virus JC virus
BKV Nephropathy:
· Up to 80% of renal transplant patients have BK viruria and 5–10% progress to BKVN
· Reactivation starts soon after transplantation and is seen in 30–50% of the patients by 3 months post transplant
· When the virus, reactivates it can present as asymptomatic deterioration of renal function, tubulo-interstitial nephritis, and ureteric stenosis
Ureteric stenosis:
· BKV rarely cause ureteral stenosis (marked inflammation and ulcerations)
· BKV-associated stenosis usually affects distal part of the ureter, especially around the site of anastomosis at the ureterovesical junction
· It remains unknown whether BKV is the primary cause of ureteric stenosis or whether BKV infects previously injured ureter (from ischemia or trauma after stenting) as a secondary insult
Hemorrhagic cystitis:
· Seen in 25–60% of the bone marrow transplant patients
· It is usually seen two weeks after transplant which is later than the hemorrhagic cystitis from chemotherapeutic agents such as cyclophosphamide which occurs immediately
· Symptoms include dysuria, urgency, frequency, suprapubic pain and varying degree of haematuria
· The diagnosis is made by detecting BK viral DNA in the urine
· Treatment is usually supportive with hyperhydration, forced diuresis, bladder irrigation and transfusion as indicated
· If the hematuria is severe with clots, cystoscopy and clot removal and cauterization of the source might be needed
BK virus and tumours (Merkel cell carcinoma):
· Aggressive skin cancer
· Typically affects elderly and immunosuppressed individuals
References
1. Etta PK, Madhavi T, Gowrishankar S. Coexistent BK-virus-associated nephropathy and ureteric stenosis in a patient with acute cellular rejection after renal transplantation: A case report and review of literature. Indian J Transplant 2020;14:147-51
2. Boothpur R, Brennan DC. Human polyoma viruses and disease with emphasis on clinical BK and JC. J Clin Virol. 2010 Apr;47(4):306-12. doi: 10.1016/j.jcv.2009.12.006. Epub 2010 Jan 8. PMID: 20060360; PMCID: PMC3774018.
What are the diseases caused by polyomaviruses in renal transplant recipients?
-There are 5 known human polyoma viruses. JC virus and BK virus are two polyoma viruses identified nearly three decades ago. Recently WU, KI and Merkel cell polyoma viruses have been isolated from humans. Merkel cell polyoma virus associates with Merkel cell carcinoma.
– Most human polyoma disease is caused by BK and JC viruses which are usually acquired in childhood. These viruses remain latent possibly in the lymphoid organs and kidney and under the circumstances of severe immunosuppression both these viruses reactivate. BKV Nephropathy
After primary infection in childhood BK virus becomes latent in the tubular epithelial cells of the urogenital tract. It mainly affects epithelial cells of collecting ducts, tubular epithelium of renal calyces and renal pelvis60. In immunosuppressed states BK may reactivate in the renal tubular epithelial cells causing asymptomatic deterioration of renal function, tubulo-interstitial nephritis, and ureteric stenosis. Hemorrhagic cystitis from BK virus is seen in 25–60% of the bone marrow transplant patients . Progressive Multifocal leukoencephalopathy (PML)
Progressive Multifocal leukoencephalopathy is a progressive demyelinating central nervous system disorder involving cerebral white matter caused by the JC virus . It most often presents as an opportunistic infection in HIV patients with lymphopenia but has recently been seen with new immunosuppressives .It has a high mortality rate. Reference:
-Raghavender Boothpur, et al. Human Polyoma Viruses and Disease with Emphasis on Clinical BK and JC. J Clin Virol. 2010 Apr; 47(4): 306–312.
Polyoma viruses are DNA viruses belonging to the polyoma viridae family. They There are 14 members of the family. Transmission is from person to person via oral and/or respiratory of BK, JC, KI and WU polyoma viruses whereas direct contact for others.
Only BK, JC, Merkel polyoma viruses have been associated with specific disease.
Human Polyoma virus 1 – Also known as BK virus. It was first isolated from urine but can also been detected in the blood and body tissues.
BK Virus nephropathy – It is characterized by progressive renal dysfunction but sometimes as asymptomatic acute or slowly progressive rise in serum creatinine which could lead to subsequent allograft loss. and ureteral stenosis in KTx. It rarely affects native kidneys.
Hemorrhagic cystitis – characterized by dysuria, frequency, urinary blood clots and obstruction. Commonly occurs following HSCT.
Human Polyoma virus 2 – Also known as JC virus. It’s a rare cause of nephropathy post kidney transplant. It was first isolated from brain tissue. It causes Hodgkin’s lymphoma and progressive multifocal leucoencephalopathy, a condition characterized by ataxia, hemiparesis, visual field defects and cognitive impairment.
Human Polyoma virus 5 – Also known as merkel cell polyoma virus. It causes merkel cell carcinoma, an aggressive neuroendocrine skin malignancy. It was first isolated in patients with merkel cell carcinoma.
Human Polyoma virus 8 – Also known as trichodysplasia spinulosa polyoma virus. It causes the development of cutaneous keratin “spines” and follicular papules especially on the face with facial spines. It was first isolated in heart transplant patients with trichodysplasia spinulosa.
Others of unknown clinical significance.
Human Polyoma virus 3 – Also known Karolinska institute polyoma virus which was initially from nasopharyngeal aspirate and feces.
Human Polyoma virus 4 – Also known as Washington university polyoma virus. Isolated first in nasopharyngeal aspirate.
Human Polyoma virus 6 – Found in normal skin of healthy adults.
Human Polyoma virus 7
Human Polyoma virus 9 – Found in blood and urine of asymptomatic kidney Tx patients.
Human Polyoma virus 10 – Also called MX,MW polyoma virus. Found in stool samples of healthy children.
Simian virus – discovered as a contaminant of polio and adenovirus vaccines.
1. What are the diseases caused by polyomaviruses in renal transplant recipients?
Dear Dr Ahmed,
The attached table summarizes the diseases caused by polyomaviruses. We can notice that kidney transplant recipients were mentioned specifically with:
1- BKV (human polyomavirus 1): can cause BK virus nephropathy and ureteric stenosis.
2- JC virus (human polyomavirus 2) may be associated with progressive multifocal leukoencephalopathy.
Regarding the remaining types of polyomaviruses, despite not being specifically linked to kidney transplant recipients. However, I believe if they can affect normal subjects, then they can affect immune-compromised patients in a more aggressive form. Nevertheless, they remain not widely studied (1).
BK Virus can cause Cystitis (haemorrhagic and non-haemorrhagic), Uterine stricture, stenosis and BK virus associated nephropathy.
JC virus causes progressive Multifocal leukoencephalopathy; a demyelinating disorder, always occurs in the setting of immunocompromise, presents with progressive focal neurologic deficits including ataxia, hemiparesis, visual field deficits, and cognitive impairment. Trichodysplasia spinulosa polyoma virus; a rare skin disease characterized by viral replication within keratinocytes and hyperproliferation of the inner root sheath cell. Human polyomavirus 6 (HPyV6) has been reported in association with pruritic, hyperpigmented skin eruptions in patients with a history of kidney and pancreas transplant. Human polyomavirus 9 (HPyV9) has been detected in several transplant recipients
Diseases caused with BK polyoma virus in renal transplant recipients BKPV:
1- BKPV Nephropathy BKPVN, as its causing tubulo-interstial nephropathy provoked by over suppression of immune system .
2- hemorrhagic cystitis , which can present with profuse hematuria.
3-Ureteric stenosis leading to obstructive nephropathy and hydronephrosis.
4-Pneumonitis.
5- Encephalitis.
References:
1-Shauna M. Bennett,a,1 Nicole M. Broekema,b,1 and Michael J. BK polyomavirus: emerging pathogen.Microbes Infect. 2012 Aug; 14(9): 672–683
John Cunningham virus JCV:
Is Polyoma virus who was reported to be associated with progressive multifocal leukoencephalopathy PML in over suppressed patient on Mycophenolate medicine.
JC was linked to some malignancy cases .
references:
2-Raghavender Boothpur, and Daniel C. Brennan.Human Polyoma Viruses and Disease with Emphasis on Clinical BK and JCJ Clin Virol. 2010 Apr; 47(4): 306–312.
.
-Human polyomaviruses (HPyVs) are members DNA viruses in the Polyomaviridae family. Fourteen HPyV species have been identified.
-It is highly prevelant with seropositivity rates ranging from 30 to 90 percent in healthy general population.
-After primary infection, the virus will remain lifelong persistence in the body.
-Most instances of primary polyomavirus infection in immunocompetent persons are presumed to be either subclinical or associated with mild nonspecific symptoms.
-In immunocompromised persons, however, either primary infection and/or reactivated infection can cause specific syndromes and lead to substantial morbidity
Common clinically relevant species: * BKV BKPyV viruria is common affecting >50 % of KTRs. However, most patients with viruria do not develop symptomatic diseases.
BKPyV viremia may follow viuria, detected in 10 to 30 % of recipients in the first six months. Mostly asymptomatic but may progress to BKPyAN. BKPyV-associated nephropathy Progressive renal dysfunction resulting in either an asymptomatic acute or slowly progressive rise in serum creatinine and can progress to renal allograft loss. BKPyV-associated hemorrhagic cystitis (BKPyV-HC) is estimated to complicate 5 to 25 % of HSCT and is typically characterized by postengraftment urinary frequency, dysuria, hematuria, urinary blood clots, and urinary obstruction that may last for several week. Ureteric Stenosis:
Association with malignancy There is no conclusive evidence of a causal relationship between BKPyV and cancer in human beings.
Various reports have indicated the presence or absence of viral genomic sequences in multiple human cancers. It has been suggested that that BKV is associated with brain tumors, adenocarcinomas, prostate cancers, and bladder carcinomas, and JCV is associated with mesotheliomas, brain tumors, osteosarcomas, and lymphomas. * JCV: progressive multifocal leukoencephalopathy (PML), a demyelinating disorder that almost always occurs in the setting of immunocompromise, and presents with progressive focal neurologic deficits including ataxia, hemiparesis, visual field deficits, and cognitive impairment. PML commonly reported in advanced HIV JCPyV is a rare cause of nephropathy in renal transplant recipients and may be due to primary infection *Merkel cell polyomavirus
An oncogenic virus associated with Merkel cell carcinoma, an aggressive neuroendocrine malignancy of the skin. *Simian polyomavirus 40
Its possible role in human diseases including cancer has been controversial.
References:
-Jiang M, Abend JR, Johnson SF, Imperiale MJ. The role of polyomaviruses in human disease. Virology. 2009 Feb 20;384(2):266-73. doi: 10.1016/j.virol.2008.09.027. Epub 2008 Nov 7. PMID: 18995875; PMCID: PMC2661150.
Nephropathy is linked to the virus. Immunosuppression severity makes people more susceptible to BKVAN.
The tubular cells are necrosed and lytically destroyed, and the interstitial inflammation is intensified.
Acute cellular rejection and graft loss
Ureteric stenosis
Hemorrhagic cystitis.
Other illnesses brought on by the BK virus include meningoencephalitis, hepatitis, and pneumonia.
Progressive multifocal leuloencephelopathy.
Malignancy like merkel cell carcinoma, RCC, urothelial.
Prof Ahmed Halawa lecturer J Clin Virol . 2010 April ; 47(4): 306–312. doi:10.1016/j.jcv.2009.12.006. Clinical Microbiology ReviewsVolume 30, Issue 2, April 2017, Pages 503-528
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Quite a short reply.
As much as I adore my academic brother Ahmed Halawa, writing that his lecture is a reference is not a complete reply in a scientific write-up.
What are the diseases caused by polyoma- viruses in renal transplant recipients? Polyomavirus: multi-bodies Small (30 to 45 nm) double-stranded DNA viruses Immunosuppressed population
Group include:
BK: Nephropathy 5-10%
JC: progressive multifocal leukoencephalopathy
Merkel cell: Merkel cell carcinoma
Diseases caused by polyomaviruses:
BKV associated nephropathy: 5-10%
The definitive diagnosis of BKV-associated nephropathy is made by histologic findings in a kidney allograft biopsy.
Tubular damage with tubulitis and interstitial inflammatory infiltrate may indicate BKV associated nephropathy.
Intra-nuclear homogeneous basophilic viral inclusions without surrounding halo seen on light and electron microscopy may make BKV-associated nephropathy more likely.
Immuno-histochemistry using antibodies against the T Ag of SV40 is used to confirm histological diagnosis.
Ureteric stenosis:
Replication of BKV in uro-epithelium may cause ureteric stenosis due to marked inflammation and ulcerations , after one month post transplantation.
Haemorrahgic cystitis:
Hemorrhagic cystitis is a serious complication that occurs in 25% of recipients of hematopoietic stem cell transplants in children and young adults.
it may be associated with pain, hematuria, and urinary obstruction
BK virus rarely cause haemorrhagic cystitis in kidney transplant, but some studies found BK viriemia in cases with hematopoietic stem cell transplants.
Central nervous system involvement:
The human polyoma virus JC virus (JCV) characterized by focal demyelination in central nervous system==> progressive leukoencephalopathy
BK virus :
1- asymptomatic viremia
2- ureteral stricture
3- BKVN: tubulo-interstitial nephritis and fibrosis which may end in graft failure.
4- hemorrhagic cystitis.
5- associated with urothelial and nonurothelial malignancies of the urinary tracts and RCCC.
BKV causes viral nephropathy otherwise known as polyomavirus-associated nephropathy as well as hemorrhagic cystitis and ureteric ulceration and stenosis with or without obstruction
JC virus causes a viral encephalopathy
Primary BK virus infection occurs in early life,resulting in almost universal seropositivity
The virus persist in urinary tract and viral shedding into the urine is relatively common in elderly, diabetics, HIV and transplant patient
There are several genotypes, although a recipient may have acquired partial immunity to one genotype, the allograft may exposure them to another
Over the last 3 decades, BKVAN has emerged as an important cause of allograft dysfunction
BKVAN occurs in ~ 5% of kidney transplant recipients
Viremia occur in a larger proportion ~ 10% and BK viruria is much more common
The risk of graft failure is high, with 3 and 5 years graft survival rates of ~ 65% and ~55% respectively
Data from animal studies suggested that BK virus infection promotes the proliferation, invasion, and migration of bladder cancer (Yigang Zeng et al.)
Other studies also showed the role of BK virus induced carcinogenesis in human
Source; Oxfordhand book of Nephrology 2 edition, BK virus promotrs growth and aggressiveness in bladder cancer byYigang Zeng et .al, Role of BK virus in human cancer byJorge Levican et al.
Diseases caused by polyoma viruses in renal transplant recipients:
Common polyomaviruses known to cause disease in humans are BK virus &JC virus
Diseases caused by the BK virus are:
-BK virus-associated nephropathy and allograft rejection
-Ureteric stenosis or obstruction
-hemorrhagic cystitis
-Associated genitourinary malignancy Disease caused by the JC virus: primary multifocal leukoencephalopathy
Around 75% of the adult population is latently infected with BK virus. Immunocompetent sub-
jects are usually asymptomatic, but immunocompromised hosts can suffer BK-related complications.
In kidney trans- plant recipients, BK and possibly other polyoma viruses
can cause:
1- Nephropathy
2- Ureteral stenosis.
3- Hemorrhagic cystitis is prevalent in hematopoietic stem cell transplantation (HSCT) patients.
Rare cases of BK disseminated disease (tubulointerstital nephritis, desquamative
pneumonitis, meningoencephalitis, and retinitis) have also been described, especially in patients with acquired immune deficiency syndrome.
References:
1-BK Polyomavirus and the Transplanted Kidney: Immunopathology and Therapeutic Approaches Transplantation November 2016 Volume 100 Number 11
What is Merkel cell tumour:
Merkel cell carcinoma (MCC) is a rare, aggressive form of skin cancer with a high risk for returning (recurring) and spreading (metastasizing), often within two to three years after initial diagnosis. How rare is it? Approximately 3,000 new cases are diagnosed annually in the U.S. Experts expect that this will increase to 3,250 cases diagnosed annually by 2025. Merkel cell carcinoma (MCC) is 40 times more rare than melanoma, with an estimated one case per 130,000 people in the U.S.
What causes MCC: UV rays from sun exposure or artificial light sources like tanning beds cause most types of skin cancer, including Merkel cell carcinoma. UV radiation can damage the genetic makeup, or DNA, of skin cells. Eight in 10 people with Merkel cell carcinoma have the Merkel cell polyomavirus (MCP). But most people infected with MCP don’t develop Merkel cell carcinoma. This common childhood virus doesn’t cause symptoms, and there isn’t a way to screen for it. Medical experts are still trying to determine how and why the virus causes skin cancer in some people.
Research suggests a weakened immune system may not be able to suppress the virus. As a result, the virus causes skin cells to make a protein that turns off the genes that normally suppress the growth of tumors. What causes Merkel cell carcinoma?UV rays from sun exposure or artificial light sources like tanning beds cause most types of skin cancer, including Merkel cell carcinoma. UV radiation can damage the genetic makeup, or DNA, of skin cells.
Eight in 10 people with Merkel cell carcinoma have the Merkel cell polyomavirus (MCP). But most people infected with MCP don’t develop Merkel cell carcinoma. This common childhood virus doesn’t cause symptoms, and there isn’t a way to screen for it. Medical experts are still trying to determine how and why the virus causes skin cancer in some people.
Research suggests a weakened immune system may not be able to suppress the virus. As a result, the virus causes skin cells to make a protein that turns off the genes that normally suppress the growth of tumors.
What are the risk factors for Merkel cell carcinoma?People of all ages, genders and skin colors can get Merkel cell carcinoma. But men who are fair-skinned and over 50 are most at risk.
Other risk factors include:
Having other types of skin cancer like basal cell carcinoma, squamous cell carcinoma or melanoma.
References 1-Skin Cancer Foundation by Sandra D’Angelo, MD Paul Nghiem, MD, PhD Last updated: August 2022 2-American Academy of Dermatology (AAD) Association. Skin Cancer Types: Merkel Cell Carcinoma Overview. (https://www.aad.org/public/diseases/skin-cancer/types/common/merkel-cell) Accessed 4/15/2022.
Three types of polyoma virus that infect humans (JCV, BKV, and SV40), BKV
polyomavirus-associated nephropathy; interstitial nephritis and graft loss
ureteral ulceration and stenosis, and obstructive uropathy
hemorrhagic cystitis JC Virus
Infection of the CNS by JC polyomavirus has been observed uncommonly in transplant recipient as PML This infection may present with focal neurologic deficits or seizures as well as more slowly progressive neurologic lesions and may progress to death
following extensive demyelination. PML may be confused with calcineurin neurotoxicity; both may respond to a reduction in drug levels. No proven therapies exist
dementia also reported in few cases Genitourinary malignancies:
Is it association or causation still unknown (Urothelial carcinoma by BKV Lymphoma by JCV, SV40?)
Introduction
Polyoma viruses are ubiquitous non-enveloped double stranded DNA viruses. There are several polyoma viruses but only three have been known to affect humans:
BK virus
JC virus
Merkel cell polyoma virus which has been postulated to cause merkel cell carcinoma
Infections Caused By Polyoma Viruses
Most human polyoma virus disease is caused by BK and JC viruses which are normally acquired in childhood (50-80%). Clinically apparent diseases in the immunocompetent individuals are rare as the immunity keeps the viral replication under control.
JC virus is neurotropic and progressive multifocal leucoencephalopathy which is a demyelinating disease of the CNS
The BK virus is urotheliotropic and remains latent in the urothelium and the tubular cells.
In the transplant patient, the polyoma viruses can be reactivated and can cause disease
BK Virus
BK virus can cause:
BK virus associated nephropathy: this occurs in 5-10% of patients with BK virus. The degree of immunosuppression predisposes to BKVAN. There is necrosis and lytic destruction of the tubular cells with increased inflammation in the interstitial. This can be misdiagnosed as ACR and drug induced interstitial nephritis. The BK virus stains positive for the SV40 stain which targets the large T Ag. This helps to make a diagnosis of BK virus. The use of EM to detect cast-like, three dimensional polyoma virus aggregates in urine called “Haufen” has been found to be sensitive and specific for BKVN
Ureteric stenosis: This will present as obstructive uropathy
Hemorrhagic cystitis: Most commonly in HSCT 2 weeks after the transplant. Will present as dysuria, hematuria and bladder outlet obstruction due to blood clots
Other disease caused by BK virus include: Pneumonitis, Hepatitis, meningoencephalitis
JC Virus
The JC virus will cause Progressive Multifocal Leucoencephalopathy
Malignancy and Polyoma Viruses:
There has been postulation that polyoma viruses can cause malignancy but no causal relation has been established
J Clin Virol . 2010 April ; 47(4): 306–312. doi:10.1016/j.jcv.2009.12.006. Clinical Microbiology ReviewsVolume 30, Issue 2, April 2017, Pages 503-528
Thank you Professor Halawa
There have been case reports of BK virus causing bladder cancer but it’s difficult to ascertain causality versus Association as most patients have already been exposed to the virus at an early age
In kidney transplant recipients, BK polyomavirus (BKPyV) replication typically develops in stages: viruria followed by viremia and then, if viral replication persists, nephropathy can ensue. BKPyV-associated nephropathy (BKPyVAN): the majority of cases occur in the first posttransplant year, BKPyVAN can occur years after transplantation. Without resolution of infection, progressive kidney allograft dysfunction and graft loss can ensue over a period of months. Within the allograft, early infection triggers interstitial inflammation, which then progresses to fibrosis and tubular injury.
Other manifestations — Hemorrhagic cystitis is a rare manifestation of BKPyV infection in kidney transplant recipients but is the most commonly reported manifestation of BKPyV infection among hematopoietic cell transplant recipients.
There is a putative link between BKPyV and the development of genitourinary cancers, largely based upon viral-associated oncogenesis in animal models and the ability of the virus to transform cells in vitro. However, a causal role for BKPyV and human malignancies has not been definitively established. Reference: Kidney transplantation in adults: BK polyomavirus-associated nephropathy. UpToDate.
Polyomaviridae variants
The human BKV belongs to the Polyomaviridae (PyV) virions, a subgroup of papovaviruses comprising BKV, JCV, and simian virus 40 (SV40). The JC virus will cause Progressive Multifocal Leucoencephalopathy
JCV and SV40 may also be associated with nephropathy, but their clinical course is less severe.
BK virus can cause BK virus-associated nephropathy, Ureteric stenosis, and Haemorrhagic cystitis. Other diseases caused by BK virus include Pneumonitis, Hepatitis, and meningoencephalitis, however, this is usually encountered in immunocompromised non-renal transplant patients, such as HIV patients.
A total of 12 additional human polyomaviruses have been isolated lately between the years 2007 till 2017.
These new group members were termed based on the site of discovery, their geographical areas, the diseases they might cause, or an order of discovery: MWPyV (Malawi); WUPyV (Washington University); KIPyV or Human polyomavirus-3 (Karolinska Institute); STLPyV (Saint Louis polyomavirus or Human polyomavirus-11); MCPyV (Merkel cell carcinoma); TSPyV (trichodysplasia spinulosa); HPyV6, HPyV7, HPyV9, and HPyV12 (human polyomaviruses 6, 7, 9, and 12); New Jersey polyomavirus (NJPyV, also known as polyomavirus-13); and Lyon IARC polyomavirus (LIPyV or human polyomavirus-14).
The definitive diagnosis of BKV-associated nephropathy is made by histologic findings in a kidney allograft biopsy.
Tubular damage with tubulitis and interstitial inflammatory infiltrate may indicate BKV associated nephropathy.
Intranuclear homogeneous basophilic viral inclusions without surrounding halo seen on light and electron microscopy may make BKV-associated nephropathy more likely.
Immunohistochemistry using antibodies against the TAg of SV40 is used to confirm histological diagnosis.
2.Ureteric stenosis,
Replication of BKV in uroepithelium may cause ureteric stenosis due to marked inflammation and ulcerations , after one month post transplantion.
3.Hemorahgic cystitis,
Hemorrhagic cystitis is a serious complication that occurs in 25% of recipients of hematopoietic stem cell transplants in children and young adults.
it may be associated with pain, hematuria,and urinary obstruction.
BK virus rarely cause hemorhagic cystitis in kidney transplant, but some studies found BK viriemia in cases with hematopoietic stem cell transplants.
4.Central nervous system involvement,
The human polyoma virus JC virus (JCV) characterized by focal demyelination in central nervous sysytem.
PML manifests as focal neurological deficits, usually with insidious onset and steady progression. Because the demyelinating lesions can involve different brain regions, specific deficits vary from patient to patien.
Polyomaviruses are
-JC virus [JCV],
-BK virus [BKV],
-Simian virus 40 [SV40])
thes are classified as members of the Polyomavirusgenus. .Polyomaviruses are non enveloped icosahedral DNA viruses that leads to subclinical or persistent infections in immunocompetent patients with the capacity for reactivation in an immunosuppression state . JCV remains latent mainly in the kidney, but its reactivation can lead to progressive multifocal leukoencephalopathy. BKV infection of the kidney and urinary tract, re-activation in immunocompromised host causes BK nephropathy and hemorrhagic cystitis. Simion Virus SV40 have been reported with occurrence of focal segmental glomerulosclerosis.
–Polyomavirus associated nephropathy:
affects between 1 and 10% of kidney transplant patients . It rarely affects patients other than kidney transplant recipients.
The pathogenesis is characterized by high-level BKV replication in renal-tubular epithelial cells of the transplanted kidney , leading to progressive graft loss
. – hemorrhagic cystitis :
Mainly diagnosed in HSCT due to bladder mucosal damage caused by cyclophosphamide treatment prior to transplantation this might make the mucosa prone to infection by this polioma Virus -Ureteric stenosis:
First reported in UK at 1971 in a Sudanese post kidney transplant with ureteric stenosis where BK virus was discovered
– Central nervous system
JC polyomavirus have been associated with progressive multifocal leukoencephalopathy -like disease caused by BK polyomavirus rather than JC polyoma viruse
Genitourinary malignancies:
Is consider as association rather than causation
thank you Sir
Merkel cell carcinoma is a rare type of skin cancer that usually appears as a flesh-colored or bluish-red nodule, often on face, head or neck.
Merkel cell carcinoma is also called neuroendocrine carcinoma of the skin.
Merkel cell carcinoma most often develops in older people.
Long-term sun exposure and a weak immune system increases risk of developing Merkel cell carcinoma. Preventionexposure to sunlight may cause Merkel cell carcinoma,
Reducing sun exposure may reduce risk of skin cancer. Try to:
Avoid the sun during peak hours.
Shield the skin and eyes by hat, full sleeves and sunglasses.
Apply sunscreen liberally and often.
Watch for changes in size shape or color of skin lesions.
What are the diseases caused by polyomaviruses in renal transplant recipients?Human polyomavirus is a member of the DNA virus BKPYV and JCPYV were the revalent species. and others species such as simian polyomavirus.
the are many diseases caused by polyomavirus in renal transplant recipients including the following:
1-BK polyomaviruses associated with nephropathy
BK virus results in lifelong infection in renal tubular and uroepithelial cells of most of the world population.
usually present as asymptomatic viremia, viremia, and acute or slowly progressive rise in serum creatinine in the first two to six months postrenal transplantation. allograft infection trigger interstitial inflammation which progresses to fibrosis and tubular injury.
2-heamorrghic cystitis
present as urinary frequency, dysuria, haematuria, urinary clot, and urinary obstruction that may last for several weeks
3-ureteric stenosis
first reported case in a Sudanese postrenal transplant recipient in 1971.
4-progressive multifocal leukoencephalopathy
JCPYV is the most common cause of PML demyelinating disorder that occurs in immunocompromized patient and presents with focal neurological deficits like ataxia,hemiparesis,visual field defect, and cognitive disorder
5-Disseminated infection in which the virus involves all the organs in the immunocommprize patient References uptodate
thanks, prof Ahmed
Merckle cell carcinoma is a rare type of skin cancer that is more common in individuals with abnormal immune systems resulting from viral infections such as BKV, on the other hand, BKV can cause severe neutropenia or pancytopenia in a kidney transplant recipient
What are the diseases caused by polyomaviruses in renal transplant recipients?
Polyomaviruses (JC virus [JCV], BK virus [BKV], and simian virus 40 [SV40]) are classified as members of the Polyomavirus genus in the family Polyomaviridae. Polyomaviruses are non enveloped icosahedral DNA viruses that have established subclinical and persistent infections in immunocompetent patients with the capacity for reactivation after solid organ transplantation due to immunosuppression . JCV after primary infection remains latent mainly in the kidney, but its reactivation results in the development of progressive multifocal leukoencephalopathy. BKV causes infection in the kidney and the urinary tract, and its activation causes a number of disorders, including nephropathy and hemorrhagic cystitis. The presence of SV40 have been reported by recent studies in the allografts of children who received renal transplants and in the urine, blood, and kidneys of adults with focal segmental glomerulosclerosis.
–Polyomavirus associated nephropathy: PyVAN affects between 1 and 10% of kidney transplant patients during the first two years post-transplantation. It rarely affects patients other than kidney transplant recipients. The pathogenesis of PyVAN is characterized by high-level BKPyV replication in renal-tubular epithelial cells of the transplanted kidney , leading to cytopathic loss, subsequent fibrosis and graft loss if left untreated .
– Polyomavirus-associated hemorrhagic cystitis : It Mainly affects patient who underwent allogeneic stem cell transplant . The bladder mucosa is subclinically damaged by the toxic metabolite of cyclophosphamide which is used as a conditioning protocol prior to stem cell transplant Though polyoma viral hemorrhagic cystitis usually affects allogeneic HSCT patients, there have been some case reports on PyVHC in other immunocompromised patients .
-Ureteric stenosis: First reported in UK at 1971 in a Sudanese post kidney transplant patient presented with ureteric stenosis where BK virus was discovered and isolated for the first time in PKT patients .
– Central nervous system involvement: It is mainly related to JC polyomavirus but there have also been case reports suggesting progressive multifocal leukoencephalopathy -like disease caused by BK polyomavirus rather than JC polyoma virus , but no confirmation in tissue has been presented.
Genitourinary malignancies:
Is debatable but is consider as association more than causation
About 14 species of human polyomaviruses have been identified (1). The most common ones that are associated with clinical manifestations are BK polyomavirus (BKPyV) and JC polyomavirus (JCPyV).
Diseases caused by polyomaviruses in the renal transplant recipient
BKPyV-associated nephropathyAssociated
with progressive allograft dysfunction and resulted in allograft loss.Histological features from minimal tubulointerstitial nephritis till tubular atrophy in late BKV nephropathy.Ureteral stricture
Haemorrhagic cystitis
Common in haemopoietic stem cell transplant (2).Progressive multifocal leukoencephalopathy
Commonly is related to JCPyVMalignacy related
Merkel cell carcinoma (3)Bladder cancer (4) References
Wu Z, Graf FE, Hirsch HH. Antivirals against human polyomaviruses: Leaving no stone unturned. Rev Med Virol 2021: e2220.Imperiale MJ. The human polyomaviruses: an overview. In: Khalili K, Stoner GL, eds. Human Polyomaviruses: Wiley; 2001:53-71.https://doi.org/10.3390/dermato3010003Curr Opin Virol. 2019 Dec; 39: 8–15.
Graft dysfunction in the form of increase in the serum creatinine associated with pyuria, hematuria and/or cellular casts
Rarely presents with hemorrhagic cystitis, it is commonly seen in hematopoietic stem cell-transplant (HSCT)
Debatable and unclear association with genitourinary malignancies
Ureteritis and ureteric stenosis secondary to BKV infection is uncommon but some studies reported association. (1-4)
BK virus can cause graft loss by the following mechanisms:
First it infects tubular epithelium causing interstitial inflammation, tubular injury with subsequent fibrosis
Once treatment is established, reduction of immunosuppression may cause the development of acute rejection in 10-12 % of cases leading to further allograft damage. (5,6)
References
1. Cavallo R, Costa C, Bergallo M, Messina M, Mazzucco G, Segoloni GP. A case of ureteral lesions in a renal transplant recipient with a co-infection of BK virus and JC virus. Nephrol Dial Transplant 2007;22:1275. Back to cited text no. 2
2. Rajpoot DK, Gomez A, Tsang W, Shanberg A. Ureteric and urethral stenosis: A complication of BK virus infection in a pediatric renal transplant patient. Pediatr Transplant 2007;11:433-5. Back to cited text no.
3. Hwang YY, Sim J, Leung AY, Lie AK, Kwong YL. BK virus-associated bilateral ureteric stenosis after haematopoietic SCT: Viral kinetics and successful treatment. Bone Marrow Transplant 2013;48:745-6. Back to cited text no. 4
4. Khan H, Oberoi S, Mahvash A, Sharma M, Rondon G, Alousi A, et al. Reversible ureteral obstruction due to polyomavirus infection after percutaneous nephrostomy catheter placement. Biol Blood Marrow Transplant 2011;17:1551-5. Back to cited text no. 5
5. McGilvray ID, Lajoie G, Humar A, Cattral MS. Polyomavirus infection and acute vascular rejection in a kidney allograft: Coincidence or mimicry? Am J Transplant 2003;3:501-4. Back to cited text no. 6
6. Ito Y, Nishi S, Imai N, Yoshita K, Saito K, Nakagawa Y, et al. The case of BK virus infection in which it was difficult to differentiate from acute rejection. Clin Transplant 2011;25 Suppl 23:44-8. Back to cited text no. 7
Thank you, Sherif You mentioned haemorrhagic cystitis. Does it happen in kidney transplant patients? What are the other diseases caused by polyomaviruses?
You mentioned haemorrhagic cystitis. Does it happen in kidney transplant patients?
– Hemorrhagic cystitis is rarely seen in renal transplant recipients it is commonly seen in hematopoietic stem cell-transplant (HSCT)
– Hemorrhagic cystitis can be seen as a complication of some drugs used in the treatment of glomerulonephritis such as cyclophosphamide
– Hemorrhagic cystitis associated with HSCT is multifactorial occurring either :
Preengraftment occurring due to due to drug toxicity that cause severe inflammation of urinary bladder mucosa(eg, cyclophosphamide, ifosfamide, busulfan) (1, 2) or due to total body irradiationPostengraftment occurring due to BK polyomavirus or adenovirus. What are the other diseases caused by polyomaviruses?
– Human polyomaviruses (HPyVs) are small, double-stranded, non-enveloped DNA viruses
– More than 13 types exist, the most common and important types that are involved in diseases in immunocompromised patients are :
JC polyomavirus (JCPyV) that can cause progressive multifocal leukoencephalopathy (PML) in immunosuppressed patients including those with HIV and hematologic malignanciesBK polyomavirus (BKPyV) is associated with BK nephropathy in renal transplant recipients and hemorrhagic cystitis in hematopoietic cell transplantation recipientsMerkel cell polyomavirus (MCPyV), which is associated with Merkel cell carcinomaTrichodysplasia spinulosa polyomavirus (TSPyV) which is associated with trichodysplasia spinulosa, a rare skin disease characterized by spiculae and alopecia in immunosupressed patientsReferences
1. Zaia J, Baden L, Boeckh MJ, et al. Viral disease prevention after hematopoietic cell transplantation. Bone Marrow Transplant 2009; 44:471.
2. Bedi A, Miller CB, Hanson JL, et al. Association of BK virus with failure of prophylaxis against hemorrhagic cystitis following bone marrow transplantation. J Clin Oncol 1995; 13:1103.
You mentioned haemorrhagic cystitis. Does it happen in kidney transplant patients?
– Hemorrhagic cystitis is rarely seen in renal transplant recipients it is commonly seen in hematopoietic stem cell-transplant (HSCT)
– Hemorrhagic cystitis can be seen as a complication of some drugs used in the treatment of glomerulonephritis such as cyclophosphamide
– Hemorrhagic cystitis associated with HSCT is multifactorial occurring either :
Preengraftment occurring due to due to drug toxicity that cause severe inflammation of urinary bladder mucosa(eg, cyclophosphamide, ifosfamide, busulfan) (1, 2) or due to total body irradiation
Postengraftment occurring due to BK polyomavirus or adenovirus.
What are the other diseases caused by polyomaviruses?
– Human polyomaviruses (HPyVs) are small, double-stranded, non-enveloped DNA viruses
– More than 13 types exist, the most common and important types that are involved in diseases in immunocompromised patients are :
JC polyomavirus (JCPyV) that can cause progressive multifocal leukoencephalopathy (PML) in immunosuppressed patients including those with HIV and hematologic malignancies
BK polyomavirus (BKPyV) is associated with BK nephropathy in renal transplant recipients and hemorrhagic cystitis in hematopoietic cell transplantation recipients
Merkel cell polyomavirus (MCPyV), which is associated with Merkel cell carcinoma
Trichodysplasia spinulosa polyomavirus (TSPyV) which is associated with trichodysplasia spinulosa, a rare skin disease characterized by spiculae and alopecia in immunosuppressed patients
References
1. Zaia J, Baden L, Boeckh MJ, et al. Viral disease prevention after hematopoietic cell transplantation. Bone Marrow Transplant 2009; 44:471.
2. Bedi A, Miller CB, Hanson JL, et al. Association of BK virus with failure of prophylaxis against hemorrhagic cystitis following bone marrow transplantation. J Clin Oncol 1995; 13:1103.
1. What are the diseases caused by polyomaviruses in renal transplant recipients?
Polyomaviruses were first discovered by Ludwig Gross in 1953 as murine leukemia viruses.
Polyoma viruses are ubiquitous, with BK and JC viruses causing most human polyoma disease, with 50-80% of humans having seropositivity.
BKPyV infections in immunosuppressed individuals can lead to distinctive pathological entities in different patient groups: in renal transplant recipients, it is associated with nephropathy and ureteral stenosis, whereas in hematopoietic stem cell transplant (HSCT) recipients with hemorrhagic cystitis.
Notably, newborn mice injected with cell-free extracts of murine leukemia tissues developed adenocarcinomas of the parotid gland in addition to leukemia, suggesting that an infectious agent was the cause of the malignancies.
The infectious agent was named using the Greek words for many (poly) and cancer (oma).
So far, about 30 species of polyoma viruses have been identified in birds and mammals, including 13 in humans: BK, JC, KI, WU, Merkel cell polyomavirus, H6, H7, H9, H10, H12, STL, trichodysplasia spinulosa-associated polyomavirus, and NJ.
BKVN is predominant (> 90%) in the first two years of transplantation, especially in the first trimester. Screening efforts have mainly been focusing on the first 6-12 months. However, due to the precocity of BKPyV viremia in most cases, the tendency has been driven for condensed screening in the first months.
BK virus can cause:-
PVN: Mode of kidney injury and dysfunctionVirally induced acute tubular injury (ATN) Focal:no/mild renal dysfunction Diffuse:pronounced renal dysfunction Early ATN:reversible changes (possible restitutio ad integrum) Chronic ATN:irreversible changes (fibrosis, tubular atrophy)
Ureteral stenosis
Interstitial nephritis
Hemorrhagic cystitis from BK virus is seen in 25–60% of the bone marrow transplant patients (BMT).
It is usually seen two weeks after transplant which is later than the hemorrhagic cystitis from chemotherapeutic agents such as cyclophosphamide which occurs immediately.
Neurotropic JC virus:_
Progressive multifocal leukencephalopathy, a demyelinating disease .
Merkel cell carcinoma
Is an aggressive neuro-endocrine skin cancer, originating from the mechano-receptor Merkel cell.
It is noted to be more common in immunosuppressed states suggesting an infectious etiology
Viruses remain latent in the lymphoid organs and kidney and reactivate, causing diseases such as multifocal leukencephalopathy, interstitial nephritis, and polyoma virus associated nephropathy.
Lamarche C, Orio J, Collette S, et al. BK Polyomavirus and the Transplanted Kidney: Immunopathology and Therapeutic Approaches. Transplantation. 2016;100(11):2276-2287. doi:10.1097/TP.0000000000001333
AJKDE1-E2, January 2001
Boothpur R, Brennan DC. Human polyoma viruses and disease with emphasis on clinical BK and JC. J Clin Virol. 2010;47(4):306-312. doi:10.1016/j.jcv.2009.12.006
Uhm J, Hamad N, Michelis FV, et al. The risk of polyomavirus BK-associated hemorrhagic cystitis after allogeneic hematopoietic SCT is associated with myeloablative conditioning, CMV viremia and severe acute GVHD; Bone Marrow Transplant: 2014.
Although uncommon, AHC usually presents within 1 year of renal transplantation with a consistent constellation of symptoms.
Hemorrhagic cystitis in post-renal transplant patients is commonlyassociated with cytomegalovirus, Epstein-Barr virus, and polyoma virus, though can rarely be caused by adenovirus.
Dorairajan, L., Manikandan, R., & Kumar, S. (2010). Hemorrhagic cystitis: A challenge to the urologist. Indian Journal of Urology, 26(2), 159. doi: 10.4103/0970-1591.65380
Hofland, C., Eron, L., & Washecka, R. (2004). Hemorrhagic adenovirus cystitis after renal transplantation. Transplantation Proceedings, 36(10), 3025–3027. doi: 10.1016
What are the diseases caused by polyomaviruses in renal transplant recipients?
Polyomavirus-associated nephropathy (PVAN) is a growing illness in renal transplant patients with an incidence of 1–10% and graft loss of up to 80%. BK virus (BKV) is the main cause,
However, the JC virus (JCV) and potentially the simian virus SV40 may be involved. Merkel cell polyomavirus and TS polyomavirus are two other polyomaviruses.
Renal transplant Pathology:
However, renal transplants preferentially manifest compared to other allografts or autologous kidneys from other organ transplants, suggesting that organ determinants and immunologic variables synergize. Renal tubular epithelial cells and their compensatory proliferation to restore tubular integrity after immunologic, ischemic, or toxic injury may provide the key cellular environment for polyomavirus replication while immune control is weakened by maintenance immunosuppression.
Risk Factors:
The severity of immunosuppressive therapy, anti-rejection treatment, and HLA-mismatches. Older age, male gender, seronegative recipient, and viral variables (genotype, serotype) may contribute.
Diagnosis
PVAN is diagnosed by allograft biopsy, which is complicated by I limited sensitivity due to (multi-)focal involvement (sampling errors); ii) varying presentations with cytopathic-inflammatory and/or fibrotic/scarring patterns; and iii) coexisting acute rejection, which is difficult to distinguish but affects intervention strategies. High-sensitivity urine and plasma polyomavirus screening complements allograft biopsy and provides noninvasive monitoring.
Manifestations of BK in kidney transplantation: BKV Nephropathy, Hemorrhagic cystitis, Non-Hemorrhagic cystitis, Ureteric stricture,and Allograft rejection
Reference : Hirsch, H. H., Brennan, D. C., Drachenberg, C. B., Ginevri, F., Gordon, J., Limaye, A. P., … & Trofe, J. (2005). Polyomavirus-associated nephropathy in renal transplantation: interdisciplinary analyses and recommendations Transplantation, 79 (10), 1277–1286.
BK virus (BKV) and JC virus (JCV) cause interstitial nephritis in 5% of renal transplant recipients, and up to 45% of the affected patients may develop allograft failure.
Also, polymerase chain reaction assays and other molecular biology studies, which were derived from polyomavirus simian virus 40 (SV40), serve as useful adjunctive diagnostic tools. However, the homology between the two human polyomaviruses (JCV and BKV) and SV40 is approximately 70%.
Merkel cell carcinoma also described.
Diseases caused by polyomaviruses in renal transplant recipients
BK polyomavirus (BKPyV) is a small DNA virus that Following primary infection, the virus establishes lifelong infection in renal tubular and uroepithelial cells. However, in immunocompromised patients,reactivation of latent infection or transmission of new infection via the donor kidney can lead to viruria, viremia, or allograft nephropathy. Viral replication most commonly occurs during the first year after transplantation when cellular immunity is most suppressed. Viruria and viremia are detected in approximately 25 to 30 and 12 percent of kidney transplant recipients, respectively.Intense immunosuppression is the most important risk factor.However,Patient determinants (older age, male gender, seronegative recipient), and viral factors (genotype, serotype) may have a contributory role.
The definitive diagnosis of PVAN requires allograft biopsy with some challenges:
i) limited sensitivity due to multi-focal involvement with sampling errors.
ii) varying PVAN presentations with cytopathic-inflammatory or fibrotic/scarring patterns.
iii) coexisting acute rejection which is difficult to differentiate, but will impacts on management strategies.
Risk factors for viral replication:
-The intensity of immunosuppression (particularly suppression of cellular immunity)
-High risk serostatus (ie, kidney transplant from a BKPyV-seropositive donor to a seronegative recipient)
-older age, ureteral stent placement, ABO incompatibility , rejection or ischemia of the transplanted kidney , delayed graft function, HLA mismatch , specific HLA-C alleles, BKPyV polymorphisms, and transplantation from an HCV-positive donor.
-Decreased risk of BKPyVAN:
-Recipient HLA-B51 positivity was associated with an approximate fivefold reduction in BKPyVAN.
-Polycystic kidney disease has been associated with a lower risk of BKPyVAN.
BKPyV-associated nephropathy (BKPyVAN) :
Asymptomatic viruria, viremia, and/or a slow progressive rise in serum creatinine are typically the only indicators of BKPyVAN. The incidence of BKPyVAN is highest in the first two to six months posttransplant.BKPyVAN can occur years after transplantation.
Without resolution of infection, progressive kidney allograft dysfunction and graft loss can occur over a period of months.Within the allograft, early infection triggers interstitial inflammation, which then progresses to fibrosis and tubular injury.
-Hemorrhagic cystitis is a rare manifestation of BKPyV infection in kidney transplant recipients but is the most commonly reported manifestation of BKPyV infection among hematopoietic cell transplant recipients.
-There is an important link between BKPyV and the development of genitourinary cancers, based upon viral-associated oncogenesis in animal models and the ability of the virus to transform cells in vitro.
What are the diseases caused by polyomaviruses in renal transplant recipients?
Polyomaviruses are a group of non-enveloped DNA viruses and more than 14 species have been known. However, BK and JC virus are the ones which causes disease in renal transplant recipients. BK VIRUS; Hemorrhagic cystitis
BK virus Nephropathy
Ureteric stenosis or stricture
Allograft rejection and genitourinary malignancy(rare) JC virus: cause polyomavirus associated nephropathy (PyVAN) and rarely progressive multifocal leukoencephalopathy REFERENCES: 1- Lecture by Dr . Ahmed Halawa-BK in Kidney Transplantation. 2- Handbook of kidney Transplantation. 3- Delbue S, Ferraresso M, Ghio L, Carloni C, Carluccio S, Belingheri M, Edefonti A, Ferrante P. A review on JC virus infection in kidney transplant recipients. Clin Dev Immunol. 2013;2013:926391
Polyomaviruses exist in the environment and contact with seropositivity usually starts at a young age. There are reports of 14 species with the possibility of infection in humans, but only three with repercussions to be considered for discussion.
In all three situations, the patient’s immunity must be severely compromised, either due to neoplasia, the HIV virus with CD4 cell counts below 10, or solid organ transplantation (mainly kidney and lung) with significant immunosuppression (induction with rATG, high doses of corticosteroids, tacrolimus, and mycophenolate).
Interestingly, the names of the viruses are the initials of the first patients affected and diagnosed with this pathology)
1. BK virus
– Latency in renal tubules and endothelium
– Reactivation in case of severe immunosuppression
– More common in kidney transplantation
– Inflammation, tubular atrophy, interstitial disease, atrophy
2. James Cunningham Virus
– Progressive multifocal leukoencephalopathy
– Reactivation in case of severe immunosuppression
– More common in HIV carriers with AIDS and CD4 with less than 10 cells
– Lesions in the white matter of the CNS with impaired movement and cognition
3. Merckel cell virus
– Associated with the neoplasm of the same name
– Immunosuppression and presumed oncogenicity
Polyomaviruses are small,nonenveloped , double stranded DNA viruses that infected a variety of organs.
Polyomaviruses are highly seroprevalent in humans but only cause clinical disease among immunocompromised patients.
Multi human subtypes have been identified.
BK virus and JC virus are the most common and the only tow associated with nephropathy.(BKVN).
Patient with BKVN present with an asymptomatic acute or slow progressive rise in serum creatinine concentration.
Urinalysis may reveal pyuria, hematuria,cellular cast and inflammatory cells.
Urine cytologic examination may reveal BK-infected cells called decoy cells.
The most common injury is tubulo interstial nephritis.
Acute kidney injury .
Acute allograft rejection.
Renal malignancy.
Most immunocompetent individuals with polyomaviruses infections have a subclinical or non-specific influenza-like symptoms, however some subtypes can cause specific syndrome.
The most commonn pathogenic subtypes are the following :
1-BK polyomavirus :
This can cause nephropathy and less commonly,uretric stenosis.
BKVyV :this subtype can cause hemorrhagic cystitis.
2- JC polyomavirus :
This subtype can cause progressive multifocal leukoencephalopathy and hematologic malignancies and nephropathy.
3-Merkel cell polyomavirus : It is associated with merkel cell carcinoma in sun-exposure skin of older adults who have recevied long-standing immunosuppression. lymphadenopathy and tonsillitis are noticed in children .
4- KI and WU viruses:
These subtypes are associated with respiratory tract disease .
5-Human polyomavirus:
It is associated with pruritic rash and viremia in lung transplant recipients.
6-TS polyomavirus:
This subtype causes trichodysplasia spinulosa ,a rare skin rash .
The human polyoma viruses type 1 & type 2 were named after the initials B.K & J.C. of the respective patients.
The JC virus causes progressive multifocal leuco-encephalopathy (PML), while the BKV causes PVAN.
Polyomavirus infection:
Defined as serological or virological evidence of virus exposure.
It does not distinguish between replicating, latent or transforming patterns.
Polyomavirus replication:
Defined as evidence for ongoing virus multiplication (lytic infection) by detecting:
Infectious virus by cell culture
Polyomavirus particles by EM
Polyomavirus structural proteins by IHC
Messenger RNA expression of late genes (e.g., VP1)
Polyomavirus DNA in non-latency sites (e.g., in plasma) Cytological (e.g., decoy cells) or histological evidence for polyomavirus replication.
If detected in a seronegative or a seropositive individual, polyomavirus replication is termed primary or secondary, respectively.
Polyomavirus disease:
Indicates histological evidence of polyomavirus-mediated organ pathology.
Polyoma virus associated nephropathy (PVAN) may present as cytopathic, cytopathic-inflammatory or immune reconstitution patterns.
Most cases of PVAN are caused by BKV.
JCV & SV40 may play a role, either alone or in combination with BKV.
PVAN manifest as:
Pattern A:
There is focality of renal involvement, particularly early in the disease.
2. Pattern B:
Inflammatory infiltrates elicited by tubular cell necrosis or result from virus-specific cellular immune responses and are difficult to differentiate from acute rejection.
3. Pattern C:
Marked tubular atrophy & fibrosis of late stages; only few viral cytopathic changes are seen to the point where they may even be undetectable (false negative).
Viruria (“decoy cells”) defines patients at risk (“possible” PVAN) who should be evaluated for plasma viral load.
BKV viremia (>10,000 copies/mL) defines “presumptive” PVAN for which an intervention of reducing IS should be considered.
Histological confirmation (“definitive PVAN”).
Clinical diseases:
BK virus can cause pneumonitis, hepatitis, retinitis, and meningoencephalitis.
Hemorrhagic cystitis from BK virus is seen in 25–60% of the bone marrow transplant patients.
It is usually seen two weeks after transplant which is later than the hemorrhagic cystitis from chemotherapeutic agents such as cyclophosphamide which occurs immediately. Symptoms include dysuria, urgency, frequency, suprapubic pain and varying degree of hematuria. The diagnosis is made by detecting BK viral DNA in the urine.
Treatment is supportive (hyperhydration, forced diuresis, bladder irrigation and transfusion as indicated). If the hematuria is severe with clots, cystoscopy and clot removal and cauterization of the source might be needed. Prophylactic ciprofloxacin decreases peak urine BK viral load and reduce the severity of hemorrhagic cystitis in BMT patients.
BKVN:
After primary infection in childhood BK virus becomes latent in the tubular epithelial cells of the urogenital tract. It mainly affects epithelial cells of collecting ducts, tubular epithelium of renal calyces and renal pelvis.
In immunosuppressed states BK reactivate in the renal tubular epithelial cells causing interstitial fibrosis and tubular atrophy.
Up to 80% of renal transplant patients have BK viruria & 5–10% progress to BKVN.
Use of newer potent IS agents (MMF or TAC) has been implicated in the recent emergence of this infection. However, it is seen with most of the other IS agents (cyclosporine & sirolimus), so it is the degree of IS rather than the type of IS that predisposes to BKVN.
Viral reactivation starts soon after TX and is seen in 30–50% of the patients by 3 months post-transplant.
Virus reactivates can present as:
Asymptomatic deterioration of renal function
Tubulo-interstitial nephritis
Ureteric stenosis.
Risk factors for PVAN:
Patient factors:
Age >50 years
Male gender
BKV seronegativity before TX
Impaired BKV specific T-cell response
White ethnicity
CMV coinfection
DM
Allograft-related:
Higher HLA mismatches
Prior episodes of AR
Prior tubular injury from rejection or drugs
Surgical injury
Warm ischemia & reperfusion injury during implantation
CNI toxicity
Deceased donor TX
Virus-related:
New BKV serotypes
Intensity of IS rather than the specific agent.
Cell-mediated immunity is important:
-low levels of interferon-gamma secreting T lymphocytes specific for BK virus correlate with higher levels of BK viremia & BKV nephropathy.
4.Humoral immunity is less important:
-seropositivity is not protective
-recipients of donors with higher antibody titers are more likely to have BK reactivation indicating donor origin of the virus.
The disease passes through three progressive stages:
Viral DNA can be seen first in the urine then in the plasma and lastly in the kidney.
Progression of viruria to viremia occurs in 10–15% of KTX patients, & sustained viremia is predictive of interstitial nephritis.
BK nephropathy is suspected with signs suggestive of interstitial nephritis. It typically presents 10–13 months post-transplant and graft failure rates can be as high as 50–80% depending on the degree of inflammation and fibrosis seen on the biopsy.
BK nephropathy is extremely rare in the native kidneys of non-renal SOT despite comparable or higher levels of IS, suggesting that BKVN is donor derived or other factors specific to the transplanted kidney play a role.
Re-transplantation can be successfully performed and usually after the virus has cleared.
References
Hans H Hirsch, Cinthia B. Drachenberg, Juerg Steiger, and Emilo Ramos, Polyomavirus-associated Nephropathy in Renal Transplantation: Critical Issues of Screening and Management, NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health. Madame Curie Bioscience Database [Internet]. Austin (TX): Landes Bioscience; 2000-2013.
Thank you Dr Mohamed This is a comprehensive answer, but YOU DID NOT ANSWER THE QUESTION. Please review the question and answer accordingly. You need to provide a focused answer.
Human polyomaviruses — Human polyomaviruses (HPyVs) are DNA viruses belonging to the family Polyomaviridae. Fourteen HPyV species have been identified.
BKPyV and JCPyV are common clinically relevant species in immunocompromised patients.
The majority of infections are benign and quiet. BKPyV can reactivate in immunocompromised patients and in certain cases cause BKPyV-associated nephropathy (BKPyVAN).
BK polyomavirus (BKPyV) replication commonly occurs in phases in kidney transplant recipients: viruria followed by viremia and, if viral replication persists, BKPyV nephropathy.
In kidney transplant recipients, hemorrhagic cystitis is a rare symptom of BKPyV infection.
It is hypothesized that BKPyV contributes to the formation of genitourinary malignancies, based mostly on viral-associated oncogenesis in animal models.
Diseases caused by Polyomaviruses in renal transplants;
Human polyomaviruses are member of DNA viruses in polyomaviridae family. Of fourteen species identified, two viruses are commonly causing disease in immunocompromised patients.
JCPyV causing progressive multifocal leukoencephalopathy and
BKyV causes;
BKV Nephropathy
Hemorrhagic cystitis
Non Hemorrhagic cystitis
Ureteric stricture
Allograft rejection
Genitourinary tract malignancies(causation not established)
Other polyomaviruses have been associated with human disease but their casual role is unclear
What are the diseases caused by polyomaviruses in renal transplant recipients?
Polyoma viruses are group of viruses that lead to cell enlargement due to inclusion bodies (tumor like cells).
There are many viruses discovered by time but the most common types affect post kidney transplant recipient are BK polyomavirus (BKPyV) and JC polyomavirus (JCPyV). 1-BK virus lead to :
Hemorrhagic cystitis.
Proximal ureteric stricture.
BK induce nephropathy.
Disseminated BKPyV infection. 2-JCPyV.
Progressive multifocal leukoencephalopathy.
Central nervous system demyelination(associated with high incidence of mortality).
3–MERKEL CELL CARCINOMA.
a rare tumor of neuroendocrine origin that usually presents as a red or red-blue papule or nodule in a sun-exposed area which caused by Merkel cell polyomavirus infection. References:
1-Epidemiology and risk factors for skin cancer in solid organ transplant recipients, Up To Date, 2023.
2-Garrett GL, Blanc PD, Boscardin J, et al. Incidence of and Risk Factors for Skin Cancer in Organ Transplant Recipients in the United States [published correction appears in JAMA Dermatol. 2017 Mar 1;153(3):357]. JAMA Dermatol. 2017;153(3):296-303. doi:10.1001/jamadermatol.2016.4920.
What are the diseases caused by polyomaviruses in renal transplant recipients?
Polyomavirus is a small about 30-45nm, icosahedral, nonenveloped, double-stranded, closed circular DNA virus.
The common polyomavirus known to cause disease in humans are:
BK virus
JC virus
Both are named after the initials of the patient that first diagnosed with the virus
Other types of polyomavirus are:
Tichodysplasia spinulosa polyomavirus
Merckel cell polyomavirus
Karolinska Instutute polyomavirus
Wisconsin University polyomavirus
Diseases caused by the BK virus are:
BK virus-associated nephropathy
Ureteric stenosis or obstruction
hemorrhagic cystitis
Association with genitourinary malignancy
Allograft rejection
Disease caused by the JC virus:
primary multifocal leukoencephalopathy
References
UpToDate
Deirdre Sawiski, Simin Goral. BK virus Infection: an update on diagnosis and treatment. Nephrol Dial Transplant. 2015; 30: 209-217
Oxford Handbook Nephrology and Hypertension. 2nd Edition.
BK in Kidney Transplantation. Lecture by Ahmed Halawa
Polyomaviruses are a common infectious agent affect mammalian including human.
Polyomaviruses include 5 different human viruses: JC & BK are known cause of diseases in immunocompromised patients. Wu, KI & Merkle cell polyoma viruses are the other species of polyomavirus.
Diseases caused by BK virus:
PK nephropathy.
ureteric stenosis.
pneumonitis
hepatitis.
retenitis.
meningoencephalitis .
increased risk of invasive urinary bladder.
Diseases caused by JC virus:
progressive multifocal leukoencephalopathy
central nervous system demyelination(associated with high incidence of mortality).
References:
Bother R. and Brennan D. Human Polyoma Viruses and Disease with emphasis on Clinical BK and JC. J Clin Viral, 2010;47(4): 306-312.
Cohen-Bucay A., Ramirez-Andrade S., Gordon C., Francis J. and Chitalia V. Advances in BK Virus Complications in Organ Transplantation and Beyond. Kidney Med, 220; 2(6):771-786.
Ahsan N. and Shah K. Polyomaviruses and human diseases. Adv Explained Med Biological, 2006.
Despite advances in understanding of BKV biology and the risk factors that predispose kidney transplant recipients to develop BKV-associated nephropathy, it continues to be one of the most challenging causes of allograft dysfunction. Screening and early diagnosis of viral replication and BKV-associated nephropathy are of paramount importance to allow effective management strategies before severe allograft damage ensues.
The characteristic histologic changes on biopsy include tubular damage with tubulitis and interstitial inflammatory infiltrate.
These characteristics are similar to allograft cellular rejection.
polyomavirus infections have been associated with diverse disease pattern which involve either cytopathic, inflammatory, immunological or oncogenic pathologies.
BKV infection has been implicated in late ureteral stenosis (>1 month posttransplantation) because BKV replication has been demonstrated in the urothelium of patients experiencing ureteral stenosis.
Hemorrhagic cystitis is a serious complication that occurs in 25% of recipients of hematopoietic stem cell transplants in children and young adults.
Cohen-Bucay A, Ramirez-Andrade SE, Gordon CE, Francis JM, Chitalia VC. Advances in BK Virus Complications in Organ Transplantation and Beyond. Kidney Med. 2020 Oct 11;2(6):771-786. doi: 10.1016/j.xkme.2020.06.015. PMID: 33319201; PMCID: PMC7729234.
Polyomavirus-associated Nephropathy
BK virus nephropathy
ureteral stenosis
hemorrhagic cystitis
could be assosciated with urothelial malignancy
Progressive multi focal leuciencephalopathy with JC virus
can cause pneumonia
BK virus: BKVAN, ureteral stenosis, hemorrhagic cystitis, ? Urothelial malignancy.
JC virus: Progressive multifocal leukoencephalopathy.
Polyoma viruses are a group of small non enveloped DNA virus which can cause diseases in animals namely simian monkey….
BK virus leads to
BK virus nephropathy, urethral stenosis, hemorrhagic cystitis..There are rare reports of BK virus causing pneumonia in lung transplant patient…there are many reports of BK virus associated with urothelial malignancies with increased incidence and less causal associations…
JC virus is another form of polyoma virus…It can cause progressive multifocal encephalopathy…more common in HIV patients
SV 40 is a simian tropic virus causing disease only in monkeys
Polyomaviruses are either BK virus or JC virus
BK virus leading to
JC virus leading to
Reference
The association of BKV with PVAN in renal transplant recipients emphasizes the role of allo-situation in addition to immunosuppression. Most likely, patient, organ and virus specific determinants interact in a complementary fashion and are subject to dose- and magnitude dependent modulators (e.g., immunosuppression).
https://www.ncbi.nlm.nih.gov/books/NBK6388/
The commonly occurring diseases due to polyomaviruses post renal transplantation are; BK virus nephropathy then interstitial nephritis, Hemorrhagic cystitis, Ureteral stenosis, chronic allograft nephropathy.
It is to be noted that another type of polyomavirus rather than BK is JCV which affects mainly CNS and brain.
BK virus-associated nephropathy
BKV-associated nephropathy begins with viruria or asymptomatic hematuria and ends with extensive irreversible injury and allograft failure.
Ureteric stenosis
The prevalence of ureteric stenosis is 2–6%
Hemorrhagic cystitis
grade I: microscopic hematuria
grade II: macroscopic hematuria
grade III: hematuria with clots
grade IV: hematuria with clots, clot retention, and renal failure secondary to obstructive nephropathy
References:
1.Dall A, Hariharan S. BK virus nephritis after renal transplantation. Clin J Am Soc Nephrol 2008; 3(Suppl 2):S68–S75.
2.Van Aalderen MC, Heutinck KM, Huisman C, Ten Berge IJ. BK virus infection in transplant recipients: clinical manifestations, treatment options and the immune response. Neth J Med 2012; 70:172–183.
3.Bohl DL, Brennan DC. BK virus nephropathy and kidney transplantation. Clin J Am Soc Nephrol 2007; 2(Suppl 1)S36–S46.
4.Hariharan S. BK virus nephritis after renal transplantation. Kidney Int 2006; 69:655–662.
5.Tremolada S, Akan S, Otte J, Khalili K, Ferrante P, Chaudhury PR et al. Rare subtypes of BK virus are viable and frequently detected in renal transplant recipients with BK virus-associated nephropathy. Virology 2010; 404:312–318.
o BK virus nephropathy.
o Interstitial nephritis.
o Haemorrhagic cystitis
o Ureteral stenosis.
o Chronic allograft nephropathy.
References
1. Cohen-Bucay A, Ramirez-Andrade SE, Gordon CE, Francis JM, Chitalia VC. Advances in BK Virus Complications in Organ Transplantation and Beyond. Kidney medicine. 2020 Nov-Dec; 2(6):771-86.
2. KDIGO clinical practice guideline for the care of kidney transplant recipients. American journal of transplantation: official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2009 Nov; 9 Suppl 3:S1-155.
● The group most commonly affected by BKV is transplant recipients, including renal transplant and BMT recipients.
● Polyomavirus BKV causes disease of the genitourinary tract in association with hematological malignancies, congenital immunodeficiency, and Wiskott-Aldrich syndrome
● Also polyomavirus is significantly associated with some cancers in humans, including malignant mesothelioma, ependymomas, osteosarcoma, and non-Hodgkin lymphoma
The diseases caused by polyomaviruses in renal transplant recipients includes Ureteral stenosis, Polyomavirus nephritis, Merkle cell carcinoma, BKV-associated vasculopathy, Haemorrhagic cystitis, Tubulointerstitial nephritis, PML, Haematological and Genitourinary malignancy.
Scenario 1:
Human polyomavirus diseases includes:
BK virus leads to BK nephropathy and BK viremia and hemorrhagic cystitis.
JC virus causes progressive multifocal leuko-encephalopathy that is a progressive demyelinating CNS disorder involving cerebral white matter.
Mercle cell polyoma virus (MpyV) causes Mercle cell carcinoma.
Simian vacualating virus 40(SV40) causes disease in rhesus monkey induced by polio vaccines.
BK virus screening after renal transplantation can reveal viruria and/or viremia.
Reference:
Boothpur R, Brennan DC. Human polyoma viruses and disease with emphasis on clinical BK and JC. J Clin Virol. 2010 Apr;47(4):306-12. doi: 10.1016/j.jcv.2009.12.006. Epub 2010 Jan 8. PMID: 20060360; PMCID: PMC3774018.
In kidney transplant recipients, BK and possibly other polyoma viruses can cause Bk virus nephropathy and ureteral stenosis,whereas hemorrhagic cystitis is prevalent in hematopoietic stem cell transplantation (HSCT) patients and uncommon in kidney transplant.Rare cases of BK disseminated disease (tubulointerstital nephritis, desquamative pneumonitis, meningoencephalitis, and retinitis) have also been described.
Polyoma viruses are composed of 14 subclasses.
Human Polyoma virus 1=BK virus can lead to BKV nephropathy and hemorrhagic cystitis.
Human Polyoma Virus 2= JC virus can lead to PMLE (progressive multi-focal leuco-encephalopathy), Hodgkin’s lymphoma and nephropathy.
Human Polyoma Virus 3= Karolinska institute Polyoma Virus of Unknown significance.
Human Polyoma Virus 4= Washington University Polyoma Virus of unknown significance.
Human Polyoma Virus 5= Merkel Cell Polyoma Virus can lead to Merkel cell carcinoma which is an aggressive neuro-endocrine skin malignancy.
Human Polyoma Virus 6: of unknown significance.
Human Polyoma Virus 7: of unknown significance.
Human Polyoma Virus 8= Trichodysplasia Spinulosa Polyoma Virus can lead to skin keratin spines and follicular papules.
Human Polyoma Virus 9: of unknown significance.
Human Polyoma Virus 10= MX MW Polyoma Virus of unknown significance.
Simian virus – discovered as a contaminant of polio and adenovirus vaccines.
BK virus (BKV) is a polyomavirus that is able to cause renal dysfunction in transplanted grafts via BK virus-associated nephritis (BKVAN). This condition was mis-diagnosed in the past due to clinical and histopthological similarities with acute rejection. Due to the prevalence of the virus in the population, it is an important pathogen in this context, and so it is important to understand how this virus functions and its’ relationship with the pathogenesis of BKVN. Screening for BKV often reveals viruria and/or viremia, which then manifests as BKVN, which can be asymptomatic or result in clinical features namely renal dysfunction. The pathogenesis of BKV infection is still unclear and needs to be further investigated; nevertheless there are a variety of hypotheses that indicate that there are a host of factors that play important roles. Treatments for BKVAN include a reduction in immunosuppression, the use of antiviral therapy or the combination of both treatment options.
The diseases caused by polyomaviruses in renal transplant recipients
References;
1. Khalili K, Stoner GL., Human polyomaviruses: molecular and clinical perspectives, 2001New YorkWiley-Liss
2. Shah KV. Fields BN, Knipe DM, Howley PM, et al. Polyomaviruses, Fields virology, 1996, vol. Vol 2 3rd ed.Philadelphia Lippincott-Raven(pg. 2027-43)
3.Butel JS, Lednicky JA. Cell and molecular biology of simian virus 40: implications for human infections and disease, J Natl Cancer Inst, 1999, vol. 91 (pg. 119–34)
4. Lednicky JA, Arrington AS, Stewart AR, et al. Natural isolates of simian virus 40 from immunocompromised monkeys display extensive genetic heterogeneity: new implications for polyomavirus disease, J Virol, 1998, vol. 72 (pg. 3980-90)
5.Lafon ME, Dutronc H, Dubois V, et al. JC virus remains latent in peripheral blood B lymphocytes but replicates actively in urine from AIDS patients, J Infect Dis, 1998, vol. 177 (pg. 1502-5)
6.Azzi A, De Santis R, Ciappi S, et al. Human polyomaviruses DNA detection in peripheral blood leukocytes from immunocompetent and immunocompromised individuals, J Neurovirol, 1996, vol. 2 (pg. 411-6)
Types of polyoma viruses:
JCV
· Nephropathy
· PML(Progressive multifocal leukoencepgalopathy) rarely in renal transplant patients and it is associated with high levels of viral genome found in the cerebrospinal fluid.
BK Virus (BKV)
· Nephropathy (PVAN)
· upper respiratory tract infections
· pneumonia
· hemorrhagic cystitis
· interstitial kidney disease
· ureter stenosis
· meningitis
· encephalitis
· retinitis
· colitis
· vasculitis
· can also cause a PML-like disease
Reference:
Delbue and Ferraresso, J Transplant Technol Res 2020
BK viruria or viremia
BKVAN- type A,B C 10-18 % graft loss
ureteric stricture – first 3 months
Hgic cystitis
bladder urothelial tumor
Polyomaviruses can affect different sites of the graft by either viremia or viruira :
tubulointerstial nephritis
Hemorrhagic cystitis
uretric stricture due to epithelial hyperplasia
malignancy
BKVAN
ureteric stricture
Acute Rejection
urothelial Ca ( cause ?/ Association)
Hemorrhagic cystitis
What are the diseases caused by BK virus in kidney transplantion?
1- Subclinical viruria
2- BKVN:
is classified into three stages according to pathological changes
– stage A : characterized by presence of cytopathic changes (25%) , minimal tubular atrophy and interstitial infiltrates or fibrosis (<10%) , and graft loss occurs in around 10%.
Stage B: more prominent tubular atrophy and interstitial infiltration and fibrosis up to 50 % , with higher incidence of graft loss (50%).
Stage C : advanced stage of tubular atrophy and interstitial fibrosis with graft loss in 85%
3-Ureteric structure .
4- Heamorragic cystitis
5- Genitourinary cancers : some reports link BKV with increased incidence of genitourinary and urolithial cancers.
Ref
Safa K, Heher E, Gilligan H, Williams W Jr, Tolkoff-Rubin N, Wojciechowski D. BK Virus After Kidney Transplantation: A Review of Screening and Treatment Strategies and a Summary of the Massachusetts General Hospital Experience. Clin Transpl. 2015;31:257-263. PMID: 28514587
What are the diseases caused by polyomaviruses in renal transplant recipients?
BK virus
– BKV viraemia
– BKV viruria
– BKV nephropathy
– Graft loss(10- 80%)
– Cystitis (Haemorrhagic & non haemorrhagic)
– Ureteric stricture
JC virus
Progressive multifocal leukoencepgalopathy
BK Virus has seropositivity rate of over 75% in normal population. Primary infection is thought to occur in the respiratory tract. However, its now established that BK virus can be latent without any symptoms in urinary tract. In immunocompromised patients especially with renal transplant, BK virus can compromise kidney function and cause tubulointerstitial inflammatory response similar to acute rejection with variable prevalence of 1-10% and graft loss up to 80%.
In renal transplant recipients, Polyomavirus especially BK virus can cause nephropathy and ureteral stenosis. In addition to hemorrhagic cystitis which is prevalent in hematopoietic stem cell transplantation (HSCT) patients.
Lamarche, Caroline MD; Orio, Julie MSc; Collette, Suzon MD; Senécal, Lynne MD; Hébert, Marie-Josée MD; Renoult, Édith MD; Tibbles, Lee Anne MD; Delisle, Jean-Sébastien MD, PhD. BK Polyomavirus and the Transplanted Kidney: Immunopathology and Therapeutic Approaches. Transplantation 100(11):p 2276-2287, November 2016. | DOI: 10.1097/TP.0000000000001333
The clinical spectrum of BKV infections include BK viruria, BK viremia, BKVN, and, less commonly, ureteral stenosis. The highest prevalence of BK viruria and viremia occurs at 2 to 3 months, and 3 to 6 months, respectively.
Serum BK viral load of at least 10,000 copies/ml has been suggested to be predictive of BKVN.
Tubulointerstitial nephritis
Ureteral stenosis or stricture
Hemorrhagic cystitis
Diseases caused by polyomaviruses in renal transplant recipients
It can cause:
Viuria:
This can occur in 50% cases in first year post transplant and mostly progresses to viremia.
Viremia:
It can occur in first six months the incidence in 10-30%. Subsequently it can be between 5-10%
Polyomavirus-associated nephropathy (PVAN):
It is an emerging disease in renal transplant patients with prevalence of 1-10% and graft loss up to 80%. BK virus (BKV) is the primary etiologic agent, but JC virus (JCV) and possibly simian virus SV40 may account for some cases.
· Hemorrhagic Cystitis
· Ureteric Stricture
· Malignancy
Early screening and surveillance for BKV nephropathy is cost effective and can improve graft survival
Scadden JR, Sharif A, Skordilis K, Borrows R. Polyoma virus nephropathy in kidney transplantation. World J Transplant. 2017 Dec 24;7(6):329-338
polyomavirus include many different types :
BK virus
JC virus
Tichodysplasia spinulosa polyomavirus
Merckel cell polyomavirus
Karolinska Instutute polyomavirus
Wisconsin University polyomavirus
The most common types that affect the humans especially the immune compromise include BK &JC virus.
Diseases caused by the BK virus are:
1.BK Nephropathy
2.Ureteric stenosis
3.Hepatitis
4.Pneumonitis
5.Retinitis
6.Hemorrhgic cystitis
7.Urogenital malignancies
8.Tubulointerstitial nephritis
9.meningoencephalitis
10.Lymphoma.
Disease caused by the JC virus:
Reference
Lecture of Dr Ahmed Halawa.
What are the diseases caused by polyomaviruses in renal transplant recipients?
1. Tubulo-interstitial nephritis
2. BKV associated Nephropathy and grfat loss
3. Ureteral Stenosis and Stricture – severe Hydronephrosis and grfat loss
4. Precipitate Acute Rejection, especially Ac ABMR.
5. Haemorrhagic Cystitis – more with HSCT
6. Malignancy – Merkel Cell Carcinoma
– associated with Cervical CIN, Bladder Cancer and Renal Cancer (causal relation not proven)
References:
Gabriel M Daonovitch: Hand book of Kidney transplantation 6th Edn
Scadden JR et al. Polyoma virus nephropathy in kidney transplantation. World J Transplant. 2017 Dec 24;7(6):329-338
human polyomaviruses (HPyVs), cand evided into:
●BK polyomavirus (BKPyV)
BKPyV-associated nephropathy after renal transplantation
● BKPyV-
Hemorrhagic cystitis — Acute hemorrhagic cystitis following engraftment among hematopoietic cell transplant (HCT) recipients
●HPyV1 (BK) from the urine
Kidney transplant recipient with ureteral stenosis
●HPyV2 (JC) from Brain tissue
Patient with Hodgkin lymphoma and progressive multifocal leukoencephalopathy
●HPyV4 (Washington University) fro Nasopharyngeal aspirate
Molecular screening of patients with acute respiratory tract infections
●HPyV5 (Merkel cell ) from Merkel cell carcinoma
Patients with Merkel cell carcinoma
●HPyV8 (Trichodysplasia spinulosa) from Facial spines
Heart transplant recipient with trichodysplasia spinulosa
●HPyV13 (New Jersey) from the Muscle tissue
Pancreas transplant recipient who presented with vasculitis, myositis, and retinal blindness
1) Tubulointerstitial nephritis
2) Ureteral stenosis or stricture
3) Malignancy
4) hemorrhagic cystitis
References
1) Hand book of kidney transplantation 6th edition
Hirsch HH, Randhawa PS, AST Infectious Diseases Community of Practice. BK polyomavirus in solid organ transplantation—Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clinical transplantation. 2019 Sep;33(9):e13528.
What are the diseases caused by polyomaviruses in renal transplant recipients?
Human polyomavirus could be the causative agent of many diseases. Its small nonenveloped DNA virus, there are four main types causing diseases.
It almost infect >90% of population at 10 years of age.
Post-renal transplant the prevalence is 1 to 10% and of graft loss up-to 80%, strong immunosuppression would be the main cause of BKV associated complication(lecture ).
On staging it could present with viruria, viremia, and BKVAN.
It remain dormant until a patient become immunocompromised.
. The earliest appearance with symptoms of viruria in first year post transplantation is up-to 50%,
. While viruria is around 10-30% with in first six month.
. BKVAN usually occurs if persistant and progressive viremia with tabulitis and decrease in eGFR.
. Hemorrhagic cystitis,
. Ureteric stenosis, hydronephrosis, obstructive nephropathy.
. Genitourinary malignancies.
polyomaviruses are belonging to virus family papovaviradiae, it is non-envelop dsDNA virus.
human polyoma virus types are BK, JC, KI, WU, and Merkle cell MC
BK, JC, KI, and WU are belonged to SV40 group
MC virus is belonged to MuPyV (mouse polyoma virus)
both SV40 and MuPyV are belonged to avian polyoma virus
diseases caused by the virus:
1- interstitial nephritis or BK viral nephropathy BKVN or polyoma virus associated nephropathy PVAN
2- JC virus cause progressive multifocal leukencephalopathy which is demyelinating disease of CNS
3-Merkel cell carcinoma is an aggressive neuro-endocrine skin cancer, originating from the mechano-receptor Merkel cell. It is noted to be more common in immunosuppressed states suggesting an infectious etiology
reference:
Raghavender Boothpur, Daniel C. Brennan.Human Polyoma Viruses and Disease with Emphasis on Clinical BK and JC. J Clin Virol. 2010 Apr; 47(4): 306–312.
— Human polyomaviruses (HPyVs) are members of a genus of DNA viruses in the
Polyomaviridae family.
Common clinically relevant species
— BKPyV and JCPyV were first reported in the 1970s.
BKPyV was isolated in tissue culture from the urine of a kidney transplant recipient with
ureteral stenosis.
JCPyV was isolated from the brain tissue of a patient with Hodgkin lymphoma and
progressive multifocal leukoencephalopathy.
Merkel cell polyomavirus, isolated in 2008, is an oncogenic virus associated with Merkel
cell carcinoma, an aggressive neuroendocrine malignancy of the skin. Trichodysplasia
spinulosa polyomavirus, isolated in 2010, is associated with trichodysplasia spinulosa,
characterized by the development of cutaneous keratin “spines” and follicular papules most commonly on the face.
Reference :
Wang C, Wei T, Huang Y, Guo Q, Xie Z, Song J, Chen A, Zheng.
Isolation and characterization of WUPyV in polarized human airway epithelial cells.
BMC Infect Dis. 2020;20(1):488. Epub 2020 Jul 9
Diseases caused by polyomaviruses in renal transplant recipients
CytopathicPredominant polyomavirus replication
Causative prototype: PML1 by JCV in AIDS
Cytopathic – inflammatoryReplication plus inflammatory infiltrate
Causative prototype: PVAN 2 pattern B (interstitial nephritis) in renal transplantation
ImmunePredominant inflammatory
Causative prototype: PML by JCV in AIDS 3
Reconstitutingimmune response subsequent to replication
Causative prototype: following initiation of HAART 4 Hemorrhagic cystitis by BKV in stem cell transplantation
AutoimmunePathologic immune response triggered by previous replication Antigenic complexes – viral DNA: host cell histones – large T-antigen: host cell DNA – viral capsid: host cell DNA
Causative prototype: Systemic lupus by BKV?
TransformingUncoupling of cell proliferation from lytic replication
Causative prototype: Urothelial carcinoma by BKV Lymphoma by JCV, SV40?
=======================================
Reference
HH Hirsch, CB Drachenberg, et al, Polyomavirus-associated nephropathy in renal transplantation: critical issues of screening and management, 2006;577:160-73.
Diseases caused by polyomaviruses in renal transplant recipients
It can cause _
· Viruria
This can occur in 50% cases in first year post transplant and mostly progresses to viremia.
· Viremia
in first six months the incidence in 10-30%. Subsequently it can be between 5-10%
· Polyomavirus-associated nephropathy (PVAN) – It is an emerging disease in renal transplant patients with prevalence of 1-10% and graft loss up to 80%. BK virus (BKV) is the primary etiologic agent, but JC virus (JCV) and possibly simian virus SV40 may account for some cases.
· Hemorrhagic Cystitis
· Ureteric Stricture
· Malignancy
Early screening and surveillance for BKV nephropathy is cost effective and can improve graft survival
Scadden JR, Sharif A, Skordilis K, Borrows R. Polyoma virus nephropathy in kidney transplantation. World J Transplant. 2017 Dec 24;7(6):329-338
Polyoma virus infection leads to following deceases in Kidney Transplant Recipient
1) Tubulointerstitial Nephritis and graft loss
2) Ureteral Stenosis
3) Hemorrhagic Cystitis in Bone marrow transplant recipient
Review BK Virus Nephropathy in Kidney Transplantation A State-of-the-Art Review Sam Kant 1,2,* , Alana Dasgupta 3, Serena Bagnasco 3 and Daniel C. Brennan 1,2
Polyomavirus-associated nephropathy is account 1-10% and associated with graft loss up to 80%. BK virus (BKV) is the primary etiologic agent, but JC virus (JCV) and possibly simian virus SV40 may account for some cases.
The main cause of BKV activation and disease is Intense immunosuppression and ABO incompatible and HLA-mismatches.
Also older age, male gender, seronegative recipient), and viral factors (genotype, serotype) may have a contributory role.
The gold standard to confirm diagnosis of PVAN is allograft biopsy. Screening for polyomavirus replication in the urine and in the plasma and presence of viruria (“decoy cells”), plasma viral load. Increasing BK viremia (>10,000 copies/mL) or urine VP-1 mRNA (>6.5×105 copies/ng total RNA) load defines “presumptive PVAN” for which an intervention of reducing immunosuppression should be considered even if the diagnosis could not be confirmed by allograft biopsy. The response to intervention should be monitored using plasma DNA or urine mRNA load.
The main disease of BKV is interstitial nephritis/ ureteric stricture and stenosis/hemorrhagic cystitis.
JC virus may lead to progressive multifocal leukoencephalopathy (PML), However in few cases shows JC nephropathy.
SV40 is a DNA virus which associated with tumor in animals especially monkeys.
Different studies indicate that SV40 can replicate productively in human cells, including spongioblasts, fetal neural cells, newborn kidney cells, and some tumor cell lines.
Human papilloma virus 6 is associated with skin cancer and merkle,s cell carcinoma.
Diseases caused by human polyoma viruses in renal transplant patients:
-BK Virus can cause cystitis ; either hemorrhagic or non-hemorrhagic, uterine stricture & stenosis and BK virus -associated nephropathy.
JC virus can cause progressive multifocal leukoencephalopathy; a demyelinating disorder with ataxia, hemiparesis, visual field deficits, and cognitive impairment.
Trichodysplasia spinulosa polyoma virus; characterized by viral replication within keratinocytes and hyperproliferation of the inner root sheath cell associated by alopecia ,facial skin lesions madarosis.
Human polyomavirus 6 can cause pruritic, hyperpigmented skin eruptions in patients with kidney and pancreas transplant.
Merkle cell virus causing Merkle cell carcinoma; a neuroendocrine skin neoplasia.
Polyomavirus infection in KTRs; Clinical Manifestations
Polyomaviruses (JC virus [JCV], BK virus [BKV], and simian virus 40 [SV40]) establish subclinical and persistent infections and share the capacity for reactivation from latency in their host under immunosuppression(1). BKV causes infection in the kidney and the urinary tract, and its activation causes a number of disorders, including:
1. The classic sequence of infections in KTRs is viruria, viremia, and BKVAN.
· The most common and earliest manifestation of BKV is viruria occurring in up to 50% of patients in the first year of transplantation.
· The presence of sustained viruria may progress to viremia, which is asymptomatic initially.
2. Skin infection: HPyV-7 was implicated in the development of pruritic, brown plaques on the trunk and extremities in patients receiving immunosuppressed therapy who also developed viremia(2).
3. BKVAN usually occurs after a period of sustained progressively worsening viremia.
a) The vast majority of BKVAN occurs within the first post-transplant year, with the first 2–6 months being periods of highest incidence.
b) Manifesting as a decline in renal function with or without urinary abnormalities..
4. BKV infection led to allograft failure in 36% of the affected patients(3).
5. Ureteral stenosis(4) and hemorrhagic cystitis(1): albeit rare in kidney transplant recipients and mostly seen in patients with hematopoietic stem cell transplants.
6. Urothelial malignancies in transplant recipients(5).
7. Merkel cell polyomavirus (MCV) was discovered in 2008 from Merkel cell carcinoma, a rare but aggressive form of skin cancer. MCV is suspected to cause the majority of cases of Merkel cell carcinoma(6).
8. PML, the best-known clinical syndrome caused by JCV(a member of polyomaviruses). Although PML is not common, it has been reported in both organ transplant and BMT recipients(7-8).
References
1. David R. Snydman, Eun Jeong Kwak, Regis A. Vilchez, Parmjeet Randhawa, Ron Shapiro, Janet S. Butel, Shimon Kusne, Pathogenesis and Management of Polyomavirus Infection in Transplant Recipients, Clinical Infectious Diseases, Volume 35, Issue 9, 1 November 2002, Pages 1081–1087, https://doi.org/10.1086/344060
2. Human Polyomavirus; From: Encyclopedia of Virology (Fourth Edition), 2021 Skin InfectionsCarlos N. Prieto-Granada, … Martin C. MihmJr., in Diagnostic Pathology of Infectious Disease (Second Edition),
3. Randhawa PS, Finkelstein S, Scantlebury V, et al. Human polyoma virus-associated interstitial nephritis in the allograft kidney, Transplantation, 1999, vol. 67 (pg. 103-9).
4. Gardner SD, Field AM, Coleman DV, Hulme B. New human papovavirus (BK) isolated from urine after renal transplantation, Lancet, 1971, vol. 1 (pg. 1253-7).
5. Hernández-Gaytán CA, Rodríguez-Covarrubias F, Castillejos-Molina RA, Hernández-Porras A, Tobia I, Dubin JM, Autrán-Gómez AM. Urological Cancers and Kidney Transplantation: a Literature Review. Curr Urol Rep. 2021 Dec 16;22(12):62. doi: 10.1007/s11934-021-01078-2. PMID: 34913107.
6. Polyomaviruses Wang-Shick Ryu, in Molecular Virology of Human Pathogenic Viruses, 2017
7. Ouwens JP, Haaxma-Reiche H, van der Bij W, et al. Visual symptoms after lung transplantation: a case of progressive multifocal leukoencephalopathy, Transpl Infect Dis, 2000, vol. 2 (pg. 29-32).
8. Seong D, Bruner JM, Lee KH, et al. Progressive multifocal leukoencephalopathy after autologous bone marrow transplantation in a patient with chronic myelogenous leukemia, Clin Infect Dis, 1996, vol. 23 (pg. 402-3).
What are the diseases caused by polyomaviruses virus in kidney transplantion?
They are small nonenveloped DNA and they are 14 types, the commonest types are BKA, JC virus and simian virus 40
BK may cause:
-Subclinical viremia and viruria:
-BK virus nephropathy:
Classified into 3 stages:
*stage A: presence of cytopathy with minimal tubular atrophy and risk of graft loss around 10%
*Stage B: cytopathy with more prominent tubular atrophy and interstitial fibrosis with risk of graft loss around 50%
*Stage C: marked tubular atrophy and interstitial fibrosis with risk of graft loss 80%.
-Hemorrhagic cystitis
-Ureteric stricture
-Cancer
Ref
Safa K, Heher E, Gilligan H, Williams W Jr, Tolkoff-Rubin N, Wojciechowski D. BK Virus After Kidney Transplantation: A Review of Screening and Treatment Strategies and a Summary of the Massachusetts General Hospital Experience. Clin Transpl. 2015;31:257-263. PMID: 28514587
Dear colleagues,
Prof Dawlat has asked this important question, please let us know your views and experience:
What is the therapeutic and economic value of surveillance policy in post transplant cases to detect and manage early cases.
Thank you prof, Yes this is important;
Many thanks Prof Sharma
Yes Prof Dawlat has asked this important question
James A, Mannon RB. The Cost of Transplant Immunosuppressant Therapy: Is This Sustainable?. Curr Transplant Rep. 2015;2(2):113-121. doi:10.1007/s40472-015-0052-y
The early screening and regular serviellance policy for prevention of BKV nephropathy is cost effective and can impact the graft survival , qauntative BKV PCR is recommended for screening , serviellance , and monitroing for BKVviremia and BKVN .
While graft biopsy is indicated in case of persistant high viralload after 3 weeks from reduction of IS , high BKV PCR viral load with more than 5log is highly indicated of associated BKVN.
Prof Ahmed Halwa lecture
What is the therapeutic and economic value of surveillance policy in post-transplant cases to detect and manage early cases? (1)
– screening for polyomavirus infection following kidney transplantation is recommended by most clinical practice guidelines
– an analysis done by Wong et al revealed that routine screening for BKV using PCR was cost-saving, improved overall quality of life and improved survival compared with no screening
– this analysis supported screening for all kidney transplant
recipients for polyomavirus infections during the 1st year following transplantation since this is the period during which the net immunosuppression load is greatest
References
1. Wong G, Myint TM, Lee YJ, Craig JC, Axelrod D, Kiberd B. Economic Evaluation of Screening for Polyomavirus Infection in Kidney Transplant Recipients: A Cost-Utility Analysis. Transplantation direct. 2022 May;8(5):e1318. PubMed PMID: 35464876. Pubmed Central PMCID: PMC9018998. Epub 2022/04/26. eng.
This can be done in the first 1 yr post transplant during which we have peak immunosuppression, the results will facilitate quick response and possibly better outcomes post transplant. Unfortunately in my centre, lack of resources has ensured that this is hardly practised.
REF;
Wong et al;Economic evaluation of screening of polymyovirus in KTR; A cost utility analysis.
What are the diseases caused by polyomaviruses in renal transplant recipients?
Polyomaviruses (JC virus [JCV], BK virus [BKV], and simian virus 40 [SV40]) establish subclinical and persistent infections and share the capacity for reactivation from latency in their host under immunosuppression.
1-JCV establishes latency mainly in the kidney, and its reactivation results in the development of progressive multifocal leukoencephalopathy. This demyelinating disease of the CNS caused by polyomavirus JCV presents with rapidly progressive focal neurological deficits, which may include hemiparesis, paresthesia, visual field deficits, ataxia, and cognitive and behavioral changes.
2-BKV causes infection in the kidney and the urinary tract, and its activation causes a number of disorders, including ;
1- The classic sequence of infections in kidney transplant recipients is viruria, viremia, and BKVAN.
2-The most common and earliest manifestation of BKV is viruria occurring in up to 50% of patients in the first year of transplantation, with most cases not progressing to viremia .
3- Viremia is present in 10–30 percent of recipients in the first six months post- transplantation and in 5–10 percent of recipients thereafter .
4- BKVAN usually occurs after a period of sustained progressively worsening viremia, manifesting as a decline in renal function with or without urinary abnormalities. The vast majority of BKVAN occurs within the first post-transplant year given attenuated cellular immunity, with the first 2–6 months being periods of highest incidence .
5- Other manifestations of the BK virus include;
1- Ureteral stenosis .
2-hemorrhagic cystitis
Are rare in kidney transplant recipients and mostly seen in patients with hematopoietic stem cell transplants.
6-There are reports of a possible link between the BK virus and genitourinary (GU) malignancies, especially given its protracted infection in epithelia of the GU tract.
Reference ;
1-Update on the Management of BK Virus Infection Ahmed Saleh, 1,4,5 Mohamed Salah El Din Khedr,1 Abeer Ezzat, Anna Takou, 3 Ahmed Halawa4
2-Review BK Virus Nephropathy in Kidney Transplantation A State-of-the-Art Review Sam Kant 1,2,* , Alana Dasgupta 3, Serena Bagnasco 3 and Daniel C. Brennan 1,2
3-Khalili ,K Stoner, GL, Human polyomaviruses: molecular and clinical perspectives 2001 New York Wiley-Liss .
That is a well-structured reply. Even though you have numbered your contents, it is not easy to read. I wish you could type headings and sub-headings as underline or in bold.
☆ Polyomavirus infection:
▪︎Polyomaviruses are small, nonenveloped DNA viruses, which are widespread in nature.
▪︎In immunocompetent hosts, the viruses remain latent after primary infection. With few exceptions, illnesses associated with these viruses occur in times of immune compromise, especially in conditions that bring about T cell deficiency [1].
☆ Diseases caused by polyomaviruses in renal transplant recipients
1. Polyomaviruses associated nephropathy
▪︎Is an emerging disease in renal transplant patients with variable prevalence of 1-10% and graft loss up to 80%.
▪︎ BK virus (BKV) is the primary etiologic agent, but JC virus (JCV) and possibly simian virus SV40 may account for some cases.
▪︎ Intense immunosuppression is viewed as the most important risk factor [2]. ▪︎Recently, transplant nephropathy due to BKV infection has been increasingly recognized as the cause for renal allograft failure.
▪︎Quantitation of polyomavirus DNA in the blood, cerebrospinal fluid, and urine, identification of virus laden “decoy cells” in urine, and histopathologic demonstration of viral inclusions in the brain parenchyma and renal tubules are the applicable diagnostic methods.
2. Neoplasia:
▪︎Genomic sequences of polyomaviruses have been reported to be associated with various neoplastic disorders and autoimmune conditions.
▪︎There are reports that link BKPyV with metastatic bladder carcinoma in immunosuppressed transplant recipients.
3. Ureteral stenosis & haorrhagic cystitis
▪︎BK virus may cause ureteral stenosis and haorrhagic cystitis which is albeit rare. genitourinary malignancies. in kidney transplant recipients reactivation of the BK virus infection may end with graft dysfunction and failure by causing tubulointerstitial nephritis/ or ureteral obstruction (W4 paper 1)
Note:
While various antiviral agents have been tried to treat polyomavirus-related illnesses, current management aims at the modification and/or improvement in the hosts’ immune status [4].
_________________________
References
[1] Polyomaviruses and human diseases Nasimul Ahsan et al. Adv Exp Med Biol. 2006.
[2] Polyomavirus-associated Nephropathy in Renal Transplantation: Critical Issues of Screening and Management Hirsch HH, Drachenberg CB, Steiger J, et al.
[4] Polyomaviruses and human diseases Nasimul Ahsan et al. Adv Exp Med Biol. 2006).
That is a well-structured reply.
Thanks, Prof Ajay
What are the diseases caused by polyomaviruses in renal transplant recipients?
Polyomaviruses are non-enveloped icosahedral double stranded DNA viruses belonging to the polyomaviridae family.
Currently 13 human polyomaviruses have been identified with the most common being: BKV, JCV and SV40.
BKV and JCV are ubiquitous in the general population, with the primary infection occurring between 1-6 years of age.
The primary infection is mainly asymptomatic then the virus remains latent in either the kidney, lymphatic tissue, brain and spleen.
Viral reactivation and replication occurs when the host immunity specifically the T cell immunity is compromised. In the transplant population this occurs within the first 3 months post-transplant though late reactivation can also occur.
Conditions include:
Asymptomatic viruriaThis is detected in 10-45% of renal transplant recipients.
Several of the polyomaviruses have been detected in the urine of transplant recipients, however the clinically significant is BK viruria for it has been associated with BKVAN.
BKVANThe histological findings include tubular atrophy, interstitial inflammation and fibrosis.
Persistent BKV viruria and viremia has been identified as important cause of progressive graft dysfunction and loss.
Though the JCV has been detected in patients with allograft nephropathy, it has not been independently associated as a cause of kidney disease.
Ureteral stenosisThis is due to the direct cytopathic effect of the virus on the uroepithelium leading to ulceration and inflammation with ensuing obstructive uropathy.
Hemorrhagic cystitisThis is the most common genitourinary manifestation of polyomavirus infection in BMT recipients.
BMT recipients shed both BKV and JCV in urine. However BKV viruria is associated with development of hemorrhagic cystitis, whereby 64% of recipients progress to hemorrhagic cystitis.
Though JCV is shed in the urine of BMT recipients no clinical syndromes have been attributed to it in this population.
Progressive multifocal leukoencephalopathy (PML)Clinical syndrome that presents with demyelination of the CNS caused by JCV.
Leading to a rapidly progressive focal neurological deficits that may include hemiparesis, paresthesia, ataxia, visual field defects ,cognitive and behaviour changes.
Was common in the HIV era prior to HAART, however with introduction of HAART its incidence in this group has reduced.
Though rare it has also been reported in SOT and BMT recipients.
Merkel cell carcinomaThe Merkel cell polyomavirus has been detected in Merkel cell carcinoma a neuroendocrine skin neoplasia.
Its DNA has also been detected in non-melanoma skin cancers like squamous cell and basal cell.
It has also been detected in upper and lower respiratory tract infections.
Trichodysplasia spinulosa (TS)This is a rare skin disease in immunocompromised hosts and is characterised by the development of facial follicular papules and keratotic protrusions (spicules or spines) with alopecia of the eyelashes and brows.
It is associated with TS polyomavirus.
SV40 is significantly associated with some malignanciesIncluding malignant mesothelioma, ependymomas, osteosarcoma, and non-Hodgkin lymphoma.
However there are very few published studies on the frequency of SV40 infections among transplant recipients.
References
Entry, infection, replication, and egress of human polyomaviruses: an update
Soumen Bhattacharjee soumenb123@rediffmail.com and Sutanuka Chattaraj
Pathogenesis and Management of Polyomavirus Infection in Transplant Recipients
David R. Snydman, Eun Jeong Kwak, Regis A. Vilchez, Parmjeet Randhawa, Ron Shapiro, Janet S. Butel, Shimon Kusne
How is SV40 useful to diagnose BK virus ?
What are the diseases caused by polyomaviruses virus in kidney transplantion?
There are 14 types of polyomaviruses , the commonest types associated with complications in kidney transplant patients are BKV, JC virus and simian virus 40 (SV40)
BKV may cause:
1- Subclinical viruria:
diagnosed by presence of decoy cells in urine can progress to BKVN so reducing IS is required .
2- BKVN:
is classified into three stages according to pathological changes
– stage A : characterized by presence of cytopathic changes (25%) , minimal tubular atrophy and interstitial infiltrates or fibrosis (<10%) , and graft loss occurs in around 10%.
Stage B: more prominent tubular atrophy and interstitial infiltration and fibrosis up to 50 % , with higher incidence of graft loss (50%).
Stage C : advanced stage of tubular atrophy and interstitial fibrosis with graft loss in 85%
3-Ureteric structure .
4- Heamorragic cystitis
5- Genitourinary cancers : some reports link BKV with increased incidence of genitourinary and urolithial cancers.
B- JCV
associated with development of multifocal leucoencephalopathy.
Ref
Safa K, Heher E, Gilligan H, Williams W Jr, Tolkoff-Rubin N, Wojciechowski D. BK Virus After Kidney Transplantation: A Review of Screening and Treatment Strategies and a Summary of the Massachusetts General Hospital Experience. Clin Transpl. 2015;31:257-263. PMID: 28514587
What is the role of SV40 in diagnosis?
Polyomaviruses are around 14 types; one of them is the BK virus which is mostly encountered in Renal transplant recipients. It can cause Nephritis/BK nephropathy and acute rejection. It was associated with ureteral stenosis. Although mostly seen when the immunosuppression is in peak but can occur late, so patients should be screened for BK at 1, 3, 6, 12, and 24 months.
Other Polyomaviruses are not encountered in renal transplantation
Hemorrhagic cystitis is rare in renal transplant patients but is mostly encountered in Hematopeitic transplant patients.
How can it cause acute rejection?
both pathologies can coexist.
Polyomaviruses include sJC virus [JCV], BK virus [BKV], and simian virus 40 [SV40]
It can lead to
Polyomavirus nephritis
BKV reactivation common to occur within the first 3 months post renal transplantation, but late reactivation can happen.
Reactivation and replication of polyomavirus BKV is more prevalent in seropositive recipients receiving grafts from seropositive donors .
BKV can lead to viruria , tubulointerstitial nephritis, that can reach to severe allograft dysfunction and graft loss.
Ureteral stenosis is one of BKV infection consequences ,through the direct cytopathic effect on the ureteral epithelium which leads to obstructive uropathy.
Also tubular casts secondary to tubular necrosis can lead to obstruction.
Fatal BKV-induced vasculopathy was detected in a renal transplant recipient with concomitant necrotizing endothelial injury.
Haemorrhagic cystitis
Hemorrhagic cystitis is the more common in bone marrow transplantion recipients
Progressive multifocal leukoencephalopathyPML.
CNS demyelinating disease caused by polyomavirus JCV presents with rapidly progressive focal neurological deficits in immunocompromised cases with disrupted cell mediated immunity
Renourinary carcinoma
BKPyV infection association with malignant tumor is controversial .
BKPyV infection for a long time was suggested to increase the possibility of renourinary carcinoma in renal transplant recipients
Reference
-David R. Snydman, Eun Jeong Kwak, Regis A. Vilchez, Parmjeet Randhawa, Ron Shapiro, Janet S. Butel, Shimon Kusne, Pathogenesis and Management of Polyomavirus Infection in Transplant Recipients, Clinical Infectious Diseases, Volume 35, Issue 9, 1 November 2002, Pages 1081–1087.
-Maenosono, R., Okumi, M., Unagami, K. et al. Total nephroureterocystectomy and urethrectomy due to urothelial carcinoma associated with the BK polyomavirus infection after kidney transplantation: a case report with literature review. Ren Replace Ther 6, 52 (2020).
Thankyou but the worst is R- D+
_polyoma viruses causing diseases in renal tranpslant recipients included:
1_ JC polyoma which causes progressive multifocal leukoencephalopathy.
2_ BK polyoma virus which can cause BKVN with pathological changed (cytopthaic changes، with inflammatory cell infiltrate in interstium followed by tubular atrophy and interstitial fibrosis), this eventually leads to graft loss in 10_80% if cases.
_ it also has been linked to be associated with increased agressiveness and invasion of urothelial carcinoma (association rather than causation).
3_ Merckle cell polyoma which can cause Merckle cell carcinoma (progressive skin cancer , appears in sun exposed areas with high risk of distant metastasis).
Short and sweet
Thanks dear professor
What are the diseases caused by polyomaviruses in renal transplant recipients?
-BK and JC virus are the associated human polyomavirus diseases.
-they cause latent kidney epithelium infection while reactivation can be occurred during immune suppression.
-BK virus can cause tubulointerstial nephritis and ureteral stenosis or stricture.
– seropositive are up 90% world-wide, while 20-60% in urine or blood of kidney transplant recipients.
-BK viruria and viremia developed BK virus associated nephropathy.
– can be presented by allograft function loss around 9 months post-transplant.
– definite diagnosis can be confirmed by kidney biopsy with immonchistochemistry staining.
– monitoring by DNA PCR than detection with urine specimen is more specific.
– management include immunosuppression reduction while close monitoring for rejection.
– protocols recommend either to reduce or stop MMF by about 50% with decrease dose of CNI if needed.
– studies suggested prevention of BKN by medical therapy ( fluroquinolones, cidofovir or leflunomide).
References:-
handbook of kidney transplantation 6th edition Gabriel M. Danovith
Thankyou but adjunctive therapy is very controversial.
What are the diseases caused by polyoma viruses in renal transplant recipients?
· Polyoma viruses are small(45nm diameter), non-enveloped ,double stranded DNA viruses belonging to the polyoma viridiae family. They were first discovered by Ludwig Gross in 1953 as murine leukemia viruses.
· They establish a state of non-replicative infection termed latency in urogenital epithelial cells with reactivation after intense immunosuppression .
· About 30 species of polyoma viruses have been identified in birds and mammals, including 13 in humans: BK, JC, KI, WU, Merkel cell polyoma virus, H6, H7, H9, H10, H12, STL, trichodysplasia spinulosa-associated polyomavirus, and NJ.
· In kidney transplant recipients, BK(primary etiologic agent) and possibly other polyoma viruses(JC virus and possibly simian virus (SV40), as BK polyoma virus genome shares about 72% nucleotide homology with JC virus and 70% with SV40 )can cause :
§ Polyoma virus-associated nephropathy (PVAN)with variable prevalence of 1-10% and graft loss up to 80%.
§ ureteral obstruction(stenosis and strictures)
· Hemorrhagic cystitis is prevalent in hematopoietic stem cell transplantation (HSCT) patients (affects 5-20% of hematopoietic stem cell transplant recipients).
· Rare cases of BK disseminated disease (tubule-interstital nephritis, desquamative pneumonitis, meningo-encephalitis, and retinitis) have also been described, especially in patients with acquired immune deficiency syndrome.
· References:
1. Lamarche C et al. BK Polyomavirus and the Transplanted Kidney: Immunopathology and Therapeutic Approaches. Transplantation, 2016;100: 2276–2287.
2. Moens U et al. ICTV Virus Taxonomy Profile: Polyoma viridae. The Journal of general virology. 2017 Jun;98(6):1159-60.
3. Handbook of kidney transplantation 6th edition.
What is the therapeutic and economic value of surveillance policy in post transplant cases to detect and manage early cases.
Yes , prof
Polyoma viral infection includes BKV and JC viral infection
Usually, affect the uroepithelial structures with reactivation after intense immunosuppression
Up to 90% of young adults are seropositive and can be reactivated during intense immunosuppression like post-kidney transplantation, donor seropositivity also another risk factor for reactivation, tacrolimus , MMF based maintenance IS protocol
What are the diseases caused by polyomaviruses in renal transplant recipients?
1. Tubulointerstitial nephritis,
2. Ureteral obstruction (stenosis, stricture)
3. BKV Nephropathy with proteinuria and interstitial inflammation
4. can trigger rejection and is associated with graft loss in the range between 10-80%
BKV viruria and BKV viremia, BKVN, Definitive diagnosis require a renal biopsy with
immunohistochemistry staining for the presence of polyomavirus. Monitoring for BK virus in the plasma by
DNA PCR is more specific for the diagnosis of BK nephropathy than is detection with urine specimens.
References
1. Kidney transplant handbook 6th edition
2 Prof Ahmed Halawa lecture week 4
Well done but how can it induce rejection ?
both pathologies can co exist what would be your plan then.?
What are the diseases caused by polyomaviruses in renal transplant recipients?1- BK virus nephropathy.
2- Interstitial nephritis.
3- Ureteral stenosis.
4- Hemorrhagic cystitis
5-Chronic allograft nephropathy.
Short and sweet
1. What are the diseases caused by polyomaviruses in renal transplant recipients?
Diseases caused by polyomaviruses include: – (1, 2)
Introduction (3)
– Polyomaviruses were first discovered in the 1950s in rodent tissues as tumor-associated viruses. SV40 was later discovered in the 1960s in a monkey cell line. These two are associated with tumors in rodents.
– Two human polyomaviruses i.e., JC virus (JCV) and BK virus (BKV) were discovered thereafter in the 1970s. They are transmitted via respiration during infancy with ~40-90% of adults being persistently infected without any apparent clinical symptoms.
– JCV can rarely cause progressive multifocal leukoencephalopathy (PML) in immunocompetent people.
– MCV (Merkel cell polyomavirus) causes merkel cell carcinoma (MCC), a rare but aggressive form of skin cancer.
BKV-associated nephropathy (BKVAN)
– BK virus can get reactivated following kidney transplantation due to the immunosuppressive state.
– BK reactivation manifests as viruria (in 30-40% of patients), viremia (in 10-20% of patients) or BKVAN (in 1-10% of patients) (1)
– BKVAN manifests as acute or progressive graft dysfunction with decreasing GFR, hematuria (in 19% of patients), and proteinuria with protein excretion <1g/day (in 48% of patients) (4)
– BKVAN occurs mostly commonly during the first 2 years post-kidney transplantation (5)
– KDIGO recommends screening for BK viruria or viremia monthly for the first 3-6 months then every 3 months until the end of the 1st year post-kidney transplant (5)
– Risk factors for development of BKVAN: – (1)
o rearrangement of the NCCR region
o degree of immunosuppression (use of ATG, higher cumulative steroid doses, steroid pulses as rejection therapy, tacrolimus-based regimens [this is controversial])
o rejection episodes
o delayed graft function
o ABO-incompatible transplantation
o Higher degree of HLA antigen mismatch
o Age (<18 and >55)
o Male sex
o African American race
o Ureteral stent placement
o Decreased cellular immunity
o Deceased donor
o DCD – donation after circulatory death
o BK seropositive donor (especially D+/ R-)
– Definitive diagnosis of BKKVAN requires a graft biopsy with histological characteristics of tubilitis and interstitial inflammatory infiltrates. These findings are similar to graft rejection, differentiating the two can be a challenge and to make matters worse, these two processes can co-exist.
– other supportive findings in BKVAN include immunohistochemistry (i.e., SV40) and intranuclear viral inclusions without a surrounding halo on light and electron microscopy
Ureteral stenosis
– BKV replication occurs in the urothelium and can cause late ureteral stenosis (>1month post kidney transplantation)
– ureteral BKV infection is characterized by marked inflammation and ulcerations resulting in ureteral stenosis (6)
– patients present with asymptomatic hydronephrosis and a declining eGFR
– ultrasound can be used to confirm the diagnosis
Hemorrhagic cystitis
– can present with pain, hematuria, urinary obstruction and is associated with decreasing eGFR (7)
– more common in hematopoietic stem cell transplant recipients
References
1. Cohen-Bucay A, Ramirez-Andrade SE, Gordon CE, Francis JM, Chitalia VC. Advances in BK Virus Complications in Organ Transplantation and Beyond. Kidney medicine. 2020 Nov-Dec;2(6):771-86. PubMed PMID: 33319201. Pubmed Central PMCID: PMC7729234. Epub 2020/12/16. eng.
2. Reploeg MD, Storch GA, Clifford DB. Bk virus: a clinical review. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2001 Jul 15;33(2):191-202. PubMed PMID: 11418879. Epub 2001/06/22. eng.
3. Moens U, Calvignac-Spencer S, Lauber C, Ramqvist T, Feltkamp MCW, Daugherty MD, et al. ICTV Virus Taxonomy Profile: Polyomaviridae. The Journal of general virology. 2017 Jun;98(6):1159-60. PubMed PMID: 28640744. Pubmed Central PMCID: PMC5656788. Epub 2017/06/24. eng.
4. Nickeleit V, Singh HK, Randhawa P, Drachenberg CB, Bhatnagar R, Bracamonte E, et al. The Banff Working Group Classification of Definitive Polyomavirus Nephropathy: Morphologic Definitions and Clinical Correlations. Journal of the American Society of Nephrology : JASN. 2018 Feb;29(2):680-93. PubMed PMID: 29279304. Pubmed Central PMCID: PMC5791071. Epub 2017/12/28. eng.
5. KDIGO clinical practice guideline for the care of kidney transplant recipients. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2009 Nov;9 Suppl 3:S1-155. PubMed PMID: 19845597. Epub 2009/10/23. eng.
6. Mylonakis E, Goes N, Rubin RH, Cosimi AB, Colvin RB, Fishman JA. BK virus in solid organ transplant recipients: an emerging syndrome. Transplantation. 2001 Nov 27;72(10):1587-92. PubMed PMID: 11726814. Epub 2001/12/01. eng.
7. Laskin BL, Denburg MR, Furth SL, Moatz T, Altrich M, Kleiboeker S, et al. The Natural History of BK Polyomavirus and the Host Immune Response After Stem Cell Transplantation. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2020 Dec 15;71(12):3044-54. PubMed PMID: 31851312. Pubmed Central PMCID: PMC7819507. Epub 2019/12/19. eng.
Thankyou very good review.
Thank you Prof.
1-What are the diseases caused by polyomaviruses in renal transplant recipients?
–Clinical syndromes that are causally linked with polyomavirus infection are best established for BKPyV, JCPyV, Merkel cell polyomavirus (MCPyV), and trichodysplasia spinulosa polyomavirus (TSPyV), and occur primarily in the setting of cellular immune deficiency.
–BKPyV-associated nephropathy;.
-BKPyV is the primary cause of polyomavirus-associated nephropathy in renal transplant recipients,
-JCPyV is a rare cause of nephropathy in renal transplant recipients and may be due to primary infection. BKPyV-associated nephropathy in native kidneys is rare but has been described in nonkidney organ transplant recipients.
-Hemorrhagic cystitis;.
-Acute hemorrhagic cystitis following engraftment among hematopoietic cell transplant (HCT) recipients (particularly allogeneic HCT recipients) may be associated with BKPyV infection,
-BKPyV-associated hemorrhagic cystitis (BKPyV-HC) is estimated to complicate 5 to 25 percent of allogeneic HCT and is typically characterized by postengraftment urinary frequency, dysuria, hematuria, urinary blood clots, and urinary obstruction that may last for several weeks,
-BKPyV viruria is common post-transplant, affecting >50 percent of HCT recipients.
-Progressive multifocal leukoencephalopathy;
-JCPyV is the main causative agent of progressive multifocal leukoencephalopathy (PML), a demyelinating disorder that almost always occurs in the setting of immunocompromise,
-PML has been reported most commonly in patients with advanced HIV (particularly before the availability of potent antiretroviral therapy), but it has also been reported in patients with hematologic malignancies and in patients receiving certain lymphocyte-targeted agents,
–Trichodysplasia spinulosa;.
-Trichodysplasia spinulosa (TS) polyomavirus (TSPyV) has been detected in lesions of TS, a rare skin disease in immunocompromised patients characterized by viral replication within keratinocytes and hyperproliferation of the inner root sheath cell.
-The diagnosis is characterized by the development of keratin spines (“spicules”) and follicular papules that often involve the face and is confirmed by a skin biopsy with characteristic histology or detection of the polyomavirus (SV-40 immunostaining, electron microscopy visualization of 40 to 45 nm viral particles in cells of the inner root sheath or molecular methods).
-Associations with malignancy
-Merkel cell carcinoma;
-MCPyV DNA or virions are commonly found on healthy skin. Although rare, the virus is implicated in the pathogenesis of Merkel cell carcinoma, an aggressive neuroendocrine malignancy that affects the skin)
-Putative associations;
-JCPyV and BKPyV have been associated with an array of malignancies but whether they play a causal role is uncertain. Viral DNA sequences and viral protein expression has been detected in some tumor involving the brain, prostate, bladder, urothelium, and other organs.
-There is also a higher than expected incidence of bladder cancer in kidney transplant recipients treated for BKPyV-associated nephropathy.
-Other disease associations
–Disseminated BKPyV infection;
-Widespread endothelial BKPyV infection in a kidney transplant recipient resulted in severe muscle weakness, anasarca, and a fatal myocardial infarction.
-BKPyV viremia, dysuria, and hematuria in a postallogeneic stem cell transplant recipient progressed to deterioration of renal function, hypertension, seizure, pancreatitis, and respiratory failure.
-Colonic ulcers were documented in a kidney transplant recipient with abdominal pain and known BKPyV infection of the kidney allograft with associated BK viremia.
-Biopsy specimens of the ulcers showed viral inclusion bodies, and in situ hybridization for BKPyV was strongly positive. Reduction in the immunosuppressive regimen led to healing of the ulcers and a decrease in serum BKPyV DNA. Studies for other viruses, including cytomegalovirus, were negative.
–Trichodysplasia spinulosa polyoma virus (TSPyV);
-Found in respiratory samples of a child with acute lymphoblastic leukemia who had cough, fever, and coryza . TSPyV has been found in blood and urine samples of otherwise asymptomatic transplant recipients.
–Karolinska Institute polyomavirus (KIPyV);
-Detected in respiratory and fecal specimens in immune competent pediatric patients but its role in respiratory tract disease remains uncertain.
-Reference; Up To Date
That is a well-structured reply. Typing only ‘Up to date’ as a reference is not a complete reply in a scientific write-up.
Noted our Prof;
Upto date- Overview and virology of JC Polyomavirus, BK Polyomavirus and other Polyomavirus infections.
%DISEASES CAUSED BY POLYOMAVIRUSES IN RENAL TRANSPLANT RECIPIENTS.
PREVALENCE.
-By adulthood,~ 50-90% of adults have detectable antibodies to BKPyV,JCPyV,Merkel cell polyomavirus ,Karolinska Institute Polyomavirus and WUPyV.
TRANSMISSION.
-Person to person.
-Oral/ Resp transmission; BKPyV, JCPyV, KIPyV & WUPyV.
-Skin contact ;MCPyV,HPyV6,HPyV7 & TSPyV.
-Other routes; Fecal oral, sexual or perinatal transmission.
CLINICAL MANIFESTATION.
1.BKPyV associated nephropathy– occurs in SOT post renal transplant mostly. Manifests as gradual renal failure with asymptomatic acute or slow rise in creatinine that can progress to graft failure.
2.Hemorrhagic cystitis – Can occur in HCT recipients esp allogenic recipients (5-25%).Manifests as post surgery urinary frequency ,dysuria,hematuria,urinary blood clots and obstructive features.Tx is supportive with some studies reporting use of cidofovir/BKPyV specific cytotoxic T cell therapy.
3.PML -Caused by JCPyV in immunocompromised pts. Manifests as gradual onset focl neurological deficits with ataxia, visual impairment and cognitive impairment. Reported in HIV and patients with hematological malignancies after recent lymphocyte targeted agents like Natalizumab.
4.Trichodysplasia spinulosa – Caused by TS polyomavirus xtised by viral replication in keratinocytes. Manifest as follicular papules or spicules on face and have SV – 40 staining on histology.TX involves topical valganciclovir, cidofovir, leflunomide, retinoids or removal of spicules physically.
5.Merkel cell Ca – A neuroendocrine malignancy with predominant derm involvement causes by MCPyV.
6.Other associated malignancies – Brain, Prostate, Bladder and urothelial tumors.
7.Other diseases associations;
REFERENCES;
1.Upto date- Overview and virology of JC Polyomavirus, BK Polyomavirus and other Polyomavirus infections.
2.Prof Halawa lecture on BK virus post transplant.
That is a well-structured reply. As much as I adore my academic brother Ahmed Halawa, writing that his lecture is a reference is not a complete reply in a scientific write-up.
Noted Prof.
WHAT ARE THE DISEASES CAUSED BY POLYOMAVIRUS IN RENAL TRANSPLANT RECIPIENTS
kidney transplant recipients receive immunosuppression for prolonged period of time. This makes these patients very susceptible for various viral infections which triggers neoplasms in these patients.
Polyomaviruses are one of the major group of viruses responsible for neoplasms, post kidney transplantation.
Following are the three viruses belonging to family of polyoma virus responsible for post kidney transplantation
Following are the diseases causes by the above viruses:
SV40 can also cause similar presentation in small percentage
Ref:
Short and precise.
Diseases caused by polyomavirus in renal transplant recipients
Introduction:
Diseases related to HPV in renal transplant recipients:
1.BKV:
A.BKVN:
B . Ureteric stenosis
C. Assocaiton with malignacy:
D: Hemorrhagic cystitis:
2. JCV:
A : Nephropathy:
B: progressive mutifocal leukoencephalopathy:
3. Merkle cell virus:
References:
1. professorAhmed Halawal lecture about BKV in renal transplant recipients.
2. Jhon E. Bennet etal. Principle and practice of infectious disease 2020
3. Mareli Coetzer D, etal. Hemorrhagic cystitis in a renal transplant recipients.OHSU
4.Molecular Virogy of Human Pthogenic Viruses. 2017
5. Masahiro Shad, Encylopia of cancer 2019
6. Serena Delbuec etal. Areview of JCV virus Infection in kdney Transplant Recepient 2013
That is a well-structured reply. As much as I adore my academic brother Ahmed Halawa, writing that his lecture is a reference is not a complete reply in a scientific write-up.
Human Polyomaviruses are small, double stranded DNA viruses belonging to the polyomaviridiae family (1). A total of 14 humanpolyomaviruses have been reported, which include BK virus, JC virus, KI virus, WU virus, and Merkel Cell virus (2).
Polyomaviruses affecting transplant recipients include:
1) BK Virus: It causes (2),
a.Polyoma virus associated nephropathy (PyVAN: affetcs 1-15% of renal transplant recipients.
b.Polyoma virus associated hemorrhagic cystitis (PyVHC): affetcs 5-20% of hematopoietic stem cell transplant recipients.
c.Polyoma virus associated urothelial cancer (PyVUC).
d.Ureteral stenosis.
2) JC Virus: It is associated with progressive multifocal leukoencephalopathy (PML). JC virus has been seen as a co-infectious agent in kidney transplant recipients with BK virus associated interstitial nephritis (3).
3) Merkel Cell virus: It is associated with Merkel Cell carcinoma, a neuro-endocrine skin malignancy.
4) TS virus: It is associated with Trichodysplasia spinulosa, a proliferative dedifferentiated skin disorder (2).
5) Human polyoma virus 7: It is associated with pruritic hyperproliferative keratinopathy (brownish, pruritic plaques on extremities and trunk).
6) SV40 virus: It has been identified in renal transplant recipients, but its importance is poorly defined (3,4).
BK virus, JC virus, and SV40 virus have been shown to be associated with mesothelioma, pediatric and adult brain tumors, osteosarcoma, and nonHodgkin lymphomas (5).
References:
Boothpur R, Brennan DC. Human polyoma viruses and disease with emphasis on clinical BK and JC. J Clin Virol. 2010 Apr;47(4):306-12. doi: 10.1016/j.jcv.2009.12.006. Epub 2010 Jan 8. PMID: 20060360; PMCID: PMC3774018.Wu Z, Graf FE, Hirsch HH. Antivirals against human polyomaviruses: Leaving no stone unturned. Rev Med Virol. 2021 Nov;31(6):e2220. doi: 10.1002/rmv.2220. Epub 2021 Mar 17. PMID: 33729628.Kwak EJ, Vilchez RA, Randhawa P, Shapiro R, Butel JS, Kusne S. Pathogenesis and management of polyomavirus infection in transplant recipients. Clin Infect Dis. 2002 Nov 1;35(9):1081-7. doi: 10.1086/344060. PMID: 12384842.Bohl DL, Brennan DC. BK virus nephropathy and kidney transplantation. Clin J Am Soc Nephrol. 2007 Jul;2 Suppl 1:S36-46. doi: 10.2215/CJN.00920207. PMID: 17699509.Ahsan N, Shah KV. Polyomaviruses and human diseases. Adv Exp Med Biol. 2006;577:1-18. doi: 10.1007/0-387-32957-9_1. PMID: 16626024.
That is a well-structured reply
BKV is a member of the Polyomaviridae family, falling into the Betapolyomavirus subcategory with JC virus and Simian virus 40 (SV40)
BK virus (BKV) is a polyomavirus that is able to cause renal
dysfunction in transplanted grafts via BK virus-associated nephritis (BKVAN).
BKV primary infection occurs in early childhood and is
asymptomatic in the majority of cases.
Transmission of BKV is thought to involve respiratory and oral routes, and results in a seroprevalence of 82% in adulthood.
BKV may stay as latent infection, and stay dormant in tissues, mainly the kidney .
This virus can reside in renal tubular epithelial cells and
in the uroepithelium. To be transmissible through kidney transplantation.
Screening for BKV often reveals viruria and/or viremia, this can manifests as
BKVN.
The recipient is characteristically asymptomatic, with the
infection presenting as progressively worsening renal function, usually in the
absence of significant or new-onset proteinuira.
BKVAN may also present as subclinical rejection
The median time to clinically apparent BKVAN is within the
first year after transplantation
* pathogenesis of BKVAN depends
on
1: Source of the viral infection either primary infection from
the transplanted kidney , or reactivation from latent infection in the
patient’s native urinary tract.
2Cellular and humoral immunity
are important in the pathogenesis of BKVAN, and both CD8+ and CD4+ T cells are
involved in the recognition and clearance of BKV.
The lack of BKV specific IgG may be important in the development
of BKVAN, Comoli et al showed that
patients that had BKVAN had fewer BKV-specific lymphocytes that secreted
interferon-γ (IFN-γ).
3 Immunosuppression
Calcineurin inhibitor (CNI) based therapies was shown to increase risk of BKVAN and
subsequent nephrotoxicity following renal transplant.
Brennan et al, showed that viruria was most common with a
drug combination of Tac-MMF (46%) and lowest with cyclosporine-MMF (13%),reduction in immunosuppression in response to
detectable viremia resulted in reductions in viral load in 95% of patients, and
without increased risk of rejection.
4 Increase HLA mishmatch found to increase the risk factor for BKVA.
5 number of risk factors between the donor and recipient increase the risk of a BKV
infection, including gender, race, age, diabetes mellitus or deceased donor.
*Stages
of BKVAN depending on the presence of viral infection in the absence of
inflammation or significant chronic damage (Grade A), with inflammation
dominating over chronic damage (Grade B), and with chronic damage (fibrosis and
tubular atrophy) as a notable component, with or without inflammation (Grade C)
*For many years, BKVAN was confused with acute rejection, as
both have the appearance of an “interstitial nephritis”. With more widespread
recognition of BKVAN, the availability of blood and urine testing for viral
load, and the utility of SV40 staining on biopsy samples, the pathological
diagnosis of BKVAN has become more straightforward. However, acute rejection
and BKVN are not mutually exclusive, and particularly in the period following
BKVAN treatment.
The two may coincide, and it may be unclear which represents
the dominant process.
although the presence of macro- or micro-vascular
inflammation points to rejection as a component at least.
Other polyomavirus that may affect recipients includs :
-JC polyomavirus (JCPyV) which may cause Progressive multifocal leukoencephalopathy.
-MCPyV DNA or carcinoma causeing Merkel cell carcinoma, an aggressive neuroendocrine malignancy of the skin
-polyomaviruses (HPyVs) causing
Hemorrhagic cystitis presents with gross hematuria
Reference
Jacob RW Scadden, Adnan Sharif.Polyoma virus nephropathy in kidney
transplantation.World J Transplant. 2017 Dec 24; 7(6): 329–338
Even though you have numbered your contents, it is not easy to read. I wish you could type headings and sub-headings as underline or in bold.
Sorry sir ,as am writing on my mobile not a Iabtop and will try to do so
Human polyomaviruses (HPyVs) are members of a genus of DNA viruses in the Polyomaviridae family.
The most common polyomaviruses associated with infectious diseases are JC polyomavirus (JCPyV) and BK polyomavirus (BKPyV).
1-BKPyV-associated nephropathy
2 endothelial BKPyV infection in a kidney transplant recipient resulted in severe muscle weakness, anasarca, and a fatal myocardial infarction
3- Colonic ulcers were documented in a kidney transplant recipient with abdominal pain and known BKPyV infection of the kidney allograft with associated BK viremia
4- Progressive multifocal leukoencephalopathy — JCPyV is the main causative agent of progressive multifocal leukoencephalopathy (PML), a demyelinating disorder that almost always occurs in the setting of immunocompromise,
5- Trichodysplasia spinulosa — Trichodysplasia spinulosa (TS) polyomavirus (TSPyV) has been detected in lesions of TS, a rare skin disease in immunocompromised patients characterized by viral replication within keratinocytes and hyperproliferation of the inner root sheath cell The diagnosis is characterized by the development of keratin spines
6-Human polyomavirus 6 (HPyV6) has been reported in association with pruritic, hyperpigmented skin eruptions in two patients, one with a history of kidney and pancreas transplant and the other with no history of immune compromise
7-Merkel cell carcinoma — MCPyV DNA or virions are commonly found on healthy skin , an aggressive neuroendocrine malignancy that affects the skin.
8-JCPyV and BKPyV have been associated with an array of malignancies involving the brain, prostate, bladder, urothelium, and other organs.
There is also a higher than expected incidence of bladder cancer in kidney transplant recipients treated for BKPyV-associated nephropathy
That is a well-structured reply
What are the diseases caused by polyomaviruses in renal transplant recipients?
Introduction:
Polyomaviridae family of the ungrouped DNA viruses, detected in vertebrate hosts including rodents, cattle, birds, monkeys, and primates. It affects almost 90% of population during life.
Polyomavirus related diseases are:
References:
UpToDtae-overview and virology of JC polyomavirus, BK polyomavirus, and other polyomavirus infections.
Many thanks for a comprehensive reply
What are the diseases caused by polyomaviruses in renal transplant recipients?
Human polyomaviruses:
1. BK
2. JC
3. KI
4. WU
5. Merckle cell
The two viruses that can cause significant diseases in humans are BK virus JC virus
BKV Nephropathy:
· Up to 80% of renal transplant patients have BK viruria and 5–10% progress to BKVN
· Reactivation starts soon after transplantation and is seen in 30–50% of the patients by 3 months post transplant
· When the virus, reactivates it can present as asymptomatic deterioration of renal function, tubulo-interstitial nephritis, and ureteric stenosis
Ureteric stenosis:
· BKV rarely cause ureteral stenosis (marked inflammation and ulcerations)
· BKV-associated stenosis usually affects distal part of the ureter, especially around the site of anastomosis at the ureterovesical junction
· It remains unknown whether BKV is the primary cause of ureteric stenosis or whether BKV infects previously injured ureter (from ischemia or trauma after stenting) as a secondary insult
Hemorrhagic cystitis:
· Seen in 25–60% of the bone marrow transplant patients
· It is usually seen two weeks after transplant which is later than the hemorrhagic cystitis from chemotherapeutic agents such as cyclophosphamide which occurs immediately
· Symptoms include dysuria, urgency, frequency, suprapubic pain and varying degree of haematuria
· The diagnosis is made by detecting BK viral DNA in the urine
· Treatment is usually supportive with hyperhydration, forced diuresis, bladder irrigation and transfusion as indicated
· If the hematuria is severe with clots, cystoscopy and clot removal and cauterization of the source might be needed
Progressive multifocal leukoencephalopathy (PML):
Rare after transplantation (JC virus)
BK virus and tumours (Merkel cell carcinoma):
· Aggressive skin cancer
· Typically affects elderly and immunosuppressed individuals
References
1. Etta PK, Madhavi T, Gowrishankar S. Coexistent BK-virus-associated nephropathy and ureteric stenosis in a patient with acute cellular rejection after renal transplantation: A case report and review of literature. Indian J Transplant 2020;14:147-51
2. Boothpur R, Brennan DC. Human polyoma viruses and disease with emphasis on clinical BK and JC. J Clin Virol. 2010 Apr;47(4):306-12. doi: 10.1016/j.jcv.2009.12.006. Epub 2010 Jan 8. PMID: 20060360; PMCID: PMC3774018.
Short and precise.
What are the diseases caused by polyomaviruses in renal transplant recipients?
-There are 5 known human polyoma viruses. JC virus and BK virus are two polyoma viruses identified nearly three decades ago. Recently WU, KI and Merkel cell polyoma viruses have been isolated from humans. Merkel cell polyoma virus associates with Merkel cell carcinoma.
– Most human polyoma disease is caused by BK and JC viruses which are usually acquired in childhood. These viruses remain latent possibly in the lymphoid organs and kidney and under the circumstances of severe immunosuppression both these viruses reactivate.
BKV Nephropathy
After primary infection in childhood BK virus becomes latent in the tubular epithelial cells of the urogenital tract. It mainly affects epithelial cells of collecting ducts, tubular epithelium of renal calyces and renal pelvis60. In immunosuppressed states BK may reactivate in the renal tubular epithelial cells causing asymptomatic deterioration of renal function, tubulo-interstitial nephritis, and ureteric stenosis. Hemorrhagic cystitis from BK virus is seen in 25–60% of the bone marrow transplant patients .
Progressive Multifocal leukoencephalopathy (PML)
Progressive Multifocal leukoencephalopathy is a progressive demyelinating central nervous system disorder involving cerebral white matter caused by the JC virus . It most often presents as an opportunistic infection in HIV patients with lymphopenia but has recently been seen with new immunosuppressives .It has a high mortality rate.
Reference:
-Raghavender Boothpur, et al. Human Polyoma Viruses and Disease with Emphasis on Clinical BK and JC. J Clin Virol. 2010 Apr; 47(4): 306–312.
Short and precise.
Polyoma viruses are DNA viruses belonging to the polyoma viridae family. They There are 14 members of the family. Transmission is from person to person via oral and/or respiratory of BK, JC, KI and WU polyoma viruses whereas direct contact for others.
Only BK, JC, Merkel polyoma viruses have been associated with specific disease.
Human Polyoma virus 1 – Also known as BK virus. It was first isolated from urine but can also been detected in the blood and body tissues.
Human Polyoma virus 2 – Also known as JC virus. It’s a rare cause of nephropathy post kidney transplant. It was first isolated from brain tissue. It causes Hodgkin’s lymphoma and progressive multifocal leucoencephalopathy, a condition characterized by ataxia, hemiparesis, visual field defects and cognitive impairment.
Human Polyoma virus 5 – Also known as merkel cell polyoma virus. It causes merkel cell carcinoma, an aggressive neuroendocrine skin malignancy. It was first isolated in patients with merkel cell carcinoma.
Human Polyoma virus 8 – Also known as trichodysplasia spinulosa polyoma virus. It causes the development of cutaneous keratin “spines” and follicular papules especially on the face with facial spines. It was first isolated in heart transplant patients with trichodysplasia spinulosa.
Others of unknown clinical significance.
Human Polyoma virus 3 – Also known Karolinska institute polyoma virus which was initially from nasopharyngeal aspirate and feces.
Human Polyoma virus 4 – Also known as Washington university polyoma virus. Isolated first in nasopharyngeal aspirate.
Human Polyoma virus 6 – Found in normal skin of healthy adults.
Human Polyoma virus 7
Human Polyoma virus 9 – Found in blood and urine of asymptomatic kidney Tx patients.
Human Polyoma virus 10 – Also called MX,MW polyoma virus. Found in stool samples of healthy children.
Simian virus – discovered as a contaminant of polio and adenovirus vaccines.
Short and precise.
1. What are the diseases caused by polyomaviruses in renal transplant recipients?
Dear Dr Ahmed,
The attached table summarizes the diseases caused by polyomaviruses. We can notice that kidney transplant recipients were mentioned specifically with:
1- BKV (human polyomavirus 1): can cause BK virus nephropathy and ureteric stenosis.
2- JC virus (human polyomavirus 2) may be associated with progressive multifocal leukoencephalopathy.
Regarding the remaining types of polyomaviruses, despite not being specifically linked to kidney transplant recipients. However, I believe if they can affect normal subjects, then they can affect immune-compromised patients in a more aggressive form. Nevertheless, they remain not widely studied (1).
References:
1) Hannah Imlay, and Ajit P Limaye. Overview and virology of JC polyomavirus, BK polyomavirus, and other polyomavirus infections. ©2023 UpToDate® (accessed on 13 February 2023).
Short and precise.
BK Virus can cause Cystitis (haemorrhagic and non-haemorrhagic), Uterine stricture, stenosis and BK virus associated nephropathy.
JC virus causes progressive Multifocal leukoencephalopathy; a demyelinating disorder, always occurs in the setting of immunocompromise, presents with progressive focal neurologic deficits including ataxia, hemiparesis, visual field deficits, and cognitive impairment.
Trichodysplasia spinulosa polyoma virus; a rare skin disease characterized by viral replication within keratinocytes and hyperproliferation of the inner root sheath cell.
Human polyomavirus 6 (HPyV6) has been reported in association with pruritic, hyperpigmented skin eruptions in patients with a history of kidney and pancreas transplant.
Human polyomavirus 9 (HPyV9) has been detected in several transplant recipients
Short and precise.
Diseases caused with BK polyoma virus in renal transplant recipients BKPV:
1- BKPV Nephropathy BKPVN, as its causing tubulo-interstial nephropathy provoked by over suppression of immune system .
2- hemorrhagic cystitis , which can present with profuse hematuria.
3-Ureteric stenosis leading to obstructive nephropathy and hydronephrosis.
4-Pneumonitis.
5- Encephalitis.
References:
1-Shauna M. Bennett,a,1 Nicole M. Broekema,b,1 and Michael J. BK polyomavirus: emerging pathogen.Microbes Infect. 2012 Aug; 14(9): 672–683
John Cunningham virus JCV:
Is Polyoma virus who was reported to be associated with progressive multifocal leukoencephalopathy PML in over suppressed patient on Mycophenolate medicine.
JC was linked to some malignancy cases .
references:
2-Raghavender Boothpur, and Daniel C. Brennan. Human Polyoma Viruses and Disease with Emphasis on Clinical BK and JCJ Clin Virol. 2010 Apr; 47(4): 306–312.
.
Quite a short reply.
-Human polyomaviruses (HPyVs) are members DNA viruses in the Polyomaviridae family. Fourteen HPyV species have been identified.
-It is highly prevelant with seropositivity rates ranging from 30 to 90 percent in healthy general population.
-After primary infection, the virus will remain lifelong persistence in the body.
-Most instances of primary polyomavirus infection in immunocompetent persons are presumed to be either subclinical or associated with mild nonspecific symptoms.
-In immunocompromised persons, however, either primary infection and/or reactivated infection can cause specific syndromes and lead to substantial morbidity
Common clinically relevant species:
* BKV
BKPyV viruria is common affecting >50 % of KTRs. However, most patients with viruria do not develop symptomatic diseases.
BKPyV viremia may follow viuria, detected in 10 to 30 % of recipients in the first six months. Mostly asymptomatic but may progress to BKPyAN.
BKPyV-associated nephropathy Progressive renal dysfunction resulting in either an asymptomatic acute or slowly progressive rise in serum creatinine and can progress to renal allograft loss.
BKPyV-associated hemorrhagic cystitis (BKPyV-HC) is estimated to complicate 5 to 25 % of HSCT and is typically characterized by postengraftment urinary frequency, dysuria, hematuria, urinary blood clots, and urinary obstruction that may last for several week.
Ureteric Stenosis:
Association with malignancy
There is no conclusive evidence of a causal relationship between BKPyV and cancer in human beings.
Various reports have indicated the presence or absence of viral genomic sequences in multiple human cancers. It has been suggested that that BKV is associated with brain tumors, adenocarcinomas, prostate cancers, and bladder carcinomas, and JCV is associated with mesotheliomas, brain tumors, osteosarcomas, and lymphomas.
* JCV:
progressive multifocal leukoencephalopathy (PML), a demyelinating disorder that almost always occurs in the setting of immunocompromise, and presents with progressive focal neurologic deficits including ataxia, hemiparesis, visual field deficits, and cognitive impairment. PML commonly reported in advanced HIV
JCPyV is a rare cause of nephropathy in renal transplant recipients and may be due to primary infection
*Merkel cell polyomavirus
An oncogenic virus associated with Merkel cell carcinoma, an aggressive neuroendocrine malignancy of the skin.
*Simian polyomavirus 40
Its possible role in human diseases including cancer has been controversial.
References:
-Jiang M, Abend JR, Johnson SF, Imperiale MJ. The role of polyomaviruses in human disease. Virology. 2009 Feb 20;384(2):266-73. doi: 10.1016/j.virol.2008.09.027. Epub 2008 Nov 7. PMID: 18995875; PMCID: PMC2661150.
-UpToDate.
-Prof. Halawa lecture.
As much as I adore my academic brother Ahmed Halawa, writing that his lecture is a reference is not a complete reply in a scientific write-up.
BK virus associated nephropathy;
Nephropathy is linked to the virus. Immunosuppression severity makes people more susceptible to BKVAN.
The tubular cells are necrosed and lytically destroyed, and the interstitial inflammation is intensified.
Acute cellular rejection and graft loss
Ureteric stenosis
Hemorrhagic cystitis.
Other illnesses brought on by the BK virus include meningoencephalitis, hepatitis, and pneumonia.
Progressive multifocal leuloencephelopathy.
Malignancy like merkel cell carcinoma, RCC, urothelial.
Prof Ahmed Halawa lecturer
J Clin Virol . 2010 April ; 47(4): 306–312. doi:10.1016/j.jcv.2009.12.006.
Clinical Microbiology ReviewsVolume 30, Issue 2, April 2017, Pages 503-528
Uptodate.com/login
Quite a short reply.
As much as I adore my academic brother Ahmed Halawa, writing that his lecture is a reference is not a complete reply in a scientific write-up.
What are the diseases caused by polyoma- viruses in renal transplant recipients?
Polyomavirus: multi-bodies
Small (30 to 45 nm) double-stranded DNA viruses
Immunosuppressed population
Group include:
BK: Nephropathy 5-10%
JC: progressive multifocal leukoencephalopathy
Merkel cell: Merkel cell carcinoma
Diseases caused by polyomaviruses:
BKV associated nephropathy: 5-10%
The definitive diagnosis of BKV-associated nephropathy is made by histologic findings in a kidney allograft biopsy.
Tubular damage with tubulitis and interstitial inflammatory infiltrate may indicate BKV associated nephropathy.
Intra-nuclear homogeneous basophilic viral inclusions without surrounding halo seen on light and electron microscopy may make BKV-associated nephropathy more likely.
Immuno-histochemistry using antibodies against the T Ag of SV40 is used to confirm histological diagnosis.
Ureteric stenosis:
Replication of BKV in uro-epithelium may cause ureteric stenosis due to marked inflammation and ulcerations , after one month post transplantation.
Haemorrahgic cystitis:
Hemorrhagic cystitis is a serious complication that occurs in 25% of recipients of hematopoietic stem cell transplants in children and young adults.
it may be associated with pain, hematuria, and urinary obstruction
BK virus rarely cause haemorrhagic cystitis in kidney transplant, but some studies found BK viriemia in cases with hematopoietic stem cell transplants.
Central nervous system involvement:
The human polyoma virus JC virus (JCV) characterized by focal demyelination in central nervous system==> progressive leukoencephalopathy
References:
2.UpToDate
Thank you
BK virus :
1- asymptomatic viremia
2- ureteral stricture
3- BKVN: tubulo-interstitial nephritis and fibrosis which may end in graft failure.
4- hemorrhagic cystitis.
5- associated with urothelial and nonurothelial malignancies of the urinary tracts and RCCC.
JC (John Cunningham): plyomavirus 2
progressive leukoencephalopathy
Very short answer Mohamed
-What are the diseases caused by polyomaviruses in renal transplant recipients?
In bone marrow transplantation;
Source; Update on the management of BKV infection by Ahmed Saleh et .al
Comme onnnnnnn Ben
Do you have time to answer the question properly?
Yes, prof;
Source; Oxfordhand book of Nephrology 2 edition, BK virus promotrs growth and aggressiveness in bladder cancer byYigang Zeng et .al, Role of BK virus in human cancer byJorge Levican et al.
Diseases caused by polyoma viruses in renal transplant recipients:
Common polyomaviruses known to cause disease in humans are BK virus &JC virus
Diseases caused by the BK virus are:
-BK virus-associated nephropathy and allograft rejection
-Ureteric stenosis or obstruction
-hemorrhagic cystitis
-Associated genitourinary malignancy
Disease caused by the JC virus: primary multifocal leukoencephalopathy
Thank you, Ahmed
Can you expand more, please?
Around 75% of the adult population is latently infected with BK virus. Immunocompetent sub-
jects are usually asymptomatic, but immunocompromised hosts can suffer BK-related complications.
In kidney trans- plant recipients, BK and possibly other polyoma viruses
can cause:
1- Nephropathy
2- Ureteral stenosis.
3- Hemorrhagic cystitis is prevalent in hematopoietic stem cell transplantation (HSCT) patients.
Rare cases of BK disseminated disease (tubulointerstital nephritis, desquamative
pneumonitis, meningoencephalitis, and retinitis) have also been described, especially in patients with acquired immune deficiency syndrome.
References:
1-BK Polyomavirus and the Transplanted Kidney: Immunopathology and Therapeutic Approaches Transplantation November 2016 Volume 100 Number 11
Thank you, Muntasir
What is Merckel cell tumours?
What is Merkel cell tumour:
Merkel cell carcinoma (MCC) is a rare, aggressive form of skin cancer with a high risk for returning (recurring) and spreading (metastasizing), often within two to three years after initial diagnosis.
How rare is it? Approximately 3,000 new cases are diagnosed annually in the U.S. Experts expect that this will increase to 3,250 cases diagnosed annually by 2025.
Merkel cell carcinoma (MCC) is 40 times more rare than melanoma, with an estimated one case per 130,000 people in the U.S.
What causes MCC:
UV rays from sun exposure or artificial light sources like tanning beds cause most types of skin cancer, including Merkel cell carcinoma. UV radiation can damage the genetic makeup, or DNA, of skin cells.
Eight in 10 people with Merkel cell carcinoma have the Merkel cell polyomavirus (MCP). But most people infected with MCP don’t develop Merkel cell carcinoma. This common childhood virus doesn’t cause symptoms, and there isn’t a way to screen for it. Medical experts are still trying to determine how and why the virus causes skin cancer in some people.
Research suggests a weakened immune system may not be able to suppress the virus. As a result, the virus causes skin cells to make a protein that turns off the genes that normally suppress the growth of tumors. What causes Merkel cell carcinoma?UV rays from sun exposure or artificial light sources like tanning beds cause most types of skin cancer, including Merkel cell carcinoma. UV radiation can damage the genetic makeup, or DNA, of skin cells.
Eight in 10 people with Merkel cell carcinoma have the Merkel cell polyomavirus (MCP). But most people infected with MCP don’t develop Merkel cell carcinoma. This common childhood virus doesn’t cause symptoms, and there isn’t a way to screen for it. Medical experts are still trying to determine how and why the virus causes skin cancer in some people.
Research suggests a weakened immune system may not be able to suppress the virus. As a result, the virus causes skin cells to make a protein that turns off the genes that normally suppress the growth of tumors.
What are the risk factors for Merkel cell carcinoma?People of all ages, genders and skin colors can get Merkel cell carcinoma. But men who are fair-skinned and over 50 are most at risk.
Other risk factors include:
References
1-Skin Cancer Foundation by Sandra D’Angelo, MD
Paul Nghiem, MD, PhD Last updated: August 2022
2-American Academy of Dermatology (AAD) Association. Skin Cancer Types: Merkel Cell Carcinoma Overview. (https://www.aad.org/public/diseases/skin-cancer/types/common/merkel-cell) Accessed 4/15/2022.
Three types of polyoma virus that infect humans (JCV, BKV, and SV40),
BKV
polyomavirus-associated nephropathy; interstitial nephritis and graft loss
ureteral ulceration and stenosis, and obstructive uropathy
hemorrhagic cystitis
JC Virus
Infection of the CNS by JC polyomavirus has been observed uncommonly in transplant recipient as PML This infection may present with focal neurologic deficits or seizures as well as more slowly progressive neurologic lesions and may progress to death
following extensive demyelination. PML may be confused with calcineurin neurotoxicity; both may respond to a reduction in drug levels. No proven therapies exist
dementia also reported in few cases
Genitourinary malignancies:
Is it association or causation still unknown (Urothelial carcinoma by BKV Lymphoma by JCV, SV40?)
Thank you, Waleed
Any other malignancies caused by polyomaviruses?
Introduction
Polyoma viruses are ubiquitous non-enveloped double stranded DNA viruses. There are several polyoma viruses but only three have been known to affect humans:
Infections Caused By Polyoma Viruses
Most human polyoma virus disease is caused by BK and JC viruses which are normally acquired in childhood (50-80%). Clinically apparent diseases in the immunocompetent individuals are rare as the immunity keeps the viral replication under control.
JC virus is neurotropic and progressive multifocal leucoencephalopathy which is a demyelinating disease of the CNS
The BK virus is urotheliotropic and remains latent in the urothelium and the tubular cells.
In the transplant patient, the polyoma viruses can be reactivated and can cause disease
BK Virus
BK virus can cause:
JC Virus
The JC virus will cause Progressive Multifocal Leucoencephalopathy
Malignancy and Polyoma Viruses:
There has been postulation that polyoma viruses can cause malignancy but no causal relation has been established
J Clin Virol . 2010 April ; 47(4): 306–312. doi:10.1016/j.jcv.2009.12.006.
Clinical Microbiology ReviewsVolume 30, Issue 2, April 2017, Pages 503-528
Thank you, Dr Hussein
Short and sweet, well done.
What about urological malignancies?
Thank you Professor Halawa
There have been case reports of BK virus causing bladder cancer but it’s difficult to ascertain causality versus Association as most patients have already been exposed to the virus at an early age
I note your supplemental reply, Dr Bagha
In kidney transplant recipients, BK polyomavirus (BKPyV) replication typically develops in stages: viruria followed by viremia and then, if viral replication persists, nephropathy can ensue.
BKPyV-associated nephropathy (BKPyVAN): the majority of cases occur in the first posttransplant year, BKPyVAN can occur years after transplantation.
Without resolution of infection, progressive kidney allograft dysfunction and graft loss can ensue over a period of months. Within the allograft, early infection triggers interstitial inflammation, which then progresses to fibrosis and tubular injury.
Other manifestations — Hemorrhagic cystitis is a rare manifestation of BKPyV infection in kidney transplant recipients but is the most commonly reported manifestation of BKPyV infection among hematopoietic cell transplant recipients.
There is a putative link between BKPyV and the development of genitourinary cancers, largely based upon viral-associated oncogenesis in animal models and the ability of the virus to transform cells in vitro. However, a causal role for BKPyV and human malignancies has not been definitively established.
Reference:
Kidney transplantation in adults: BK polyomavirus-associated nephropathy. UpToDate.
Thank you, Fakhriya
This is not enough.
Polyomaviridae variants
The human BKV belongs to the Polyomaviridae (PyV) virions, a subgroup of papovaviruses comprising BKV, JCV, and simian virus 40 (SV40).
The JC virus will cause Progressive Multifocal Leucoencephalopathy
JCV and SV40 may also be associated with nephropathy, but their clinical course is less severe.
BK virus can cause BK virus-associated nephropathy, Ureteric stenosis, and Haemorrhagic cystitis. Other diseases caused by BK virus include Pneumonitis, Hepatitis, and meningoencephalitis, however, this is usually encountered in immunocompromised non-renal transplant patients, such as HIV patients.
A total of 12 additional human polyomaviruses have been isolated lately between the years 2007 till 2017.
These new group members were termed based on the site of discovery, their geographical areas, the diseases they might cause, or an order of discovery: MWPyV (Malawi); WUPyV (Washington University); KIPyV or Human polyomavirus-3 (Karolinska Institute); STLPyV (Saint Louis polyomavirus or Human polyomavirus-11); MCPyV (Merkel cell carcinoma); TSPyV (trichodysplasia spinulosa); HPyV6, HPyV7, HPyV9, and HPyV12 (human polyomaviruses 6, 7, 9, and 12); New Jersey polyomavirus (NJPyV, also known as polyomavirus-13); and Lyon IARC polyomavirus (LIPyV or human polyomavirus-14).
2.Ureteric stenosis,
3.Hemorahgic cystitis,
4.Central nervous system involvement,
Thank you, Mohamed
Polyomaviruses are
-JC virus [JCV],
-BK virus [BKV],
-Simian virus 40 [SV40])
thes are classified as members of the Polyomavirusgenus.
.Polyomaviruses are non enveloped icosahedral DNA viruses that leads to subclinical or persistent infections in immunocompetent patients with the capacity for reactivation in an immunosuppression state .
JCV remains latent mainly in the kidney, but its reactivation can lead to progressive multifocal leukoencephalopathy.
BKV infection of the kidney and urinary tract, re-activation in immunocompromised host causes BK nephropathy and hemorrhagic cystitis.
Simion Virus SV40 have been reported with occurrence of focal segmental glomerulosclerosis.
–Polyomavirus associated nephropathy:
affects between 1 and 10% of kidney transplant patients . It rarely affects patients other than kidney transplant recipients.
The pathogenesis is characterized by high-level BKV replication in renal-tubular epithelial cells of the transplanted kidney , leading to progressive graft loss
.
– hemorrhagic cystitis :
Mainly diagnosed in HSCT due to bladder mucosal damage caused by cyclophosphamide treatment prior to transplantation this might make the mucosa prone to infection by this polioma Virus
-Ureteric stenosis:
First reported in UK at 1971 in a Sudanese post kidney transplant with ureteric stenosis where BK virus was discovered
– Central nervous system
JC polyomavirus have been associated with progressive multifocal leukoencephalopathy -like disease caused by BK polyomavirus rather than JC polyoma viruse
Genitourinary malignancies:
Is consider as association rather than causation
References:
1 .Prof Ahmed Halawa lecturer
3.© 2013 APMIS. Published by John Wiley & Sons Ltd.
2. .Clinical Infectious Diseases, Volume 35, Issue 9, 1 November 2002,
Thank you, Ahmed
Do not forget the Mercjel cell tumour.
thank you Sir
Merkel cell carcinoma is a rare type of skin cancer that usually appears as a flesh-colored or bluish-red nodule, often on face, head or neck.
Merkel cell carcinoma is also called neuroendocrine carcinoma of the skin.
Merkel cell carcinoma most often develops in older people.
Long-term sun exposure and a weak immune system increases risk of developing Merkel cell carcinoma.
Preventionexposure to sunlight may cause Merkel cell carcinoma,
Reducing sun exposure may reduce risk of skin cancer. Try to:
What are the diseases caused by polyomaviruses in renal transplant recipients?Human polyomavirus is a member of the DNA virus BKPYV and JCPYV were the revalent species. and others species such as simian polyomavirus.
the are many diseases caused by polyomavirus in renal transplant recipients including the following:
1-BK polyomaviruses associated with nephropathy
BK virus results in lifelong infection in renal tubular and uroepithelial cells of most of the world population.
usually present as asymptomatic viremia, viremia, and acute or slowly progressive rise in serum creatinine in the first two to six months postrenal transplantation. allograft infection trigger interstitial inflammation which progresses to fibrosis and tubular injury.
2-heamorrghic cystitis
present as urinary frequency, dysuria, haematuria, urinary clot, and urinary obstruction that may last for several weeks
3-ureteric stenosis
first reported case in a Sudanese postrenal transplant recipient in 1971.
4-progressive multifocal leukoencephalopathy
JCPYV is the most common cause of PML demyelinating disorder that occurs in immunocompromized patient and presents with focal neurological deficits like ataxia,hemiparesis,visual field defect, and cognitive disorder
5-Disseminated infection in which the virus involves all the organs in the immunocommprize patient
References uptodate
Thank you, Manal
What about the Merckel Cell tumour?
Any association with urological malignancies?
thanks, prof Ahmed
Merckle cell carcinoma is a rare type of skin cancer that is more common in individuals with abnormal immune systems resulting from viral infections such as BKV, on the other hand, BKV can cause severe neutropenia or pancytopenia in a kidney transplant recipient
What are the diseases caused by polyomaviruses in renal transplant recipients?
Polyomaviruses (JC virus [JCV], BK virus [BKV], and simian virus 40 [SV40]) are classified as members of the Polyomavirus genus in the family Polyomaviridae. Polyomaviruses are non enveloped icosahedral DNA viruses that have established subclinical and persistent infections in immunocompetent patients with the capacity for reactivation after solid organ transplantation due to immunosuppression .
JCV after primary infection remains latent mainly in the kidney, but its reactivation results in the development of progressive multifocal leukoencephalopathy.
BKV causes infection in the kidney and the urinary tract, and its activation causes a number of disorders, including nephropathy and hemorrhagic cystitis.
The presence of SV40 have been reported by recent studies in the allografts of children who received renal transplants and in the urine, blood, and kidneys of adults with focal segmental glomerulosclerosis.
–Polyomavirus associated nephropathy:
PyVAN affects between 1 and 10% of kidney transplant patients during the first two years post-transplantation. It rarely affects patients other than kidney transplant recipients.
The pathogenesis of PyVAN is characterized by high-level BKPyV replication in renal-tubular epithelial cells of the transplanted kidney , leading to cytopathic loss, subsequent fibrosis and graft loss if left untreated .
– Polyomavirus-associated hemorrhagic cystitis :
It Mainly affects patient who underwent allogeneic stem cell transplant . The bladder mucosa is subclinically damaged by the toxic metabolite of cyclophosphamide which is used as a conditioning protocol prior to stem cell transplant Though polyoma viral hemorrhagic cystitis usually affects allogeneic HSCT patients, there have been some case reports on PyVHC in other immunocompromised patients .
-Ureteric stenosis:
First reported in UK at 1971 in a Sudanese post kidney transplant patient presented with ureteric stenosis where BK virus was discovered and isolated for the first time in PKT patients .
– Central nervous system involvement:
It is mainly related to JC polyomavirus but there have also been case reports suggesting progressive multifocal leukoencephalopathy -like disease caused by BK polyomavirus rather than JC polyoma virus , but no confirmation in tissue has been presented.
Genitourinary malignancies:
Is debatable but is consider as association more than causation
References:
1 .Clinical Infectious Diseases, Volume 35, Issue 9, 1 November 2002, Pages 1081–1087, https://doi.org/10.1086/344060
2. Prof Ahmed Halawa lecturer
3.© 2013 APMIS. Published by John Wiley & Sons Ltd. DOI 10.1111/apm.12134 .
Thank you, Nada
Short and sweet, well done.
Thank you prof Halawa you are more than wellcome .
Introduction
About 14 species of human polyomaviruses have been identified (1). The most common ones that are associated with clinical manifestations are BK polyomavirus (BKPyV) and JC polyomavirus (JCPyV).
Diseases caused by polyomaviruses in the renal transplant recipient
BKPyV-associated nephropathyAssociated
with progressive allograft dysfunction and resulted in allograft loss.Histological features from minimal tubulointerstitial nephritis till tubular atrophy in late BKV nephropathy.Ureteral stricture
Haemorrhagic cystitis
Common in haemopoietic stem cell transplant (2).Progressive multifocal leukoencephalopathy
Commonly is related to JCPyVMalignacy related
Merkel cell carcinoma (3)Bladder cancer (4)
References
Wu Z, Graf FE, Hirsch HH. Antivirals against human polyomaviruses: Leaving no stone unturned. Rev Med Virol 2021: e2220.Imperiale MJ. The human polyomaviruses: an overview. In: Khalili K, Stoner GL, eds. Human Polyomaviruses: Wiley; 2001:53-71.https://doi.org/10.3390/dermato3010003Curr Opin Virol. 2019 Dec; 39: 8–15.
Thank you, Maisarah
Short and sweet, well done.
Clinical presentation of BK virus
BK virus can cause graft loss by the following mechanisms:
References
1. Cavallo R, Costa C, Bergallo M, Messina M, Mazzucco G, Segoloni GP. A case of ureteral lesions in a renal transplant recipient with a co-infection of BK virus and JC virus. Nephrol Dial Transplant 2007;22:1275. Back to cited text no. 2
2. Rajpoot DK, Gomez A, Tsang W, Shanberg A. Ureteric and urethral stenosis: A complication of BK virus infection in a pediatric renal transplant patient. Pediatr Transplant 2007;11:433-5. Back to cited text no.
3. Hwang YY, Sim J, Leung AY, Lie AK, Kwong YL. BK virus-associated bilateral ureteric stenosis after haematopoietic SCT: Viral kinetics and successful treatment. Bone Marrow Transplant 2013;48:745-6. Back to cited text no. 4
4. Khan H, Oberoi S, Mahvash A, Sharma M, Rondon G, Alousi A, et al. Reversible ureteral obstruction due to polyomavirus infection after percutaneous nephrostomy catheter placement. Biol Blood Marrow Transplant 2011;17:1551-5. Back to cited text no. 5
5. McGilvray ID, Lajoie G, Humar A, Cattral MS. Polyomavirus infection and acute vascular rejection in a kidney allograft: Coincidence or mimicry? Am J Transplant 2003;3:501-4. Back to cited text no. 6
6. Ito Y, Nishi S, Imai N, Yoshita K, Saito K, Nakagawa Y, et al. The case of BK virus infection in which it was difficult to differentiate from acute rejection. Clin Transplant 2011;25 Suppl 23:44-8. Back to cited text no. 7
Thank you, Sherif
You mentioned haemorrhagic cystitis. Does it happen in kidney transplant patients?
What are the other diseases caused by polyomaviruses?
You mentioned haemorrhagic cystitis. Does it happen in kidney transplant patients?
– Hemorrhagic cystitis is rarely seen in renal transplant recipients it is commonly seen in hematopoietic stem cell-transplant (HSCT)
– Hemorrhagic cystitis can be seen as a complication of some drugs used in the treatment of glomerulonephritis such as cyclophosphamide
– Hemorrhagic cystitis associated with HSCT is multifactorial occurring either :
Preengraftment occurring due to due to drug toxicity that cause severe inflammation of urinary bladder mucosa(eg, cyclophosphamide, ifosfamide, busulfan) (1, 2) or due to total body irradiationPostengraftment occurring due to BK polyomavirus or adenovirus.
What are the other diseases caused by polyomaviruses?
– Human polyomaviruses (HPyVs) are small, double-stranded, non-enveloped DNA viruses
– More than 13 types exist, the most common and important types that are involved in diseases in immunocompromised patients are :
JC polyomavirus (JCPyV) that can cause progressive multifocal leukoencephalopathy (PML) in immunosuppressed patients including those with HIV and hematologic malignanciesBK polyomavirus (BKPyV) is associated with BK nephropathy in renal transplant recipients and hemorrhagic cystitis in hematopoietic cell transplantation recipientsMerkel cell polyomavirus (MCPyV), which is associated with Merkel cell carcinomaTrichodysplasia spinulosa polyomavirus (TSPyV) which is associated with trichodysplasia spinulosa, a rare skin disease characterized by spiculae and alopecia in immunosupressed patientsReferences
1. Zaia J, Baden L, Boeckh MJ, et al. Viral disease prevention after hematopoietic cell transplantation. Bone Marrow Transplant 2009; 44:471.
2. Bedi A, Miller CB, Hanson JL, et al. Association of BK virus with failure of prophylaxis against hemorrhagic cystitis following bone marrow transplantation. J Clin Oncol 1995; 13:1103.
You mentioned haemorrhagic cystitis. Does it happen in kidney transplant patients?
– Hemorrhagic cystitis is rarely seen in renal transplant recipients it is commonly seen in hematopoietic stem cell-transplant (HSCT)
– Hemorrhagic cystitis can be seen as a complication of some drugs used in the treatment of glomerulonephritis such as cyclophosphamide
– Hemorrhagic cystitis associated with HSCT is multifactorial occurring either :
What are the other diseases caused by polyomaviruses?
– Human polyomaviruses (HPyVs) are small, double-stranded, non-enveloped DNA viruses
– More than 13 types exist, the most common and important types that are involved in diseases in immunocompromised patients are :
References
1. Zaia J, Baden L, Boeckh MJ, et al. Viral disease prevention after hematopoietic cell transplantation. Bone Marrow Transplant 2009; 44:471.
2. Bedi A, Miller CB, Hanson JL, et al. Association of BK virus with failure of prophylaxis against hemorrhagic cystitis following bone marrow transplantation. J Clin Oncol 1995; 13:1103.
I note your supplemental reply, Dr Yusuf
1. What are the diseases caused by polyomaviruses in renal transplant recipients?
BK virus can cause:-
PVN: Mode of kidney injury and dysfunctionVirally induced acute tubular injury (ATN)
Focal:no/mild renal dysfunction
Diffuse:pronounced renal dysfunction
Early ATN:reversible changes (possible restitutio ad integrum)
Chronic ATN:irreversible changes (fibrosis, tubular atrophy)
Neurotropic JC virus:_
Merkel cell carcinoma
Other
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Reference:
Thank you, Mahmoud
You mentioned haemorrhagic cystitis. Dose it happen in kidney transplant patients?
Thanks alot Prof.Halawa
=======================================================
Reference
I note your supplemental reply, Dr wadi.
Many thanks Prof.Sharma
What are the diseases caused by polyomaviruses in renal transplant recipients?
Polyomavirus-associated nephropathy (PVAN) is a growing illness in renal transplant patients with an incidence of 1–10% and graft loss of up to 80%. BK virus (BKV) is the main cause,
However, the JC virus (JCV) and potentially the simian virus SV40 may be involved. Merkel cell polyomavirus and TS polyomavirus are two other polyomaviruses.
Renal transplant Pathology:
However, renal transplants preferentially manifest compared to other allografts or autologous kidneys from other organ transplants, suggesting that organ determinants and immunologic variables synergize. Renal tubular epithelial cells and their compensatory proliferation to restore tubular integrity after immunologic, ischemic, or toxic injury may provide the key cellular environment for polyomavirus replication while immune control is weakened by maintenance immunosuppression.
Risk Factors:
The severity of immunosuppressive therapy, anti-rejection treatment, and HLA-mismatches. Older age, male gender, seronegative recipient, and viral variables (genotype, serotype) may contribute.
Diagnosis
PVAN is diagnosed by allograft biopsy, which is complicated by I limited sensitivity due to (multi-)focal involvement (sampling errors); ii) varying presentations with cytopathic-inflammatory and/or fibrotic/scarring patterns; and iii) coexisting acute rejection, which is difficult to distinguish but affects intervention strategies. High-sensitivity urine and plasma polyomavirus screening complements allograft biopsy and provides noninvasive monitoring.
Manifestations of BK in kidney transplantation: BKV Nephropathy, Hemorrhagic cystitis, Non-Hemorrhagic cystitis, Ureteric stricture,and Allograft rejection
Reference :
Hirsch, H. H., Brennan, D. C., Drachenberg, C. B., Ginevri, F., Gordon, J., Limaye, A. P., … & Trofe, J. (2005). Polyomavirus-associated nephropathy in renal transplantation: interdisciplinary analyses and recommendations Transplantation, 79 (10), 1277–1286.
Thank you, Weam
Excellent, but NOT a focused answer. Are there other diseases caused by polyomaviruses affecting transplant patients?
BK virus (BKV) and JC virus (JCV) cause interstitial nephritis in 5% of renal transplant recipients, and up to 45% of the affected patients may develop allograft failure.
Also, polymerase chain reaction assays and other molecular biology studies, which were derived from polyomavirus simian virus 40 (SV40), serve as useful adjunctive diagnostic tools. However, the homology between the two human polyomaviruses (JCV and BKV) and SV40 is approximately 70%.
Merkel cell carcinoma also described.
Diseases caused by polyomaviruses in renal transplant recipients
BK polyomavirus (BKPyV) is a small DNA virus that Following primary infection, the virus establishes lifelong infection in renal tubular and uroepithelial cells. However, in immunocompromised patients,reactivation of latent infection or transmission of new infection via the donor kidney can lead to viruria, viremia, or allograft nephropathy. Viral replication most commonly occurs during the first year after transplantation when cellular immunity is most suppressed. Viruria and viremia are detected in approximately 25 to 30 and 12 percent of kidney transplant recipients, respectively.Intense immunosuppression is the most important risk factor.However,Patient determinants (older age, male gender, seronegative recipient), and viral factors (genotype, serotype) may have a contributory role.
The definitive diagnosis of PVAN requires allograft biopsy with some challenges:
i) limited sensitivity due to multi-focal involvement with sampling errors.
ii) varying PVAN presentations with cytopathic-inflammatory or fibrotic/scarring patterns.
iii) coexisting acute rejection which is difficult to differentiate, but will impacts on management strategies.
Risk factors for viral replication:
-The intensity of immunosuppression (particularly suppression of cellular immunity)
-High risk serostatus (ie, kidney transplant from a BKPyV-seropositive donor to a seronegative recipient)
-older age, ureteral stent placement, ABO incompatibility , rejection or ischemia of the transplanted kidney , delayed graft function, HLA mismatch , specific HLA-C alleles, BKPyV polymorphisms, and transplantation from an HCV-positive donor.
-Decreased risk of BKPyVAN:
-Recipient HLA-B51 positivity was associated with an approximate fivefold reduction in BKPyVAN.
-Polycystic kidney disease has been associated with a lower risk of BKPyVAN.
BKPyV-associated nephropathy (BKPyVAN) :
Asymptomatic viruria, viremia, and/or a slow progressive rise in serum creatinine are typically the only indicators of BKPyVAN. The incidence of BKPyVAN is highest in the first two to six months posttransplant.BKPyVAN can occur years after transplantation.
Without resolution of infection, progressive kidney allograft dysfunction and graft loss can occur over a period of months.Within the allograft, early infection triggers interstitial inflammation, which then progresses to fibrosis and tubular injury.
-Hemorrhagic cystitis is a rare manifestation of BKPyV infection in kidney transplant recipients but is the most commonly reported manifestation of BKPyV infection among hematopoietic cell transplant recipients.
-There is an important link between BKPyV and the development of genitourinary cancers, based upon viral-associated oncogenesis in animal models and the ability of the virus to transform cells in vitro.
-JC virus (JCV) and possibly simian virus SV40 may account for some cases of BK polyomavirus (BKPyV) associated nephropathy.
References:
Knowles WA, Pipkin P, Andrews N, et al. Population-based study of antibody to the human polyomaviruses BKV and JCV and the simian polyomavirus SV40. J Med Virol 2003; 71:115.
Helle F, Brochot E, Handala L, et al. Biology of the BKPyV: An Update. Viruses 2017; 9.
Thangaraju S, Gill J, Wright A, et al. Risk Factors for BK Polyoma Virus Treatment and Association of Treatment With Kidney Transplant Failure: Insights From a Paired Kidney Analysis. Transplantation 2016; 100:854.
Thank you, Mohamed
Excellent, but NOT a focused answer. Are there other diseases caused by polyomaviruses affecting transplant patients?
What are the diseases caused by polyomaviruses in renal transplant recipients?
Polyomaviruses are a group of non-enveloped DNA viruses and more than 14 species have been known. However, BK and JC virus are the ones which causes disease in renal transplant recipients.
BK VIRUS; Hemorrhagic cystitis
BK virus Nephropathy
Ureteric stenosis or stricture
Allograft rejection and genitourinary malignancy(rare)
JC virus: cause polyomavirus associated nephropathy (PyVAN) and rarely progressive multifocal leukoencephalopathy
REFERENCES:
1- Lecture by Dr . Ahmed Halawa- BK in Kidney Transplantation.
2- Handbook of kidney Transplantation.
3- Delbue S, Ferraresso M, Ghio L, Carloni C, Carluccio S, Belingheri M, Edefonti A, Ferrante P. A review on JC virus infection in kidney transplant recipients. Clin Dev Immunol. 2013;2013:926391
Thank you Batool
What are the other polyoma viruses that can infect renal transplant recipients?
Polyomaviruses exist in the environment and contact with seropositivity usually starts at a young age. There are reports of 14 species with the possibility of infection in humans, but only three with repercussions to be considered for discussion.
In all three situations, the patient’s immunity must be severely compromised, either due to neoplasia, the HIV virus with CD4 cell counts below 10, or solid organ transplantation (mainly kidney and lung) with significant immunosuppression (induction with rATG, high doses of corticosteroids, tacrolimus, and mycophenolate).
Interestingly, the names of the viruses are the initials of the first patients affected and diagnosed with this pathology)
1. BK virus
– Latency in renal tubules and endothelium
– Reactivation in case of severe immunosuppression
– More common in kidney transplantation
– Inflammation, tubular atrophy, interstitial disease, atrophy
2. James Cunningham Virus
– Progressive multifocal leukoencephalopathy
– Reactivation in case of severe immunosuppression
– More common in HIV carriers with AIDS and CD4 with less than 10 cells
– Lesions in the white matter of the CNS with impaired movement and cognition
3. Merckel cell virus
– Associated with the neoplasm of the same name
– Immunosuppression and presumed oncogenicity
Polyomaviruses are small,nonenveloped , double stranded DNA viruses that infected a variety of organs.
Polyomaviruses are highly seroprevalent in humans but only cause clinical disease among immunocompromised patients.
Multi human subtypes have been identified.
BK virus and JC virus are the most common and the only tow associated with nephropathy.(BKVN).
Patient with BKVN present with an asymptomatic acute or slow progressive rise in serum creatinine concentration.
Urinalysis may reveal pyuria, hematuria,cellular cast and inflammatory cells.
Urine cytologic examination may reveal BK-infected cells called decoy cells.
The most common injury is tubulo interstial nephritis.
Acute kidney injury .
Acute allograft rejection.
Renal malignancy.
Most immunocompetent individuals with polyomaviruses infections have a subclinical or non-specific influenza-like symptoms, however some subtypes can cause specific syndrome.
The most commonn pathogenic subtypes are the following :
1-BK polyomavirus :
This can cause nephropathy and less commonly,uretric stenosis.
BKVyV :this subtype can cause hemorrhagic cystitis.
2- JC polyomavirus :
This subtype can cause progressive multifocal leukoencephalopathy and hematologic malignancies and nephropathy.
3-Merkel cell polyomavirus :
It is associated with merkel cell carcinoma in sun-exposure skin of older adults who have recevied long-standing immunosuppression.
lymphadenopathy and tonsillitis are noticed in children .
4- KI and WU viruses:
These subtypes are associated with respiratory tract disease .
5-Human polyomavirus:
It is associated with pruritic rash and viremia in lung transplant recipients.
6-TS polyomavirus:
This subtype causes trichodysplasia spinulosa ,a rare skin rash .
Other rare manifestations are :
Vascluopathy .
Retinitis.
Hepatitis.
Guillain-Barre.
Malignancy.
Refference:
Uptodate .
Thank you
2. Pattern B:
3. Pattern C:
4.Humoral immunity is less important:
Thank you Dr Mohamed
This is a comprehensive answer, but YOU DID NOT ANSWER THE QUESTION. Please review the question and answer accordingly. You need to provide a focused answer.
Thank you, dear Prof.,
Diseases caused by BK polyoma virus:
Diseases caused by JC polyoma virus:
I note your supplemental reply, Dr Mohamed.
Human polyomaviruses — Human polyomaviruses (HPyVs) are DNA viruses belonging to the family Polyomaviridae. Fourteen HPyV species have been identified.
BKPyV and JCPyV are common clinically relevant species in immunocompromised patients.
The majority of infections are benign and quiet. BKPyV can reactivate in immunocompromised patients and in certain cases cause BKPyV-associated nephropathy (BKPyVAN).
I agree
Diseases caused by Polyomaviruses in renal transplants;
Human polyomaviruses are member of DNA viruses in polyomaviridae family. Of fourteen species identified, two viruses are commonly causing disease in immunocompromised patients.
Other polyomaviruses have been associated with human disease but their casual role is unclear
Reference UpToDate Topic 8280 Version 12.0 2023.
What are the diseases caused by polyomaviruses in renal transplant recipients?
Polyoma viruses are group of viruses that lead to cell enlargement due to inclusion bodies (tumor like cells).
There are many viruses discovered by time but the most common types affect post kidney transplant recipient are BK polyomavirus (BKPyV) and JC polyomavirus (JCPyV).
1-BK virus lead to :
Hemorrhagic cystitis.
Proximal ureteric stricture.
BK induce nephropathy.
Disseminated BKPyV infection.
2-JCPyV.
Progressive multifocal leukoencephalopathy.
Central nervous system demyelination(associated with high incidence of mortality).
3–MERKEL CELL CARCINOMA.
a rare tumor of neuroendocrine origin that usually presents as a red or red-blue papule or nodule in a sun-exposed area which caused by Merkel cell polyomavirus infection.
References:
1-Epidemiology and risk factors for skin cancer in solid organ transplant recipients, Up To Date, 2023.
2-Garrett GL, Blanc PD, Boscardin J, et al. Incidence of and Risk Factors for Skin Cancer in Organ Transplant Recipients in the United States [published correction appears in JAMA Dermatol. 2017 Mar 1;153(3):357]. JAMA Dermatol. 2017;153(3):296-303. doi:10.1001/jamadermatol.2016.4920.
I like reading your response, dear Dr Saad.
Thanks a lot professor Sharma.
I do appreciate .
What are the diseases caused by polyomaviruses in renal transplant recipients?
Polyomavirus is a small about 30-45nm, icosahedral, nonenveloped, double-stranded, closed circular DNA virus.
The common polyomavirus known to cause disease in humans are:
Both are named after the initials of the patient that first diagnosed with the virus
Other types of polyomavirus are:
Diseases caused by the BK virus are:
Disease caused by the JC virus:
References
I agree
References:
What do you mean by ‘increased risk of invasive urinary bladder’?
Polyoma virus not a cause of urinary bladder cancer, but it was found that infection of polyoma virus increase the aggressiveness of cancer.
I understand you point now, dear Dr Noaman.