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3. A 47-year-old man had a successful second renal transplant 15 months ago, 022 mismatch, no DSA and negative FAXM. His creatinine has risen from 143 µmol/L to 215 µmol/L. USS is shown below (left). Antegrade nephrostogram was performed (right). He is currently on Tacrolimus (trough 8.8 ng/ml), MMF 750 bd and prednisolone 5 mg od. There is BK viraemia (plasma PCR 5.5 log 10).
- How do you manage this case?
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Obstructive uropathy most likely caused by BKV ureteric stenosis
Management:percutaneous nephrostomy , antegrade stenting decrease MMF dose or stop and decrease dose of tacrolimus
Dx is BKV associated ureteral stenosis.
Management : urinary diversion by percutaneous nephrostomy or antegrade Stenting. Also reduce the dose of MMF by 50% & reduce the dose of TAC…if no improvement of BK viral load then completely stop MMF & change the TAC to cyclosporine.
How do you manage this case?
The likely diagnosis is BK-associated ureteric stenosis leading to obstructive uropathy. The management is as follows:
The patient is a post renal transplant recipient after his second transplant ….there is an increase in the creatinine and USG shows hydronephrosis of the graft…..There is significant BK viremia…the most likely diagnosis is BK virus causing obstructive uropathy and allograft dysfunction….Antegrade nephrostogram has been done and it demonstrates stricture of the ureter….
The first step is to see if the stenting clears the azotaemia after the obstruction….The antgrade stent can be kept in place for a month and see if it heals the stricture and trial removal of the stent can be attmepted after a month…if there is recurrence of the stricture after removal of the stent we need to consider revision procedure that is ureteroneocystostomy…long term antegrade stents is another option..
simultaneous reduction in immunosuppression should be done…
first step is to reduce the antimetabolite to 50% and re check Plasma BK virus PCR…if there is no redcution in 2 weeks complete stopping of anti metabolite is recommended ….if there is no further reduction in BK virus PCR we have to change Tac to CYC ….Other adjucntive therapies can be added if all other measure fail and can be added as a trial basis with no major evidence in anyone of them
This case imaging reveals marked hydronephrosis in ultrasound and ureteric stenosis in antegrade nephrostogram due to BK infection.
Management options include reduction of immunosuppression, other agents can be tried as IVIG, leflunamide, quinolones, cidofovir yet their effect is still doubtful.
Surgical interventions based on expert urological opinion to perform urinary diversion by percutaneous nephrostomy insertion.
Then temporary antegrade ureteric stent placement follow after improvement of renal function.
Cases with recurrence of ureteric stenosis, surgical revision or long-term ureteric stenting is recommended.
Surgical management is the last option in case of failure of the previous lines of treatment. Ureteroneocystostomy with excision of the stenotic segment and reimplantation is the definitive treatment policy in this case.
-This highly sensitized 2nd transplant male suffers from BKV infection evidenced by the +ve PCR .
-MDT approach is needed for graft salvage including
.Reduction of IS starting with the antimetabolites by 50% , and may be even stopped completely and FK trough levels targeted less .
.Hand in hand with Uro-surgical intervention either percutaneous nephrostomy or DJ insertion for the evident ureteric stenosis caused by the virus with follow up .
-Treatment of this case is both medical and surgical without delay .
● This is a case for intensive Immunocompromised renal recipient who complained 50 % decreased graft function with hydronephrosis in ultrasound and ureter stenosis in antegrade nephrostogram which mostly resulted from BK infection so
● The case belongs ureter stenosis as a complication to BKV infection
● Ureteral stenosis is the most common urological complication following kidney transplantation is which occurred in 2–10%
of patients receiving kidney transplantation
● Almost 70% of ureteral obstructions following kidney transplantation were observed within 3 months .
● BK virus is known to cause severe renal dysfunction, ureteric stenosis, and hemorrhagic cystitis in renal transplant patients.
● 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.
● The other factors may cause ureter stenosis include : technical error and external compression (hematoma, lymphocele, abscess, kinking redundant ureter, ureteral stone, anastomotic edema, and ureteral ischemia .
● Management by urinary diversion by percutaneous nephrostomy insertion.
● Retrograde stent insertion may be used, but it is technically challenging.
● Once renal function has improved a percutaneous balloon dilatation if technically feasible, followed by temporary antegrade ureteric stent placement.
● If the stenosis recurs after stent removal, surgical revision or long-term ureteric stenting is advocated
● Surgical management is indicated if minimally invasive procedures fail . It include ureteroneocystostomy with excision of the stenotic segment and reimplantation.
☆ S Kumar, Ameli-Renani, A Hakim , J H Jeon, S Shrivastava, U Patel. Ureteral obstruction following renal transplantation: causes, diagnosis and management. Radiol . December 2014; 87(1044): 20140169
☆ Gampo A. Irdam,Bobby Sutojo,and Putu A. R. Raharja . Risk Factors of Ureteral Stenosis in Kidney Transplant Recipients: A Retrospective Study in National Referral Hospital in Indonesia . Hindawi . Advances in Urology . Volume 2021, Article ID 2410951, 4 pages.
☆ B. F. Schwartz, J. R. Chatham, P. Bretan, R. Goharderakhshan, and M. L. Stoller, “Treatment of refractory kidney transplant ureteral strictures using balloon cautery endoureterotomy,” Urology, vol. 58, no. 4, pp. 536–539, 2001.
How do you manage this case?
· Decrease antimetabolites by 50%, and reduce Tacrolimus to keep the trough level between 4-6 ng/ml.
· If no decrease in BK viral load within 2-4 weeks, completely stop MMF.
· A switch from Tacrolimus to cyclosporine may be also done if no decrease in viral load (keep trough level between 50-75 mcg/L).
· After BK viremia resolve, increase immunosuppression dose to previous levels to prevent rejection episodes.
References:
1. Sawinski D, Trofe-Clark J. BK Virus Nephropathy. Clin J Am Soc Nephrol. 2018 Dec 7; 13(12):1893-1896. 7)
2. Mallat SG et al. CMV and BKPyV Infections in Renal Transplant Recipients Receiving an mTOR Inhibitor-Based Regimen Versus a CNI-Based Regimen: A Systematic Review and Meta-Analysis of Randomized, Controlled Trials. Clin J Am Soc Nephrol. 2017 Aug 7; 12(8):1321-1336.
3. Saleh A, El Din Khedr MS, Ezzat A, Takou A, Halawa A. Update on the Management of BK Virus Infection. Exp Clin Transplant. 2020 Nov; 18(6):659-670.
4. Kumar S, Ameli-Renani S, Hakim A, Jeon JH, Shrivastava S, Patel U. Ureteral obstruction following renal transplantation: causes, diagnosis and management. Br J Radiol. 2014 Dec; 87(1044):20140169.
Diagnosis of the above case is likely ureteric stenosis due to BK virus as is evident by the dilatation of pelvicalyceal system with no dye in bladder indicating obstruction at the distal third of ureter on antegrade nephrostogram and history of second transplant with intensive immunosuppression and high viral load of BK virus with plasma PCR 5.5 log 10 (i.e > 4.4 log 10)
suboptimal HLA match
Management
First step in the management will be to go for decompression via percutaneous nephrostomy with double-J stenting to relive the pressure and avoid permanent damage to the graft. Then, definitive treatment includes various options : placement of antegrade stent sometimes if possible ,otherwise ureteroneocystostomy with excision of the stenotic segment and reimplantation can be offered in few cases. In the meantime, also reduce MMF to half dose as viral load > 1000 copies/ml –if no response then will stop MMF followed by reduction of steroids and tacrolimus to maintain trough level-5-7ng/ml with close monitoring of graft function. Sometimes switch of tacrolimus to mTORi can also be considered.
REFERENCES:
1-Hirsch HH, Randhawa P; AST Infectious Diseases Community of Practice. BK polyomavirus in solid organ transplantation. Am J Transplant. 2013 Mar;13 Suppl 4:179-88.
2-Kumar S, Ameli-Renani S, Hakim A, Jeon JH, Shrivastava S, Patel U. Ureteral obstruction following renal transplantation: causes, diagnosis and management. Br J Radiol. 2014 Dec;87(1044):20140169. doi: 10.1259/bjr.20140169. Epub 2014 Oct 6. PMID: 25284426; PMCID: PMC4243200
Obstructive uropathy associated with ureteral stenosis in addition to positive BKPCR in blood shows BK virus infection. Management includes the reduction of immunosuppression. Stop MMF, if no response does not appear and switch to mTOR inhibitor. Decrease the dose of tacrolimus to a trough level of 4-6 ng/ml. Treatment with IVIG or leflunomide may be tiring but they have no definite effect. To relieve stenosis, urologic consultation, and DJ stent are necessary as well.
Reference:
Geetha V, Rao L, Monappa V, Susmitha M, Prabhu R. Decoy cells in urine cytology: A useful clue to post-transplant polyoma virus infection. J Cytol. 2012 Apr;29(2):133-4. doi: 10.4103/0970-9371.97157.
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.
Here Usg and Antegrade nephrostogram shows obstructive uropathy along with ureteric stenosis,.Since the stenosis developed more than 1 year of transplantation, it is less likely to be due to surgical factors.It is most likely due to Bk virus as BK viremia is also present. If there is concurrent rejection,it may also cause ureteric stenosis.
Managment-Surgical consulation for ureteric stensosis and plan of procedure -DJ stenting.Along with surgery to relieve pressure,we should reduce the dose of the antimetabolite by 50 percent. If the BKPyV viral load does not decrease within two to four weeks, we completely discontinue the antimetabolite. If there is still no decrease in viral load after another two weeks, we decrease the dose of the calcineurin inhibitor by 25 to 50 percent, targeting a whole blood tacrolimus trough level of 4 to 6 ng/mL or a whole blood cyclosporine trough level of 60 to 100 ng/mL.
This patient is a high immunological risk patient with 022 mismatch on CNI, MMF and steroids
Presented with AKI and marked hydronephrosis suggesting ureteric stricture may by due to BK viremia, other infections or stones or ureteral ischemia
DD on top is BK virus stricture
Management of this case 1st to relieve the back pressure with nephrostomy
Then
A step wise approach
Exclude the evidence of rejection, other wise treat rejection first
Then reduce MMF to 50 %
Reduction of dose of CNI with trough level 4-6 ng per ml
Stop MMF
Change Tacrolimus to CNI
Adjuvant therapy : IVIG, leflunomide, fluoroquinolones
Plus Surgical management of the ureteric stricture/ stenosis
With monitor of BK levels every 2 weeks
Once BK virus is cleared, return back to usual immunosuppression to avoid rejection
· How do you manage this case?
Typical presentation of BK ureteric stricture that requires MDT among nephrologist, urologist , transplant surgeon and interventional radiologist.
Release of obstruction by either transplant nephrostomy of insertion of JJ stent in the transplant ureter.
Reduction of immunosuppression: stop MMF, aim lower therapeutic trough level of tacrolimus.
No single agent was deemed effective against BKV.
CONTINOUS REGULAR FOLLOW-UP.
Management of the case
Management of Stricture
Management of BK viremia
most likely urestric stricture due to BK virus
likely to be ureteric stricture post BKV infection
reduction of IS is mainstay
antegrade DJ stenting for ureteric stricture through nephrostomy can be tried to make recipient tube free
chang MMF to mTOR
decrease TAC trough level to 5
moniter the viral load
Managemnt of this case
1- Decrease dose of IS , tacrolimus by 25-50%,MMF by 50% .
2- Monitoring of graft function , if no improvement , switch MMF to m TOR
3- Adjuvant therapy include
– Cidofovir
– Ciprofloxacin
– Leflunamide
– IVIG
USS- Gross hydronephrosis
Antegrade nephrogram- Ureteric stenosis
– Urological consultation for intervention
– Reduction of immunosuppression
a) Lower dose of tacrolimus (25-50%)
b) Lower dose of MMF (50%)
– Adjuvant drug ( Leflunomide, cidofovir, quinolone)
Ureteral stenosis due to BK virus.
Management:
Urological intervention: DJ stenting with antibiotic cover. Stent should be kept for 6-8 weeks.
BK virus:
Reduction of immunosuppression.
Tacrolimus to cyclosporin switch or CNI to mTOR switch
Stopping MMF/AZA
CNI levels
Monitoring for rejection
Antiviral agents:
May consider adjunctive antiviral agents in BKV-associated disease refractory to reduction or manipulation of immunosuppression although benefit is unclear.
How do you manage this case:
Management:
Other adjunctive therapies
· IVIG.
· Quinolones.
· Cidofovir.
· Leflunomide.
Urgent urological intervention:
· Percutaneous nephrostomy.
· Stenting if possible via retrograde route.
· Open intervention (re-implantation, native ureter or vesico-pelvic anastomosis)
References:
Kant, S.; Dasgupta, A.; Bagnasco, S.; Brennan, D.C. BK Virus Nephropathy in Kidney Transplantation: A State-of-the-Art Review. Viruses 2022, 14, 1616. https://doi.org/10.3390/v14081616
Background
Recipient of second transplant recipient – must have received induction + heavy immunosuppression
15months post-transplant presented with graft dysfunction, hydronephrosis, lower ureter stricture associated with BKV viremia
· Graft dysfunction could be mainly due to BKV nephropathy
· Obstructive Uropathy might have some effect, as mild to moderate hydronephrosis (renal parenchyma is preserved), which should have been relieved after the nephrostomy drainage, with decrease serum creatinine to near baseline level.
Cause of stricture –
Urine BKV PCR could supplement to diagnosis
definitive diagnosis be made from Renal Allograft Biopsy and ureter stricture excision biopsy (if surgery / reimplantation done)
1. Surgical management for the lower ureter stricture –
antegrade balloon dilatation of the stricture with DJ stent placement
– stent to be kept for 6-8 weeks with appropriate antibiotic cover
– chances of recurrence high
Recurrence of stricture or persistent obstruction after stent removal following complete BKV medical management, would require ureteric reimplantation.
2. Medical management of BKV
– MMF should be reduced to 500mg total daily dose, with reduction of Tacrolimus, targeting C0 levels 4-5ng/ml.
– If no improvement by 4 weeks – to stop MMF, which can be resumed after viremia clearance
– Prednisone should be maintained at 5mg to prevent acute rejection, but may be reduced to 2.5mg daily or 5mg alternate day if BKV viremia still persists.
· Monitoring creatinine to look for any deterioration due to Rejection
· Monitoring plasma BKV PCR every 2 weeks, till it falls below threshold / undetectable
– Persistent viremia beyond 6-8 weeks: IVIg or other adjunctive treatment may be administered
References:
· Ahmed Saleh, Mohamed Salah El Din Khedr, Ahmed Halawa, et al. Update on the Management of BK Virus Infection. Exp Clin Transplant 2020 Nov;18(6):659-670
· Praveen K Etta, Madhavi T, Swarnalata G. 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 Transplantation 2020; (14); 147-51.
· Kumar S, Ameli-Renani S, Hakim A, et al. Ureteral obstruction following renal transplantation: causes, diagnosis and management. Br J Radiol 2014; 87:1044
This 47 year old S/P second transplantation presented with AKI , hydroureteronephrosis on renal U/S and on Antegrade nephrostogram there is distal uretric stenosis the cause of this stenosis could be ischemic stricture or secondary to PKV infection
This scenario goes with PKV infection due
1- second transplantation with 0 2 2 MM , so surely this patient receive ATG as induction therapy
2- He is on tac , MMF combination with relatively high tac level ( recommended level in the second year of transplantation is 6 – 8 )
3- There is BK viraemia (plasma PCR 5.5 log 10)
The definite diagnosis of BKVN requires characteristic cytopathic changes on the renal biopsy plus positive immunohistochemistry (against BKV or against SV40 large T antigens), which has a specificity of 100%, and pathognomonic results for BKV infection or we can rely on a presumptive diagnosis if there is sustained (more than 2-week duration) urinary viral shedding and significant BKV replication (plasma DNA PCR load > 10 000 copies/mL) , So in this patient we have to do urinary BKV PCR and Decoy cell for confirmation of diagnosis .
Management divided in two lines the surgical management of obstruction and management of BKV infection
1- Lower the dose of tacrolimus by 25-50 %
2- lower the dose of prednisilone
3- lower the dose of MMF by 50 %
4- consider changing of MMF to mTOR inhibitor ( may have some benefits )
5- Follow up blood PCR should be done every 2-4 weeks until the viral load fall below the threshold value and preferably to undetected level
6- Close follow up of kidney function looking for any evidence of rejection
7- Some adjuvent treatment such as cidofovir , IVIG , leflonomide and Quinolones still controversial no enough RCT supporting this medication usage .
antegrade balloon dilatation of the stricture and antegrade placement of DJ stent.
If this conservative management along with BKV medical management doesn’t treat the stricture, then he would require ureteric reimplantation.
References :
1) Update on the Management of BK Virus Infection Ahmed Saleh,1,4,5 Mohamed Salah El Din Khedr,1 Abeer Ezzat,2 Anna Takou,3 Ahmed Halaw
This second transplant recipient has lower ureteric stricture post 15 months of his transplant.
This could be secondary to
To confirm if the stricture is due to BK virus, we need to perform BK virus PCR in urine as plasma BK virus levels are high.
The increase in the creatinine of this patient could be due to
The management of this patient would be
Surgical management:
The antegrade nephrostogram is suggestive of lower ureteric stricture, we can perform antegrade balloon dilatation of the stricture and antegrade placement of DJ stent.
If this conservative management along with BKV medical management doesn’t treat the stricture, then he would require ureteric reimplantation.
Medical management of BKV:
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.
· How do you manage this case?
· This is a ultrasound KUB and retrograde cyctourethrography showing moderate hydronephrosis and some loss of cupping secondary to distal uretric stenosis.
· Further need confirmation of BKVN, genitourinary tuberculosis, and previous instrumentation for treatment of obstructive nephropathy.
· The key treatment of BKV management is immunosuppression modification,
· Consult urologist and relieve of obstruction, by retrograde stenting, percutaneous nephrostomy catheter placement, and ballooning accordingly, in addition, other treatment options are
· Corticosteroid dose reduction,
· Tacrolimus dose reduction by 25 to 50%,
· MMF dose reduction by 50%, however, if no response and persistent increase in viral load and still symptomatic then hold antimetabolite and can switch to mTORi, although there is no consolidated evidence, but there published articles.
· Other options are IVIG and other drugs like leflonemide, cidofivir, but no consensus and no recommendation in using all these drugs.
Refrences;
1. https://mdanderson.elsevierpure.com/en/publications/reversible-ureteral-obstruction-due-to-polyomavirus-infection-aft
2. https://europepmc.org/article/med/30896679.
3. uptodate :Prevention and management of BK virus-induced (polyomavirus-induced) nephropathy in kidney transplantation.
4. https://academic.oup.com/ndt/article/30/2/209/2337134.
Ultrasound and Cystoscope shows hydrouretronephrosis
Ureteric stricture due to BK virus
Patient need evaluation by urologist and per cutaneous nephrestomy and antegrade DJ stent
or surgical removal of stenotic ureteric part
reduce MMF to half
How do you manage this case?
Ultrasound (USG) and Doppler showed mild graft hydroureteronephrosis.
Antegrade nephrostogram show ureteric stenosis.
BK viremia.
Diagnosis:
BK ureteric stenosis.
Other investigation:
Voiding cystourethrogram.
Urine PCR for T.B.
Biopsy.
Management:
Retrograde stenting,
Insertion of DJ stent.
Pulse steroids.
50% dose reduction of MMF .then follow up after two weeks. If no response stop
TAC dose reduced to attain and maintain the target trough level of 3–4 ng/ml.
References:
1. Kumar S, Ameli-Renani S, Hakim A, Jeon JH, Shrivastava S, et al. (2014) Ureteral
obstruction following renal transplantation: causes, diagnosis and management. Br J
Radiol. 87(1044): 20140169.
this is a case of ureteric stricture due to BK infection
management:
1- RIS as soon as possible MMF reduced 50% or stopped totally , and tacrolimus decreased to 25-50% of her trough level, steroid decreased or even stopped , we can maintain on tacrolimus only if there is no response.
2-percutaneous nephrostomy and evacuation of dilated pelvicalyceal system
3-insertion of antegrade DJ
4-insertion of folys catheter
5-follow up by graft function, u/s and PCR for BK
references:
Praveen Kumar Etta, Thatipamula Madhavi, Swarnalata Gowrishankar. 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 Journal Of Transplantation. 2020: (14); 147-51.
Jorge C. Garces.BK Virus–Associated Nephropathy in Kidney Transplant Recipients. Ochsner J. 2010 Winter; 10(4): 245–249.
Aaron Dall, Sundaram Hariharan. BK Virus Nephritis after Renal Transplantation. Clin J Am Soc Nephrol. 2008 Mar; 3(Suppl 2): S68–S75.
How do you manage this case?
Management:
Other adjunctive therapies
· IVIG.
· Quinolones.
· Cidofovir.
· Leflunomide.
Urgent urological intervention:
· Percutaneous nephrostomy.
· Stenting if possible via retrograde route.
· Open intervention (re-implantation, native ureter or vesico-pelvic anastomosis)
References:
Kant, S.; Dasgupta, A.; Bagnasco, S.; Brennan, D.C. BK Virus Nephropathy in Kidney Transplantation: A State-of-the-Art Review. Viruses 2022, 14, 1616. https://doi.org/10.3390/v14081616
The ultrasound image shows hydronephrosis and dilated renal pelvis.
The second image shows a nephrostogram with Ureteric stricture.
Keeping in view the BK virus viremia, it can be due to BK virus.
In this situation a Urological and IR consultation in mandatory. Patient will need Antegrade stent.
I will monitor Renal functions and BK virus PCR levels.
The first step would be to decrease MMF by 50% and watch BK virus PCR Log. If no improvement then stop MMF.
If still no response then decrease Tacrolimus with trough levels between 4-6ng/l.
Khan H, Oberoi S, Mahvash A, Sharma M, Rondon G, Alousi A, Shpall EJ, Kontoyiannis DP, Champlin RE, Ciurea SO. Reversible ureteral obstruction due to polyomavirus infection after percutaneous nephrostomy catheter placement. Biol Blood Marrow Transplant. 2011 Oct;17(10):1551-5.
Urological reference and antegrade DJ stenting to relive the obstruction.
Monitor the renal function and Plasma BK PCR level.
Sustain BK viremia is associated with BKVAN then
Reduce the dose of MMF by 50 %
if No reduction in Plasma BK PCR Log
Completely stop the MMF
If No response then decrease the dose of tacrolimus to the trough level of 4-6 ng/L.
Management:
– BK viral load >4 log10 c/mL is associated with increased rates of biopsy-proven BKV associated nephropathy..
-As US shows pelvicalyceal dilation with the distal ureteral stenosis seen in antegrade nephrostogram; the diagnosis of BKVN with ureteral stenosis is most likely.
– Urological care to relief the obstruction through retrograde ureteric stenting.
-Reduction of immunosuppression.
=reducing dose of MMF by 50%.
=Monitoring serum creatinine & plasma BK PCR levels every 2 weeks.
= If viral loads not responding, then to stop MMF.
= if not responding, then to reduce calcineurin-inhibitor trough level.
Management of this patient:
References:
1. Sam Kant, etal. BK Virus Nephropathy in Kidney Transplantation: A State-of-the-Art Review, viruses 2020,14,16,16
2. Praveen Kumaer, 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. 2020 Indian Journal of Transplantation | Published by Wolters Kluwer ‑ Medknow
Management of this patient:
It seems Ureteric stenosis due to BK viral infection with hydronephrosis
So first step , the case must be managed as MDT by Urologist and Nephrologist
-Relief the obestruction by stenting
-reduction of immunosuppressive drugs: reduce MMF by 50% and follow up but if still high stop MMF
-If still viral load not reduced after 4 weeks of stopping MMF, reduce CNI with level of tac at blood 4-6 and cyclosporine 50-100.
-Others : IVIG , leflunamide, quinolones, cidofovir but their rule is controversial
Reference ;
Saleh A, El Din Khedr MS, Ezzat A, Takou A, Halawa A. Update on the Management of BK Virus Infection. Exp Clin Transplant. 2020 Nov;18(6):659-670. doi: 10.6002/ect.2019.0254. Epub 2020 Jun 16. PMID: 32552624.
This case most probably a case of Ureteric stenosis due to BKV , Since the stenosis developed more than 1 year of RT, it is less likely to be due to surgical factors.
BKV‑associated stenosis usually affects distal part of the ureter, especially around the site of anastomosis at the ureterovesical
junction.
Management:
-first step urologic consultation to relief
the obstruction (percutaneous
nephrostomy under USG guidance followed by antegrade insertion of DJ stent).
-50% dose reduction of MMF
The cornerstone of management of BKVN is to decrease
immunosuppression. The KDIGO suggests reducing immunosuppressive medications
when BKV plasma NAT is persistently >104 copies/mL.
Recently published AST‑IDCOP guidelines recommend step‑wise
immunosuppression reduction for RTRs patients with plasma BKV‑DNAemia of
>1000 copies/mL sustained for 3 weeks or increasing to >10,000 copies/mL
reflecting “probable” and “presumptive” BKVN, respectively.
The goal is to restore immunity against the virus without
triggering rejection.
-Reduce tacrolimus dose to target trough level of 3–4 ng/ml.
-follow up of creatinine level and viremia if no response stop MMF or switching
to mTORi
-switch tacrolimus to cyclosporine‑A.
-Graft biopsy and staining for SV40 (IHC or ISH) to confirm BKVAN and
detect if there is associated rejection after improvement of hydronephrosis.
– In refractory cases, other agents such as IVIG, leflunomide, or cidofovir may be
tried; however, the efficacy of these agents has not been established.
Reference
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.
Positive findings @ case scenario:
· A KTR with PH of renal transplant and 0-2-2 mismatch in his second transplant(suggestive of intense IS).
· Allograft dysfunction in the presence of BKV infection and USS showed pelvicalyceal dilatation due to ureteric stricture and stenosis as shown on antegrade nephrostogram.
· Trough level for TAC is high( above the target).
Management plan:
1. The first step in managing this patient is to relieve the obstruction;
a) Ureteric stricture and stenosis are the underlying for this obstruction.
b) Urologist should be involved in a MDT including transplant nephrologist.
c) The first step of the management is a urinary diversion with endo-ureteral prosthesis or a nephrostomy placement. The surgical gold standard is the pyelo-ureterostomy(1).
d) BKV infection may be associated with reversible upper urinary tract obstruction that is amenable to temporary percutaneous nephrostomy catheter placement(2).
2. Reduction of immunosuppression
a) I will reduce the dose of antimetabolite(MMF) by half while continuing on the same doses of calcineurin inhibitor and/or prednisone.
b) If viral loads continue to be at similar levels or increase, proceed with complete cessation of anti-metabolite(MMF).
c) The next step is to reduce calcineurin-inhibitor trough goals if viral loads do not reduce over 4 weeks despite cessation of anti-metabolite (4–6 ng/mL for tacrolimus).
3. Ruling out BKVN and concomitant rejection: graft biopsy and staining for SV40 (IHC or ISH) may be needed if no improvement of KFT after relieve of obstruction.
4. Intravenous immunoglobulin (IVIG): IVIG administration appeared to be safe and effective in treating BK viremia and BKVN and in preventing graft loss.
References
1. Rolland E, Barrou B. Surgical treatment of ureteral stenosis after kidney transplantation. Ann Urol (Paris). 2007 Oct;41(5):254-9. French. doi: 10.1016/j.anuro.2007.08.001. PMID: 18265751.
2. Khan H, Oberoi S, Mahvash A, Sharma M, Rondon G, Alousi A, Shpall EJ, Kontoyiannis DP, Champlin RE, Ciurea SO. Reversible ureteral obstruction due to polyomavirus infection after percutaneous nephrostomy catheter placement. Biol Blood Marrow Transplant. 2011 Oct;17(10):1551-5. doi: 10.1016/j.bbmt.2011.03.002. Epub 2011 Mar 9. PMID: 21396475; PMCID: PMC4343193.
How do you manage this case?
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1-Clinical approaches ;
This patient is heavily immune suppressed ,rising serum creatinine ,BK viramia and the presence of radiological feature o ureteric stricture associated with graft obstruction raises the possibility of BKN and BK ureteric stricture .
2-MDT approach;
Urologist and Transplant nephrologists should be involved in the management o this case .
3-Therapeutic approach ;
Reduction of immunosuperression; we will use the step wise approach
A-The first step ;
Reduction of anti MMF dose by 50% and the doses of Tacrolimus to the corresponding therapeutic level (5-7 ng/mL) and continuing the same dose prednisone. Monitor serum creatinine and serial plasma BK PCR every 2 weeks .
B. The second step ;
If viral loads continue to be at similar levels or increase, proceed with complete cessation of anti-metabolite.
C.The The next step is to reduce calcineurin-inhibitor trough goals if viral loads do not reduce over 4 weeks despite cessation of anti-metabolite (4–6 ng/mL for tacrolimus ).
Surgical intervention ;
1-antegrade nephrostomy and ureteric stenting (DJ insertion) to relief the obstruction and to be removed later .
Reference ;
1-Danovitch G.M .Handbook of kidney transplantation. sixth edition. Wolters Kluwer .Press:2017.
2-https://www.ijtonline.in/article.asp?issn=2212 EttCoexistent BK-virus-associated nephropathy and ureteric stenosis in a patient with acute cellular rejection after renal transplantation: A case report and review of literature
3-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
👉 The current case is high immunological risk (2nd transplant , 022 mismatch on tripple maintenance therapy (TAC with high trough level 8, MMF high dose and steroids) , (High risk of infection) , presented with rising creatinine and obstruction (distal obstruction in antegrade nephrostogram and has dilated pelvicalyceal system in ultrasonography)
👉 The most probable diagnosis is BKVN with ureteric obstruction
👉 The management needs MDT:.
_relif of obstruction is the priority here be antegrade nephrostomy and ureteric stenting (DJ insertion).
_After stabilization of the case, relief of obstruction and clearance of infection, removal of DJ stent is warranted.
_Recurrence of stenosis after removal of DJ may indicate resection of stenotic segment and reanastomosis (ureteroneocystostomy.
_ Most important step in BKN is to reduce immunosupression, start with 50% reduction of MMF and 25-50% reduction of CNI to trough level around 5, if no reduction of viral load after 2 weeks , we can stop MMF .
⭐ close monitoring of graft function for fear of rejection with the reduction of immunosupression.
⭐ monitoring of BKV viral load by PCR every 2 weeks until clearance of infection is a must.
⭐ graft biopsy and IHC staining with SV40 is the golden standard to diagnose BKN . however, it is unfeasible in such hydronephrotic kidney so diagnosis depends on viremia (BKV PCR , clinical manifestations and decoy cell in urine).
👉 References:
Danovitch G.M .Handbook of kidney transplantation. sixth edition. Wolters Kluwer .Press:2017.
Danovitch G.M .Handbook of kidney transplantation. sixth edition. Wolters Kluwer .Press:2017.
This is a case of BKV nephropathy complicated by ureteric stenosis and obstruction in a second renal transplant recipient having low immunological risk with rising serum creatinine along with US and anterograde nephrostogram revealing finding of back pressure changes also the BK viraemia plasma PCR level 5.5 log 10 is highly suggestive.
Allograft biopsy is mandatory for tubulitis and inclusion bodies detection which can be difficult to differentiate from rejection. Coexistent BKVN and acute rejection can occur rarely; however, more commonly rejection is precipitated following a reduction in immunosuppression to treat BKV viremia or BKVN.
BKVAN requires tissue immunehistopathology for simian virus 40 large T-antigen (SV-40T),, electron microscopy or BKV-PCR of a biopsy sample
For the current case urgent releasing of obstruction is indicated with surgical intervention with cystoscopy and ureteric stenting.
For BKV nephropathy, Reduction of immunosuppression is the main stay.
A common practice of immunosuppressive dose reduction is the withdrawal of antimetabolite MMF and reduction in Tac dosage by 50%.
In refractory cases, other agents such as IVIG, leflunomide, or cidofovir may be tried; but their efficacy was not established. Appropriate RCTs are lacking to generally recommend treatment by switching from TAC to CsA, or reduce Tac to reach trough 3-5 ng/ml and from MMF to mammalian target of rapamycin inhibitors or leflunomide, or by the adjunct use of IVIG, leflunomide, or cidofovir.
Viral levels can be analysed with 2–4-week intervals. Upon no change or increased levels of BKV DNA, an additional decrease of immunosuppression , also renal function need to be closely monitored to detect any rejection signs
Reference
-Reddy YN, Trabert J, Wunderer F, Abraham G, Reddy YN. Recurrent renal allograft dysfunction due to ureteric stenosis in a patient with the BK virus infection. Saudi J Kidney Dis Transpl 2014;25:101-4
-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
-Jamboti, J. S. (2016) BK virus nephropathy in renal transplant recipients. Nephrology, 21: 647– 654.J
-Tina Dalianis, Britt-Marie Eriksson, Marie Felldin, Vanda Friman, Anna-Lena Hammarin, Maria Herthelius, Per Ljungman, Johan Mölne, Lars Wennberg & Lisa Swartling (2019) Management of BK-virus infection – Swedish recommendations, Infectious Diseases, 51:7, 479-484
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.
I agree that a reduction of immunosuppression is the key. One may have to discontinue MMF for some time
This patient high risk for BKV nephropathy with the given BKV PCR log in addition to the BKV-induced ureteral stricture and obstructive uropathy, if no improvement in the graft function after nephrostomy and reduction of IS by 50% or complete stopped MMF with BKV PCR surveillance every two weeks next step to go for graft biopsy with IHC staining with SV40, c4d staining, and looking for tubultitis, IFTA degree in order to exclude BKVAN or BKVN with rejection. the reduction of IS is the cornerstone management for BKVN and if no rejection can be shifted to sirolimus or everolimus based IS with cyclosporine with target trough level 50-100 or tacrolimus trough level 4-6ng with close monitoring every 2 weeks if no clearance then consider IVIG 0.5 mg /kg every 3 weeks as per protocol (evidence limited to observational studies).
also for further management of ureteric obstruction need MDT approach and urology transplant team consultation for the need for surgical repair ( if long segment of the stenosis , stricture .
Yes MDT approach
-How do you manage this case?
This is a case of acute graft dysfunction caused by obstructive uropathy (ureteric stricture), associated with BK viremia.
–The USS shows dilated calyceal systems with hydronephrosis,
–In this highly sensitized patient (second renal transplant 15 months ago, 022 mismatch and potent immunosuppression, BK viremia is an expected complication.–Ureteritis and ureteric stenosis secondary to BKV infection is uncommon but some studies reported association. and this may explain the dilatation of pelviureteric system in the current case.-Treatment;
Treatment urinary tract obstruction;
–Insert uretheral catheter to monitor urine output.
–Urology consultation (urgent).
–Timely management helps restore the graft function and offers better long-term graft outcome.
–Precutaneous nephrostomy catheter placement, so we can save the allograft from progressive injury.
–DJ stenting may be decided by the urologist.
–Adequate hydration following relieve of obstruction.
–After removal of the stent, if stenosis recurs, surgical revision or long term stenting of the ureter is advised.
Treatment BK viremia;
1-Reduce MMF 750 mg bid to (250 mg bid).
2-If viral loads continue to be at similar levels or increase, proceed with complete cessation of anti-metabolite.
3-The next step is to reduce calcineurin-inhibitor trough goals if viral loads do not reduce over 4 weeks despite cessation of anti-metabolite (4–6 ng/mL for tacrolimus and 50–100 ng/L for cyclosporine).
4-Continue on the same steroid dose 5 mg od.
5-Monitoring graft function and F/U PCR every 2-4 weeks.
-References;
Kidney transplantation in adults: BK polyomavirus-associated nephropathy.
(Up To Date. Jan 2023).
Yes, reduction of immunosuppression is the key. One may have to discontinue MMF for some time
3. A 47-year-old man had a successful second renal transplant 15 months ago, 022 mismatch, no DSA and negative FAXM. His creatinine has risen from 143 µmol/L to 215 µmol/L. USS is shown below (left). Antegrade nephrostogram was performed (right). He is currently on Tacrolimus (trough 8.8 ng/ml), MMF 750 bd and prednisolone 5 mg od. There is BK viraemia (plasma PCR 5.5 log 10).
How do you manage this case?
– current issues: –
– this clinical picture is suggestive of BK viremia with ureteral stenosis
– BK virus can cause localized ulceration and inflammation within the urothelium resulting in narrowing of the ureteric lumen (1)
– ureteral stenosis affects 3-10% of patients following kidney transplantation and can present early (<3months) or late onset (>3months) (2)
– Causes of early onset ureteral stenosis: – (3)
– Causes of late onset ureteral stenosis: – (3)
– Risk factors for ureteral stenosis: – (3)
– in our case, the ureteral stenosis is late onset and may be due to BKV and possibly rejection if present
– BKV-associated stenosis mostly affects the distal ureter at the ureterovesical junction (the area around the anastomotic site)
– requires a multidisciplinary approach i.e., interventional radiologist, urologist
– comprehensive history i.e., dysuria, frequency, bladder pain/ spasms, hematuria
– focused investigations i.e., FHG, LFTs, coagulation profile, urinalysis, blood sugar, urine LAM (screen for TB)
Management options: –
– percutaneous nephrostomy under ultrasound guidance then followed by anterograde insertion of DJ stent
– temporary ureteral nephrostomy tube placement is done to relieve the obstruction – this helps improve the kidney function
– definitive management involves ureteric reconstruction i.e., excision of the stenotic segment and re-anastomosis/ re-implantation ± ureteroneocystostomy
– timely management helps restore the graft function and offers better long-term graft outcome
– check serum creatinine and BKV viral load to monitor progress
– since the BKV viral load is > 104 copies/mL we should reduce the immunosuppressive therapy with an aim of restoring the immunity without triggering rejection e.g., reduce MMF by 50% then monitor the BKV viral load in 2 weeks, if still high, withdraw the MMF completely and reduce CNI dose by 50% targeting a tacrolimus trough level of 4-6ng/mL (4)
– if there is evidence of co-existing acute rejection, then antirejection therapy takes priority after which it is followed by immunosuppression reduction as a second step – usually after 2 weeks (5)
– several adjunctive therapies have been shown to have in vitro activity against BKV activity but the efficacy of these agents has not been established neither have they been shown to be superior to immunosuppression reduction (6)
References
1. Coleman DV, Mackenzie EF, Gardner SD, Poulding JM, Amer B, Russell WJ. Human polyomavirus (BK) infection and ureteric stenosis in renal allograft recipients. Journal of clinical pathology. 1978 Apr;31(4):338-47. PubMed PMID: 205555. Pubmed Central PMCID: PMC1145271. Epub 1978/04/01. eng.
2. Rigg KM, Proud G, Taylor RM. Urological complications following renal transplantation. A study of 1016 consecutive transplants from a single centre. Transplant international : official journal of the European Society for Organ Transplantation. 1994;7(2):120-6. PubMed PMID: 8179799. Epub 1994/01/01. eng.
3. Fusaro F, Murer L, Busolo F, Rigamonti W, Zanon GF, Zacchello G. CMV and BKV ureteritis: which prognosis for the renal graft? J Nephrol. 2003 Jul-Aug;16(4):591-4. PubMed PMID: 14696764. Epub 2003/12/31. eng.
4. 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.
5. Hirsch HH, Randhawa PS. 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. PubMed PMID: 30859620. Epub 2019/03/13. eng.
6. Johnston O, Jaswal D, Gill JS, Doucette S, Fergusson DA, Knoll GA. Treatment of polyomavirus infection in kidney transplant recipients: a systematic review. Transplantation. 2010 May 15;89(9):1057-70. PubMed PMID: 20090569. Epub 2010/01/22. eng.
I like your clinical approach well supported by scientific evidence
Thank you Prof.
,
This is a case of ureteric stricture. BKV infection is the suspected cause
1- Emergency management of the obstruction :
by nephrostomy tube fixation
2- Management of BKV:
3- Definitive treatment of stricture:
a- IF no obstruction and the dye passes to the bladder: clamp nephrostomy for 1-2 days with monitoring of the urine output and the kidney function. if kidney function maintained at the nadir level, remove PCN.
b- IF obstruction persist and no dye pass: trial antegrade JJ stent fixation
Good surgical plan.
you can change Tac. To cyclosporine plus Sirolimus.
How do you manage this case?
This is a case of a 47 year old presenting 15 months post transplant with a rise in his serum creatinine. Of note he had low immunological risk with negative DSA, 022 mismatch and negative FAXM.
The U/S done showed hydronephrosis and the antegrade nephostogram showed dilatation of the calyces with ureteral stenosis.
Further work up done showed a high BKV plasma PCR at 5.5 log 10.
The most likely diagnosis is ureteral stenosis secondary to the BKV infection.
The BKV can cause direct cytopathic effects on the uroepithelium leading to obstructive uropathy.
The first line of management is release of the obstruction with placement of a temporary nephrostomy catheter.
The rise in the Scr can be due to direct pressure effect on the kidney due to the obstruction.
Since this patient has a high plasma viral load the next thing to do is reduce his immunosuppressive agents.
The first to reduce would be the antimetabolite (MMF) by 25-50%. The Scr and plasma viral load should be monitored in an interval of every 2 weeks.
If the viral load fail to decrease then the next step would be to complete withdraw the antimetabolite.
Monitoring of the Scr and plasma PCR should also continue at this rate.
After 4 weeks of complete withdrawal of the antimetabolite and the plasma PCR are not reducing warrants the reduction of the CNI trough levels targeting trough levels of 3-6ng/ml.
Another diagnosis to consider in this patient with a second graft with rising Scr is the possibility of rejection. T cell mediated rejection may present as BKVAN and it would be difficult to differentiate the two based on clinical presentation alone. The gold standard of diagnosis and differentiating the two would be biopsy however in this patient with this hydronephrosis it would not be feasible to carry out a biopsy.
With relief of the obstruction and resolution of the hydronephrosis a biopsy should considered.
References
Reversible Ureteral Obstruction due to Polyomavirus Infection after Precutaneous Nephrostomy Catheter Placement Hassan Khan, Shilpa Oberoi, […], and Stefan O. CiureaUpdate on the Management of BK Virus Infection
Ahmed Saleh, Mohamed Salah El Din Khedr, Abeer Ezzat, Anna Takou, Ahmed Halawa
BK Virus Nephropathy in Kidney Transplantation: A State-of-the-Art Review
Sam Kant, Alana Dasgupta, Serena Bagnasco and Daniel C. Brennan
Thankyou well done
The above left image is USS image of kidney showing pelvicalyceal dilatation where as the image on right is antegrade nephrostogram showing obstruction in ureter likely at VUJ junction.
With the background of BK viremia in post transplant patient, this is likely ureteric stenosis at VUJ junction presenting as complication of BK viremia.
Management:
REF:
Thankyou but you are right about adjunctive therapy !
Managemnt of this case
1- Decrease dose of IS , tacrolimus by 25-50%,MMF by 50% .
2- Monitoring of graft function , if no improvement , switch MMF to m TOR .
3- Relieve obstruction : by DJ catheter or percutaneous nephrostomy or endoscopic dilatation.
4- Surgical intevention as ureteric stenting and/or surgical resection of strictured segment may be needed.
Thankyou
As we can see in US and nephrostogram, there is a stenosis at the level of ureteral anastomosis. This alone will increase the creation level, but BK viremia, in this case, entails a reduction of immunosuppression. MMF can be stopped, and the Tacrolimus dose reduces as the level is 8.8; we can target 4-5 ng/dl. We need to relieve the stenosis as well by DJ, nephrostomy then surgical revision.
Monitoring viremia every 2 weeks and renal function tests is needed.
Thankyou
Kidney transplant recipient presented with allograft dysfunction, obstructive nephropathy, BK viremia of more than 5000 copies on PCR testing, toxic Tacrolimus trough level and high dose of anti-metabolites.
Kidney biopsy might be contemplated to prove the diagnosis of BKPN and exclude underlying rejection which might be a predisposing factor for BKPN.
Its a classical BKPN with obstructive nephropathy.
Management involves reducing level of immune suppression by stopping Mycophenolic acid and reducing tacrolimus to a trough level of 4-5 ng/ml.
close observation is warranted.
BK PCR follow up is crucial as with proper reduction of immune suppression it has to turn negative.
On the other hand, reduction of immunosuppression is rendering the patient increasingly prone for acute rejection.
follow up with urology team to tackle and follow up obstructive uropathy issue.
refence:
1] Ajit P Limaye.Kidney transplantation in adults: BK polyomavirus-associated nephropathy.Uptodate.Jan 2023.
You are right,BKVN is a tissue needed diagnosis, in this case there is viremia and impaired kidney function would you need a biopsy in an obstructed graft?
How do you manage this case?
–This case of distal ureteric stenosis secondary to BK nephropathy.
Management:
Medical treatment : reduction of immunosuppression with close monitoring for rejection.
-Recommended protocols include either 50% reduction or cessation of mycophenolate mofetil, followed by dose reduction of CNI if this change is not effective.
Surgical treatment: proper renal drainage by DJ catheter or percutaneous nephrostomy is required. Further endoscopic dilatation, long-term stenting and/or surgical resection of strictured segment are possible therapeutic options.
References:
-Danovitch G.M .Handbook of kidney transplantation. sixth edition. Wolters Kluwer .Press:2017.
-Wojciech Krajewski et al. Pathogenicity of BK virus on the urinary system. Cent European J Urol. 2020; 73(1): 94–103.
Thankyou
The USS and nephogram show distal ureteric stenosis and obstruction with dilated pelvicalyceal system and hydronephrosis likely secondary to BK infection given significant BK viremia and location of the obstruction.
Management:
Relive of obstruction:
Urgent percutaneous nephrostomy
Percutaneous endoscopic stenting with or without dilatation and surgical reconstruction: Double J stent followed by ureteric reconstruction, with excision of the strictured section of the ureter and re implantation if the proximal healthy ureter is long enough to reach the bladder, otherwise for anastomosis with the native ureter.
Treatment of BK viremia:
Reduction of immunosuppression, reduce MMF by 50%, if no improvement in 2 weeks, stop MMF, assess in 2 weeks if no improvement then reduces Tac by 25%-50% aiming for Tac level around 4-6.
Close monitoring of renal function
Counselling patient about risk of rejection with reduction of IS
Monitoring BK PCR and continue treatment until two consecutive undetectable levels at least one week apart
Decision about increasing IS after resolution of viremia should be balanced between the risk of rejection and the risk of recurrent BK infection.
Thankyou well done
surgical management
medical management
reduction of IS
Stop MMF
consider reduction of Tacrolimus
This patient has a successful second transplant with 022 mismatch with rising serum creatinine 143 µmol/L to 215 µmol/L. The US showed hydronephrosis , antegrade nephrostogram showed ureteric stenosis . He is currently on Tacrolimus (trough 8.8 ng/ml), MMF 750 bd and prednisolone 5 mg od. There is BK viraemia (plasma PCR 5.5 log 10). most likely diagnosis ureteral stenosis caused by BK virus.
Management :
After initial decompression with a percutaneous nephrostomy tube, early excision and reimplantation of the ureter to the bladder or a transplant ureter to native ureter anastomosis is the most expedient way to correct the stricture and relieve the obstruction.
Early surgical correction is preferred because: it can remove infected ureteral tissue,is less likely to be associated with persistent stenosis, and is more convenient.
2. Reduction of immunosuppression : The goals of decreased immunosuppressive therapy are to restrain viral replication without triggering rejection. The optimal method of lowering immunosuppression to attain these goals is unclear.
● Decrease the dose of tacrolimus with target trough level ( 4-6 ng/ml ) plus decrease MMF by 50% or even stopping it according to the response by checking BK virus PCR .
Other options :
● Changing from tacrolimus to low-dose cyclosporine not only reduces the effect of the calcineurin inhibitor, but also reduces mycophenolate concentrations .
●Replacing the calcineurin inhibitor with sirolimus, with or without discontinuation of the antimetabolite, has the advantage of avoiding the long-term calcineurin inhibitor-related nephrotoxic effects.
3. Antiviral therapy:There are no available specific antiviral medications for BKV infections, and there are few controlled studies available on management of BKV infection in renal transplant recipients.Antiviral agents like Intravenous immune globulin, leflunamide ,quinolone ,cidofovir are studied but still there no firm conclusions about their therapeutic efficacy.
Reference :
1.https://www.uptodate.com/contents/ureteral-stenosis-due-to-bk-virus-infection-among-kidney-transplant-recipients/abstract/2.
2. Saleh A, El Din Khedr MS, Ezzat A, Takou A, Halawa A. Update on the Management of BK Virus Infection. Exp Clin Transplant. 2020 Nov;18(6):659-670. doi: 10.6002/ect.2019.0254. Epub 2020 Jun 16. PMID: 32552624.
3.Uptodate ( Ureteral stenosis due to BK virus infection among kidney transplant recipients).
Well done
OUR CASE;
DX ; Graft dysfunction from obstructive uropathy secondary to BKV infection post transplant.
MANAGEMENT.
1.Ureteric stenosis ;
2.BK Nephropathy.- RIS
3.Refractory cases ;Considerations;
REFERENCES.
Thankyou but adjunctive agents are controversial.
Thanks Prof.
How do you manage this case?
1- Reduction of Tacrolimus for a target trough level of 5 ng/ml OR changing to Cyclosporine as it is less potent OR changing to Sirolimus
2- Reduction of MMF dose by 50%
Thankyou
How do you manage this case?The index patient is high immunological risk transplant recipient (2nd transplant, 022 mismatch) on tacrolimus based triple drug immunosuppresssion, presenting 15 months post-transplant with graft dysfunction. Ultrasound revealed dilated pelvicalyceal system, suggesting hydronephrosis. Anterograde nephrostogram revealed a lower ureteric obstruction, possibly a ureteric stricture.
The causes of late ureteric stricture/ stenosis in transplant recipient include ureteral ischemia, fibrosis from immunosuppressive medications, tuberculosis, BK virus infection, vasculitis secondary to rejection, lymphocele, and ureteric stone (1).
The patient has elevated plasma BK virus PCR levels. The likely diagnosis in this scenario points towards BK virus associated nephropathy (2,3).
The management includes:
1) Urgent urinary diversion: Percutaneous nephrostomy should be done for relief of obstruction (4).
2) Response to graft dysfunction after urinary diversion should be evaluated.
3) If graft function normalizes post urinary diversion:
a. Medical management: It involves immunosuppression reduction and monitoring of plasma BK viral load. The stepwise approach includes (5,6):
1) The dose of anti-metabolite (MMF) should be reduced by 50%. Monitor plasma BKV PCR every 2 weeks. If no reduction, then step 2.
2) The dose of calcineurin inhibitor (Tacrolimus) should be reduced to attain target trough level 4-6 ng/ml. Monitor plasma BKV PCR every 2 weeks. If no reduction, then step 3.
3) Stop anti-metabolite (MMF). Monitor plasma BKV PCR every 2 weeks. If no reduction, then step 4.
4) Shift from Tacrolimus to Cyclosporine (trough level 50-75 microg/l) or Sirolimus (1). A trend towards decreased incidence of BK virus associated nephropathy is seen in patients on mTOR inhibitors (7).
5) Use of adjunctive therapies (IVIG, Cidofovir, Leflunomide, Fluoroquinolones) can be considered in case of sustained BK viremia despite immunosuppression reduction (4). But the evidence regarding role of antivirals is weak (8).
b. Surgical management of the ureteric stricture/ stenosis: The surgical management depends on the involved length of ureter (4). Open neoureterocystostomy or endourological procedures (balloon dilatation and endoureterotomy) can be used.
4) If graft dysfunction does not improve, then the patient requires additional laboratory testing in form of complete blood count, donor specific antibodies (DSA), urine examination (routine microscopic examination, and urine protein creatinine ratio), a graft kidney biopsy including c4d staining should be done to rule out other causes of graft dysfunction like associated rejection, tacrolimus toxicity, or basic disease recurrence (6). In presence of acute rejection, first acute rejection should be treated and immunosuppression reduction should take place 2 weeks later (5).
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;14:147-151.
2) Kumar S, Ameli-Renani S, Hakim A, Jeon JH, Shrivastava S, Patel U. Ureteral obstruction following renal transplantation: causes, diagnosis and management. Br J Radiol. 2014 Dec;87(1044):20140169. doi: 10.1259/bjr.20140169. Epub 2014 Oct 6. PMID: 25284426; PMCID: PMC4243200.
3) 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.
4) Duty BD, Barry JM. Diagnosis and management of ureteral complications following renal transplantation. Asian J Urol. 2015 Oct;2(4):202-207. doi: 10.1016/j.ajur.2015.08.002. Epub 2015 Aug 24. PMID: 29264146; PMCID: PMC5730752.
5) 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. Clin Transplant. 2019 Sep;33(9):e13528. doi: 10.1111/ctr.13528. Epub 2019 Apr 10. PMID: 30859620.
6) Sawinski D, Trofe-Clark J. BK Virus Nephropathy. Clin J Am Soc Nephrol. 2018 Dec 7;13(12):1893-1896. doi: 10.2215/CJN.04080318. Epub 2018 Sep 21. PMID: 30242026; PMCID: PMC6302319.
7) Mallat SG, Tanios BY, Itani HS, Lotfi T, McMullan C, Gabardi S, Akl EA, Azzi JR. CMV and BKPyV Infections in Renal Transplant Recipients Receiving an mTOR Inhibitor-Based Regimen Versus a CNI-Based Regimen: A Systematic Review and Meta-Analysis of Randomized, Controlled Trials. Clin J Am Soc Nephrol. 2017 Aug 7;12(8):1321-1336. doi: 10.2215/CJN.13221216. Epub 2017 Jun 2. PMID: 28576905; PMCID: PMC5544521.
8) Saleh A, El Din Khedr MS, Ezzat A, Takou A, Halawa A. Update on the Management of BK Virus Infection. Exp Clin Transplant. 2020 Nov;18(6):659-670. doi: 10.6002/ect.2019.0254. Epub 2020 Jun 16. PMID: 32552624.
Thankyou. But what is IS induced stricture?,!
Late ureteral stricture formation can take place due to vasoconstriction caused by immunosuppressants like corticosteroids and calcineurin inhibitors (1,2).
Reference:
1) Karam G, Hétet JF, Maillet F, Rigaud J, Hourmant M, Soulillou JP, Giral M. Late ureteral stenosis following renal transplantation: risk factors and impact on patient and graft survival. Am J Transplant. 2006 Feb;6(2):352-6. doi: 10.1111/j.1600-6143.2005.01181.x. PMID: 16426320.
2) Kumar S, Ameli-Renani S, Hakim A, Jeon JH, Shrivastava S, Patel U. Ureteral obstruction following renal transplantation: causes, diagnosis and management. Br J Radiol. 2014 Dec;87(1044):20140169. doi: 10.1259/bjr.20140169. Epub 2014 Oct 6. PMID: 25284426; PMCID: PMC4243200.
This is a case of a second transplant, 13months before. He presented with acute on chronic allograft nephropathy due to obstructive uropathy with significant BK viruria. The most probable cause is BK virus associated ureteric stenosis.
The ultrasound image shows significant hydronephrosis, which is further delineated by the antegrade nephrostogram. The latter further shows the abrupt loss of the ureteric calibre which indicates complete ureteric stenosis at the distal ureter.
The differential diagnoses:
1-BK virus related ureteric stenosis.
2-Ischemic stenosis of distal ureter
3-Odema of ureter due to rejection.
Management of obstructive uropathy, first should focus on relief of obstruction by nephrostomy and or DJ stent insertion. Then, later on definite management by dilatation or ureteric re anastomosis.
Treatment of the cause is the most important point. Checking serum BK PCR will help in diagnosing BK viremia.
For BK virus related stenosis we need to cut the antimetabolite by 50% and reduce FK to level of 3-5.
Further management with second line options, leflunomide, cidofovir and quinolones is an options, but no strong evidence.
For other causes: treatment of distal ischemia is by resection of ischemic part and re anastomosis or anastomosis to native ureter.
For rejection, treatment is by treating rejection after confirming biopsy, which is very challenging to do with this significant hydronephrosis. So we need to decompress the graft first and if no improvement of graft function, then to consider the biopsy.
References :
Krajewski W, Kamińska D, Poterek A, et al. Pathogenicity of BK virus on the urinary system. Cent European J Urol. 2020; 73: 94-103.
Is there a role for IvIg
Immunoglobulin
IVIG were proposed to treat BK nephropathy. As
for other viral infections, the main effect of such treatment
would be from neutralizing antibodies preventing cellular
infection.There is evidence supporting that this treatment
might be useful in some refractory cases. In vitro,
c-incubation of BK virus with IVIG for 2 hours before
WI-38 cells infection led to more than 90% diminution
of viral DNA after 7 days in culture. However, this
effect was significantly diminished if IVIG treatment
was given directly to cells before or 2 hours after the infection,
suggesting direct neutralization of BK virus by BK-specific antibodies.
So no strong evidence for its role, however it can be tried for refractory cases or it is associated with AMR.
References:
BK Polyomavirus and the Transplanted Kidney:
Immunopathology and Therapeutic Approaches,Transplantation 2016;100: 2276–2287)
I appreciate your understanding of ‘no conclusive evidence of IVIG in BK’.
How do you manage this case?
From the given history, it is evident that there is ureteric stenosis at the distal third, with significant hydronephrosis, the laboratory result indicates BK viremia,
Ureteric stenosis post kidney transplant occurs in 3% of cases, 50-300 days after transplantation, caused by ureteritis and granulation tissues.
As the patient has high serum BKV titer which has a specificity of 88%, and sensitivity of 100%, for the diagnosis of BKVN.
First, I would take the decision of treatment, in a multidisciplinary team work, including urologist, transplant surgeon, and infectious disease.
With acute obstructive uropathy, it worthy to relief obstruction, by doing Antegrade nephrostomy.
Medical treatment: by stopping the antimetabolites and keeping the CNI at lower therapeutic dose (50% dose reduction), and low dose prednisolone as the patient is high risk for rejection with 022 missmatch, second transplantation, so close monitoring of graft function and urinalysis, and follow up the serum BKV PCR every one to two weeks, till it is undetectable.
If BKV PCR, not decreasing, can consider, leflunomide, quinolones show anti-viral activity but of low clinical evidence, cidofovir- is not a good choice because of potential nephrotoxicity.
Intravenous immunoglobulins may be used, but with little clinical evidence.
Adoptive immunotherapy is a promising tool for BKV treatment.
Then to evaluate for the obstruction if permanent then can consider a ureteric reconstruction/ reimplantaion with double j insertion for 4-6 weeks.
References:
(1) Pahari A, Rees L. BK virus-associated renal problems–clinical implications. Pediatr Nephrol. 2003 Aug;18(8):743-8. doi: 10.1007/s00467-003-1184-3. Epub 2003 Jun 12. PMID: 12802640.
(2) Prof. Ahmad Halawa lecture- module 4 clinical fellowship of transplantation, BK in kidney transplantation.
Well done
Antigrade Nephrogram and USS shows evidence of obstructive uropathy secondary to distal ureteric stricture or stenosis , one of the urological complications of BKV infection, which is highly suggestive in this high risk recipient with high BK viral load and heavy IS.
The management plan include urgent decompression of obstruction by percutaneous Nephrostomy until lowering of renal function with treatment of associated UTI with AB and hydration .Then ureteric DJ stent inserted . If the stenosis recure, perminant stent inserted or open surgical options can be recommended.
The medical treatment includes:
The cornerstone in the managing BKV infection is RI .
Start by MMF reduction to 50% and monitor viral load after 2 weeks, if no response stop MMF and replace it by mTORi .
If still no response, reduce CNIs by 25-50% with monitoring of viral load .
Monitoring of renal function and viral load every 2 weeks.
Antiviral drugs used still controversy.
Adaptive immunotherapy is promising .
Thankyou but it is adoptive not adaptive.
Treatment
reference
Up to date
Why not discontinue MMF for some time rather than waiting for effect of reduction in MMF ? Typing ‘Up to date’ as a reference is not a complete reply in a scientific write-up.
Ok. Thank you. I will note that.
This patient has multiple risk factor to develop BK nephropathy;
1. Second transplant
2. Immunosupression drugs
3. Viremia
4. Significant rise of creatinine
5. Ultrasound findings consistent with BK nephrolpathy
Hydronephrosis was detected by ultrasound, and the antegrade pyelogram revealed that the ureter’s distal end was completely blocked.
Management;
Tissue diagnosis and immunohistchemistry is required for definite diagnosis after removal of obstruction by ureteral stent placement.
Further urine for decoy cell and graft biopsy.
Medical treatment of BK nephropathy.
Reduction in immunosuppression is the first step
BKPyV DNA is undetectable for two successive tests taken at least one week apart, check the plasma quantitative PCR every one to two weeks.
Additionally, we check the serum creatinine level every week.
When immunosuppression is being lowered, if the serum creatinine level rises by more than 25% from baseline at any point, the patient should be assessed for the likelihood of acute rejection.
In patients who do not have concurrent acute rejection
Further reduction of the dose of the antimetabolite by 50% in patients who are receiving a triple immunosuppressive regimen that consists of prednisone, a calcineurin inhibitor, and an antimetabolite
We fully stop the antimetabolite if the BKPyV virus load does not diminish in two to four weeks.
After a further two weeks, if the viral load has not decreased, we reduce the dosage of the calcineurin inhibitor by 25 to 50 percent, aiming for a whole blood tacrolimus or cyclosporine trough level of 4 to 6 ng/mL or 60 to 100 ng/mL.
Add on or other therapy that amy helpfull for BK nephropathy
Cidofovir, qunilones, leflunomide.
Update on the Management of BK Virus Infection
Ahmed Saleh, 1,4,5 Mohamed Salah El Din Khedr,1 Abeer Ezzat,2 Anna Takou, 3 Ahmed Halawa
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. Clin Transplant 2019; 33:e13528.
Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group. KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Transplant 2009; 9 Suppl 3:S1.
Why not discontinue MMF for some time rather than waiting for effect of reduction in MMF ?
yes prof. need to stop antimetabolite with reduction on CNIs
Approach to this patient
1. Reduction in CNI dose of Tacrolimus to trough level of 4-6 ng/mL,
2- Next step would be reduction in the MMF dose by 50%/
3- If there is still no decrease in viral load in further two weeks, decrease the dose of the calcineurin inhibitor further by 25 to 50 percent
4-If still these steps fails, then discontinuation of the antimetabolite is recommended.
Meanwhile needs Nephrostomy tube to relive the obstruction and improve the renal functions.
Why not discontinue MMF for some time rather than waiting for effect of reduction in MMF ?
A 47-year-old man had a successful second renal transplant 15 months ago, 022 mismatch, no DSA and negative FAXM. His creatinine has risen from 143 µmol/L to 215 µmol/L. USS is shown below (left). Antegrade nephrostogram was performed (right). He is currently on Tacrolimus (trough 8.8 ng/ml), MMF 750 bd and prednisolone 5 mg od. There is BK viraemia (plasma PCR 5.5 log 10).
How do you manage this case?
The U/S Image revealed hydronephrosis, and antegrade pyelogram showed complete distal obstruction of the ureter
Management:
1- Immediate decompression with percutaneous nephrostomy tube by IR or Urologist on call
CT, MR Urography: If the stenosis recurs after stent removal, surgical revision or long-term ureteric stenting is advocated
Surgical intervention: is indicated if minimally invasive procedures fail. Options include:
1. Ureteroneocystostomy with excision of the stenotic segment and reimplantation
2. Ureteroureterostomy using the recipient ipsilateral ureter (pyeloureterostomy between the donor renal pelvis and recipient ureter),
3. Boari flap
2- MEDICAL MANAGEMENT:
– Decrease immunosuppression medication (1st step)
– MMF 50% reduction of MMF or completely discontinue the MMF if no response within two weeks.
–
– Decrease the dose of CNI by 25% to 50% to target blood trough level Tac. of 4 to 6bng/m; and cyclo.in 60 to 100ng/ml
– IVIG if no respond to a reduction in IS and who have hypogammaglobinemia IgG <400ng/dl====>IVIG treatment 0.5 gm /kg EOD for 4 doses, to avoid confounding result when DSA is checked., to check DSA do it 2-3 week after IVIG.
– Leflunomide==>.Replacing anti-proliferative. ==> is an IS drug used to treat rheumatoid arthritis, but with antiviral properties, BK viraemia cleared in some patients with 10 or 20mg daily
– ► side effects include ↑BP, hepatotoxicity, haemolysis and TMA)
– Adjunctive therapies – Leflunomide
– Switch MMF / MPA to Leflunomide 40-60 mg /day to therapeutic level 50-100 mcg/ml
– Prodrug whose anti-metabolite, A77 1726, has both immunosuppressive and anti-viral activity.
– Dosage: 100mg/d X 5 days followed by 20–60 mg daily
– target trough blood level 50–100 mg/ml
– 10-20mg/daily (>40µg/ml)
– 85% clearance of viraemia <2500copies/ml
– Study 1:
– 12/13 pts treated – exchanging leflunomide for MMF & lowering trough level of calcineurin-inhibitor cleared the virus.[1]
– Study 2:
– 5/12 pts treated – exchanging leflunomide for MMF & decreasing immunosuppression cleared the virus.[2]
[1] Teschner S et al. Transplant Proc. 2009 Jul-Aug;41(6):2533-8.
[2] Faguer S. Transpl Int. 2007 Nov;20(11):962-9. Epub 2007 Jul 30.
Johnston O et al. Transplantation. 2010 May 15;89(9):1057-70
Krisl J et al CJASN June 2012
– Cidofovir ==> is an antiviral drug used to treat resistant CMV disease. It is nephrotoxic, but low doses may clear BK viraemia in some patients. Reported doses are 0.25–1mg/kg given IV once each 1–3 weeks
– A nucleotide analogue of cytosine that is active against various DNA viruses. Ooriginally used for CMV retinitis in patients with AIDS
Has in vitro activity against BK virus
Dosage: 0.25-0.33mg/kg/dose X 1-3 doses every 2-3 weeks
IV Cidovir – 0.25-1mg/Kg IV weekly ? 5 doses
– Problem with cidofovir – NEPHROTOXIC, P& D RTA, Crystal deposition & vascular injury
– A few studies have shown improvement in patients treated with cidofovir, but no RCTs. [1-3]
– In one study patients treated with cidofovir had no decline in BKV & had decreased renal function compared to those not treated.[4]
– 1 Vats A et al. Transplantation 2003; 75: 105.
– 2 Kadambi PV et al. Am J Transplant 2003; 3: 186.
– 3 Vats A et al. Am J Transplantation 2003; 3: 190 (Abstract #148).
– 4 Pallet N. Transplantation. 2010 Jun 27;89(12):1542-4.
– 5 Hirsch HH et al. Transplantation. 2005 May 27;79(10):1277-86.
– Quinolone Antibiotics ==> (antiviral activity by inhibiting DNA helicase), for example
– ciprofloxacin 500mg BD for 10 days
– mTOR inhibitors, (antiproliferative) ==> Few studies have recommended its use in lowering the rate of BKV, especially by switching from antimetabolites to mTORi in viral infection that occurs in solid organ transplantation
Summary:
– Immediate decompression with percutaneous nephrostomy tube by IR or Urologist on call
– Reduce MMF dose to by 50 % or discontinue if no response
– Reduction CNI by 25–50% targeting lower level to 4-6 (Tac level 8 is considered
high at 15 months post KT)
– Continuing on the same doses of prednisone.
– Close monitoring of viral load and renal function every 2 weeks.
– If no improvement in viral load in 2 weeks; discontinuation of the anti-metabolite.
– If viral loads do not reduce over 4 weeks despite cessation of anti-metabolite; consider reduce CNI trough goals 3–5
-Additional strategies have been:
switching from tacrolimus to low-dose cyclosporine or low-dose sirolimus
or switching from MMF to leflunomide or to low dose sirolimus
-Adjunctive therapy role is controversial.
References:
– BKV in Kidney Transplantation lecture By Ahmed Halawa
– Kumar S, Ameli-Renani S, Hakim A, Jeon JH, Shrivastava S, Patel U. Ureteral obstruction following renal transplantation: causes, diagnosis and management. Br J Radiol. 2014 Dec;87(1044):20140169. doi: 10.1259/bjr.20140169. Epub 2014 Oct 6. PMID: 25284426; PMCID: PMC4243200.
– Uptodate
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.
He is a patient with very high immunosuppression (sensitized patient, HLA mismatch, probable induction with rATG, high-dose tacrolimus, and triple immunosuppression), which configures a high risk for BK virus reactivation. One of its complications is ureteral obstruction.
It is essential in this case to change and reduce the axis of immunity. Switch mycophenolate to another class of drug and decrease the dose to decrease serum tacrolimus levels.
Adjuvant treatments with antivirals are debatable and remain in the background. Decreasing immunosuppression is the priority. Avoid mycophenolate and evaluate the use of mTOR inhibitors. And immediately consider nephrostomy to protect the kidney.
Which class of drug would you switch MMF to?
Leflunomide or mTOR inhibitors
How do you manage this case?
*Ultrasound revealed hydronephrosis, and antegrade pyelogram showed complete distal obstruction of the ureter
*Immediate decompression with percutaneous nephrostomy tube (with Folley catheter) is required to minimize allograft injury (risk of bleeding, adequate platelet and haemoglobin count and coagulation time are needed)
*Following decompression, the cause of obstruction should be identified
*Possible causes of late ureteric stricture:
1. Ischaemic fibrosis caused by a deficient vascular supply
2. Vasculitis in the context of an acute rejection episode
3. Vasoconstriction caused by immunosuppressant therapy (corticosteroids and CNIs)
4. Malignant ureteric stricture (bladder carcinoma is three times higher in the transplant population)
5. Ureterolithiasis (infrequent)
6. Infection (Tuberculosis, BKV)
*Imaging: CT (offers greater anatomical detail). Others if needed, MR urography and scintigraphy
*Percutaneous balloon dilatation if technically feasible, followed by temporary antegrade ureteric stent placement
*If the stenosis recurs after stent removal, surgical revision or long-term ureteric stenting is advocated
Surgical intervention: is indicated if minimally invasive procedures fail. Options include
1. Ureteroneocystostomy with excision of the stenotic segment and reimplantation
2. Ureteroureterostomy using the recipient ipsilateral ureter (pyeloureterostomy between the donor renal pelvis and recipient ureter),
3. Boari flap
*In a study, temporary percutaneous nephrostomy catheter placement relieved the obstruction and improved significantly the kidney function, successfully preventing progression to more advanced renal disease in these patients
BKV infection:
· Complete history and examination
· BK virus should be considered in patients with a decline in renal function and ureteric stricture one year following renal transplantation
· Urinalysis for low grade proteinuria and pyuria/microscopic haematuria. RFT and electrolytes
· Screen for tuberculosis (ESR, sputum for AFB, chest x-ray)
· Urine cytology for Decoy cells (not specific)
· Quantitative PCR of blood for BK virus:
1. If > 10,000 – presumptive diagnosis – Treat as BKVN
2. 5000 – 10,000 and rising trend – treat as BKVN & consider biopsy
3. <5,000 – Confirmatory renal biopsy before treating as BKVN
· Renal histology if increasing serum-creatinine levels and/or the finding of >10,000 BKV DNA copies/mL in serum/plasma
· The cornerstone of management of BKVN is to decrease immunosuppression (The KDIGO suggests reducing immunosuppressive medications when BKV plasma NAT is persistently > 104 copies/mL). Suppress viral replication without triggering acute rejection
1. Discontinue the anti-metabolite (mycophenolate or azathioprine)
2. Reduce calcineurin inhibitor (Target trough levels: Tacrolimus 4 to 6ng/ml, cyclosporin 50 to 100ng/ml)
3. Maintain low-dose prednisolone (<10mg/day)
BKV stenosis notes:
· 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
References
1. Kumar S, Ameli-Renani S, Hakim A, Jeon JH, Shrivastava S, Patel U. Ureteral obstruction following renal transplantation: causes, diagnosis and management. Br J Radiol. 2014 Dec;87(1044):20140169. doi: 10.1259/bjr.20140169. Epub 2014 Oct 6. PMID: 25284426; PMCID: PMC4243200.
2. 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
3. Khan H, Oberoi S, Mahvash A, Sharma M, Rondon G, Alousi A, Shpall EJ, Kontoyiannis DP, Champlin RE, Ciurea SO. Reversible ureteral obstruction due to polyomavirus infection after percutaneous nephrostomy catheter placement. Biol Blood Marrow Transplant. 2011 Oct;17(10):1551-5. doi: 10.1016/j.bbmt.2011.03.002. Epub 2011 Mar 9. PMID: 21396475; PMCID: PMC4343193.
4. BK Polyomavirus Interstitial Nephritis in Renal Transplant UHL Renal Transplant Guideline
That is a well-structured reply.
*The index patient is 15 months post 2nd -KT.
*HLA mismatch.
*Deterioration in graft function.
*On triple IS with high Tacrolimus level ( for 15 months post Tx)
*BKV PCR; 5.5 log 10.
*Antegrade nephrostogram showed distal ureteral stricture/stenosis, that resulted in pelvicalyceal dilatation.
*Renal US showed; pelvicalcyeal dilatation.
Diagnosis: acute graft dysfunction secondary to obstructive uropathy; BKV induced ureteric stricture.
Urinary tract obstruction:
-Urological complications in KTR are still common and their occurrence is associated with significant morbidity, impairment of graft function and, in some cases, graft loss and even recipient death. It can occurs early< 3 months post KT or late >3 months post-KT
-Ureteral stenosis with fibrosis, and ulceration of the donor ureter associated with BKV infection is rare (2 to 6%).
-It is usually clinically asymptomatic with progressing oliguria and impaired renal function. Classic colic symptoms or discomfort over the graft are not present in all cases, since the transplanted kidney is denervated
Management of obstruction:
– MDT including urologist, transplant surgeon, interventional radiologist and nephrologist.
– Urgent drainage is required; percutaneous nephrostomy.
– Consider antegrade endoscopic stenting.
– Further endoscopic dilatation, long-term stenting and/or surgical resection of strictured segment are possible therapeutic options.
Medical management BKV:
– Viremia is present in nearly all patients with BKAN.
– It has a 40 to 65 % PPV for the development of BKAN
– BKAN can quickly follow viremia (eg, within 1-2 weeks) and cause damage to the graft can be irreversible
– Higher incidence of graft loss especially if creatinine > 200 umol/l.
– There is no specific antiviral therapy against BKV infection
– Reduction of IS is the mainstay to restore immunity and control viral replication.
– There is no generally accepted regimen for reduction of IS.
-Therefore, IS should be tailored for each patient according to the clinical situation.
– IS reduction may increase the risk of rejection the index case; high immunological risk ( 2nd KT, HLA- mismatch).
Approach to reduce IS:
– Reduce MMF dose to by 50 %.
– Reduction CNI by 25–50% targeting lower level to 4-6 (Tac level 8 is considered high at 15 months post KT)
– Continuing on the same doses of prednisone.
– Close monitoring of viral load and renal function every 2 weeks.
– If no improvement in viral load in 2 week; discontinuation of the anti-metabolite.
– If viral loads do not reduce over 4 weeks despite cessation of anti-metabolite; consider reduce CNI trough goals 3–5
-Additional strategies have been:
switching from tacrolimus to low-dose cyclosporine or low-dose sirolimus
or switching from MMF to leflunomide or to low-dose sirolimus
-Adjunctive therapy role is controversial.
References:
-Krajewski W, Kamińska D, Poterek A, Małkiewicz B, Kłak J, Zdrojowy R, Janczak D. Pathogenicity of BK virus on the urinary system. Cent European J Urol. 2020;73(1):94-103. doi: 10.5173/ceju.2020.0034. Epub 2020 Feb 27. PMID: 32395331; PMCID: PMC7203775.
– Hirsch HH, Randhawa P; AST Infectious Diseases Community of Practice. BK polyomavirus in solid organ transplantation. Am J Transplant. 2013 Mar;13 Suppl 4:179-88. doi: 10.1111/ajt.12110. PMID: 23465010.
-Shanmugham S, Bhadauria D, Agrawal V, Jain M, Yaccha M, Kaul A, Vamsidhar V, Meyyappan J, Prasad N. The diagnostic and therapeutic dilemma of the co-existence of BK virus nephropathy with acute rejection – an experience from a single Centre and review of the literature. Transpl Immunol. 2022 Jun;72:101581. doi: 10.1016/j.trim.2022.101581. Epub 2022 Mar 14. PMID: 35301106.
-Hirsch HH, Randhawa P; AST Infectious Diseases Community of Practice. BK polyomavirus in solid organ transplantation. Am J Transplant. 2013;13 Suppl 4:179-88. doi:10.1111/ajt.12110
-Saleh A, El Din Khedr MS, Ezzat A, Takou A, Halawa A. Update on the Management of BK Virus Infection. Exp Clin Transplant. 2020 Nov;18(6):659-670. doi: 10.6002/ect.2019.0254. Epub 2020 Jun 16. PMID: 32552624.
-Kant S, Dasgupta A, Bagnasco S, Brennan DC. BK Virus Nephropathy in Kidney Transplantation: A State-of-the-Art Review. Viruses. 2022 Jul 25;14(8):1616. doi: 10.3390/v14081616. PMID: 35893681; PMCID: PMC9330039.
Why not discontinue MMF for some time rather than waiting for effect of reduction in MMF dose for 2 weeks?
That is a well-structured reply, however.
Thank you Prof.
Absolutely that can consider for better response and to save the time.
How do you manage this case?
left side: US
hydronephrosis
Right side: antegrade pylpgraphy . showing lower ureteric stricture
A. MEDICAL :
treatment of BKV via reduction or alteration of immunosuppressive medication after proper counseling and co-ordination between nephrologist and virologist
B.SURGICAL:
transplant surgeon responsisbility
several approaches
– PCN
-ante grade flexible URS and laser + JJ stent
Thankyou you need to be more specific in IS management and follow up.
Thanks sir
The image on the left showed dilated pelvicalceal system and antegradnephrostogram showed ureteric obstruction and dilated pelvi calceal system
How to manage
1- MDT
2- Patient education about the current situation including the risk assessment
3- Urology and interventional radiology for Relief of obstruction by DJ stent insertion leave the catheter till resolution of infection and inflammation in the urinary tract
4- Early detection and treatment of any superadded infection
5- As this lesion raise the suspicion of BKV diagnosis so management OF BKV by reduction of immunosuppression
MMF by 50% and TAC by 25% follow up with BKV PCR after2 weeks along with kidney function test
a- Remission and kidney function normal continue
b- Remission and raised s. creatinine èadjust trough level of TAC between 4-6 ng/ml
c- Still high viral load so additional line of management like antiviral ( Cidofovir ) luflonamide ( can cause nephrotoxicity ) can be used
The value of adjunctive therapy is very controversial with no acceptable regimens.
yes thanks prof , it is illdefined
adjuvant therapy \
1- Cidofovir: Nucleoside analog IV: 0.25–1.0 mg/Kg at 1–3 weeks Used in refractory cases; Nephrotoxicity is the most serious adverse effect
2- Brincidofovir: Investigational Prodrug of Cidofovir; Anti-viral activity PO: 2 mg/Kg twice weekly Reasonably well tolerated; Investigational.
3- Intravenous immunoglobulin (IVIG): Immunoglobulin preparation with high titers of neutralizing antibodies to BK virus IV: 0.25–2.0 g/Kg Can be used as an adjunct to other measures in refractory cases
4- Levofloxacin: Fluoroquinolones; Antiviral, inhibit helicase activity of large T antigen PO: 500 mg qD (renally adjusted) Levofloxacin failed to show benefit in randomized controlled trials.
5- Everolimus: Inhibits mammalian target of rapamycin (mTOR) kinase activity, inhibiting T and B lymphocyte activation and proliferation. PO 0.75 mg twice daily adjusted to trough levels of 3–8 ng/mL. Can be used following discontinuation of MMF. Limited literature supporting its use.
The images in the current scenario revealed pelvicalceal dilatation secondary to ureteric obstruction with proved BKVN which is the most common cause in the current index case.
BKV infection may be associated with reversible upper urinary tract obstruction secondary to to inflammation and hemorrhage involving the upper uroepithelium, causing ureteral stenosis.
Management:
-Insertion of temporary percutaneous nephrostomy catheter to relieve the obstruction to avoid permanent damage.
-Treatment of BKVN by reduction of immunsuppression.
What is the plan of reduction!
-How do you manage this case?
Management is MDT and involved Nephrologist/ urologist/ interventional radiologist/ virologist/ counselor
Source; Prof Halawa lecture, up date in BKV infections by Ahmed Saleh et. al
Well done .
what is the value of decoy cells here with this degree of viremia.
Thanks prof, certainly will not add any thing in terms of management but it is something you like put in mind
Management:
Reduction of immunosuppression
– Reduction in CNI dose to achieve a trough level of 4-6 ng/mL,
– If no response, 50% reduction in the MMF dose .
– if no response after two weeks, we decrease the dose of CNI by 25 – 50%
– Discontinuation of the antimetabolite is performed further if needed.
-Urological approach: nephrostomy and stenting.
Thankyou
The image shows dilated renal pelvis secondary to ureteric stricture as denoted with red arrow.
In the background of BK viremia, ureteric stricture could be secondary to BKV.
RX
Immediate Nephrostomy tube to relieve the obstruction and later percutaneous stenting, usually with dilatation of the ureter,
! What about the BK virus issue
relief of obstruction should be done in concurrent with the reduction of immune suppressants and monitoring of BK viremia.
This patient has graft dysfunction 15 months post transplant. He is on triple immunosuppression as this is his second transplant. His BK viral PCR is high (more than 4 log 10)
The USS shows hydronephrosis and antegrade nephrogram shows ureteric obstruction the distal part of the ureter
Since this is a late distal ureteric obstruction with a high BK viral PCR, this is most likely ureteric stenosis secondary to BKV
Management
He will require urgent decompressive nephrostomy and stent placement. The urology and interventional radiology team need to be involved. If retrograde stunting will be unsuccessful, he will require percutaneous nephrostomy under USS guidance
He will also require reduction in immunosuppression – The tacrolimus dose should be reduced by 25-50% and the MMF dose should be reduced by 50%
The viral PCR should be regularly monitored as well as the graft function
If the viral PCR is not reducing, the antimetabolite should be stopped and an mTOR inhibitor can be added due to its antiviral effects
Indian Journal of Transplantation.14(2)2020;147-151
Thankyou
·How do you manage this case?
Treatment options include:
A.Medical
B.Surgical:
References
Thankyou
History
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How do you manage this case?
MTD(Urology ,Virology and Nephrology)
management
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Refernce
HSCT !,,,,
Can you elaborate more on steps of IS reduction.
for your information 3step reduction as an example is
step1 reduce Tac level to6-8ng/ml
step2 reduce TAc level to 4-6ng/ml
step 3 reduce MMF by 50% to be discontinued if no improvement.
Many thanks Prof.Dawlat
A case of AKI due to ureteric obstruction which mainly due to BK Polyoma virus infection.
USS: dilatation of pelvicalyceal system mild to moderate hydronephrosis in the Antegrade nephrostogram.
BK viremia (plasma PCR 5.5 log 10).We should exclude any prior history of nephrolithiasis or urethral strictures.
How do you manage this case?
-We should urgently decompress the obstruction by temporary nephrostomy catheter placement to improve renal function and may help prevent irreversible renal failure in these patients.
– The catheters remained in place for a median time of approximately one month before resolution of BKV infection. Improvement in immune system followed by resolution of BKV infection, decrease in inflammation of the upper urinary tract and resolution of stenosed ureters (1).
– Lower the dose of tacrolimus, with the aim to lower its concentration by 25–50%
-Lower the dose of Mycophenolate mofetil. usually by 50% (2).
– Blood BKV PCR, until the viral level is undetectable.
-Serial follow up of the USG/KUB.
References:
1- Khan H, Oberoi S, Mahvash A, et al. Reversible ureteral obstruction due to polyomavirus infection after percutaneous nephrostomy catheter placement. Biol Blood Marrow Transplant. 2011;17(10):1551-1555. doi:10.1016/j.bbmt.2011.03.002.
2- Dalianis T, Eriksson BM, Felldin M, et al. Management of BK-virus infection – Swedish recommendations. Infect Dis (Lond). 2019;51(7):479-484. doi:10.1080/23744235.2019.1595130.
Thankyou
Antegrade nephrostogram showed lower severe ureteric stenosis with moderate hydronephrosis.The patient has a high level of BKV PCR. One of the presentations of BKAN is ureteric stenosis. Other urological complications include urethral stenosis and cystitis.
Donor age, recipient age, number of arteries > 2, and prolonged warm ischemia time were associated with ureteral stenosis after kidney transplantation.
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
Management:
First: nephrostomy along with double-J stenting to relieve the back pressure.
Surgical intervention is indicated if minimally invasive procedures fail. Options include ureteroneocystostomy with excision of the stenotic segment and reimplantation, ureteroureterostomy using the recipient ipsilateral ureter (pyeloureterostomy between the donor renal pelvis and recipient ureter).
Stepwise reduction of immunosuppressive drugs: immunosuppressive dose reduction is the withdrawal of antimetabolite (MMF) followed by a 50% reduction in calcineurin inhibitor dosage if there is no response to the former treatment.
In this case, I will reduce the dose of tacrolimus from the beginning, as it is already above the therapeutic range.
Kazory, A., & Ducloux, D. (2007). BK virus-associated urologic complications. Pediatric transplantation, 11(7), 821
Kumar, S., Ameli-Renani, S., Hakim, A., Jeon, J. H., Shrivastava, S., & Patel, U. (2014). Ureteral obstruction following renal transplantation: causes, diagnosis and management. The British Journal of Radiology, 87(1044), 20140169.
Thankyou
The pictures show us a hydronephrosis of transplanted kidney .
Two types of hydronephrosis, obstructive and nonobstructive, have been described. Causes of obstructive hydronephrosis in early post transplant period include blood clots within ureter or bladder and edema of ureteroneocystostomy. Late obstruction usually occurs in a distal ureter secondary to ureteric stricture, occurring as a result of ischemia, rejection and infection due to CMV and polyoma virus.
Less common causes include periureteric fibrosis, sloughed papillae, extrinsic compression by pelvic fluid collection such as hematoma, urinoma, seroma, lymphocele, abscess, and lymphadenopathy or pelvic tumor.
This case highlights the importance of awareness of nonobstructive
hydronephrosis in a transplant kidney and noninvasive assessment by using MAG3 diuretic scintigraphy with high sensitivity and specificity in order to avoid unnecessary invasive intervention and its associated complication.
Percutaneous nephrostomy to relieve the obstruction.
BKV tests.
Reduce immune suppression if tests come positive.
Refference:
1-Berger PM, Diamond JR. Ureteral obstruction as a complication of renal transplantation: A review. J Nephrol 1998;11(1):20-3.
2-Reyes-Acevedo R, Bezaury-Rivas P, Alberd J, Bordes-Azna J. Post transplant perirenal collections: Clinical significance. Transplant Proc 1996;28(6):3312.
What are (BK) tests?
how do the influence your management plan.
This is a kidney allograft located in the right pelvis.
The antegrade nephrostogram demonstrated a dilated pelvicalyceal system with the absence of the die in the bladder, hence showing an obstruction at the distal third of the ureter
Based on the history of :
The diagnosis is most likely ureteral stenosis
Management
References
What is your follow up plan:
for viremia
graft function.
why do you need a uretheral catheter?
Thank you Prof for the response.
For the viremia, the serum PCR of BKV will be checked every two weeks until there is a consecutive drop in a viral load then it will be monthly for the next 3 months.
The kidney function test will be checked twice a week to see a sustained drop in creatinine which is the expected following relief of the obstruction
The catheter is just to measure urine output in the first 48 hours than to be removed
References:
Your plan is fine but the role of adjuvant therapies as antivirals,leflonamide ,quinolones is very controversial,
TMain issue is reduction of IS with the risk of acute rejection.
How do you manage this case?
Management
A- Urinary diversion
B- Definitive treatment of urinary tract obstruction
C- Manipulation of immunosuppression
– All patients with viremia (viral load > 1000 copies/ml) are indicated for reduction of immunosuppression
– Monitor renal functions and viral load (plasma PCR) /2 weeks. Target PCR is < 1000 copies/ml
So … In the current high immunological risk case (second transplant, 022 mismatch), I will do the following:
REFERANCES
1. Sandhu C, Patel U. Renal transplantation dysfunction: the role of interventional radiology. Clin Radiol 2002; 57: 772–83.
2. Duty BD, Conlin MJ, Fuchs EF, Barry JM. The current role of endourologic management of renal transplantation complications. Adv Urol 2013; 2013: 246520
3. 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
4. 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.
5. 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
6. 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
Well done
MNAGING BK ITSELF,
Well done.
would you consider replacing Tac with cyclosporine at this advanced stage of complication.?
thanks prof Dawlat,
i think this is the second transplant , and he is 47, we need to maintain this graft as much as we can.as he may need third transplant as i guess. so minimizing dose of tac and switching MMF to azathioprine will be a better choice in my opinion.
Acute kidney injury due to obstruction/stenosis caused by BK virus and needs to address by placing percutaneous nephrostomy catheter and subsequently manage with;
Your IS reduction is feasible but is after the per cutaneous nephrostomy.
How frequent is the BK ureteric problems.?
Less frequent search literature but couldn’t find exact frequency
This is a clear case of obstructive acute kidney injury, as shown in pictures 1 and 2, demonstrating dilatation in the pelvicalyceal system and hydronephrosis, and ureteral obstruction or stenosis, respectively.
In this clinical scenario of a probably highly sensitized patient (multiple kidney transplantations) and potent immunosuppression, BK viremia is an expected complication.
BKPyV has been linked to ureteral stenosis in kidney transplant recipients. Several studies reported the ureteral obstruction due to BKPyV.Inflammation and bleeding of the upper uroepithelium, resulting in ureteral stenosis, are responsible for polyomavirus-associated obstructive uropathy of the urinary tract.
In our patient, initial step should aim to decompress renal collecting system by urgent precutaneous nephrostomy catheter placement, so we can save the allograft from progressive injury.The next step should be to treat underlying BK viremia to avoid progression to BKPyVN.
It is not clear as to what changes in immunosuppression would you recommend?
Approach to immunosuppression
1. Reduction in CNI dose as the patient has a high Tacrolimus trough level; to achieve a trough level of 4-6 ng/mL,
2- If the previous step failed, reduction in the MMF dose by 50%
3- If there is still no decrease in viral load after another two weeks, we decrease the dose of the calcineurin inhibitor by 25 to 50 percent
4-If initial steps fail, discontinuation of the antimetabolite is recommended.
Thank you, Mohamed