Appraise the influence of OPERA & PRIMO trials on KDIGO 2017 guide.
OPERA and PRIMO trials led to a change in KDIGO guidance for CKD MBD management CKD3A to 5 in that routine use of calcitriol was no longer indicated.
However if severe and progressive SHPT can be used
The trial did not show any any improvement in clinically siginficant outcome but showed a tendency to hypercalcaemia. It is worth noting that primo trial was not based on biochemical parameters of SHPT but on cardiovascular end point looking at LVH.
It is also worth noting that patient in that trial were on high dose active vitamin D and oral calcium binders which might influence hypercalcaemia
Discuss the rationale for needing to establish cut-off targets for safe upper PTH levels in non-dialysis patients.
High PTH levels has been associated with fracture and cardiovascular mortality therefore important to think of cut off and also lower PTH level too as PTH has U shape for mortality and morbidity and early treatment with clear cut off will help patients
Discuss the value of individualized treatment of SHPT.
It could be that one size fit all approach might not work and it is better to consider personalised view in keeping of things like age, sex , comorbidities , novel and traditional markers. Block et al using this approach discovered that patient with raised PTH and raised calcium and raised phosphate had greater all cause mortality and cardiovascular mortality than just PTH alone. This reflects a category of person who could benefit from treatment
Discuss extended-release calcifediol (ERC) as a future option for treatment of SHPT.
It a long acting vitamin d and does not cause surge of active vitamin D over short time triggering deactivation.
It is safe and does not decrease PTH without hypercalcaemia or hyperphosphataemia.
However evidence of hard end points like fractures mortality are lacking
Appraise the influence of OPERA & PRIMO trials on KDIGO 2017 guide.
since the PRIMO and OPERA studies failed to demonstrate improvements in clinically relevant outcomes but demonstrated increased risks of hypercalcaemia, the 2017 guideline update no longer recommends routine use of calcitriol or its analogues in adults with CKD G3a–G5 .However, it should be emphasized that the PRIMO and OPERA studies focussed on cardiovascular endpoints and were not specifically targeted at PTH control or any other hard- or patient-centred outcomes. The fact that active vitamin D increases the risk of hypercalcaemia is well recognized, and was recently confirmed in these patients, even excluding these two studies .Nevertheless, this 2017 recommendation represented a major paradigm shift with regard to previous clinical practice.
Discuss the rationale for needing to establish cut-off targets for safe upper PTH levels in non-dialysis patients.
In fact, it has recently been shown that increased iPTH before dialysis inception predicts a higher PTH level 9–12 months later and a greater use of anti-parathyroid treatments .Untreated SHPT results in progressively increasing PTH levels, as observed in randomized clinical trials in placebo-treated patients ,and parathyroid hyperplasia with progressive SHPT due to delayed treatment is accompanied by progressive reduction in sensitivity to calcium and vitamin D regulation and the consequent risk of treatment resistance later in the disease course .Therefore, either excessive suppression of PTH, possibly causing low turnover bone disease, or insufficient SHPT control resulting in hyperparathyroid bone disease and osteitis fibrosa should be avoided to improve the long-term bone (in terms of fractures) and cardiovascular outcomes.
Interestingly, the independent effects and potential interactions of SHPT, hyperphosphataemia and hypercalcaemia on CKD progression and registered cardiovascular outcomes were also recently analysed in the Spanish NEFRONA low- risk CKD G3–G5 cohort .Authors found that SHPT and hyperphosphataemia (as defined by the KDOQI guideline targets) and higher iPTH and/or phosphate levels as continuous variables were independently associated with an increased risk of both CKD progression and/or cardiovascular events (a trend for SHPT in the fully adjusted model). These results offer support for the claim that iPTH levels higher than those previously recommended by the KDOQI for non-dialysis CKD patients were indeed associated with clinically significant hard outcomes .Although these interesting results are flawed by the observational nature of the study and that an important impact on clinical practice and guidelines is out of the question ,they do underline the need to improve, or at least better define, the control of SHPT in non-dialysis patients in order to improve outcomes. Moreover, these results stress the need to establish cut-off targets for safe upper PTH levels in non- dialysis patients and whether reservation of active vitamin D analogues only for severe SHPT is exceedingly cautious .It should also be considered that optimal PTH targets may be quite different depending on whether bone, renal or cardiovascular parameters are taken into account .
Discuss the value of individualized treatment of SHPT.
personalising treatment of CKD-MBD represents the new therapeutic challenge. Besides considering age, sex, race and comorbidities, traditional and novel markers should be evaluated aimed at recognising possibly different patient phenotypes, as suggested for example by Block et al. in a prevalent population of dialysis patients. In this study, the contemporary occurrence of either low, within or above empirically identified reference range values for the three most frequently assayed biomarkers (namely, calcium, phosphate and PTH) allowed identification of 36 possible CKD-MBD phenotypes, with possibly different cardiovascular or any- cause mortality risk.
Also, there is evidence in incident dialysis patients that changes over time of these same parameters may have significant implications in the clinical outcome of a patients .As illustrated by Vervloet in a commentary, besides therapeutic interventions, a number of other factors (e.g. in- flammation, microbiota etc.) may be responsible for modifications occurring during follow-up in the concentration of MBD biomarker serum levels, independent of the therapies adopted for SHPT. For this reason, prospective observational studies examining the trajectory of biomarkers are warranted, but, to the best of our knowledge, no similar studies are available in the early phases of CKD, which are the phases where SHPT starts. Recently a retrospective clinical observation in CKD stages 3–4 clearly demonstrated that the abnormalities of mineral metabolism accelerate their development ∼5 years before patients reach end-stage kidney disease ,thus suggesting a time frame for prompt therapeutic choices. Clinical research and large databases are necessary to evaluate the complexity of SHPT development in CKD and to select the best available therapy for the individual patient. Also, new therapeutic strategies, if available, deserve exploration.
Discuss extended-release calcifediol (ERC) as a future option for treatment of SHPT.
ERC was approved in the USA in 2016 and may become an interesting alternative treatment option for ND-CKD patients in stages G3–G4 who develop progressive SHPT. ERC is an orally administered prohormone of calcitriol in an extended (or prolonged) release formulation. This formulation creates specific pharmacokinetic properties—as a consequence, a slow and steady release of calcifediol over its full intestinal transport confers a steady low-level uptake of the prohormone .Therefore ERC does not cause peaks of 25(OH)D and calcitriol levels, avoiding the induction and upregulation of 24-hydroxylases and thus overcoming rapid inactivation and degradation ,especially of subsequently and constantly rising calcitriol concentrations .By this kind of substrate availability, endogenous calcitriol remains in charge of vitamin D receptor activation in target tissues to a much greater degree than otherwise possible in these stages of CKD, effectively contributing to suppressing PTH synthesis and secretion by the parathyroid glands.
Nevertheless, and despite promising biochemical endpoint data on SHPT progression in ND-CKD patients, it needs to be emphasised that there are no hard endpoint data available on ERC with regard to meaningfully ameliorating the clinical disease burden (fractures, cardiovascular events etc.) of affected patients.
Appraise the influence of OPERA & PRIMO trials on KDIGO 2017 guide. The results of the PRIMO and OPERA studies led to the revision and reformulation of previous KDOQI and KDIGO statements , now considering it reasonable to reserve use of active oral vitamin D sterol for patients with CKD G4–G5 with severe and progressive SHPT. Discuss the rationale for needing to establish cut-off targets for safe upper PTH levels in non-dialysis patients. The need to establish cut-off targets for safe upper PTH levels in non-dialysis patients and whether reservation of active vitamin D analogues only for severe SHPT is exceedingly cautious. It should also be considered that optimal PTH targets may be quite different depending on whether bone, renal or cardiovascular parameters are taken into account Untreated SHPT results in progressively increasing PTH levels, as observed in randomized clinical trials in placebo-treated patients , and parathyroid hyperplasia with progressive SHPT due to delayed treatment is accompanied by progressive reduction in sensitivity to calcium and vitamin D regulation and the consequent risk of treatment resistance later in the disease course . Therefore, either excessive suppression of PTH, possibly causing low turnover bone disease, or insufficient SHPT control resulting in hyperparathyroid bone disease and osteitis fibrosa should be avoided to improve the long-term bone (in terms of fractures) and cardiovascular outcomes. Discuss the value of individualized treatment of SHPT. Personalising treatment of CKD-MBD represents the new therapeutic challenge. Besides considering age, sex, race and comorbidities, traditional and novel markers should be evaluated aimed at recognising possibly different patient phenotypes Discuss extended-release calcifediol (ERC) as a future option for treatment of SHPT. ERC was approved in the USA in 2016 and may become an interesting alternative treatment option for ND-CKD patients in stages G3–G4 who develop progressive SHPT. ERC is an orally administered prohormone of calcitriol in an extended (or prolonged) release formulation. By this kind of substrate availability, endogenous calcitriol remains in charge of vitamin D receptor activation in target tissues to a much greater degree than otherwise possible in these stages of CKD, effectively contributing to suppressing PTH synthesis and secretion by the parathyroid glands. despite promising biochemical endpoint data on SHPT progression in ND-CKD patients, it needs to be emphasised that there are no hard endpoint data available on ERC with regard to meaningfully ameliorating the clinical disease burden (fractures, cardiovascular events etc.) of affected patients.
Appraise the influence of OPERA & PRIMO trials on KDIGO 2017 guide.
The PRIMO and OPERA studies on CKD patients Not on dialysis failed to demonstrate improvements in clinically relevant outcomes but demonstrated increased risks of hypercalcaemia. These studies focussed on cardiovascular endpoints and were not specifically targeted at PTH control or any other hard- or patient-centred outcomes.
The influence of the OPERA and PRIMO trials on the KDIGO 2017 guidance, both trials had some limitations ,
These factors are likely to explain the increased prevalence of hypercalcaemic events. Additionally, this study design may have resulted in ‘oversuppression’ of PTH production on the one hand and overstimulation of fibroblast growth factor 23 (FGF23) on the other, which could severely effect cardiac remodeling and therefore the lack of efficacy to improve the cardiovascular study endpoint of left ventricular hypertrophy amelioration
Discuss the rationale for needing to establish cut-off targets for safe upper PTH levels in non-dialysis patients.
The rationale for needing to establish cut-off targets for safe upper PTH levels in non-dialysis patients:A main reason of absent consensus about the optimal iPTH target in non- dialysis CKD is the fact that optimal PTH targets may be quite different depending on the observed bone, renal or cardiovascular outcome.
Discuss the value of individualized treatment of SHPT.
In terms of individualized SHPT treatment, these different phenotypes may be distinguished by age, gender, race, or even laboratory indicators of CKD-MBD
Discuss extended-release calcifediol (ERC) as a future option for treatment of SHPT.
No hard endpoint data available on ERC with regard ameliorating the clinical disease burden (fractures, cardiovascular events etc.)
It has specific formulation with different pharmacokinetic leading to steady level of vitamin D in circulation which suppresses iPTH more effectively without safety concerns of hypercalcemia and hyperphosphatemia
Appraise the influence of OPERA & PRIMO trials on KDIGO 2017 guide.
These studies were done in patients with Secondary Hyperparathyroidism, and all the studies were negative studies.
There was an increased risk of developing Hypercalcemia, and based on this the KDIGO 2017 guidelines advised against the routine use of Vit D and its analogues
Discuss the rationale for needing to establish cut-off targets for safe upper PTH levels in non-dialysis patients.
CKD and the associated Secondary Hyperparathyroidism is know to be risk factors for cardiovascular risk and based upon this these targets needed to be implemented
Discuss the value of individualized treatment of SHPT.
We will use certain parameters to identify different phenotypes within the CKD-MBD population
Thus far 36 different phenotypes has been identified
The parameters being used included Calcium, Phosphate and PTH
These parameters stratifies the population into risk groups, which will have implications for long term outcomes
Discuss extended-release calcifediol (ERC) as a future option for treatment of SHPT.
Uncontrolled Secondary Hyperparathyroidism would result in Tertiary Hyperparathyroidism
The use of ERC’ s has shown that there is not any peaks of 25(OH)D and Calcitriol, and thus has better effect on PTH levels
1. The OPERA and PRIMO trials that conducted on CKD patients Not on dialysis showed that using active vitamin D (Paricalcitol) will cause high risk of hypercalcemia without improving hard end points like cardiovascular events. So the kadigo guidelines 2017 reserve the usage of paricalcitol to sever progessive PTH in advanced stage CKD.
2. The rationale of establishing cutoff targets on ND CKD patient is important because is still not known until now. (For CKD on dialysis , it is 2-9 the UL.)
The absence of clear cutoff for CK- ND will lead to overtreatment causing low turnover bone disease and increasing cardiovascular calcification, high risk for hypercalcemia and hyperphosphatemia.
On the other hand, not treating high PTH level in CKD -ND patient will causes following risk:
*High PTH level in predialysis patient is associated with higher PTH after 1 year on HD with more anti parathyreoid medical usage.
* Resistance of parathyroid gland to medical treatment, loss of sensitivity to. Calcium and vitamin D in later course of CKD.
*High turnover bone disease, osteitis fibrosa cystica and increased risk of fracture and cardiovascular outcome.
*Spanish study NEFRONA showed that hyperphosphatemia and high iPTH are independent factors that associated with increased risk of CKD progression and increased cardiovascular events.
* High PTH is also associated with increased risk of atrial fibrillation, CKD progression, graft failure and nephrocalcinosis.
3. Individualized treatment of sHPT is based on sex, age ,race and comorbidities recognition of different patient phenotypes. For example having high PTH above 600 pg/mL , calcium above 10.2 snd phosphate sbove 5.5 carried significant risk of cardiovascular death.Elevated PTH alone was not associated with death if other parameters under good control.
4. ERC as future option for treatment of sHPT :
They are very effective in reducing iPTH above 30 percent in 6 month in more than one third of patient. They are safe and don’t cause hypercalcemia and hyperphophatemia. In order to fully suppress PTH, 25 OH vitamin D should go above 50.
ERC don’t activate 24 hydroxylase, which mean that more endogenous Calcitriol remaining in charge.
There is no hard data about end points like fractures and cardiovascular events.
thanks dr Nour for your effort
he influence of OPERA & PRIMO trials on KDIGO 2017 guide
In fact, both trials had some limitations
-First, the primary goal of the PRIMO and OPERA studies was not the biochemical control of SHPT, but the potential prevention of left ventricular hypertrophy development.
-Second, study participants only had moderate SHPT, comparably quite high doses of paricalcitol were used in these trials (2 and 1 μg/day, respectively)
– Also, significant percentage of patients received calcium-based phosphate binders.
These reasons could probably explain the high incidence of hypercalcaemic episodes. Furthermore, this study design may have led to ‘oversuppression’ of PTH secretion on the one hand and to fibroblast growth factor 23 (FGF23) overstimulation which could negatively impact myocardial remodeling, and thus the lack of efficacy to improve the cardiovascular study endpoint of left ventricular hypertrophy amelioration
**Appraise the influence of OPERA & PRIMO trials on KDIGO 2017 guide.
The trails of opera and primo did not demonstrate improvement in clinical outcomes but show increase in risk of hypercalcimia, these studies focused on the cv endpoints and not targeting PTH control specifically or patients outcome , the 2017 kdigo guidelines no longer recommend routine use of calcitriol or its analogues in ckd stage 3 a – 5, active vitamin D increase risk of hypercalcimia is confirmed without the previous studies
The goal of these studies is prevention of LVH, they use high doses of paricalcitol and calcium based phosphate binders and patients show moderate SHPT but with episodes of hypercalcimia, show overstmulation of FGF23 which potentiate negative myocardial remodeling
**Discuss the rationale for needing to establish cut-off targets for safe upper PTH levels in non-dialysis patients.
PTH is a uremic toxins increase FGF23 which associated with fractures, atrial fibrillation, CV event, rapid progression to dialysis and rapid deterioration of residual renal function, excessive use of health care resources and death.
Also associated with arrhythmia and CV events in normocalcimic and /or hypercalcimia primary HPT and risk of nephrocalcinosis and graft failure in Kidney Transplant patient.
**Discuss the value of individualized treatment of SHPT.
To identify different patients phenotypes the use of clinical and biochemical data as age, gender, race and comorbidities and most frequently biomarkers used were Calcium, phosphorous, PTH.
These data allow identification of CKD-MBD phenotype and different CV or any causes of mortality risk.
Example PTH above 600pg/ml, CA above 10.2 mg/dl, phosphorous above 5.5 mg/dl carry high risk of CV hospitalization or death compared with PTH 150-300pg/ml, Ca 8.2-10.2mg/dl and phosphate 3.5-5.5 mg/dl
**Discuss extended-release calcifediol (ERC) as a future option for treatment of SHPT
Uses in patients with stage 3-4 CKD, is given orally and is provide slow and steady transport of calcifediol from the intestinal lumen.
It is mechanism the same as vitamin D lower PTH, increase 1,25 dihydroxy vitamin D but without increasing calcium and phosphorus significantly and no negative feedback
thanks dr Esraa great effort About the rationale for needing to establish cut-off targets for safe upper PTH levels in non-dialysis patients:
. A main reason of absent consensus about the optimal iPTH target in non- dialysis CKD is the fat that optimal PTH targets may be quite different depending on the observed bone, renal or cardiovascular outcome.
regarding ERC, It is noteworthy to mention that no hard endpoint data available on ERC with regard ameliorating the clinical disease burden (fractures, cardiovascular events etc.)
Discuss the rationale for needing to establish cut-off targets for safe upper PTH levels in non-dialysis
Spanish NEFRONA low risk CKD G3-G5 study,
demonstrated that, sHPT and hyperphosphatemia were independent risk factors for both:-
CKD progression
cardiovascular events.
Discuss the value of individualized treatment of SHPT.
different phenotype with possible different cardiovascular or any cause mortality risk (Block et al. demonstrated 36 phenotypes of CKD-MBD)
inflammation and gut microbiota.
Discuss extended release calcifediol (ERC) as a future option for treatment of SHPT.
According to the data from 2 phase -3 RCT, PTH reduction was in intervention group 33%, 34% versus 8%, 7 % in placebo group respectively.
> 80% of patients had vitamin D levels > 30 ng/ml.
Another study by Fadda et al. revealed that, 40% of the participant had > 30% reduction in PTH.
In this phase-3 data, minimal alterations in Ca & PO4 were noted in both intervention & placebo arm and therefore, a low risk for hypercalcemia and hyperphosphatemia.
Appraise the influence of OPERA & PRIMO trials on KDIGO 2017 guidelines
primary goal was potential prevention of LVH in sHPT
They were given high doses of paricalcitol 1 mg & 2 mg as well as calcium- based phosphate binders. high risk of hypercalcemia.
Bases on these trials, KDIGO-2017 guideline recommended against the routine use of calcitriol or its analogues in adults with CKD G3a-G5a. (2C)
The objective was not biochemical control of PTH.
They were given high doses of paricalcitol 1 mg & 2 mg as well as calcium- based phosphate binders. This may explain the risk of hypercalcemia.
The design favors over suppression of PTH as well as overstimulation of FGF-23 which by itself have a negative cardiovascular consequence.
This may be the reason the intervention was not effect.
thanks dr Mahmoud, please try to further explain your answers:
regarding individualized treatment of SHPT these different phenotypes may may be distinctive in age, sex, race or even laboratory markers of CKD-MBD which was noted by BLOK et al.
also regarding ERC, it has specific formulation with different pharmacokinetic leading to steady level of vitamin D in circulation which suppresses iPTH more effectively without safety concerns of hypercalcemia and hyperphosphatemia, however further studies wit hard clinical endpoints are still needed
lastly, A main reason of absent consensus about the optimal iPTH target in non- dialysis CKD is the fat that optimal PTH targets may be quite different depending on the observed bone, renal or cardiovascular outcome.
1-Appraise the influence of OPERA & PRIMO trials on KDIGO 2017 guide.
PRIMO and OPERA thought to avoid left ventricular hypertrophy, not biochemically regulating secondary hyperparathyroidism. In addition, research participants had moderate secondary hyperparathyroidism, received high doses of paricalcitol 2 and 1 μg/day and a considerable fraction got calcium-based phosphate binders. So several factors may explain hypercalcemia’s prevalence. The research design may have caused “over suppression” of PTH secretion and “overstimulation” of FGF23, which might cause unfavorable myocardial remodeling and hence failed to enhance the cardiovascular study endpoint of left ventricular hypertrophy ameliorations
2-Discuss the rationale for needing to
establish cut-off targets for safe upper PTH levels in non-dialysis patients.
Because rising in pth start earlier before diyalisis so high PTH is associated with increased risk of progression of CKD.
Untreated hyperparathyroidism will progress secondary hyperparathyroidism and even tertiary hyperparathyroidism
That lead to increase cardiovascular complications e.g arrythmia and LVH
High PTH is associated with increased risk of nephrolithiasis .
On the other hand oversuppression of parathyroid gland will result in adynamic bone disease
3-Discuss the value of individualized treatment of SHPT.
Individualized treatment of secondary hyperparathyroidism was preferred approach for managing this condition in non-dialysis chronic kidney disease patients.
Guidelines suggest start the use of vitamin D derivatives for patients with severe and progressive hyperparathyroidism, and this approach should be stopped when risks associated with excessive suppression of PTH.
4-Discuss extended-release calcifediol (ERC) as a future option for treatment of SHPT
Is a prohormone of calcitriol in prolonged release formulation resulting in a slow and steady release of the drug no peak lead to increase vitamin D without need for activation and no negative feed back.
ERC associated with lower hospitalization and decreased LVH.
And need further study to detect ideal uses and cut end point
thanks dr Rabab for your effort
About the rationale for needing to individualie iPTH target:
. A main reason of absent consensus about the optimal iPTH target in non- dialysis CKD is the fat that optimal PTH targets may be quite different depending on the observed bone, renal or cardiovascular outcome. MOREOVER, Blok et al reported >35 phenotypes of patients with SHPT different in lab markers of KD-MBD with different prognosis for each phenotypes. the prognosis also is affected by other factors e.g age, sex, race and trends of the lab markers rather than the absolute values. all these factors have an impact on treatment strategies and therapeutic targets of iPTH
1. Appraise the influence of OPERA & PRIMO trials on KDIGO 2017 guide. The PRIMO and OPERA studies’ findings -which did not mention hard endpoints and threshold data- led to the revision of the earlier KDOQI and KDIGO guidelines. It became reasonable to reserve the use of an active oral vitamin D for patients with CKD 4 and 5 who had severe and progressive SHPT. There was no definition given for “severe and progressive SHPT.” The main objective of the PRIMO and OPERA was to avoid the development of left ventricular hypertrophy, not hyperparathyroidism. Participants exhibited a moderate level of SHPT; nevertheless, participants received comparably high doses of paricalcitol (2 and 1 g/day, respectively), and the increased number of patients using calcium-based phosphate binders resulted in a significant incidence of hypercalcemia. Additionally, the design of the study stimulated FGF23 and over-suppressed PTH. 2. Discuss the rationale for needing to establish cut-off targets for safe upper PTH levels in non-dialysis patients. While cut-off values are available for CKD-5D, such values are missing for ALL non-dialysis CKD stages. SHPT starts very early in the course of CKD, and missing such targets leaves CKD-MBD either overtreated (leading to adynamic bone disease) or undertreated (leading to SHPT). In both cases there is excess CVD morbidity and mortality. 3. Discuss the value of individualized treatment of SHPT. One should be careful when labelling a patient as having SHPT, two individuals with the same iPTH may have 2 opposing diseases (ABD vs SHPT), so careful consideration should be done for other markers of bone activities to reach a conclusion of SHPT. Once diagnosed, treatment options should be tailored to patients’ other biochemical profiles 4. Discuss extended-release calcifediol (ERC) as a future option for treatment of SHPT. In phase 3 clinical studies for CKD 3-4, oral ERC was safe and effective. 429 patients with SHPT and vitamin D insufficiency got 30 g ERC or placebo daily for 12 weeks, followed by a possible uptitration to 60 g ERC and an open-label extension study. At six months, one-third of patients achieved the primary objective of a 30% PTH drop. In the open-label extension phase, placebo patients switched to ERC and had a similar decline in serum PTH as those in the RCTs. Throughout the 12-month investigation, ERC therapy was constant and effective. To completely block SHPT, serum total 25(OH)D levels must reach 50 ng/ml on average. Extended Release Calcifediol (ERC) was authorized in 2016 for CKD patients in stages 3-4 with progressing SHPT. ERC is taken orally and provides a delayed and consistent release across its entire intestinal transit and stable low-level prohormone absorption. It does not stimulate 24-a-hydroxylase, so the drug remain active
thanks dr Hassan for your effort:
About the rationale for needing to establish cut-off targets for safe upper PTH levels in non-dialysis patients:
. A main reason of absent consensus about the optimal iPTH target in non- dialysis CKD is the fat that optimal PTH targets may be quite different depending on the observed bone, renal or cardiovascular outcome. MOREOVER, Blok et al reported >35 phenotypes of patients with SHPT different in lab markers of KD-MBD with different prognosis for each phenotypes. the prognosis also is affected by other factors e.g age, sex, race and trends of the lab markers rather than the absolute values. all these factors have an impact on treatment strategies and therapeutic targets of iPTH
also regarding ERC, it has specific formulation with different pharmacokinetic leading to steady level of vitamin D in circulation which suppresses iPTH more effectively without safety concerns of hypercalcemia and hyperphosphatemia, however further studies wit hard clinical endpoints are still needed
The influence of OPERA & PRIMO trials on KDIGO 2017 guide
PRIMO and OPERA, do not recommend the routine use of calcitriol or its analogues in CKD G3a-G5.
PRIMO and OPERA focused on cardiovascular outcomes and not the targeted PTH control and other outcomes.
Confirmed hypercalcemia in patients treated with vit
The rationale for needing to establish cut-off targets for safe upper PTH levels in non-dialysis patients
Recently noted that an increase in iPTH before dialysis predicts a higher PTH level 9-12 months later and greater use of anti-parathyroid treatments.
Untreated sHPT results in a progressive increase in PTH level.
Parathyroid hyperplasia with progressive sHPT due to delayed treatment and accompanying reduction sensitivity to calcium and vitD regulation, and resistance sequel.
Balanced treatment to avoid hyper or hypoPTH, and to improve long-term CV outcomes.
The independent effects of sPTH, hyperphosphatemia, and hypercalcemia, on CKD progression and CV outcomes, were recently analyzed by a Spanish NEFRONA study; sHPT, iPTH, and hyperphosphatemia were independently associated with increased progression of CKD and CV outcomes.
All these point results press
a) The need to establish cut-off targets for safe upper PTH levels in dialysis patients. b) Reservation of vitD to treat a severe sHPT. c) The optimal target of which bone- renal- and CV outcomes is taken into an account.
The value of individualized treatment of SHPT.
Individualization of the therapy of sPTH is should be based on the following;
a) BLAP, bone-specific AP. b) intact-Purine nucleoside phosphorylase, PNP. c) Tartarate-resistant acid phosphatase 5b (TRAB5P).
The association of the above biomarker better reflects bone activity.
Assess bone fragility and fracture risk, with advancing reducing eGFR.
Treatment should take into consideration, a metabolic profile, and mechanical competence of bone, when treating sHPT.
When treating sHPT considered;
a) Age. b) Sex. c) Race. d) Comorbidities. e) Traditional and novel biomarkers. f) Inflammation. g) Microbiota. In summary, the result of the evaluation gives different patient phenotypes and plans a treatment strategy for extended-release calcifediol (ERC) as a future option for the treatment of SHPT
Great concern should be provided for managing MBD, by preventing early autonomy of sHPT and good PTH control.
ERC is a prohormone of calcitriol extended formulation.
has specific pharmacokinetic properties, slowly released with maintenance time.
Does not cause a peak of 25 or 1,25 (OH)vitD, avoiding induction and upregulation of the 24-(OH), hence avoiding rapid inactivation and degradation.
Does not affect but it augument of endogenous vitD.
Effectively suppress PTH.
Effective and safe in CKD-G3-4.
No significant hyperphosphatemia and hypercalcemia.
thanks dr Kamal for your effort
The influence of OPERA & PRIMO trials on KDIGO 2017 guide
In fact, both trials had some limitations
-First, the primary goal of the PRIMO and OPERA studies was not the biochemical control of SHPT, but the potential prevention of left ventricular hypertrophy development.
-Second, study participants only had moderate SHPT, comparably quite high doses of paricalcitol were used in these trials (2 and 1 μg/day, respectively)
– Also, significant percentage of patients received calcium-based phosphate binders.
These reasons could probably explain the high incidence of hypercalcaemic episodes. Furthermore, this study design may have led to ‘oversuppression’ of PTH secretion on the one hand and to fibroblast growth factor 23 (FGF23) overstimulation which could negatively impact myocardial remodeling, and thus the lack of efficacy to improve the cardiovascular study endpoint of left ventricular hypertrophy amelioration
1- Appraise the influence of OPERA & PRIMO trials on KDIGO 2017 guide.
– results of the PRIMO and OPERA led to reformulation of previous KDOQI and KDIGO as it became reasonable to reserve use an active oral vitamin D sterol for patients with CKD G4–G5 with severe and progressive SHPt, but they did not mentioned hard endpoints and threshold data, also definition of ‘severe and progressive SHPT not be provided, primary goal of the PRIMO and OPERA prevention of left ventricular hypertrophy development not hyperparathyroidism also participants had moderate SHPT, comparably high doses of paricalcitol (2 and 1 μg/day, respectively) and increase no. of patients received calcium-based phosphate binders lead to high incidence of hypercalcemic. Furthermore, study design led to PTH over suppression and FGF23) overstimulation
2- Discuss the rationale for needing to establish cut-off targets for safe upper PTH levels in non-dialysis patients.
Due to adverse effects of secondary hyperparathyroidism on long-term health outcomes.
A) Cardiovascular disease and mortality.
B) If left untreated sever progressive increase in PTH levels,
C) Increased risk of fractures, cardiac arrhythmias,
D) Increase risk of progression to dialysis.
E) Greater risk of Nephrocalcinosis
F) Graft failure in renal transplant patients.
G) Cut-off targets for safe upper PTH levels in non-dialysis patients is necessary in order to improve outcomes.
3- Discuss the value of individualized treatment of SHPT.
Individualized treatment of SHPT is the preferred approach in non-dialysis chronic kidney disease .
Guidelines recommend the use of vitamin D derivatives for severe and progressive hyperparathyroidism, and should be weighed against the risks of excessive suppression of PTH.
4- Discuss extended-release calcifediol (ERC) as a future option for treatment of SHPT. extended-release calcifediol an oral prohormone of calcitriol in an prolonged release formulation resulting in a slow and steady release of the drug lead to increase vitamin D and decrease PTH in ND-CKD patients with moderate SHPT. ERC associated with lower hospitalization and decreased LVH..
no data on ERC regarding endpoints ie fractures, cardiovascular events so further studies needed to evaluate the long-term efficacy and safety of ERC for the treatment of SHPT in ND-CKD patients.
About the rationale for needing to individualie iPTH target:
. A main reason of absent consensus about the optimal iPTH target in non- dialysis CKD is the fat that optimal PTH targets may be quite different depending on the observed bone, renal or cardiovascular outcome. MOREOVER, Blok et al reported >35 phenotypes of patients with SHPT different in lab markers of KD-MBD with different prognosis for each phenotypes. the prognosis also is affected by other factors e.g age, sex, race and trends of the lab markers rather than the absolute values. all these factors have an impact on treatment strategies and therapeutic targets of iPTH
Appraise the influence of OPERA & PRIMO trials on KDIGO 2017 guide.
First of all, the OPERA AND PRIMO TRIALS is focused on the cardiovascular endpoint rather than the level of PTH or any other hard or patient-centred outcomes. PRIMO and OPERA are not addressed the fact that active vit D increase the risk of hypercalcemia.
While the KIDOGO 2017 recommendation is not to use vit D and calcitriol on a routine
base.
Both Trial PRIMO and OPERA confirm that active vit D increases hypercalcemia risk.
Discuss the rationale for needing to establish cut-off targets for safe upper PTH levels in non-dialysis patients.
It is important to have a cut-off limit for the PTH level in CKD stages 3 to 5 for trying to control the PTH level and minimizing the complications like cardiovascular and mortality.
For that, it is crucial to have a cute off level for the PTH in CKD stge 3 to 5 non D .
Discuss the value of individualized treatment of SHPT.
To treat the SHPTH case by case, this is the approach which is highly recommended now. As you will try to avoid early use of VItD drivatevs and keep it for a very high PTH level
adding to that, PTH need to look for the trend and need to check with the lab the type of assay used in PTH analysis and need to consider other biomarkers in the context of clinical scenario to take the decision about the type of bone disease the patient has and treated accordingly.
Discuss extended-release calcifediol (ERC) as a future option for treatment of SHPT.
it is a prohormone of calcitriol, so far, it has shown a decrease in PTH level without causing Hypercalcem ia or hyperphosphatemia.
It is not activated 24 hydroxyls and has no negative feedback
thanks dr Rihab for your effort
The influence of OPERA & PRIMO trials on KDIGO 2017 guide
In fact, both trials had some limitations
-First, the primary goal of the PRIMO and OPERA studies was not the biochemical control of SHPT, but the potential prevention of left ventricular hypertrophy development.
-Second, study participants only had moderate SHPT, comparably quite high doses of paricalcitol were used in these trials (2 and 1 μg/day, respectively)
– Also, significant percentage of patients received calcium-based phosphate binders.
These reasons could probably explain the high incidence of hypercalcaemic episodes. Furthermore, this study design may have led to ‘oversuppression’ of PTH secretion on the one hand and to fibroblast growth factor 23 (FGF23) overstimulation which could negatively impact myocardial remodeling, and thus the lack of efficacy to improve the cardiovascular study endpoint of left ventricular hypertrophy amelioration
also regarding ERC, despite promising biochemical endpoint data on SHPT progression in ND-CKD patients, no hard endpoint data available affeting disease burden (fractures, cardiovascular events etc)
1. Appraise the influence of OPERA & PRIMO trials on KDIGO 2017 guide. The primary goal of the PRIMO and OPERA studies was to potentially prevent left ventricular hypertrophy development, however, their results failed to demonstrate improvements in clinically relevant outcomes and instead demonstrated increased risks of hypercalcemia. The 2017 guideline update no longer recommends the routine use of calcitriol or its analogs in adults with CKD G3a-G5. This 2017 recommendation represented a major paradigm shift with regard to previous clinical practice and is an important influence of the OPERA and PRIMO trials on the KDIGO 2017 guidelines.
2. Discuss the rationale for needing to establish cut-off targets for safe upper PTH levels in non-dialysis patients.
The establishment of cut-off targets for safe upper PTH levels in non-dialysis patients is necessary due to the potential adverse effects of secondary hyperparathyroidism (SHPT) on long-term health outcomes, including cardiovascular disease and mortality. If left untreated, SHPT can lead to a progressive increase in PTH levels, which can result in an increased risk of fractures, cardiac arrhythmias, and other cardiovascular events, as well as an increase in the risk of progression to dialysis. Additionally, elevated PTH levels have been associated with a greater risk of nephrocalcinosis and graft failure in renal transplant patients. Therefore, establishing cut-off targets for safe upper PTH levels in non-dialysis patients is necessary in order to reduce the risk of these potentially serious health consequences and improve or better define the control of SHPT in order to improve outcomes.
3. Discuss the value of individualized treatment of SHPT.
Individualized treatment of secondary hyperparathyroidism (SHPT) is increasingly becoming the preferred approach for managing this condition in non-dialysis chronic kidney disease (ND-CKD) patients. Guidelines suggest reserving the use of vitamin D derivatives for patients with severe and progressive hyperparathyroidism, and this approach should be weighed against the risks associated with excessive suppression of PTH. For individualized treatment of SHPT to be successful, doctors must have access to accurate biomarkers that can be used to make treatment decisions.
4. Discuss extended-release calcifediol (ERC) as a future option for treatment of SHPT.
ERC is an orally administered prohormone of calcitriol in an extended (or prolonged) release formulation which creates specific pharmacokinetic properties, resulting in a slow and steady release of calcifediol. This formulation has been shown to increase vitamin D levels and decrease PTH levels in ND-CKD patients with moderate SHPT. Clinical studies have also demonstrated that ERC is associated with lower hospitalization rates and decreased LVH. Excessive suppression of PTH could result in low-turnover bone disease or inadequate SHPT control causing hyperparathyroid bone disease. Currently no data on ERC regarding endpoints such as fractures or cardiovascular events. Therefore, further studies are needed to evaluate the long-term efficacy and safety of ERC for the treatment of SHPT in ND-CKD patients.
About the rationale for needing to individualize iPTH target:
. A main reason of absent consensus about the optimal iPTH target in non- dialysis CKD is the fat that optimal PTH targets may be quite different depending on the observed bone, renal or cardiovascular outcome. Moreover, Block et al reported >35 phenotypes of patients with SHPT different in lab markers of CKD-MBD with different prognosis for each phenotypes. the prognosis also is affected by other factors e.g age, sex, race and trends of the lab markers rather than the absolute values. all these factors have an impact on treatment strategies and therapeutic targets of iPTH
also, The influence of OPERA & PRIMO trials on KDIGO 2017 guide
In fact, both trials had some limitations
-First, the primary goal of the PRIMO and OPERA studies was not the biochemical control of SHPT, but the potential prevention of left ventricular hypertrophy development.
-Second, study participants only had moderate SHPT, comparably quite high doses of paricalcitol were used in these trials (2 and 1 μg/day, respectively)
– Also, significant percentage of patients received calcium-based phosphate binders.
These reasons could probably explain the high incidence of hypercalcaemic episodes. Furthermore, this study design may have led to ‘oversuppression’ of PTH secretion on the one hand and to fibroblast growth factor 23 (FGF23) overstimulation which could negatively impact myocardial remodeling, and thus the lack of efficacy to improve the cardiovascular study endpoint of left ventricular hypertrophy amelioration
Thanks dr Mohammed for your effort
1-The influence of OPERA & PRIMO trials on KDIGO 2017 guide
In fact, both trials had some limitations
-First, the primary goal of the PRIMO and OPERA studies was not the biochemical control of SHPT, but the potential prevention of left ventricular hypertrophy development.
-Second, study participants only had moderate SHPT, comparably quite high doses of paricalcitol were used in these trials (2 and 1 μg/day, respectively)
– Also, significant percentage of patients received calcium-based phosphate binders.
These reasons could probably explain the high incidence of hypercalcaemic episodes. Furthermore, this study design may have led to ‘oversuppression’ of PTH secretion on the one hand and to fibroblast growth factor 23 (FGF23) overstimulation which could negatively impact myocardial remodeling, and thus the lack of efficacy to improve the cardiovascular study endpoint of left ventricular hypertrophy amelioration
2-About the rationale for needing to individualie iPTH target:
. A main reason of absent consensus about the optimal iPTH target in non- dialysis CKD is the fat that optimal PTH targets may be quite different depending on the observed bone, renal or cardiovascular outcome. MOREOVER, Blok et al reported >35 phenotypes of patients with SHPT different in lab markers of KD-MBD with different prognosis for each phenotypes. the prognosis also is affected by other factors e.g age, sex, race and trends of the lab markers rather than the absolute values. all these factors have an impact on treatment strategies and therapeutic targets of iPTH
Appraise the influence of OPERA & PRIMO trials on KDIGO 2017 guide.
PRIMO and OPERAtrials was potential prevention of LVH in sHPT
Most patients had modest sHPT
They were given high doses of paricalcitol 1 mg & 2 mg as well as calcium- based phosphate binders.
The trials were negative.
high risk of hypercalcemia.
Bases on these trials, KDIGO-2017 guideline recommended not use calcitriol and its analogues as routine in adults with CKD G3a-G5a. (2C).
2-Discuss the rationale for needing to establish cut-off targets for safe upper PTH levels in non-dialysis patients. HPT increase progression of CKD and mortality due to increase vascular calcification.
HPT increase nephrolithiasis incidence. low PTH result in ABD .
3- Discuss the value of individualized treatment of SHPT.
PTH level alone is not the target as shown by Block et al
PTH within the target levels is not associated with complications if there is normal S.Ca or normal Pi
(PTH> 600 with Hypercalcemia and hyperphosphatemia) was associated with vascular calcification with cardiovascular complications.
4- Discuss extended-release calcifediol (ERC) as a future option for treatment of SHPT.
ERC is a prohormone of calcitrol,
encapsulated in a lipophilic so released over 12 hours
no peak
not activate of 24-hydroxylase so no -ve feedback.
decrease PTH, without hypercalcemia and hyperphosphatemia.
thanks dr Ashraf for your effort
about individualized treatment of SHPT
the prognosis also is affected by other factors e.g age, sex, race and trends of the lab markers rather than the absolute values. all these factors have an impact on treatment strategies and therapeutic targets of iPTH
Appraise the influence of OPERA & PRIMO trials on KDIGO 2017 guide.
PRIMO and OPERA sought to avoid left ventricular hypertrophy, not biochemically regulating SHPT. In addition, research participants had moderate SHPT, received high doses of paricalcitol (2 and 1 μg/day, respectively), and a considerable fraction got calcium-based phosphate binders. Several factors may explain hypercalcemia’s prevalence. This research design may have caused “over suppression” of PTH secretion and “overstimulation” of FGF23, which might cause unfavorable myocardial remodeling and hence failed to enhance the cardiovascular study endpoint of left ventricular hypertrophy amelioration.
Discuss the rationale for needing to establish cut-off targets for safe upper PTH levels in non-dialysis patients.
Several new clinical recommendations advise doctors neither to wait until severe SHPT is apparent nor to entirely correct PTH levels in CKD non-dialysis patients.
CKD’s bone hyporesponsiveness to PTH and PTH’s phosphaturic characteristics explain this final advice. PTH, a uraemic toxin, elevates FGF23 and is independently linked with fractures, atrial fibrillation, cardiovascular events, progression to dialysis, faster loss in residual renal function, healthcare resource consumption, and mortality in observational studies. PTH is also linked to arrhythmias, cardiovascular events, and nephrocalcinosis in normocalcemic and hypercalcemic primary HPT.
Discuss the value of individualized treatment of SHPT.
Personalizing CKD-MBD therapy is the latest therapeutic challenge. In addition to age, sex, race, and comorbidities, classic and new indicators should be investigated to identify possible patient phenotypes, as recommended by Block et al.
in a prevalent dialysis patient group. In this study, the contemporary occurrence of either low, within, or above empirically identified reference range values for the three most frequently assayed biomarkers—calcium, phosphate, and PTH—identified 36 possible CKD-MBD phenotypes with potentially different cardiovascular or any cause mortality risk.
For instance, having all three parameters in the “high” category (PTH >600 pg/ml, calcium >10.2 mg/dl, and phosphate >5.5 mg/dl) increased the risk of death and pooled cardiovascular hospitalization or death compared to the reference phenotype (PTH 150–300, calcium 8.2–10.2, and phosphate 3.5–5.5). If calcium and phosphate were effectively regulated, PTH >600 pg/mL alone did not increase risk.
Discuss extended-release calcifediol (ERC) as a future option for the treatment of SHPT
ERC was authorized in 2016 for ND-CKD patients in stages G3–G4 with progressing SHPT. Extended-release calcitriol prohormone ERC is taken orally. This formulation provides particular pharmacokinetic features, resulting in a delayed and consistent release of calcifediol across its entire intestinal transit and stable low-level prohormone absorption.
Oral ERC was safe and effective in phase 3 clinical studies for CKD stages G3–G4. 429 individuals with SHPT and vitamin D deficiency received 30 μg ERC or placebo daily for 12 weeks, followed by possible up-titration to 60 μg and an open-label extension research.
One-third of patients met the main goal of a 30% PTH decrease after six months. In the open-label extension phase, placebo patients switched to ERC and had a similar drop in serum PTH as those in the RCTs. ERC therapy was consistent and successful throughout the 12-month experiment. To inhibit SHPT fully, mean serum total 25(OH)D levels are required to rise to 50 ng/ml.
Appraise the influence of OPERA & PRIMO trials on KDIGO 2017 guide. PRIMO was a multicentric, multinational, double blinded randomized, placebo controlled trial included 227 patients ( ckd+ Lt.ventricle hypertrophy+ preserved ej.fraction), 112 received placebo, while 115 received oral paricalcitol 2 μg for 48 wks, hypercalcemia was developed in 22.6% of parcalcitol arm vs 0.9% in placebo arm (P<0.001), and higher number of patients withdraw from the study because of adverse effects mainly hypercalcemia 9.6% vs 4.5% respectively. OPERA compared lower dose of oral parcalcitol 1 μg vs placebo. hypercalcemia was developed in 43.3% of parcalcitol arm vs 3.3% in placebo arm (P<0.001), So,2017 guidelines state that on longer routine use of calcitrol or its analogues in adults with CKD G3a-G5, only can be used for patient with progressively increased PTH Discuss the rationale for needing to establish cut-off targets for safe upper PTH levels in non-dialysis patients High PTH is associated with increased risk of progression of CKD Increased predialysis PTH herald high post dialysis PTH and need of higher doses of anti-parathyroid drugs Untreated hyperparathyroidism will progress Untreatment of hyperparathyroid decrease sensitivity of parathyroid gland High PTH is associated with cardiovascular complications e.g arrythmais High PTH is associated with increased risk of nephrolithiasis and censored graft loss On the other hand oversuppression of parathyroid gland will result in adynamic bone disease
Discuss the value of individualized treatment of SHPT PTH level alone should not be the target as shown by Block et al that PTH within the target levels is not associated with any complications if there is no hypercalcemia or hyperphosphatemia, while (PTH> 600 + Hypercalcemia+ hyperphosphatemia) was associated with greater risk of death mainly from cardiovascular complications. So ttt of Hyperparathyroidism: should consider other parameters like bone formation and bone resorption biomarkers, calcium and phosphorus levels should depend on trend not single reading Extended release calcifedol It is a prohormone of calcitrol, kept in a lipophilic, wax- like capsule, so released over 12 hours, so no peak, thus preventing activation of 24-hydroxylase. ERC effectively increase 25(oh) vit D, decrease PTH, without causing hypercalcemia and hyperphosphatemia.
thanks dr Ahmed for your effort
The influence of OPERA & PRIMO trials on KDIGO 2017 guide
In fact, both trials had some limitations
-First, the primary goal of the PRIMO and OPERA studies was not the biochemical control of SHPT, but the potential prevention of left ventricular hypertrophy development.
-Second, study participants only had moderate SHPT, comparably quite high doses of paricalcitol were used in these trials (2 and 1 μg/day, respectively)
– Also, significant percentage of patients received calcium-based phosphate binders.
These reasons could probably explain the high incidence of hypercalcaemic episodes. Furthermore, this study design may have led to ‘oversuppression’ of PTH secretion on the one hand and to fibroblast growth factor 23 (FGF23) overstimulation which could negatively impact myocardial remodeling, and thus the lack of efficacy to improve the cardiovascular study endpoint of left ventricular hypertrophy amelioration
2-regarding ER no available studies with hard outcomes ameliorating the clinical disease burden
1.Appraise the influence of OPERA & PRIMO trials on KDIGO 2017 guidelines
OPERA & PRIMO trials primary goal was potential prevention of LVH in sHPT
Most patients had modest sHPT
They were given high doses of paricalcitol 1 mg & 2 mg as well as calcium- based phosphate binders.
The trials were negative.
There was high risk of hypercalcemia.
Bases on these trials, KDIGO-2017 guideline recommended against the routine use of calcitriol or its analogues in adults with CKD G3a-G5a. (2C)
-Critical appraisal of OPERA & PRIMO trials
The objective was not biochemical control of PTH.
They were given high doses of paricalcitol 1 mg & 2 mg as well as calcium- based phosphate binders. This may explain the risk of hypercalcemia.
The design favors over suppression of PTH as well as overstimulation of FGF-23 which by itself have a negative cardiovascular consequence. This may be the reason the intervention was not effect.
2.Discuss the rationale for needing to establish cut-off targets for safe upper PTH levels in non-dialysis
Data from Spanish NEFRONA low risk CKD G3-G5 study, demonstrated that, sHPT and hyperphosphatemia were independent risk factors for both CKD progression and or cardiovascular events.
3.Discuss the value of individualized treatment of SHPT.
CKD-MBD may have a different phenotype with possible different cardiovascular or any cause mortality risk (Block et al. demonstrated 36 phenotypes of CKD-MBD)
Other factors must be put int consideration e.g., inflammation and gut microbiota.
-Examples
All 3 parameters (PTH > 600, Ca >10.2, & PO4 >5.5 are high) = high phenotype: This is associated with a significantly higher risk of death, CVD hospitalization compared to the reference phenotype (PTH 150-300, Ca 8.2 to 10.2, & PO4 3.5-5.5)
PTH > 600 alone with a well-controlled Ca & PO4: This phenotype is not associated with any adverse risk.
4.Discuss extended release calcifediol (ERC) as a future option for treatment of SHPT.
Calcifediol is oral prohormone of 1,25 (OH)2 D.
It has two forms; immediate-release calcifediol (IMR) or extended-release calcifediol (ERC)
-Features of ERC
Encapsulated in a lipophilic, wax like structure.
Which allows prolonged calcifediol release over an extended period of 12 hours.
Does not activate negative feedback loop that leads to increase activity of 24 hydroxylase which degrades vitamin D into inactive forms.
-Efficacy of ERC
According to the data from 2 phase -3 RCT, PTH reduction was in intervention group 33%, 34% versus 8%, 7 % in placebo group respectively.
> 80% of patients had vitamin D levels > 30 ng/ml.
Another study by Fadda et al. revealed that, 40% of the participant had > 30% reduction in PTH.
-Safety
In this phase-3 data, minimal alterations in Ca & PO4 were noted in both intervention & placebo arm and therefore, a low risk for hypercalcemia and hyperphosphatemia.
Appraise the influence of OPERA & PRIMO trials on KDIGO 2017 guide.
OPERA and PRIMO trials led to a change in KDIGO guidance for CKD MBD management CKD3A to 5 in that routine use of calcitriol was no longer indicated.
However if severe and progressive SHPT can be used
The trial did not show any any improvement in clinically siginficant outcome but showed a tendency to hypercalcaemia. It is worth noting that primo trial was not based on biochemical parameters of SHPT but on cardiovascular end point looking at LVH.
It is also worth noting that patient in that trial were on high dose active vitamin D and oral calcium binders which might influence hypercalcaemia
Discuss the rationale for needing to establish cut-off targets for safe upper PTH levels in non-dialysis patients.
High PTH levels has been associated with fracture and cardiovascular mortality therefore important to think of cut off and also lower PTH level too as PTH has U shape for mortality and morbidity and early treatment with clear cut off will help patients
Discuss the value of individualized treatment of SHPT.
It could be that one size fit all approach might not work and it is better to consider personalised view in keeping of things like age, sex , comorbidities , novel and traditional markers. Block et al using this approach discovered that patient with raised PTH and raised calcium and raised phosphate had greater all cause mortality and cardiovascular mortality than just PTH alone. This reflects a category of person who could benefit from treatment
Discuss extended-release calcifediol (ERC) as a future option for treatment of SHPT.
It a long acting vitamin d and does not cause surge of active vitamin D over short time triggering deactivation.
It is safe and does not decrease PTH without hypercalcaemia or hyperphosphataemia.
However evidence of hard end points like fractures mortality are lacking
since the PRIMO and OPERA studies failed to demonstrate improvements in clinically relevant outcomes but demonstrated increased risks of hypercalcaemia, the 2017 guideline update no longer recommends routine use of calcitriol or its analogues in adults with CKD G3a–G5 .However, it should be emphasized that the PRIMO and OPERA studies focussed on cardiovascular endpoints and were not specifically targeted at PTH control or any other hard- or patient-centred outcomes. The fact that active vitamin D increases the risk of hypercalcaemia is well recognized, and was recently confirmed in these patients, even excluding these two studies .Nevertheless, this 2017 recommendation represented a major paradigm shift with regard to previous clinical practice.
In fact, it has recently been shown that increased iPTH before dialysis inception predicts a higher PTH level 9–12 months later and a greater use of anti-parathyroid treatments .Untreated SHPT results in progressively increasing PTH levels, as observed in randomized clinical trials in placebo-treated patients ,and parathyroid hyperplasia with progressive SHPT due to delayed treatment is accompanied by progressive reduction in sensitivity to calcium and vitamin D regulation and the consequent risk of treatment resistance later in the disease course .Therefore, either excessive suppression of PTH, possibly causing low turnover bone disease, or insufficient SHPT control resulting in hyperparathyroid bone disease and osteitis fibrosa should be avoided to improve the long-term bone (in terms of fractures) and cardiovascular outcomes.
Interestingly, the independent effects and potential interactions of SHPT, hyperphosphataemia and hypercalcaemia on CKD progression and registered cardiovascular outcomes were also recently analysed in the Spanish NEFRONA low- risk CKD G3–G5 cohort .Authors found that SHPT and hyperphosphataemia (as defined by the KDOQI guideline targets) and higher iPTH and/or phosphate levels as continuous variables were independently associated with an increased risk of both CKD progression and/or cardiovascular events (a trend for SHPT in the fully adjusted model). These results offer support for the claim that iPTH levels higher than those previously recommended by the KDOQI for non-dialysis CKD patients were indeed associated with clinically significant hard outcomes .Although these interesting results are flawed by the observational nature of the study and that an important impact on clinical practice and guidelines is out of the question ,they do underline the need to improve, or at least better define, the control of SHPT in non-dialysis patients in order to improve outcomes. Moreover, these results stress the need to establish cut-off targets for safe upper PTH levels in non- dialysis patients and whether reservation of active vitamin D analogues only for severe SHPT is exceedingly cautious .It should also be considered that optimal PTH targets may be quite different depending on whether bone, renal or cardiovascular parameters are taken into account .
personalising treatment of CKD-MBD represents the new therapeutic challenge. Besides considering age, sex, race and comorbidities, traditional and novel markers should be evaluated aimed at recognising possibly different patient phenotypes, as suggested for example by Block et al. in a prevalent population of dialysis patients. In this study, the contemporary occurrence of either low, within or above empirically identified reference range values for the three most frequently assayed biomarkers (namely, calcium, phosphate and PTH) allowed identification of 36 possible CKD-MBD phenotypes, with possibly different cardiovascular or any- cause mortality risk.
Also, there is evidence in incident dialysis patients that changes over time of these same parameters may have significant implications in the clinical outcome of a patients .As illustrated by Vervloet in a commentary, besides therapeutic interventions, a number of other factors (e.g. in- flammation, microbiota etc.) may be responsible for modifications occurring during follow-up in the concentration of MBD biomarker serum levels, independent of the therapies adopted for SHPT. For this reason, prospective observational studies examining the trajectory of biomarkers are warranted, but, to the best of our knowledge, no similar studies are available in the early phases of CKD, which are the phases where SHPT starts. Recently a retrospective clinical observation in CKD stages 3–4 clearly demonstrated that the abnormalities of mineral metabolism accelerate their development ∼5 years before patients reach end-stage kidney disease ,thus suggesting a time frame for prompt therapeutic choices. Clinical research and large databases are necessary to evaluate the complexity of SHPT development in CKD and to select the best available therapy for the individual patient. Also, new therapeutic strategies, if available, deserve exploration.
ERC was approved in the USA in 2016 and may become an interesting alternative treatment option for ND-CKD patients in stages G3–G4 who develop progressive SHPT. ERC is an orally administered prohormone of calcitriol in an extended (or prolonged) release formulation. This formulation creates specific pharmacokinetic properties—as a consequence, a slow and steady release of calcifediol over its full intestinal transport confers a steady low-level uptake of the prohormone .Therefore ERC does not cause peaks of 25(OH)D and calcitriol levels, avoiding the induction and upregulation of 24-hydroxylases and thus overcoming rapid inactivation and degradation ,especially of subsequently and constantly rising calcitriol concentrations .By this kind of substrate availability, endogenous calcitriol remains in charge of vitamin D receptor activation in target tissues to a much greater degree than otherwise possible in these stages of CKD, effectively contributing to suppressing PTH synthesis and secretion by the parathyroid glands.
Nevertheless, and despite promising biochemical endpoint data on SHPT progression in ND-CKD patients, it needs to be emphasised that there are no hard endpoint data available on ERC with regard to meaningfully ameliorating the clinical disease burden (fractures, cardiovascular events etc.) of affected patients.
Appraise the influence of OPERA & PRIMO trials on KDIGO 2017 guide.
The results of the PRIMO and OPERA studies led to the revision and reformulation of previous KDOQI and KDIGO statements , now considering it reasonable to reserve use of active oral vitamin D sterol for patients with CKD G4–G5 with severe and progressive SHPT.
Discuss the rationale for needing to establish cut-off targets for safe upper PTH levels in non-dialysis patients.
The need to establish cut-off targets for safe upper PTH levels in non-dialysis patients and whether reservation of active vitamin D analogues only for severe SHPT is exceedingly cautious. It should also be considered that optimal PTH targets may be quite different depending on whether bone, renal or cardiovascular parameters are taken into account
Untreated SHPT results in progressively increasing PTH levels, as observed in randomized clinical trials in placebo-treated patients , and parathyroid hyperplasia with progressive SHPT due to delayed treatment is accompanied by progressive reduction in sensitivity to calcium and vitamin D regulation and the consequent risk of treatment resistance later in the disease course . Therefore, either excessive suppression of PTH, possibly causing low turnover bone disease, or insufficient SHPT control resulting in hyperparathyroid bone disease and osteitis fibrosa should be avoided to improve the long-term bone (in terms of fractures) and cardiovascular outcomes.
Discuss the value of individualized treatment of SHPT.
Personalising treatment of CKD-MBD represents the new therapeutic challenge. Besides considering age, sex, race and comorbidities, traditional and novel markers should be evaluated aimed at recognising possibly different patient phenotypes
Discuss extended-release calcifediol (ERC) as a future option for treatment of SHPT.
ERC was approved in the USA in 2016 and may become an interesting alternative treatment option for ND-CKD patients in stages G3–G4 who develop progressive SHPT. ERC is an orally administered prohormone of calcitriol in an extended (or prolonged) release formulation. By this kind of substrate availability, endogenous calcitriol remains in charge of vitamin D receptor activation in target tissues to a much greater degree than otherwise possible in these stages of CKD, effectively contributing to suppressing PTH synthesis and secretion by the parathyroid glands.
despite promising biochemical endpoint data on SHPT progression in ND-CKD patients, it needs to be emphasised that there are no hard endpoint data available on ERC with regard to meaningfully ameliorating the clinical disease burden (fractures, cardiovascular events etc.) of affected patients.
Appraise the influence of OPERA & PRIMO trials on KDIGO 2017 guide.
Discuss the rationale for needing to establish cut-off targets for safe upper PTH levels in non-dialysis patients.
Discuss the value of individualized treatment of SHPT.
Discuss extended-release calcifediol (ERC) as a future option for treatment of SHPT.
1. The OPERA and PRIMO trials that conducted on CKD patients Not on dialysis showed that using active vitamin D (Paricalcitol) will cause high risk of hypercalcemia without improving hard end points like cardiovascular events. So the kadigo guidelines 2017 reserve the usage of paricalcitol to sever progessive PTH in advanced stage CKD.
2. The rationale of establishing cutoff targets on ND CKD patient is important because is still not known until now. (For CKD on dialysis , it is 2-9 the UL.)
The absence of clear cutoff for CK- ND will lead to overtreatment causing low turnover bone disease and increasing cardiovascular calcification, high risk for hypercalcemia and hyperphosphatemia.
On the other hand, not treating high PTH level in CKD -ND patient will causes following risk:
*High PTH level in predialysis patient is associated with higher PTH after 1 year on HD with more anti parathyreoid medical usage.
* Resistance of parathyroid gland to medical treatment, loss of sensitivity to. Calcium and vitamin D in later course of CKD.
*High turnover bone disease, osteitis fibrosa cystica and increased risk of fracture and cardiovascular outcome.
*Spanish study NEFRONA showed that hyperphosphatemia and high iPTH are independent factors that associated with increased risk of CKD progression and increased cardiovascular events.
* High PTH is also associated with increased risk of atrial fibrillation, CKD progression, graft failure and nephrocalcinosis.
3. Individualized treatment of sHPT is based on sex, age ,race and comorbidities recognition of different patient phenotypes. For example having high PTH above 600 pg/mL , calcium above 10.2 snd phosphate sbove 5.5 carried significant risk of cardiovascular death.Elevated PTH alone was not associated with death if other parameters under good control.
4. ERC as future option for treatment of sHPT :
They are very effective in reducing iPTH above 30 percent in 6 month in more than one third of patient. They are safe and don’t cause hypercalcemia and hyperphophatemia. In order to fully suppress PTH, 25 OH vitamin D should go above 50.
ERC don’t activate 24 hydroxylase, which mean that more endogenous Calcitriol remaining in charge.
There is no hard data about end points like fractures and cardiovascular events.
thanks dr Nour for your effort
he influence of OPERA & PRIMO trials on KDIGO 2017 guide
In fact, both trials had some limitations
-First, the primary goal of the PRIMO and OPERA studies was not the biochemical control of SHPT, but the potential prevention of left ventricular hypertrophy development.
-Second, study participants only had moderate SHPT, comparably quite high doses of paricalcitol were used in these trials (2 and 1 μg/day, respectively)
– Also, significant percentage of patients received calcium-based phosphate binders.
These reasons could probably explain the high incidence of hypercalcaemic episodes. Furthermore, this study design may have led to ‘oversuppression’ of PTH secretion on the one hand and to fibroblast growth factor 23 (FGF23) overstimulation which could negatively impact myocardial remodeling, and thus the lack of efficacy to improve the cardiovascular study endpoint of left ventricular hypertrophy amelioration
**Appraise the influence of OPERA & PRIMO trials on KDIGO 2017 guide.
The trails of opera and primo did not demonstrate improvement in clinical outcomes but show increase in risk of hypercalcimia, these studies focused on the cv endpoints and not targeting PTH control specifically or patients outcome , the 2017 kdigo guidelines no longer recommend routine use of calcitriol or its analogues in ckd stage 3 a – 5, active vitamin D increase risk of hypercalcimia is confirmed without the previous studies
The goal of these studies is prevention of LVH, they use high doses of paricalcitol and calcium based phosphate binders and patients show moderate SHPT but with episodes of hypercalcimia, show overstmulation of FGF23 which potentiate negative myocardial remodeling
**Discuss the rationale for needing to establish cut-off targets for safe upper PTH levels in non-dialysis patients.
PTH is a uremic toxins increase FGF23 which associated with fractures, atrial fibrillation, CV event, rapid progression to dialysis and rapid deterioration of residual renal function, excessive use of health care resources and death.
Also associated with arrhythmia and CV events in normocalcimic and /or hypercalcimia primary HPT and risk of nephrocalcinosis and graft failure in Kidney Transplant patient.
**Discuss the value of individualized treatment of SHPT.
To identify different patients phenotypes the use of clinical and biochemical data as age, gender, race and comorbidities and most frequently biomarkers used were Calcium, phosphorous, PTH.
These data allow identification of CKD-MBD phenotype and different CV or any causes of mortality risk.
Example PTH above 600pg/ml, CA above 10.2 mg/dl, phosphorous above 5.5 mg/dl carry high risk of CV hospitalization or death compared with PTH 150-300pg/ml, Ca 8.2-10.2mg/dl and phosphate 3.5-5.5 mg/dl
**Discuss extended-release calcifediol (ERC) as a future option for treatment of SHPT
Uses in patients with stage 3-4 CKD, is given orally and is provide slow and steady transport of calcifediol from the intestinal lumen.
It is mechanism the same as vitamin D lower PTH, increase 1,25 dihydroxy vitamin D but without increasing calcium and phosphorus significantly and no negative feedback
thanks dr Esraa great effort About the rationale for needing to establish cut-off targets for safe upper PTH levels in non-dialysis patients:
. A main reason of absent consensus about the optimal iPTH target in non- dialysis CKD is the fat that optimal PTH targets may be quite different depending on the observed bone, renal or cardiovascular outcome.
regarding ERC, It is noteworthy to mention that no hard endpoint data available on ERC with regard ameliorating the clinical disease burden (fractures, cardiovascular events etc.)
Discuss the rationale for needing to establish cut-off targets for safe upper PTH levels in non-dialysis
Discuss the value of individualized treatment of SHPT.
Discuss extended release calcifediol (ERC) as a future option for treatment of SHPT.
Appraise the influence of OPERA & PRIMO trials on KDIGO 2017 guidelines
thanks dr Mahmoud, please try to further explain your answers:
regarding individualized treatment of SHPT these different phenotypes may may be distinctive in age, sex, race or even laboratory markers of CKD-MBD which was noted by BLOK et al.
also regarding ERC, it has specific formulation with different pharmacokinetic leading to steady level of vitamin D in circulation which suppresses iPTH more effectively without safety concerns of hypercalcemia and hyperphosphatemia, however further studies wit hard clinical endpoints are still needed
lastly, A main reason of absent consensus about the optimal iPTH target in non- dialysis CKD is the fat that optimal PTH targets may be quite different depending on the observed bone, renal or cardiovascular outcome.
1-Appraise the influence of OPERA & PRIMO trials on KDIGO 2017 guide.
PRIMO and OPERA thought to avoid left ventricular hypertrophy, not biochemically regulating secondary hyperparathyroidism. In addition, research participants had moderate secondary hyperparathyroidism, received high doses of paricalcitol 2 and 1 μg/day and a considerable fraction got calcium-based phosphate binders. So several factors may explain hypercalcemia’s prevalence. The research design may have caused “over suppression” of PTH secretion and “overstimulation” of FGF23, which might cause unfavorable myocardial remodeling and hence failed to enhance the cardiovascular study endpoint of left ventricular hypertrophy ameliorations
2-Discuss the rationale for needing to
establish cut-off targets for safe upper PTH levels in non-dialysis patients.
Because rising in pth start earlier before diyalisis so high PTH is associated with increased risk of progression of CKD.
Untreated hyperparathyroidism will progress secondary hyperparathyroidism and even tertiary hyperparathyroidism
That lead to increase cardiovascular complications e.g arrythmia and LVH
High PTH is associated with increased risk of nephrolithiasis .
On the other hand oversuppression of parathyroid gland will result in adynamic bone disease
3-Discuss the value of individualized treatment of SHPT.
Individualized treatment of secondary hyperparathyroidism was preferred approach for managing this condition in non-dialysis chronic kidney disease patients.
Guidelines suggest start the use of vitamin D derivatives for patients with severe and progressive hyperparathyroidism, and this approach should be stopped when risks associated with excessive suppression of PTH.
4-Discuss extended-release calcifediol (ERC) as a future option for treatment of SHPT
Is a prohormone of calcitriol in prolonged release formulation resulting in a slow and steady release of the drug no peak lead to increase vitamin D without need for activation and no negative feed back.
ERC associated with lower hospitalization and decreased LVH.
And need further study to detect ideal uses and cut end point
thanks dr Rabab for your effort
About the rationale for needing to individualie iPTH target:
. A main reason of absent consensus about the optimal iPTH target in non- dialysis CKD is the fat that optimal PTH targets may be quite different depending on the observed bone, renal or cardiovascular outcome. MOREOVER, Blok et al reported >35 phenotypes of patients with SHPT different in lab markers of KD-MBD with different prognosis for each phenotypes. the prognosis also is affected by other factors e.g age, sex, race and trends of the lab markers rather than the absolute values. all these factors have an impact on treatment strategies and therapeutic targets of iPTH
1. Appraise the influence of OPERA & PRIMO trials on KDIGO 2017 guide.
The PRIMO and OPERA studies’ findings -which did not mention hard endpoints and threshold data- led to the revision of the earlier KDOQI and KDIGO guidelines. It became reasonable to reserve the use of an active oral vitamin D for patients with CKD 4 and 5 who had severe and progressive SHPT. There was no definition given for “severe and progressive SHPT.”
The main objective of the PRIMO and OPERA was to avoid the development of left ventricular hypertrophy, not hyperparathyroidism.
Participants exhibited a moderate level of SHPT; nevertheless, participants received comparably high doses of paricalcitol (2 and 1 g/day, respectively), and the increased number of patients using calcium-based phosphate binders resulted in a significant incidence of hypercalcemia. Additionally, the design of the study stimulated FGF23 and over-suppressed PTH.
2. Discuss the rationale for needing to establish cut-off targets for safe upper PTH levels in non-dialysis patients.
While cut-off values are available for CKD-5D, such values are missing for ALL non-dialysis CKD stages. SHPT starts very early in the course of CKD, and missing such targets leaves CKD-MBD either overtreated (leading to adynamic bone disease) or undertreated (leading to SHPT).
In both cases there is excess CVD morbidity and mortality.
3. Discuss the value of individualized treatment of SHPT.
One should be careful when labelling a patient as having SHPT, two individuals with the same iPTH may have 2 opposing diseases (ABD vs SHPT), so careful consideration should be done for other markers of bone activities to reach a conclusion of SHPT.
Once diagnosed, treatment options should be tailored to patients’ other biochemical profiles
4. Discuss extended-release calcifediol (ERC) as a future option for treatment of SHPT.
In phase 3 clinical studies for CKD 3-4, oral ERC was safe and effective. 429 patients with SHPT and vitamin D insufficiency got 30 g ERC or placebo daily for 12 weeks, followed by a possible uptitration to 60 g ERC and an open-label extension study.
At six months, one-third of patients achieved the primary objective of a 30% PTH drop. In the open-label extension phase, placebo patients switched to ERC and had a similar decline in serum PTH as those in the RCTs. Throughout the 12-month investigation, ERC therapy was constant and effective. To completely block SHPT, serum total 25(OH)D levels must reach 50 ng/ml on average.
Extended Release Calcifediol (ERC) was authorized in 2016 for CKD patients in stages 3-4 with progressing SHPT. ERC is taken orally and provides a delayed and consistent release across its entire intestinal transit and stable low-level prohormone absorption.
It does not stimulate 24-a-hydroxylase, so the drug remain active
thanks dr Hassan for your effort:
About the rationale for needing to establish cut-off targets for safe upper PTH levels in non-dialysis patients:
. A main reason of absent consensus about the optimal iPTH target in non- dialysis CKD is the fat that optimal PTH targets may be quite different depending on the observed bone, renal or cardiovascular outcome. MOREOVER, Blok et al reported >35 phenotypes of patients with SHPT different in lab markers of KD-MBD with different prognosis for each phenotypes. the prognosis also is affected by other factors e.g age, sex, race and trends of the lab markers rather than the absolute values. all these factors have an impact on treatment strategies and therapeutic targets of iPTH
also regarding ERC, it has specific formulation with different pharmacokinetic leading to steady level of vitamin D in circulation which suppresses iPTH more effectively without safety concerns of hypercalcemia and hyperphosphatemia, however further studies wit hard clinical endpoints are still needed
The influence of OPERA & PRIMO trials on KDIGO 2017 guide
The rationale for needing to establish cut-off targets for safe upper PTH levels in non-dialysis patients
a) The need to establish cut-off targets for safe upper PTH levels in dialysis patients.
b) Reservation of vitD to treat a severe sHPT.
c) The optimal target of which bone- renal- and CV outcomes is taken into an account.
The value of individualized treatment of SHPT.
a) BLAP, bone-specific AP.
b) intact-Purine nucleoside phosphorylase, PNP.
c) Tartarate-resistant acid phosphatase 5b (TRAB5P).
a) Age.
b) Sex.
c) Race.
d) Comorbidities.
e) Traditional and novel biomarkers.
f) Inflammation.
g) Microbiota.
In summary, the result of the evaluation gives different patient phenotypes and plans a treatment strategy
for extended-release calcifediol (ERC) as a future option for the treatment of SHPT
thanks dr Kamal for your effort
The influence of OPERA & PRIMO trials on KDIGO 2017 guide
In fact, both trials had some limitations
-First, the primary goal of the PRIMO and OPERA studies was not the biochemical control of SHPT, but the potential prevention of left ventricular hypertrophy development.
-Second, study participants only had moderate SHPT, comparably quite high doses of paricalcitol were used in these trials (2 and 1 μg/day, respectively)
– Also, significant percentage of patients received calcium-based phosphate binders.
These reasons could probably explain the high incidence of hypercalcaemic episodes. Furthermore, this study design may have led to ‘oversuppression’ of PTH secretion on the one hand and to fibroblast growth factor 23 (FGF23) overstimulation which could negatively impact myocardial remodeling, and thus the lack of efficacy to improve the cardiovascular study endpoint of left ventricular hypertrophy amelioration
1- Appraise the influence of OPERA & PRIMO trials on KDIGO 2017 guide.
– results of the PRIMO and OPERA led to reformulation of previous KDOQI and KDIGO as it became reasonable to reserve use an active oral vitamin D sterol for patients with CKD G4–G5 with severe and progressive SHPt, but they did not mentioned hard endpoints and threshold data, also definition of ‘severe and progressive SHPT not be provided, primary goal of the PRIMO and OPERA prevention of left ventricular hypertrophy development not hyperparathyroidism also participants had moderate SHPT, comparably high doses of paricalcitol (2 and 1 μg/day, respectively) and increase no. of patients received calcium-based phosphate binders lead to high incidence of hypercalcemic. Furthermore, study design led to PTH over suppression and FGF23) overstimulation
2- Discuss the rationale for needing to establish cut-off targets for safe upper PTH levels in non-dialysis patients.
Due to adverse effects of secondary hyperparathyroidism on long-term health outcomes.
A) Cardiovascular disease and mortality.
B) If left untreated sever progressive increase in PTH levels,
C) Increased risk of fractures, cardiac arrhythmias,
D) Increase risk of progression to dialysis.
E) Greater risk of Nephrocalcinosis
F) Graft failure in renal transplant patients.
G) Cut-off targets for safe upper PTH levels in non-dialysis patients is necessary in order to improve outcomes.
3- Discuss the value of individualized treatment of SHPT.
Individualized treatment of SHPT is the preferred approach in non-dialysis chronic kidney disease .
Guidelines recommend the use of vitamin D derivatives for severe and progressive hyperparathyroidism, and should be weighed against the risks of excessive suppression of PTH.
4- Discuss extended-release calcifediol (ERC) as a future option for treatment of SHPT.
extended-release calcifediol an oral prohormone of calcitriol in an prolonged release formulation resulting in a slow and steady release of the drug lead to increase vitamin D and decrease PTH in ND-CKD patients with moderate SHPT. ERC associated with lower hospitalization and decreased LVH..
no data on ERC regarding endpoints ie fractures, cardiovascular events so further studies needed to evaluate the long-term efficacy and safety of ERC for the treatment of SHPT in ND-CKD patients.
About the rationale for needing to individualie iPTH target:
. A main reason of absent consensus about the optimal iPTH target in non- dialysis CKD is the fat that optimal PTH targets may be quite different depending on the observed bone, renal or cardiovascular outcome. MOREOVER, Blok et al reported >35 phenotypes of patients with SHPT different in lab markers of KD-MBD with different prognosis for each phenotypes. the prognosis also is affected by other factors e.g age, sex, race and trends of the lab markers rather than the absolute values. all these factors have an impact on treatment strategies and therapeutic targets of iPTH
First of all, the OPERA AND PRIMO TRIALS is focused on the cardiovascular endpoint rather than the level of PTH or any other hard or patient-centred outcomes. PRIMO and OPERA are not addressed the fact that active vit D increase the risk of hypercalcemia.
While the KIDOGO 2017 recommendation is not to use vit D and calcitriol on a routine
base.
Both Trial PRIMO and OPERA confirm that active vit D increases hypercalcemia risk.
Discuss the rationale for needing to establish cut-off targets for safe upper PTH levels in non-dialysis patients.
It is important to have a cut-off limit for the PTH level in CKD stages 3 to 5 for trying to control the PTH level and minimizing the complications like cardiovascular and mortality.
For that, it is crucial to have a cute off level for the PTH in CKD stge 3 to 5 non D .
Discuss the value of individualized treatment of SHPT.
To treat the SHPTH case by case, this is the approach which is highly recommended now. As you will try to avoid early use of VItD drivatevs and keep it for a very high PTH level
adding to that, PTH need to look for the trend and need to check with the lab the type of assay used in PTH analysis and need to consider other biomarkers in the context of clinical scenario to take the decision about the type of bone disease the patient has and treated accordingly.
it is a prohormone of calcitriol, so far, it has shown a decrease in PTH level without causing Hypercalcem ia or hyperphosphatemia.
It is not activated 24 hydroxyls and has no negative feedback
thanks dr Rihab for your effort
The influence of OPERA & PRIMO trials on KDIGO 2017 guide
In fact, both trials had some limitations
-First, the primary goal of the PRIMO and OPERA studies was not the biochemical control of SHPT, but the potential prevention of left ventricular hypertrophy development.
-Second, study participants only had moderate SHPT, comparably quite high doses of paricalcitol were used in these trials (2 and 1 μg/day, respectively)
– Also, significant percentage of patients received calcium-based phosphate binders.
These reasons could probably explain the high incidence of hypercalcaemic episodes. Furthermore, this study design may have led to ‘oversuppression’ of PTH secretion on the one hand and to fibroblast growth factor 23 (FGF23) overstimulation which could negatively impact myocardial remodeling, and thus the lack of efficacy to improve the cardiovascular study endpoint of left ventricular hypertrophy amelioration
also regarding ERC, despite promising biochemical endpoint data on SHPT progression in ND-CKD patients, no hard endpoint data available affeting disease burden (fractures, cardiovascular events etc)
1. Appraise the influence of OPERA & PRIMO trials on KDIGO 2017 guide.
The primary goal of the PRIMO and OPERA studies was to potentially prevent left ventricular hypertrophy development, however, their results failed to demonstrate improvements in clinically relevant outcomes and instead demonstrated increased risks of hypercalcemia.
The 2017 guideline update no longer recommends the routine use of calcitriol or its analogs in adults with CKD G3a-G5. This 2017 recommendation represented a major paradigm shift with regard to previous clinical practice and is an important influence of the OPERA and PRIMO trials on the KDIGO 2017 guidelines.
2. Discuss the rationale for needing to establish cut-off targets for safe upper PTH levels in non-dialysis patients.
The establishment of cut-off targets for safe upper PTH levels in non-dialysis patients is necessary due to the potential adverse effects of secondary hyperparathyroidism (SHPT) on long-term health outcomes, including cardiovascular disease and mortality. If left untreated, SHPT can lead to a progressive increase in PTH levels, which can result in an increased risk of fractures, cardiac arrhythmias, and other cardiovascular events, as well as an increase in the risk of progression to dialysis. Additionally, elevated PTH levels have been associated with a greater risk of nephrocalcinosis and graft failure in renal transplant patients.
Therefore, establishing cut-off targets for safe upper PTH levels in non-dialysis patients is necessary in order to reduce the risk of these potentially serious health consequences and improve or better define the control of SHPT in order to improve outcomes.
3. Discuss the value of individualized treatment of SHPT.
Individualized treatment of secondary hyperparathyroidism (SHPT) is increasingly becoming the preferred approach for managing this condition in non-dialysis chronic kidney disease (ND-CKD) patients.
Guidelines suggest reserving the use of vitamin D derivatives for patients with severe and progressive hyperparathyroidism, and this approach should be weighed against the risks associated with excessive suppression of PTH.
For individualized treatment of SHPT to be successful, doctors must have access to accurate biomarkers that can be used to make treatment decisions.
4. Discuss extended-release calcifediol (ERC) as a future option for treatment of SHPT.
ERC is an orally administered prohormone of calcitriol in an extended (or prolonged) release formulation which creates specific pharmacokinetic properties, resulting in a slow and steady release of calcifediol.
This formulation has been shown to increase vitamin D levels and decrease PTH levels in ND-CKD patients with moderate SHPT. Clinical studies have also demonstrated that ERC is associated with lower hospitalization rates and decreased LVH.
Excessive suppression of PTH could result in low-turnover bone disease or inadequate SHPT control causing hyperparathyroid bone disease.
Currently no data on ERC regarding endpoints such as fractures or cardiovascular events. Therefore, further studies are needed to evaluate the long-term efficacy and safety of ERC for the treatment of SHPT in ND-CKD patients.
About the rationale for needing to individualize iPTH target:
. A main reason of absent consensus about the optimal iPTH target in non- dialysis CKD is the fat that optimal PTH targets may be quite different depending on the observed bone, renal or cardiovascular outcome. Moreover, Block et al reported >35 phenotypes of patients with SHPT different in lab markers of CKD-MBD with different prognosis for each phenotypes. the prognosis also is affected by other factors e.g age, sex, race and trends of the lab markers rather than the absolute values. all these factors have an impact on treatment strategies and therapeutic targets of iPTH
also, The influence of OPERA & PRIMO trials on KDIGO 2017 guide
In fact, both trials had some limitations
-First, the primary goal of the PRIMO and OPERA studies was not the biochemical control of SHPT, but the potential prevention of left ventricular hypertrophy development.
-Second, study participants only had moderate SHPT, comparably quite high doses of paricalcitol were used in these trials (2 and 1 μg/day, respectively)
– Also, significant percentage of patients received calcium-based phosphate binders.
These reasons could probably explain the high incidence of hypercalcaemic episodes. Furthermore, this study design may have led to ‘oversuppression’ of PTH secretion on the one hand and to fibroblast growth factor 23 (FGF23) overstimulation which could negatively impact myocardial remodeling, and thus the lack of efficacy to improve the cardiovascular study endpoint of left ventricular hypertrophy amelioration
Thanks dr Mohammed for your effort
1-The influence of OPERA & PRIMO trials on KDIGO 2017 guide
In fact, both trials had some limitations
-First, the primary goal of the PRIMO and OPERA studies was not the biochemical control of SHPT, but the potential prevention of left ventricular hypertrophy development.
-Second, study participants only had moderate SHPT, comparably quite high doses of paricalcitol were used in these trials (2 and 1 μg/day, respectively)
– Also, significant percentage of patients received calcium-based phosphate binders.
These reasons could probably explain the high incidence of hypercalcaemic episodes. Furthermore, this study design may have led to ‘oversuppression’ of PTH secretion on the one hand and to fibroblast growth factor 23 (FGF23) overstimulation which could negatively impact myocardial remodeling, and thus the lack of efficacy to improve the cardiovascular study endpoint of left ventricular hypertrophy amelioration
2-About the rationale for needing to individualie iPTH target:
. A main reason of absent consensus about the optimal iPTH target in non- dialysis CKD is the fat that optimal PTH targets may be quite different depending on the observed bone, renal or cardiovascular outcome. MOREOVER, Blok et al reported >35 phenotypes of patients with SHPT different in lab markers of KD-MBD with different prognosis for each phenotypes. the prognosis also is affected by other factors e.g age, sex, race and trends of the lab markers rather than the absolute values. all these factors have an impact on treatment strategies and therapeutic targets of iPTH
2-Discuss the rationale for needing to establish cut-off targets for safe upper PTH levels in non-dialysis patients.
HPT increase progression of CKD and mortality due to increase vascular calcification.
HPT increase nephrolithiasis incidence.
low PTH result in ABD .
3- Discuss the value of individualized treatment of SHPT.
4- Discuss extended-release calcifediol (ERC) as a future option for treatment of SHPT.
ERC is a prohormone of calcitrol,
sought to avoid left ventricular hypertrophy,
thanks dr Ashraf for your effort
about individualized treatment of SHPT
the prognosis also is affected by other factors e.g age, sex, race and trends of the lab markers rather than the absolute values. all these factors have an impact on treatment strategies and therapeutic targets of iPTH
PRIMO and OPERA sought to avoid left ventricular hypertrophy, not biochemically regulating SHPT. In addition, research participants had moderate SHPT, received high doses of paricalcitol (2 and 1 μg/day, respectively), and a considerable fraction got calcium-based phosphate binders. Several factors may explain hypercalcemia’s prevalence. This research design may have caused “over suppression” of PTH secretion and “overstimulation” of FGF23, which might cause unfavorable myocardial remodeling and hence failed to enhance the cardiovascular study endpoint of left ventricular hypertrophy amelioration.
Several new clinical recommendations advise doctors neither to wait until severe SHPT is apparent nor to entirely correct PTH levels in CKD non-dialysis patients.
CKD’s bone hyporesponsiveness to PTH and PTH’s phosphaturic characteristics explain this final advice. PTH, a uraemic toxin, elevates FGF23 and is independently linked with fractures, atrial fibrillation, cardiovascular events, progression to dialysis, faster loss in residual renal function, healthcare resource consumption, and mortality in observational studies. PTH is also linked to arrhythmias, cardiovascular events, and nephrocalcinosis in normocalcemic and hypercalcemic primary HPT.
Personalizing CKD-MBD therapy is the latest therapeutic challenge. In addition to age, sex, race, and comorbidities, classic and new indicators should be investigated to identify possible patient phenotypes, as recommended by Block et al.
in a prevalent dialysis patient group. In this study, the contemporary occurrence of either low, within, or above empirically identified reference range values for the three most frequently assayed biomarkers—calcium, phosphate, and PTH—identified 36 possible CKD-MBD phenotypes with potentially different cardiovascular or any cause mortality risk.
For instance, having all three parameters in the “high” category (PTH >600 pg/ml, calcium >10.2 mg/dl, and phosphate >5.5 mg/dl) increased the risk of death and pooled cardiovascular hospitalization or death compared to the reference phenotype (PTH 150–300, calcium 8.2–10.2, and phosphate 3.5–5.5). If calcium and phosphate were effectively regulated, PTH >600 pg/mL alone did not increase risk.
Discuss extended-release calcifediol (ERC) as a future option for the treatment of SHPT
ERC was authorized in 2016 for ND-CKD patients in stages G3–G4 with progressing SHPT. Extended-release calcitriol prohormone ERC is taken orally. This formulation provides particular pharmacokinetic features, resulting in a delayed and consistent release of calcifediol across its entire intestinal transit and stable low-level prohormone absorption.
Oral ERC was safe and effective in phase 3 clinical studies for CKD stages G3–G4. 429 individuals with SHPT and vitamin D deficiency received 30 μg ERC or placebo daily for 12 weeks, followed by possible up-titration to 60 μg and an open-label extension research.
One-third of patients met the main goal of a 30% PTH decrease after six months. In the open-label extension phase, placebo patients switched to ERC and had a similar drop in serum PTH as those in the RCTs. ERC therapy was consistent and successful throughout the 12-month experiment. To inhibit SHPT fully, mean serum total 25(OH)D levels are required to rise to 50 ng/ml.
thanks dr Weam for your comprehensive answers
Appraise the influence of OPERA & PRIMO trials on KDIGO 2017 guide.
PRIMO was a multicentric, multinational, double blinded randomized, placebo controlled trial included 227 patients ( ckd+ Lt.ventricle hypertrophy+ preserved ej.fraction), 112 received placebo, while 115 received oral paricalcitol 2 μg for 48 wks, hypercalcemia was developed in 22.6% of parcalcitol arm vs 0.9% in placebo arm (P<0.001), and higher number of patients withdraw from the study because of adverse effects mainly hypercalcemia 9.6% vs 4.5% respectively.
OPERA compared lower dose of oral parcalcitol 1 μg vs placebo. hypercalcemia was developed in 43.3% of parcalcitol arm vs 3.3% in placebo arm (P<0.001),
So,2017 guidelines state that on longer routine use of calcitrol or its analogues in adults with CKD G3a-G5, only can be used for patient with progressively increased PTH
Discuss the rationale for needing to establish cut-off targets for safe upper PTH levels in non-dialysis patients
High PTH is associated with increased risk of progression of CKD
Increased predialysis PTH herald high post dialysis PTH and need of higher doses of anti-parathyroid drugs
Untreated hyperparathyroidism will progress
Untreatment of hyperparathyroid decrease sensitivity of parathyroid gland
High PTH is associated with cardiovascular complications e.g arrythmais
High PTH is associated with increased risk of nephrolithiasis and censored graft loss
On the other hand oversuppression of parathyroid gland will result in adynamic bone disease
Discuss the value of individualized treatment of SHPT
PTH level alone should not be the target as shown by Block et al that PTH within the target levels is not associated with any complications if there is no hypercalcemia or hyperphosphatemia, while (PTH> 600 + Hypercalcemia+ hyperphosphatemia) was associated with greater risk of death mainly from cardiovascular complications.
So ttt of Hyperparathyroidism:
should consider other parameters like bone formation and bone resorption biomarkers, calcium and phosphorus levels
should depend on trend not single reading
Extended release calcifedol It is a prohormone of calcitrol, kept in a lipophilic, wax- like capsule, so released over 12 hours, so no peak, thus preventing activation of 24-hydroxylase. ERC effectively increase 25(oh) vit D, decrease PTH, without causing hypercalcemia and hyperphosphatemia.
thanks dr Ahmed for your effort
The influence of OPERA & PRIMO trials on KDIGO 2017 guide
In fact, both trials had some limitations
-First, the primary goal of the PRIMO and OPERA studies was not the biochemical control of SHPT, but the potential prevention of left ventricular hypertrophy development.
-Second, study participants only had moderate SHPT, comparably quite high doses of paricalcitol were used in these trials (2 and 1 μg/day, respectively)
– Also, significant percentage of patients received calcium-based phosphate binders.
These reasons could probably explain the high incidence of hypercalcaemic episodes. Furthermore, this study design may have led to ‘oversuppression’ of PTH secretion on the one hand and to fibroblast growth factor 23 (FGF23) overstimulation which could negatively impact myocardial remodeling, and thus the lack of efficacy to improve the cardiovascular study endpoint of left ventricular hypertrophy amelioration
2-regarding ER no available studies with hard outcomes ameliorating the clinical disease burden
1.Appraise the influence of OPERA & PRIMO trials on KDIGO 2017 guidelines
-Critical appraisal of OPERA & PRIMO trials
2.Discuss the rationale for needing to establish cut-off targets for safe upper PTH levels in non-dialysis
3.Discuss the value of individualized treatment of SHPT.
-Examples
4.Discuss extended release calcifediol (ERC) as a future option for treatment of SHPT.
-Features of ERC
-Efficacy of ERC
-Safety
thanks dr Ben Lomatayo for your great effort