1) MENTORing on Rituxumab for Membranous Nephropathy
Results of the multi-center, open label, MENTOR trial comparing rituximab (RTX) with Cyclosporine (CSA) are here: “Of 130 randomised, 39 of 65 patients (60%) in the RTX group and 34 of 65 (52%) in the CSA group had a complete or partial remission (risk difference, 8 percentage points; 95% CI, −9 to 25; P=0.004 for non-inferiority) at 12 months. At 24 months, 39 patients (60%) in the RTX group and 13 (20%) in the cyclosporine group had a complete or partial remission (risk difference, 40 percentage points; 95% CI, 25 to 55; P<0.001 for both non-inferiority and superiority)”. Authors conclude that RTX is non inferior to CSA at 12 months and was superior to CSA at 24 months in inducing remission of proteinuria.
This data furthers the role of RTX in this disease, but definitely should not be considered enough to use it as first line in most high risk patients with MN. First, choice of the comparator (considered ‘clever’ by accompanying editorial), is not the standard of care for most of us. Both short and long term response rates (proteinuria and ESRD) are reported to be far better in the RCTs involving CYP (about 80-90% vs 60 % with RTX in MENTOR). Second, the strange CSA treatment protocol-in patients who responded CSA was tapered over 2 months, more rapidly than one would generally do in practice [not surprisingly, over half (18 of 34) of those in remission on CSA at 12 months, didn’t maintain the remission at 24 months) and third, an unusually higher rates of side effects and discontinuation in CSA treated patients: 15/65 (23%) in CSA group vs 4/65 (6.15%) in RTX either discontinued therapy due to side effects or were unavailable for final data assessment.
‘Biocreep’ is a trap in non-inferiority trials: if you have a standard of care,say A , based on pivotal studies, you evaluate B to see if its non inferior to A and find that it indeed is. Then you come with an option C and evaluate its non-inferiority against B and show that it indeed is. But then, if we assume that C is non-inferior to A, we end up accepting progressively worse treatments as standard of care, a phenomenon called as biocreeep.
2 Amlodipine is better than Hydrochlorothiazide in BP reduction
In this 3 arm, multi-centre RCT-CREOLE-, involving 728 black hypertensives across 6 countries in Sub-Saharan Africa, combination involving amlodipine [with hydrochlorothiazide (HCTZ) or perindopril] was better at BP lowering as assessed by 24hr ABPM at 6 months (when compared with perindopril plus HCTZ), (between group difference in the change from baseline, −3.14 mm Hg; 95%CI −5.90 to −0.38; P = 0.03; and −3.00 mm Hg; 95% CI, −5.8 to −0.20; P = 0.04, respectively). Authors propose non-BP mechanism like increased endothelial NO bioavailability (which apparently is compromised in blacks), but simpler explanation of the benefit may be: longer half life, improved adherence and better BP lowering efficacy of amlodipine. Also the thiazide arm of the trial might have had a better BP lowering with longer acting and more potent chlorthalidone.
Most important attribute of an anti-hypertensive agent is ‘BP lowering’, which often is forgotten in the noise of evidence, guidelines and propaganda of ‘pleiotropic’ effects. Similar superiority of amlodipine -not only for BP lowering but also for hard CV outcomes-was demonstrated by ACCOMPLISH trial published a decade ago. Its unfortunate to see so many practitioners here switching to fancier ‘dipins’ for the fear of edema at the cost of both rupees and BP control. I love you amlodipine.
3 DOT (Directly Observed Therapy) for apparently treatment resistant hypertension
How do we assess the compliance issue in patients referred for apparently treatment resistant hypertension? Pill counts, pharmacy refill data and direct questioning -which are commonly used tools-can be ‘non-revealing’ in a significant proportion of such patients as highlighted by this work from hypertension clinic, Ottawa, Canada. About 30% of the ‘resistant’ patient showed marked (26mmHg)BP decrease after DOT, while others had less impressive decrease (3mmHg).
Study highlights the major role of compliance in the BP management and the limitations of the conventional tools to assess it. Young hypertensives progressing from onset of CKD to ESRD within months due to uncontrolled BP is a common scenario in our practice and every attempt at controlling BP is likely to yield large benefits, DOT deserves wider exploration.
4 Ready to get TRANSFORMed? Better wait
12 month outcomes of TRANSFORM trial were reviewed previously. Here are 24 month results: “In de novo kidney transplants with low‐to‐moderate immunological risk, the EVR + rCNI regimen is a valid alternative to the standard‐of‐care regimen comprising MPA + sCNI, providing comparable antirejection efficacy, stable renal function, and low rates of mortality and
dnDSA, with an advantage of significantly reduced viral infections,
up to 2 years post-transplantation.” concluded the authors of the largest RCT (TRANSFORM) evaluating non inferiority of ‘de-novo Everolimus facilitated reduced dose CNI regimen’ as compared to standard triple immunosuppression.
Primary endpoint of treated biopsy-proven acute rejection (tBPAR) or eGFR <50 mL at month 24 (47.9% vs 43.7%; difference = 4.2%; 95%CI = −0.3, 8.7; P = .006). You may get transformed, if you can forgo these: the higher rates of rejections, proteinuria, drug discontinuation in the everolimus treated patients. Moreover, proportion of those with eGFR<50ml at 24 months (can’t we now expect at least the better eGFR number with mTOR), was significantly higher in in everolimus treated patients. [474 (46.4%) vs 423 (41.6%) p=040].
As described earlier, Everolimus was protective against CMV and BK infections. While Novartis deserves applause for conducting the largest ever clinical trial in kidney transplantation, where do we go from here? Considering the overall poor efficacy in preventing rejections, poor tolerability, inferior graft function (eGFR) and higher risk of death shown by this meta analysis in patients treated with mTOR, there is no reason for its de-novo use. Probably, the only place for mTOR today may be a patient with documented CNI toxicity on biopsy, preserved GFR and no/minimum proteinuria after careful discussion with the patient.
5 Power of positive thinking
Nephrology community is on the verge of depression for multiple reasons: lack of innovations, workforce crisis and ‘negative trials’-to name a few. Kidney International seems to have realized this and has some lessons on ‘positive thinking’ in this issue. We are referring to the results of the three arm, open label, ATHENA trial evaluating de-novo everolimus (EVERO/TAC vs EVERO/CSA vs TAC/MMF) use in kidney transplantation. Not only did trial failed to show the non inferiority of de novo everolimus arm which was the primary end point, but also, once again, highlighted many of the previously noted serious issues with de-novo mTOR use: higher rejections, higher graft loss and one of the highest rate of study drug discontinuation due to side effects-over 50%!
Inspired by ATHENA– the Greek goddess of the war and courage-, authors fight their best and use the ‘power of positive thinking’ to go on discussing how this defeat can be TRANSFORMED into a win if you change your point of view. They attribute the failure of everolimus to higher than desired TAC levels in the everolimus treated arm (will that not further increase the risk of AR? such questions don’t bother people motivated by the power of positive thinking). This power is further manifest in an accompanying editorial by Novartis (sorry, I mean authors, commentators and sponsors) which conclude that de-novo everolimus/CNI is a viable alternative option for kidney transplant recipients in 2019. Aren’t you still feeling positive and motivated?
6 Serious Adverse Gastrointestinal Events Associated With Sodium Polystyrene Sulfonate
Sodium polystyrene sulfonate (SPS) is in use for hyperkalemia since 1950s , its use has been associated with rare but serious adverse events like colonic necrosis. While initial reports of serious GI issues like colonic necrosis were attributed to sorbitol, these were also reported when SPS was used without sorbitol. Evidence supporting this link was largely case reports and small cohort studies. Here is the largest population-based retrospective cohort study, looking at this issue.
SPS dispensed in an outpatient setting to adults of advanced age (66 years or more) was associated almost 2 fold risk of serious GI adverse events (hospitalization or emergency department visit with intestinal ischemia/thrombosis, GI ulceration/perforation, or resection/ostomy) within 30 days of initial prescription.
SPS use (n=27704) compared with non-use (n=20020) was associated with a higher risk of an adverse GI event over the following 30 days (37 events [0.2%]; incidence rate, 22.97 per 1000 person-years vs 18 events [0.1%]; incidence rate, 11.01 per 1000 person-years) (hazard ratio, 1.94; 95% CI, 1.10-3.41) and risk was consistent irrespective of eGFR, potassium level or presence of other co-morbidity like diabetes or CHF.
Although limited by retrospective design and high risk patient group (mean age of 78 years, many comorbidities,with 20% residing in long-term care facilities), this is the largest documentation of a rare but potentially life threatening complication of SPS use. Time to resort to other measures of K control: diuretics, decreasing dose of RASi, dietary K restriction. While newer agents like patiromer have shown efficacy, they aren’t yet available, cost may be a barrier and their long term GI safety remains to be established.