August 2017

Glomerulonephritis and Hypertension

 TESTING Corticosteroids in the treatment of IgA nephropathy

TESTING  was a multicenter, double-blind, randomized clinical trial which planned to enroll 750 participants with IgA nephropathy (proteinuria greater than 1 g/d and estimated glomerular filtration rate [eGFR] of 20 to 120 mL/min/1.73 m2) after at least 3 months of blood pressure control with renin-angiotensin system blockade. Steroid (oral methylprednisolone 0.6-0.8mg/kg/day for 8 weeks followed by monthly taper by 8mg) was compared with placebo.  After 1/3rd of the sample size (n=262) was reached, the significantly higher incidence of serious adverse events, in particular, infections in the steroid arm,  led to the decision to terminate the trial early.  Improvement in proteinuria and rate of GFR decline was reported in the treatment arm, however, due to premature termination of the trial, results can’t be considered conclusive. Limited power due to premature termination of the trial might have overestimated both benefits and harms of immunosuppression and this is for sure not the time to abandon immunosuppression in IgA nephropathy. However, several lessons are learned from recently published trials:

One, steroid treatment reduces proteinuria and may slow down the rate of GFR decline. This systematic review of literature summarizes the evidence on corticosteroid use and concluded that steroids have beneficial effect in reducing proteinuria and slowing GFR decline.  Reduction in proteinuria (without an effect on renal function) was also evident in recently published STOP IgA trial which also raised safety concern due to a higher incidence of side effects. Second, lack of systematic reporting of steroid side effects might have underestimated the harm of prolonged steroid therapy in previous trials. Both STOP IgA and TESTING call for a careful assessment of risk-benefit before choosing to immunosuppress. The role of aggressive RASi (as shown by STOP IgA) is underestimated and this should be offered to all the patients. Current guidelines of prolonged steroid treatment in IgA nephropathy with subnephrotic proteinuria will need to be reviewed in the light of  STOP IgA and TESTING trials. We need better tools to identify right patients, the degree of proteinuria alone may be too crude a measure. Third, whether the risk-benefit profile of immunosuppression can be improved by adding steroid sparing agent, antibiotic prophylaxis, incorporating pathology features that predict response, testing for galactose deficient IgA1 in serum remains to be seen. Targeted release formulation of steroids showed promise in NEFIGAN trial(reviewed here) and let’s hope that these results will replicate. Finally, as suggested by authors, caution is needed in the interpretation of eGFR in patients on corticosteroids as it can be affected by steroids (due to sarcopenia and  hyperfiltration)  

We know that some patients with IgA nephropathy need immunosuppression, however, several issues like patient selection, appropriate drug, and dosage, remains to be sorted out.  

 Redefining Lupus Nephritis

Discussion on lupus case by Prof Hase will never be complete without this quote-“The course of the disease is highly variable and unpredictable-this is the only certain thing about lupus nephritis.” A patient who is in remission for years can come with such bad flare that will lead to end stage renal disease. A patient with class IV disease may quickly go into remission and same class IV in an another patient may manifest as renal failure needing dialysis and may recover slowly, often incompletely over months. 

ISN/RPS classification was an improvement over previous WHO classification, however, it does not consider various important histopathological lesions that are increasingly recognized as predictors of outcome. This excellent review in Nature Reviews Nephrology discusses molecular heterogeneity and pathologic complexity of this disease and proposes several modifications in ISN/RPS classification of lupus nephritis. Failure to understand this heterogeneity may underly failure of seemingly promising treatment options in trials. Authors review the evidence showing that two subclasses of class IV disease behave differently. Class IV‑S lesions tend to have more glomerular fibrinoid necrosis and fewer immune deposits than IV‑G lesions, whereas IV‑G lesions behave as a typical immune complex-mediated glomerulonephritis, suggesting pathogenic differences. They propose a treatment algorithm based on histological features that are identified as important predictors of outcome. This article in KI published online studied 32 cases of lupus nephritis who had concomitant MPO ANCA antibodies and compared them with 222 ANCA negative lupus nephritis cases.  ANCA-positive patients had anti-MPO antibodies and were characterized by more class IV-S with glomerular necrosis, higher creatinine, lower C4, higher anti-dsDNA titer. There was no significant difference in the outcome between the two groups, however, as authors conclude, ANCAs appear to influence the histopathologic pattern. Another cohort study in CJASN ( editorial) reports a cohort of 105 patients with lupus nephritis (80% class III or IV) where clinical and histological characteristics associated with renal outcomes were studied. Authors conclude that ISN/RPS classes had a poor association with the clinically relevant outcomes, and prognostication in LN may benefit from the specific assessment of clinical variables and lesions currently obscured in the classification. Awaiting validation of a formal index, authors suggest that at least fibrinoid necrosis, fibrous crescents, and IF/TA warrant explicit independent scoring to assess the risk of progressive renal dysfunction in conjunction with clinical findings. All these are interesting developments, and raise the hope for better assessment of risk and better treatment selections in patients with lupus nephritis. 

 Treating Hypovitaminosis D in children with nephrotic syndrome

Almost every child on steroids for nephrotic syndrome gets calcium and vitamin D supplementation with the hope that it will help minimize steroid induced bone loss. In an RCT published in Pediatric Nephrology involving 48 children with relapse of steroid sensitive nephrotic syndrome, authors studied the effect of vitamin D3 (60,000 IU orally, weekly for 4 weeks) and calcium supplements on bone mineral content and bone mineral density over 6months. In addition, the effect of this intervention on relapse frequency (considering pleiotropic effects) was evaluated. Only thing Vit D supplementation did was to increase blood levels of vitamin D. There was no difference in bone mineral content or density between the groups, in addition, hypercalciuria was noted in a significantly higher number of treated patients which is a safety issue. The practice of looking at serum levels and loading doses can be tempered.  

Hypertension after Hypertensive disorders of  pregnancy 

Pregnancy is a stress test of the vascular health of a woman and 5% of all pregnancies test positive by manifesting preeclampsia. Accumulating evidence suggests that these women continue to carry this ‘vascular risk’ years after delivery as shown in this large cohort study of over 90000 women demonstrating an increased risk of morbidity due to atherosclerotic complications in long term and interestingly odds ratio for renal hospitalisations following preeclampsia (OR 3.7; 95% CI 2.2 to 6.0) was higher than cardiovascular events (OR 2.4; 95% CI 2.2 to 2.8). Here is nationwide cohort study in BMJ from Denmark which adds to our understanding of this risk. 23,235 of 4,82,972 women had a hypertensive disorder of pregnancy in their first pregnancy, and 16 611 developed hypertension during follow-up. 14-32% of women with a hypertensive disorder of pregnancy in their first pregnancy developed hypertension in the decade after delivery, compared with 4-11% of women with normotensive first pregnancies. Rates of post- pregnancy hypertension in women with a hypertensive disorder of pregnancy in the most recent pregnancy was 12-fold to 25-fold higher in the first year post-partum and up to 10-fold higher in the decade after delivery. Risk persisted long after delivery-remained doubled more than 20 years later. So follow up should begin soon after delivery and continue for at least 2-3 decades.

What can be done to modify this risk? This prospective cohort study reports data from Nurses Health Study II on 54,588 parous women aged 32 to 59 years having data on reproductive history. They studied various risk factors for the development of chronic hypertension including 4 lifestyle factors-post pregnancy BMI, DASH diet, physical activity and sodium/potassium intake. Being overweight or obese was the only lifestyle factor consistently associated with higher risk of chronic hypertension. It’s difficult to separate the effect of first 3 lifestyle factors though. So whatever way you achieve it, help them maintain a healthy weight after pregnancy. 

If I’d been born a woman and given a chance, I’d choose Denmark. For millions of less fortunate women preeclampsia is not just a stress test or an opportunity to address metabolic risk; for them, surviving through a preeclamptic pregnancy is still a difficult challenge. For them to get admitted to the casualty, convulsing, with severe hypertension, intrauterine fetal death, and multi-organ dysfunction is not a rare scenario.


What is AKI risk attributable to contrast after intra-arterial contrast exposure in the primary percutaneous coronary intervention(pPCI)?

In this report from Israel, 2025 patients with ST-segment–elevation myocardial infarction who underwent pPCI (cases) and 1025 patients receiving fibrinolysis or no reperfusion and were not exposed to contrast material during the first 72 hours of hospital stay (control group) were studied. AKI rates were similar in the pPCI and control groups (10.3% versus 12.1%, respectively; P=0.38). Even after propensity score matching, AKI rates were not significantly different with and without PCI (8.6% versus 10.9%, P=0.12). 

In addition to general limitations of the propensity score matching, some important limitation of this data should be noted. The study spanned over 15 long years and indication for pPCI changed over time–the possibility of patients at high risk of AKI getting preferentially treated by thrombolysis remains. Over years, awareness and practices might have improved and this could well be the reason for better outcomes after pPCI (after 2007 all cases were treated with pPCI). Finally, it’s not clear if missing data on creatinine favored pPCI group. Nevertheless, this study represents the first to include a control group of patients who were not exposed to contrast in the setting of STEMI.  

 So, intra-arterial contrast associated AKI  is going through the same difficult time as intravenous contrast AKI. “Oh, come on, the risk may not be great, but it exists, there is a strong basic science support to this entity. What is the harm in being just cautious?” is another argument. A couple of weeks ago, we treated a young female on maintenance dialysis who got admitted with dengue hemorrhagic fever, massive hematemesis, hematochezia, requiring multiple pack cells and platelet transfusions. Upper and lower gastrointestinal endoscopies didn’t reveal any bleeder and it was decided to go for an angiogram and endovascular intervention. Radiology fellow who initially just refused to carry out the scan got convinced only after we threatened to wake up his professor in the middle of the night. How can we blame him-this is what ‘scared to marrow’ means. I know of one of the largest cardiac centers in this region which as a policy denies any diagnostic/therapeutic procedure involving contrast in all patients with serum creatinine>2mg/dl. This harm of being ‘just cautious’ will never ever be reported in the literature. Another problem is the disproportionate academic and research space that this entity occupied for years in nephrology-was it worth? 1/3 of AKI guidelines talk about contrast AKI. Are not obstetrics, tropical and cardiac surgery associated AKI specific enough entities? Serum creatinine may increase around the time of contrast administration but is not worth the scare, space, priority.  Disclosure: I am neither married to a cardiologist nor have joined hands with the radiologist (as some of my colleagues are suspicious). 

APOL1 and CKD: is mystery over?

What came into being as survival advantage against sleeping sickness, –polymorphisms in the APOL1 genes (that encode apolipoprotein L; G1 and G2 being risk variants and G0 the reference allele)– is now one of the most important risk factors for kidney disease that is peculiar to African-Americans i.e. non-diabetic CKD, FSGS, and HIV associated nephropathy. While epidemiological observations and genetic studies (reviewed here) have strongly suggested the role of APOL1 in mediating kidney disease in this population, not all individuals and animal models carrying this risk genotype develop kidney disease –suggesting the role of a ‘second hit’ for disease expression. suPAR was reported to be the ‘circulating permeability factor’ causing FSGS but is now considered to be independently associated with incident chronic kidney disease and an accelerated decline in the eGFR. 

To study molecular mechanisms involved in kidney disease expression by APOL1, authors studied two large, unrelated cohorts [Emory Cardiovascular Biobank (EmCAB) and the African American Study of Kidney Disease and Hypertension (AASK)] for APOL1 genetic variants and plasma suPAR levels.  The apol1-related risk was attenuated in patients with lower suPAR and strengthened in those with higher suPAR levels. Using surface plasma resonance (a powerful technique to monitor affinity and selectivity of biomolecular interactions) experiments in mice, they noted that the presence of AOPL1 risk alleles (G1, G2) augments alfa5,beta3 integrin activation on podocytes leading to proteinuria in the presence of high suPAR concentrations. Authors conclude that the synergy of circulating factor suPAR and APOL1 G1 or G2 onalfa5,beta3 integrin activation is a mechanism for CKD in this population. suPAR is a marker of inflammation and immune system activation-it can originate at podocytes or circulation. While these are novel and exciting findings, what are the upstream events leading to elevated suPAR? This keeps open possibilities of ’ second hit’ before clinical manifestation of APOL1 risk alleles. Let’s hope that we get to see a replication of these findings soon and more information on interactions between this tripartite.  

Proton Pump Inhibitors and CKD

PPI and kidney disease has been a topic of discussion and debate recently – this review in Indian Journal of Nephrology by Malavade and Hiremath summarizes the evidence and briefly discusses the shortcomings of observational data. While large observational studies have found that PPI use is associated with a higher risk of CKD,  limitations like unmeasured confounding, residual confounding, confounding by indication, outcome misclassification, inability to account for different eras when drugs were used-all should be carefully considered and therefore PPI-CKD relationship can’t be considered causal. A host of other complications like hip fracture, community acquired pneumonia, Clostridium difficile infection, and dementia have been linked to PPI use, and, as the authors point out, findings could relate to the same sources of bias. Large RCTs to answer this question are unlikely, and this is an opportunity to learn basics of pharmacoepidemiology, and various pitfalls of observational research excellently reviewed in this NDT article. PPI will be definitely indicated to prevent ulcer bleedings and avoid surgeries in some patients, however, unnecessary use has to be actively recognized and discouraged. The article provides a clinically useful algorithm to decide if PPIs can be deprescribed in an individual case. Huge scope for deprescribing here. 

  Dialysis and Transplantation  

Morbidity and mortality after parathyroidectomy (PTX) 

Approximately 10% of the US patients on dialysis undergo PTX for unremitting hyperparathyroidism-this remains so even with the advent of calcimimetics. This large retrospective national database review of over 21000 PTXs, give important insight about surgical complications following this procedure. Morbidity and mortality were significantly higher when PTX was done for secondary versus primary HPT (26.8 versus 4.9%). Pre operative renal function, hypertension, and alkaline phosphatase were predictors of complicated postoperative course. Patients with tertiary hyperparathyroidism faired better (morbidity and mortality 21.8%) probably because their operative risk was modified by RRT (dialysis or transplant). Most of the complications were respiratory, related to neck hematoma and airway compromise indicating the need for intensive post operative monitoring. Although retrospective design and lack of information on outcomes after 30 days are important limitations of the study, this is an important piece of evidence that calls for a more careful assessment of risk-benefit before resorting to PTX. So PTX in secondary HPT is not as safe a procedure as it is in primary HPT. In real life, identifying the right patient for surgery may be an easier task than finding right hand and center to do PTX -not many surgical centers have required interest, surgical skills, and expertise to manage postoperative medical and surgical issues.

Treating the itch

Almost 50 percent of patients on dialysis complain of itching and in some of them, it may interfere with sleep and quality of life. This systematic review of the literature (RCTs) summarizes the evidence on treatment of this poorly understood symptom and found that whatever best evidence we have supports the use of gabapentin for itch.

I was amazed to know that 39 different treatment options are available and they were studied in 44 randomized trials-very few other ‘issues’ that our patients face having been studied so extensively. Most studies that compared active treatment against placebo reported some benefit. Overall RCTs examining this question are characterized by all those features that a good RCT shouldn’t have: the small sample size, high risk of bias, flawed methodology. Study heterogeneity didn’t allow for a meta analysis, however, this review highlights the need for a large well designed RCT which will not only assess itch more objectively but also will report on more relevant outcome measures like sleep and quality of life.

Gabapentin/Pregabalin can put patients to sleep, produce dizziness, imbalance and falls, and I try to reserve them for those few not happy with coconut oil/other topicals. A timely NEJM perspective on use and abuse of gabapentin is here.

RAS inhibition in patients on dialysis 

Survival of patients on dialysis remains poor, and nephrology community is desperately (and rightly) in search of treatments that will improve the same. Statins, more dialysis,  phosphate binding, PTH lowering, anemia correction—nothing is working as expected. CV disease being common in the dialysis population, some believe that strategies like RAS inhibition may work as it does in general population, however, there is a lack of good quality data from large RCTs to specifically answer this question. This meta-analysis in BMC Nephrology tries to compile the available evidence from RCTs looking at the effect of RAS blockade on CV events, residual renal function (RRF), and mortality. Authors concluded that RAS blockade protected residual renal function in PD, however, was largely ineffective in reducing the CV events/mortality. ARB may have a favorable effect of reducing heart failure.  

While the debate about ‘utility of large RCT versus meta-analysis’ in guiding therapy decisions will continue infinitely, quality of meta-analysis (nice CJASN review here) will be largely dependent upon the quality of trials that it contains-garbage in and garbage out. Unfortunately, most of the RCTs addressing this important questions are underpowered, and therefore inconclusive. Larger, and blinded trials were more likely to be negative, and benefit on ‘heart failure’ is questionable if this endpoint is not adjudicated (as is the case with RCT showing benefit). In a survey that I conducted on

TwitterTwitter pole

(responders n=87, this also happens to be the combined sample size of two RCTs showing the efficacy of ramipril and valsartan in preserving RRF!) to understand the prevalent practice,  44% believed that RASi offers BP reduction and that’s all. I am with this majority and manage a dialysis population that has been traditionally practicing ‘incremental’ dialysis -well before this terminology appeared in nephrology literature a few years ago. Some may go for ‘decremental’ dialysis-where patient for various reasons may decrease dialysis frequency to 2 per week/1 per week/1 dialysis whenever needed. Those nightmares aren’t rare when patients land up into casualty with potassium report reading “too high” and an ECG that resembles drawing of a ‘sleeping line’ that my 4-year old daughter makes. So we are not in any better position to decide on the use of RASi in dialysis after this meta-analysis. Cardioprotection from hyperkalemia is a priority and given the available evidence, we currently aren’t obliged to follow the recommendation to use these agents preferentially for the treatment of HTN in patients on dialysis if others are serving the purpose.


Initiation of Sevelamer and Mortality among Hemodialysis Patients Treated with Calcium-Based Phosphate Binders

Here is another retrospective database analysis on the treatment of hyperphosphatemia. 2606 (of total 12,564) patients (from DOPPS) were treated with sevelamer after being initially treated with calcium based phosphate binder. They were compared with matched controls who didn’t switch. Conclusion: use of sevelamer as an add-on or alternative therapy to calcium-based phosphate binders is associated with improved survival. 

Residual confounding, lack of information on reason for switch/addition of sevelamer, possibility of better nutrient intake by add on group, reliance on prescribed information  (and not actual drug intake)—all make it another addition to the heap of retrospective analyses in a sub specialty called as “surrogate nephrology” where P stands for ‘predictions’ and ‘phosphorus’. For a change, you may put anything targeting PTH, FGF 23, fetuin A, vascular calcification, in place of phosphorus and expect statistically significant improved survival. Till date, not a single RCT, has shown that treating phosphorus with sevelamer affects the way patients feel, function and survive. The cost of a month’s treatment with sevelamer is equal to that of 4 dialysis treatments;  few drugs have this privilege of being used so commonly with so little evidence to support its use. Hyperphosphatemia is an important medical issue that starts bothering me once I am done with dialysis adequacy, blood pressure, nutrition, and anemia. Sevelamer may be useful in patients having hypercalcemia, low PTH, and calcified vessels (detected accidentally on imaging done for other reasons). If I use it here, I hope that phosphorus will decrease without calcium going up and I am not as optimistic as others to expect any effect on mortality.

Novel desensitization method using virulence protein of Streptococcus pyogen

We completed graduation studying streptococcus as the villain that “Licks the joint and bites the heart” and spent nights remembering those dozen(10 or 12?) nephritogenic M protein serotypes (only to forget at the time of viva). IgG degrading enzyme of Streptococcus(IdeS) is one of the major virulence factors of this organism that cleaves IgG and thus prevents downstream events like antibody dependent cellular cytotoxicity (ADCC) and complement dependent toxicity (CDC). This article in NEJM   (editorial here)   reports results of a novel method of desensitizing highly sensitized patients using IdeS in 25 recipients who were transplanted in the US (14) and Sweden(11). Dramatic reductions in class 1 and class 2 anti HLA antibody titers were observed following infusion of IdeS 4-6 hours prior to surgery and all (except 1) recipients underwent a successful kidney transplant and had excellent graft and patient outcomes until last follow up at 1.5years. 10 patients developed ABMR and all were treated successfully. 

Lack of long term follow up (will the rebound of anti HLA antibody occur?), the absence of control group, differences in the immunosuppression protocols across two cohorts, are important limitations of this data. Patients with preformed antibody to IdeS (due to previous infections) may theoretically have reduced efficacy and risk of reactions (although this wasn’t observed in this study). Being a virulence factor, whether IdeS will increase the risk of infections, remains to be seen. It is estimated that about 30% of the waitlisted patients are sensitized. Traditional desensitization tools are expensive, imperfect (some patients fail to get desensitized) and are associated with risks like bleeding and infections. Highly sensitized prospective recipients are eagerly awaiting large, randomized, trials with appropriate control groups and longer follow-up duration.

Everolimus: drug in search of an indication in kidney transplantation  

While nephrologists are longing for good quality evidence to guide many day-to-day issues, how much more evidence will be needed to inform us enough that replacing CNI by mTOR without valid indication, is associated with significant harm as indicated by a higher incidence of acute rejection, side effects necessitating discontinuation, graft loss, and mortality? After HERAKLES trial that we discussed last month, here is an international multi centric RCT involving 715 de novo kidney transplant recipients randomized patients to everolimus conversion at 10-12 weeks or to continue standard triple immunosuppression. This is author’s conclusion: conversion to everolimus at 10–14 weeks post-transplant was associated with a similar renal function to standard therapy overall. Rates of BPAR were low in all groups, but lower with tacrolimus than everolimus.

Novartis’s optimism and medical writer’s skills make everolimus non-inferior to standard CNI based immunosuppression in ELEVATE trial, even when composite efficacy endpoint involving outcomes of patient interest  (graft loss, rejections, and death) occurred more often (27 versus 8 patients p=0.02) with everolimus. In addition, patients receiving everolimus were more likely to develop de novo DSA and proteinuria. 

Why don’t they identify the right population (no past rejections, biopsy evidence of CNI toxicity with preserved GFR, low immunological risk) where mTOR may possibly do some good? The way it’s being studied in RCTs of same design one after another is ‘medical assistance in dying’ for everolimus. 

Author: lastmonthinnephrology

Clinicians, interested in 'what matters at bedside', readers, researchers. Tukaram Jamale and Vaibhav Keskar

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