June 2017

 

1. Targeted-release formulation (TRF) of Budesonide for IgA nephropathy

RCT in Nephrology is that rare occasion to celebrate especially if it is positive. Here is a multi-centre, double-blind, placebo-controlled trial (NEFIGAN) of Targeted-release formulation ((TRF) budesonide versus placebo in patients with IgA nephropathy. Gut mucosal B lymphocytes synthesise abnormally galactose deficient IgA which after complexing with IgG antibodies get deposited in the mesangium and initiate sequence of downstream events: stimulation of cell proliferation, release of inflammatory mediators that promote proteinuria, and fibrotic remodelling, ultimately leading to loss of renal function. High dose systemic corticosteroids have poor safety-efficacy profile especially in patients with sub-nephrotic proteinuria and preserved GFR, best illustrated by STOP IgA and TESTING  (results presented at ERA-EDTA 2016-prematurely terminated for safety concerns) trials )Targeting gut mucosal immune system by TRF-budesonide 8 and 16mg capsules (which delivered drug at distal ileum where density of Payers patches is maximum) was compared with placebo in total of 150 patients who were on optimal RAS blockade at the start. TRF Budesonide group had significantly reduced proteinuria, better GFR and lesser microhematuria at the end of 12months than placebo. Short follow up (to conclude on effect of TRF Budesonide on GFR), and predominantly white population are the limitations of this study.  IgA nephropathy in this part of the world is characterised by marked severity -a disease type that hasn’t been represented in any of the IgA nephropathy trials so far. Nonetheless TRF Budesonide appears promising and larger studies involving diverse patient populations are highly desirable.

 

2. Accepting kidneys from HCV positive donors

Discovery of Directly Acting Anti-viral agents (DAAs) for hepatitis C will be rated as pathbreaking research similar to HAART or penicillins. After initial studies of DAAs, considering exorbitant cost, one of the BMJ bloggers  wrote,”now all the billionaires in the world will be cured of hepatitis C!”  Thanks to the generics and competition in Indian pharmaceutical industry, DAAs are within the reach of most patients needing it today (~INR 30000 for 3 month therapy).  DAAs may also give a new lease of life to the kidney transplant recipients by allowing usage of kidneys from deceased donors with HCV infection (which otherwise would be discarded). THINKER study in NEJM reported, outcomes of 10 HCV-negative adults (of blood group A, B or O, who were undergoing dialysis and who had long anticipated waiting times for a kidney transplant) after deceased donor kidney transplant from a donor with HCV genotype 1 infection. Immunosuppression consisted of IV Steroids and rabbit ATG followed by tacrolimus, MMF, and prednisone. Once the virus was detected in recipient’s blood (which was seen on 3rd post-op day in all the recipients), therapy with elbasvir–grazoprevir was started and continued for 12weeks. All recipients were cured of HCV-defined as a sustained virologic response 12 weeks after the end of treatment. One recipient had delayed graft function, transiently elevated aminotransferase levels developed in two recipients. One patient had proteinuria with kidney biopsy showing FSGS. No graft loss was reported. Although small, this data is highly encouraging and we may be able to recycle most of the kidneys from HCV positive donors in future. 

3.  Looking beyond one year post transplant

Dramatic improvement in short-term results after kidney transplantation today, is in sharp contrast to the static long-term outcome figures. This comprehensive review in Lancet summarises strategies  to improve long-term outcomes after KTR. (unfortunately many potential and few actual). A lot of what was once thought to be -IFTANOS(Interstitial Fibrosis and Tubular Atrophy Not Otherwise Specified)- is attributable to chronic ongoing immune injury to the graft and we are far from precisely diagnosing and treating it. In addition to DSA monitoring which is already the part of standard of care, more sensitive matching techniques like epitope matching done by computer programmes like HLAMatchmaker may add to the precision in assessment of immunological risk. Simple intervention like behavioural change training (specifically for patients with history of non-compliance, wide variations in trough CNI concentrations), minimising pill burden (a risk factor for non adherence), and treatment of common CV risk factors can help improve outcomes. Tolerogenic immunomodulation, revolution in omics technologies and bioinformatics to improve precision in matching and monitoring, and novel tolerance induction methods ….are all in the ‘pipeline’-length of which I am not aware of.

4. Management of patients at risk of AKI

Yes, I agree, we need to start very early in AKI and I am not talking about dialysis. While nephrologist are busy debating timing, mode and dose of dialysis in AKI, this review in Lancet -Management of patients at risk of acute kidney injury  identifies the correct time of action in the course of AKI where simple intervention may potentially improve the prognosis of AKI in ICU (which remains almost unchanged over years). Being used to reading RIFLE, AKIN, KDIGO definitions and classifications, this review is probably the first of its kind in daring to ignore all of them!  Interventions early in the course of AKI (electronic alerts, restrictive fluid strategy after initial resuscitation, avoidance of additional insults, and close monitoring) are simple, not necessarily delivered by nephrologist and are more likely to be fruitful and may be more important than RRT timing, dose, modality. We probably have reached the the limit of mortality benefit by dialysis strategies in AKI.

5. Update on Oxford classification of IgA Nephropathy 

Oxford Classification of IgA nephropathy 2016—the role of crescentic lesion: an update from the IgA Nephropathy Classification Working Group is ready with their recommendation to add C (Crescent) to the earlier MEST score. So now its MEST-C (C0 no crescents, C1 crescent in at least 1, C2 crescent in >25% of the glomeruli). I am not sure how it will exactly alter the way you treat your IgA nephropathy patients, but it will definitely affect score of fellows preparing for their examinations. As nephrologist, we know crescent as the sign of severe injury to the glomerular capillary wall and such patient will need closer monitoring, may be better immunosuppression and will carry a poorer outcome. Whatever said, only biopsy finding that changes treatment plan definitely is “all glomeruli sclerosed with frequent foci of IFTA” — and finally its the old friends who come for help: proteinuria, and GFR trajectory.

6. Liver as a guard for kidney 

Transplantation in sensitized recipients is a nightmare for transplant nephrologist. This thought provocative work by Taner et al from Mayo clinic may be that ray of hope for highly sensitized recipients who are either not transplanted or experience a poorer graft outcomes after transplant. In a case control study by the same group last year, they demonstrated markedly improved graft outcome in 14 recipients of simultaneous liver-kidney transplants (SLK) who had DSA at the time of transplant when compared with 28 recipients of kidney transplant alone (KTA) having DSA (ABMR 46 vs 7%, TG 54 vs 0%, combined endpoint of allograft loss or >50% decrease in eGFR 20 vs 7%). In this paper in KI, authors studied molecular signatures of this protective effect, and found that liver offers more than just DSA adsorption.In some way liver favourably modified B and T cell immunity-SLK recipients expressed less pro inflammatory transcripts, they expressed more transcripts encoding metabolic processes involved in the maintenance of tissue integrity.  This raises hopes whether liver, part of liver, or molecules from liver will optimise outcomes for highly sensitised recipients. With the help of transcriptomics used by authors, there is potential for early identification of antibody mediated injury to graft before histologic changes of TG (which is characterised by relentless progression with or without treatment ) .

7. Disease eradication before therapy getting discovered -story of contrast AKI

I used to wonder if I was missing Contrast Induced Nephropathy (CIN) in our AKI patients. I am yet to see a patient of AKI needing dialysis that can be solely attributed to contrast (at a centre where AKI caseload is about 100 per month). If you still believe that AKI following intravenous contrast is a major problem, this issue of ACKD is for you. Scared to the marrow: pitfalls and pearls in renal imaging, Intravenous contrast: friend or foe?, Intravenous contrast induced nephropathy-the rise and fall of a threatening idea, all of them will help clear the delusion of CIN after IV contrast. CIN after iV contrast will be a unique example of a disease getting eradicated even before a therapy coming into being. Risk of CIN after IV contrast appears much lower (if not nil) than previously emphasised- first suspected by radiologist who were questioning its very existence. Finally nephrologists are in agreement. Absence of appropriate control group, attribution of all rises in creatinine to contrast, random variations in measurement of creatinine especially if high at baseline, lack of data on clinically meaningful outcomes (length of hospital stay, morbidity, mortality etc) call into question the observational data linking contrast with AKI. Same may not be true with intra-arterial contrast use and general measure (that every wise clinician would take-correcting hypovolemia, minimising amount being used, withholding other drugs like diuretics, RAS blockers around the time of procedure) which are considered good clinical practice around any preoperative period should apply here too. Here is an excellent blogpost summarising  the issue.

NSF (Nephrogenic Systemic Fibrosis) reminds me of Gary Cooper’s masterpiece movie High Noon. A vicious outlaw (who is sent to Jail by town Marshal) is getting released and coming back to take revenge. Without a single scene of violence, director succeeds in creating the atmosphere of terror. Finally outlaws come. NSF seems to be that outlaw who isn’t just coming back. Terror continues. No new case of NSF is registered over last several years to the NSF registry.

This article discusses Potential use of MRI in noninvasive assessment of kidney fibrosis looks promising interesting.

8. Comparing safety of Rituximab with Cyclophosphamide in membranous nephropathy

In this retrospective observational study from Italy in JASN, rituximab (RTX) had better safety profile than cyclophosphamide (CP). Adjusted hazard ratios (95% confidence intervals) between RTX and ST-CP groups were 0.27 (0.16 to 0.44) for any first adverse event, 0.32 (0.15 to 0.68) for serious adverse events, and 0.23 (0.13 to 0.41) for nonserious adverse events.

Study’s primary objective was to compare safety of RTX with CP and I find no reason to agree with authors on their bold conclusions regarding efficacy which goes like this: “RTX might be considered as an alternative to ST-CP–based immunosuppression as first-line therapy in patients with IMN and persistent nephrotic syndrome, despite conservative treatment”.

Really? Centre where CP was used was different from that where RTX was used, CP was used in unusually high dosages (36 gm-believe me this isn’t a typo), and time period during which these treatments were used differed considerably (CP from1995 and 2012 and RTX 2001 onwards) producing ‘ era effect’ ; all of these make it almost impossible to conclude anything definitely about safety and efficacy. Although adjustments for baseline confounders was made and sensitivity analyses were performed, patients in CP group were older, had more severe disease at baseline-higher proteinuria, lower albumin, higher cholesterol, lower albumin level, higher statin use! Given the CP dosing protocol in this study, its no surprise that incidence of side effects was considerably higher (when compared to previous studies by Ponticelli and Jha). Authors attribute this difference to the fact that ICH-GCP guidelines (of adverse effect reporting) came into being after pivotal trials and their late adoption in India. I am not convinced by this argument as RCT design is much more robust than observational studies to record all clinically meaningful side effects.

Overall this retrospective, observational study is nothing less than a race of dead horse versus sheep, and I sincerely hope that the RTX will soon find an appropriate disease indication in the field of glomerulonephritis.

9. IgM Nephropathy -a precursor to FSGS?

If you are a believer in IgM nephropathy, then this retrospective cohort study in NDT is for you. Presence of mesangial deposits on electron microscopy and exclusion of systemic disease were required to define the cases in addition to dominant IgM staining. Response rate of 40% with steroid is similar to previously reported series, and predictors of loss of GFR were: presentation with eGFR 20% of glomeruli, interstitial fibrosis and tubular atrophy affecting >20%. 8 of 10 patients undergoing repeat biopsy in this series developed FSGS, with disappearance of mesangial deposits on EM in all eight despite continued positivity for IgM. Authors speculate that IgM nephropathy progresses to FSGS. 

Author: lastmonthinnephrology

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

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