January 2018

1 ELAIN trial one year follow up

If you initiate dialysis a few hours earlier in the course of AKI-that essentially means dialyzing almost every AKI that needs nephro consult–you get almost everything that you will like to offer your critically ill patient with AKI: 15.4% absolute risk reduction in mortality, two weeks shorter duration of RRT need, a month less of hospital stay-according to the ELAIN trial published in 2016. Impressed by the results, my cardiac surgery colleagues are after me-why should we not offer RRT to all of their post-op patients whether or not they have AKI. Like them, if you are able to digest ‘the biological plausibility’ of these dramatic benefits, then this article in JASN reporting 1-year outcomes of ELAIN participants emphasizing all goods of earlier RRT start, is for you. Those dialyzed early experienced fewer MAKE (Major Adverse Kidney Events)-a composite of death, RRT, and persistent renal dysfunction at 1 year. This was largely driven by death (which already was much lower in the earlier RRT start trial participants at 90 days) and by persistent renal dysfunction (soft endpoint of 25% decrease in eGFR).

For me, making sense of these massive benefits (attributed to a few hours earlier RRT start) is far more difficult than understanding the original trial results. IMHO, respiratory and circulatory failure, are the predominant determinants of outcome in this population and AKI very rarely-if at all-kills. In spite of randomisation, delayed start group was numerically more likely to have severe respiratory, circulatory and liver failure (Ref Table 1 from original ELAIN), I suspect that this imbalance at least partly underlie the results.

BTW, given the rising number of publications on long-term AKI outcomes, have we given up on almost unchanged in-hospital mortality of AKI?

2 Target blood pressure in dialysis patients 

“I instruct my patients to skip BP medicines: on the morning of AV fistula surgery, when they are sick due to fever or diarrheal illness, or any other intercurrent illness. I prefer to have it somewhere between 150-160”, -when a very senior nephrology Professor told us this in one of our case presentations, we ridiculed him as a proponent of Eminence Based Medicine. It took almost a decade to understand his point, and today we call this ‘individualization of the targets’ in medicine. Guidelines suggested BP targets in dialysis patients (if you are practicing one today) is one of those practices in nephrology that are supported by a very poor evidence base, and are largely extrapolated from data coming from trials involving general population.

Here is a much needed randomised controlled, BP in Dialysis (BID) Pilot Study in JASN addressing this crucial issue in 126 hypertensive patients on hemodialysis randomised to a standardized predialysis systolic BP of 110–140 mmHg (intensive arm) or 155–165 mmHg (standard arm). Attempt at intensive control resulted in more major adverse cardiovascular events [1.18 (0.40 to 3.33)], hospitalizations [1.61 (0.87 to 2.97)], and vascular access thrombosis [3.09 (0.96 to 8.78)]. Access thrombosis in my practice has consequences that are only slightly worse than massive myocardial infarction.

Being a pilot study results cannot be considered definite, but I sincerely hope that BID investigators will come back soon with the full-scale study that will guide BP treatment in this population. Meanwhile, it’s important to respect gray hair, especially in gray areas of medicine.

3 Symptomatic treatment versus antibiotic for uncomplicated cystitis

Antibiotic stewardship, aimed at reducing antimicrobial resistance involves ‘deferring treatment for low-risk bacterial infections’ as one of the components. A German randomized controlled pilot trial showed clinical outcomes of treatment with ibuprofen similar to those of antibiotic treatment with ciprofloxacin. This sparked interest in this concept which is evaluated in a randomised,double-blinded, non-inferiority trial in BMJ. Norfloxacin (antibiotic) was compared with diclofenac (symptomatic) for the treatment of uncomplicated lower urinary tract infections in the ambulatory setting in 253 women across 17 general practices in Switzerland. Women in both the group could use fosfomycin 3g single dose if they continued to remain symptomatic at day 3.

Diclofenac was found inferior to norfloxacin for primary outcome i.e. symptom relief of UTI at day 3 (risk difference 27%, 95% confidence interval 15% to 38%, P=0.98 for non-inferiority, P<0.001 for superiority) and was more likely to be associated with pyelonephritis (5%  versus none in norfloxacin group, Number Needed to Harm 22). Conversely, women who received diclofenac were 37% less likely to receive antibiotics until day 30 after randomisation. 71% of women in diclofenac group ultimately took antibiotics, so this group was rather ‘deferred start antibiotic group’ and not just symptomatic treatment group.

 In the setting where I practice, resistance to quinolones (and not just quinolones but many other oral options for uropathogens) is almost ubiquitous even in community-acquired uropathogens, and community-acquired ESBL producing E-coli UTIs are increasingly common. So there is no reason to believe that norfloxacin will work better than analgesics. Having seen one of the kidneys contracted in women coming with recurrent UTIs, the concept of symptomatic treatment of cystitis with NSAIDs without antibiotics scares me. ‘Deferred start antibiotic strategy’ however is worth further exploration, as the authors suggest, using commonly available tests like C reactive protein (values >10 mg/L were more common at baseline in women who subsequently had a diagnosis of pyelonephritis).

4 Medical Expulsion Therapy (MET) for distal ureteric stone

Not just pain and nuisance, nephrolithiasis is one of the leading causes of preventable ESRD in this part of the world. Many such patients see us after seeing our surgery colleagues (who already have suggested intervention) hoping that a kidney doctor who doesn’t operate will probably be more affordable. Urological guidelines recommend MET for patients with distal ureteric calculus based on the results of BMJ, Lancet and Cochrane meta-analyses, which, however, have been criticised for the poor quality of the studies included and significant heterogeneity. This issue became highly controversial after the publication of a large UK multicenter SUSPEND trial (2015) that showed no statistical difference between placebo and either tamsulosin or nifedipine in terms of the primary study endpoint-need of any intervention at week 4. A smaller Australian trial (2016) similarly showed no effect of tamsulosin on stone passage at 4 weeks as confirmed by CT scan. This led to a heated debate for and against MET in the management of nephrolithiasis.

On this background, double-blind, placebo-controlled study of 3296 patients with distal ureteral stones, across 30 centers in China (the largest of the trials till date) is published. In addition to a higher stone expulsion rate (primary endpoint) than the placebo (86% vs 79%; p < 0.001) for distal ureteral stones, tamsulosin treatment was associated with several other benefits: a shorter time to expulsion (148.3 vs 248.7hp < 0.001), required lower use of analgesics compared with placebo (89 vs 236 mg, p < 0.001), and significantly relieved renal colic (p < 0.001).

Apparent discrepancies in the results of these trials stem from the difference in the stone size (the UK and Australian trial had stones <5mm which are less likely to pass with MET), and different endpoints (need of intervention at week 4 in UK trial and CT surveillance in Chinese trial). Even the largest of the three-Chinese trial failed to show any benefit for stones that were <5mm.

So MET is there to stay. But be sure you have a urology friend who doesn’t hate MET and will provide continuity of the care if needed.

5 High-Cutoff Hemodialysis and Myeloma Cast Nephropathy (MYRE study)

See NephJC summary by @SLeonMD and editorial by @kdjhaveri and @RubenNiesvizky

In a multi-center RCT, Bridoux et al randomized 98 patients with multiple myeloma and biopsy-proven cast nephropathy who had indication to start hemodialysis for acute kidney injury (hyperkalemia, metabolic acidosis, fluid overload, or symptoms of uremia) to receive intensive hemodialysis (eight 5-hour sessions over 10 days) with either a high-cutoff dialyzer or a conventional high-flux dialyzer. All the patients received bortezomib- and dexamethasone-based chemotherapy. At 3 months, there was no statistically significant difference in the primary endpoint of discontinuation of hemodialysis [41.3% (n = 19) in the high-cutoff group vs 33.3% (n = 16) in the conventional group; P = .42]. However, among the secondary endpoints, more patients in the high-cutoff group vs the conventional group no longer required hemodialysis at 6 months (56.5% vs 35.4%, respectively; P = .04) and at 12 months (60.9% vs 37.5%; P = .02). Did the tubules take a longer period to recover? We don’t know. These are secondary endpoints and the study was obviously not powered to assess them. If only we could have a bigger study!

Albumin infusion was required for 41% of the high-cutoff hemodialysis sessions and 4% of the conventional hemodialysis sessions because the predialysis albumin level was less than 25 g/L.

Plasmapheresis and HCO dialysis (EuLITE trial-(awaits publication, presented at UK Kidney Week) haven’t worked in previous controlled trials (sorry UpToDate). Does high-cutoff dialysis work? We don’t know for sure after this RCT. The most efficient way to treat cast nephropathy is to decrease the light chain burden, and with dramatic improvements in overall survival after Bortezomib based regimens, demonstrating clinically significant further improvement by extracorporeal treatments may be difficult.

6 The Banff 2017 Kidney Meeting Report

Banff workgroup –2017 revision of Banff classification with regards to Chronic T cell-mediated rejection (TCMR) and ABMR is here. Changes pertaining to TCMR and ABMR are as follows: 

Unlike older schemata, inflammation in the areas of IFTA (i-IFTA) is now considered as a sign of the response to the injury to nephrons and renal tissue. This is a predictor of disease progression as a result of an active injury process and is classified as Chronic Active TCMR. The clinical implication of this change, to me, is to suspect inadequate immunosuppression and step up if possible; it will be interesting to see the long-term outcome of such a strategy.

While DSA testing is now standard of care in the diagnosis and monitoring of ABMR, current methods do not detect all the antibodies that are potentially injurious to the allograft, including some non-HLA antibodies. Addition of molecular diagnostic markers ‘ABMR classifier’ (consisting of 30 non-redundant probes, selected from comparisons between biopsies with versus without histologic changes of ABMR) and non-HLA antibody testing e.g. anti-angiotensin type 1 receptor will detect a significant subset of ABMR cases where current diagnostic methods fall short. 

Revised Banff 2017 Classification: Chronic Active T Cell-Mediated Rejection
Grade 1a Interstitial inflammation involving >25% of the total cortex (ti score 2 or 3) and >25% of the sclerotic cortical parenchyma (i-IFTA score 2 or 3) with moderate tubulitis (t2) involving 1 or more tubules, not including severely atrophic tubules;

other known causes of i-IFTA should be ruled out

Grade 1b Interstitial inflammation involving >25% of the total cortex (ti score 2 or 3) and >25% of the sclerotic cortical parenchyma (i-IFTA score 2 or 3) with severe tubulitis (t3) involving 1 or more tubules, not including severely atrophic tubules; other known causes of i-IFTA should be ruled out
Grade 2 Chronic allograft arteriopathy (arterial intimal fibrosis with mononuclear cell inflammation in fibrosis and formation of neointima)

In short, the definition of ABMR has become more sensitive (only if you have access to newer technology) and scope of TCMR has widened. And whether basing treatment decisions on sensitive diagnostic criteria will save more grafts without killing more patients remains to be seen.

7 The Banff Working Group Classification of Definitive Polyomavirus Nephropathy

They say some centers have polyomavirus nephropathy/ BK virus nephropathy more common than acute rejection as a cause of graft dysfunction. 15-50% of the people who get nephropathy, lose their graft. In an attempt to develop a clinically relevant morphologic classification for polyomavirus nephropathy (PVN), Banff Working Group on Polyomavirus Nephropathy analyzed clinical and histopathologic data on 192 patients with PVN. Two independent histologic variables to be most significantly associated with the clinical presentation: intrarenal polyomavirus load levels and Banff interstitial fibrosis ci scores. Classification based on these features correlated with the important clinical parameters: presentation at the time of biopsy, serum creatinine levels/renal function over 24 months of follow-up, and graft failure.

Polyomavirus Nephropathy: Classification
Class Definition Graft Failure at 24 months
Class 1 pvl 1, ci ≤1 16%
Class 2 pvl 1, ci ≥2

OR pvl 2, any ci

OR pvl 3, ci≤1

31%
Class 3 pvl 3, ci ≥2 50%
Polyomavirus replication/load level (pvl)

Pvl 1:  ≤1% positive tubules/ducts;

pvl 2: 1%–10% positive tubules/ducts;

pvl 3: >10% positive tubules/ducts.

 

Quantitative criteria for interstitial fibrosis: ci score

ci0- Interstitial fibrosis in up to 5% of cortical area

ci1- Interstitial fibrosis in 6–25% of cortical area (mild interstitial fibrosis)

ci2- Interstitial fibrosis in 26–50% of cortical area (moderate interstitial fibrosis)

ci3- Interstitial fibrosis in >50% of cortical area (severe interstitial fibrosis)

 

The new classification may help standardize the reporting and hence improve comparability of the studies. BK virus nephropathy is badly needs specific therapies and in the absence of these, I can’t imagine what am I to do with the new classification when I see this in the clinic.

8 Valganciclovir prophylaxis versus preemptive therapy

Preemptive treatment and valganciclovir prophylaxis are effective ways to prevent cytomegalovirus (CMV) infection after renal transplantation. For the high-risk patients (D+/R-, recent anti-lymphocyte therapy, potent immunosuppression including desensitization or ABO incompatible protocols etc.) most centers prefer prophylaxis. However, it is unclear if one approach is better than the other for intermediate risk patients (for example D+/R+ or D-/R+).

VIPP study published in 2012 randomized 299 renal transplant recipients with a positive CMV serostatus (R+) to receive valganciclovir prophylaxis for 100 days or preemptive treatment for ≥14 days if viral load ≥400 CMV copies/mL (PCR), followed by secondary prophylaxis. At 12 months, preemptive group had more CMV infections (38.7% vs. 11.0%, P<0.0001).

The long-term (84 months) follow up results are published here. 47% patients completed the follow-up. Significantly fewer patients in the prophylaxis compared to preemptive group developed a CMV infection or disease (11.5% [95% CI: 6.8%,17.8%] vs. 39.7% [31.9%,48.0%], p<0.0001 and 4.7% [1.9%,9.5%] vs. 15.9% [10.5%,22.7%], p=0.002). Incidences of graft loss (7.4% vs. 8.6%), death (9.5% vs. 11.3%), rejection (29.1% vs. 28.5%), and renal function (eGFR [mean±SD]: 58.2±26.3 vs. 59.9±25.7 mL/min/1.73m) were similar between the groups.

In resource-poor setting, considering the cost of monitoring and that of possible hospital admissions, valganciclovir prophylaxis for at least 100 days would be less expensive than the preemptive treatment strategy.

 

 

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Author: lastmonthinnephrology

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

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