October 2018

1. The timing of RRT in Patients with AKI and Sepsis

IDEAL ICU VA Divya

Visual abstract by Dr. Divya Bajpai (@divyaa24)

 

As an anxious first-year nephrology fellow, I had to discuss all the labs with my boss before he leaves department-typically at around 6 in the evening.

“Sir, that bed 2, Gastroenteritis- AKI patient’s serum creatinine is up to 10mg/dl. Now what?”

“Tell me something about the patient whose creatinine you are talking about.”- he would reply coldly.

Results of much awaited IDEAL-ICU trial are out and are largely consistent with the existing evidence that “earlier initiation of RRT doesn’t improve survival and exposes about 40% of patients with AKI to RRT who otherwise have recovered renal function before ever needing it.”

The trial was terminated early for futility after enrolling 488 patients. By then 58% of the patients in the early- strategy group (138 of 239 patients) and 54% in the delayed-strategy group (128 of 238 patients) had died (P=0.38). In the delayed-strategy group, 38% (93 patients) did not receive RRT. These lines from the paper bother me, “The second limitation is the choice of a delay of only 48 hours, which may not be sufficiently long to allow recovery of renal function in some patients or to detect a difference between early and delayed initiation of RRT. However, we thought that a longer delay would be unethical and unsafe for patients who actually needed renal-replacement therapy.” 

How do you know that delay of 72hrs or 96 hrs necessarily ends up into emergency dialysis and is unsafe? Watchful waiting, in my humble opinion, can continue until an indication develops, irrespective of the timing in hours.

AKI is one of the most common renal emergency and lets’ respect these words of wisdom. “Don’t be in hurry, we are in an emergency” –Anonymous “wise” emergency room physician to his junior colleague.

 

Here is a nice Twitter thread

 

2. Targeted Polymyxin B Hemoperfusion in patients with severe sepsis

Last week a senior surgery colleague was asking me if we can offer extracorporeal therapy to cut down dismally high mortality of perforative peritonitis. She and I were equally hopeful and skeptical respectively about this treatment, and after reviewing the literature we finally settled for the need of a pilot trial if she manages to get funding.

EUPHRATES (Evaluating the Use of Polymyxin B Hemoperfusion in a Randomized Controlled trial of Adults Treated for Endotoxemia and Septic Shock) investigators must be congratulated for a very well conceived and executed RCT addressing this question. In critically ill patients with severe sepsis with high risk of death, this technique did not reduce 28 day mortality (treatment group, 84 of 223 [37.7%] vs sham group 78 of 226 [34.5%]; risk difference [RD], 3.2%; 95% CI, −5.7% to 12.0%; relative risk [RR], 1.09; 95% CI, 0.85-1.39; P = .49). Findings were consistent in patients with more severe sepsis as well. Authors recommend against the use of this strategy.

Blinding by sham hemoperfusion, the inclusion of patients with very severe illness, so, high risk of death, and including endotoxemia >0.60 (indicating high endotoxin activity)  make trial results generalizable to the real world scenarios where such desperate measures are actually used.

Endotoxin was about to become ‘creatinine of intensivists’; thanks to EUPHRATES, it won’t.

3. Antibody-Mediated Rejection of Solid-Organ Allografts

Chronic ABMR is one of those helpless situations in the life of transplant nephrologist where you watch the progressive loss of graft function without much to offer. In spite of significant improvements in the understanding of pathophysiology, (this principally includes new definitions, classifications, revisions that take birth when transplant physicians-pathologist gather at a resort town along Trans-Canada Highway and more sensitive assays of antibody detection which add to the confusion!). Chronic ABMR remains a difficult nut to crack, and if we don’t ‘let go’ beyond a limit, one can potentially add to the number of ‘death with functioning graft’ as a consequence of overtreatment. Here is a NEJM review summarising current standards of treatment and possible future therapies.

Here is a quote from the article- “An improved understanding of the natural history of antibody-mediated rejection has led to a more complex interpretation of the various clinical scenarios encountered in clinical practice, given the heterogeneity, diverse polymorphism, and temporal dependency of the clinical and histologic manifestations of antibody-mediated rejection.”

Yes, ABMR is just as difficult to treat as making sense of these lines!

4. Phosphate binders for preventing and treating chronic kidney disease-mineral and bone disorder (CKD-MBD)

This 2018 revision of 2011 Cochrane review on phosphate binders concludes this

“Overall, we are not very sure whether specific phosphate binders are beneficial to patients with CKD. There is a possibility that sevelamer may prevent death compared to calcium-based binders, but we don’t know whether this may be caused by an increased risk of calcium-based binders, a lower risk with sevelamer treatment, or the possibility that both may be true. Patients need to know that it is not certain whether phosphate binders help to prevent complications of kidney disease, but sevelamer may be preferred to calcium binders.”

 

What will a man in severe debt feel if asked, “Which credit card you would like to buy? Platinum/ silver/ gold?” A very similar feeling a patient with CKD is likely to get if we (dare to) put the results of this review in context and involve him in shared decision making before choosing to use and then choosing amongst the P binders.

Let me just give you a glimpse of the “very low” quality evidence that suggests a possible advantage of sevelamer over other binders. In an analysis of 248 participants with a median follow up of less than a year showed RR  of death in controls or placebo to be high as compared to sevelamer (RR 2.16). The confidence interval (CI) was 0.2 to 22.8. After what limit a CI become ‘No Confidence Interval’?

 

5.Effects of Sacubitril/Valsartan Versus Irbesartan in Patients with Chronic Kidney Disease A Randomized Double-Blind Trial

We reviewed renal effects of sacubitril/valsartan and enalapril in participants of PARADIGM-HF trial in our May 2018 blog post.  Sacubitril/ valsartan leads to increase in albuminuria and still preserves eGFR better. While this was not the prespecified analysis, we now have an RCT examining the effects of sacubitril/valsartan on kidney function and cardiac biomarkers in people with moderate to severe chronic kidney disease.

The UK HARP-III trial (United Kingdom Heart and Renal Protection-III), a randomized double-blind trial, included 414 participants with an estimated glomerular filtration rate (GFR) 20 to 60 mL/min/1.73 m2 who were randomly assigned to sacubitril/valsartan 97/103 mg twice daily versus irbesartan 300 mg once daily. Participants ≥18 years of age were eligible to participate if they had CKD with either (1) an estimated glomerular filtration rate (eGFR) of ≥45 and <60 mL/min/1.73 m2 and a urine albumin:creatinine ratio (uACR) >20 mg/mmol (177 mg/g), or (2) an eGFR of ≥20 and <45 mL/min/1.73 m2 (regardless of uACR).

At 12 months, there was no difference in the primary endpoint: measured (wow!) GFR (51Cr-EDTA, 99mTcDTPA, or iohexol methods)- 29.8 (SE 0.5) among those assigned sacubitril/valsartan versus 29.9 (SE, 0.5) mL/min/1.73 m2 among those assigned irbesartan; difference, ‒0.1 (0.7) mL/min/1.73 m2.

Compared with irbesartan, sacubitril/valsartan further reduces both blood pressure and biomarkers of cardiovascular risk (troponin I and N-terminal pro-B-type natriuretic peptide). Albuminuria was not different in the two groups.

Authors conclude that “sacubitril/ valsartan could be an acceptable treatment to reduce cardiovascular risk in people with chronic kidney disease, a high-risk population with an unmet need”.

Will we have an RCT with hard endpoints? Hard to say given the track record.

 

6. Effect of Increased Daily Water Intake in Premenopausal Women With Recurrent Urinary Tract Infections: A Randomized Clinical Trial

In an open-label, controlled trial funded by Danone (which sells bottled water), Hooton et al randomized 140 healthy women with recurrent cystitis (3 episodes in past year) drinking less than 1.5 L in a day to drink, in addition to their usual fluid intake, 1.5 L of water daily (water group) or no additional fluids (control group) for 12 months. The primary outcome measure was the self-reported frequency of cystitis. During the 12-month study period, the mean (SD) number of cystitis episodes was 1.7 (95% CI, 1.5-1.8) in the water group compared with 3.2 (95% CI, 3.0-3.4) in the control group, with a difference in means of 1.5 (95% CI, 1.2-1.8; P < .001)

This low-cost intervention seems to be an effective antimicrobial-sparing strategy in this group of individuals.

7. Are NSAIDs safe in patients with CKD?

Choosing wisely campaign suggests avoiding the use of NSAIDs in patients with hypertension, heart failure, and CKD to which most of us comply. Here is a retrospective cohort NSAID in elderly adults visiting the primary care physician for musculoskeletal complaints. 9.3% of such visits were followed by NSAID prescription, 11% of the physicians chose NSAIDs for these patients. Authors  study in JAMA Int Med evaluating the frequency of identified 35 552 pairs (for each patient exposed to NSAID and they identified (by propensity score matching) a control patient not exposed but the similar likelihood of exposure.

Rates of cardiac complications(288 [0.8%] vs 279 [0.8%]), renal complications(34 [0.1%] vs 33 [0.1%]), and death (27 [0.1%] vs 30 [0.1%]) were similar among cases and control, leading to this rather bold conclusion, “NSAID use in this population is not associated with short term safety concerns”. This should not be overinterpreted to challenge the “choosing wisely recommendations”.

Firstly, as a nephrologist I am  interested in what happens long term rather than within a week. Moreover, we don’t have any information on severity of renal dysfunction of the population (physicians are more likely to use NSAIDs for patients with mild CKD which may well include patients labelled as CKD due to age related GFR decline). Apart from this confounding by indications, several other  limitations of propensity score method like residual confounding, unmeasurable imbalances etc should be taken into account before we put these results into practice.

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.