August 2018

1) Transplanting kidneys from hepatitis C donors 

After revolutionizing the management of hepatitis C, DAAs (Directly Acting Antivirals) are all set to expand the donor pool in deceased donor kidney transplantation.  After the exciting report (reviewed previously in our June 2017 post) of successfully transplanting 10 kidneys from hepatitis C positive donors into hepatitis C negative recipients, THINKER 1 (Transplanting Hepatitis C kidneys Into Negative KidnEy Recipients), authors report here the intermediate term data (12 months) on their cohort including additional 10 such patients. All 20 patients achieved HCV cure despite the use of intense immunosuppression (primary outcome), they also experienced improved quality of life as assessed by RAND 36.

Recipients of the HCV positive kidneys also had higher eGFR post-transplant at 12 months (median, 72.8 vs. 57.7 mL/ min/1.73 m2; CI for the between-group difference, 7.9 to 19.2 mL/min/1.73 m2) probably related to the younger age of deceased donors who are hepatitis c positive. A new chapter in expanding the donor pool indeed!

 

2) Copeptin in the evaluation of polyuria

 

v5

Visual abstract by Divya Bajpai (@divyaa24)

In ‘hypotonic polyuria’ (these endocrinologists want to tease us- hypotonic polyuria is any polyuria that is not due to solute diuresis) water restriction test is often performed by endocrinologist at our center (they bother us twice: once by sending samples to our lab for osmolality measurements and later when they find themselves clueless after the results of the test). Almost 30% of the patients with primary polydipsia can be labeled as central diabetes insipidus even after this test. While this age-old method is still standard test, its interpretation is difficult when one wants to differentiate central DI from primary polydipsia due to two reasons: any water diuresis may compromise the renal medullary concentration gradient and promote a down-regulation of kidney aquaporin-2 water channels, which could potentially affect reading values of urinary osmolality measurements.

In this prospective, multi-center study, authors evaluated the diagnostic utility of Copeptin -based approach (copeptin is a degradation product of ADH and is much easier to measure reliably as compared to ADH), in differentiating central DI from primary polydipsia. Direct measurement of Copeptin after administration of hypertonic saline (250 ml bolus followed by 0.15ml/kg/hr infusion targeting serum Na of at least 150), showed significantly improved diagnostic accuracy over water deprivation test (96.5% vs 76.6%, P<0.001).Water deprivation one of that cruel and risky thing that doctors do to their patients (only another comparison I can imagine is the unscientific ritual of clamping urinary catheters in patients on diuretics!) Hoping to get copeptin measurements available, so that nephrologists who are well versed with using hypertonic saline (your turn to get teased by endocrinologists now!) can increasingly evaluate  patients with polyuria.

 

3) BP threshold to initiate therapy in elderly

Most Indian television daily soaps feature the nauseating age-old “saas-bahu’ (mother in law-daughter in-law) drama. Directors of these serials usually have IQ that competes with room temperature but we must acknowledge their unique skill:  both wife and mother can identify themselves as the victim of the situation (who in fact is a third person called ‘the husband’- regularly getting in trouble in such situations). But happy husbands are those who can hear both the sides carefully and listen to none.

Annals of Int Med features ‘Beyond the guidelines’ where they discuss a case of elderly hypertensive Mr. L who is in similar dilemma-identifying right BP threshold that will benefit him most and harm least in the light of conflicting guidelines by “saas-bahu ”- ACC/AHA vs ACP (you can choose to assign ‘saas or bahu’ status as per your discretion; a sorry situation! No choice here).

Husbands here are those smart physicians who can read them both and listen to no one but the interests of the patient sitting in front of them.

This is a worth reading piece for those who care about patients more than guidelines and individualize BP threshold to best suit patient’s need.

While some of us can afford to debate the debatable, here is what I like the most about blood pressure research-extensive over intensive approach. In a multicenter trial involving 700 patients from Sri Lanka, fixed low-dose triple-drug-combination was more likely to achieve BP control than the conventional approach (70% vs 55%, respectively; risk difference, 12.7% [95% CI, 3.2% to 22.0%]; P < .001). Although limited by short follow up and pragmatic nature, results shown are encouraging especially in developing countries where BP treatment is far from optimum due to various barriers like complex drug supply chain, limited access to medications, and the shortage of healthcare workers to titrate medications.

4) Technique failure in the first year after PD initiation 

Whether it occurs in the first year or later, ‘technique failure’ is a catastrophe for a patient who chooses PD as a modality of dialysis. This is more likely early after initiation, and authors of this AJKD study evaluated data from Australia and New Zealand Dialysis and Transplant Registry (ANZDATA) Study, involving 16,748 patients included in the study, 4,389 developed early technique failure. Age >70 years, diabetes or vascular disease, prior renal replacement therapy, late referral to a nephrology service, or management in a smaller center were associated with higher risk of technique failure while Asian or other race and use of continuous ambulatory PD were associated with reduced risk, as was initiation of PD therapy in 2010 through 2014.

Admitting the retrospective nature and possible residual confounding, this data represents the largest evaluation of early technique failure using the recommended definition of this complication (which remains the major limitation of the previous studies).

I disagree with the preamble of this article that goes like this, “concerns regarding technique failure is a major barrier to increased uptake of peritoneal dialysis”. In many parts of the world, the major barrier may be the skewed incentive structure of HD vs PD. This leads to the selection of patients who have exhausted all the access options for HD (this is the most common reason why the patient chooses PD as last resort and comes for catheter implantation at our center)

 

5) Acute Kidney Injury in Sugarcane Workers at Risk for Mesoamerican Nephropathy

In a prospective study in a Mesoamerican nephropathy hotspot in Nicaragua, Kupferman et al observed that a substantial fraction of sugarcane workers, who had no clinical evidence of kidney disease before the harvest season, developed AKI during the harvest season. Follow-up of the workers with AKI revealed that as a group, these workers had a partial recovery of kidney function.

Of the 326 sugarcane workers with normal preharvest serum creatinine values and no history of CKD, 34 (10%) had AKI (rise in creatinine >0.3 mg/dL). Of 34 workers with AKI, 29 participated in the first follow-up about 6 months later. 10 of 29 (34.5%) workers had eGFRs <60 mL/min/1.73 m2 and 11 of 29 (37.9%) developed an eGFR decrease > 30% by the time of their last follow-up. Working as a cane cutter (compared to working as a seed cutter, weeder, pesticide applicator, or irrigator) was associated with a 20% higher creatinine level.

AKI burden in this population is likely to be underestimated. Recurrent episodes of even minor renal injury may add up and lead to chronic tubulointerstitial damage. The fact that most of the AKI occurred in cane cutters indicates that strenuous work probably contributes to the injury. Hypothesis-generating studies like this would go a long way to help devise a preventive strategy at the community level.

 

6) Consumerism, Innovation, and the Future of Pediatric Primary Care

Alexander G. Fiks and colleagues wrote an opinion piece in JAMA Pediatrics to highlight the limitations of the healthcare model from the point of view of the families who avail pediatric primary care in its current form in the USA. They cite the example of Blockbuster, an US-based provider of home movie and video game rental services going bankrupt failing to see the changing needs of its consumers, as opposed to Netflix,  who now has more than 100 million subscribers, achieved dominance by betting on emerging technology for streaming video.

Creative destruction, what happened to Blockbuster, is driven by changes in technology and consumer priorities. Healthcare systems could learn a lot from this example.

Almost all the current healthcare systems deliver expensive services through inflexible infrastructure. These systems are often inefficient and have high fixed costs. Nephrology is not an exception. We could do a much better job if we identify how our patients’ needs are changing.

Much of the nephrology research is about fixing numbers- how to lower phosphate, how to keep PTH in the range, how to jack up the Kt/V, and for that matter, years on dialysis. We are in search of a renal troponin for a long time. Home dialysis and palliative care are ignored right from the training years. It’s time we wake up as a community and align our priorities with those of our patients and their families.

 

7) When the color of peritoneal dialysis effluent can be used as a diagnostic tool

What do you do when your PD patient comes to the clinic with an effluent bag that is red, orange, cloudy, milky white, green, yellow, purple or black? A lucid review article in Seminars in Dialysis by Thomas Dossin and Eric Goffin is a must-read. Authors describe various causes of discoloration of PD fluid. They briefly discuss investigations and management issues in such cases. I must admit I did not know nifedipine could cause chyloperitoneum in PD patients!

 

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.

 

 

December 2017

1 ‘Normal BP’ becomes a rare disease now

Half of the globe was fast asleep then [when it was 3:15pm (PST) on 13th November at Anaheim, California]. I had just completed reading Murakami’s ‘Samsa in love’. This is an amazing story of events in the life of a Cockroach who, on one fine morning gets up metamorphosed into a human being. Upon meeting a girl, he neglects basic sexual instincts and prefers to follow the ‘neocortical attribute’ of love. After vivid dreams about ‘metamorphoses’ in early morning hours, I got up and checked my blood pressure and alas! I was no more a proud healthy young adult that went to sleep last night and found myself metamorphosed into someone with ‘elevated blood pressure’. I was one of that majority of the world’s population who was declared having ‘abnormal’ BP at the release of ACC/AHA guidelines on blood pressure. It was 122/81 on 3 consecutive measurements that need lifestyle and diet modifications and 3-6 monthly follow up to see what happens to me as per Guideline 8.1.2…to see if I get another metamorphosis into stage 1 hypertension. 

Hypertension is largely treated by primary care doctors, who are not necessarily graduates of modern medicine here whose degree can be various 4 letter permutations and combinations (heard of DEMS?). While one can doubt their qualifications, same can’t be said about their confidence, which, generally is inversely related to the knowledge, which is periodically boosted by pharma food and cocktails. Although guideline claims not advocating drugs for everyone at stage 1 hypertension (>130/80 now), this change of number is likely to lead pharma to a goldmine. Unlike ‘Samsa in love’, basic instincts ‘to prescribe’ and ‘get prescribed’ won’t be easily overcome by doctors and patients. Also, some of the experts think that hypertension is a ‘progressive vascular disease’ and not just the risk factor and therefore needs earlier and more aggressive drug treatment. Exercise, diet and lifestyle modifications were and will continue to be regarded by most doctors and patients as posthumous metaphysical experiences. 

Two good points worth putting into practice 1. better measurement of blood pressure with the emphasis on out of office records and 2. assessing CV risk beyond numbers which is a long due change in BP treatment guideline. 

Moral of the story is: don’t remain awake late night reading fictions, early morning dreams can come true. Enough of ‘coach’ing, I’m going for a walk now to improve my numbers.  

 

2. Association of BP lowering with mortality and cardiovascular disease across blood pressure levels

 

Is benefit of BP reduction same at various pretreatment BP thresholds?

Probably not. In this systematic review and meta-analysis involving 74 trials and 306273 participants association of BP-lowering treatment with major cardiovascular events was dependent on baseline systolic BP (SBP). For primary prevention (i.e. in patients without prior heart disease),  with baseline SBP 160 or above, treatment was associated with reduced risk for death (RR, 0.93; 95% CI, 0.87-1.00) and a substantial reduction of major cardiovascular events (RR, 0.78; 95% CI, 0.70-0.87). For SBP range 140-159, the association of treatment with mortality was similar (RR, 0.87; 95% CI, 0.75-1.00), but the association with major cardiovascular events was less pronounced (RR, 0.88; 95% CI, 0.80-0.96) and with baseline SBP below 140, treatment was not associated with mortality (RR, 0.98; 95% CI, 0.90-1.06) and major cardiovascular events (RR, 0.97; 95% CI, 0.90-1.04). However, for people with previous CHD and mean baseline SBP of 138 mm Hg, treatment was associated with reduced risk for major cardiovascular events (RR, 0.90; 95% CI, 0.84-0.97), but was not associated with survival (RR, 0.98; 95% CI, 0.89-1.07).

Authors caution about industry bias here, as all the trials involving patients with CHD were industry sponsored. Moreover, limited information on non-BP determinants of outcomes, underrepresentation of women, rather crude division into primary and secondary preventive trials (only 13 trials were truly primary preventive, and 17 trials truly secondary preventive), are limitations to note. Funnel plot asymmetry at highest BP levels (signifying possible publication bias-negative studies remaining unpublished)  might suggest an overestimation of benefit here.

BP lowering benefits decrease with decreasing starting BP, and risks of treatment (as a primary prevention measure) below 140 mmHg may outweigh any possible benefit. Sounds contrasting to SPRINT, however, authors feel that cutoff of 140 may not be very different than SPRINT 120, given the different method of measurement in SPRINT.  

The goal of BP treatment is not to bring down numbers but to reduce the risk of complications and this risk can be different for different individuals at same BP number. A risk-based approach is likely to be more cost-effective and avoid overtreatment in mild hypertension. This is one thing that’s worth adopting from ACC/AHA.    

3. Who develops CKD after recovery from AKI?

A six variable model using commonly used measurements -age, sex, baseline serum creatinine value, albuminuria, acute kidney injury severity, and discharge serum creatinine value was developed in 9973 patients hospitalized in Alberta and was externally validated in with data from a cohort of 2761 patients hospitalized in Ontario, Canada. The main outcome measure was advanced CKD -sustained reduction in eGFR less than 30 mL/min/1.73 m2 for at least 3 months during the year after discharge. Authors propose that this will provide an accurate but simple strategy that could be used to identify patients who can be benefited by follow up. Information on albuminuria wasn’t available in all the patients and so was the etiology of AKI, which IMHO can independently affect recovery.

Aren’t most of these factors (baseline CKD, age, sex, proteinuria) independently associated with advanced CKD, even without AKI intervening? The only conclusion from the observational data on ‘AKI-CKD interconnection’ research that can be made for now is: CKD is one of the most important risk factors for AKI and AKI  accelerates the progression of CKD. This probably can’t be extrapolated to one of the most common AKI in our practice i.e. the one associated with tropical infections, where baseline kidney function is normal.

4. Sertraline for depression in CKD

About 1 in 4 patients with CKD have depression which is 4 times higher incidence as compared to general population. Antidepressant use is common in this population although placebo-controlled trials are lacking. Here is a double-blind, placebo-controlled, parallel- design, 12-week flexible-dose randomised clinical trial (CAST)conducted at 3  medical centers comparing sertraline with placebo in patients with CKD stage 3-5 (about 50% had CKD 4,5), not on dialysis. This drug was no more effective than placebo and was associated with higher incidence of nausea and diarrhea. Similar findings were reported with use of SSRI in the treatment of depression associated with major medical conditions, which probably is different than depression in general population. 

While ‘negative results’ may add to the depression of nephrologists desperate for ‘positive trials’, some important takeaways from this research:

-almost 1/4th of the patients responded to placebo, worth trying option before anything else.

-if one is required to use SSRI for severe depression (trial didn’t include such patients), up to 200mg/day of sertraline was tolerated well except for GI intolerance.

Exclusion of dialysis population and limited duration of follow up are important limitations of the trial. 

5. Tolvaptan in ADPKD

After promising results of TEMPO 3:4 trial (only prerequisites to understand this promise are-accept kidney volume as valid surrogate and neglect high discontinuation rate due to adverse effects) in early-stage CKD-ADPKD, here is a phase 3, randomized withdrawal, multi-center, placebo-controlled, double-blind trial of this drug in late-stage CKD. The primary end point-change in the eGFR from baseline to 12 months follow-up-−2.34 ml per minute per 1.73 m2 (95% CI −2.81 to −1.87) in the tolvaptan group, as compared with −3.61 ml per minute per 1.73 m2 (95% CI, −4.08 to −3.14) in the placebo group (difference, 1.27 ml/min 95% CI, 0.86 to 1.68; P<0.001). 5.6% in treated group vs 1.2% in the placebo group developed a significant increase in ALT level.

1.27 ml per minute difference in eGFR is thought to be clinically significant by authors and Otsuka-they postulate that this will translate into postponing CKD stage 5 from 6.2 years to 9.0 years. To understand this, one needs to assume that medicine is mathematics and need to stretch your optimism to assume that drug will continue to make a difference of 1.27ml per year without acceptable side effects over several years of follow up. This trial, in its run in phase, excluded patients who didn’t tolerate tolvaptan. Longer follow-up studies with hard outcome endpoints are desperately needed now and until they are available, freely available ADH suppression i.e. liberal water intake seems enough to me. Considering variable and generally slow disease course of ADPKD, further trials also should target high-risk population where drug’s cost and side-effects will be justified better. Will precision medicine help do this for ADPKD?

6. No need to wait for few minutes to check orthostatic hypotension

Checking for orthostatic BP change in routine clinical visits is a ‘vital sign’,  especially in patients on multiple drugs that can affect blood pressure and volume. This becomes all the more relevant if you are serious about SPRINT and  ACC/AHA 2017. As a newly joined resident in medicine, I recall doing this exercise for 40-50 patients in the outpatient nephrology department and used to argue with our registrar about the time gap between supine and standing readings. We used to complete the measurement in 2 min and he insisting for a 5min gap.

In this prospective cohort study involving 11,249 middle-aged adults (mean age, 54; many with cardiovascular disease or risk factors, or on medications), orthostatic hypotension (defined as systolic drop of ≥20 mm Hg or diastolic drop of ≥10 mm Hg) was assessed at baseline, with BP readings taken with an automatic cuff every 25 seconds as many as 5 times after a patient rose from a supine to a standing position. During the median follow-up of 23 years, about 12,000 adverse events, that included falls, fractures, syncopal episodes, motor vehicle accidents, and death, were recorded and these were found most consistently and closely associated with measurements made within first 60 seconds upon standing. Waiting for more than 2 minutes may, in fact, miss some of these patients.

7. Outcomes after Angiography with Sodium Bicarbonate and Acetylcysteine

(See the excellent summary of the article by @hswapnil on NephJC here). This large randomized 2 X 2 factorial trial enrolled 5177 patients (more than any of the previous trials) who were scheduled for angiography to receive 1.26% sodium bicarbonate or 0.9% sodium chloride and oral acetylcysteine or placebo. The primary endpoint was a composite of death, the need for dialysis, or a persistent increase of at least 50% from baseline in the serum creatinine level at 90 days. The trial was stopped prematurely after a prespecified interim analysis after the primary endpoint occurred in similar proportion (about 4 to 5%) of patients in all the four groups. Contrast-associated acute kidney injury, which was defined as an increase in serum creatinine of either at least 25% or at least 0.5 mg per deciliter from baseline at 3 to 5 days after angiography occurred in about 8-9 % patients and there were no significant between-group differences in these rates.

Does it change what we practice? We have stopped using N-acetylcysteine already. We could use normal saline and sodium bicarbonate interchangeably. But do we need to?

The trial did give a very clear answer to the research question it asked. However, contrast-induced AKI is going through the existential crisis and ~4% incidence of significant renal dysfunction at day 90 in PRESERVE population may be argued as an evidence for its existence. However, as we don’t have a control group here (who didn’t receive contrast), and not all kidney events were adjudicated to contrast use, so, for now, we don’t have any definitive answer to this existential crisis.

8. One-Day Donor Assessment Model in a Living Kidney Donor Transplant Program

Being evaluated as a donor for organ transplantation is an emotionally complex journey. A thorough evaluation is required to make sure the donation doesn’t put the donor at undue risk. However, a lengthy process of donor evaluation would significantly slow the entire program of living donor transplantation. Graham and Courtney in an article published in AJKD describe their experience with a ‘1-day donor assessment pathway’ as quality improvement project that led to a sustained increase in the living donor renal transplantation rate. To decrease the donor fatigue and subsequent dropout, they introduced a pathway where the prospective donor would undergo all the investigations and consultations over one day. Over 5 years, the program assessed 431 potential donors, of which 66% went ahead for actual donation. Of course, the people undergoing the evaluation were happy, most of them rating this process as ‘very good’. There was a sustained increase in the living donation rate from <5 per million population per annum (pmp pa) before 2010 to >32 pmp pa by 2015. This is incredible!

While it is likely that this increase is the result of multiple factors, authors feel that the 1-day assessment process has been the main driving force behind this improvement.

By making appropriate changes according to the local needs, this concept is likely to work in any program.