December 2018

1 Effect of Oral Alfacalcidol on Clinical Outcomes in Patients Without Secondary Hyperparathyroidism Receiving Maintenance Hemodialysis

Japanese investigators of J DAVID trial set out to evaluate the impact of active vitamin d administration to the patients on hemodialysis who otherwise wouldn’t have received this treatment i.e. PTH levels <180 (Do we really know if these drugs save lives in patients with SHPT either?). The primary outcome was a composite measure of fatal and nonfatal cardiovascular events, including myocardial infarctions, hospitalizations for congestive heart failure, stroke, aortic dissection/rupture, amputation of lower limb due to ischemia, and cardiac sudden death; coronary revascularization; and leg artery revascularization during 48 months of follow-up (too much to expect from poor Alfacalcidol!).

Oral alfacalcidol compared with usual care did not reduce the risk of these events :103 of 488 patients (21.1%) in the intervention group and 85 of 476 patients (17.9%) in the control group experienced primary outcome (absolute difference, 3.25% [95% CI, −1.75% to 8.24%]; hazard ratio, 1.25 [95% CI, 0.94-1.67]; P = .13). Are you surprised? I am not. In fact, there was a signal of harm (in per protocol analysis) although these findings can’t be considered definitive. In addition, significant drop out (?due to side effects like hypercalcemia and hyperphosphatemia), crossover and unblinded nature are significant limitations to note.

Vitamin D is the Vitamin C of our times that once claimed to be effective for the common cold and cancer. Although such claims have failed the tests of rigorous research methods, their use will continue in nephrology until we continue to be happy with “surrogate nephrology”-which is a synonym for CKD MBD therapy.

 

2 Lanreotide for Autosomal Dominant Polycystic Kidney Disease

Slide1

Visual abstract by Dr. Divya Bajpai (divyaa24). From NephJC.

Effect of the somatostatin analog lanreotide on the rate of kidney function loss in patients with later-stage ADPKD (eGFR 30-60ml/min) was evaluated in an open-label,  trial (DIPAK 1) involving 309 patients from 4 centers in Netherland. At the end of 2.5 years, the primary outcome of annual rate of eGFR decline for the lanreotide vs the control group was −3.53 vs −3.46 mL/min/1.73 m2 per year (difference, −0.08 [95% CI, −0.71 to 0.56]; P = .81). Findings were consistent across various prespecified subgroups studied, including patients with more rapidly progressive disease, such as patients with class 1C, 1D, or 1E Mayo-classified ADPKD.

Findings are in contrast with the previous smaller ALADIN trial, which showed a benefit of octreotide in reducing rate of TKV increase at 1 year (46·2 mL vs 143·7 mL, p=0·32) and at 3 years (220·1 mL vs 454·3 mL, p=0·25). The inclusion of higher risk patients (eGFR 30-60 vs >40)  in DIPAK 1 (although they dropped eGFR by just 3-4 ml by 2.5 yrs! much lesser than predicted), eGFR vs mGFR (ALADIN used gold standard mGFR, highly desirable and rarely done in most nephrology trials), imbalance in baseline characteristics that favoured octreotide in ALADIN trial. Both trials brought out cholecystitis and liver cyst infections as important side effects of somatostatin analog.

From clinician and patient’s standpoint, the most important question here is ‘who to treat’ rather than ‘with what’. In spite of the improved understanding of genetics and availability of the risk score, identifying candidates who can be benefited (and harmed least) by the treatment remains poor. Especially as both of the promising looking drugs have significant tolerability issues.

3 Efficacy and safety of mycophenolate mofetil versus levamisole in frequently relapsing nephrotic syndrome

Levamisole is often the first steroid-sparing drug used in children with frequently relapsing nephrotic syndrome. This inexpensive drug is often tolerated well. We did not have high-quality data about the efficacy and safety of levamisole. Last year we reviewed an RCT comparing levamisole and placebo demonstrating superiority of levamisole. But we don’t give these children a placebo in the real world, do we?

In a single-center, randomized, open-label trial Sinha et al randomized 149 children ages 6-18 years with frequently relapsing or steroid-dependent nephrotic syndrome to receive therapy with mycophenolate mofetil (750-1000 mg/m2 daily) or levamisole (2-2.5 mg/kg on alternate days) for 1 year; prednisolone was discontinued by 2-3 months.

Just over a quarter of this population was steroid dependent.

Both the regimens were tolerated well. Over the study duration, relapse rates declined to almost one-third of the baseline for both treatment groups. Therapy with MMF was not superior to levamisole in terms of the proportions of participants with sustained remission (40.8% vs. 34.2%), frequent relapses (14.5% vs. 16.4%), or treatment failure, a composite outcome of frequent relapses, steroid resistance, or significant steroid toxicity (15.8% vs. 20.6%). The average prednisolone dose at the end of the study was low in both the groups (0.21 vs 0.3 mg/kg/day).

4 Safety and cardiovascular efficacy of spironolactone in dialysis-dependent ESRD (SPin-D)

Spironolactone reduces cardiovascular mortality in people with systolic heart failure. Considering CVD to be a major cause of death in the dialysis population, can it similarly work in dialysis patients?  In a larger open-label trial of 309 oligo-anuric Japanese HD patients, 25 mg/day spironolactone reduced the composite of cardiovascular hospitalization or death by 60%, and all-cause mortality by 65%.

In a double-blind, placebo-controlled, multiple dosage RCT, double-blind, placebo-controlled, multiple dosage RCT, Charytan et al sought to study safety, tolerability and feasibility and cardiovascular efficacy of spironolactone in 129 maintenance hemodialysis patients: placebo (n=51) or spironolactone 12.5 mg (n=27), 25 mg (n=26), or 50 mg (n=25) daily for 36 weeks.

For the primary safety outcomes of potassium concentration > 6.5 mEq/l and hypotension requiring hospitalization or emergency department visit, there was not an overall difference between spironolactone and placebo groups; however, hyperkalemia and intra-dialytic hypotension was more frequent in patients on 50mg of spironolactone. Change in diastolic function (assessed by Doppler echocardiography) was similar with spironolactone and placebo. This study wasn’t aimed at evaluating CV outcomes, although it reassures about this drug’s safety in a carefully selected dialysis population (e.g. failure to achieve Qb>300ml/min was an exclusion criterion). In the real world of dialysis, where patients often choose (?) the frequency and duration of therapy based on largely nonmedical reasons, and admission with life-threatening hyperkalemia remains one of the commonest reason of emergency room visits, I will prefer to wait until more compelling data to support this therapy. 

CV disease in dialysis is a tough nut to crack and considering the disappointing history of extrapolations from cardiology (statins, ICD, RASi), all the best spironolactone. 

5 The relationship between Cerebral Blood Flow and Cognitive Function in Hemodialysis Patients

Hemodialysis induces a decline in cerebral blood flow. In an elegant study, Findlay et al explored whether hemodialysis was associated with changes in cerebral blood flow and determine whether these changes relate to intradialytic cognitive dysfunction. They recruited 97 adults receiving chronic hemodialysis. Transcranial Doppler ultrasound to measure cerebral arterial mean flow velocity (MFV) throughout dialysis. Cognitive function during and off dialysis and after 12 months of treatment. MFV declined significantly during dialysis, correlating with ultrafiltrate volumes. Percentage of decline in MFV correlated with the intradialytic decline in cognitive function.

In a subgroup of patients followed for 12 months of continued dialysis, the percentage of decline in MFV correlated significantly with lower global and executive function and with the progression of white matter hyperintensities burden (a marker of small vessel disease).

We need interventions to limit this ‘cerebral stunning’. Some time back, Chris McIntyre’s group showed that the patients who dialyzed at 0.5°C below core body temperature exhibited complete protection against white matter changes at 1 year. We need to find out such simple but effective solutions to address this problem.

6 Bleeding Complications after Pediatric Kidney Biopsy

In a meta-analysis of 23 studies of 5504 biopsies, Varnell et al found that 13 studies specifically looked for post-biopsy hematoma. While the studies before 2001 reported a higher proportion of children getting hematoma (40-85%), studies after 2001 reported that 11% had a perinephric hematoma. The risk for blood transfusion in native kidney biopsies was 0.6% (P=0.60; 95% CI, 0.2% to 2.4%), and the risk for blood transfusion in transplant kidney biopsies was 0.8% (P=0.70; 95% CI, 0.4% to 1.6%). The risk of additional intervention after biopsy (cystoscopy, embolization, surgery, or nephrectomy) was 0.7% (95% CI, 0.4% to 1.1%). They could not analyze the available data for laboratory values, needle gauges, number of needle passes, the age of patients, or performer (trainee versus attending physician).

This data seems reassuring and will help counseling anxious parents of the children needing a kidney biopsy.

7 Voclosporin in achieving remission in patients with active lupus nephritis

Increased potency and decreased metabolite exposure of Voclosporin (VCS) results in more pharmacokinetic and pharmacodynamic predictability than CsA, and therefore drug level monitoring is not required (cost of monitoring can exceed that of the drug for CSA/TAC, thanks to generics!). 

In this phase 2, multicentre double-blind RCT involving 256 patients across 20 countries, initial treatment with VCS high dose (39.5mg), VCS low dose (23.7mg), and placebo were compared when added to standard treatment with MMF 2g/d. The primary outcome of CRR (Complete Renal Remission) at 24 weeks was achieved by 29 (32.6%) subjects in the low-dose voclosporin group, 24 (27.3%) subjects in the high-dose voclosporin group, and 17 (19.3%) subjects in the placebo group (OR[2.03 for low- dose voclosporin versus placebo). There were more serious adverse events in both voclosporin groups, and more deaths in the low-dose group compared to placebo and high-dose voclosporin groups (11.2%, 1.1%, and 2.3%, respectively).

Patients with SLE die more often due to infections and CV disease than SLE related causes,  whether the benefits of VCS persists in long-term without additional harm remains to be seen. Also, the possibility of ‘pseudo-remission’ due to nonimmunological effects of CNI and possible ‘CNI dependence’ will need longer follow up after withdrawal of CNI. 

8 Exome sequencing for CKD 

In one of the largest genetic evaluation of CKD, exome sequencing was performed in 3315 patients with CKD (AURORA trial participants and CUMC-Columbia University Medical Centre cohort): about 10% of patients revealed a diagnostic genetic variant. Likelihood of finding such a variant was highest in patients with congenital or cystic renal diseases OR 24.4 (10.6–56.4) followed by Nephropathy of unknown origin (are CKDu researchers listening?) 14.2 (6.0–33.9), and glomerulopathies 6.7 (2.9–15.6).

Medical management was altered by testing in some patients: For example, 56 of the 91 patients (62%) with COL4A3, COL4A4, or COL4A5 mutations did not have clinical diagnoses of the classically associated nephropathies (the Alport syndrome or thin basement membrane disease). For these patients, the genetic diagnosis would indicate ophthalmologic and otolaryngologic referral and, among the 15 patients (16%) with a clinical diagnosis of focal segmental glomerulosclerosis, would disfavor immunosuppressive therapy.

After all, AURORA wasn’t a negative trial!

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November 2018

1. Efficacy and Safety of Sparsentan in Patients with FSGS

Sparsentan is a dual endothelin receptor and angiotensin receptor blocker and was evaluated in this phase 2 randomized, double-blind, active-control, dose-escalation study (DUET trial) involving 109 patients with primary FSGS from 44 centers across the US and Europe. This treatment was after patients were on stable immunosuppressive regimens and after RAS blockade washout period of 2 weeks. They had to have proteinuria >1.5gm and eGFR>30ml/min.

At the end of 8 weeks, compared to irbesartan, sparsentan-treated patients had greater reductions in UP/C than irbesartan-treated patients did when all doses (45% versus 19%; P=0.006) or the 400 and 800 mg doses (47% versus 19%; P=0.01) were pooled for analysis. Results are exciting and hopefully will translate into long-term renoprotection, addressing a major unmet therapeutic need in this population.

 

2. Recombinant Alkaline Phosphatase (rALP) for sepsis-associated AKI             

Alkaline phosphatase is supposed to exert detoxifying effects through dephosphorylation of various compounds, including bacterial endotoxins and proinflammatory mediators such as extracellular adenosine triphosphate.

In this phase 2a/2b clinical trial evaluating the efficacy, safety, and doses of rALP in the treatment of sepsis-associated AKI, rALP in various dosages studied was no more effective than placebo with regards to the primary endpoint of change in the mean daily creatinine clearance (absolute difference, 9.5 mL/min [95% CI, −23.9 to 25.5]; P = .47). No safety issues were noted with rALP. Authors hypothesize various reasons for the lack of efficacy (most of which are related to the study design)-imbalanced randomization with rALP arm having more severe AKI than placebo, imprecise estimation of renal function by creatinine clearance in the nonsteady state, the short time frame of 7 days to look at efficacy and they emphasize the need of further trials.

Given the heterogeneous and multifactorial nature of AKI, it is not surprising that “magic bullets” (dopamine, ANP, fenoldopam, and so on) have consistently misfired. My gut (ALP) feeling is that rALP won’t be any different!

 

3. Impact of ACC/AHA guidelines 

Here is a JAMA study which found that if the ACC/AHA guideline was used, the overall prevalence of hypertension in Nepal would approximately double (from 21.2% to 44.2%), mostly by shifting more individuals out of the normal and prehypertension categories. Hey you all skeptics, look here, guidelines do have the impact! While Kibria and colleagues should be congratulated, this “overnight” doubling of the hypertension prevalence needs to be understood on the background of overburdened public health programmes in Nepal.

With the doctor-patient ratio is 0·17 per 1000 population, it will be quite a task to address the health needs of these ‘newborn’ hypertensives. Don’t miss this invited commentary on this article, putting results into context. 

 

4. ACE inhibitor use and cancer risk 

“Commonly used BP drug increases lung cancer risk”, this became a headline in media after the publication of this population-based cohort study in BMJ. 

Using UK Clinical Practice Research Datalink, 7952 incident lung cancer events were detected among patients on various antihypertensive medications after a median follow up of 6.4 yrs. Patients using ACE inhibitors had a 14% higher risk as compared to other drugs (incidence rate 1.6 v 1.2 per 1000 person-years; HR 1.14, 95% CI 1.01 to 1.29), compared with the use of angiotensin receptor blockers. Proposed hypothesis underlying is tumorogenic effects of bradykinin and substance P that accumulates in the lung tissue as a result of ACE inhibition.

Absolute risk attributable to the drug is extremely small when one considers the known risk factors like smoking, and I hope patients and primary care doctors won’t stop these drugs with established efficacy in preventing CV deaths. In the observational design like this, residual confounding and ‘detection bias’ (ACE inhibitors—->cough—->higher chance of chest imaging—–>increased detection) may well explain the results (confidence interval is almost touching 1). Rapid responses published are worth reading.

I can, of course, use the results to persuade hypertensive smokers to quit!

 

5. Association of Angiotensin-Converting Enzyme Inhibitor or Angiotensin Receptor Blocker Use With Outcomes After Acute Kidney Injury

Acute kidney injury is associated with increased risk of CKD, ESRD, and death. We keep searching for interventions that can modify this risk. I think common sense is one thing that should top the list (if we choose to make such a list). It is known that follow up with a nephrologist improves all-cause mortality of acute kidney injury survivors. Wonder why that would be? We don’t have any magic bullet with us. I think the answer lies in common sense. Common things that we do all the time, for example, tweaking the doses of diuretics, restarting essential medicines, identifying new risk factors etc would help the most.

In a large retrospective study using an administrative database from Alberta Kidney Disease Network, Brar et al explored if RAAS blockade improves outcome in people who have had AKI in the recent past. Of the 46,253 adults who had an episode of AKI during hospitalization and survived, 48% were prescribed an ACEi or ARB (41.6% were on ACEi/ARB prior to the index hospitalization while 6.9% were given a new prescription.) ACEi or ARBs were associated with lower mortality (adjusted HR 0.85, 95% CI 0.81-0.89). However, they were also associated with a higher risk of hospitalization for a renal cause, mainly AKI, CHF, and hyperkalemia (adjusted HR 1.28, 95% CI 1.12-1.46). No association was found between ACEi/ARB and progression to ESRD.

The group that was on ACEi /ARB prior to the hospitalization but did not receive it within 6 months fared worse in terms of mortality. This group was at high CV risk and it makes sense to start/ restart RAAS blockers in such a population. In short, previous AKI episodes should not deter us to restart ACEi/ ARB. At the same time, close monitoring is required to detect adverse effects.

 

6. ABO-incompatible kidney transplant outcomes- a meta-analysis

With ever increasing the burden of ESRD, we keep looking for the ways to expand the kidney donor pool, be it paired kidney transplant, desensitization protocols or ABO incompatible transplants. But its only natural that risks tend to escalate as we become more aggressive.

de Weerd and Betjes performed a meta-analysis of single-center studies comparing patients who were ABO-incompatible with ABO-compatible controls reporting patient and graft survival. Twenty-six studies were included, describing 1346 patients who were ABO-incompatible and 4943 ABO-compatible controls. Older studies using splenectomy were excluded.

One-year uncensored graft survival of patients who were ABO-incompatible was 96% versus 98% in ABO-compatible controls (relative risk, 0.97; 95% confidence interval, 0.96 to 0.98; P,0.001). However, 49% of reported causes of death in patients who were ABO-incompatible were of infectious origin, versus only 13% in patients who were ABO-compatible (P=0.02). Antibody-mediated rejection (3.86; 95%confidence interval, 2.05 to 7.29; P,0.001), severe nonviral infection (1.44; 95%confidence interval, 1.13 to 1.82; P=0.003), and bleeding (1.92; 95% confidence interval, 1.36 to 2.72; P,0.001) were also more common after ABO-incompatible transplantation. CMV and BK viremia was common in ABO-incompatible group as well.

Publication bias is a limitation here and the risks reported could be an underestimate. And make no mistakes, these risks are expensive to manage. These outcomes are certainly better than remaining on dialysis. However, paired kidney transplantation has the potential to minimize these costly consequences. We have to know our options better.

 

7. Duration of Treatment with Corticosteroids and Recovery of Kidney Function in Acute Interstitial Nephritis

Majority of us use corticosteroids to treat drug-induced acute interstitial nephritis. However, there are no RCTs guiding us in this area. Available data are mainly retrospective and conflicting. In one such retrospective (and probably the largest) analysis, Fernandez-Juarez et al studied the association between the length of corticosteroid treatment and serum creatinine at 6 months.

The study included 182 patients with biopsy-proven drug-induced acute interstitial nephritis from 13 Spanish centers. The most frequent offending drugs were nonsteroidal anti-inflammatory drugs (n=49; 27%), followed by antibiotics (n=41; 22%), and proton-pump inhibitors (n=8; 4%). All patients presented with acute kidney disease and were treated with corticosteroids. The mean initial dose of prednisone was 0.8 ±0.2 mg/kg per day. High-dose corticosteroid treatment was maintained for 2 weeks (interquartile range, 1–4). After 6 months of follow-up, the mean recovered GFR was 34 ±26 ml/min. Seventy-five patients (41%) achieved complete recovery of kidney function, 83 patients (46%) achieved partial recovery, and 24 patients (13%) did not recover kidney function. Within this group, ten patients needed maintenance dialysis.

In the multivariable analysis, delayed onset of steroid treatment and the presence of interstitial fibrosis of >50% on the kidney biopsy specimen were both associated with serum creatinine level at month 6 of >75%, with respect to baseline values. Keeping in mind all the drawbacks of a retrospective study, this paper supports what we practice usually: start early, don’t give the high dose and not for a prolonged period.

8. Diagnostic application of kidney allograft-derived absolute cell-free DNA levels during transplant dysfunction

It will be a dream come true to diagnose rejection without graft biopsy.

Cell-free  DNA (cfDNA)  is fragmented, degraded  DNA that is detectable in body fluids, including plasma and urine. The majority of detectable cfDNA in plasma is thought to arise from cell-turnover within the haematopoetic system. Injury to the allograft results in increased release of graft-derived cell-free  DNA  (gd-cfDNA) into recipient plasma via graft-cell apoptosis and necrosis. And the same could be used to detect graft injury, mainly rejection, non- invasively.

In a cross-sectional study done in two transplant centers in Melbourne, Whitlam et al studied the diagnostic validity of absolute measurements of graft-derived cell-free  DNA,  as well as calculated graft fraction (proportion of total cell-free DNA  that is graft-derived), for the diagnosis of graft dysfunction. Plasma graft-derived cell-free  DNA, total cell-free DNA and graft fraction were correlated with biopsy diagnosis as well as individual Banff scores. Adult kidney  transplant  recipients  undergoing  standard-of-care allograft biopsy  for investigation  of graft  dysfunction  were  included in  the  study.

61 samples were included in the analysis.  For the diagnosis of antibody-mediated rejection,  the receiver-operator characteristic area under the curves of graft-derived cell-free  DNA and graft fractions were  0.91  (95%  CI  0.82-0.98)  and  0.89  (95%  CI 0.79-0.98),  respectively.

That means we could rule out antibody-mediated rejection based on a blood test. As of now, we cannot replace graft biopsy with cell-free DNA alone but it may become an alternative to serial biopsies (for example, monitoring the response to treatment of ABMR or screening in high-risk population).

 

 

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.

September 2018

 

1 Folly of surrogates 

validity ajkd

Visual abstract by Dr. Divya Bajpai (@divyaa24)

Whether its phosphorus, blood pressure, PTH, or albuminuria- the numbers guide us all in our practice. Being easily modifiable with treatments, surrogates are attractive outcomes not only in nephrology but also in other areas of medicines. However, more often than not, that’s not what patients want from us. They want us to improve the way they ‘feel, function and survive’. Here is something that highlights this once again for us: in a meta-analysis of BP lowering treatment trials (22 trials involving 69,642 participants), there was limited correlation between drug effects on surrogates (albuminuria, eGFR/creatinine) and risk of ESRD.

These findings contrast the NKF and USFDA’s view that proteinuria is a reliable surrogate of kidney disease progression. For decades, we have been deluded by surrogates, not surprisingly, we see dissociation between soft endpoints and patient-centered outcomes. Are CANVAS, EMPAREG, and LEADER  listening?

2 Biocompatible Solutions and Long-Term Changes in Peritoneal Solute Transport

Speaking of surrogate endpoints, if faster peritoneal solute transport rate is associated with poor outcomes(read technique failure and mortality and encapsulating peritoneal sclerosis), a fluid that preserves the transport characteristics of the peritoneal membrane would be an ideal PD solution.

Elphick et al analyzed the data from the multinational prospective Global Fluid Study to test the hypothesis that biocompatible solutions use would be associated with stable membrane function. This hypothesis proved false, because “solute transport rate, although starting slower in patients using biocompatible solutions, rose to similar levels seen in standard solutions after 2 years of treatment. After 2 years, there was a potentially beneficial effect of biocompatible solutions on solute transport rate, with abrogation of the increases in solute transport rate observed in patients using standard solutions. In addition, the increases in solute transport rate associated with peritonitis episodes were absent in patients using biocompatible solutions. The magnitude of these effects was less than the effect of using higher dialysate dextrose concentrations.” There may be a long-term benefit; only a large study with long-term follow up would tell us that.

3 Uric acid lowering and CKD progression 

febuxostat ajkd 2018final

Visual abstract by Dr. Aakash Shingada (@aakashshingada)

Monsoon is the lifeblood for Indian farmers and it regularly defies meteorological department’s predictions, so much so that some farmers recently filed a police complaint against the department and a farmers’ organization had threatened to close down their office.  We desperately need a better tool to predict rains. In absence of such a tool, some farmers look at the height at which a weaver bird builds its nest on a tree to predict the rains. I find myself in no better position when a patient with CKD (especially those with no significant HTN and proteinuria) asks me about the future course of his disease and if I would be able to change the trajectory in a better way.  Uric acid, for some of us, is that weaver bird’s nest.

In the multicenter, placebo-controlled, double-blind, FEATHER (Febuxostat Versus Placebo Randomized Controlled Trial Regarding Reduced Renal Function in Patients With Hyperuricemia Complicated by  Chronic Kidney Disease Stage 3). Compared to placebo, febuxostat did not mitigate the decline in kidney function among patients with stage 3 CKD and asymptomatic hyperuricemia. Not convinced by the futility of this therapy, the authors try and speculate on various reasons for the negative results of the trial like higher eGFR (65-year-old, eGFR, and stage 3 CKD—you know what I mean), a generally slower decline of eGFR in their patients, no significant proteinuria etc. Diastolic BP was lower in the febuxostat group (not surprising as they were more likely to be on ACEi/ARBs)

Only thing I am sure about febuxostat today is that it’s an effective urate-lowering agent and FEATHER just confirms this observation.

4 TRANSFORMing long-term outcome after kidney transplantation, really?

Everolimus sept 2018 final

Visual abstract by Dr. Aakash Shingada (@aakashshingada)

Set out to address the burning issue of chronic allograft injury, here is a report (yet another), an RCT comparing everolimus with reduced CNI exposure with conventional immunosuppression i.e. MMF with standard CNI dosing (arguably TAC trough levels of 8-12  vs 3-8 in everolimus arm will qualify for ‘high dose CNI’ strategy). Everolimus arm was non-inferior to conventional arm for the primary endpoint which was (novel according to Novartis): binary composite of tBPAR(treated biopsy-proven acute rejection) or eGFR<50 ml/min at 12 months post-transplant [48.2% (493) with everolimus and 45.1% (457) with MPA (difference 3.2%; 95% confidence interval, 21.3% to 7.6%)]. Infections (especially CMV and BKV) were less common in everolimus arm.

Are you ready to get transformed? You may if you are willing to forgo the following flaws: the fallacy of eGFR as efficacy endpoint, generous 10% noninferiority margin, two components of the binary endpoints not necessarily changing linearly, and exclusion of high-risk patients. Also please let go of the tolerability-mTOR arm was more than two times likely to discontinue medication due to side effects (23% vs 11.9%). So we are no further than this Cochrane review as of now.

When will we move to patient-centered research in transplantation? Neither I nor my patients will be ready to get transformed just by good-looking numbers at 12 months. They deserve much more than that.

5 Patient-Reported Experiences of Dialysis Care

 Moving away from surrogates, here is an interesting report of patient-reported experiences of dialysis care patients from a national ESRD registry receiving in-center hemodialysis in the United States. In-Center Hemodialysis Consumer Assessment of Healthcare Providers and Systems (ICH-CAHPS) survey, (this contains questions like-how often did you feel your kidney doctors really cared about you as a person? never/sometimes/usually/ always).

2939 (59.1%) reported mean ICH-CAHPS scores. Patient experience of the dialysis centers was poor (lower ICH-CAHPS score) if the center has the following characteristics: for-profit units, stand-alone centers, fewer nurses and technicians per patient, centers belonging to LDO (Large Dialysis Organisation), had more patients with minority race/ethnicity.

Although limited by various factors (39% centers didn’t report, the interplay of medical and nonmedical factors etc), this exercise should be done more and more often to better understand the gaps in the delivery of complex treatment like dialysis. Inputs derived can potentially help improve the quality of dialysis care.

6 What happens when hemodialysis is free of cost?

andhra

Visual abstract by Dr. Divya Bajpai (@divyaa24)

While patient-reported experiences of care may be less favorable in for-profit hemodialysis units, a paper published from India enlightens us about a government-sponsored program where patients are provided maintenance hemodialysis free of cost. Andhra Pradesh, a southern state in India, implements the Rajiv Aarogyasri Community Health Insurance Scheme (RACHIS) where a private insurer provides a health insurance and is paid in full by the state government. Beneficiaries are able to utilize hospital services through a network of public and private hospitals and are covered up to INR 150,000 ($ 8876) per year.

A total of 13,118 patients received HD for ESRD during the study period (mid-2008-mid-2012). The program had a good reach and the number of patients who received HD for ESRD increased from 29.5 per million of the population in 2008–2009 to 122.2 per million of the population in 2011–2012.

Of all the subjects who started HD, 2.3% received a kidney transplantation, 17.1% were reported as dead, and 63.5% had ceased treatment of their ESRD (i.e., stopped reporting to dialysis centers).

The total cost of HD-related care was $ 63.2 million. The mean annual expenditure per patient on HD-related care was $ 4821. (This contrasts with $ 89,900 in the United States!)

Costs other than dialysis costs (commuting, loss of wages, drugs, caregiver burden) could be the reason for the high dropout rate; but what is most striking here is the high mortality rate.

Maintaining low-cost services alone is not enough; the model must have in-built checks to improve the outcomes.

In authors’ word, “In conclusion, removal of out-of-pocket of cost leads to an increase in uptake of HD, confirming a previously high unmet need. The high mortality and dropout rates suggest that insurance coverage does not address all inequities in access and the barriers to maintaining long-term care.”

[Let me thank Dr. Krishna Penmatsa (@krishnadoctor1) who gave me insights into the Rajiv Aarogyasri Community Health Insurance Scheme (RACHIS)]

Monitoring the urine flow to prevent overcorrection of hyponatremia

Urine output is probably the most important parameter to monitor when one treats hyponatremia; arguably more useful at the bedside than urine lytes and osmolality (given the typical turnaround time). Once the component of volume contraction (or whatever is the cause of high ADH level) is taken care of, the stimulus for ADH secretion is taken away and this leads to water diuresis leading to a rapid rise in serum sodium. The best strategy at our disposal is frequently checking the sodium level (and using DDAVP of course).

If you are a nephrologist, you must read (and pretend that you understood every single word of it) this article published in AJKD last month. Florian Buchkremer et al have derived on theoretical grounds a safe upper limit of urine flow, dependent only on body weight, that can be easily used at the bedside.

Edelman is the root of almost all good in nephrology. Based on the Edelman equation, authors suggest using a urine flow rate of 24 mL/kg/24 h or 1 mL/kg/h (up to a maximum of 2,400 mL/24 h or 100 mL/h) as a safe upper limit during correction of hyponatremia.

If you have been called for a hyponatremia consult and are seen doing narcissistic calculations trying to predict the next morning’s sodium and find that you are terribly wrong, you are welcome to the club! Discrepancies between actual plasma sodium changes and those predicted by the Edelman equation have been reported, but most of that is related to the things we assume. The equation stands tall! But one thing we can take from this paper is the order we are going to write- “Document total urine volume [as voided or every 2 hours in patients with catheters]. Notify the treating physician as soon as the cumulatively voided volume exceeds 6mL/kg in 6 hours.”

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

 

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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!

 

Thank you, Sir!

Prof. N K Hase, a nephrologist, and a teacher par excellence retired recently from the services of the Seth GS Medical College and KEM Hospital, Mumbai. He was very reluctant to have a grand send-off and after lots of requests, he agreed to have a roundtable meeting with the members of his department. This three-hour meeting was the most memorable send-off I have ever been to; everyone including Dr. Hase, was tearful while expressing themselves. Dr. Amar Sultan, one of his students, gave a very apt tribute by presenting Dr. Hase’s own life in a case presentation format. Here it is for you all:

 

PHOTO-2018-07-25-10-32-04

 

MR. NKH, a 65 years old gentleman, married, father of two, right-handed, residing at Thane, hailing from Sangamner, a physician and a teacher by profession, presented with symptoms of awesomeness and brilliance for last several decades.

These symptoms appeared to be progressive and to an extent, contagious.

Sir, I would like to start my history from the year 2004, when I first met this gentleman for the first time in ward number 5 of L.T.M.Medical College and Sion Hospital during ward rounds when he complimented me by saying, “very good” for correctly telling the antidote of heparin in my second year MBBS posting; however this phenomenon of complimenting occurred only once and has not recurred till date.

During the same round, at the bedside of the next patient, he asked us about symptoms of yellow phosphorus poisoning. Now, having recently studied yellow phosphorus in my twelfth standard chemistry, I knew that as a highly inflammable element. I spontaneously answered that it tears our the GI tract. (I wasn’t aware of medical terminologies like ‘erodes’, ‘corrodes’ or ‘perforates’ by then; I had to use the word ‘tears’). Stunned with my answer, he turned to me, took out his magic wand (i.e. his right index finger) waved at me and said, “If you don’t know, say ‘I don’t know’. Don’t bluff.” (Unlike symptom of complimenting me, this phenomenon of waiving his magic wand at the fellows was strikingly recurrent, particularly in 2015 during my transplant rotation in nephrology training under him).

In the same year (2003-04) while teaching a CNS case to PG students in Friday clinics at the Sion hospital, this person had surprised all exam-going students by quoting the then-recent classification of ataxic disorders which probably was not even published. By this time, he was famous as an outstanding teacher among undergraduate and postgraduate students.

From 2004, he was lost to follow up and had opted to explore alternative horizons of medicine. Details of the events during this period are not available to me. However according to his close associates, symptoms of excellent teaching, extraordinary clinical judgment were relentlessly progressive during this time.

Thanks to my good fortune, I encountered him again in August 2014 when I noticed that the above-mentioned symptoms had significantly progressed. At this time, his awesomeness was associated with an increased responsibility, increased enthusiasm along with increased teaching activity and hard work. His punctuality and clinical acumen had no comparison. These symptoms were present throughout the year without any diurnal or seasonal variations and were present even during sleep (evident by the immediate response to the midnight phone calls from the clueless residents). There were no relieving factors.

On inquiry, he also gave the history of immunity to the fatigue and stress from his hectic daily routine.

There was a recurrent history of attending patients outside clinic hours in his cabin, corridor, lift and even at the entrance of the hospital. There was a history of postponing lunch while attending to the patients in his chamber. History of playing a role of a father when he took all the responsibility for the mistakes made by his children particularly the younger two (read- the 1st year residents).

He never lost his patience. There was no history of refusal to see patients, to solve a query or to teach undergraduate or postgraduate students. There was no history of shortcuts while examining a patient, writing medical notes, filling up the lab request forms (which is not so easy in a municipal hospital with paper-based records) or while arriving at a diagnosis.
There was no history of craving for fame, appreciation, spotlight or money.

Past history
Similar complaints in past ever since he has joined medicine.

Personal history
Mixed diet; the voracious appetite for reading. Addicted to Halls and Mentos 🙂
Unable to sleep unless he reads for a couple of hours
Sleep is disturbed due to frequent calls by on-call Nephrology Residents.
Very neat handwriting just as his character is.

Family history
Similar symptoms, albeit in early stages are found in his son as well as his daughter.

On examination
He is calm and quiet and appears radiant. Pulse rate( I swear, I have measured it for one complete minute) is normal.
Blood pressure checked in an ideal calm environment of Tuesday Nephrology OPD (read- chaos) is normal.

Systemic examination: massive cardiomegaly enough to accommodate mistakes of his residents. Rest of the examination is normal.

To summarise-
I am dealing with a 65-year-old gentleman with progressive symptoms of excellence, brilliance, and hard work, for whom age is just a number.
He also is a good doctor, teacher, and a mentor and has limitless empathy for his patients.
He also is one of the best human beings on this planet and has a big heart.

Diagnosis
There are no differential diagnoses here. A thorough literature review revealed that presence of and more importantly, the persistence of these symptoms till the age of 65 is rare and only one case has been reported till date which is from western India. This symptom complex is characteristic and diagnostic of the persona called PROF. NIWRUTTI K HASE.

Amar Sultan (@sultan_amar8)

July 2018

1 Sodium bicarbonate therapy for patients with severe metabolic acidaemia in the intensive care unit (BICAR-ICU)

BICAR ICU

(Visual abstract by Divya Bajpai @divyaa24 )

While the threshold for starting treatment may differ, most of us use sodium bicarbonate in acidemic patients in ICU, especially in the setting of acute kidney injury. This is one of those practices where very little evidence exists to guide decisions (in fact nearly equal basic science data exists for and against bicarbonate use).

Much-needed evidence addressing this dilemma now comes from this multicentre, open-label RCT of 389 adult patients who were admitted within 48 h to the ICU with severe acidemia (pH ≤7⋅20, PaCO2 ≤45 mm Hg, and bicarbonate concentration ≤20 mmol/L) and with a SOFA score of ≥4 OR an arterial lactate concentration of ≥2 mmol/L randomized to receive either no sodium bicarbonate (control group) or 4⋅2% of iv sodium bicarbonate infusion (bicarbonate group) to maintain the arterial pH above 7⋅30. The primary outcome -a composite of death from any cause by day 28 and the presence of at least one organ failure at day 7- was not different in the two arms: 138 (71%) of 194 patients in the control group and 128 (66%) of 195 in the bicarbonate group (absolute difference estimate –5⋅5%, 95% CI –15⋅2 to 4⋅2; p=0⋅24) without significant effect of the treatment group (crude OR 0⋅775, 95% CI 0⋅505–1⋅190; p=0⋅24).

In the pre-specified subgroup involving 182 (47% ) patients with AKI-AKIN stage 2 or 3, therapy offered some benefit: the primary outcome occurred in 74 (82%) of 90 patients in the control group and 64 (70%) of 92 patients in the bicarbonate group (absolute difference estimate –12⋅3%, 95% CI –26⋅0 to –0⋅1; p=0·0462)

More patients in control group underwent renal-replacement therapy during their ICU stay (52% vs 35%, absolute difference estimate –16⋅7 days, 95% CI –26⋅4 to –7⋅0; p=0⋅0009; figure 3); and when indicated, renal replacement therapy was started earlier in the control group than in the bicarbonate group (7 hours vs 19 hours). Hyperkalemia and acidosis were the main reasons for RRT in the control group and Serum creatinine and serum blood urea nitrogen were the main reasons to start renal-replacement therapy in the bicarbonate group.

Do these findings change my practice? Not really; IV bicarbonate in lactic acidosis is unlikely to offer any survival advantage where the primary treatment is the treatment of the underlying cause. But in presence of renal insufficiency, bicarbonate therapy may be useful in postponing dialysis and at least is not associated with significant harm. In this sense, the study findings support what we do. See an excellent post on PulmCrit blog here.

 

2 Canagliflozin and renal outcomes in type 2 diabetes

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(Visual abstract by Divya Bajpai @divyaa24 )

Results of CANVAS program were published last year. We discussed the paper here. The trials concluded that patients treated with canagliflozin had a lower risk of cardiovascular events than those who received placebo but a greater risk of amputation.

The results of a prespecified exploratory analysis of the effects of canagliflozin on a range of renal outcomes were published last month in the Lancet. CANVAS program included two comparable studies- CANVAS and CANVAS-R. Participants in CANVAS were randomized to receive 300 mg canagliflozin, 100 mg canagliflozin, or matching placebo once daily. Participants in CANVAS-R were randomized to receive canagliflozin at an initial dose of 100 mg daily, with optional uptitration to 300 mg from week 13 or matching placebo. People with type 2 diabetes and an HbA1c of 7·0–10·5% who were aged at least 30 years and had a history of a symptomatic atherosclerotic vascular disease, or who were aged at least 50 years and had at least two cardiovascular risk factors were included in the study.

The composite outcome of sustained doubling of serum creatinine, end-stage kidney disease, and death from renal causes occurred less frequently in the canagliflozin group compared with the placebo group (1·5 per 1000 patient-years in the canagliflozin group vs 2·8 per 1000 patient- years in the placebo group; hazard ratio 0·53, 95% CI 0·33–0·84). After an initial drop in the eGFR, Canagliflozin preserved the eGFR better. New onset albuminuria (micro/macroalbuminuria) occurred less frequently in the canagliflozin group.

Rates of acute kidney injury and hyperkalemia did not differ in the two groups. The heightened risk of amputation and fractures in canagliflozin group was similar in participants with eGFR above and below 60 mL/min per 1·73 m².

Considering very few clinically relevant renal events, these results are hypothesis generating at the best and as authors admit, aren’t enough for the drug to get formally approved for renoprotection in diabetes. The number needed to treat (NNT) for the primary composite outcome in this trial was 771! If we think 40% reduction in MDRD eGFR is a clinically relevant outcome, 296.2 patients would have to receive canagliflozin (instead of control treatment) for one additional patient to NOT have 40% reduction in MDRD eGFR. For surrogate like albuminuria though, the NNT was 36.9.

 

3 Gabapentin and Pregabalin Use and Association with Adverse Outcomes among Hemodialysis Patients

Gabapentin and pregabalin are often prescribed for neuropathic pain in patients on hemodialysis. KDIGO suggests the use of gabapentin for pruritus and restless leg syndrome. Not surprisingly, many of these patients do not tolerate these medications dependent on renal clearance for their elimination.

From the US Renal Data System, Ishida et al identified 140,899 Medicare-covered adults receiving hemodialysis and investigated the association between gabapentin and pregabalin, and time to first emergency room visit or hospitalization for altered mental status, fall, and fracture.

19% and 4% of patients received gabapentin and pregabalin, respectively. Not unexpectedly, gabapentin was associated with 50%, 55%, and 38% higher hazards of altered mental status, fall, and fracture, respectively, in the highest dose category (>300 mg/day), but even lower dosing was associated with a higher hazard of altered mental status (31%–41%) and fall (26%–30%). Pregabalin was associated with up to 51% and 68% higher hazards of altered mental status and fall, respectively.

Finding the safer doses of these drugs or the safer alternatives to improve the quality of life of these patients is the need of the hour.

 

4 Efficacy of Rituximab vs Tacrolimus in Pediatric Corticosteroid-Dependent Nephrotic Syndrome (RITURNS)

Vitamin R is rocking again!

In an RCT from Kolkata, Basu et al randomized 176 children aged 3 to 16 years with the corticosteroid-dependent nephrotic syndrome to receive either tacrolimus (along with tapering alternate-day prednisolone) for 12 months or a single course of rituximab (2 infusions of 375mg/m2). Rituximab therapy was associated with a higher 12-month relapse-free survival rate than tacrolimus (54 [90.0%] vs 38 [63.3%] children; P < .001; odds ratio, 5.21; 95%CI, 1.93-14.07). Among the patients who experienced relapse, the median time to the first relapse was 40 weeks in the rituximab group and 29 weeks in the tacrolimus group. Rituximab group had lower cumulative corticosteroid dose (25.8 ±27.8 vs 86.3 ± 58.0 mg/kg) and better catch-up growth.

Mild to moderate infections were twice as common in the tacrolimus group.

Authors conclude that in children with the corticosteroid-dependent nephrotic syndrome, rituximab is more effective than tacrolimus in maintaining disease remission.

A significant number of children with this disease suffer morbidity and mortality that can be associated with immunosuppression and until long-term safety data become available, we need to involve patient families in shared decision making before resorting to the vitamin R.

 

Effect of Tamsulosin on Passage of Symptomatic Ureteral Stones

TAMSULOSIN VA

(Visual abstarct by Aakash Shingada @aakashshingada)

Meltzer et al randomized 512 adults presenting to the emergency department with symptomatic ureteric stones <9 mm in diameter on CT to receive either Tamsulosin or placebo. The primary outcome was the passage of a ureteral stone within 28 days after randomization, as determined by the participant’s visualization or physical capture of the stone. At the end of the 28-day treatment period, the urinary stone passage rate of 49.6% among participants assigned to Tamsulosin did not differ significantly from the placebo passage rate of 47.3%(relative risk, 1.05; 95.8%CI,0.87-1.27;P = .60)

In a large study done in China, tamsulosin arm had a higher stone expulsion rate compared to the placebo (86% vs 79%; p<0.001) for distal ureteral stones of size 4-7 mm. In the subgroup analysis, stones larger than 5 mm had higher odds of expulsion.

It is possible that Tamsulosin does not facilitate expulsion of small stones or the stones in the upper ureter. In the case of larger stones, will this study change the current practice?

 

Belimumab in kidney transplantation

While T-cell mediated rejections are largely treatable, antibody-mediated rejections pose a significant threat to the renal allografts. B cells also have a regulatory role and thus could play both a positive and negative role. Strategies targeting B cells with preservation of their regulatory functions would be a boon to transplantation.

B lymphocyte stimulator (BLyS) is a cytokine that promotes B cell proliferation. High serum concentrations of BLyS are associated with the development of de-novo donor specific antibodies.

We know belimumab as an FDA-approved therapy for non-severe auto-antibody positive SLE. Belimumab is a monoclonal antibody that prevents the survival of B lymphocytes by blocking the binding of soluble human BLyS to receptors on B lymphocytes. This reduces the activity of B-cell mediated immunity.

In a double-blind, randomised, placebo-controlled phase 2 trial sponsored by GSK (manufacturer of belimumab), 28 kidney transplant recipients were randomly assigned to receive iv belimumab 10 mg per kg bodyweight or placebo, given at day 0, 14, and 28, and then every 4 weeks for a total of seven infusions, in addition to the standard immunosuppression (Basiliximab, tacrolimus, MMF, prednisolone).

Belimumab effectively removed circulating free BLyS. However, the co-primary endpoint of a reduction in naive B cells from baseline to week 24 was not met. There was no major safety concern observed. There was a nonsignificant trend towards reduction in naive B cells and kidney specific IgG, with significant reductions in activated memory B cells and circulating plasmablasts. In authors’ words, ‘the reduction in activated memory B cells and preformed IgG indicates the drug’s potential in sensitized kidney transplant recipients.’

In larger studies, it will be interesting to see the long-term safety and efficacy of belimumab.

 

7) Analysis of Luminex-based algorithms to define unacceptable HLA antibodies in CDC-crossmatch negative kidney transplant recipients

With the solid phase assays for identifying anti-HLA antibodies, we now can hope to improve transplant outcomes by avoiding transplantation if anti-HLA antibodies are present. However, this approach will result in a smaller donor pool available for a growing waiting list. CDC cross match may be negative even when anti-HLA antibodies are present. However, relevance of a positive single antigen bead assay in presence of negative CDC cross match is less clear.

In a study from Germany, transplant-day sera of CDC cross-match negative kidney transplant patients were screened retrospectively for the presence of anti-HLA class I and class II IgG antibodies using solid-phase microsphere-based assay. If pretransplant sera revealed the presence of anti-HLA IgG antibodies, the corresponding HLA were classified as unacceptable HLA-antigen mismatches.

Among the 211 patients studied, 115 (54.5%) had anti-HLA-specific IgG antibodies retrospectively detected by the Luminex assay using day of transplant sera. 67/211 patients (31.8%) had donor-specific anti-HLA-antibodies. Among the 67 DSA-positive patients, 16 (23.9%) experienced AMR during a median follow up of 4.9 years, majority occurring within the first year.

Of these 16 patients with AMR, 11 could be identified if the threshold of positive DSA test was kept at MFI value 3000 SAB assay [according to the German Society of Immunogenetics (DGI) consensus, algorithm I]. Authors also tested two more algorithms.

  • Algorithm II (ME algorithms): all antibodies against HLA A, B or DR with MFI above 5000 or antibodies against HLA DQ with MFI above 10,000.
  • Algorithm III (MFI_10,000): all anti-HLA antibodies with MFI above 10.000.

Algorithms (I) and (II) had comparable efficacy but were superior to (III) in identifying at-risk patients.

To calculate the extent of the Eurotransplant donor pool that would be excluded during organ allocation due to the presence of this kind of unacceptable antigen match due to donor specific antibody, the virtual panel-reactive antibody (vPRA) level was calculated. Median vPRA was between 69.2 and 79.1%, translating into a potential prolongation of waiting time between 1.5 and 1.8 years, respectively.

Donor specific antibodies in absence of CDC cross match positivity reflect a high immunologic risk. At the expense of a better match, this will shrink the donor pool and prolong waiting time.

In order to minimize this impact, we need to understand how to identify those who had DSAs but did not develop rejection.