June 2019

1) MENTORing on Rituxumab for Membranous Nephropathy

Results of the multi-center, open label, MENTOR trial comparing rituximab (RTX) with Cyclosporine (CSA) are here: “Of 130 randomised, 39 of 65 patients (60%) in the RTX group and 34 of 65 (52%) in the CSA group had a complete or partial remission (risk difference, 8 percentage points; 95% CI, −9 to 25; P=0.004 for non-inferiority) at 12 months. At 24 months, 39 patients (60%) in the RTX group and 13 (20%) in the cyclosporine group had a complete or partial remission (risk difference, 40 percentage points; 95% CI, 25 to 55; P<0.001 for both non-inferiority and superiority)”. Authors conclude that RTX is non inferior to CSA at 12 months and was superior to CSA at 24 months in inducing remission of proteinuria.

This data furthers the role of RTX in this disease, but definitely should not be considered enough to use it as first line in most high risk patients with MN. First, choice of the comparator (considered ‘clever’ by accompanying editorial), is not the standard of care for most of us. Both short and long term response rates (proteinuria and ESRD) are reported to be far better in the RCTs involving CYP (about 80-90% vs 60 % with RTX in MENTOR). Second, the strange CSA treatment protocol-in patients who responded CSA was tapered over 2 months, more rapidly than one would generally do in practice [not surprisingly, over half (18 of 34) of those in remission on CSA at 12 months, didn’t maintain the remission at 24 months) and third, an unusually higher rates of side effects and discontinuation in CSA treated patients: 15/65 (23%) in CSA group vs 4/65 (6.15%) in RTX either discontinued therapy due to side effects or were unavailable for final data assessment.

‘Biocreep’ is a trap in non-inferiority trials: if you have a standard of care,say A , based on pivotal studies, you evaluate B to see if its non inferior to A and find that it indeed is. Then you come with an option C and evaluate its non-inferiority against B and show that it indeed is. But then, if we assume that C is non-inferior to A, we end up accepting progressively worse treatments as standard of care, a phenomenon called as biocreeep.

2 Amlodipine is better than Hydrochlorothiazide in BP reduction

In this 3 arm, multi-centre RCT-CREOLE-, involving 728 black hypertensives across 6 countries in Sub-Saharan Africa, combination involving amlodipine [with hydrochlorothiazide (HCTZ) or perindopril] was better at BP lowering as assessed by 24hr ABPM at 6 months (when compared with perindopril plus HCTZ), (between group difference in the change from baseline, −3.14 mm Hg; 95%CI −5.90 to −0.38; P = 0.03; and −3.00 mm Hg; 95% CI, −5.8 to −0.20; P = 0.04, respectively). Authors propose non-BP mechanism like increased endothelial NO bioavailability (which apparently is compromised in blacks), but simpler explanation of the benefit may be: longer half life, improved adherence and better BP lowering efficacy of amlodipine. Also the thiazide arm of the trial might have had a better BP lowering with longer acting and more potent chlorthalidone.

Most important attribute of an anti-hypertensive agent is ‘BP lowering’, which often is forgotten in the noise of evidence, guidelines and propaganda of ‘pleiotropic’ effects. Similar superiority of amlodipine -not only for BP lowering but also for hard CV outcomes-was demonstrated by ACCOMPLISH trial published a decade ago. Its unfortunate to see so many practitioners here switching to fancier ‘dipins’ for the fear of edema at the cost of both rupees and BP control. I love you amlodipine.

3 DOT (Directly Observed Therapy) for apparently treatment resistant hypertension

How do we assess the compliance issue in patients referred for apparently treatment resistant hypertension? Pill counts, pharmacy refill data and direct questioning -which are commonly used tools-can be ‘non-revealing’ in a significant proportion of such patients as highlighted by this work from hypertension clinic, Ottawa, Canada. About 30% of the ‘resistant’ patient showed marked (26mmHg)BP decrease after DOT, while others had less impressive decrease (3mmHg).

Study highlights the major role of compliance in the BP management and the limitations of the conventional tools to assess it. Young hypertensives progressing from onset of CKD to ESRD within months due to uncontrolled BP is a common scenario in our practice and every attempt at controlling BP is likely to yield large benefits, DOT deserves wider exploration.

4 Ready to get TRANSFORMed? Better wait

12 month outcomes of TRANSFORM trial were reviewed previously. Here are 24 month results: “In de novo kidney transplants with low‐to‐moderate immunological risk, the EVR + rCNI regimen is a valid alternative to the standard‐of‐care regimen comprising MPA + sCNI, providing comparable antirejection efficacy, stable renal function, and low rates of mortality and
dnDSA, with an advantage of significantly reduced viral infections,
up to 2 years post-transplantation.” concluded the authors of the largest RCT (TRANSFORM) evaluating non inferiority of ‘de-novo Everolimus facilitated reduced dose CNI regimen’ as compared to standard triple immunosuppression.

Primary endpoint of treated biopsy-proven acute rejection (tBPAR) or eGFR <50 mL at month 24 (47.9% vs 43.7%; difference = 4.2%; 95%CI = −0.3, 8.7; P = .006). You may get transformed, if you can forgo these: the higher rates of rejections, proteinuria, drug discontinuation in the everolimus treated patients. Moreover, proportion of those with eGFR<50ml at 24 months (can’t we now expect at least the better eGFR number with mTOR), was significantly higher in in everolimus treated patients. [474 (46.4%) vs 423 (41.6%) p=040].

As described earlier, Everolimus was protective against CMV and BK infections. While Novartis deserves applause for conducting the largest ever clinical trial in kidney transplantation, where do we go from here? Considering the overall poor efficacy in preventing rejections, poor tolerability, inferior graft function (eGFR) and higher risk of death shown by this meta analysis in patients treated with mTOR, there is no reason for its de-novo use. Probably, the only place for mTOR today may be a patient with documented CNI toxicity on biopsy, preserved GFR and no/minimum proteinuria after careful discussion with the patient.

5 Power of positive thinking

Nephrology community is on the verge of depression for multiple reasons: lack of innovations, workforce crisis and ‘negative trials’-to name a few. Kidney International seems to have realized this and has some lessons on ‘positive thinking’ in this issue. We are referring to the results of the three arm, open label, ATHENA trial evaluating de-novo everolimus (EVERO/TAC vs EVERO/CSA vs TAC/MMF) use in kidney transplantation. Not only did trial failed to show the non inferiority of de novo everolimus arm which was the primary end point, but also, once again, highlighted many of the previously noted serious issues with de-novo mTOR use: higher rejections, higher graft loss and one of the highest rate of study drug discontinuation due to side effects-over 50%!

Inspired by ATHENA– the Greek goddess of the war and courage-, authors fight their best and use the ‘power of positive thinking’ to go on discussing how this defeat can be TRANSFORMED into a win if you change your point of view. They attribute the failure of everolimus to higher than desired TAC levels in the everolimus treated arm (will that not further increase the risk of AR? such questions don’t bother people motivated by the power of positive thinking). This power is further manifest in an accompanying editorial by Novartis (sorry, I mean authors, commentators and sponsors) which conclude that de-novo everolimus/CNI is a viable alternative option for kidney transplant recipients in 2019. Aren’t you still feeling positive and motivated?

6 Serious Adverse Gastrointestinal Events Associated With Sodium Polystyrene Sulfonate

Sodium polystyrene sulfonate (SPS) is in use for hyperkalemia since 1950s , its use has been associated with rare but serious adverse events like colonic necrosis. While initial reports of serious GI issues like colonic necrosis were attributed to sorbitol, these were also reported when SPS was used without sorbitol. Evidence supporting this link was largely case reports and small cohort studies. Here is the largest population-based retrospective cohort study, looking at this issue.

SPS dispensed in an outpatient setting to adults of advanced age (66 years or more) was associated almost 2 fold risk of serious GI adverse events (hospitalization or emergency department visit with intestinal ischemia/thrombosis, GI ulceration/perforation, or resection/ostomy) within 30 days of initial prescription.
SPS use (n=27704) compared with non-use (n=20020) was associated with a higher risk of an adverse GI event over the following 30 days (37 events [0.2%]; incidence rate, 22.97 per 1000 person-years vs 18 events [0.1%]; incidence rate, 11.01 per 1000 person-years) (hazard ratio, 1.94; 95% CI, 1.10-3.41) and risk was consistent irrespective of eGFR, potassium level or presence of other co-morbidity like diabetes or CHF.

Although limited by retrospective design and high risk patient group (mean age of 78 years, many comorbidities,with 20% residing in long-term care facilities), this is the largest documentation of a rare but potentially life threatening complication of SPS use. Time to resort to other measures of K control: diuretics, decreasing dose of RASi, dietary K restriction. While newer agents like patiromer have shown efficacy, they aren’t yet available, cost may be a barrier and their long term GI safety remains to be established.


May 2019

The Nephrology Social Media Collective (NSMC) internship was established in 2015 with the goal of training doctors to effectively harness social media in order to be leaders in medicine. NSMC mentors and interns have contributed to our blog from time to time. This month, NSMC interns Vicki Sandys from Dublin City, Ireland and Charlie Hall from London have written some of the summaries for our blog. Divya Bajpai  has created a beautiful visual abstract and has written a part of the post.

1 Preterm birth and CKD

More than 60% of the fetal nephrogenesis occurs in the third trimester of the pregnancy, and preterm birth leads to low nephron endowment. Low nephron number is associated with hypertension and progressive CKD in later life.

Here is a large, nationwide cohort study involving 4 186 615 singleton live births from Sweden, evaluating relation between preterm birth (gestational age <37 weeks) and risk of CKD from childhood into mid-adulthood. Preterm (<37 weeks) and very preterm(<28 weeks) were significantly associated with development of CKD in childhood and mid-adulthood (adjusted HR for preterm 1.94, 95% CI 1.74 to 2.16; P<0.001; HR for very preterm 3.01, 1.67 to 5.45; P<0.001). Even early term birth (37-38 weeks) carried a similar although lesser risk (1.30, 1.20 to 1.40; P<0.001).

This massive study underscores the importance of preterm birth as a risk factor for CKD, which carries practical significance with regards to management of other risk factors (like nephrotoxins, diabetes, smoking, obesity, UTIs) and counselling prior to acceptance as kidney donors. Birth history becomes the vital information in the evaluation. Thirteen percent of all the newborns in India are preterm (10% in US and 5-6% in Europe). This implies a huge non-modifiable CKD risk.

2 Octreotide LAR in ADPKD

ALADIN trial evaluating use of octreotide LAR in early stage CKD showed that, octreotide LAR use, as compared to placebo, was associated with statistically significant decrease in the rate of total kidney volume (TKV) increase. Difference persisted even at 3 year follow up, however, wasn’t statistically significant.

ALADIN 2, evaluating the renoprotective effect of octreotide-LAR in ADPKD patients at high risk of ESRD because of later-stage ADPKD, in a parallel-group, double blind phase 3 clinical trial, is published in PLOS One.

Compared to placebo, octreotide-LAR reduced median (95% CI) TKV growth from baseline by 96.8 (10.8 to 182.7) ml at 1 year (p = 0.027) and 422.6 (150.3 to 695.0) ml at 3 years (p = 0.002). Fewer patients treated with octreotide LAR experienced the composite end point: a doubling of serum creatinine or ESRD (HR 0.127 to 0.742], p = 0.009). A strange observation was no difference in the rate of mGFR by iohexol clearance decline in the two groups. (Why should mGFR by iohexol clearance not be a mandatory measurement in all CKD progression trials?) Is GFR a sensitive and reliable indicator of progression in kidney diseases that predominantly affect tubulointerstitium?

Tubular disruption in ADPKD can cause iohexol accumulation or back-leakage, further compromising accuracy of GFR assessment. Also, tubular disruption may affect creatinine tubular handling. Is it the reason that in ALADIN 2, serum creatinine levels are disproportionately low in patients progressing to ESKD and treatment effect is largely driven by protection against progression to ESKD rather than against serum creatinine doubling over time? This is an issue that needs further investigation, probably in experimental models of the disease (Personal communication, Giuseppe Remuzzi).

3 Drinking water salinity and risk of hypertension

Ground water salinity is found high in some geographic regions (especially the coastal areas where sea water intrusion is common). While high sodium content in drinking water is likely to contribute to increased dietary sodium intake and thus hypertension, it is unclear how high calcium and magnesium content interact, as both have been associated with a salutary effect on blood pressure and CV risk. Exploring this issue, here is a study led by International Centre for Diarrhoeal Disease Research, Bangladesh, evaluating drinking water salinity, urinary macro‐mineral excretions, and BP across three seawater intrusion affected districts in southwest coast of this country.

Compared with fresh water drinkers, mild-salinity water drinkers had lower mean systolic BP (-1.55 [95% CI: -3.22–0.12] mm Hg) and lower mean diastolic BP (-1.26 [95% CI: -2.21–0.32] mm Hg). The adjusted odds ratio among mild-salinity water drinkers for stage 1 hypertension was 0.60 (95% CI: 0.43–0.84) and for stage 2 hypertension was 0.56 (95% CI: 0.46–0.89). Mild-salinity water drinkers had high urinary Ca2+, and Mg2+, and both urinary Ca2+ and Mg2+ were associated with lower BP.

Several limitations should be noted: EC (Electrical conductivity) was used as a surrogate of cation content (and not the actual mineral levels), lack of data on mineral intake through other foods, bias by over or under-collection of 24 hr urinary measurements, and residual confounding by other risk factors for hypertension.

Water hardness and CV risk is an area of debate, although not conclusive, this study is an important addition to the previous epidemiological data showing similar association of higher calcium and magnesium content in the drinking water with better CV risk profiles. With widespread use of drinking water treated by reverse osmosis (this is undertaken as a policy in areas of endemic CKDu in some parts of Maharashtra, India) this definitely merits further research.

4 Exostosin 1/2 in the diagnosis of secondary membranous GN

Visual abstarct by Divya Bajpai  

Discovery of PLA2R as a target antigen in primary Membranous nephropathy was a major breakthrough in the field of biomarkers in nephrology and brought a paradigm shift in the diagnosis and classification of the disease. There is increasing interest in the use of this biomarker in order to obviate the need of kidney biopsy. While PLA2R and THSD7A are identified as target antigens in 70%–80% and 1%–5% cases of primary MN respectively, the antigen for secondary MN was not known until this study in JASN by Sethi et al

They studied 224 cases of biopsy-proven PLA2R negative MN and 102 controls (47 PLA2R positive MN, 13 Proliferative Gn, 42 others) to identify new antigens using laser microdissection and mass spectroscopy. Accumulation of Exostosin 1/Exostosin 2 (EXT1/EXT2) in the GBM was found in 26/224 cases but in none of the controls. 80.7% of these 26 EXT1/EXT2 positive cases had clinical evidence of autoimmune features. The association with autoimmunity was further confirmed in the ‘Validation cohort’ where 8 out of 18 pure class V LN cases were positive for  EXT1/EXT2 while only one of the 14 cases of mixed class LN was positive. Also, 3 out of 16 cases with PLA2R negative primary MN were positive and all had autoimmune features. It is interesting to note that 2 of these EXT1/EXT2 positive patients were initially diagnosed as primary MN but later developed full-blown MN.

Small sample size and failure to demonstrate circulating anti-exostosin antibodies in patients with EXT1/EXT2 associated MN, are the major limitations to note. Absence of antibodies can also mean that exostosin proteins may not actually be target antigens for MN but just a biomarker protein. Can the demonstration of exostosin antibodies diagnose class V LN in patients with appropriate secondary features without a biopsy?

While we need to wait for further studies to answer these questions, this is surely an exciting development in the world MN biomarkers!

5 Pre-Eclampsia and risk of later kidney disease

In a previous meta-analysis, the relative risk of developing ESRD was higher in women with history of pre-eclampsia [Relative risk 4.7, 6.7 and 6.4 for women who had preeclampsia during the 1st, 2nd, and both pregnancies respectively] . Women with a history of pre-eclampsia have an increased risk of microalbuminuria-risk similar to patients with type 1 diabetes mellitus. 

Here is another massive (of course Danish!) nationwide cohort study in the BMJ examining the association between pre-eclampsia and incident postpartum CKD, in 1,072,330 women followed up for average 18.6 years between 1978-2015. Overall, 14,816 women developed kidney disease, higher risk of chronic renal conditions (mainly, hypertensive kidney disease, and glomerular/proteinuric disease.) was noted in women with history of pre-eclampsia: HR 3.93 [95% CI 2.90 to 5.33, for early preterm pre-eclampsia (delivery <34 weeks); 2.81 (2.13 to 3.71) for late preterm pre-eclampsia (delivery 34-36 weeks); 2.27 (2.02 to 2.55) for term pre-eclampsia (delivery ≥37 weeks)]. 

The association of preeclampsia with CKD and glomerular/ proteinuric diseases was much stronger within five years of the latest pregnancy (HR 6.11, and 4.77, respectively). However, even > 5 years after the pregnancy, the risks remained 100% and 50% higher than the risks observed in women with no history of preeclampsia (HR 2.06 and 1.50, respectively).

6 CREDENCE of SGLT 2 inhibitors in nephrology

Presentation of the results of CREDENCE trial was one of the most remarkable events at WCN 2019 for the obvious reason. Dramatic benefits of a pharmacotherapy in CKD came as the much awaited showers after a ‘drought of 18 years (back to back publication of RENAAL and IDNT trials in 2001). We have been criticized as being hypercritical of SGLT2 inhibitors in our previous blog posts and hereby we must congratulate the patients, investigators and sponsors for the successful completion of CREDENCE.

Trial was stopped early due to overwhelming benefit: primary outcome ESRD, doubling of serum creatinine, renal or cardiovascular (CV) death, for canagliflozin vs. placebo, was 43.2 vs. 61.2 per 1,000 patient-years (p = 0.00001). Importantly, there was no increased risk of amputations or fractures. Dramatic benefits indeed!

Two caveats: One, trials terminated early-truncated trials- overestimate the benefit. Overall smaller the number of endpoints, higher the chance of overestimation. Important overestimates occurred with 200 to 500 events (CREDENCE is here); large overestimate for those with events <200 and trials with over 500 events showed small overestimates. Second, the crucial issue of safety. Serious genitourinary infections and lower extremity amputations continue to be reported in the post-marketing data, and so, in real world, vigilance is needed to identify and address these risks.

7 Oral protein supplementation and exercise training on physical function in hemodialysis patients

The effect of exercise on the health of our haemodialysis (HD) patients has been extensively reviewed in the latest Nephmadness playoffs.

Protein malnutrition increases the risk of death in patients on hemodialysis. Oral nutrient supplements during dialysis can offer some benefit, although evidence supporting this treatment is very poor.

Theoretically, protein supplements given during HD may result in increased skeletal muscle amino acid uptake and this effect is potentiated by exercise. IHOPE trial evaluated the effect of 30gm whey protein supplementation with or without intradialytic exercise (30 -45 min cycling) on physical function and the quality of life (QOL) in 120 patients from 5 dialysis clinics is Illinois.

Over the 12 months of study period, primary outcome (change in physical function as assessed by ‘shuttle walk test‘) did not differ between the groups. Improvement in some secondary measures was noted but did not reach statistical significance.

A large number of variables affect wellbeing of dialysis patients and it is very difficult to tease out effects of protein supplementation and exercise in such a small group over a period of one year. Or maybe these interventions are simply not enough to overcome the overwhelming burden of comorbidities that a typical dialysis patient has. Also note the dropout rate of 41% at the end of 12 months in the exercise group indicating the practical difficulties of implementing exercise programmes in these patients.

March-April 2019

1) Plazomicin for complicated UTIs

Given the reputation of being birthplace of some of the superbugs of global concern, India needs to have an ‘antibiotic stewardship’ policy, even better, a law! Crisis is no less urgent than global climate change and melting glaciers. Developing new antibiotics with novel mechanisms of actions is another important although very difficult way out.

Aminoglycosides are effective against many ESBL producing organisms and are often used as an alternative to carbapenems in the treatment of urosepsis. Carbapenem resistance is rising and about 80% of such organisms are also producing ‘amino glycoside modifying enzymes’ limiting our treatment options further. Plazomicin is an aminoglycoside that is engineered to evade modification by aminoglycoside- modifying enzymes, and it maintains activity in the presence of most mechanisms that lead to resistance in Enterobacteriaceae, including mutations in sites targeted by fluoroquinolones and the production of aminoglycoside-modifying enzymes, extended-spectrum β-lactamases, and carbapenemases.

Here is the EPIC study in NEJM reporting efficacy of once daily plazomicin vs meropenem, for complicated urinary tract infections (UTIs): composite cure (clinical cure and microbiologic eradication) at day 5 [88.0% (168 of 191 patients) in the plazomicin group and in 91.4% (180 of 197 patients) in the meropenem group (–3.4 95% CI –10.0 to 3.1)], and at the test-of-cure visit-15 to 19 days after initiation of therapy-[81.7% (156 of 191 patients) and 70.1% (138 of 197 patients) respectively (11.6 ; 95% CI, 2.7 to 20.3). 

Plazomicin performed better in UTIs by ESBL producers, aminoglycoside resistant organisms and also had higher microbiological cure rates and lower relase rates: these finding can only be hypothesis generating given the “noninferiority”design of the trial. Renal dysfucntion, as expected, was more common with Plazomicin (11 vs 4 patients). As with all antibiotic therapies, local susceptibility patterns and selection pressures make it important to see data in other geographic areas. 

Welcome Plazomicin! 

2) Genetic basis for CKD in adult

While children with CKD are often evaluated with genetic testing, adults typically are not. You may consider expanding genetic evaluation even in adults after reading this clinical investigation in Kidney International. Whole exome sequencing (WES) was performed in a multi- centre cohort of 114 families including 138 affected individuals with CKD, across nephrology services in Ireland. Pathogenic mutation in known monogenic CKD genes was detected in more than one-third of families. The yield was highest in those with extrarenal features (69%), followed by those with positive family history (36%) and least (15%) in those without either of these. 

Authors hypothesize that later-onset disease is due to allelic heterogeneity, with “milder” phenotypes likely attributable to “milder” missense mutations. 

This exercise is likely to be further more fruitful in populations (like the one we encounter) where aetiology of CKD is uncertain in large majority of young and middle aged adults. Screening for extra renal disease, and potential avoidance of kidney biopsies and donor risk stratification are other proposed advantages of this testing. 

Irish population, higher than usual prevalence of familial CKD and possibility of missing deletion–insertion, copy-number variants, or mutations residing within a promotor or other intronic region (WES doesn’t capture these) are the limitations. Another important issue is the uncerainty about how to deal with the other genetic information that is typically unmasked by WES and this can potentially create anxiety and initiate additional diagnostic workup. Don’t miss this accompanying editorial.

CKDu researcher community can consider incorporating WES along with other evaluations. 

3) Rate of correction of hypernatremia and health outcomes in critically il

Rapid correction of hyponatremia is associated with definite harm. What should be the rate of correction for hypernatremia? We don’t know. “Go-slow- strategy” is extrapolated from the principles of hyponatremia management . Here is a retrospective observational study in CJASN, reporting the association of the rate of hyponatremia correction and outcomes (in hospital mortality and length of hospital stay).

In hospital 30-day mortality in rapid (>0.5 mmol/L per hour) and slower (<0.5 mmol/L per hour) correction rate groups was not significant either in patients with hypernatremia at admission (25% versus 28%; P=0.80) or in patients with hospital acquired hypernatremia (44% vs 40%;P=0.50). There was no difference in aOR of mortality for rapid vs slow correction in either admission (aOR, 1.3; 95% CI, 0.5 to 3.7) or hospital-acquired hypernatremia (aOR, 1.3; 95% CI, 0.8 to 2.3). 

This is now the largest cohort study addressing the issue of rate of hypernatremia correction, and can reassure us to correct dehydration in these patients (there were no cases of cerebral edema in the 78 patients who had serum sodium correction of 12 mmol/L per day). 

Several important limitations should be noted though: inability to identify exact timing of onset of hyponatremia, exclusion of patients with milder hypernatremia limiting generalisability to patients with serum Na 145-155 (>155 was inclusion criteria), lack of information about etiology, types of fluids used for treatment, reliance on ICD coding and patient chart. 30-40% patients were DNR-highlighting the type of patient population that generally develop severe hyponatremia and outcomes here will be principally driven by underlying illness, with hypernatremia being just a marker of its severity. 

4) Contribution of non-HLA incompatibility to kidney allograft survival: genome-wide analysis study 

Why do half of the renal allografts fail by 15 years post transplant? Chronic antibody mediated graft injury underlies many of the graft losses after initial few years, even in HLA matched individuals, highlighting the importance of non HLA alloimmunity. 
In this prospective genome wide association study involving 477 pairs of deceased donors and recipients, genome wide mismatches in non-synonymous single nucleotide polymorphism (nsSNPs) were calculated to identify incompatibilities in transmembrane and secreted proteins. In 25 patients with biopsy-confirmed chronic antibody-mediated rejection, customised peptide arrays were generated to screen for antibodies against genotype-derived mismatched epitopes. 
The degree of nsSNP mismatch was independently associated with graft loss in a multivariable model adjusted for HLA eplet mismatch. Each increase by a unit of one IQR had an HR of 1·68 (95% CI 1·17–2·41, p=0·005). 5-year death censored graft survival was 98% in the quartile with the lowest mismatch, 91% in the second quartile, 89% in the third quartile, and 82% in the highest quartile (p=0·003, log-rank test). 

In the absence of effective therapy, chronic ABMR is almost the point of no return for recipients. Whether immunological risk stratification using non HLA mismatches help prevent this process will be interesting to see. 

5) Low dose daily versus alternate day prednisolone in frequently relapsing nephrotic syndrome

Initial strategy for children with frequently relapsing nephrotic syndrome is to use long term alternate day prednisolone. However, many children do relapse on this regimen.

In a single-centre open-label randomised controlled trial, Yadav et al tested efficacy and safety of 12-month therapy with prednisolone administered daily low-dose versus on alternate days (standard therapy) in 61 patients with FRNS.

Children receiving daily prednisolone had significantly fewer relapses than those on alternate day therapy (0.55 relapses/person-year VS 1.94). Daily therapy was associated with higher rates of sustained remission at six months and lower rates of treatment failure (defined as frequent relapses, steroid toxicity or infections) at six months and one year. The cumulative prednisolone dose was similar in both the groups. Adverse effects were not different in the two groups.
If an adequately powered study confirms this observation, it will strengthen the KDIGO suggestion of using daily prednisolone at the lowest dose where alternate day prednisolone therapy is not effective. 

6) SGLT-2 inhibitors and GLP-1 receptor agonists for nephroprotection and cardioprotection in patients with diabetes mellitus and chronic kidney disease

Fellows preparing for their final theory exam, here is a theory long question stuff for you: “Unmet need of Renoprotection addressed by newer antidiabetic drugs”. EUropean REnal and CArdiovascular Medicine (EURECA-m) and Diabesity workgroup of ERA-EDTA summarise the cardioprotective and nephroprotective effects of SGLT-2 inhibitors and GLP-1 receptor agonists. You will have to squint to find the limitations of the trials though (reviewed in depth here and here by us before).

Here is a quote from this review: “Although EMPA-REG OUTCOME, CANVAS and DECLARE-TIMI 58 were not studies with primary renal endpoints, an objective (!) reader cannot overlook that a 40–50% reduction in the composite outcome is much larger than relevant reductions in seminal trials in DKD.” Curiously missing mentions about FDA warnings- DKA, foot amputations, genital infections, fractures. Everyone is smitten with SGLT2 inhibitors! 
Let’s wait for CREDENCE.

7) Effects of Hemodiafiltration versus Conventional Hemodialysis in Children with ESKD

Alternative RRT techniques like HDF are looked upon as a hope to improve the dismal long term survival of dialysis patients. RCTs do not show clear survival benefit, however, jury isn’t out yet and HDF is increasingly used (18% of ESRD cases in Europe) for many of its possible benefits.

There is little data on efficacy of HDF in children and this observational study is a important first step. In this prospective cohort study of 190 children from 28 centers, Shroff et al noted that the children on HDF grew better: annualized change in height SD score remained static in HD, but showed a small but statistically significant increase in HDF (Δ=20.16; P=0.02), so that patients on HDF were taller than patients on HD at 12 months (P=0.04).

Carotid intima media thickness (cIMT) is a non-invasive surrogate marker for atherosclerotic changes in the artery. HDF group fared better in terms of cMIT SD score. At 1-year follow-up, the cIMT SD score increased by median 0.41 in the HD group and decreased by 0.07 in the HDF group (P=0.02).

Patient-reported outcomes like post-dialysis recovery time, headaches, dizziness, and cramps favoured HDF group. There was no difference in sleep disturbances, pruritus, or restless leg syndrome between groups. If transplant isn’t an option, children are expected to have maximum dialysis vintage, so may benefit by alternative dialysis therapies. Lets hope to see more data from randomised controlled trials.


January 2019

1 Diuretic use in incident ESRD

Hospitalizations in patients initiated on dialysis are common-especially in the first year- and are associated increased risk of death. What if a drug can address this burning issue?

According to this retrospective, database analysis of a large dialysis organization, the continuation of loop diuretics after hemodialysis initiation was associated with lower rates of hospitalization (adjusted incidence rate ratio, 0.93; 95% CI 0.89 to 0.98) and intradialytic hypotension (adjusted incidence rate ratio, 0.95; 95% CI 0.92 to 0.99) as well as lower interdialytic weight gain (P=0.03). No difference in the 1 yr mortality was observed (adjusted hazard ratio, 0.92; 95% CI, 0.84 to 1.01)! Oh dear confidence interval, couldn’t you limit yourself to <1 here, like you did it for hospitalizations and hypotension? You just prevented a breakthrough in dialysis medicine that kidney doctors are longing for!

Confounding by indication (which can still exist even after sophisticated analysis you do for adjusting) is the major issue with data like this, where patients who are more likely to receive drug (diuretic here) are also the ones who are less likely to experience the adverse outcome that one plans to evaluate (hospitalizations, hypotension, and interdialytic weight gain) because they are inherently different. Why upon the earth one would put someone on diuretic when the last hyperfiltrating nephron has stopped making urine?

It won’t be a surprise if another such large database analysis shows the mortality benefit of diuretic; based upon the results, we need not start or stop prescribing diuretics to HD starters. One ml by the kidney is worth liters by machine!

 

2 Total versus subtotal parathyroidectomy for secondary hyperparathyroidism

Compared with parathyroidectomy (PTX) for primary hyperparathyroidism, the mortality and morbidity rates are higher in secondary hyperparathyroidism. Reviewed here by us before.

In a retrospective study of 824 patients in the Swedish Renal Registry, the outcome of the cardiovascular event (a composite outcome of acute myocardial infarction, transitory ischaemic attack, ischaemic or hemorrhagic stroke, ruptured aortic aneurysm, and acute limb ischemia) was a lower after subtotal parathyroidectomy (436 patients) compared with total parathyroidectomy (388 patients): adjusted HR of 0.43 (95% CI 0.25–0.72). The 90-day mortality was 2% both after subtotal parathyroidectomy and total parathyroidectomy.

The risk of re-PTX was higher after subtotal PTX compared with total PTX, with an adjusted HR (95 % CI) of 3.33 (1.33–8.32). There were no differences in the adjusted risk of hip fracture.

The paper does not describe the indications for which total v/s subtotal parathyroidectomy was done. We could assume that all these patients were refractory to medical management and the decision of subtotal v/s total PTX was based on the clinical or biochemical severity. Confounding by indication is the elephant in the room here. Clinical practices and surgical expertise vary widely making it difficult to extrapolate these results to day-to-day practice.

The only thing we know for sure in CKD-MBD literature is that we don’t know enough about CKD-MBD. While we can go on finding the optimum PTH target, the lower PTH level achieved by parathyroidectomy does not appear to help reduce cardiovascular mortality.


3 Zoledronic Acid to Prevent Bone Loss in the First Year after Kidney Transplantation

If you are one of those whose prescription of the post KTR patient is incomplete without a bisphosphonate, then here is a news for you. In an open-label, a single center trial evaluating the safety (risk of adynamic bone disease) and efficacy of zoledronic acid (effect on bone histomorphometry, DXA, HR-pQCT-this stands for high resolution peripheral quantitative CT, and bone biochemical measures like sclerostin, bone-specific ALP, tartarate resistant ALP -quite a list!). This probably will be the first RCT in this area and also first in CKD-MBD actually using bone biopsy.

Zoledronate didn’t increase the risk of ABD, and KTR itself decreased the bone turnover questioning the routine use of bisphosphonates in the contemporary immunosuppression era where steroids aren’t used in high doses and calcium+vitamin D use is a routine.

The study is limited by the small sample size and short follow up. Whether the promising effect of zoledronate on some surrogate bone markers and BMD at the peripheral skeleton (like radius, tibia where fractures after KTR are more likely than central skeleton) will become relevant after longer follow up remains to be seen.

If one is seriously considering bisphosphonate in KTR recipient with high fracture risk, zolendronate obviously scores over others in terms of cost and compliance.

4 APOL1 in non-African Americans

APOL1 risk allele is implicated in a higher prevalence of HTN, CKD, faster GFR decline and earlier onset ESRD among African-Americans. According to this NEJM letter reporting global frequencies of APOL1 risk variants among 111 populations in two large studies [the Population Architecture using Genomics and Epidemiology Study (https://pagestudy.org) and the Consortium on Asthma among African-ancestry Populations in the Americas (www.caapa-project .org)], this risk may not be restricted to the African -Americans as traditionally believed.

Authors found other populations with elevated frequencies, including Jamaican, Barbadian, Grenadian, and Brazilian from Salvador (>10 to 22%); Trinidadian, Panamanian, Honduran, Haitian, Garifunan, and Palenque (>5 to 10%); and Guyanese, Dominican, Peruvian, Belizean, and Native American (1 to 5%). These findings show that the risk alleles are present in populations of persons who are not typically screened, which may result in the underdiagnosis and undertreatment of kidney disease and related coexisting conditions.

5 Tweaking Nephrogenesis to Boost Nephron Number

What can be offered to patients with such elevated risk of kidney disease apart from a genetic diagnosis? This ‘Clinical Implications of Basic Research’ series article  “Tackling Tsc1 to Promote Nephrogenesis” (I just love their graphic!), discusses exciting findings of basic research by Volovelsky et al.

Nephron number at birth is variable (200,000 to more than 2.5 million per kidney) and ‘lower nephron endowment’ is believed to be a nonmodifiable risk. 14 different cell types at ‘ureteric bud-mesenchymal niche interface’ regulated by various genes and growth factors make modulating the complex process of nephrogenesis difficult. Volovelsky et al in an interesting experiment in mice showed that it’s not impossible though.

They noted that deletion of both copies of Tsc gene  (Tsc1 encodes for a protein hemartin which prolonged nephrogenesis in vitro), led to a lethal phenotype with markedly aberrant kidneys while deleting only one Tsc1 allele, they observed slightly prolonged nephrogenesis, which involved an increase in nephron progenitor cells within the niche and resulted in an increase of 25% in nephron endowment. Hamartin (and its downstream effectors) is a candidate target for experimental approaches to protecting at-risk infants and perhaps to treat- ing kidney disease in children and adults. Bravo! Waiting to see more.

 

6 SGLT2 inhibition repairs pumps, pipes, and filter! 

Ibsen’s play An Enemy of the People was elegantly transported to India in his last movie Ganshatru (although not among the best of Satyajit Ray.) The film depicts Dr. Ashoke Gupta (Soumitra Chatterji) as an idealistic doctor working in a town near Calcutta who discovers that the water at a popular temple is the source of an outbreak of typhoid and hepatitis. In order to save lives, he risks his career by voicing the issue. His efforts are thwarted by a local group of building contractors. Here is an adaptation of Ganshatru for our readers:

The city engineer Intmed was in charge of the water supply and drainage. He was the master of his job and citizens were happy with his services. Occasionally, he used to call plumbing agency Corona, pumping company Cardio, and filter supplier Kidnee. Water was clean, citizens responsible, everything going fine. 

For some strange reason, the city got afflicted with a curious habit: the habit of flushing greasy food into the drain water leading to blockade of the pipes and repeated breakdowns. Intmed warned citizens of this potential problem but his words fell on the dumb ears. Services of plumber Corona and pump Cardio were needed with increasing frequency, which led them to separate from Intmed’s City Engineering department and formation of separate agencies of their own-now no more in control of Intmed. Sometimes chronic stagnation of the contaminated water also started affecting filtration and clogging of filters was reported. Albus was a protein that used to start leaking as filters started getting damaged. Interruption of water supply due to filter clogging was actually a rare event, however as soon as Albus appeared in the water (filter suppliers educated citizens to check Albus in the water regularly to detect filter clogging early, however, neither citizens, not agencies were aware of how best to treat the clogged filters and which filters will ultimately need to be replaced). Intmed questioned this strategy of Albus testing and its relation with actual filter clogging but by now everyone including regulators had accepted Albus testing as a valid method to predict filter failures. 

With a close watch on disruption in the city, 3 industrialist Jansyn, Astrazi, and Boingel claimed that they can address this burning issue without routinely requiring plumbing, pumping and filter agencies. They invented a bullet- Flozina that required to be fired into the water at the supply and claimed to address pipe blockades, pump failures, and clogged filters all at once-last one being most effectively addressed.

To convince authorities, they just needed to show that Albus level in the water has gone down and the flow rates past the filters are marginally better. Whether this would actually translate into prevention of filter failures is yet to be proven however this news that a bullet can save the city became viral after getting publicity in the leading newspapers Fancet, LEJM and others. Volumes are already been written (find the latest here) and many more are in making-praising the role of Flozina in restoring city’s messed up water supply system to order. Will Flozina be effective and safe? Will plumbers, and filter agencies go out of the job? Stay tuned for more to come.

 

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!

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.