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).