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).

 

 

December 2017

1 ‘Normal BP’ becomes a rare disease now

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

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

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

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

 

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

 

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

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

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

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

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

3. Who develops CKD after recovery from AKI?

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

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

4. Sertraline for depression in CKD

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

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

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

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

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

5. Tolvaptan in ADPKD

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

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

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

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

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

7. Outcomes after Angiography with Sodium Bicarbonate and Acetylcysteine

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

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

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

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

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

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

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