July 2020

1. Uric acid lowering doesn’t fix CKD progression 

Uric acid has long been viewed as a risk marker of  CV disease, hypertension, CKD, metabolic syndrome and has been a target of treatment (more so after generic febuxostat appeared in the market) without clear evidence of benefit. Almost alternate patient in our CKD clinic is on urate lowering therapy (in their first visit, because by second or third visit it can be safely deprescribed in most cases IMHO). Studies supporting febuxostat use for retarding CKD progression are small, single centre, and of too short a duration to conclude on such an effect. A larger controlled FEATHER trial showed no such benefit.

Things that you cannot explain by the laws of science are called ‘supernatural’ and when believers in medicine talk about them they are called as ‘pleiotropic effects’. So, what about pleiotropic benefits of allopurinol? Two large trials in NEJM should inform us now that urate lowering is ineffective as an intervention to retard CKD progression. CKD FIX randomised  369 patients with CKD 3&4 (with albuminuria and at least 3ml eGFR decline in last 1 year), to allopurinol or placebo. After a followup of over  2 years, the change in eGFR did not differ significantly between the allopurinol group and the placebo group (−3.33 ml/min per year [95%CI −4.11 to −2.55] and −3.23 ml/min/per year [95% CI, −3.98 to −2.47], respectively). Insufficient power because of incomplete enrolment and ~30% discontinuation rate in allopurinol group are the major limitation of the trial, however between the group difference in the urate level was well maintained and a futility analysis showed that even if they had enrolled 1006 patients (needed to maintain sufficient power, with drop out accounted for, they would have had a relatively low probability of finding a significant effect of the drug). 

In another double-blind RCT PERL involving 570 patients with type 1 diabetes and mild-to-moderate kidney disease (age ~51, GFR baseline 67-68ml/min, UACR ~40mg), after 3 years of treatment with allopurinol, iohexol measured GFR (kudos, very few trials have dared to do this), was no better in treatment group: decreased by −3.0 ml/min/year with allopurinol and −2.5 ml/min/per year with placebo (between-group difference, −0.6 ml per minute per 1.73 m2 per year; 95% CI, −1.5 to 0.4). The mean UACR was 40% (95% CI, 0 to 80) higher with allopurinol than with placebo. Taken together, both these trials showed the futility of urate lowering with allopurinol in CKD stage 1 to 4. 

However, accompanying editorial doesn’t seem to be convinced, and falls back on in vitro cell culture studies (inflammation, endothelial dysfunction…….. and do I need to elaborate further?), subgroup analysis of FEATHER trial (whose main results showed futility of febuxostat), and their own small study (n=60) in young hypertensives where uric acid lowering normalised blood pressure. Cognitive biases are just as difficult as retarding CKD progression, and it would be no surprise, if folks using unnecessary aggressive urate lowering will continue to do so, putting everything aside and highlighting just the one finding of these trial to their benefit -allopurinol was well tolerated with no major adverse effects. 

2. RAS inhibition and COVID 19

Corona virus spike (S) protein binds to ACE2, which serves as the cell membrane receptor for SARS-CoV-2, but that’s not enough. S protein needs priming by the action of the serine protease TMPRSS2 (transmembrane protease serine S2).  Thus, the host enzymes, ACE2 and TMPRSS2, act in concert to facilitate viral entry, which subsequently leads to the development of COVID-19. Actions of ACE and ACE2 are opposite of each other, ACE generates angiotensin 2 (vasoconstrictor) while ACE2 catalyzes degradation of angiotensin 2 to angiotensin 1-7 (vasodilator). ACE inhibitors and ARBs upregulate expression of ACE2, and ever since the first report of the epidemic, hypertension, RAS blockade and their association with risk and severity of COVID 19have been a matter of debate and discussion. Given the higher risk of COVID 19 in patients with hypertension and CV disease, it was no surprise that the use of RAS blockade was higher in these patients, but does association mean causation?  
Four different  observational studies involving large database analyses have largely settles this question (put together over 40000 patients with COVID 19 from New York, Lombardy, Florida, Ohio and Denmark). Authors used various statistical methods to address the imbalance in the characteristic in the groups at baseline, which probably was the reason for the observed ‘association of RAS blockade with COVID 19. Results of all the four studies were consistent and showed no association of use of RAS blockade with either development or severity of COVID 19. This is reassuring news and can now inform us about how to answer those panic calls from patients with hypertension.

We have always been hypercritical about the observational research in nephrology here, but rarely, such studies are so important, welcome and comforting. At the same time, let’s not buy the hypothesis that RAS blockade protects against COVID 19, which is another observed association, that should be similarly scrutinised.

For a change, we are seeing NEJM editorial office busy handling observational research apart from large RCTs.


One of the large early report of COVID 19, noted overall AKI incidence of 1.6% which increased to 4.3% in severe cases.  More recent reports show that this might be an  underestimate and the  largest report of COVID 19 associated AKI-estimating it to be as high as 34%. Of 5,449 patients admitted with COVID-19, AKI developed in 1,993 (36.6%), importantly, 53.5% of the AKI cases were stage 2 or 3 and 14.3% required dialysis, so it’s definitely more than minor bumps in serum creatinine.

Of 1993 patients with AKI, 694 died (35%), 519 (26%) were discharged, and 780 (39%) were still hospitalized. Respiratory failure and mechanical ventilation were closely associated with the development of AKI:  276/285 (96.8%) of patients requiring RRT were on ventilators. Considering the high mortality (60-80%) of AKI in ventilated patients in ICUs in general, 35% mortality in this cohort is likely to be significantly lower than the actual-as about 39% of their patients are still in the hospital and death rate in this population will add to the final estimate of the entire cohort’s mortality.

Several mechanisms have been postulated about COVID 19-AKI, like direct viral cytotoxicity, interleukins, endothelial dysfunction, micro thrombosis, and VIKI (stands for Ventilator Associated Kidney Injury-please don’t remove ventilator for this!). The largest autopsy study looking at renal pathology showed tubular necrosis as the dominant feature, with electron microscopic invasion of tubular epithelial cells and podocytes. 

NEJM features a case of COVID 19-AKI that would fit in the characteristic of the AKI cohort reported in KI, notable features being difficulty preventing filter clotting in CRRT-this has also been observed before. It’s not a time to debate about the relative superiority of one modality over another and given the logistic challenges of coping with the sudden increase in the demand of RRT, whatever is feasible, available and working locally should serve the purpose including peritoneal dialysis. A review in Lancet Infectious Diseases discussing the management of AKI in COVID, speculates that early, and aggressive CRRT (considering the role of cytokines -haven’t we learnt from sepsis?)-to be potentially useful.

These speculations don’t make our lives easy, and it’s clear that AKI identifies most critical of the ICU patients with high risk of death and every effort should be made to tackle usual suspects to prevent the development and progression of AKI, minimise the complications once it develops like: minimising nephrotoxin exposure, sepsis control, hemodynamic stabilisation, restrictive fluid strategy.

Remdesvir and dexamethasone are the only agents currently recommended outside trial settings, and former was found to be effective in reducing time to recovery. It has sulfobutylether-β-cyclodextrin (SBECD) carrier -similar to intravenous voriconazole-which might accumulate in those with GFR<30ml/min. However, if the patient is a suitable candidate for remdesvir, this review in JASN should ease the anxiety over its use in patients with renal impairment -after informed consent.

4. Kidney transplant and COVID

Although speculations are made about possible protective effect of calcineurin inhibitors on cytokine storm, this doesn’t appear to be the case in real life and high mortality in kidney transplant recipients is the consistent feature of several reports including this largest cohort in NEJM. At least 2 other published reports (here and here) reported similar high mortality, ranging from 25 to 30%. Majority of the patients in these series were recipients of deceased donor kidneys (probably received higher cumulative immunosuppression including ATG), were over 50 yrs of age, had diabetes and hypertension- explaining higher mortality-this appears to be lower ~20% in our cohort (unpublished observations). General principals of treating severe viral pneumonia should apply to patients presenting with severe COVID 19-withholding MMF, decreasing/withholding Tac in those with ARDS, and supportive care. An interesting report showing the benefit of switching Tac to CSA here, however, it’s difficult to be sure of the antiviral benefit of CSA from this, as a change to CSA essentially lowers overall immunosuppression as well and this finding needs to be confirmed in further studies before this strategy can be considered useful. Utility of antivirals, immunosuppressive and other interventions is largely unknown in this population.  

5. Selfie time: Timing of RRT initiation in AKI

Individual patient data meta analysis of 10 randomised controlled trials involving 1879 patients with severe acute kidney injury, proportion of patients who died by day 28 did not significantly differ between the delayed RRT group (366 [44%] of 837) and the early RRT group (355 [43%] of 827; risk ratio 1·01 [95% CI 0·91 to 1·13], p=0·80), corresponding to an overall risk difference of 0·01 (95% CI −0·04 to 0·06). Notably, 390 (42%) of 929 patients allocated to the delayed RRT group and who had available data did not receive RRT.

There was no heterogeneity across studies (I2=0%; τ2=0), and most studies had a low risk of bias. Result are robust and were consistent across multiple sensitivity analyses and should inform decision making of dialysis initiation in AKI.  

START AKI trial which has completed enrollment of over 3000 patients (more than all the ‘timing trials’ so far put together) should hopefully put to the rest one of the most controversial issues in nephrology practice. 

6. Cardiorenal conflict in times of COVID

Nationwide lockdown was announced, and I thought of making courtesy calls to my friends whom I haven’t talked for long. I called my cardiologist friend (why did I?)

“Hi,  how are you doing?”

Unfortunately, he misunderstood me, and thinking I’m teasing him about slack in the practice because of lockdown, he put down the phone without answering.

He is one of the leading interventional cardiologists in his city and doesn’t read our blog and nor does he waste time on debates surrounding contrast AKI. Cardiologists are straightforward guys and generally have very little spare time. He has a formula (that he uses to explain his patient when he doesn’t want to intervene) to calculate dialysis risk after cardiac cath: Risk=serum creatinine x10.

“There is 50% chance of you needing dialysis after procedure,” he told one of my patients with CKD stage 4 due to type 1 diabetes. This lady had angina on minimum exertion and when I called up to explain my point, he calmly replied “your patient will anyway land up with dialysis in few months or year, why you want to bring the blame on me?” This is cardiorenal syndrome 6, where patient dies because of a coronary event as cardiologist fears contrast. 

She was keen to enjoy the dialysis free life and stopped seeing me until she developed choking sensation after more than routine exertion.

“If you don’t want to wake up (or not wake up) in the middle of the night with a heart attack, go for angiogram at the earliest. Don’t consider dialysis as the end, it can be a fresh beginning.” I was trying to be loud and affirmative at the same time. 

After having made financial and mental preparation for cardiac cath, she came back after 3 months, this time asymptomatic, asking me to connect to the cardiac colleague. “Ok, but before I do that, let me tell you something. Life is not all the same after lock-down. We have results of ISCHEMIA-CKD trial now.”

Kudos to the investigators of ISCHEMIA CKD trial, who enrolled and maintained 777 patients with advanced CKD (57% on dialysis) and CAD (a positive stress test) in this trial for over 2 years. Patients received either an initial invasive strategy (CAG followed by revascularisation if needed) or initial conservative management and intervention if needed. Primary outcome (death or non-fatal MI) occurred in 123 patients in the invasive-strategy group and in 129 patients in the conservative-strategy group (estimated 3-year event rate, 36.4% vs. 36.7%; adjusted hazard ratio, 1.01; 95% confidence interval [CI], 0.79 to 1.29; P = 0.95). Invasive strategy group experienced a higher risk -disability (stroke), dialysis and death.

ISCHEMIA and ISCHEMIA-CKD trials are robust, multi-centric, adequately powered and should caution against the initial invasive strategy in both general and CKD population with stable CAD-such strategy is highly common in the former group but less common in the latter because of a scare of contrast. These results, however, should not foster the therapeutic nihilism- renalism-as deferring interventions is not advisable in unstable CAD, severely symptomatic cases, those with depressed LV function and heart failure-ISCHEMIA-CKD excluded such patients. Although event rates were less than expected (which might decrease the power of the study), ISCHEMIA-CKD is now the first and the largest RCT to inform decision making in this group of patients with CAD.

I called my friend, thanked him for deferring the procedure, “you are nut” was his response-case of serious misunderstanding once again. 

March 2020

1 suPAR in AKI

Like rituximab in renal therapeutics, suPAR has almost acquired the status ‘wandering spirit’ in renal diagnostics. Once considered as the much sought for ‘soluble permeability factor’ in FSGS, elevated suPAR has been associated with CKD, diabetic nephropathy, secondary FSGS, other GNs and a host of non renal conditions like small cell lung cancer, sepsis, CV disease. It appeared that its almost ‘good for nothing’ as a diagnostic bio-marker.

But wait, now suPAR is all set to make news in the ‘ever-novel’ area of AKI biomarkers (ever-novel in nephrology is something that continues to be discussed over decades without making to bedside), and this time in NEJM. In a retrospective cohort study of 4769 patients (3827 undergoing coronary angiography, 250 undergoing cardiac surgery, and 692 were critically ill), High suPAR levels were associated with acute kidney injury just like higher age, history of diabetes, heart failure, and CKD.

So what’s the big deal? Authors went ahead to evaluate the mechanistic link between suPAR and kidney injury using experimental models where iohexol induced renal injury occurred in experimental mouse models with
endogenous suPAR overexpression or exogenous suPAR administration. This is possibly related to increased energy demand and mitochondrial superoxide generation in podocytes which suggest that suPAR by itself may have roles in the pathogenesis of acute kidney injury. Further support to this hypothesis comes from the observation that neutralizing biologic effects of suPAR by pretreatment with a monoclonal antibody attenuated kidney injury in
suPAR-overexpressing mice.

suPAR story appears very exciting and before you try speculating role of suPAR pheresis in management of AKI (like accompanying editorial), some caveats of the study should be noted. Most AKI cases in this cohort were mild (KDIGO stage 1,2) and very few -only 3 of 3827 patients-developed clinically relevant stage 3 AKI. Even as a risk marker, suPAR added only a little to the conventional risk scores. The AUC for the NCDR (National Cardiovascular Data Registry is supposed to predict contrast AKI-anyone out there using this?) risk score was 0.579 (95% CI, 0.560 to 0.597). The addition of suPAR to the NCDR score modestly improved the AUC to 0.628 (95% CI, 0.610 to 0.647), with a change in the AUC of 0.050 (95% CI, 0.013 to 0.087). Also the interpretation of elevated suPAR can be challenging in complex clinical settings like sepsis, liver disease, cancer etc, where suPAR elevation may not be kidney specific.

2 Difelikefalin in Hemodialysis Patients with Pruritus

Over half of your dialysis patients have itch, and in about a quarter of them its severe enough to impair the quality of life. Most commonly used drugs in practice-like antihistaminics- are least supported by evidence and the one which is most supported-gabapentin– is tolerated poorly, sometimes putting patients to sleep and predisposing to fall/fractures. In addition, gabapentin also received a recent FDA warning for respiratory depression.

Difelikefalin is a selective opioid kappa receptor agonist and was evaluated in a phase 3 KALM 1 trial in patients on hemodialysis. As compared to placebo, it significantly reduced itch intensity and improved itch related quality of life at 3 months and produced diarrhea, vomiting and drowsiness more often than placebo. As other opioid receptor involved in dependence aren’t its target there was no signal of dependence- although this will need careful long-term follow up to establish its safety.

Not that every pruritus needs medications and we should optimize dialysis adequacy and try getting away with topical options instead of and before drugs. 5 ml of coconut oil added to the last bath mug full water at the end of the bath is one of my favorites. Also this new drug was compared with placebo and not the currently available best therapy-gabapentin-so further studies are needed to understand relative anti-itch efficacy of this new drug.

3 Is hydration necessary before intravenous contrast use in patients with stage 3 CKD?

Finally someone did it. Better late than never. After increasing realisation of the inflated risk of Contrast-AKI (you can choose ‘induced’ or ‘associated’ in place of ‘-‘ as per your standpoint), we are starting to deconstruct this elusive entity that has dominated AKI research space over last few decades. Authors of the Kompas randomised controlled trial evaluated risk of elevation of serum creatinine following intravenous contrast use 523 patients: 7 of 262 (2.7%) in the no prehydration group and 4 of 261 (1.5%) in the prehydration group, which resulted in a relative risk of 1.7 (95% CI, 0.5-5.9; P = .36). Let’s stop bothering patients with ‘hydration’ before elective contrast CT studies.

Results of course can’t be extrapolated to patients receiving intra-arterial contrast, where, Kompas needs to point its needle now.

P.S. Once a famous spiritual teacher was asked if ‘self’ is real. He said, “It’s not that self isn’t real. It is real, but when you start believing that it’s ‘really real’, you exaggerate it.”

4 Plasmapheresis and steroid dosing in patients with Severe ANCA-Associated Vasculitis

“The primary results of PEXIVAS, regarding both the use of plasma exchange and dosing of glucocorticoids, will have immediate and substantial impact on the standard of care for patients with ANCA-associated vasculitis.” read the conclusion of the abstract of PEXIVAS trial when it was first released at American College of Rheumatology annual meeting in Oct 2018. Word ‘immediate’ in today’s era of scientific publishing can be as short as 1.5 year, as we see the publication of PEXIVAS in this issue of NEJM.

Primary outcome, which was a composite of death and ESRD, didn’t differ in the group receiving or not receiving plasmapheresis (100 of 352 patients (28.4%) in the plasma-exchange group and in 109 of 352 patients (31.0%) in the control group (hazard ratio, 0.86; 95% confidence interval [CI], 0.65 to 1.13; P=0.27).

In addition to futility of plasmapheresis, PEXIVAS also showed lower dose glucocorticoid regimen to be just as good as the conventional high dose. Results of this large RCT clearly should put a full stop to routine use of plasmapheresis in severe ANCA vasculitis, although accompanying editorial doesn’t seem to be impressed by the result and expresses concern that in the absence of kidney biopsy in all patients its difficult to rule out benefit of therapy in subset of patients where activity is more than scarring. Also editorialists continue to advocate plasmapheresis for pulmonary hemorrhage based on their previous small study, turning a blind eye to the fact that the number of such cases in PEXIVAS was many times more than their study reporting dramatic benefit.

About 50% of the study population received intravenous cyclophosphamide which turns out to be almost half the total oral cyclophosphamaide dose. A previous trial has showed that IV cyclophosphamaide is better and safer option for inducing remission. Although a higher relapse rate on follow up was noted, this was not associated with increased morbidity or mortality. It would be interesting to see if PEXIVAS data supports IV and therefore lower dose cyclophosphamide.

5 Empagliflozin to Increase Plasma Sodium Levels in Patients with SIADH

I always have a tough time convincing physicians to defer initiation of kidney blockade (RASi and SGLT2i) in patients with AKI and unstable kidney function. In one of the latest such encounters I was made aware of this yet another news on SGLT2i and its initiation in hospitalised patients.

In patient with SIADH, addition of SGLT2i increased serum sodium by about 10 mEq as compared to 7 mEq achieved by conventional therapies in this RCT evaluating use of empagliflozin in 43 patients with SIADH. Of note, control could achieve an increase (although lower) in serum sodium at day 4, which reassures (people who are not in love with this molecule) that it’s possible to treat most SIADH cases even without ‘novel’ options. So here is yet another novel indication for this metabolodiuretic, in addition to sugar, BP, weight control, cardio and renal protection.

Just to highlight that this was a proof of concept study and doesn’t establish empagliflozin as the treatment of choice here. More patient in the treatment arm withdrew consent (why?), and experienced a bump in serum creatinine-which may can’t be disregarded when you are talking about an elderly inpatient with comorbidities.

6 Times of COVID 19

It is 6pm at a South Mumbai suburb. I am at at our regular grocery shop on the way back to home from work. I am standing in a safe distance queue of ‘masked’ people. With only eyes and forehead visible, most women around look pretty. Birds chirping, sound of vigorous movements of the ancient looking huge peepal tree, occasional sound of the police van patrolling-I am in a whole new Mumbai until unknown to me. Usually noise level at this time here is at peak (I invariably miss my wife’s call intended to remind me of curd or butter or my wallet which I have forgotten at home). After a wait of about half an hour, having sanitised my hands at the entry, I go in picking up various items from the shelf. Only sound I hear is of the keyboard clicks at billing desk and occasional whisper around- attendant is asking us to be faster. Amidst this pin-drop silence, a lady in the corner sneezes aloud enough to make everyone pauses for that second and give her a frowned look. People around her move away as if a bomb has exploded in the crowd. I take out sterillium out of my pouch and do 7 step hand hygiene -for the 5th time in last 30 minutes. Bad time to start reading Albert Camus’s Plague (1947)

Finally novel corona-virus is here and as we are just beginning to see its spread in our overcrowded cities, nephrologists already perplexed by issues like unit shut downs, shortage of technicians and challenges adhering to standard precautions aimed at preventing spread at smaller stand alone units. AKI is common and may or may not be necessarily due to ‘viral nephropathy’, but doesn’t make much differecnce to the treating nephrologists who might have to bother about more pressing issues like setting up HD units at bedside, keeping up the morale of the HD staff working in high risk environment, filter clotting during CRRT etc. Here is a timely review for nephrologists. Amidst the speculations about worsening of lung injury in patients on RAS blockade for hypertension (virus has affinity for ACE2 which is up-regulated in patients on these drugs) and also about their protective effects (from animal studies), we can meanwhile follow ESC position statement as well as statement from Hypertension Canada asking us to continue treating hypertensive patients like before, and a nice NEJM review here. Also stay tuned to this an excellent NephJC resource here.

While fear, anxiety and uncertainty is looming everywhere , our response so far has been quite swift and sensible with all the stakeholders working on war footing to contain spread in the country. This has already changed our lives like never before with implications so far and wide that coming generations will have their history taught as BC/AC -Before Covid/After Covid.

October 2019

Pharmacotherapy of severe hypertension in pregnancy

In a parallel group, open label, three arm randomised controlled trial involving pregnant women >28 weeks of gestation and severe hypertension, 894 women were randomised: 298 (33%) to receive nifedipine, 295 (33%) to receive labetalol, and 301 (33%) women to receive methyldopa. The primary outcome was BP control (defined as SBP 120–150 mm Hg, DBP 70–100 mm Hg) within 6 h without adverse effects ( hypotension, fetal distress, caesarean section for fetal distress up to 2 h after the end of the study period, severe headache, severe headache requiring discontinuation of drug, or eclampsia).

Primary outcome was significantly more common in women in the nifedipine group than in those in the methyldopa group (249 [84%] women vs 230 [76%] women; p=0·03). However, the primary outcome did not differ between the nifedipine and labetalol groups (249 [84%] women vs 228 [77%] women; p=0·05) or the labetalol and methyldopa groups (p=0·80). However a higher incidence of NICU admissions was noted in nifedipine group: nifedipine versus labetalol (p=0·009) and methyldopa (p=0·004). Authors conclude about near equivalence of the three commonly used oral drugs to control BP in this setting, these findings are reassuring especially when there is an acute (artificial) shortage of methyldopa across the country. Moreover, labetalol is manifolds costly than other 2 drugs, results should comfort physicians and gynecologists working in resource poor settings.

Trial was completed at 2 public hospitals in India (you just need to look more carefully to locate 3 of the 9 authors there from here!), and participants and healthcare workers must be congratulated for their work. Several important points should not be missed however. First, they could enrol only a third of the screened patients, largely excluding mothers who were at the highest risk of complications, we should be cautious before extrapolating results to such patients. Second, higher rates of NICU admissions in nifedipine group (although they were mainly for low birth weight, given the acute BP drop with this drug and higher incidence of maternal tachycardia, this needs further evaluation). Third, significant differences were noted with regards to severity of illness in the 2 centres. One of the centers being a maternity hospital, whether the lower systolic BP at enrollment, higher gestational age, lesser need of iv MgSO4, lower incidence of abnormal renal, hepatic and coagulation profiles, at this center reflected better antenatal care and monitoring or simply cared for less sick women? Finally, elevated BP is only one of the features of the multisystem involvement in this disease, and ultimately the multidisciplinary protocolised care would have far greater impact on maternal outcomes than achievement of goal BP; this precisely happened here, maternal outcomes were better than expected in trial participants (no maternal deaths, adverse CNS outcomes, maternal admissions for critical care, or need for dialysis and <1% incidence of eclampsia despite use of magnesium sulphate in 12% of women).

What should be the first line antihypertensive drug?

Hypertension has almost reached epidemic proportions and is second only to ‘being alive’ as a CV risk factor. All credit to our changing lifestyle and ACC/AHA guidelines-about 103 million adults are affected in USA alone. When you get to see a new hypertensive adult, what is the best first choice antihypertensive agent? Guidelines recommend multiple first-line drug classes: thiazide, ACEis, ARBs, CCBs and rarely beta blockers.

ACEi/ARBs are the most commonly chosen (63%), followed by thiazides (17%), CCBs (~20%) as seen in a massive retrospective database analysis published in this issue of Lancet. Authors used state of art statistical methods (to study the effect of these choices on CV outcomes in 4.9 million patients who got initiated on monotherapy for HTN across 9 different databases from 4 countries. Effect estimates after propensity score matching favoured diuretics with regards to three primary (acute myocardial infarction, hospitalisation for heart failure, and stroke) favoured thiazide users: AMI (HR 0·84, 95% CI 0·75–0·95), hospitalisation for heart failure (0·83,
0·74–0·95), and stroke (0·83, 0·74–0·95) risk while on initial treatment.

What do the results mean? By choosing other drugs, are we depriving majority of the hypertensives on monotherapy of the CV benefits of diuretics ? While the huge size of the databases is a strength of this study, results can’t be considered definitive. Whatever methods we use to address confounding [confounding by indication being an obvious (table 2) and likely to be a big issue here: patients at high CV risk are much more likely to receive ACEi/ARBs], effect of residual confounding can’t be completely eliminated. Patients getting initial monotherapy are likely to be at lower risk of CV events (than those getting combinations), chance of type 1 error with huge sample size remains. Also it is difficult to comprehend how a median on treatment time of few months bring such CV benefit with thiazide use. So, while results are interesting and question the preferential use of ACEi/ARBs, they are hypothesis generating at the best and warrant head to head comparison of the first line antihypertensives. Until then, ‘How well’ is far more important in BP control than ‘with what.’

Baclofen toxicity in CKD

Importance of kidney function is most realised when it is lost. This is best understood when renally excreted drugs create havoc in patients with reduced kidney function. Any new symptom in patient with CKD therefore should alert us to check the medication list (and the box, virtually anything is available OTC here, I always ask fellows to complete examination with ‘box-check’. Some of my memorable “box check surprises” were inadvertent replacement methotrexate for Metformin and Daonil (glibenclamide) for Diamox (acetazolamide)!

Encephalopathy in patients on dialysis can be due to variety of reasons but prescription or OTC medication can be one of the common, serious and potentially life threatening reasons for this situation. In this retrospective population-based cohort study of 15 942 patients with CKD, 9707 [61%] patients started baclofen at ≥20 mg/d and 6235 [39%] at <20 mg/d). 30 day risk of hospitalisation with encephalopathy was significantly higher in high dose group: 108/9707 (1.11%) for greater than or equal to 20 mg per day and 26/6235 (0.42%) who started baclofen at less than 20 mg per day; weighted RR, 3.54 (95% CI, 2.24 to 5.59).

Baclofen is predominantly excreted unchanged by kidney, and it’s no surprise that it can produce problems in those with CKD. A nice review of its pharmacokinetics here in this teaching case. Manufacturers only suggest caution while using this drug in CKD and don’t recommend any specific dose adjustment. Results of this study provide a rationale for reduction in the dose if its used. Also it is wise to ask oneself (or patient’s primary care doctor), whether baclofen is needed in the first place.

Angiotensin Receptor Blocker use and suicide

‘Marriage is strongly associated with happiness’ one group of social scientist concluded, only to realise latter that results were confounded by the fact that happy people are more likely to get married. Interested folks can check this.

I recalled this after reading this nested case control study that associates ARB use with risk of suicide. Compared with ACEI exposure, ARB exposure was associated with higher risk of death by suicide (adjusted odds ratio, 1.63; 95% CI, 1.33-2.00). Although findings were consistent in a sensitivity analysis excluding individuals with a history of self-harm, several characteristics of ARB users like higher comorbidity burden, higher prevalence of psychiatric disorders, higher antidepressant use and higher likelihood of prior self harm suggest that result may be due to residual confounding .

Remember the breaking news claiming association of ARB to cancer which was subsequently refuted by 2 different studies (here and here)?

September 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 intern Dr. Lovy Gaur (@drlovygaur) has summarized an article for us.

1 Keen to screen CAD before transplant? Why it may not be a good idea in asymptomatic patients..

Cardiovascular disease is indeed an important cause of death with a functioning graft and its prevention is therefore of paramount importance since the strategy focuses on saving a precious resource. The fact that predisposition to CV mortality and morbidity is a complex interplay of the traditional and non traditional risk factors, it is difficult to apply the conventional knowledge to this population.  Even for general population, the CARP (Coronary Artery Revascularization Prophylaxis) study  concluded that the coronary revascularization before an elective vascular surgery does no good to reduce mortality perioperatively.

In a narrative review published in AJKD, Adnan Sharif from University of Birmingham summarizes the evidence available so far and argues that “current cardiac screening algorithms for asymptomatic kidney transplantation candidates are overzealous, counterproductive, and not in the best interests of the majority of people living with kidney failure and should be abolished“.

The first of the very few RCTs done in pre-transplant population include the one published by Manske et al in 1992. The study enrolled insulin dependent diabetes mellitus patients with chronic kidney disease and significant coronary artery disease with patients randomized to receive either revascularization therapy or the medical treatment alone . The trial was prematurely terminated in view of excess mortality in the arm receiving medical treatment alone. But this is to be taken with a pinch of salt since the “optimal” medical therapy comprised calcium channel blockers and aspirin; only one-third received beta-blockers as per the standard medical treatment recommended in that era.

The newer studies recognize that while dobutamine stress ECHO may be effective in identifying coronary artery disease in high risk patients, but coronary interventions are not associated with improved survival. The ongoing CARSK study is an ambitious trial designed to recruit 3200 prospective transplant recipients. It aims to explore if initial screening on entry to transplantation wait list is sufficient, or if multiple periodic screening till transplant offers some benefit.

But the question remains – why screen the asymptomatic individuals if intervention does not offer any benefit. And more so, should an asymptomatic ESRD patient be denied transplant based on a positive screening.

Guidelines don’t seem to help either. The recommendations of American Society of Transplantation, ACC/AHA, Renal Association, ERBP et can all be narrowed to a single statement – “there is no common consensus”.

The screening strategy and further intervention appear to soothe the physician anxiety more than affecting the patient outcomes. It’s time that we introspect the perceived advantages versus observed benefits.

Dr. Lovy Gaur, Nephrologist.

2 Patiromer enables continued use of spironolactone in CKD

Fear of hyperkalemia limits the use of mineralocorticoid receptor antagonists (MRAs) in patients with CKD and resistant hypertension. Indeed, in the prior evaluations of MRAs in resistant HTN, compromised kidney function turned out to be the most important determinant of raised potassium. Hyperkalemia can take away the life in sleep, while renoprotection benefit needs years to be realised.

AMBER -a phase 2, randomised, double-blind, placebo-controlled trial, evaluated the use of ‘patiromer+spironolactone versus placebo+spironolactone’ in 295 adult CKD (eGFR 15-45 ml/min) and uncontrolled hypertension. At week 12, 98 (66%) of 148 patients in the placebo group and 126 (86%) of 147 patients in the patiromer group remained on spironolactone (between-group difference 19·5%, 95% CI 10·0–29·0; p<0·0001). Availability of these newer, safer and more efficacious potassium binders will definitely expand the use of renoprotective therapies like MRAs, ACE inhibitors and ARBs.

Cost of the binders is currently prohibitive and will remain a barrier until its out of patent for most patients paying out of their pockets. Trial duration was short-12 weeks, so the long term efficacy and safety remains to be studied. Also at the end of 12 weeks, BP reduction with spironolactone wasn’t better in patients receiving patiromer than those in placebo raising a question : will MRA be as effective in CKD as in non CKD population?

3 Association Between Dialysis Facility Ownership and Access to Kidney Transplantation

In his amazing work ‘Sapiens: A Brief History of Humankind’, Yuval Noa Harari reviews how the ‘marriage of empire and science’ in the history made possible many amazing scientific discoveries. Not all marriages are happy like this and the wedlock between capitalism and health care can sometimes be especially problematic.

It’s assumed that patients will be put on chronic dialysis only if they don’t have a live donor, are medically unfit for transplant or are simply unwilling to choose the best option inspite of being adequately informed. Yes, thats what is expected to happen but there are concerns that this may not be true for many ‘for profit dialysis centres in US’, and patients receiving treatment there are far less likely to have access to kidney transplantation, according to this retrospective cohort study of 1478564 patients treated at 6511 US dialysis facilities studied from 2000-2016. As compared to ‘not for profit centres’, these patients were less likely to be wait listed for deceased donor transplant (−13.2% [95% CI, −13.4% to −13.0%], less likely to get a live donor (−2.3% [95% CI, −2.4% to −2.3%) or a deceased donor kidney transplant (−4.3% [95% CI, −4.4% to −4.2%]).

Clinician perception of patient’s candidacy, poor medical follow-up, time spent with patients, format of transplant education, resource allocation for staffing to enable transplant education-might have contributed to these findings. While it’s possible that systematic differences (higher hospitalisation rates, and location in areas with low background transplantation rates in for profit units) in the population of patients at for profit and no profit facilities may still remain, similar observations have been reported previously as well and can’t be completely disregarded. As inferred by this editorial , for-profit dialysis organisations might have systematically and disproportionately focused on the delivery of dialysis services while paying less attention to transplants.

Drawing analogy with “fistula first, catheter last” [what worked here was not the catchy slogan but linkage to reimbursement -dialysis clinic did their best to have AVF first after AVF rates were linked to payments], this editorial nicely put the findings of this research in context and rightly suggests us to adopt a policy of “transplant first, dialysis last”.

4 Roxadustat for anemia in CKD

Roxadustat by inhibiting HIF prolyl hydroxylase inhibitor (nice review here) mimics the natural response to hypoxia with resultant increase in HIF transcriptional activity, which induces the expression of erythropoietin, erythropoietin receptors, and proteins that promote intestinal absorption of iron and recycling of iron from the macrophage iron storage system.

In these twin trials of roxadustat in predialysis CKD and dialysis patients , with regards to primary endpoint of mean change in Hb from baseline to average, roxadustat was better than erythropoietin in pre dialysis CKD and was non-inferior in dialysis patients. Moreover, serum hepcidin levels (a marker of functional iron deficiency) and serum cholesterol decreased significantly in roxadustat group. Hyperkalemia and metabolic acidosis were noted as adverse events significantly more often in roxadustat group.

Roxadustat is already approved for use in China, and these studies are likely to get it approval in other parts of the world. Prof Hase always reminded us of the postmortem examinations in kidney transplant recipients, where almost every organ used to be loaded with iron. Indeed, we probably aren’t paying as much attention to the possibility of this iatrogenic harm. Most promising feature of HIF stabilisers in anemia therapy is that apart from being an ESA, it addresses a key problem in the pathophysiology of anemia in our patients i.e. inflammatory blockade of available iron due to up regulation of hepcidin by cytokines: both trials demonstrated an impressive lowering of hepcidin levels following treatment with roxadustat. While we administer iron to most of our dialysis patients long term safety of parenteral iron is unknown, HIF stabilisers can potentially minimise iron overload that is common in dialysis population.

Landmark anemia trials in CKD have taught us an important lesson: total correction of anemia is not only unnecessary but also hazardous and we continue to debate the pathogenesis of this harm. Whether HIF stabilisers will dissociate benefit of full correction from the risks observed with other ESA will be interesting to see. Both trials were of limited duration and long term safety-efficacy is yet not known.

5 CKD: A Call for an Age-Adopted Definition

With each new disease definition or its revision, incidence of that disease increases and sometimes can reach epidemic proportions. Can you recall an instance where adopting the new definition of a disease condition, has led to decrease in its incidence?

Apart from rising incidence of diabetes and hypertension, introduction of CKD definition and classification has contributed significantly to the current epidemic of CKD. Large proportion of ‘such CKD’ affects elderly in whom GFR decline is probably no more consequential than wrinkling of skin, graying of hairs etc. In this review, authors discuss the evidence and rationale for relaxing the GFR based cutoffs for CKD in elderly in the absence of albuminuria, based on 3 important observations. First, in large epidemiological studies, there is no increased risk of mortality for elderly with GFR between 45-60ml/min (in the absence of albuminuria), second, there is important structural difference between pathological GFR decline and an age associated decline: there is no compensatory increase in the single nephron GFR in the former setting, and finally, older living kidney donors, who are carefully selected based on good health, have a lower predonation GFR compared with younger donors.

This is an important and must read review, but will this call be responded appropriately by guideline developers?

6 Straight Versus Coiled Peritoneal Dialysis Catheters: A Randomized Controlled Trial.

ISPD guideline acknowledge the clinical equipoise with regards to the PD catheter design straight vs coiled and recommends the use of catheters with either a straight or coiled tip. This is largely due to small numbers and methodological issues with the available studies.

In a Chinese multicenter, open-label, randomized, controlled trial evaluating use of straight vs coiled double-cuffed peritoneal dialysis catheters in 308 patients (153 straight catheters; and 155 coiled catheters), during a mean follow-up of 21 months, the primary outcome of catheter dysfunction or drainage failure occurred in 9 (5.8%) patients who received a coiled catheter and 1 (0.7%) patient who received a straight catheter. Straight catheters had 5.1% lower risk for catheter dysfunction (95% CI, 1.2%-9.1%; P=0.02). The HR of the primary outcome for coiled versus straight catheters was 8.69 (95% CI, 1.10-68.6; P=0.04).

Patients who received a coiled catheter had similar risk for peritonitis but had higher infusion pain scores than those who received straight catheters. Authors concluded that use of straight Tenckhoff catheters compared with coiled catheters reduced the rate of catheter dysfunction requiring surgical intervention. While this is the largest RCT so far examining the issue of catheter design, clinical equipoise probably persist, given the important limitations. Apart from the open label design, and possibility of ascertainment bias, trial was limited by the low event rates and consequent under-powering.

August 2019

1) ABO incompatible kidney transplantation

While the transplant community has largely accepted ABO incompatible (ABOi) kidney transplantation as a viable option based on the ‘excellent’ early results, we haven’t given due importance to the concerns raised by the recent registry data. RCTs evaluating outcomes of ABOi kidney transplantation are impossible to conduct. Here is a paper in Lancet by Scurt et al -probably the best data published so far.

In this systematic review and meta-analysis involving 7098 recipients of ABOi kidney transplants from 49 studies (1 involving children), most outcomes of interests were inferior in these patients when compared to ABO compatible kidney transplantation: significantly higher mortality at 1 year (OR 2∙17 [1∙63–2∙90], p<0∙0001), 3 years (OR 1∙89 [1∙46–2∙45], p<0∙00012), and 5 years (OR 1∙47 [1∙08–2∙00], p=0∙010). Death-censored graft survival was lower with ABOi kidney transplantation than with ABO compatible kidney transplantation at 1 year (OR 2∙52 [1∙80–3∙54], p<0∙0001) and 3 years (OR 1∙59 [1∙15–2∙18], p=0∙0040), and remained lower at 5 year although at this time the difference wasn’t statistically significant.

Higher mortality could be a result of an over-suppressed immune system following the desensitization with the emergence of life-threatening infections of bacterial (sepsis) and viral origin (eg, cytomegalovirus). Moreover, risk of bleeding events and surgical revisions was higher in ABOi KTR.

Given the observational nature of the most studies in the analysis, data on important determinants like recipient comorbidities, donor characteristics, various desensitization methods used were not available. So what do we take away from this important and revealing data? It is imperative to maximize other options like paired exchange and deceased donor KTR, and consider ABOi as the last resort after a careful discussion of the risks and benefits with the recipients. All ABOi transplant are not the same in terms of immunological risk (low isoagglutinin titres, A2 blood groups) may pose a lower rejection risk, require less intense immunosuppression and may fare better. A simple question to ask ourselves is: do we have a fully functional swap transplant program? If not, work for it before breaching the blood group barrier.

2) No need to deprive of water for evaluation of polyuria

14 years ago, when I performed water deprivation test successfully for the first time on a young college girl, I received a pat on the back from my MD teacher, an endocrinologist. It was surely a pain in the neck for us residents and patients alike. The procedure is tedious, sometimes risky and needs close monitoring . Interpretation is often challenging. Here is good news (albeit 12 years late for me): you can reach the diagnosis of diabetes insipidus (DI) with a simple blood test.

Arginine stimulates release of various pituitary hormones and is useful in the evaluation of growth hormone deficiency. It turns out that it can similarly work in cases of defective ADH secretion in diabetes insipidus. ADH itself is difficult to measure but copeptin-a degradation product of the C terminal peptide precursor of ADH-can be assayed easily. In this multi center diagnostic study, 52 patients from a center with polyuria due to central complete or partial DI and primary polydipsia were enrolled alongside 52 healthy controls.

Serial measurements (at baseline and 30, 45, 60, 90, and 120 min) of plasma copeptin concentration after arginine stimulation were measured. At 60 minutes, plasma copeptin level of less than 3·8 pM gave an excellent sensitivity (93%, 95% CI 86–98) and specificity 92% (95% CI 84–100). The test was safe and well tolerated. This is going to simplify the diagnosis of polyuria greatly. Time to wave goodbye to water deprivation-a test based on data of only 36 patients and a diagnostic accuracy of just 70%!

3 New(er) chapters in renoprotection in diabetes

The dust hasn’t settled after the publication of CREDENCE yet. After all the excitement CREDENCE trial brought about, here are a few new chapters in renoprotection in diabetes.

In an exploratory analysis of the renal endpoint among the REWIND trial participants, composite renal endpoint (first occurrence of new macroalbuminuria (UACR >33·9 mg/mmol), a sustained decline in eGFR of 30% or more from baseline, or ESRD) was lower in patients treated with dulaglutide [ 848 (17·1%) participants in the dulaglutide group and in 970 (19·6%) in the placebo group HR 0·85, 95% CI 0·77–0·93; p=0·0004].

Most of this benefit was driven by occurrence of new macroalbuminuria with a between the group difference of 1-2 percentage points. Such effects have also been reported previously in at least half dozen trials of GLP 1 analogues (LEADER, LIRA-RENAL, SUSTAIN6, ELIXA, EXSCEL, AWARD 7). Being a secondary analysis, these results can’t be considered definitive and need to be further studied in RCTs with meaningful renal endpoints over and above albuminuria.

After Canagliflozin, other SGLT2i are all set to prove equivalence in terms of renoprotection. A prespecified secondary analysis of DECLARE–TIMI 58 trial evaluating dapagliflozin demonstrated a lesser likelihood of composite renal endpoint of sustained 40% eGFR reduction, ESRD or confirmed sustained eGFR <15mL/min [HR for the renal-specific
outcome was 0·53 (0·43–0·66; p<0·0001)]. The participants had creatinine clearance >60 ml/min at the time of enrollment. Once again the results should be interpreted with caution given the secondary nature of the endpoints and very few renal events (number of events of ESRD are in single digits for a trial involving thousands of patients!). Nonetheless, against the backdrop of CREDENCE, a class effect of SGLT2i looks more promising (than that of GLP1 analogues).

DELIGHT trial evaluated albuminuria-lowering effect of dapagliflozin alone and in combination with saxagliptin at a short term follow up of 6 month among patients with CKD and diabetes (UACR >30 and eGFR 25-75) and showed promising effect of dapagliflozin.

It’s time to consider renaming CKD G3a/A1 as ‘clinical trialist CKD’-most DKD trials relate to this class of kidney disease. Many elderly diabetics in real life would get this label due to age related GFR decline. Microalbuminuria in these patients with multiple CV risk factors may not necessarily be a marker of progression of CKD.

4 Hematuria evaluation

Should CT be performed for all the patients with hematuria?

Guideline recommendations vary, reflecting the uncertainty of scientific evidence. AUA guideline recommend it for all patients over 35, others [Dutch, Canadian Urological Association (CUA), Kaiser Permanente (KP)] don’t . HRI (Hematuria Risk Index) recommends risk stratification: none for low-risk, cystoscopy and ultrasonography for moderate-risk, and cystoscopy and CT for high-risk patients. Multiphase CT imaging of the abdomen and pelvis has been associated with the highest median radiation dose and, in turn, the highest adjusted lifetime-attributable risk for cancer among common CT protocols. Although absolute risk is low, approximately 1 fatal cancer can be avoided for every 2,000 abdominal CT scan avoided.

Against this backdrop, in a microsimulation modeling study of a hypothetical cohort of 100 000 adults with hematuria, uniform computed tomography scanning (as under AUA guideline) appeared to be associated with more than 500 secondary cancers from imaging-associated radiation exposure and was approximately twice the cost of alternative approaches.

The AUA guideline missed detection for the fewest number of cancers. It detected 82 [2.3%] cancers compared to the detection rate of the HRI (116 [3.3%]) and KP (130 [3.7%]) guidelines. However, the simulation model projected 108 (95% CI, 34-201) radiation-induced cancers under the KP guidelines, 136 (95% CI, 62-229) under the HRI guidelines, and 575 (95% CI, 184-1069) under the AUA guidelines per 100 000 patients.

Can’t agree more with this conclusion of authors: well-intentioned efforts may lead to the widespread dissemination of clinical practices before their safety and effectiveness are clearly understood. This model-based comparison of 5 different guidelines for the diagnostic evaluation of hematuria suggests that, in addition to its substantial costs, the potential harms of the intensive application of uniform CT urography may outweigh the advantages of early diagnosis of urinary tract malignant neoplasms.

5 Urinary dickkopf-3, acute kidney injury, and subsequent loss of kidney function in patients undergoing cardiac surgery

Troponins fascinate nephrologists, who keep talking about possibility of a ‘renal troponin’ for early detection of ‘renal angina’ or ‘kidney attack’. Several of such ‘renal troponins’ have appeared and disappeared from the literature before ever making to the bedside.

Here is a news for biomarker enthusiasts: urinary dickkopf-3 (DKK3 sounds better) predicted not only the AKI but also subsequent CKD in patients undergoing cardiac surgery according to this observational cohort study. This involved 733 participants in the derivation cohort and 216 participants in validation cohort from RenalRIP trial [this showed a reduced AKI and RRT risk after cardiac surgery with remote ischemic preconditioning(RIP)]. Urinary DKK3:creatinine concentrations higher than 471 pg/mg were associated with a significantly higher risk for AKI (OR 1·94, 95% CI 1·08–3·47, p=0·026), persistent renal dysfunction (OR 6·67, 1·67–26·61, p=0·0072), and dialysis dependency (OR 13·57, 1·50–122·77, p=0·020) after 90 days compared with DKK3:creatinine concentrations of 471 pg/mg or less.

AKI risk and dialysis dependency was only observed in the patients who didn’t receive RIP. After publication of this 2017 cochrane review on RIP, I thought it has no place in AKI prevention-results of this study seems to be putting new life into RIP.

Transplantation of Kidneys From Hepatitis C Infected Donors To Hepatitis C Negative Recipients

In a single-center retrospective study, Molnar et al studied short-term outcome of deceased donor renal transplant recipients who received kidneys from HCV NAT positive donors. They accepted HCV NAT positive and/or HCV antibody-positive donors who were younger than 45 years old and had a donor biopsy showing less than 10% glomerular sclerosis. They offered these organs to recipients who previously agreed to accept HCV infected donor kidneys.

All 53 recipients became viremic after transplantation. Treatment with a direct-acting antiviral regimen (DAA) regimen was initiated when HCV RNA was detected. The time between transplant and treatment initiation was 76 days (IQR:68 -88 days). One patient developed fibrosing cholestatic hepatitis with complete resolution. All recipients completed antiviral treatment and 100% were HCV -RNA negative and achieved 12 -week sustained virologic response. There were no graft losses or patient deaths during the study period. Thirty four percent recipients had BK viremia and 60% had CMV viremia, which is concerning.

Overall the results look encouraging. However, the risks need to be discussed in details with the waitlisted patients.

In the same journal, Kapila et al present two cases of HCV negative recipients who underwent kidney transplantation from viremic donors and developed fibrosing cholestatic hepatitis (FCH).

Fibrosing cholestatic hepatitis is characterized by the rapid development of inflammation, cholestasis, hepatocyte ballooning, and advanced fibrosis with the potential for hepatic injury and death. Although DAAs have improved the outcome of this potentially fatal condition, we need to have a high index of suspicion to diagnose and treat FCH early.

Both patients presented after transplant with abnormal liver function tests and HCV viral loads of greater than 100,000,000 IU/mL. FCH was diagnosed by histology and/or clinical data. Both patients were started on DAA therapy within 24 hours of admission with improvement in LFTs.

Every decision we make has various possible outcomes. The papers discussed above emphasize the importance of shared decision-making in medicine.

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.

Hemolytic Uremic Syndrome in a Developing Country: Consensus Guidelines

This month’s guest blog post is written by Dr. Jyoti Sharma, a Pediatric Nephrologist at the KEM Hospital, Pune .  Dr. Sharma is one of the authors of the Hemolytic uremic syndrome in a developing country: Consensus guidelines. published in Pediatric Nephrology in April 2019.

Dr. Jyoti Sharma

Hemolytic uremic syndrome (HUS) is a significant cause of acute kidney injury in children. Rapid diagnosis and prompt management are essential to limit irreversible renal damage. These guidelines were developed since the epidemiology of the HUS in Indian children is different, the diagnostic facilities are limited and eculizumab, the standard of care for atypical HUS, is expensive and not easily available.

Though the diagnosis of HUS is based on the presence of microangiopathic hemolytic anemia, thrombocytopenia, and AKI, patients may occasionally have a sub-acute presentation with AKI, systemic hypertension, and the diagnosis is established only on renal biopsy and demonstration of histological features of TMA; DIC and TTP must be excluded.

The classification of HUS is based on the etiology. It is important to differentiate between infection-associated illness, cobalamin C (cblC) deficiency, secondary HUS, and atypical HUS; however, a practical approach without compromising the principles of management is recommended. Since TTP and cblC deficiency are relatively infrequent causes, units lacking the facility to screen for these disorders may store samples for subsequent analysis.

Circulation of S. dysenteriae has been low in recent years and there is limited data regarding the epidemiology of Shiga toxin-producing Escherichia coli (STEC) since microbiological diagnosis is difficult. The present guidelines suggest suspecting STEC-HUS in patients with prior history of bloody diarrhea, or if occurring during an outbreak of STEC infection with a caveat that ~ 30–40% cases of STEC-HUS may not have dysentery.
Atypical HUS is characterized by dysregulation of the alternative complement pathway, resulting in endothelial damage and microvascular thrombosis. Atypical HUS is suspected when STEC and pneumococcal HUS, TTP, and secondary HUS are excluded based on the clinical and laboratory features as well as in those with positive non-synchronous family history, or recurrent disease. In these patients, blood samples for C3 and anti-FH antibodies should be drawn prior to instituting therapy.

Anti-FH antibody-associated illness constitutes ~ 50% of pediatric patients with aHUS in India, affecting children between the age of 5–15 years. Most patients have high levels of antibodies (1000 to 20,000 AU/ml, normal 150 AU/ml).

Genetic screening for CFH, CFI, CFB, C3, CD46, THBD, CFHR1–5, and DGKE and for rearrangements of CFH-CFHR5 by multiplex ligation-dependent probe amplification (MLPA) is advised in children with early age of onset, relapsing course, family history of HUS, illness that is refractory to therapy with PEX, and prior to renal transplantation. Estimation of levels CFH and CFI is useful only if a variant is found in the corresponding gene.
Renal biopsy is indicated when the diagnosis of HUS is not clear e.g. unexplained renal dysfunction, proteinuria and/or hypertension in a child who does not show hemolysis or thrombocytopenia; when the clinical response is inadequate; to determine the extent of renal damage; post-transplant to distinguish between causes of allograft dysfunction, including recurrent HUS.

Therapy of Shiga toxin-associated HUS: Patients with HUS due to proven or presumed STEC infection show an association between dehydration and adverse outcomes hence early and adequate hydration is recommended in patients with dysentery, starting from the onset of bloody diarrhea along with antibiotics, while monitoring for development of AKI and fluid overload. PEX in patients with STEC HUS may only be considered for patients with severe neurological or cardiac involvement.

For children with anti-FH antibody-associated HUS, a combination of prompt PEX (within 24 hours of diagnosis) with fresh frozen plasma as replacement fluid and immunosuppressive therapy is recommended. PEX is preferred to plasma infusions for initial therapy since large volumes of plasma can be infused even in patients with oliguria and also enables removal of antibodies. It should be performed daily until hematological remission and then tapered over 3–5 weeks; 5–7 PEX sessions are expected to achieve 80% reduction in antibody titers. Immunosuppression inhibits further production of antibodies with improved short and medium-term outcomes. Induction is instituted with oral corticosteroids (starting dose 1mg/kg/day) and IV cyclophosphamide.
Antibody titers should be monitored between days 7–28 and then every 3–6 months. Elevated titer (> 1500 AU/ml) during the first 12–24 months is associated with an increased risk of relapse.

Atypical HUS without anti-FH antibodies due to inherited defects of the alternative pathway is the chief cause of aHUS in Europe and North America. The standard of care for patients is complement blockade with humanized anti-C5 antibody eculizumab. However, eculizumab is expensive and unlikely to be available soon in India and other developing countries. Thus, PEX or plasma infusions remain the chief option for patients with aHUS, especially those with genetic defects in the complement pathway.
Efforts to enable therapy with eculizumab should be made when there is lack of remission despite 7–10 days of PEX, life-threatening features (seizures, cardiac dysfunction), complications due to PEX or vascular access, and an inherited defect in complement regulation.

Supportive care and monitoring: Standard recommendations for the management of AKI should be adhered to. In addition, the guidelines suggest avoiding platelet transfusions unless the count is < 10,000/μl, or to enable vascular catheter insertion. Blood transfusion is recommended for patients with hemoglobin < 6 g/dl or hemodynamic instability. Standard measures are instituted to retard CKD progression, especially control of hypertension and proteinuria. Patients and their families should be counseled regarding the risk and recognition of relapses.

Transplantation: Patients with aHUS show variable risk of recurrent disease in the allograft, with the risk being high in patients with dysregulation of the alternate pathway and low in those with STEC-HUS and abnormalities in membrane anchored CD46 and intracellular DGKE. Live-related donation should be avoided in patients at high risk of disease recurrence. These patients require either combined liver-kidney transplantation or therapy with eculizumab pre- and post-transplant. Patients with high titer of anti-FH antibodies and no additional defects are managed by PEX prior to and following transplantation, and use of rituximab. Live donors should be tested by MLPA for copy number variations in CFHR1/3. Patients should be monitored for the recurrence following transplantation.

Dr. Jyoti Sharma
Consultant, Pediatric Nephrologist
KEM Hospital, Pune.

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.