September 2017

1. Prevention of AKI in intensive care unit 

 2017 update on AKI prevention by Working Group on Prevention, AKI section, European Society of Intensive Care Medicine is here. There is no magic bullet at our disposal to do so, however, a number of factors can be modified in the course of critically ill patients to protect their kidneys, and to prevent complications once AKI develops. Authors have summarized the evidence pertaining to volume expansion, diuretics, vasopressor use, sedation use, hormonal manipulations, metabolic interventions, remote ischemic preconditioning, statin use and use of AKI bundle care.

Not delaying urgent contrast-enhanced investigations/interventions for potential preventive measures and a possible preventive role of propofol/dexmedetomidine when used for sedation in ICUs (BPSs-best practice statements which represent ungraded strong recommendations) are some of the new recommendations they propose. A 2B recommendation on the use of atorvastatin or rosuvastatin to prevent contrast-associated AKI in high-risk patients undergoing coronary angiography is controversial. While most of such patients are likely to have one or other indications to use the statin, guidelines suggest their initiation for AKI prevention probably based on the result of this 2016 meta-analysis published in Annals of Internal Medicine. However, as @hswapnil points out in a PubMed comment, the majority of these patients were at low risk of AKI and when only high-risk participants were analyzed, no benefit of statin treatment was observed. Another feature of these guidelines on AKI prevention that strikes to me is the absence of any mention about quality improvement initiatives like NINJA for AKI prevention which can be easily adopted in diverse clinical settings Good that we are realizing the correct time point of action in the course of AKI, where simple interventions and avoidance of harm are likely to be maximally effective.

2. Pharmacogenetics  of Thiazides Induced hyponatremia (TIH) in elderly

About 9% of patients initiated on thiazides develop hyponatremia and elderly are especially prone to get it, some of them develop almost an idiosyncratic response and develop severe dyselectrolytemia. TIH is unpredictable and mechanisms underlying are poorly understood however there is a susceptible subgroup of the population in whom TIH can be reproduced with a single dose of thiazide. This study in JCI was set out to explore this pharmacogenetic predisposition to TIH in two cohorts of patients admitted to the hospital with severe symptomatic TIH in the UK. Phenotype and genotype of TIH cases were compared with controls (patients on thiazides but normonatremic, and general population not on thiazides).  

Cases were typically above 70, predominantly female, had: low plasma osmolarity, inappropriately concentrated urine, more than minimal urinary sodium excretion, and normal thyroid function, low or normal ADH levels, severe hypochloremia, mild hyperglycemia, and intravascular volume expansion. GWAS (Genome Wide Association Study) was done in 48 TIH cases and 2,922 controls (from the 1958 British birth cohort) that showed an association with a variant in SLCO2A1 gene, which encodes prostaglandin transporter (PGT) in the distal nephron (co-localizing with AQP1 and AQP2). Authors hypothesize that under low ADH conditions, apical PGT in the renal collecting duct scavenges PGE2 from the lumen, resulting in AQP2 internalization and minimal osmotic water reabsorption. In the presence of the genetic defect,  apical PGT is reduced or absent, so more PGE2 reaching the lumen is able to stimulate apical EP4 (E prostanoid 4) receptors, resulting in the insertion of AQP2 and thus increased osmotic water reabsorption.

While sample size studied was small, and findings need to be confirmed in other populations, this is by far the largest phenotype-genotype documentation of TIH, and have generated an interesting hypothesis about the poorly understood entity of TIH. After seeing some of the most severe dyselectrolytemia cases with thiazides, I am scared to start someone above 60 on these drugs, and thanks to JNC 8 who have controlled enthusiasm with this class of antihypertensives.   

3. Belatacept versus Tacrolimus in Kidney Transplantation  

Here is a (very) small, single center, open label, Dutch RCT comparing belatacept with tacrolimus based immunosuppression after kidney transplant that showed a higher incidence of biopsy proven acute rejection in belatacept treated group (55% vs. 10%; p = 0.006). Authors tried exploring potential biomarkers, namely CD8+CD28-, CD4+CD57+PD1- and CD8+CD28++ EMRA T cells (all of these reported to be associated with AR in belatacept treated patients) -none of these predicted AR in this study. Also, flow-cytometric measurement of CD86 occupancy on monocytes by belatacept was assessed as a marker of the adequacy of its dose (which was found to be adequate).

Interpretation of these results is limited by very small sample size and therefore the chance of type 2 error. Belatacept is widely viewed as a promising agent that will address burning issues like chronic CNI toxicity, and antibody mediated chronic allograft injury. However, this trial and some recent observational data (here and here) highlight the need for larger trials comparing belatacept with tacrolimus based immunosuppression which is the current standard of care. Here is a 2017 review summarizing potentials and limitations of this agent. 

 

4. Dialysis Following Transcatheter Aortic Valve Implantation (TAVI)

This analysis of UK TAVI registry, involving 6,464 procedures performed between 2007 to 2014, reported data on predictors of post procedure dialysis and impact of pre- and post- procedure dialysis on mortality in short (30 days) and long term (4 years). Dialysis need decreased with time (6.1% to 2.3% over 7 years). Lower baseline renal function, year of procedure, impaired left ventricular function, diabetes, use of an Edwards valve, a non-transfemoral approach, need for open surgery, and moderate-to-severe aortic regurgitation after the procedure independently predicted need of dialysis after the procedure. Dialysis need after TAVI was associated with high mortality at 30 days (HR 6.44; 95% CI 4.87 to 8.53) and at 4 years (HR 3.54; 95% CI 2.99 to 4.19; p < 0.001 for all) compared with patients without dialysis requirement. This risk was probably unrelated to dialysis procedure itself as patients already on dialysis before procedure had a lower risk of death as compared to those who needed it post procedure.

This study is the largest report the incidence rate of the need for dialysis after TAVR and registry included all the procedures performed over 7 years. However, as is expected in registry data, several important risk factors like the need for prior balloon aortic valvuloplasty, contrast volume, bleeding, and recovery of renal function after dialysis might not have been included. TAVI use is increasing worldwide and be prepared to see this ‘aortorenal syndrome’ following TAVI especially if your center has started it recently, and patients have other traditional risk factors for AKI like diabetes and heart failure.

5. Renal denervation for the treatment of hypertension 

After it failed to demonstrate its utility in resistant hypertension in SIMPLICITY 3, I thought renal denervation (RDN) was dead as an antihypertensive measure. According to authors of SPIRAL HTN-OFF MED trial in Lancet, RDN is not dead and it’s the failure of ‘complete’ denervation with the previous techniques used, that underlies the lack of efficacy in large trials. So authors speculate that if enough nerves are dead, RDN may again take a breath of life in the therapy of hypertension. This is a proof of concept, double blind, multi center, sham controlled RCT involving 80 patients (38 RDN, 48 sham control) after a renal angiogram. All of them had moderate hypertension (unlike severe/resistant HTN where it was initially tried) and had to be off the drug for at least 3-4 weeks before getting randomized. The primary endpoint, the change in 24-h blood pressure at 3 months was significantly better in intervened patients 24-h SBP –5·0 mm Hg (95% CI –9·9 to –0·2; p=0·0414), 24-h DBP –4·4 mm Hg (–7·2 to –1·6; p=0·0024). 

These results should be interpreted with caution as they are the results of the third interim analysis (BTW, how many are allowed per trial?) planned to see if RDN works or is futile so that trial can be continued or stopped. It wasn’t powered to conclude on efficacy, moreover, compromised adherence to the assigned treatment (7/38 couldn’t be kept off drugs) lack of long term efficacy/safety data (renal artery stenosis is reported a complication of circumferential RDN), lack of data on patient-centered hard outcomes are important limitations of this trial. With a decrease in SBP ~5 mmHg, most patients treated with RDN  will still need medications to optimally control their BP. Nobody will be ready to expose patients to an intervention reporting some reduction in BP at 3 months. Excellent editorial putting results in context is here.

So we have evidence justifying further evaluation of this technique in large RCT and let’s hope that history doesn’t repeat itself. Let’s wait and see if subsequent SPIRAL HTN-OFF MED trials confirm this proof or challenge the concept itself as was the case with SIMPLICITY. 

6. Early versus late removal of DJ stent after kidney transplantation

Prophylactic ureteric stenting after kidney transplant reduces the risk of major ureteric complications however this benefit comes at the cost of increased risk of UTIs. This multicenter RCT of Early Versus Late removal of DJ stent enrolled 227 participants from  6 transplant centers in the UK. The intervention was early stent removal at day 5 without cystoscopy (the ureteric stent was attached to the urethral catheter using the string of the stent to allow this) or late removal at 6 weeks after transplantation with cystoscopy. Stent-related complications were significantly higher in the late as compared to early stent removal group [36 of 126 (28.6%) vs. 6 of 79 (7.6%); p < 0.001]. This was largely driven by a lower incidence of UTIs in early removal group.

However, this didn’t remain the trial of early or late stent removal alone, as those assigned to early removal were spared of cystoscopy for stent removal but, were exposed to an additional intervention of fixing stent and tip of urethral catheter together intra-op. Due to this, unique set of complications were encountered in early removal group: urethral catheter and stent fell out early (n = 2), string snapped during removal, requiring cystoscopic removal (n = 1), occlusion of the catheter balloon with the string (n = 1) required percutaneous deflation; and difficulty with catheter removal required cystoscopic removal (n = 1). Authors acknowledge the learning curve issues with this technique. Increase in the size of ureteroneocystostomy in an attempt to localize balloon of the catheter may theoretically increase the risk of reflux /ureteric stenosis; however, the study didn’t aim to study these issues. 

Less we mess with the urothelium is better and what matters most in preventing urological complications is not the duration of the stent but the experience of the operator (as suggested in this study and a previous Cochrane meta-analysis). 

7. Clinical Practice Guidelines for Screening and Management of High Blood Pressure in Children and Adolescents

American Academy of Pediatrics (AAP) has released updated clinical practice guideline for screening and management of high blood pressure in children and adolescents. A nice summary that highlights differences between the new and the old guideline (the 4th report)  is here. The document is a comprehensive review; it tries to find answers to a range of key questions: diagnosis, work up, BP goal, the role of lifestyle changes vs antihypertensive drugs, for example.

Unlike adults, hypertension in children is defined statistically rather than a BP cut-off above which there are adverse CV outcomes. Of note, the new BP tables presented in the paper exclude overweight and obese children. Obviously, the BP cut-offs to define hypertension are lower compared to those in the previous guidelines. So buckle up guys, we are going to diagnose an underrecognized problem more often and only long term prospective studies are going to tell us if we using a right cut off.

The BP tables that have BP percentiles according to gender and height percentile are not user-friendly. In fact, these scary looking tables are an impediment to the diagnosis of hypertension (here).  For busy clinicians, the guideline includes a new, simplified table for initial BP screening. These are the numbers above which one should reassess to confirm the presence of hypertension. These numbers are based on the 90th percentile BP for age and sex for children at the 5th percentile of height, which gives the values in the table a negative predictive value of >99%. Even if this could simplify things, I think it has a potential to add to the confusion. The simplest thing would be to develop an iOS/ android app that all the nurses, pediatricians and nephrologists can easily have on their phones and see if the BP reading is high for the age, gender and height!

Guidelines emphasize on the specific role of ambulatory BP monitoring in diagnosis and monitoring of hypertension. In healthy children, the committee recommends BP be measured annually in children aged 3 years or above.

BP treatment targets in the 2017 AAP CPG are: goal BP is <90th percentile for age, or <130/80 mm Hg, whichever is lower (based on office/casual BP readings). Based on the data from ESCAPE trial, the guidelines recommend that in children with CKD, BP should be monitored by ABPM, and the recommended goal BP is a 24-hour mean arterial pressure < 50th percentile.

 

8.Mycophenolate mofetil is inferior to tacrolimus in sustaining remission in children with idiopathic steroid-resistant nephrotic syndrome LMIN Sep

CNIs are effective in achieving and maintaining remission in children with the steroid resistant nephrotic syndrome (SRNS) side effects like nephrotoxicity are a concern in long term.   In this randomised trial by Sinha et al, 60 children with SRNS who had achieved complete or partial remission on tacrolimus and ramipril were assigned to either MMF or tacrolimus with the tapering dose of prednisolone for 12 months. The primary endpoint-the proportion of patients with a favorable outcome (sustained remission, infrequent relapses) at one year was significantly lower (44.8%) in the MMF group than in the tacrolimus group (90.3%). Replacing tacrolimus with MMF after six months of tacrolimus therapy for SRNS in children was associated with significant risk of frequent relapses or recurrence of resistance.

In an NIH sponsored RCT of children and adults with steroid-resistant focal segmental glomerulosclerosis, although statistically non-inferior, MMF with high dose dexamethasone was only able to achieve complete or partial proteinuria remission in 33% of patients, compared with the 48% of CNI-treated patients. Moreover, in this trial, it’s difficult to separate the effect of high dose dexamethasone from MMF. So it looks like CNIs are the best available therapy for inducing and maintaining remission in SRNS.

 

9. Furosemide/Fludrocortisone Test and Clinical Parameters to Diagnose Incomplete Distal Renal Tubular Acidosis (dRTA) in Kidney Stone Formers

Ammonium chloride loading test is considered the gold standard to diagnose incomplete dRTA whose only feature may be nephrolithiasis. However, many patients do not tolerate ammonium chloride because of GI side effects.

Furosemide/fludrocortisone test could be an alternative. Fludrocortisone stimulates electrogenic sodium absorption in the collecting duct via ENaC channel. Furosemide delivers sodium from the thick ascending limb to the collecting duct, stimulating the epithelial sodium channel–driven, luminal-negative potential difference. A person without distal RTA can increase H+ excretion and urine pH would decrease below 5.3.  In this prospective cohort study of 170 stone formers, by Dhayat et al  8% were diagnosed to have incomplete dRTA based on ammonium chloride loading test. Considering this as the gold standard, sensitivity, and specificity of the furosemide/fludrocortisone test were 77% and 85%, respectively, yielding a positive predictive value of 30% and a negative predictive value of 98%. In other words, if a person can acidify urine in furosemide/fludrocortisone test, distal RTA is almost ruled out.

Ok, now if you do not want to perform a ‘provocative test’,  a fasting morning urinary threshold pH < 5.3 with a plasma potassium threshold > 3.8mEq/L may be good enough screening test (negative predictive value of 98% with a sensitivity of 85% and a specificity of 77% for the diagnosis of incomplete dRTA). In busy clinics, simply checking urine pH and serum K may help detect dRTA and this diagnosis may change the life of that recurrent stone formers.

 

10. Liraglutide and renal outcomes
It seems everyone else than nephrologists is interested in protecting kidneys of diabetics. After CANVAS and CANVAS R that we reviewed in detail in July, prespecified secondary analysis of LEADER trial in this weeks NEJM concludes that liraglutide offers renoprotection: renal outcome occurred in fewer participants in the liraglutide group than in the placebo group (268 of 4668 patients vs. 337 of 4672; hazard ratio, 0.78; 95% confidence interval [CI], 0.67 to 0.92; P=0.003). And what is that renal outcome benefit exactly?-fewer patients on this drug progressed to dipstick positive proteinuria :161 vs. 215 patients; hazard ratio, 0.74; 95% CI, 0.60 to 0.91; P=0.004). Almost all the shortcomings of CANVAS hold true for LEADER as well and I’m not willing to buy this renoprotection benefit until it is replicated in well-designed trials looking at outcomes of patient interests.

P.S.

In an interesting report, nephrologists from Cape Town, South Africa used 1000 mg of rabbit ATG (yes, some grafts are extraordinarily precious),  10 mg/ day of tacrolimus,  2 gm/ day of mycophenolate, injections of methyl prednisone (500, 250, 250 mg) followed by  30 mg/ day of prednisone for 3 months for induction immunosuppression. Arterial thrombosis needing re-exploration and re-anastomoses, urethrocutaneous fistula needing a suprapubic catheter, catheter occlusion due to bladder clots, fungal infection due to Alternaria alternata and finally a successful outcome! This is not a kidney transplant of a high immunologic risk recipient (although nephrologists were in charge of immunosuppression), but a sensational story of first successful penile allotransplantation done in South Africa making the place as original research with an editorial in the Lancet.

The superhuman physical strength and endurance, that this 21-year-old recipient showed, is nothing less than that of Hercules. Many African young men starting their sexual life face penile amputation as a consequence of ceremonial traditional circumcision done under all ‘septic care’-something that Hercules didn’t have to face, except once when his opponent wrestler Diomedes caught hold of his penis as Hercules was about to throw him down [and on a second occasion posthumously when  people started stealing penis of Hercules statue in Paris leading government to decide to put a removable one there!). 

Penile transplant recipient is happy at the end of 24 months, however, unfortunately, couldn’t become a father due to intrauterine fetal death at the term. The result of this transplant might have opened a new chapter in penile reconstruction, but I hope that some resources are also allocated for education to prevents complications arising out of such rituals and a good perinatal care to save mothers and newborns.

Author: lastmonthinnephrology

Clinicians, interested in 'what matters at bedside', readers, researchers. Tukaram Jamale and Vaibhav Keskar

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