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 gliptins. You will have to squint to find the limitations of the trials though (reviewed in depth here and here by us before).

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

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

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

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

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

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


January 2019

1 Diuretic use in incident ESRD

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

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

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

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

 

2 Total versus subtotal parathyroidectomy for secondary hyperparathyroidism

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

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

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

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

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


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

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

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

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

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

4 APOL1 in non-African Americans

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

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

5 Tweaking Nephrogenesis to Boost Nephron Number

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

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

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

 

6 SGLT2 inhibition repairs pumps, pipes, and filter! 

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

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

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

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

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

 

December 2018

1 Effect of Oral Alfacalcidol on Clinical Outcomes in Patients Without Secondary Hyperparathyroidism Receiving Maintenance Hemodialysis

Japanese investigators of J DAVID trial set out to evaluate the impact of active vitamin d administration to the patients on hemodialysis who otherwise wouldn’t have received this treatment i.e. PTH levels <180 (Do we really know if these drugs save lives in patients with SHPT either?). The primary outcome was a composite measure of fatal and nonfatal cardiovascular events, including myocardial infarctions, hospitalizations for congestive heart failure, stroke, aortic dissection/rupture, amputation of lower limb due to ischemia, and cardiac sudden death; coronary revascularization; and leg artery revascularization during 48 months of follow-up (too much to expect from poor Alfacalcidol!).

Oral alfacalcidol compared with usual care did not reduce the risk of these events :103 of 488 patients (21.1%) in the intervention group and 85 of 476 patients (17.9%) in the control group experienced primary outcome (absolute difference, 3.25% [95% CI, −1.75% to 8.24%]; hazard ratio, 1.25 [95% CI, 0.94-1.67]; P = .13). Are you surprised? I am not. In fact, there was a signal of harm (in per protocol analysis) although these findings can’t be considered definitive. In addition, significant drop out (?due to side effects like hypercalcemia and hyperphosphatemia), crossover and unblinded nature are significant limitations to note.

Vitamin D is the Vitamin C of our times that once claimed to be effective for the common cold and cancer. Although such claims have failed the tests of rigorous research methods, their use will continue in nephrology until we continue to be happy with “surrogate nephrology”-which is a synonym for CKD MBD therapy.

 

2 Lanreotide for Autosomal Dominant Polycystic Kidney Disease

Slide1

Visual abstract by Dr. Divya Bajpai (divyaa24). From NephJC.

Effect of the somatostatin analog lanreotide on the rate of kidney function loss in patients with later-stage ADPKD (eGFR 30-60ml/min) was evaluated in an open-label,  trial (DIPAK 1) involving 309 patients from 4 centers in Netherland. At the end of 2.5 years, the primary outcome of annual rate of eGFR decline for the lanreotide vs the control group was −3.53 vs −3.46 mL/min/1.73 m2 per year (difference, −0.08 [95% CI, −0.71 to 0.56]; P = .81). Findings were consistent across various prespecified subgroups studied, including patients with more rapidly progressive disease, such as patients with class 1C, 1D, or 1E Mayo-classified ADPKD.

Findings are in contrast with the previous smaller ALADIN trial, which showed a benefit of octreotide in reducing rate of TKV increase at 1 year (46·2 mL vs 143·7 mL, p=0·32) and at 3 years (220·1 mL vs 454·3 mL, p=0·25). The inclusion of higher risk patients (eGFR 30-60 vs >40)  in DIPAK 1 (although they dropped eGFR by just 3-4 ml by 2.5 yrs! much lesser than predicted), eGFR vs mGFR (ALADIN used gold standard mGFR, highly desirable and rarely done in most nephrology trials), imbalance in baseline characteristics that favoured octreotide in ALADIN trial. Both trials brought out cholecystitis and liver cyst infections as important side effects of somatostatin analog.

From clinician and patient’s standpoint, the most important question here is ‘who to treat’ rather than ‘with what’. In spite of the improved understanding of genetics and availability of the risk score, identifying candidates who can be benefited (and harmed least) by the treatment remains poor. Especially as both of the promising looking drugs have significant tolerability issues.

3 Efficacy and safety of mycophenolate mofetil versus levamisole in frequently relapsing nephrotic syndrome

Levamisole is often the first steroid-sparing drug used in children with frequently relapsing nephrotic syndrome. This inexpensive drug is often tolerated well. We did not have high-quality data about the efficacy and safety of levamisole. Last year we reviewed an RCT comparing levamisole and placebo demonstrating superiority of levamisole. But we don’t give these children a placebo in the real world, do we?

In a single-center, randomized, open-label trial Sinha et al randomized 149 children ages 6-18 years with frequently relapsing or steroid-dependent nephrotic syndrome to receive therapy with mycophenolate mofetil (750-1000 mg/m2 daily) or levamisole (2-2.5 mg/kg on alternate days) for 1 year; prednisolone was discontinued by 2-3 months.

Just over a quarter of this population was steroid dependent.

Both the regimens were tolerated well. Over the study duration, relapse rates declined to almost one-third of the baseline for both treatment groups. Therapy with MMF was not superior to levamisole in terms of the proportions of participants with sustained remission (40.8% vs. 34.2%), frequent relapses (14.5% vs. 16.4%), or treatment failure, a composite outcome of frequent relapses, steroid resistance, or significant steroid toxicity (15.8% vs. 20.6%). The average prednisolone dose at the end of the study was low in both the groups (0.21 vs 0.3 mg/kg/day).

4 Safety and cardiovascular efficacy of spironolactone in dialysis-dependent ESRD (SPin-D)

Spironolactone reduces cardiovascular mortality in people with systolic heart failure. Considering CVD to be a major cause of death in the dialysis population, can it similarly work in dialysis patients?  In a larger open-label trial of 309 oligo-anuric Japanese HD patients, 25 mg/day spironolactone reduced the composite of cardiovascular hospitalization or death by 60%, and all-cause mortality by 65%.

In a double-blind, placebo-controlled, multiple dosage RCT, double-blind, placebo-controlled, multiple dosage RCT, Charytan et al sought to study safety, tolerability and feasibility and cardiovascular efficacy of spironolactone in 129 maintenance hemodialysis patients: placebo (n=51) or spironolactone 12.5 mg (n=27), 25 mg (n=26), or 50 mg (n=25) daily for 36 weeks.

For the primary safety outcomes of potassium concentration > 6.5 mEq/l and hypotension requiring hospitalization or emergency department visit, there was not an overall difference between spironolactone and placebo groups; however, hyperkalemia and intra-dialytic hypotension was more frequent in patients on 50mg of spironolactone. Change in diastolic function (assessed by Doppler echocardiography) was similar with spironolactone and placebo. This study wasn’t aimed at evaluating CV outcomes, although it reassures about this drug’s safety in a carefully selected dialysis population (e.g. failure to achieve Qb>300ml/min was an exclusion criterion). In the real world of dialysis, where patients often choose (?) the frequency and duration of therapy based on largely nonmedical reasons, and admission with life-threatening hyperkalemia remains one of the commonest reason of emergency room visits, I will prefer to wait until more compelling data to support this therapy. 

CV disease in dialysis is a tough nut to crack and considering the disappointing history of extrapolations from cardiology (statins, ICD, RASi), all the best spironolactone. 

5 The relationship between Cerebral Blood Flow and Cognitive Function in Hemodialysis Patients

Hemodialysis induces a decline in cerebral blood flow. In an elegant study, Findlay et al explored whether hemodialysis was associated with changes in cerebral blood flow and determine whether these changes relate to intradialytic cognitive dysfunction. They recruited 97 adults receiving chronic hemodialysis. Transcranial Doppler ultrasound to measure cerebral arterial mean flow velocity (MFV) throughout dialysis. Cognitive function during and off dialysis and after 12 months of treatment. MFV declined significantly during dialysis, correlating with ultrafiltrate volumes. Percentage of decline in MFV correlated with the intradialytic decline in cognitive function.

In a subgroup of patients followed for 12 months of continued dialysis, the percentage of decline in MFV correlated significantly with lower global and executive function and with the progression of white matter hyperintensities burden (a marker of small vessel disease).

We need interventions to limit this ‘cerebral stunning’. Some time back, Chris McIntyre’s group showed that the patients who dialyzed at 0.5°C below core body temperature exhibited complete protection against white matter changes at 1 year. We need to find out such simple but effective solutions to address this problem.

6 Bleeding Complications after Pediatric Kidney Biopsy

In a meta-analysis of 23 studies of 5504 biopsies, Varnell et al found that 13 studies specifically looked for post-biopsy hematoma. While the studies before 2001 reported a higher proportion of children getting hematoma (40-85%), studies after 2001 reported that 11% had a perinephric hematoma. The risk for blood transfusion in native kidney biopsies was 0.6% (P=0.60; 95% CI, 0.2% to 2.4%), and the risk for blood transfusion in transplant kidney biopsies was 0.8% (P=0.70; 95% CI, 0.4% to 1.6%). The risk of additional intervention after biopsy (cystoscopy, embolization, surgery, or nephrectomy) was 0.7% (95% CI, 0.4% to 1.1%). They could not analyze the available data for laboratory values, needle gauges, number of needle passes, the age of patients, or performer (trainee versus attending physician).

This data seems reassuring and will help counseling anxious parents of the children needing a kidney biopsy.

7 Voclosporin in achieving remission in patients with active lupus nephritis

Increased potency and decreased metabolite exposure of Voclosporin (VCS) results in more pharmacokinetic and pharmacodynamic predictability than CsA, and therefore drug level monitoring is not required (cost of monitoring can exceed that of the drug for CSA/TAC, thanks to generics!). 

In this phase 2, multicentre double-blind RCT involving 256 patients across 20 countries, initial treatment with VCS high dose (39.5mg), VCS low dose (23.7mg), and placebo were compared when added to standard treatment with MMF 2g/d. The primary outcome of CRR (Complete Renal Remission) at 24 weeks was achieved by 29 (32.6%) subjects in the low-dose voclosporin group, 24 (27.3%) subjects in the high-dose voclosporin group, and 17 (19.3%) subjects in the placebo group (OR[2.03 for low- dose voclosporin versus placebo). There were more serious adverse events in both voclosporin groups, and more deaths in the low-dose group compared to placebo and high-dose voclosporin groups (11.2%, 1.1%, and 2.3%, respectively).

Patients with SLE die more often due to infections and CV disease than SLE related causes,  whether the benefits of VCS persists in long-term without additional harm remains to be seen. Also, the possibility of ‘pseudo-remission’ due to nonimmunological effects of CNI and possible ‘CNI dependence’ will need longer follow up after withdrawal of CNI. 

8 Exome sequencing for CKD 

In one of the largest genetic evaluation of CKD, exome sequencing was performed in 3315 patients with CKD (AURORA trial participants and CUMC-Columbia University Medical Centre cohort): about 10% of patients revealed a diagnostic genetic variant. Likelihood of finding such a variant was highest in patients with congenital or cystic renal diseases OR 24.4 (10.6–56.4) followed by Nephropathy of unknown origin (are CKDu researchers listening?) 14.2 (6.0–33.9), and glomerulopathies 6.7 (2.9–15.6).

Medical management was altered by testing in some patients: For example, 56 of the 91 patients (62%) with COL4A3, COL4A4, or COL4A5 mutations did not have clinical diagnoses of the classically associated nephropathies (the Alport syndrome or thin basement membrane disease). For these patients, the genetic diagnosis would indicate ophthalmologic and otolaryngologic referral and, among the 15 patients (16%) with a clinical diagnosis of focal segmental glomerulosclerosis, would disfavor immunosuppressive therapy.

After all, AURORA wasn’t a negative trial!

November 2018

1. Efficacy and Safety of Sparsentan in Patients with FSGS

Sparsentan is a dual endothelin receptor and angiotensin receptor blocker and was evaluated in this phase 2 randomized, double-blind, active-control, dose-escalation study (DUET trial) involving 109 patients with primary FSGS from 44 centers across the US and Europe. This treatment was after patients were on stable immunosuppressive regimens and after RAS blockade washout period of 2 weeks. They had to have proteinuria >1.5gm and eGFR>30ml/min.

At the end of 8 weeks, compared to irbesartan, sparsentan-treated patients had greater reductions in UP/C than irbesartan-treated patients did when all doses (45% versus 19%; P=0.006) or the 400 and 800 mg doses (47% versus 19%; P=0.01) were pooled for analysis. Results are exciting and hopefully will translate into long-term renoprotection, addressing a major unmet therapeutic need in this population.

 

2. Recombinant Alkaline Phosphatase (rALP) for sepsis-associated AKI             

Alkaline phosphatase is supposed to exert detoxifying effects through dephosphorylation of various compounds, including bacterial endotoxins and proinflammatory mediators such as extracellular adenosine triphosphate.

In this phase 2a/2b clinical trial evaluating the efficacy, safety, and doses of rALP in the treatment of sepsis-associated AKI, rALP in various dosages studied was no more effective than placebo with regards to the primary endpoint of change in the mean daily creatinine clearance (absolute difference, 9.5 mL/min [95% CI, −23.9 to 25.5]; P = .47). No safety issues were noted with rALP. Authors hypothesize various reasons for the lack of efficacy (most of which are related to the study design)-imbalanced randomization with rALP arm having more severe AKI than placebo, imprecise estimation of renal function by creatinine clearance in the nonsteady state, the short time frame of 7 days to look at efficacy and they emphasize the need of further trials.

Given the heterogeneous and multifactorial nature of AKI, it is not surprising that “magic bullets” (dopamine, ANP, fenoldopam, and so on) have consistently misfired. My gut (ALP) feeling is that rALP won’t be any different!

 

3. Impact of ACC/AHA guidelines 

Here is a JAMA study which found that if the ACC/AHA guideline was used, the overall prevalence of hypertension in Nepal would approximately double (from 21.2% to 44.2%), mostly by shifting more individuals out of the normal and prehypertension categories. Hey you all skeptics, look here, guidelines do have the impact! While Kibria and colleagues should be congratulated, this “overnight” doubling of the hypertension prevalence needs to be understood on the background of overburdened public health programmes in Nepal.

With the doctor-patient ratio is 0·17 per 1000 population, it will be quite a task to address the health needs of these ‘newborn’ hypertensives. Don’t miss this invited commentary on this article, putting results into context. 

 

4. ACE inhibitor use and cancer risk 

“Commonly used BP drug increases lung cancer risk”, this became a headline in media after the publication of this population-based cohort study in BMJ. 

Using UK Clinical Practice Research Datalink, 7952 incident lung cancer events were detected among patients on various antihypertensive medications after a median follow up of 6.4 yrs. Patients using ACE inhibitors had a 14% higher risk as compared to other drugs (incidence rate 1.6 v 1.2 per 1000 person-years; HR 1.14, 95% CI 1.01 to 1.29), compared with the use of angiotensin receptor blockers. Proposed hypothesis underlying is tumorogenic effects of bradykinin and substance P that accumulates in the lung tissue as a result of ACE inhibition.

Absolute risk attributable to the drug is extremely small when one considers the known risk factors like smoking, and I hope patients and primary care doctors won’t stop these drugs with established efficacy in preventing CV deaths. In the observational design like this, residual confounding and ‘detection bias’ (ACE inhibitors—->cough—->higher chance of chest imaging—–>increased detection) may well explain the results (confidence interval is almost touching 1). Rapid responses published are worth reading.

I can, of course, use the results to persuade hypertensive smokers to quit!

 

5. Association of Angiotensin-Converting Enzyme Inhibitor or Angiotensin Receptor Blocker Use With Outcomes After Acute Kidney Injury

Acute kidney injury is associated with increased risk of CKD, ESRD, and death. We keep searching for interventions that can modify this risk. I think common sense is one thing that should top the list (if we choose to make such a list). It is known that follow up with a nephrologist improves all-cause mortality of acute kidney injury survivors. Wonder why that would be? We don’t have any magic bullet with us. I think the answer lies in common sense. Common things that we do all the time, for example, tweaking the doses of diuretics, restarting essential medicines, identifying new risk factors etc would help the most.

In a large retrospective study using an administrative database from Alberta Kidney Disease Network, Brar et al explored if RAAS blockade improves outcome in people who have had AKI in the recent past. Of the 46,253 adults who had an episode of AKI during hospitalization and survived, 48% were prescribed an ACEi or ARB (41.6% were on ACEi/ARB prior to the index hospitalization while 6.9% were given a new prescription.) ACEi or ARBs were associated with lower mortality (adjusted HR 0.85, 95% CI 0.81-0.89). However, they were also associated with a higher risk of hospitalization for a renal cause, mainly AKI, CHF, and hyperkalemia (adjusted HR 1.28, 95% CI 1.12-1.46). No association was found between ACEi/ARB and progression to ESRD.

The group that was on ACEi /ARB prior to the hospitalization but did not receive it within 6 months fared worse in terms of mortality. This group was at high CV risk and it makes sense to start/ restart RAAS blockers in such a population. In short, previous AKI episodes should not deter us to restart ACEi/ ARB. At the same time, close monitoring is required to detect adverse effects.

 

6. ABO-incompatible kidney transplant outcomes- a meta-analysis

With ever increasing the burden of ESRD, we keep looking for the ways to expand the kidney donor pool, be it paired kidney transplant, desensitization protocols or ABO incompatible transplants. But its only natural that risks tend to escalate as we become more aggressive.

de Weerd and Betjes performed a meta-analysis of single-center studies comparing patients who were ABO-incompatible with ABO-compatible controls reporting patient and graft survival. Twenty-six studies were included, describing 1346 patients who were ABO-incompatible and 4943 ABO-compatible controls. Older studies using splenectomy were excluded.

One-year uncensored graft survival of patients who were ABO-incompatible was 96% versus 98% in ABO-compatible controls (relative risk, 0.97; 95% confidence interval, 0.96 to 0.98; P,0.001). However, 49% of reported causes of death in patients who were ABO-incompatible were of infectious origin, versus only 13% in patients who were ABO-compatible (P=0.02). Antibody-mediated rejection (3.86; 95%confidence interval, 2.05 to 7.29; P,0.001), severe nonviral infection (1.44; 95%confidence interval, 1.13 to 1.82; P=0.003), and bleeding (1.92; 95% confidence interval, 1.36 to 2.72; P,0.001) were also more common after ABO-incompatible transplantation. CMV and BK viremia was common in ABO-incompatible group as well.

Publication bias is a limitation here and the risks reported could be an underestimate. And make no mistakes, these risks are expensive to manage. These outcomes are certainly better than remaining on dialysis. However, paired kidney transplantation has the potential to minimize these costly consequences. We have to know our options better.

 

7. Duration of Treatment with Corticosteroids and Recovery of Kidney Function in Acute Interstitial Nephritis

Majority of us use corticosteroids to treat drug-induced acute interstitial nephritis. However, there are no RCTs guiding us in this area. Available data are mainly retrospective and conflicting. In one such retrospective (and probably the largest) analysis, Fernandez-Juarez et al studied the association between the length of corticosteroid treatment and serum creatinine at 6 months.

The study included 182 patients with biopsy-proven drug-induced acute interstitial nephritis from 13 Spanish centers. The most frequent offending drugs were nonsteroidal anti-inflammatory drugs (n=49; 27%), followed by antibiotics (n=41; 22%), and proton-pump inhibitors (n=8; 4%). All patients presented with acute kidney disease and were treated with corticosteroids. The mean initial dose of prednisone was 0.8 ±0.2 mg/kg per day. High-dose corticosteroid treatment was maintained for 2 weeks (interquartile range, 1–4). After 6 months of follow-up, the mean recovered GFR was 34 ±26 ml/min. Seventy-five patients (41%) achieved complete recovery of kidney function, 83 patients (46%) achieved partial recovery, and 24 patients (13%) did not recover kidney function. Within this group, ten patients needed maintenance dialysis.

In the multivariable analysis, delayed onset of steroid treatment and the presence of interstitial fibrosis of >50% on the kidney biopsy specimen were both associated with serum creatinine level at month 6 of >75%, with respect to baseline values. Keeping in mind all the drawbacks of a retrospective study, this paper supports what we practice usually: start early, don’t give the high dose and not for a prolonged period.

8. Diagnostic application of kidney allograft-derived absolute cell-free DNA levels during transplant dysfunction

It will be a dream come true to diagnose rejection without graft biopsy.

Cell-free  DNA (cfDNA)  is fragmented, degraded  DNA that is detectable in body fluids, including plasma and urine. The majority of detectable cfDNA in plasma is thought to arise from cell-turnover within the haematopoetic system. Injury to the allograft results in increased release of graft-derived cell-free  DNA  (gd-cfDNA) into recipient plasma via graft-cell apoptosis and necrosis. And the same could be used to detect graft injury, mainly rejection, non- invasively.

In a cross-sectional study done in two transplant centers in Melbourne, Whitlam et al studied the diagnostic validity of absolute measurements of graft-derived cell-free  DNA,  as well as calculated graft fraction (proportion of total cell-free DNA  that is graft-derived), for the diagnosis of graft dysfunction. Plasma graft-derived cell-free  DNA, total cell-free DNA and graft fraction were correlated with biopsy diagnosis as well as individual Banff scores. Adult kidney  transplant  recipients  undergoing  standard-of-care allograft biopsy  for investigation  of graft  dysfunction  were  included in  the  study.

61 samples were included in the analysis.  For the diagnosis of antibody-mediated rejection,  the receiver-operator characteristic area under the curves of graft-derived cell-free  DNA and graft fractions were  0.91  (95%  CI  0.82-0.98)  and  0.89  (95%  CI 0.79-0.98),  respectively.

That means we could rule out antibody-mediated rejection based on a blood test. As of now, we cannot replace graft biopsy with cell-free DNA alone but it may become an alternative to serial biopsies (for example, monitoring the response to treatment of ABMR or screening in high-risk population).

 

 

October 2018

1. The timing of RRT in Patients with AKI and Sepsis

IDEAL ICU VA Divya

Visual abstract by Dr. Divya Bajpai (@divyaa24)

 

As an anxious first-year nephrology fellow, I had to discuss all the labs with my boss before he leaves department-typically at around 6 in the evening.

“Sir, that bed 2, Gastroenteritis- AKI patient’s serum creatinine is up to 10mg/dl. Now what?”

“Tell me something about the patient whose creatinine you are talking about.”- he would reply coldly.

Results of much awaited IDEAL-ICU trial are out and are largely consistent with the existing evidence that “earlier initiation of RRT doesn’t improve survival and exposes about 40% of patients with AKI to RRT who otherwise have recovered renal function before ever needing it.”

The trial was terminated early for futility after enrolling 488 patients. By then 58% of the patients in the early- strategy group (138 of 239 patients) and 54% in the delayed-strategy group (128 of 238 patients) had died (P=0.38). In the delayed-strategy group, 38% (93 patients) did not receive RRT. These lines from the paper bother me, “The second limitation is the choice of a delay of only 48 hours, which may not be sufficiently long to allow recovery of renal function in some patients or to detect a difference between early and delayed initiation of RRT. However, we thought that a longer delay would be unethical and unsafe for patients who actually needed renal-replacement therapy.” 

How do you know that delay of 72hrs or 96 hrs necessarily ends up into emergency dialysis and is unsafe? Watchful waiting, in my humble opinion, can continue until an indication develops, irrespective of the timing in hours.

AKI is one of the most common renal emergency and lets’ respect these words of wisdom. “Don’t be in hurry, we are in an emergency” –Anonymous “wise” emergency room physician to his junior colleague.

 

Here is a nice Twitter thread

 

2. Targeted Polymyxin B Hemoperfusion in patients with severe sepsis

Last week a senior surgery colleague was asking me if we can offer extracorporeal therapy to cut down dismally high mortality of perforative peritonitis. She and I were equally hopeful and skeptical respectively about this treatment, and after reviewing the literature we finally settled for the need of a pilot trial if she manages to get funding.

EUPHRATES (Evaluating the Use of Polymyxin B Hemoperfusion in a Randomized Controlled trial of Adults Treated for Endotoxemia and Septic Shock) investigators must be congratulated for a very well conceived and executed RCT addressing this question. In critically ill patients with severe sepsis with high risk of death, this technique did not reduce 28 day mortality (treatment group, 84 of 223 [37.7%] vs sham group 78 of 226 [34.5%]; risk difference [RD], 3.2%; 95% CI, −5.7% to 12.0%; relative risk [RR], 1.09; 95% CI, 0.85-1.39; P = .49). Findings were consistent in patients with more severe sepsis as well. Authors recommend against the use of this strategy.

Blinding by sham hemoperfusion, the inclusion of patients with very severe illness, so, high risk of death, and including endotoxemia >0.60 (indicating high endotoxin activity)  make trial results generalizable to the real world scenarios where such desperate measures are actually used.

Endotoxin was about to become ‘creatinine of intensivists’; thanks to EUPHRATES, it won’t.

3. Antibody-Mediated Rejection of Solid-Organ Allografts

Chronic ABMR is one of those helpless situations in the life of transplant nephrologist where you watch the progressive loss of graft function without much to offer. In spite of significant improvements in the understanding of pathophysiology, (this principally includes new definitions, classifications, revisions that take birth when transplant physicians-pathologist gather at a resort town along Trans-Canada Highway and more sensitive assays of antibody detection which add to the confusion!). Chronic ABMR remains a difficult nut to crack, and if we don’t ‘let go’ beyond a limit, one can potentially add to the number of ‘death with functioning graft’ as a consequence of overtreatment. Here is a NEJM review summarising current standards of treatment and possible future therapies.

Here is a quote from the article- “An improved understanding of the natural history of antibody-mediated rejection has led to a more complex interpretation of the various clinical scenarios encountered in clinical practice, given the heterogeneity, diverse polymorphism, and temporal dependency of the clinical and histologic manifestations of antibody-mediated rejection.”

Yes, ABMR is just as difficult to treat as making sense of these lines!

4. Phosphate binders for preventing and treating chronic kidney disease-mineral and bone disorder (CKD-MBD)

This 2018 revision of 2011 Cochrane review on phosphate binders concludes this

“Overall, we are not very sure whether specific phosphate binders are beneficial to patients with CKD. There is a possibility that sevelamer may prevent death compared to calcium-based binders, but we don’t know whether this may be caused by an increased risk of calcium-based binders, a lower risk with sevelamer treatment, or the possibility that both may be true. Patients need to know that it is not certain whether phosphate binders help to prevent complications of kidney disease, but sevelamer may be preferred to calcium binders.”

 

What will a man in severe debt feel if asked, “Which credit card you would like to buy? Platinum/ silver/ gold?” A very similar feeling a patient with CKD is likely to get if we (dare to) put the results of this review in context and involve him in shared decision making before choosing to use and then choosing amongst the P binders.

Let me just give you a glimpse of the “very low” quality evidence that suggests a possible advantage of sevelamer over other binders. In an analysis of 248 participants with a median follow up of less than a year showed RR  of death in controls or placebo to be high as compared to sevelamer (RR 2.16). The confidence interval (CI) was 0.2 to 22.8. After what limit a CI become ‘No Confidence Interval’?

 

5.Effects of Sacubitril/Valsartan Versus Irbesartan in Patients with Chronic Kidney Disease A Randomized Double-Blind Trial

We reviewed renal effects of sacubitril/valsartan and enalapril in participants of PARADIGM-HF trial in our May 2018 blog post.  Sacubitril/ valsartan leads to increase in albuminuria and still preserves eGFR better. While this was not the prespecified analysis, we now have an RCT examining the effects of sacubitril/valsartan on kidney function and cardiac biomarkers in people with moderate to severe chronic kidney disease.

The UK HARP-III trial (United Kingdom Heart and Renal Protection-III), a randomized double-blind trial, included 414 participants with an estimated glomerular filtration rate (GFR) 20 to 60 mL/min/1.73 m2 who were randomly assigned to sacubitril/valsartan 97/103 mg twice daily versus irbesartan 300 mg once daily. Participants ≥18 years of age were eligible to participate if they had CKD with either (1) an estimated glomerular filtration rate (eGFR) of ≥45 and <60 mL/min/1.73 m2 and a urine albumin:creatinine ratio (uACR) >20 mg/mmol (177 mg/g), or (2) an eGFR of ≥20 and <45 mL/min/1.73 m2 (regardless of uACR).

At 12 months, there was no difference in the primary endpoint: measured (wow!) GFR (51Cr-EDTA, 99mTcDTPA, or iohexol methods)- 29.8 (SE 0.5) among those assigned sacubitril/valsartan versus 29.9 (SE, 0.5) mL/min/1.73 m2 among those assigned irbesartan; difference, ‒0.1 (0.7) mL/min/1.73 m2.

Compared with irbesartan, sacubitril/valsartan further reduces both blood pressure and biomarkers of cardiovascular risk (troponin I and N-terminal pro-B-type natriuretic peptide). Albuminuria was not different in the two groups.

Authors conclude that “sacubitril/ valsartan could be an acceptable treatment to reduce cardiovascular risk in people with chronic kidney disease, a high-risk population with an unmet need”.

Will we have an RCT with hard endpoints? Hard to say given the track record.

 

6. Effect of Increased Daily Water Intake in Premenopausal Women With Recurrent Urinary Tract Infections: A Randomized Clinical Trial

In an open-label, controlled trial funded by Danone (which sells bottled water), Hooton et al randomized 140 healthy women with recurrent cystitis (3 episodes in past year) drinking less than 1.5 L in a day to drink, in addition to their usual fluid intake, 1.5 L of water daily (water group) or no additional fluids (control group) for 12 months. The primary outcome measure was the self-reported frequency of cystitis. During the 12-month study period, the mean (SD) number of cystitis episodes was 1.7 (95% CI, 1.5-1.8) in the water group compared with 3.2 (95% CI, 3.0-3.4) in the control group, with a difference in means of 1.5 (95% CI, 1.2-1.8; P < .001)

This low-cost intervention seems to be an effective antimicrobial-sparing strategy in this group of individuals.

7. Are NSAIDs safe in patients with CKD?

Choosing wisely campaign suggests avoiding the use of NSAIDs in patients with hypertension, heart failure, and CKD to which most of us comply. Here is a retrospective cohort NSAID in elderly adults visiting the primary care physician for musculoskeletal complaints. 9.3% of such visits were followed by NSAID prescription, 11% of the physicians chose NSAIDs for these patients. Authors  study in JAMA Int Med evaluating the frequency of identified 35 552 pairs (for each patient exposed to NSAID and they identified (by propensity score matching) a control patient not exposed but the similar likelihood of exposure.

Rates of cardiac complications(288 [0.8%] vs 279 [0.8%]), renal complications(34 [0.1%] vs 33 [0.1%]), and death (27 [0.1%] vs 30 [0.1%]) were similar among cases and control, leading to this rather bold conclusion, “NSAID use in this population is not associated with short term safety concerns”. This should not be overinterpreted to challenge the “choosing wisely recommendations”.

Firstly, as a nephrologist I am  interested in what happens long term rather than within a week. Moreover, we don’t have any information on severity of renal dysfunction of the population (physicians are more likely to use NSAIDs for patients with mild CKD which may well include patients labelled as CKD due to age related GFR decline). Apart from this confounding by indications, several other  limitations of propensity score method like residual confounding, unmeasurable imbalances etc should be taken into account before we put these results into practice.

September 2018

 

1 Folly of surrogates 

validity ajkd

Visual abstract by Dr. Divya Bajpai (@divyaa24)

Whether its phosphorus, blood pressure, PTH, or albuminuria- the numbers guide us all in our practice. Being easily modifiable with treatments, surrogates are attractive outcomes not only in nephrology but also in other areas of medicines. However, more often than not, that’s not what patients want from us. They want us to improve the way they ‘feel, function and survive’. Here is something that highlights this once again for us: in a meta-analysis of BP lowering treatment trials (22 trials involving 69,642 participants), there was limited correlation between drug effects on surrogates (albuminuria, eGFR/creatinine) and risk of ESRD.

These findings contrast the NKF and USFDA’s view that proteinuria is a reliable surrogate of kidney disease progression. For decades, we have been deluded by surrogates, not surprisingly, we see dissociation between soft endpoints and patient-centered outcomes. Are CANVAS, EMPAREG, and LEADER  listening?

2 Biocompatible Solutions and Long-Term Changes in Peritoneal Solute Transport

Speaking of surrogate endpoints, if faster peritoneal solute transport rate is associated with poor outcomes(read technique failure and mortality and encapsulating peritoneal sclerosis), a fluid that preserves the transport characteristics of the peritoneal membrane would be an ideal PD solution.

Elphick et al analyzed the data from the multinational prospective Global Fluid Study to test the hypothesis that biocompatible solutions use would be associated with stable membrane function. This hypothesis proved false, because “solute transport rate, although starting slower in patients using biocompatible solutions, rose to similar levels seen in standard solutions after 2 years of treatment. After 2 years, there was a potentially beneficial effect of biocompatible solutions on solute transport rate, with abrogation of the increases in solute transport rate observed in patients using standard solutions. In addition, the increases in solute transport rate associated with peritonitis episodes were absent in patients using biocompatible solutions. The magnitude of these effects was less than the effect of using higher dialysate dextrose concentrations.” There may be a long-term benefit; only a large study with long-term follow up would tell us that.

3 Uric acid lowering and CKD progression 

febuxostat ajkd 2018final

Visual abstract by Dr. Aakash Shingada (@aakashshingada)

Monsoon is the lifeblood for Indian farmers and it regularly defies meteorological department’s predictions, so much so that some farmers recently filed a police complaint against the department and a farmers’ organization had threatened to close down their office.  We desperately need a better tool to predict rains. In absence of such a tool, some farmers look at the height at which a weaver bird builds its nest on a tree to predict the rains. I find myself in no better position when a patient with CKD (especially those with no significant HTN and proteinuria) asks me about the future course of his disease and if I would be able to change the trajectory in a better way.  Uric acid, for some of us, is that weaver bird’s nest.

In the multicenter, placebo-controlled, double-blind, FEATHER (Febuxostat Versus Placebo Randomized Controlled Trial Regarding Reduced Renal Function in Patients With Hyperuricemia Complicated by  Chronic Kidney Disease Stage 3). Compared to placebo, febuxostat did not mitigate the decline in kidney function among patients with stage 3 CKD and asymptomatic hyperuricemia. Not convinced by the futility of this therapy, the authors try and speculate on various reasons for the negative results of the trial like higher eGFR (65-year-old, eGFR, and stage 3 CKD—you know what I mean), a generally slower decline of eGFR in their patients, no significant proteinuria etc. Diastolic BP was lower in the febuxostat group (not surprising as they were more likely to be on ACEi/ARBs)

Only thing I am sure about febuxostat today is that it’s an effective urate-lowering agent and FEATHER just confirms this observation.

4 TRANSFORMing long-term outcome after kidney transplantation, really?

Everolimus sept 2018 final

Visual abstract by Dr. Aakash Shingada (@aakashshingada)

Set out to address the burning issue of chronic allograft injury, here is a report (yet another), an RCT comparing everolimus with reduced CNI exposure with conventional immunosuppression i.e. MMF with standard CNI dosing (arguably TAC trough levels of 8-12  vs 3-8 in everolimus arm will qualify for ‘high dose CNI’ strategy). Everolimus arm was non-inferior to conventional arm for the primary endpoint which was (novel according to Novartis): binary composite of tBPAR(treated biopsy-proven acute rejection) or eGFR<50 ml/min at 12 months post-transplant [48.2% (493) with everolimus and 45.1% (457) with MPA (difference 3.2%; 95% confidence interval, 21.3% to 7.6%)]. Infections (especially CMV and BKV) were less common in everolimus arm.

Are you ready to get transformed? You may if you are willing to forgo the following flaws: the fallacy of eGFR as efficacy endpoint, generous 10% noninferiority margin, two components of the binary endpoints not necessarily changing linearly, and exclusion of high-risk patients. Also please let go of the tolerability-mTOR arm was more than two times likely to discontinue medication due to side effects (23% vs 11.9%). So we are no further than this Cochrane review as of now.

When will we move to patient-centered research in transplantation? Neither I nor my patients will be ready to get transformed just by good-looking numbers at 12 months. They deserve much more than that.

5 Patient-Reported Experiences of Dialysis Care

 Moving away from surrogates, here is an interesting report of patient-reported experiences of dialysis care patients from a national ESRD registry receiving in-center hemodialysis in the United States. In-Center Hemodialysis Consumer Assessment of Healthcare Providers and Systems (ICH-CAHPS) survey, (this contains questions like-how often did you feel your kidney doctors really cared about you as a person? never/sometimes/usually/ always).

2939 (59.1%) reported mean ICH-CAHPS scores. Patient experience of the dialysis centers was poor (lower ICH-CAHPS score) if the center has the following characteristics: for-profit units, stand-alone centers, fewer nurses and technicians per patient, centers belonging to LDO (Large Dialysis Organisation), had more patients with minority race/ethnicity.

Although limited by various factors (39% centers didn’t report, the interplay of medical and nonmedical factors etc), this exercise should be done more and more often to better understand the gaps in the delivery of complex treatment like dialysis. Inputs derived can potentially help improve the quality of dialysis care.

6 What happens when hemodialysis is free of cost?

andhra

Visual abstract by Dr. Divya Bajpai (@divyaa24)

While patient-reported experiences of care may be less favorable in for-profit hemodialysis units, a paper published from India enlightens us about a government-sponsored program where patients are provided maintenance hemodialysis free of cost. Andhra Pradesh, a southern state in India, implements the Rajiv Aarogyasri Community Health Insurance Scheme (RACHIS) where a private insurer provides a health insurance and is paid in full by the state government. Beneficiaries are able to utilize hospital services through a network of public and private hospitals and are covered up to INR 150,000 ($ 8876) per year.

A total of 13,118 patients received HD for ESRD during the study period (mid-2008-mid-2012). The program had a good reach and the number of patients who received HD for ESRD increased from 29.5 per million of the population in 2008–2009 to 122.2 per million of the population in 2011–2012.

Of all the subjects who started HD, 2.3% received a kidney transplantation, 17.1% were reported as dead, and 63.5% had ceased treatment of their ESRD (i.e., stopped reporting to dialysis centers).

The total cost of HD-related care was $ 63.2 million. The mean annual expenditure per patient on HD-related care was $ 4821. (This contrasts with $ 89,900 in the United States!)

Costs other than dialysis costs (commuting, loss of wages, drugs, caregiver burden) could be the reason for the high dropout rate; but what is most striking here is the high mortality rate.

Maintaining low-cost services alone is not enough; the model must have in-built checks to improve the outcomes.

In authors’ word, “In conclusion, removal of out-of-pocket of cost leads to an increase in uptake of HD, confirming a previously high unmet need. The high mortality and dropout rates suggest that insurance coverage does not address all inequities in access and the barriers to maintaining long-term care.”

[Let me thank Dr. Krishna Penmatsa (@krishnadoctor1) who gave me insights into the Rajiv Aarogyasri Community Health Insurance Scheme (RACHIS)]

Monitoring the urine flow to prevent overcorrection of hyponatremia

Urine output is probably the most important parameter to monitor when one treats hyponatremia; arguably more useful at the bedside than urine lytes and osmolality (given the typical turnaround time). Once the component of volume contraction (or whatever is the cause of high ADH level) is taken care of, the stimulus for ADH secretion is taken away and this leads to water diuresis leading to a rapid rise in serum sodium. The best strategy at our disposal is frequently checking the sodium level (and using DDAVP of course).

If you are a nephrologist, you must read (and pretend that you understood every single word of it) this article published in AJKD last month. Florian Buchkremer et al have derived on theoretical grounds a safe upper limit of urine flow, dependent only on body weight, that can be easily used at the bedside.

Edelman is the root of almost all good in nephrology. Based on the Edelman equation, authors suggest using a urine flow rate of 24 mL/kg/24 h or 1 mL/kg/h (up to a maximum of 2,400 mL/24 h or 100 mL/h) as a safe upper limit during correction of hyponatremia.

If you have been called for a hyponatremia consult and are seen doing narcissistic calculations trying to predict the next morning’s sodium and find that you are terribly wrong, you are welcome to the club! Discrepancies between actual plasma sodium changes and those predicted by the Edelman equation have been reported, but most of that is related to the things we assume. The equation stands tall! But one thing we can take from this paper is the order we are going to write- “Document total urine volume [as voided or every 2 hours in patients with catheters]. Notify the treating physician as soon as the cumulatively voided volume exceeds 6mL/kg in 6 hours.”

August 2018

1) Transplanting kidneys from hepatitis C donors 

After revolutionizing the management of hepatitis C, DAAs (Directly Acting Antivirals) are all set to expand the donor pool in deceased donor kidney transplantation.  After the exciting report (reviewed previously in our June 2017 post) of successfully transplanting 10 kidneys from hepatitis C positive donors into hepatitis C negative recipients, THINKER 1 (Transplanting Hepatitis C kidneys Into Negative KidnEy Recipients), authors report here the intermediate term data (12 months) on their cohort including additional 10 such patients. All 20 patients achieved HCV cure despite the use of intense immunosuppression (primary outcome), they also experienced improved quality of life as assessed by RAND 36.

Recipients of the HCV positive kidneys also had higher eGFR post-transplant at 12 months (median, 72.8 vs. 57.7 mL/ min/1.73 m2; CI for the between-group difference, 7.9 to 19.2 mL/min/1.73 m2) probably related to the younger age of deceased donors who are hepatitis c positive. A new chapter in expanding the donor pool indeed!

 

2) Copeptin in the evaluation of polyuria

 

v5

Visual abstract by Divya Bajpai (@divyaa24)

In ‘hypotonic polyuria’ (these endocrinologists want to tease us- hypotonic polyuria is any polyuria that is not due to solute diuresis) water restriction test is often performed by endocrinologist at our center (they bother us twice: once by sending samples to our lab for osmolality measurements and later when they find themselves clueless after the results of the test). Almost 30% of the patients with primary polydipsia can be labeled as central diabetes insipidus even after this test. While this age-old method is still standard test, its interpretation is difficult when one wants to differentiate central DI from primary polydipsia due to two reasons: any water diuresis may compromise the renal medullary concentration gradient and promote a down-regulation of kidney aquaporin-2 water channels, which could potentially affect reading values of urinary osmolality measurements.

In this prospective, multi-center study, authors evaluated the diagnostic utility of Copeptin -based approach (copeptin is a degradation product of ADH and is much easier to measure reliably as compared to ADH), in differentiating central DI from primary polydipsia. Direct measurement of Copeptin after administration of hypertonic saline (250 ml bolus followed by 0.15ml/kg/hr infusion targeting serum Na of at least 150), showed significantly improved diagnostic accuracy over water deprivation test (96.5% vs 76.6%, P<0.001).Water deprivation one of that cruel and risky thing that doctors do to their patients (only another comparison I can imagine is the unscientific ritual of clamping urinary catheters in patients on diuretics!) Hoping to get copeptin measurements available, so that nephrologists who are well versed with using hypertonic saline (your turn to get teased by endocrinologists now!) can increasingly evaluate  patients with polyuria.

 

3) BP threshold to initiate therapy in elderly

Most Indian television daily soaps feature the nauseating age-old “saas-bahu’ (mother in law-daughter in-law) drama. Directors of these serials usually have IQ that competes with room temperature but we must acknowledge their unique skill:  both wife and mother can identify themselves as the victim of the situation (who in fact is a third person called ‘the husband’- regularly getting in trouble in such situations). But happy husbands are those who can hear both the sides carefully and listen to none.

Annals of Int Med features ‘Beyond the guidelines’ where they discuss a case of elderly hypertensive Mr. L who is in similar dilemma-identifying right BP threshold that will benefit him most and harm least in the light of conflicting guidelines by “saas-bahu ”- ACC/AHA vs ACP (you can choose to assign ‘saas or bahu’ status as per your discretion; a sorry situation! No choice here).

Husbands here are those smart physicians who can read them both and listen to no one but the interests of the patient sitting in front of them.

This is a worth reading piece for those who care about patients more than guidelines and individualize BP threshold to best suit patient’s need.

While some of us can afford to debate the debatable, here is what I like the most about blood pressure research-extensive over intensive approach. In a multicenter trial involving 700 patients from Sri Lanka, fixed low-dose triple-drug-combination was more likely to achieve BP control than the conventional approach (70% vs 55%, respectively; risk difference, 12.7% [95% CI, 3.2% to 22.0%]; P < .001). Although limited by short follow up and pragmatic nature, results shown are encouraging especially in developing countries where BP treatment is far from optimum due to various barriers like complex drug supply chain, limited access to medications, and the shortage of healthcare workers to titrate medications.

4) Technique failure in the first year after PD initiation 

Whether it occurs in the first year or later, ‘technique failure’ is a catastrophe for a patient who chooses PD as a modality of dialysis. This is more likely early after initiation, and authors of this AJKD study evaluated data from Australia and New Zealand Dialysis and Transplant Registry (ANZDATA) Study, involving 16,748 patients included in the study, 4,389 developed early technique failure. Age >70 years, diabetes or vascular disease, prior renal replacement therapy, late referral to a nephrology service, or management in a smaller center were associated with higher risk of technique failure while Asian or other race and use of continuous ambulatory PD were associated with reduced risk, as was initiation of PD therapy in 2010 through 2014.

Admitting the retrospective nature and possible residual confounding, this data represents the largest evaluation of early technique failure using the recommended definition of this complication (which remains the major limitation of the previous studies).

I disagree with the preamble of this article that goes like this, “concerns regarding technique failure is a major barrier to increased uptake of peritoneal dialysis”. In many parts of the world, the major barrier may be the skewed incentive structure of HD vs PD. This leads to the selection of patients who have exhausted all the access options for HD (this is the most common reason why the patient chooses PD as last resort and comes for catheter implantation at our center)

 

5) Acute Kidney Injury in Sugarcane Workers at Risk for Mesoamerican Nephropathy

In a prospective study in a Mesoamerican nephropathy hotspot in Nicaragua, Kupferman et al observed that a substantial fraction of sugarcane workers, who had no clinical evidence of kidney disease before the harvest season, developed AKI during the harvest season. Follow-up of the workers with AKI revealed that as a group, these workers had a partial recovery of kidney function.

Of the 326 sugarcane workers with normal preharvest serum creatinine values and no history of CKD, 34 (10%) had AKI (rise in creatinine >0.3 mg/dL). Of 34 workers with AKI, 29 participated in the first follow-up about 6 months later. 10 of 29 (34.5%) workers had eGFRs <60 mL/min/1.73 m2 and 11 of 29 (37.9%) developed an eGFR decrease > 30% by the time of their last follow-up. Working as a cane cutter (compared to working as a seed cutter, weeder, pesticide applicator, or irrigator) was associated with a 20% higher creatinine level.

AKI burden in this population is likely to be underestimated. Recurrent episodes of even minor renal injury may add up and lead to chronic tubulointerstitial damage. The fact that most of the AKI occurred in cane cutters indicates that strenuous work probably contributes to the injury. Hypothesis-generating studies like this would go a long way to help devise a preventive strategy at the community level.

 

6) Consumerism, Innovation, and the Future of Pediatric Primary Care

Alexander G. Fiks and colleagues wrote an opinion piece in JAMA Pediatrics to highlight the limitations of the healthcare model from the point of view of the families who avail pediatric primary care in its current form in the USA. They cite the example of Blockbuster, an US-based provider of home movie and video game rental services going bankrupt failing to see the changing needs of its consumers, as opposed to Netflix,  who now has more than 100 million subscribers, achieved dominance by betting on emerging technology for streaming video.

Creative destruction, what happened to Blockbuster, is driven by changes in technology and consumer priorities. Healthcare systems could learn a lot from this example.

Almost all the current healthcare systems deliver expensive services through inflexible infrastructure. These systems are often inefficient and have high fixed costs. Nephrology is not an exception. We could do a much better job if we identify how our patients’ needs are changing.

Much of the nephrology research is about fixing numbers- how to lower phosphate, how to keep PTH in the range, how to jack up the Kt/V, and for that matter, years on dialysis. We are in search of a renal troponin for a long time. Home dialysis and palliative care are ignored right from the training years. It’s time we wake up as a community and align our priorities with those of our patients and their families.

 

7) When the color of peritoneal dialysis effluent can be used as a diagnostic tool

What do you do when your PD patient comes to the clinic with an effluent bag that is red, orange, cloudy, milky white, green, yellow, purple or black? A lucid review article in Seminars in Dialysis by Thomas Dossin and Eric Goffin is a must-read. Authors describe various causes of discoloration of PD fluid. They briefly discuss investigations and management issues in such cases. I must admit I did not know nifedipine could cause chyloperitoneum in PD patients!