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!

Author: lastmonthinnephrology

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

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