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Table of Contents
Year : 2021  |  Volume : 4  |  Issue : 1  |  Page : 42-44

Journal scan

Department of Pediatrics, Division of Nephrology, All India Institute of Medical Sciences, New Delhi, India

Date of Web Publication30-Jun-2021

Correspondence Address:
Priyanka Khandelwal
Department of Pediatrics, Division of Nephrology, All India Institute of Medical Sciences, New Delhi
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ajpn.ajpn_26_21

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How to cite this article:
Khandelwal P. Journal scan. Asian J Pediatr Nephrol 2021;4:42-4

How to cite this URL:
Khandelwal P. Journal scan. Asian J Pediatr Nephrol [serial online] 2021 [cited 2022 Dec 2];4:42-4. Available from: https://www.ajpn-online.org/text.asp?2021/4/1/42/320182

  Abbreviated therapy for relapses in nephrotic syndrome Top

Nearly 80% of children with nephrotic syndrome will have at least one relapse, frequently associated with minor infections, and more than half of children will develop a frequent relapsing and/or steroid-dependent course, necessitating frequent exposure to corticosteroids and their resultant side effects. The Indian Society of Pediatric Nephrology guidelines recommend 6-weeks' therapy of relapse, based on results of small randomized controlled trials and retrospective studies (Grade 1C). However, well-powered studies evaluating the dose and duration of steroids for relapses are required.

Two single-center, open-label, noninferiority, randomized controlled trials published recently in the Clinical Journal of the American Society of Nephrology and Pediatric Nephrology have addressed the issue of duration and dose of steroids in patients with relapse of steroid-sensitive nephrotic syndrome. In the former study, Kainth et al. compared the efficacy of a shortened corticosteroid regimen (40 mg/m2 on alternate days, for 2 weeks) to the standard corticosteroid regimen (40 mg/m2 on alternate days, for 4 weeks) in 117 children 1–16 years of age who had attained remission following conventional daily therapy with 60 mg/m2; the primary outcome was proportion of children developing frequent relapse/steroid dependence at 12 months of follow-up. In the other study, Sheikh et al. examined the efficacy of a lower dose of prednisolone (1 mg/kg/day) compared to the standard dose (2 mg/kg/day) for inducing remission followed by the standard regimen of 1.5 mg/kg on alternate days for 4 weeks in both groups, in 60 patients aged 1–12 years; the primary outcome was time to remission. While the former study focused on the optimal duration of oral prednisolone in children with infrequently relapsing nephrotic syndrome, the latter also included patients having frequent relapses/steroid dependence. The proportion of patients developing a frequent relapsing and/or steroid-dependent nephrotic syndrome course was similar in the standard and intervention arms (24% vs. 23%) in the former study; however the noninferiority of the short-course therapy could not be established, likely due to the modest sample size. The secondary outcomes of time to frequent relapses or steroid dependence, time to relapse, relapse rate, and steroid-related adverse events (AEs) were similar in both groups. In the other study, time to remission was similar in the low-dose and standard-dose groups (9.0 vs. 8.6 days). Over mean follow-up of about 10 months, there was a trend to being newly diagnosed as frequently relapsing/steroid dependent in the low-dose group (37% vs. 17%), with the time to first relapse being shorter (86 vs. 150 days; P = 0.39). The cumulative steroid exposure was significantly lower in the short -duration/low-dose regimen in both the trials.

These two trials published recently indicate that there is a potential to reduce steroid exposure in relapsing nephrotic syndrome. Results of the ongoing, double-blind, randomized, placebo-controlled, noninferiority RESTERN trial examining 2-weeks compared to 6-weeks therapy with prednisone for relapses of steroid-sensitive nephrotic syndrome are awaited. A paradigm shift in the conventional treatment of relapse in nephrotic syndrome appears imminent. However, well-powered, multicenter trials including younger children and with a longer duration of follow-up are required to address the question of abbreviated therapy for relapse of nephrotic syndrome.

Kainth D, Hari P, Sinha A, Pandey S, Bagga A. Short-duration prednisolone in children with nephrotic syndrome relapse: A noninferiority randomized controlled trial. Clin J Am Soc Nephrol 2021;16:225-32.

Sheikh S, Mishra K, Kumar M. Low-dose versus conventional-dose prednisolone for nephrotic syndrome relapses: A randomized controlled non-inferiority trial. Pediatr Nephrol 2021 Apr 16. doi: 10.1007/s00467-021-05048-1. Online ahead of print.

  Small interfering ribonucleic acid-based therapeutics for primary hyperoxaluria Top

Primary hyperoxaluria (PH) are autosomal recessive disorders characterized by accumulation of glyoxylate, which is metabolized to excessive oxalate in the liver. Three genetic types (-1, -2, and -3) are identified that result from defects in enzymes in glyoxylate metabolism. Normally, glyoxylate is converted to glycine (by alanine: glyoxylate aminotransferase, defective in PH-1), glycolate (by glyoxylate reductase/hydroxypyruvate reductase, defective in PH-2), or oxalate (by lactate dehydrogenase, LDH) in the liver. Defective metabolism of glyoxylate results in systemic oxalosis, nephrocalcinosis, and end-stage kidney failure. Therapy is unsatisfactory, and liver–kidney transplantation remains the only option for patients progressing to kidney failure. This unmet need of therapeutics has led to interest in gene therapy using ribonucleic acid (RNA) interference to target silencing of genes involved in glyoxylate metabolism to reduce hepatic oxalate production. Small interfering RNA (siRNA), comprising a duplex of two 21-nucleotide RNA molecules, harnesses and guides the natural RNA-induced silencing complex (RISC) to the corresponding messenger RNA of the targeted gene that is cleaved by the slicer activity of RISC. Lumasiran and nedosiran are siRNA agents targeting the glyoxylate metabolism. Lumasiran inhibits messenger RNA of the HAO1 gene encoding the glycolate oxidase enzyme, that acts upstream to AGT to convert glycolate to glyoxylate; lumasiran thereby prevents the formation of glyoxylate. Nedosiran targets LDHA encoding LDH, that catalyzes the final common pathway of conversion of glyoxylate to oxalate. Conjugation to N-acetylgalactosamine, a carbohydrate with high affinity for receptors highly expressed in the liver, achieves preferential delivery of these molecules to the hepatocytes, the site of glyoxylate metabolism.

In November 2020, subcutaneous lumasiran was approved for treatment of PH-1 in all age groups in Europe and North America. The results of the double-blind, multinational, ILLUMINATE-A phase 3 trial, published in the February 2021 issue of the New England Journal of Medicine, show that treatment with subcutaneous lumasiran (3 mg/kg monthly for 3 months, then once every 3 months) resulted in clinically significant decline in 24-hr urinary oxalate excretion at 6-month follow-up compared to placebo (53.5% greater decline) in 39 adults and children aged ≥6 years with PH-1 with estimated glomerular filtration rate (eGFR) of >30 mL/min/1.73 m2 (primary outcome). The treatment effect was irrespective of age, baseline urinary oxalate excretion, pyridoxine use, or kidney function. Improvements were also observed in a number of secondary endpoints, including the proportion of patients achieving normal or near-normal levels of urinary oxalate, with 84% of lumasiran-treated patients meeting this endpoint compared with no patients on placebo. Patients treated with lumasiran also experienced favorable effects on exploratory endpoints related to nephrocalcinosis and the rate of renal stone events compared with placebo. Lumasiran administration was associated with an encouraging safety and tolerability profile, with no serious or severe AEs. The most common AEs that occurred more frequently with lumasiran than placebo were injection site reactions (38% vs. 0%). All these reactions were mild and transient and did not result in discontinuation of treatment. Results of the long-term effects of lumasiran in the open-label extension of this trial over 60 months, and its efficacy in children aged <6 years (ILLUMINATE-B trial) and in patients with eGFR of ≤45 mL/min/1.73 m2 (ILLUMINATE-C trial) are awaited.

Inhibition of the subunit A of LDH enzyme (LDHA) by nedosiran has a potential to treat all types of PH, unlike lumasiran that is effective in PH1 alone. Data from animal models showed the efficacy of this drug to reduce urinary oxalate excretion and lack of off-target effects in muscles, since LDHA is chiefly expressed in the liver and muscles. In the February issue of Kidney International Reports, Ariceta et al. describe the safety and tolerability of subcutaneous nedosiran in human volunteers from the placebo-controlled, participant-blind, single-ascending dose phase I PHYOX1 study. Participants, 18–55 years, were randomized into 5 sequential dose cohorts (0.3, 1.5, 3.0, 6.0, and 12.0 mg/kg nedosiran or placebo) with 5 participants (3 active and 2 placebo) in each cohort. Clinical, laboratory and musculoskeletal AE data in the study were compared to a cohort of 14 patients with congenital LDHA deficiency, based on a comprehensive review of cases published in the literature. In this phase 1 study, healthy volunteers treated with nedosiran experienced no clinical or biochemical drug-related musculoskeletal AEs, providing evidence of the safety of siRNA inhibition of LDHA in PH. Results of the ongoing pivotal (PHYOX2) and open-label extension (PHYOX3) multidose trials to evaluate the safety and efficacy of nedosiran are awaited.

These trials represent important milestones in effective drug development for PH; lumasiran is the third siRNA drug approved for clinical use. Long-term follow-up data of these agents, especially in infants and young childhood, and in those with renal dysfunction, is eagerly awaited.

Garrelfs SF, Frishberg Y, Hulton SA, Koren MJ, O'Riordan WD, Cochat P, et als. Lumasiran, an RNAi therapeutic for primary hyperoxaluria type 1. N Engl J Med 2021;384:1216-26.

Ariceta G, Barrios K, Brown BD, Hoppe B, Rosskamp R, Langman CB. Hepatic lactate dehydrogenase a: An RNA interference target for the treatment of all known types of primary hyperoxaluria. Kidney Int Rep 2021;6:1088-98.

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