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Table of Contents
Year : 2022  |  Volume : 5  |  Issue : 2  |  Page : 140-144

Journal scan

1 Department of Child Health, Division of Pediatric Nephrology, Christian Medical College, Vellore, Tamil Nadu, India
2 Department of Pediatric Nephrology, All India Institute of Medical Sciences, New Delhi, India

Date of Web Publication31-Jan-2022

Correspondence Address:
Priyanka Khandelwal
Department of Pediatric Nephrology, All India Institute of Medical Sciences
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Source of Support: None, Conflict of Interest: None

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How to cite this article:
Mathew G, Khandelwal P. Journal scan. Asian J Pediatr Nephrol 2022;5:140-4

How to cite this URL:
Mathew G, Khandelwal P. Journal scan. Asian J Pediatr Nephrol [serial online] 2022 [cited 2023 Mar 24];5:140-4. Available from: https://www.ajpn-online.org/text.asp?2022/5/2/140/366544

  Corticosteroids for IgA Nephropathy: Settling the Debate Top

IgA nephropathy (IgAN) is a slowly progressive glomerulonephritis with almost one-third risk of end-stage kidney disease by 20–25 years in adults. The role of immunosuppression for adults at high risk for kidney function decline (typically defined as having proteinuria ≥1 g/d) is controversial. A previous randomized trial, the STOP-IgAN study, found a higher rate of remission of proteinuria in patients treated with steroids compared to placebo but showed no difference in kidney function endpoints at 3 years. The largest multicenter, randomized double-blind clinical trial, the TESTING study, evaluated the safety and efficacy of methylprednisolone (0.6–0.8 mg/kg/day, maximum 48 mg; tapered over 6–9 months) in patients with IgAN with a high risk of progression. Patients enrolled in the TESTING trial had relatively higher proteinuria at randomization (2.5 g/day) compared to the STOP-IgAN trial (1.6 g/d and 1.8 g/d), with baseline estimated glomerular filtration rate (eGFR) of 61.5 mL/min per 1.73 m2. Following interim analysis, enrollment was halted after the randomization of 262 of a planned 750 patients, due to an 11% greater risk of infection-related serious adverse events (AEs) in the methylprednisolone group, including two deaths due to pneumocystis pneumonia and cryptococcal meningitis. However, the primary composite outcome of decline of kidney function, kidney failure, or death was significantly less frequent in the glucocorticoid group (hazard ratio 0.37), suggesting its efficacy. The steering committee resumed the study with a revised protocol of reduced steroid dose and antibiotic prophylaxis for pneumocystis pneumonia.

In the latest issue of The Journal of the American Medical Association, Lv et al. report updated results of the TESTING study, following the enrolment of additional 241 patients (a total of 503 patients). Authors showed similar efficacy of a lower-dose steroid regimen (0.4 mg/kg/d; maximum 32 mg of methylprednisolone) in reducing proteinuria and preserving kidney function over the mean of 4.2 years follow-up compared to a full-dose regimen while reducing AE. Specifically, the trial showed that the composite outcome of 40% reduction in eGFR, kidney failure, and death due to kidney disease was significantly lower in patients treated with methylprednisolone compared to placebo (28.8% vs. 43.1%; hazard ratio, 0.53). The annual decline in eGFR was 2.5 mL/min per 1.73 m2 in patients administered methylprednisolone compared with 4.9 mL/min per 1.73 m2 in the placebo group. While there was a significant reduction in time-averaged proteinuria, the effect peaked at month 6, waned, and was no longer apparent by 3 years. Treatment-emergent AEs were more common in the methylprednisolone group (10.9% vs. 2.8%), although 22 of 28 serious AEs in the intervention limb were attributed to the high-steroid dose regimen.

Pending the updated results of the TESTING trial, the Kidney Disease: Improving Global Outcomes 2021 clinical practice guidelines suggested a cautious trial of corticosteroids in patients with IgAN with a high risk of progression, following discussion of the risk of toxicity with patients (level of evidence 2B). Given the long-term outcome data of the STOP-IgAN cohort after a median follow-up of 7 years did not show the benefit of immunosuppression on adverse kidney outcomes, questions on the lasting protective effect of steroids on the decline of kidney function remain unresolved. Despite concerns over the safety of corticosteroids, the TESTING trial provides important evidence regarding the benefit of immunosuppression and will enable balanced decisions on the use of steroids and its dose.

Lv J, Wong MG, Hladunewich MA, Jha V, Hooi LS, Monaghan H, et al. Effect of oral methylprednisolone on decline in kidney function or kidney failure in patients with IgA nephropathy: The TESTING randomized clinical trial. JAMA 2022;327:1888-98.

  Clinical Practice Guidelines for Obesity and Metabolic Syndrome in Children with Chronic Kidney Disease Top

Children with chronic kidney disease (CKD) are at increased risk for cardiovascular risk factors predisposing to metabolic syndrome (hypertension, obesity, dyslipidemia, and abnormal glucose metabolism). To address the lack of evidence-based guidelines for the assessment and management of obesity and metabolic syndrome, the Pediatric Renal Nutrition Taskforce, an international group of pediatric renal dieticians and nephrologists, developed practice guidelines for adjustments in diet, physical activity, and behavior modification in children and adolescents with CKD stages 2–5, on dialysis and following kidney transplantation. These were published in Pediatric Nephrology. Following a systematic literature search, a Delphi survey was conducted to obtain 87% consensus on 22 clinical practice recommendation statements.

The definition of overweight and obesity is based on weight-for-height >2 standard deviation score (SDS) and >3 SDS, respectively, in patients aged 2–5 years. The respective definitions for patients older than 5 years were body mass index (BMI) for age >1 SDS and >2 SDS, equivalent to BMI >25 and 30 kg/m2 at 19 years. Authors recommended using BMI-height-age to define overweight or obesity in children who are below the 3rd centile for height (Level B; moderate recommendation). Age-based cutoffs of blood pressure, triglycerides, high-density lipoprotein, and blood glucose, to define metabolic syndrome are provided, with a recommendation to carefully monitor these levels in patients with BMI >1 SDS.

A healthy diet, regular exercise, and behavioral modifications are recommended to help prevent and treat obesity and metabolic syndrome. Emphasis on the intake of fruits, vegetables, whole grains, low or nonfat dairy products, peas, beans, lentils, fish, and lean meat, and avoidance of processed foods, foods with high saturated fats, and sugar-sweetened beverages is suggested (Level B; weak recommendation). Individualized exercise intensity and duration according to age, CKD stage, physical tolerance, and comorbidities are suggested (Level B; moderate recommendation). In addition, the authors suggest adequate sleep, reduced screen time, and psychosocial support for the management of stressors. Pharmacological and surgical treatment is recommended only in patients refractory to therapy; antiobesity medication was not recommended. Bariatric surgery is recommended in adolescents with BMI ≥40 kg/m2, or BMI ≥35 kg/m2 with diabetes, severe steatohepatitis, pseudotumor cerebri, and moderate-to-severe obstructive sleep apnea. The authors additionally recommended dietary sodium restriction (adjusted downward of 2 g/day based on energy requirements) for hypertension and suggest lifestyle modifications for the treatment of dyslipidemia. Overall, the emphasis was on a multidisciplinary team-based individualized approach to the management of obesity and metabolic syndrome.

Stabouli S, Polderman N, Nelms CL, Paglialonga F, Oosterveld MJS, Greenbaum LA, et al. Assessment and management of obesity and metabolic syndrome in children with CKD stages 2-5 on dialysis and after kidney transplantation-clinical practice recommendations from the pediatric renal nutrition taskforce. Pediatr Nephrol 2022;37:1-20.

  Plasma Exchange for Antineutrophil Cytoplasmic Antibody Vasculitis: Scope of a Nuanced Approach Top

Plasma exchanges (PEXs) have been the cornerstone of management of severe antineutrophil cytoplasmic antibody (ANCA) associated vasculitis (AAV) based on the landmark MEPEX trial that showed a 50% relative reduction in the need for kidney replacement therapy in patients receiving PEX in addition to immunosuppression. The open-label PEXIVAS trial, recruiting 704 patients in the largest randomized controlled trial ever performed in severe AAV, challenged the beneficial role of PEX for renal survival or mortality. The chief criticism of the trial was the absence of prognostic information on kidney histology on outcomes, and it is possible that PEX is beneficial in carefully selected subgroups with histologically active disease.

To address this question, Nezam et al. identified a subset of patients within a nationwide cohort of 425 French patients with AAV who could benefit from PEX, in a retrospective study published recently in the Journal of the American Society of Nephrology. In this study, PEX did not reduce the risk of death or kidney failure at 1 year in the overall cohort. A subset of patients with a better-than-expected outcome with PEX was identified statistically, using a prognostic model predicting the average treatment effect of PEX conditional on patients' characteristics. The average treatment effect of PEX within this subset showed a remarkably large absolute risk reduction for death or kidney failure of 24.6% at 12 months. Authors proposed a prognostic score incorporating serum creatinine, renal biopsy findings (crescentic and sclerotic classes, higher Brix score), and serology (myeloperoxidase-ANCA); those patients who may benefit appeared to differ largely in that their serum creatinine was almost double that of the group in which PEX was not beneficial. While the study is limited by inherent biases of a retrospective design and further validation of the results is required, it compels for defining a more nuanced approach to therapy of severe AAV and a strategy based on kidney histology to better identify patients who could benefit from PEX.

Nezam D, Porcher R, Grolleau F, Morel P, Titeca-Beauport D, Faguer S, et al. Kidney Histopathology can predict kidney function in ANCA-associated vasculitides with acute kidney injury treated with plasma exchanges. J Am Soc Nephrol 2022;33:628-37.

  Repeated Courses of Rituximab in Children with Difficult-to-Treat Nephrotic Syndrome Top

Nephrotic syndrome (NS) in children is characterized by a remitting and relapsing course in childhood. Nearly half to two-thirds of children with NS have multiple relapses and require therapy with agents other than corticosteroids. Initial therapy for frequent relapses/steroid dependence (FR/SD) comprises levamisole or mycophenolate mofetil. Children failing this therapy are managed with cyclophosphamide (better results in FR compared to SD; those >8–10 years old), calcineurin inhibitors (CNI; efficacy limited by nephrotoxicity), and rituximab (RTX). The order of introduction is still under debate; with RTX ascending the therapeutic ladder due to widespread availability and efficacy. Many centers have initiated therapy with multiple courses of RTX in those failing other agents, and those with significant steroid toxicity. Even prophylactic courses of RTX are being used worldwide to keep children off steroids and to promote maximal growth potential.

In this context, two recent papers (Chan et al., CJASN; Sinha et al., NDT) have explored the safety and efficacy of RTX in children with FR/SD NS. The former, an international multicenter, described 346 children, and the latter single-center study described 250 children. Both retrospective cohorts described children who received at least two doses of sequential RTX therapy and followed them for a minimum of 24 months after the last dose. Of this large cohort of 596 patients, 196 had a history of steroid resistance. Nearly 80% of patients in both cohorts required at least two steroid-sparing agents. Both cohorts reported long relapse-free intervals; 12.5 and 24–36 months in the latter report. The median relapse-free period was observed to be increasing after sequential courses in the multicenter report. This enabled corticosteroid therapy to be discontinued, with improved weight and BMI percentiles at follow-up.

The chief aspect of both papers is the safety profile of repeated/sequential RTX doses. Hypogammaglobulinemia (HG) was an important AE; 51% and 35% prevalence were observed in the respective cohorts. Among the patients with HG, 53% and 24% patients had immunoglobulin G (IgG) levels <200 mg/dL or were associated with infections. Nearly, one-fourth of all children required IgG replacement therapy. Both papers report a high risk of younger patients to HG, especially those <8 years at the initiation of sequential RTX therapy. The single-center study from India observed significant failure of response to tetanus and hepatitis B vaccines in patients who were on RTX therapy. One-sixth of patients tested for the human anti-chimeric antibodies to RTX. Two patients succumbed to pneumococcal sepsis in one cohort.

These two papers describe in detail the efficacy of sequential RTX in children with failure of multiple immunosuppressive therapies, providing for prolonged periods of quiescence and permitting growth and development. Both papers underscore the need for monitoring of AEs (seen in one-third to one-half of children).

Chan EY, Yu EL, Angeletti A, Arslan Z, Basu B, Boyer O, et al. Long-term efficacy and safety of repeated rituximab to maintain remission in idiopathic childhood nephrotic syndrome: An international study. J Am Soc Nephrol 2022;33:1193-207.

Sinha A, Mathew G, Arushi A, Govindarajan S, Ghanapriya K, Grewal N, et al. Sequential rituximab therapy sustains remission of the nephrotic syndrome but carries a high risk of adverse effects. Nephrol Dial Transplant 2022;gfac228. DOI: 10.1093/ndt/gfac228.

  Dapagliflozin in Proteinuric Kidney Diseases: The New Kid on the Block Top

Dapagliflozin, a sodium–glucose cotransporter inhibitor, blocks the reabsorption of glucose in the kidney and is an effective drug in diabetes mellitus, approved in 2014. Cardioprotective effects of dapagliflozin were observed in large randomized trials over the years along with significant antiproteinuric effects. Along with angiotensin-converting enzymes (ACEi) and angiotensin receptor blockers (ARB), dapagliflozin became an important weapon for managing proteinuria in CKD. Common AEs are osmotic diuresis and consequent dehydration/hypovolemia, and urinary tract infections (bacterial and Candida).

A large randomized trial (n = 4094, 386 sites in 21 countries) showed a significant reduction in the composite outcome of sustained decline of eGFR of ≤50%, end-stage kidney disease, or death from renal causes by 44% (95% confidence interval [CI] 32%–55%; P < 0.001), irrespective of their having diabetes mellitus. The trial was terminated in view of efficacy.

A recent pilot study was performed in children with inherited proteinuric kidney disease with normal glycemic status (2). Nine patients, with Alport syndrome, Dent disease, and genetic/nongenetic focal segmental glomerulosclerosis were enrolled and followed up for 12 weeks with therapy. Reduction in 24-hr proteinuria was 33% at 4 weeks and 23% from baseline at 12 weeks. No significant change in serum albumin or eGFR was observed. One patient experienced asymptomatic bacteriuria; no patient stopped dapagliflozin due to any AE. Long-term studies on safety and efficacy in children with proteinuric kidney diseases, glomerular, or nonglomerular in origin, are required. If both efficacy and safety are proven in children, it will be a shot in the arm for improving the benefits of ACEi/ARB therapy and prolonging the time to end-stage kidney disease.

Heerspink HJ, Stefánsson BV, Correa-Rotter R, Chertow GM, Greene T, Hou FF, et al. Dapagliflozin in patients with chronic kidney disease. N Engl J Med 2020;383:1436-46.

Liu J, Cui J, Fang X, Chen J, Yan W, Shen Q, et al. Efficacy and safety of dapagliflozin in children with inherited proteinuric kidney disease: A pilot study. Kidney Int Rep 2022;7:638-41.

  Prednisolone in Nephrotic Syndrome 2: Negating the Role of Prednisolone During Upper Respiratory Infections to Preventrelapses of Nephrotic Syndrome Top

Relapses in NS are associated with infections, often coinciding temporally with upper respiratory tract infections (URTIs). Relapses of NS are associated with significant morbidity risks including sepsis, hypovolemia, and thrombosis. Randomized controlled trials done in the past showed that low-dose prednisolone given for 5–7 consecutive days during the URTI reduced the incidence of infection-associated relapses. However, certain limitations were observed, including comparatively small patient numbers, biases in design, and paucity of AE reporting that dictated the need for a robust study to clarify this question.

Prednisolone in Nephrotic Syndrome (PREDNOS) 2 was a phase 3, parallel-group, double-blinded, randomized controlled trial to test the efficacy of low-dose prednisolone in reducing the risk of relapse associated with URTI. It was performed in 122 pediatric centers across the United Kingdom, from 2013 to 2020. Children enrolled were administered prednisolone at 15 mg/m2 (maximum 40 mg) or an equivalent number of placebo tablets after randomization. There was no restriction to the background immunosuppressive therapy. The primary outcome was the incidence of the first URTI-related relapse during 12 months of follow-up. Although the study was initially designed to detect an absolute difference of 17.5% between the groups (assuming 50% relapse incidence with URTI), it was seen that a large number of patients were completing 12 months without experiencing a URTI; hence, the sample size was increased to 250 patients (360 with an attrition rate of 30%).

The modified intention-to-treat analysis comprised 271 children (mean age 7.6 years), who were compliant (98.6% study visit data available and ~90% adherence) to the interventions administered. Relapse frequency was not different between groups (42.7% in the prednisolone arm vs. 44.3% in the placebo arm with an adjusted risk difference of −0.02; 95% CI −0.14–0.10; P = 0.70) and in the subgroups of background therapy and baseline scores. Post hoc analysis, based on observations of increased relapses in the South Asian ethnicity, found that daily prednisolone was more effective in this population, although the result was not significant (P = 0.09). No significant differences were observed in cumulative prednisolone dosages, corticosteroid AEs, serious AEs, quality of life, and behavior scores. Per protocol analysis also observed an adjusted risk difference of −0.05 (95% CI −0.17–0.08), lending strength to the main finding.

Through a well-conducted study (with size greater than that of all four previous studies combined), PREDNOS 2 demonstrated that administering low-dose prednisolone at the time of URTI does not reduce the risk of relapse of NS. AE reporting was rigorous. However, interesting facets emerge from the study; the incidence of relapses of NS in children of varied ethnicities can be different and they can respond to prednisolone in a different manner. For the readers of this journal in Asia, larger and well-conducted randomized trials in this population can lead us closer to the truth. The findings from this study are echoed in the latest guidelines from the International Pediatric Nephrology Association.

Christian MT, Webb NJ, Mehta S, Woolley RL, Afentou N, Frew E, et al. Evaluation of daily low-dose prednisolone during upper respiratory tract infection to prevent relapse in children with relapsing steroid-sensitive nephrotic syndrome: The PREDNOS 2 randomized clinical trial. JAMA Pediatr 2022;176:236-43.

Trautmann A, Boyer O, Hodson E, Bagga A, Gipson DS, Samuel S, et al. IPNA clinical practice recommendations for the diagnosis and management of children with steroid-sensitive nephrotic syndrome. Pediatr Nephrol 2022;21:1-43. doi: 10.1007/s00467-022-05739-3.

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