Asian Journal of Pediatric Nephrology

: 2019  |  Volume : 2  |  Issue : 2  |  Page : 106--109

Journal scan

Priyanka Khandelwal 
 Division of Pediatric Nephrology, Department of Pediatrics, ICMR Center for Advanced Research in Nephrology, All India Institute of Medical Sciences, New Delhi, India

Correspondence Address:
Priyanka Khandelwal


How to cite this article:
Khandelwal P. Journal scan.Asian J Pediatr Nephrol 2019;2:106-109

How to cite this URL:
Khandelwal P. Journal scan. Asian J Pediatr Nephrol [serial online] 2019 [cited 2020 Aug 4 ];2:106-109
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 Guidelines for Multidisciplinary Management of X-Linked Hypophosphatemic Rickets

Evidence-based, systematically developed recommendations for the diagnosis and management of X-linked hypophosphatemic rickets have been published in a recent issue of Nature Reviews Nephrology. These consensus guidelines, developed using the Delphi method between June 2017 and December 2018, have been endorsed by the European Societies of Pediatric Nephrology and Pediatric Endocrinology. A core group of specialists from pediatric nephrology, pediatric endocrinology, pediatric orthopedic surgery, rheumatology, dentistry, neurosurgery, and a 41-member voting panel provided the level of agreement to reach at least 70% consensus. The guideline recommends the diagnosis of X-linked hypophosphatemic rickets based on clinical, biochemical, and radiological parameters. While high fibroblast growth factor 23 levels support the diagnosis, sequencing of the phosphate-regulating endopeptidase homolog, X-linked (PHEX) gene is recommended in patients lacking family history to enable definitive diagnosis in 70%–90% of patients. The authors advise holistic evaluation of the musculoskeletal system, growth, hearing and spine, and for manifestations related to craniosynostosis, Chiari 1 malformation and/or intracranial hypertension and maxillary dysmorphosis. In addition, adult patients require attention to enthesopathies and osteoarthritis. Therapy with oral phosphorus (20–60 mg/kg/day) and active Vitamin D (20–30 ng/kg/day) is recommended as the first-line approach while monitoring for hypercalcemia, hyperparathyroidism, and nephrocalcinosis. Given the considerable expense of burosumab and the lack of long-term safety data, the authors recommend considering its use, only beyond infancy, in patients with overt radiographic abnormalities or refractory disease, and in those with complications or noncompliance to conventional therapy. Although majority of patients have markedly decreased adult height, evidence to support routine use of recombinant growth hormone is limited. Guided growth techniques are favored over osteotomies in early childhood, as the latter have fewer complications when performed after skeletal maturity. Biannual dental assessment is emphasized, and recommendations for neurosurgical and hearing assessment are outlined. This consensus document provides an in-depth evidence-based guidance for comprehensive multidisciplinary care for both children and adults with X-linked hypophosphatemic rickets.

Haffner D, Emma F, Eastwood DM, Duplan MB, Bacchetta J, Schnabel D, et al. Clinical practice recommendations for the diagnosis and management of X-linked hypophosphataemia. Nat Rev Nephrol 2019;15:435-55.

 Timing Of Initiation Of Dialysis In Children: Is Sooner The Better?

The timing of initiation of chronic dialysis is controversial. Information from a single randomized trial and a few observational studies show conflicting results in adult patients; evidence in children is further limited. The Initiating Dialysis Early and Late trial, published in 2010, had randomized adult patients to initiate dialysis at estimated glomerular filtration rate (eGFR) of 10–14 vs. 5–7 ml/min/1.73 m2. While the trial failed to show a survival benefit of “early” initiation of dialysis, it was ultimately underpowered with a narrow between-group difference in eGFR of 2.2 ml/min/1.73 m2. In the August 2019 issue of the Journal of the American Society of Nephrology, Winnicki et al. examined the US Renal Data System registry records for an association between the timing of dialysis initiation with overall survival in 15,170 children (1–18 years old) starting dialysis between 1995 and 2015. The dialysis was initiated early, at a median eGFR of 12.8 ml/min/1.73 m2, in 29% patients, compared to 6.5 ml/min/1.73 m2 in others. Compared to patients initiated on the dialysis at lower eGFR, those with a higher eGFR at dialysis initiation were younger and more often had an underlying glomerulonephritis. There was a chronological trend toward early initiation of dialysis; the proportion of patients initiated on the dialysis at eGFR above 10 ml/min/1.73 m2 steadily increased from 16.6% in 1995 to 40.7% in 2015. Over a median follow-up of 6.1 years and 9.6 years, respectively, for the early and late-start groups, early dialysis initiation showed 1.3-times increased risk of mortality in the unadjusted model. On adjusting for covariates known to be unequally distributed between groups, the mortality risk remained 36% higher (95% confidence interval [CI]: 1.24–1.50) for those with higher versus lower eGFR at the dialysis initiation. Further, compared with patients who began dialysis at eGFR below 5 ml/min/1.73 m2, there was a stepwise increment in hazards of death with every 5 ml/min/1.73 m2 increase in eGFR at the start of dialysis. Sensitivity analyses, examining a relatively recent cohort and censoring at transplantation, yielded results consistent with the primary analysis. Notably, dialysis modality influenced the association between early initiation of dialysis and outcome such that the risk of mortality was more pronounced for patients initially managed with hemodialysis (hazard ratio [HR]: 1.56; 95% CI: 1.39–1.75); the association was attenuated in patients on peritoneal dialysis (HR, 1.07; 95% CI: 0.91–1.25). The authors suggest better preservation of residual renal function with peritoneal dialysis compared to hemodialysis to explain the interaction. While limited by the retrospective nature of the analysis, this large study has important ramifications for clinical practice. Later initiation of dialysis in asymptomatic patients is expected to potentially allow for reduced dialysis vintage and increased rates of preemptive transplantation, which, in turn, might improve long-term outcomes.

Winnicki E, Johansen KL, Cabana MD, Warady BA, McCulloch CE, Grimes B, et al. Higher eGFR at dialysis initiation is not associated with a survival benefit in children. J Am Soc Nephrol 2019;30:1505-13.

 a Tale Of Two Trials On Membranous Nephropathy: Is A Paradigm Shift Imminent?

There is lingering equipoise on the management of membranous nephropathy in adults. The GEMRITUX trial had previously demonstrated the superior efficacy of rituximab as compared to supportive care in adult patients with membranous nephropathy followed over 1–2 years. In a recent issue of the New England Journal of Medicine, Fervenza et al. report the findings of Membranous Nephropathy Trial of Rituximab (MENTOR). This trial was a prospective, multicenter, randomized controlled trial examining noninferiority of intravenous rituximab (two doses of 1000 mg, repeated after 6 months in cases with partial response) compared to oral cyclosporine (3.5 mg/kg/day for 12 months, targeting trough levels of 125–175 ng/ml) in adults with membranous nephropathy. Rituximab (n = 64) was non-inferior to cyclosporine (n = 63) in inducing the primary composite outcome of complete or partial remission at 24 months (60% vs. 20%; 95% CI for risk difference, 25–55). The result was statistically significant for non-inferiority in both the intention-to-treat and per-protocol analyses and for superiority in the intention-to-treat population (Pet al. recently reviewed the effect of rituximab dose in a post hoc analysis of participants in the GEMRITUX (n = 27) and NICE (n = 28) cohorts in the latest issue of the Clinical Journal of the American Society of Nephrology. The former were treated with two infusions of rituximab at 375 mg/m2 administered 1-week apart, whereas the latter cohort received two doses of 1 g each at 2-week interval, similar to the MENTOR trial. Compared to the lower dose GEMRITUX protocol, the higher dose NICE protocol was more often associated with remission (64% vs. 30% patients), which also occurred sooner (3 vs. 9 months). Rituximab dosed at 1 g 2-weeks apart was associated with higher rituximab levels, lower CD19 counts, and lower level of anti-PLA2R antibodies. Patients with epitope spreading, i.e., those in whom anti-PLA2R antibodies were directed to additional domains apart from the immune-dominant N-terminal domain, were less likely to achieve remission or required higher or more doses of rituximab to enter remission; in contrast, all patients without epitope spreading entered remission irrespective of the protocol.

Due to the rarity of membranous nephropathy in children, evidence from studies in adults is usually extrapolated to individualize care in childhood-onset disease. While the MENTOR trial is an important study showing the superiority of rituximab in maintaining long-term remission, the study by Seitz-Polski et al. highlights the appropriateness of higher dose of rituximab in patients with elevated titers of anti-PLA2R antibodies. These studies have the potential to alter the current standard of care in membranous nephropathy and open new doors to research on innovative targeted therapy and individualization of care, especially those testing positive for anti-PLA2R antibodies.

Fervenza FC, Appel GB, Barbour SJ, Rovin BH, Lafayette RA, Aslam N, et al. Rituximab or cyclosporine in the treatment of membranous nephropathy. N Engl J Med 2019;381:36-46.

Seitz-Polski B, Dahan K, Debiec H, Rousseau A, Andreani M, Zaghrini C, et al. High-dose rituximab and early remission in PLA2R1-related membranous nephropathy. Clin J Am Soc Nephrol 2019;14:1173-82.

 Prednos I: Settling The Steroid Debate

In the early 1970s, the International Study of Kidney Disease in Children (ISKDC) empirically recommended 8 weeks of prednisone for the initial episode of nephrotic syndrome, which was extended to 12 weeks based on the results of a randomized trial. Over the next five decades, guidelines suggested that further prolongation of therapy was even better, based on meta-analysis that included studies with a high risk of bias. Three recent high-quality multicenter double-blind trials evaluated the role of extending initial therapy with prednisolone from 2 to 3 months to 6 months. These studies found no significant difference in the time to relapse and the proportions of children with relapse and frequent relapses. Most recently, Webb et al. reported the results of Prednisolone in Nephrotic Syndrome (PREDNOS 1) trial in the British Medical Journal. This multicenter, randomized, double–blind, placebo-controlled trial compared two regimens of prednisolone for the initial treatment of steroid sensitive nephrotic syndrome: one recommended earlier by the ISKDC (2240 mg/m2 in 8 weeks; n = 118) versus an extended course (3150 mg/m2 in 16 weeks; n = 119). The study showed that the two regimens were equivalent with respect to the time to first relapse (primary outcome; HR: 0.87, 95% CI: 0.65–1.17, log rank P = 0.28), proportion of patients with frequently relapsing disease, steroid dependence, or requirement of alternative immunosuppression at 4-year follow-up. Therefore, there is now sufficient and consistent evidence to suggest that prolonged therapy does not alter the disease course but leads to a phase shift in the relapse pattern.

The authors of PREDNOS 1 included a detailed economic assessment to conclude that the extended regimen might be cost saving and improves the quality of life while not making any statistically meaningful impact on clinical endpoints compared to standard therapy. Similar to the prior observation by Sinha et al., there was a suggestion that the extended course delayed the time to first relapse in younger patients (HR: 0.72, 95% CI: 0.50–1.05). Therefore, while the bottom line is that an extended prednisone regimen does not improve clinical outcomes, longer courses merit further examination in younger patients.

Webb NJ, Woolley RL, Lambe T, Frew E, Brettell EA, Barsoum EN, et al. Long term tapering versus standard prednisolone treatment for first episode of childhood nephrotic syndrome: Phase III randomised controlled trial and economic evaluation. BMJ 2019;365:l1800.

 under The Scanner: Immunological Memory Following Rituximab

While anti-CD20 therapy enables steroid and calcineurin inhibitor sparing in severe steroid-dependent nephrotic syndrome, its potential long-term toxicity needs careful examination, especially its effect on the B-cell repertoire. In an observational study of 27 patients with frequently relapsing or steroid dependent nephrotic syndrome, Colucci et al. examined the delayed effect of therapy with anti-CD20 monoclonals (rituximab or ofatumumab) after a minimum of 4 years from the first infusion (median follow-up: 74 months). In this study, published in the July issue of Frontiers in Immunology, the levels of circulating B-cell subpopulations, serum immunoglobulin subclasses, and vaccine competence against hepatitis B and tetanus were compared between patients receiving anti-CD20 agents and those administered other intense immunosuppression. Eleven patients were treated with ≥2 infusion of IV rituximab; two of these also received IV ofatamumab. Nine (33%) patients never relapsed after the last anti-CD20 administration. At the last follow-up, while total, transitional, and mature-naïve B-cells showed a complete recovery in almost all patients, the authors observed persistent depletion of total memory and switched memory B-cells. Interestingly, six patients showed the baseline low levels of serum immunoglobulin G (IgG) that correlated inversely with the number of relapses in the previous one year. The finding of concern in this study is that de novo hypogammaglobulinemia occurred in 5 of 13 patients, three of whom had severely depressed IgG levels prompting therapy with intravenous IG (IVIG), and four additional patients developed severe de novo IgA deficiency. Notably, the depressed levels of memory B-cells and hypogammaglobulinemia were independent of number of infusions such that even a single dose of IV rituximab might be associated with either. Younger age at the time of first infusion was independently associated with an increased risk of hypogammaglobulinemia (odds ratio: 2.14, 95% CI: 1.25–3.68 per year). IgG directed against hepatitis B virus and tetanus was depressed at baseline, declined further on follow-up, and remained low despite re-vaccination. This study highlights the importance of prolonged immunological monitoring following anti-CD20 therapy, particularly in younger patients, and cautions against indiscriminate use of these agents.

Colucci M, Carsetti R, Serafinelli J, Rocca S, Massella L, Gargiulo A, et al. Prolonged impairment of immunological memory after anti-CD20 treatment in pediatric idiopathic nephrotic syndrome. Front Immunol 2019;10:1653.

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