Idiopathic nephrotic syndrome newly affects 1–3 per 100,000 children per year. Approximately 85% of cases show complete remission of proteinuria following glucocorticoid treatment. Patients who do ...not achieve complete remission within 4–6 weeks of glucocorticoid treatment have steroid-resistant nephrotic syndrome (SRNS). In 10–30% of steroid-resistant patients, mutations in podocyte-associated genes can be detected, whereas an undefined circulating factor of immune origin is assumed in the remaining ones. Diagnosis and management of SRNS is a great challenge due to its heterogeneous etiology, frequent lack of remission by further immunosuppressive treatment, and severe complications including the development of end-stage kidney disease and recurrence after renal transplantation. A team of experts including pediatric nephrologists and renal geneticists from the International Pediatric Nephrology Association (IPNA), a renal pathologist, and an adult nephrologist have now developed comprehensive clinical practice recommendations on the diagnosis and management of SRNS in children. The team performed a systematic literature review on 9 clinically relevant PICO (
P
atient or
P
opulation covered,
I
ntervention,
C
omparator,
O
utcome) questions, formulated recommendations and formally graded them at a consensus meeting, with input from patient representatives and a dietician acting as external advisors and a voting panel of pediatric nephrologists. Research recommendations are also given.
Rituximab offers an alternative to current immunosuppressive therapies for difficult-to-treat nephrotic syndrome. The best outcomes are seen in patients with steroid-dependent nephrotic syndrome who ...have failed to respond to multiple therapies. By contrast, the benefits of rituximab therapy are limited in patients with steroid-resistant nephrotic syndrome, particularly those with focal segmental glomerulosclerosis (FSGS). Therapy with plasma exchange and one or two doses of rituximab has shown success in patients with recurrent FSGS. Young patients and those with normal serum albumin at recurrence of nephrotic syndrome are most likely to respond to rituximab therapy. A substantial proportion of rituximab-treated patients with idiopathic membranous nephropathy show complete or partial remission of proteinuria, and reduced levels of phospholipase A(2) receptor autoantibodies, which are implicated in the pathogenesis of this disorder. Successful rituximab therapy induces prolonged remission and enables discontinuation of other medications without substantially increasing the risk of infections and other serious adverse events. However, the available evidence of efficacy of rituximab therapy is derived chiefly from small case series and requires confirmation in prospective, randomized, controlled studies that define the indications for use and predictors of response to this therapy.
Background
Data on therapy and outcome of dense deposit disease (DDD), C3 glomerulonephritis (C3GN), and immune-complex MPGN (IC-MPGN) in children are limited.
Methods
In this retrospective ...single-center study from 2007 to 2019, kidney biopsies were reviewed to include patients aged <18-years with C3 glomerulopathy and IC-MPGN. Initial immunosuppression comprised prednisolone, mycophenolate mofetil (
n
= 51), tacrolimus (
n
= 11), and/or IV cyclophosphamide (
n
= 20). Clinicopathological features, response to therapy, and adverse outcome (eGFR
cr
< 15 mL/min/1.73 m
2
or death) were evaluated.
Results
A total of 92 patients were classified as DDD (
n
= 48, 52.2%), C3GN (
n
= 26, 28.3%), and IC-MPGN (
n
= 18, 19.6%) by immunohistochemistry and electron microscopy; 8 patients with DDD were misclassified as IC-MPGN on immunofluorescence. At last follow-up (median 4.3 years), complete or partial remission occurred in 28.5, 36.1, and 16.7% patients with DDD, C3GN, and IC-MPGN, respectively. Serum albumin at onset < 2.5 g/dL (HR = 0.29,
P
= 0.005) and persistently low serum C3 (HR = 0.34,
P
= 0.02) were associated with lack of remission. The 5-year kidney survival was 62.6, 85.5, and 88.5% in patients with DDD, C3GN, and IC-MPGN, respectively (log-rank,
P
= 0.006). Presentation as rapidly progressive GN (HR = 11.2,
P
< 0.001), age > 10 years at onset (HR = 4.0,
P
= 0.004), and DDD (HR = 4.2,
P
= 0.02) were independently associated with adverse outcome; achieving remission was protective (HR = 0.04;
P
< 0.001).
Conclusion
Outcome in patients with C3 glomerulopathy and IC-MPGN was unsatisfactory, and only a small proportion of patients achieved complete or partial remission. Patients with DDD were more likely to present with rapidly progressive GN and were at higher risk of adverse outcomes, including kidney failure.
Rituximab is an effective treatment for steroid-dependent/ frequently-relapsing nephrotic syndrome (SDFRNS) in children. However, the optimal rituximab regimen remains unknown. To help determine this ...we conducted an international, multicenter retrospective study at 11 tertiary pediatric nephrology centers in Asia, Europe and North America of children 1-18 years of age with complicated SDFRNS receiving rituximab between 2005-2016 for 18 or more months follow-up. The effect of rituximab prescribed at three dosing levels: low (375mg/m2), medium (750mg/m2) and high (1125-1500mg/m2), with or without maintenance immunosuppression (defined as concurrent use of corticosteroids, mycophenolate motile or calcineurin inhibition at first relapse or for at least six months following the rituximab treatment) was examined. Among the 511 children (median age 11.5 year, 67% boys), 191, 208 and 112 received low, medium and high dose rituximab, respectively. Within this total cohort of 511 children, 283 (55%) received maintenance immunosuppression. Renal biopsies were performed in 317 children indicating the predominant histology was minimal change disease (74%). Without maintenance immunosuppression, low-dose rituximab had a shorter relapse-free period and a higher relapse risk (8.5 months) than medium (12.7 months; adjusted hazard ratio, 0.62) and high dose (14.3 months; adjusted hazard ratio, 0.50; all significant). With maintenance immunosuppression, the relapse-free survival in low-dose rituximab (14 months) was similar to medium (10.9 months; adjusted hazard ratio, 1.23) and high dose (12.0 months; adjusted hazard ratio, 0.92; all non-significant). Most adverse events were mild. Thus, children receiving low-dose rituximab without maintenance immunosuppression had the shortest relapse-free survival. Hence, both rituximab dose and maintenance immunosuppression have important effects on the treatment outcomes.
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Background
Information on the course of SARS-CoV-2 infection in children with chronic kidney disease (CKD) is limited.
Methods
We retrospectively reviewed the presentation and outcomes of SARS-CoV-2 ...infection in patients with CKD followed at any of the four pediatric nephrology centers in New Delhi from April 2020 to June 2021. Outcomes, including cardiopulmonary and renal complications, were reported in relation to underlying disease category and illness severity at presentation.
Results
Underlying illness in 88 patients included nephrotic syndrome (50%), other CKD stages 1–4 (18.2%), CKD 5D (17%), and CKD 5T (14.8%). Thirty-two of 61 patients with symptomatic COVID-19 and 9/27 asymptomatic patients were admitted for median 10 (interquartile range 7–15) days. Seventeen (19.3%) patients developed moderate or severe COVID-19. Systemic complications, observed in 30 (34.1%), included acute kidney injury (AKI, 34.2%), COVID-19 pneumonia (15.9%), unrelated pulmonary disease (2.3%), and shock (4.5%). Nineteen (21.6%) had severe complications (AKI stage 2–3, encephalopathy, respiratory failure, shock). Eight (11%) of twelve (16.4%) patients with severe AKI required dialysis. Three (3.4%) patients, two with steroid-resistant nephrotic syndrome in relapse and one with CKD 1–4, died due to respiratory failure. Univariate logistic regression indicated that patients presenting with nephrotic syndrome in relapse or moderate to severe COVID-19 were at risk of AKI (respective odds ratio, 95%CI: 3.62, 1.01–12.99; 4.58, 1.06–19.86) and/or severe complications (respective odds ratio, 95%CI: 5.92, 1.99–17.66; 61.2, 6.99–536.01).
Conclusions
Children with CKD presenting with moderate-to-severe COVID-19 or in nephrotic syndrome relapse are at risk of severe complications, including severe AKI and mortality.
Graphical abstract
A higher resolution version of the Graphical abstract is available as
Supplementary information
Academic stress is the most common mental state that medical students experience during their training period. To assess academic stress, to find out its determinants, to assess other sources of ...stress and to explore the various coping styles against academic stress adopted by students. Methods: It was a cross sectional study done among medical students from first to fourth year. Standard self-administered questionnaires were used to assess academic stress and coping behaviour. Mean age of the 400 participants was 20.3 ± 1.5 years. 166(41.5%) of them were males. The academic stress was found to be of mild, moderate and severe level among 68(17%), 309(77.3%) and 23(5.7%) participants respectively. Overall coping with stress was found to be poor, average and good among 15(3.8%), 380(95%) and 5(1.2%) participants respectively. Passive emotional (
p
= 0.054) and passive problem (
p
= 0.001) coping behaviours were significantly better among males. Active problem coping behaviour (
p
= 0.007) was significantly better among females. Active emotional coping behaviour did not vary significantly between genders (
p
= 0.54). Majority of the students preferred sharing their personal problems with parents 211(52.7%) followed by friends 202(50.5%). Binary logistic regression analysis found worrying about future (
p
= 0.023) and poor self-esteem (
p
= 0.026) to be independently associated with academic stress. Academic stress although a common finding among students, the coping style to deal with it, was good only in a few. The coping behaviours were not satisfactory particularly among male participants. This along with other determinants of academic stress identified in this study need to be addressed during counselling sessions.
Transplantation rates are very low for the broadly sensitized patient (panel reactive antibody PRA>80%; HS). Here, we examine the efficacy, outcomes, and cost-effectiveness of desensitization using ...high-dose intravenous immunoglobulin (IVIG) and rituximab to improve transplantation rates in HS patients.
From July 2006 to December 2011, 207 HS (56 living donors/151 deceased donors) patients (donor-specific antibody positive, PRA>80%) were desensitized using IVIG and rituximab. After desensitization, responsive patients proceeded to transplantation with an acceptable crossmatch. Cost and outcomes of desensitization were compared with dialysis.
Of the 207 treated patients, 146 (71%) were transplanted. At 48 months, patient and graft survival by Kaplan-Meier were 95% and 87.5%, respectively. The total 3-year cost for patients treated in the desensitization arm was $219,914 per patient compared with $238,667 per patient treated in the dialysis arm. Thus, each patient treated with desensitization is estimated to save the U.S. healthcare system $18,753 in 2011 USD. Overall, estimated patient survival at the end of 3 years was 96.6% for patients in the desensitization arm of the model (based on Cedars-Sinai survival rate) compared with 79.0% for an age, end-stage renal disease etiology, and PRA matched group of patients remaining on dialysis during the study period.
We conclude that desensitization with IVIG+rituximab is clinically and cost-effective, with both financial savings and an estimated 17.6% greater probability of 3-year survival associated with desensitization versus dialysis alone. However, the benefits of desensitization and transplantation are limited by organ availability and allocation policies.
Newborn bloodspot screening (NBS) for cystic fibrosis (CF) is an effective strategy for the early recognition of infants with a CF diagnosis. Some infants with a positive NBS result for CF have an ...inconclusive diagnosis and evidence suggests the number of these infants is increasing, as more extensive gene analysis is integrated into screening protocols. There is an internationally agreed, but complex, designation for infants with an unclear diagnosis after a positive screening result: cystic fibrosis transmembrane conductance regulator (CFTR)-related metabolic syndrome/cystic fibrosis screen positive, inconclusive diagnosis (CRMS/CFSPID). Infants with a CRMS/CFSPID designation have no clinical evidence of disease and do not meet the criteria for a CF diagnosis, but the NBS result indicates some risk of developing CF or a CFTR-related disorder. In this review, we describe the accurate designation of these and reflect on emerging management pathways, with particular attention given to clear and consistent communication.
To clarify the definition of the global harmonised designation: cystic fibrosis transmembrane conductance regulator-related metabolic syndrome (CRMS)/cystic fibrosis screen positive, inconclusive diagnosis (CFSPID).To understand what impact a CRMS/CFSPID result has for the patient and their family.
The treatment of idiopathic nephrotic syndrome is often complicated by a refractory and relapsing course, with risk of drug toxicity and progressive renal failure. We report the efficacy and safety ...of rituximab in patients with steroid-resistant (SRNS) and steroid-dependent nephrotic syndrome (SDNS) refractory to standard therapy.
This was a cohort study in academic, tertiary care centers in India and the United States. Patients with SRNS or SDNS, not responding to medications or showing calcineurin inhibitor toxicity, treated with two to four doses of intravenous rituximab, and followed ≥12 months were included. Remission was termed as complete, partial, or no response.
Thirty-three patients with SRNS (24 initial, 9 late resistance) and 24 with SDNS, with mean ages of 12.7 ± 9.1 and 11.7 ± 2.9 years, respectively, were included. Six months after rituximab therapy, 9 (27.2%) patients with SRNS showed complete remission, 7 (21.2%) had partial remission, and 17 (51.5%) had no response. At 21.5 ± 11.5 months, remission was sustained in 15 (complete: 7, partial: 8) patients. Of 24 patients with SDNS, remission was sustained in 20 (83.3%) at 12 months and in 17 (71%) at follow-up of 16.8 ± 5.9 months. The mean difference in relapses before and 12 months after treatment with rituximab was 3.9 episodes/patient per year.
Therapy with rituximab was safe and effective in inducing and maintaining remission in a significant proportion of patients with difficult SRNS and SDNS.
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