|Year : 2021 | Volume
| Issue : 2 | Page : 95-97
Division of Nephrology, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India
|Date of Web Publication||28-Dec-2021|
Division of Nephrology, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Khandelwal P. Journal scan. Asian J Pediatr Nephrol 2021;4:95-7
| Extending the duration of therapy for relapse of nephrotic syndrome is unnecessary: Prospective Randomized study to Optimize Prednisone therapy for relapses of Idiopathic Nephrotic Syndrome in Children|| |
Optimization of therapy for relapsing steroid-sensitive nephrotic syndrome is a compelling issue due to the risk of corticosteroid toxicity with repeated exposure of steroids administered for relapses. There is a paucity of adequately powered randomized controlled trials evaluating the dose and duration of steroids for relapse of nephrotic syndrome. The Indian Society of Pediatric Nephrology guidelines recommend the conventional 6-week therapy of relapse, based on results of small randomized controlled trials and retrospective studies (Grade 1C). Almost four decades ago, studies conducted by the International Study of Kidney Disease in Children demonstrated that an 8-week course of prednisolone for relapse was associated with longer duration of remission after completing therapy. Recently, two single-center, open-label randomized controlled trials have demonstrated the efficacy of reduced dose and a shorter corticosteroid regimen, indicating that there is a potential to reduce steroid exposure in relapsing nephrotic syndrome.
Results of the Prospective Randomized study to Optimize Prednisone therapy for relapses of Idiopathic NEphrotic syndrome in children (PROPINE), a multicentric, open-label, randomized, superiority trial, have recently been published in the Kidney International. In this study, Gargiulo et al. compared the efficacy of a short corticosteroid regimen (40 mg/m2 on alternate days for 36 days) to a longer regimen (same cumulative dose, tapered over 72 days) in 78 children 3–17 years of age who had attained remission of a relapse. The trial focused on children with infrequently relapsing nephrotic syndrome who had not received steroid-sparing medications during the previous 12 months. The primary outcome was the proportion of patients with relapse(s) at 6 months. The investigators found no difference between groups with the primary and secondary outcomes. The proportion of patients with a relapse at 6 months was similar in the short and long arms (42% vs. 58%). However, this study was underpowered to demonstrate superiority of the long-course therapy, enrolling 78 subjects versus 126 patients intended, as defined by initial power estimates. To increase statistical power, the investigators incorporated a secondary crossover study involving 40 of the original 78 subjects. No difference in subsequent relapses was also demonstrated in the secondary analysis. Further, there were no differences in the rates of weight gain and blood pressure.
This trial suggests that a regimen of prolonged tapering of corticosteroids for relapses of steroid-sensitive nephrotic syndrome is unnecessary. Results of the ongoing, double-blind, randomized, placebo-controlled, noninferiority RESTERN trial, examining 2-week compared to 6-week prednisolone for relapses of steroid-sensitive nephrotic syndrome, are awaited. 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 relapses of nephrotic syndrome.
Gargiulo A, Massella L, Ruggiero B, Ravà L, Ciofi Degli Atti M, Materassi M, et al. Results of the PROPINE randomized controlled study suggest tapering of prednisone treatment for relapses of steroid-sensitive nephrotic syndrome is not necessary in children. Kidney Int 2021;99:475-83.
| Long-term outcomes following severe acute kidney injury|| |
Pediatric acute kidney injury (AKI) is often associated with adverse short-term outcomes. Information of long-term outcomes following pediatric AKI, especially dialysis-requiring AKI, is limited. Existing studies of long-term outcomes of pediatric AKI are limited by relatively short follow-up, attrition bias, small proportion of patients with severe AKI, and lack of comparison between patients with AKI with or without dialysis requirement. While meta-analyses of studies of adult AKI substantiate the increased risk of long-term kidney failure and chronic kidney disease (CKD) in survivors of severe AKI, such information cannot be extrapolated to pediatric patients due to higher rates of preexisting CKD, cardiovascular disease, and diabetes among adults. Therefore, long-term outcomes among survivors of pediatric AKI who received dialysis remain uncertain.
In a recent issue of the Journal of American Society of Nephrology, Robinson et al. aimed to determine the long-term risk of kidney failure, death, and adverse kidney events in children who survived an episode of dialysis-treated AKI. Data were obtained retrospectively from health administrative databases in Ontario over a 22-year period. Authors compared 1688 dialysis-treated AKI survivors to 6752 matched hospitalized patients with AKI not requiring dialysis; included, 116 neonates were included representing one of the largest neonatal cohorts with severe AKI. Over a 10-year follow-up, about 10%–13% of the cohort had kidney failure or death, CKD, or hypertension. These risks were significantly higher than matched comparators and were greatest in the first year after discharge. It is worthwhile to note that AKI survivors remained at significantly higher risks of kidney failure, CKD, and hypertension even after 5-year posthospital discharge, indicating requirement of enhanced long-term surveillance of kidney function and blood pressure after episodes of severe childhood AKI. While the cohort was assembled by authors retrospectively and is subjected to a number of associated biases, it remains the single largest cohort of pediatric dialysis-treated AKI survivors. Pediatric-specific AKI guidelines must incorporate postdischarge follow-up care to improve long-term kidney and patient survival.
Robinson CH, Jeyakumar N, Luo B, Wald R, Garg AX, Nash DM, et al. Long-term kidney outcomes following dialysis-treated childhood acute kidney injury: A population-based cohort study. J Am Soc Nephrol 2021;32:2005-19.
| Everolimus, low-dose tacrolimus, and steroid withdrawal in pediatric renal transplantation|| |
Long-term outcomes following renal transplantation remain suboptimal, especially due to detrimental side effects of corticosteroids and calcineurin inhibitors (CNI), including metabolic derangements, poor growth, ocular complications, and graft dysfunction. Alternative immunosuppressive regimens that allow early steroid withdrawal along with reduction of CNI have been tried with varying success in children. These include steroid avoidance or withdrawal and useof themammalian target of rapamycin inhibitors (mTOR) with and without CNI.
In the American Journal of Transplantation, Tönshoff et al. report 36-month outcomes of the CRADLE trial, a Phase III, multicenter, open-label, randomized controlled trial in pediatric renal transplant patients with low immunological risk. Patients were randomized at 4–6 weeks posttransplant to receive everolimus and reduced dose tacrolimus with steroid withdrawal at 6 months (n = 52) or continue standard triple-drug immunosuppression (n = 54). Midterm outcomes at 3 years, including a composite of biopsy-proven rejection, allograft loss, and death, were comparable between groups (~10%). The rates of graft loss were low (2%–4%) with no deaths. However, acute rejection was the chief cause of drug discontinuation in the everolimus/low-dose tacrolimus group. Since CNI was not completely avoided, benefit of reduced dose CNI was not evident on allograft function at 36 months, and consequently, renal function was comparable between both groups (estimated glomerular function rate ~70 mL/min/1.73 m2). Compared to previous data on sirolimus, the rates of posttransplant lymphoproliferative disorder were similar. Recipients on everolimus with low-dose tacrolimus and steroid withdrawal developed less de novo donor-specific antibodies and showed improvement in height and body mass index; prepubertal patients showed sustained improvement in growth and metabolic parameters.
While limited by a modest sample size, the CRADLE trial demonstrates the medium term safety and efficacy of an everolimus, tacrolimus, and steroid withdrawal protocol. This regimen may be especially beneficial for Epstein–Barr virus seronegative recipients, and for prepubertal recipients with metabolic derangements or poor growth.
Tönshoff B, Tedesco-Silva H, Ettenger R, Christian M, Bjerre A, Dello Strologo L, et al. Three-year outcomes from the CRADLE study in de novo pediatric kidney transplant recipients receiving everolimus with reduced tacrolimus and early steroid withdrawal. Am J Transplant 2021;21:123-37.
| A snapshot of the metabolome in pediatric chronic kidney disease|| |
The use of metabolomics to discover biomarkers and potential therapeutic targets for CKD progression is an area with potentially huge translational impact. While scientific literature pertaining to metabolomics in CKD is still in its infancy, such information is available from prospective and cross-sectional adult CKD cohorts. In a recent issue of the Clinical Journal of American Society of Nephrology, Denburg et al. utilized stored samples from 645 patients from the prospective CKD in Children (CKiD) cohort to identify novel biomarkers of progression of CKD in children. Plasma levels of 825 metabolites were measured using ultra-high-performance liquid chromatography-tandem mass spectrometry. Authors examined the association between metabolite concentrations and progression of CKD, defined as requirement of kidney replacement therapy or 50% reduction in estimated glomerular filtration rate (eGFR) that occurred in about one-third of the cohort after approximately 5-year follow-up. Two-fold elevation in levels of seven metabolites were associated with CKD progression in patients with eGFR >60 ml/min/1.73 m2. Among these, two amino acids involved in tryptophan and pyrimidine metabolism have also been reported in studies on adult CKD. A higher level of tetrahydrocortisol sulfate was associated lower risk of progression in patients with baseline eGFR below 60 ml/min/1.73 m2; this was independent of established clinical predictors.
The study was limited by semiquantitative measurements, hindering comparability with other cohorts. While authors highlight the role of select biologic pathways for the progression of CKD in children, further research should include absolute quantification of metabolites to enable reproducibilityof these findings and studies to ascertain their causal association.
Denburg MR, Xu Y, Abraham AG, Coresh J, Chen J, Grams ME, et al. Metabolite biomarkers of CKD progression in children. Clin J Am Soc Nephrol 2021;16:1178-89.
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