IPNA clinical practice recommendations for the diagnosis and management of children with steroid-sensitive nephrotic syndrome

Abstract

Idiopathic nephrotic syndrome is the most frequent pediatric glomerular disease, affecting from 1.15 to 16.9 per 100,000 children per year globally. It is characterized by massive proteinuria, hypoalbuminemia, and/or concomitant edema. Approximately 85-90% of patients attain complete remission of proteinuria within 4-6 weeks of treatment with glucocorticoids, and therefore, have steroid-sensitive nephrotic syndrome (SSNS). Among those patients who are steroid sensitive, 70-80% will have at least one relapse during follow-up, and up to 50% of these patients will experience frequent relapses or become dependent on glucocorticoids to maintain remission. The dose and duration of steroid treatment to prolong time between relapses remains a subject of much debate, and patients continue to experience a high prevalence of steroid-related morbidity. Various steroid-sparing immunosuppressive drugs have been used in clinical practice; however, there is marked practice variation in the selection of these drugs and timing of their introduction during the course of the disease. Therefore, international evidence-based clinical practice recommendations (CPRs) are needed to guide clinical practice and reduce practice variation. The International Pediatric Nephrology Association (IPNA) convened a team of experts including pediatric nephrologists, an adult nephrologist, and a patient representative to develop comprehensive CPRs on the diagnosis and management of SSNS in children. After performing a systematic literature review on 12 clinically relevant PICO (Patient or Population covered, Intervention, Comparator, Outcome) questions, recommendations were formulated and formally graded at several virtual consensus meetings. New definitions for treatment outcomes to help guide change of therapy and recommendations for important research questions are given.

Keywords: Children; Frequently relapsing nephrotic syndrome; Immunosuppressive treatment; Pediatrics; SSNS; Steroid toxicity; Steroid-dependent nephrotic syndrome; Steroid-sensitive nephrotic syndrome.

Fig. 1

Matrix for grading of evidence and assigning strength of recommendations as currently used by the American Academy of Pediatrics. Reproduced with permission from [23]

Fig. 2

Algorithm for the initial management of a child with nephrotic syndrome. Patients are managed according to age, clinical presentation, and response to a 4-week treatment with oral prednisolone/prednisone (PDN). ^aIn children with congenital NS, we recommend following the published guideline for CNS [27]. ^bIn children between 3 and 12 months of age at onset (infantile NS), there is no evidence-based clear-cut approach to management. We suggest following one of the following three options in children without extrarenal manifestations: (i) primary genetic testing, if the results are rapidly available, with standard PDN treatment given if genetic testing is negative; (ii) primary kidney biopsy, followed by standard PDN treatment in the case of MCD and FSGS, genetic testing in the case of DMS, and specific treatment in the case of other underlying kidney histopathologies; (iii) starting standard PDN treatment, assessing at 4 weeks and then initiating genetic testing and kidney biopsy in case of SRNS. Patients > 1 year of age at onset are characterized according to response to a 4-week-treatment with oral prednisolone (PDN). We suggest that the decision of performing a kidney biopsy in older children (> 12 years) be made on a case-by-case basis. ^cPatients showing incomplete remission at 4 weeks enter the confirmation period in which responses to further oral prednisolone (PDN) with or without methylprednisolone (MPDN) pulses in conjunction with either angiotensin-converting enzyme inhibitors (ACEi) or angiotensin-receptor blockers (ARBs) are ascertained, and genetic and histopathological evaluation is initiated [19]. ^dIn children with SRNS, we recommend following the published recommendations for SRNS [19]. Further details are given in Table 2 and in the text. NS nephrotic syndrome, AKI acute kidney injury, CNS congenital NS, SSNS steroid-sensitive NS, SRNS steroid-resistant NS, MCD minimal change disease, FSGS focal segmental glomerulosclerosis, DMS diffuse mesangial sclerosis

Fig. 3

Algorithm for management of children with SSNS. Details on the risk and benefit profile of the various steroid-sparing agents are given in Table 5 and Supplementary Table S6. IRNS infrequently relapsing nephrotic syndrome, FRNS frequently relapsing nephrotic syndrome, SDNS steroid-dependent nephrotic syndrome, PDN prednisone/prednisolone, CNI calcineurin inhibitors. ^aAs recommended in the text

Fig. 4

Algorithm for the management of edema and hypovolemia in SSNS. First, the volemic state of the child should be assessed. In case of maintained intravascular volume, we suggest treating moderate edema by low salt diet only, approximately 2 to 3 mEq per day (2000 mg/day in larger children), the amount of sodium required for a growing child, but not fluid restriction. In case of severe edema, fluid restriction is advocated in a hospital setting, with loop diuretics. Fluid restriction is also indicated in case of hyponatremia < 130 meq/L (considering false hyponatremia due to hyperlipidemia). In case of contracted intravascular volume but normal blood pressure, IV albumin infusion (20% or 25% to avoid fluid overload) should be administered over 4–6 h + / − furosemide if volemia is restored. Hypovolemic shock should be treated following specific resuscitation guidelines, starting with volume expansion by 20 mL/kg of 4% or 5% albumin over 20–30 min. ^aAlternatively, isotonic saline can be used if 4% or 5% albumin is not readily available. BP blood pressure