Management of Steroid Sensitive Nephrotic Syndrome
- Executive Summary
Nephrotic syndrome in children is usually primary (85–90%) showing glomerular involvement without an identifiable cause as infection, drugs, malignancy, or autoimmune disease. Evaluation might reveal an underlying systemic illness in 5–10% of patients. Most common histopathology is minimal change disease [1]. Most nephrotic children have steroid-sensitive nephrotic syndrome (SSNS) with MCD pathology, while 20% are steroid-resistant (SRNS), depending on the geographic area [2]. SRNS children show mostly focal segmental glomerulosclerosis (FSGS), minimal change disease (MCD), mesangial proliferative glomerulonephritis, and rarely membranoproliferative (MP) or membranous (MN) pathology [3]. SSNS outcome is satisfactory, 50% show frequent relapses or steroid dependence, and 3–10% show late steroid resistance [3]. A kidney biopsy is performed at disease onset only in children with atypical features and in all children with steroid resistance. Repeated kidney biopsy is indicated when prolonged (> 2 to 3 years) exposure to CNIs or in children with secondary steroid resistance. Egyptian children with idiopathic NS justified for biopsy showed MCD in 32.2%, FSGS in 45.2%, mesangio-proliferative in 9.7%, MP in 9.7%, and membranous in 3.2%. Indications for biopsy were SRNS in 79.5%, positive family history in 12.8%, age < 1 year in 2.5% or > 10 y in 10.3%, hypertension in 5.1%, and FR in 2.5% [4]. Genetic testing is not recommended in first presentation of the disease unless positive family history or syndromic or < 1y age. While it is of little value in SSNS, it is crucial in SRNS. IPNA clinical practice recommendations 2020, and KDIGO 2021 guidelines recommended routine evaluation of genetic mutations in children with SRNS if available [5–10]. Comorbidities of Idiopathic SSNS as infection, thrombosis, drug side effects are less marked than that observed in SRNS. The mainstay of treatment for IPNS is corticosteroids. Most children respond well to steroids within 4 weeks (SSNS); those who do not respond will be defined as SRNS patients at six weeks. Kidney outcomes in SSNS remain excellent, with < 5% risk of progression to chronic kidney diseases at 10 years after diagnosis [11]. In contrast, SRNS increased risk of progression to (ESRD) [5]. SSNS prognosis is correlated with morbidity of prolonged exposure to corticosteroids and steroid-sparing agents prescribed in frequently-relapsing or steroid-dependent disease. Idiopathic SSNS disease has a chronic, relapsing–remitting course, which tends to resolve spontaneously following puberty. However, in 15% to 25% of cases, it may progress to adulthood, maintaining the peculiar rapid response to corticosteroids in relapse. Small percentage of children may, become secondarily steroid-resistant with high chance both of progressing to kidney failure and to relapse after transplantation.
➡️Purpose and Scope
These guidelines have been developed to standardize the delivery of services and to implement the guidance on the diagnosis, evaluation, management and follow-up of nephrotic children for Steroid sensitive nephrotic syndrome (SSNS). It provides guidance to primary health care providers, pediatricians and specially trained nurses.
The guidelines aimed to aid in diagnosis, evaluation, management and follow-up of nephrotic SSNS.
This version of the guideline includes recommendations and good practice statements for
· Management and diagnosis, of nephrotic children for Steroid sensitive nephrotic syndrome in children
· Evaluation of nephrotic children for Steroid sensitive nephrotic syndrome in children
· Follow-up of nephrotic children for Steroid sensitive nephrotic syndrome in children
This guideline focuses on diagnosis, evaluation, management and follow-up of nephrotic children for (SSNS)
After reviewing all the inclusion and exclusion criteria and quality appraisal results, the GDG/ GAG recommended using the following source original clinical practice guidelines (CPGs):
1- IPNA clinical practice recommendations for the diagnosis and management of children with steroid-resistant nephrotic syndrome 2020,
2- KDIGO Clinical Practice Guideline on Glomerular Diseases2021
3- Evidence-Based Clinical Practice Guidelines for Nephrotic Syndrome JSPN 2014
We conducted Adolopment for these guidelines : (Adoption, Adaptation, and Development)
- Adoption for most of the guideline recommendations.
- Adaptation for 2 recommendations according to GRADE criteria to be suitable to our Economic implications (Evidence-to-Decision (EtD) table was done)
- Development of Good Practice Statements
This version of the CPG includes recommendations and good practice statements on the following four sub-sections:
A. Evaluation of nephrotic children for Steroid sensitive nephrotic syndrome
B. Diagnosis of nephrotic children for Steroid sensitive nephrotic syndrome
C. Management of nephrotic children for Steroid sensitive nephrotic syndrome
D. Follow-up of nephrotic children for Steroid sensitive nephrotic syndrome
We can summarize the guidelines’ recommendations for Steroid sensitive nephrotic syndrome in the following:
EPG recommends the following three practice points and R2 (1–5) to make a proper diagnosis for NS in children:
· R 2: At Primary health care settings, we recommend for primary diagnosis of NS:
(Good Practice Statement).
· Clinical assessment of oedema, blood pressure, urinary symptoms. Good history taking about: patient age at onset of disease, family history of similar complaints, previous infections, recent drugs, systemic disease) (Good Practice Statement).
· Basic laboratory assessment: Urine analysis for sediments (hematuria, proteinuria), Protein/creatinine ratio, and urine culture, GFR, serum albumin, s. LDL-Cholesterol, complete blood count. Nephrotic range proteinuria with low s albumin with and without oedema make a primary diagnosis of NS (Table 2 IPNA 2020 and KDIGO 2021: refer to the Appendix) (Good Practice Statement).
· R 2: We recommend referral of children with the primary diagnosis of NS to pediatric nephrologist, for proper extended diagnosis &management (
· R 2: (Good Practice Statement). 3) We recommend for pediatric nephrologists to extend their assessment as recommended by IPNA 20 to classify a nephrotic patient as steroid sensitive or steroid resistant, as each type will follow a separate guidance addressed to specific end users.SSNS Guidance is addressed to practitioners, pediatricians, and pediatric nephrologists. Whereas SRNS guidance will be addressed to pediatric nephrologists.
· R 2.1: We recommend for extended Clinical assessment to follow Table 2 (refer to the Appendix) IPNA 2020 and EPG flow-chart (Fig. 1), focusing on; age at onset of disease, consanguinity, positive family history of kidney disease, extra renal manifestations, disease severity, degree of oedema, hypertension.
· R 2.2: We recommend for extended laboratory assessment in atypical cases to follow EPG flowchart and Table 2 IPNA 2020 focusing on:
· C3, C4, Anti ds DNA, ASOT, APLR, ANCA (Strong recomendation).
· Infection screen (blood, urine culture, tuberculin test ©viral serology; HBsAg, HC, CMV, Epstein Bar, HIV, COVID Sars-2 antibodies conditional recomendation
· Imaging: abdominal and renal US, X-ray chest
R 2.3: Genetic tests for selected cases
R 2.3.1: Good Practice Statement: We recommend Early genetic testing not waiting for 4 weeks steroid response If: Familial (Conditional recomendation), Syndromic (Conditional recomendation), < 1 year age of onset (Conditional recomendation), extra renal involvement suggesting hereditary disease ( Conditional recomendation).
R 2.3.2: We recommend genetic testing after 4 weeks of start of oral prednisone, for all steroid resistant if possible (Strong Recomendation) IPNA or our high priority target groups (SR/FSGS or DMS, CNI resistant…. Refer to SRNS CPG to identify our target group).
IPNA 2020 recommends GT for infantile, familial syndromic and all SR, as early as possible in the transitional period (4–6 weeks) after steroid use with no response and before biopsy.
KDIGO 2021 also recommended GT in SRNS when congenital and infantile (< 1 year of age), with syndromic features, familial KDIGO 2021 (Fig. 43 Ps 152).
R 2.4: Renal biopsy for selected cases WHEN to do KIDNEY BIOPSY in the first episode?
Rationale: Since the prognosis for childhood NS is best predicted by patient response to steroid therapy &frequency of relapses in the first year after treatment, Therefore KDIGO 2021 recommend renal biopsy at first episode only for those with atypical presentation or steroid resistance PP: 4.2.1. KDIGO 2021.
R2.4.1: Good Practice Statement We recommend Early biopsy for atypical cases and not to wait for 4 weeks steroid therapy transitional period if:
· There is high index of suspicion for a different underlying pathology as macroscopic haematuria, hypertension, hypocomplementemia, etc.
· Children presenting with NS at age of > 12 years with hypertension and or haematuria.
· Early onset or rapid decline in GFR is not related to hypovolemia.
2.4.2: We recommend late biopsy as IPNA &KDIGO recommend for Good Practice Statement:
· Steroid resistant NS (4 weeks after steroid therapy).
· Late failure to respond after initial response to steroids (secondary SR).
· Decreasing kidney function in children while receiving CNIs or those with prolonged exposure (2–3 years).
R 2.5: WHO should manage nephrotic children? Referral Red Flags?
R 2.5.A (Good Practice Statement): EPG Work group panel recommend early referral of children with nephrotic syndrome to Pediatric Nephrologist at its first episode once diagnosed. Since Practitioners or pediatricians are commonly who make the primary diagnosis of Nephrotic syndrome; therefore, they should be informed about all criteria of referral. Early referral (upon diagnosis at its first episode) is better than late emergency referral of critical cases. Early referral helps in early classification as SSNS or SRNS, proper treatment of each type as well as management of complications cases by pediatric nephrologists.
Red flags justifying referral:
R 2.5.B (Good Practice Statement) Pre-treatment indications:
· Age < 1 year, > 12 years, familial clustering of similar cases, extrarenal features
· Macroscopic hematuria, Hypertension, complement consumption, renal impairment,
· Hypo-complementemia, high antibody titer (ANCA, ADNA, APL),
· Positive viral serology (hepatitis B SA, hepatitis, or HIV antibodies), (+ tuberculin test + Blood culture in congenital or rheumatic cardiac patients or hydrocephalous with shunts).
R 2.5.C: (Good Practice Statement) Post-treatment indications of cases difficult to manage:
· Failure to achieve partial or complete remission after 6-week standard dose steroids (primary SRNS).
· Secondary SRNS after initial response.
· Frequently relapsing or steroid dependent.
· Uncontrolled hypertension, infection, thrombosis.
· Steroid toxicity-renal impairment.
R 3 (1–6): Treatment of Initial Episode of NS? (Fig. 2A).
R 3.1: We suggest adopting KIDIGO 2021 recommendations as oral corticosteroids to be given for 8 weeks (4-week daily steroids followed with 4 weeks at alternate day) OR 6 weeks daily followed with 6 weeks at alternate day (Strong Recommendation). The standard dosing regimen for the initial treatment of NS is oral prednisone or prednisolone 60 mg/m2/day or 2 mg/kg/day (max 60 mg/day) for 4 weeks followed by alternate day 1.5 mg/kg/alternate day or 40 mg/m2 (maximum 50 mg/alternate day) for other 4 weeks or prednisone or prednisolone 6o mg/m2/day maximum 60 mg/day for 6 weeks followed with alternate day regimen 40 mg/m2/day max. 50 mg/d for other 6 weeks KDIGO 2021 PP: 4.3.1.1.
We add the following local practice points:
R 3.1.A: Good Practice Statement divided dose is accepted in children with gastric upset since single dose is preferred for better adherence and not superiority. (KDIGO 2021).
R 3.1.B: Good Practice Statement although dose calculation per surface area is more accurate in children. Per kg calculation may be accepted for simplification provided no under dosing [24,25,26,27].
R 3.1.C: 12-week total duration for steroids may be prolonged in late responders (KDIGO 2021 draft), therefore total steroid duration remains as open point of research Good Practice Statement.
R 3.2: HOW to maintain long remission on recurrence for:
Infrequently relapsing? Frequently relapsing, steroid dependent?
R 3.2 The initial approach for induction should include prednisone as a single daily dose of 60 mg/m2 or 2 mg/kg (maximum 60 mg/day) until the child remits completely for at least three days. KDIGO 21 PP: 4.3.2.1. Then:
R 3.2.1: Steroid maintenance for infrequently relapsing: after achieving complete 3 days remission with single daily dose of prednisone 60 mg/m2 or 2 mg/kg (maximum of 60 mg/day) KDIGO 21 PP:4.3.2.2. Children are suggested to have alternate days (40 mg/m2 per dose or 1.5 mg/kg per dose (maximum 50 mg/day) for at least 4 weeks. (Conditional recomendation).) KDIGO2021.
R 3.2.2. A: Frequently relapsing SSNS Children without steroid toxicity are suggested to be treated with the same glucocorticoid regimen in subsequent relapses. Prednisone is suggested to be given on alternate days in the lowest dose (Optimal dose ≤ 0.5 mg/kg) to maintain remission without major adverse effects PP: 4.3.2.4. KDIGO2021.
R 3.2.2. B: does not accept daily low-dose steroids on failure of alternate day low dose unless total weekly dose is kept the same but divided as daily dose Good Practise Statement . KDIGO 2021 suggests daily prednisone at the lowest dose to maintain remission in children without major adverse effects in FR/SSNS when alternate-day prednisone therapy is not effective (Conditional recomendation).
R 3.2.3: Steroid Dependent SSNS children: We accept low-dose steroids for low dose–dependent patients (alternate day dose ≤ 0.5 mg/kg) provided; no steroid toxicity, continuous patient monitoring with dose titration, patient preference and accept of potential harm (KDIGO 2012) [28] Good Practice statement. KDIGO2021 does not recommend low-dose steroids for SD as they recommend steroid-sparing drugs for all SD to avoid steroid toxicity. KDIGO 2021 (Strong Recomendation) PP 4.3.2.2.
R 3.3: We recommend for frequently relapsing or steroid dependents children who are currently on alternate-day prednisone or off glucocorticoids during episodes of the upper respiratory tract and other infections, daily prednisone (0.5 mg/kg) for 5 to 7 days to reduce the risk for relapse. (Strong Recomendation).
R 3.4: WHICH STEROID SPAIRING DRUGS to recommend for FR and SD?
Rationale:
It has been well accepted that corticosteroid-sparing agents were recommended to be prescribed for children with (FR) SSNS and (SD) SSNS, who develop steroid-related adverse effects. (Strong Recomendation) KDIGO 2012.
KDIGO 2021 Suggests low dose steroids (optimally alternate day dose ≤ 0.5 mg/kg) as maintenance only for FR who respond to the low glucocorticoid dose without serious toxicity PP: 4.3.2.4. (Strong Recomendation) KDIGO2021. Whereas all SD should use steroid-sparing drugs to avoid long-term use of steroids. (Strong Recomendation) KDIGO 2021, PP 4.3.2.2
· Patients should be ideally in remission with glucocorticoids prior to initiation of steroid-sparing drugs. Coadministration of glucocorticoids is recommended for 2 w following initiation of steroid-sparing drugs PP 4.3.2.5. KDIGO 2021
· Choosing the most appropriate drug is related to patient resources, adherence, tolerance, adverse effects, contraindications, and drug availability. PP: 4.3.2.6. KDIGO 2021
· For FR, levamisole and oral cyclophosphamides are preferred. For SD MMF, rituximab, cyclosporine, and to a lesser extent cyclophosphamides are suggested PP: 4.3.2.6. (Strong Recomendation). KDIGO 2021. Dose, duration, efficacy, and complications for each are summarized in Table 3 (refer to the Appendix. IPNA 2020 P 1541).
R 3.4: We suggest for frequently Relapsing (Fig. 2B) EPG-GPP, in case of resistance to low and safe steroid dose, to use levamisole as our first choice, to be replaced with cyclophosphamides considering its cumulative dose, or azathioprine. (Strong recomendation).
We suggest in steroid-dependent, Good Practice Statement. CNIs as our second choice after levamisole in children. Rituximab is an expensive drug, not covered by medical insurance and its use looks risky in countries endemic to hepatitis and other infectious diseases (conditional recomendation). Our limited experience in the use of Mizorbine unlike adults also restricts its common use in children (Good Practice Statement.).
R3.5: Management of complications (oedema, infections)
R. 3.5.1: EDEMA
Rationale
Patients with mild oedema do not require diuretic therapy. Corticosteroid therapy for relapse results in diuresis within 1 week, enabling loss of retained extracellular fluid. Patients are advised to limit sodium intake.
For patients with moderate oedema without hypovolemia
· We recommend oral furosemide as first-line therapy (2–4 mg/kg/day) (Strong Recomendation) Japanese 2014
· We suggest additional use of hydrochlorothiazide (2–4 mg/kg/day) or metolazone (0.1–0.2 mg/kg q12–24 h) to augment diuresis with Monitoring for hypovolemia, hypokalemia (Strong Recomendation) Japanese. Spironolactone has limited diuretic efficacy but a potassium-sparing agent in patients receiving high-dose furosemide. Use of amiloride is not advised. EPG-GPP [20]
· We suggest that patients with furosemide-refractory oedema be managed as follows: (i) combination of loop diuretics with thiazide and (ii) co-administration of human albumin with IV furosemide. (X) IPNA2020. Unresponsive to oral furosemides due to gut oedema indicates switching to IV therapy as 1–2 mg/kg q 8–12 h.
· Patients with severe oedema. We recommend loop diuretics furosemide unless hypovolemic to avoid thrombosis and AKI. IPNA 2020. Hypovolemia in NS results after vomiting, diarrhea, and diuresis.
· We suggest treating patients with severe and refractory oedema with hypovolemia, human albumin infusion (Conditional recommendation) IPNA 2020. Starting dose 20–25% albumin, 0.5–1 g/kg IV over 4–8 h, adding furosemide 1–2 mg/kg iv in the middle and at the end of infusion (Conditional recommendation) IPNA 2020. Blood pressure and heart rate monitoring with slowing infusion with any sign of overload. IPNA 2020.
R 3.5.2: Infection
· We suggest that serious bacterial infections associated with nephrotic syndrome be managed as indicated. IPNA2020. Referral to pediatric nephrologists is crucial. Good Practice Statement.
· Follow-up to prevent Infection with infection control measures and vaccinations.
· We suggest immune globulins for children with recurrent infections or low serum IgG levels (Conditional recommendation) IPNA2020.
· We do not recommend routine antibiotics. (Conditional recommendation)) IPNA2020 We suggest cotrimoxazole in patients on rituximab (5–10 mg/kg/day 3 times weekly 3–6 m) (Conditional recommendation) IPNA2020 We recommend receiving all vaccinations as recommended below.
Rationale:
Infections are the chief complication in patients with SSNS, accounting for most hospitalizations. Contributing factors include the use of immunosuppressive agents, anasarca, and urinary losses of IgG. Peritonitis is the most common severe infection, followed by pneumonia and cellulitis [26]. The diagnosis and treatment of severe infections should follow standard guidelines. Apart from vaccines, there is no evidence of routine antibiotics (Conditional recommendation) IPNA 2020.
Viral infections several viruses, including rhinovirus, adenovirus, influenza, parainfluenza, enterovirus, and respiratory syncytial and Epstein–Barr viruses, might trigger disease relapses. varicella, zoster, and influenza might cause serious morbidities KDIGO 2012/2021. Infections such as severe acute respiratory syndrome coronavirus 2 infection with severe acute respiratory syndrome coronavirus 2 (SARS COVID 2), the etiological agent of coronavirus disease (COVID-19) poses challenges in the management of patients with nephrotic syndrome [29, 30]. While children show mild disease, patients on immunosuppression constitute a high-risk group that is predisposed to adverse outcomes. Affected patients are at risk of AKI, particularly if associated with hypovolemia or aggressive use of diuretics [29]. Most expert groups advise reduction of immunosuppression or steroids to acceptable levels, limiting the use of biological agents, balancing the risk of disease relapse against infection.
R 3.5.3: Prevention of thrombosis
We recommend mobilization and avoiding central lines except for specific and transient need strong recommendation. Insufficient evidence for routine anticoagulant with no previous history or risk of thrombosis (not graded). We suggest low molecular weight heparin in those patients with: *previous history of thrombosis, central lines, hereditary thrombophilia predisposition, infection or dehydration (Conditional recommendation). We suggest thrombophilia screen for protein C, S, Anti thrombin, factor V genes in those with a positive family history of thrombophilic predisposition (Conditional recommendation) IPNA 2020.
R: 4.1: How to follow your patient?
· Diet: We recommend fat restricted diet (C1) Japanese 2014 balanced fluids uptake (Conditional recommendation) IPNA 2020, salt moderation IPNA 2020(Conditional recommendation) , and moderate exercise (Conditional recommendation) Japanese 2014.
· Family orientation with relapsing course of the disease, how to use uro-strips, adherence to steroid therapy and monitoring for its side effects.
· Blood pressure assessment and control.
· Laboratory testing to follow proteinuria, GFR, lipids profile, urine & blood glucose.
· Infection screen and drug monitoring for those under immunosuppressive.
· Vaccinations refer to (R 4.2) (Strong recomendation) Japanese 2014, IPNA 2020 (Strong recommendation).
· Growth follow-up.
· Vitamin D and calcium supplements, pump inhibitors (Conditional recommendation) IPNA 2020, KDIGO 2021 (Fig. 43 P.s152).
· In patients with SSNS and normal vit amin D levels, supplementation is not required. However, in FRNS or SDNS children with a known vitamin D deficiency, a reduction of bone mineral content can be prevented by oral supplementation of calcium and vitamin D.
· KDIGO 2021 reported absence of sufficient evidence to recommend prophylactic use of proton-pump inhibitors in children with NS in absence of risk factors as gastric symptoms.
· Management of complications (infection, thrombosis, steroid toxicity, immunosuppressive side effects) with immediate referral to Pediatric Nephrologists for urgent interference. (Good Practice Statement).
R 4.2: IMMUNIZATIONS IN CHILDREN WITH SSNS
R 4.2: To reduce the risk of serious infections in children with SSNS, IPNA 2020 suggest reviewing the child vaccination status at disease onset completing all vaccinations without delay especially for encapsulated bacteria (pneumococcal, meningococcal, Hemophilus influenza) and if possible, varicella-zoster virus
· Give pneumococcal, meningococcal, and varicella vaccination to the children (Strong recommendation) IPNA 2020.
· Give influenza vaccination annually to the children and their household contacts (Strong recommendation) IPNA 2020.
· Live vaccines are contraindicated in children receiving corticosteroid-sparing immunosuppressive agents (Strong recommendations) IPNA 2020.
· Immunize healthy household contacts with live vaccines to minimize the risk of transfer of infection to the immunosuppressed child but avoid direct exposure of the child to gastrointestinal, urinary, or respiratory secretions of vaccinated contacts for 3–6 weeks after vaccination.
· Following close contact with varicella infection, give nonimmune children on immunosuppressive agents, varicella zoster immune globulin, if available (Strong recommendation). Treatment with acyclovir 10 mg/kg/7 days (Good practice statement), varicella vaccine in remission (conditional) IPNA 2020.
➡️Guideline Registration
PREPARE (Practice guideline REgistration for transPAREncy), WHO Collaborating Center for Guideline Implementation and Knowledge Translation, EBM Center, University of Lanzhou, Lanzhou, China. Registration Number: ((submitted and in process)). Link: http://www.guidelines-registry.org/