Management of Steroid Sensitive Nephrotic Syndrome

- Recommendations

Table 3. Recommendations
N	Health questions	Source Guideline	Recommendations	Quality of evidence	Strength of Recommendation
A1	Definitions WHAT are the Common Definitions Related to Nephrotic Syndrome?	IPNA 2020 and KDIGO 2021	Definitions are summarized in IPNA 2020 and KDIGO 2021 (Table 1: refer to the Appendix).		Good practice statement
A2	Diagnosis. (EPG: Figs. 1 and 2A) How to make a proper diagnosis of NS at its first episode?	IPNA 2020 and KDIGO 2021	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: 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). 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
			We recommend referral of children with the primary diagnosis of NS to pediatric nephrologist, for proper extended diagnosis &management.		Good Practice statement
		IPNA 2020	R 2: 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		Good Practice statement
		IPNA 2020	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.		Good Practice Statement
		IPNA 2020	R 2.2: We recommend for extended laboratory assessment in atypical cases to follow EPG flowchart (Fig. 1) and Table 2 IPNA 2020 (refer to the Appendix) focusing on: ·        C3, C4, Anti ds DNA, ASOT, APLR, ANCA	Moderate	Strong
			·        Infection screen (blood, urine culture, tuberculin test ©viral serology; HBsAg, HC, CMV, Epstein Bar, HIV, COVID Sars-2 antibodies  ·        Imaging: abdominal and renal US, X-ray chest.	Low	Conditional
R 2.3	Genetic tests for selected cases WHEN to ask for GENETIC TESTING in first episode?		R 2.3.1: We recommend Early genetic testing not waiting for 4 weeks’ steroid response  If: Familial (C), Syndromic (C), < 1 year age of onset (C), extra renal involvement suggesting hereditary disease (C).	Low	Good Practice Statement     Conditional
		IPNA 2020   KDIGO 2021	R 2.3.2: We recommend genetic testing after 4 weeks of start of oral prednisone, for all steroid resistant if possible 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	Moderate	Strong
R 2.4	Renal biopsy for selected cases WHEN to do KIDNEY BIOPSY in the first episode?	KDIGO 2021	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: 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.		Good Practice Statement
		IPNA 2020   KDIGO 2021	We recommend late biopsy as IPNA &KDIGO recommend for: ·        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).		Good Practices Statement
R 2.5	WHO should manage nephrotic children? Referral Red Flags?		R 2.5.A : 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.		Good Practice Statement
			Red flags justifying referral: R 2.5.B 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).		Good Practice Statement
R 3	R 3 (1–6): Treatment of Initial Episode of NS?	KIDIGO 2021	R 2.5.C:  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: 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 . 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	Moderate	Good Practice Statement                               Strong
		KDIGO 2021	We add the following local practice points: R 3.1.A: 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: although dose calculation per surface area is more accurate in children. Per kg calculation may be accepted for simplification provided no under dosing 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?	KDIGO 2021	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
		KDIGO2021	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) 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.	Low	Conditional
		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:
		KDIGO2021	R 3.2.2. B: EPG-GPP 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.      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	Very Low	Good Practice Statement               Conditional
		KDIGO2021	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
		KIDIGO 2021	KDIGO2021 does not recommend low-dose steroids for SD as they recommend steroid-sparing drugs for all SD to avoid steroid toxicity.	moderate	Strong
		KIDIGO 2021	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.	Low	Conditional
R 3.4:	WHICH STEROID SPAIRING DRUGS to recommend for FR and SD?	KDIGO 2012.	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.	Moderate	Strong
		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. Whereas all SD should use steroid-sparing drugs to avoid long-term use of steroids. KDIGO 2021 Patients should be ideally in remission with glucocorticoids prior to initiation of steroid-sparing drugs. Co administration of glucocorticoids is recommended for 2 w following initiation of steroid-sparing drugs KDIGO 2021 Choosing the most appropriate drug is related to patient resources, adherence, tolerance, adverse effects, contraindications, and drug availability.	Moderate	Strong
		KDIGO 2021	For FR, levamisole and oral cyclophosphamides are preferred. For SD MMF, rituximab, cyclosporine, and to a lesser extent cyclophosphamides are suggested. Dose, duration, efficacy, and complications for each are summarized in Table 3	Moderate	Strong
			R 3.4: We suggest for frequently Relapsing (Fig. 2B)  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.		Good Practice Statement
			We suggest in steroid-dependent, 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	Low	Good Practice Statement       Conditional
			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	Japanese 2014	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)	Moderate	Strong
		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	Moderate	Strong
			Spironolactone has limited diuretic efficacy but a potassium-sparing agent in patients receiving high-dose furosemide. Use of amiloride is not advised.		Good Practice Statement
		IPNA2020	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.  Unresponsive to oral furosemides due to gut oedema indicates switching to IV therapy as 1–2 mg/kg q 8–12 h.		Good Practice Statement
		IPNA 2020	Patients with severe oedema. We recommend loop diuretics furosemide unless hypovolemic to avoid thrombosis and AKI.  Hypovolemia in NS results after vomiting, diarrhea, and diuresis		Good Practice Statement
		IPNA 2020.	We suggest treating patients with severe and refractory oedema with hypovolemia, human albumin infusion 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	Low	Conditional
		IPNA 2020.	Blood pressure and heart rate monitoring with slowing infusion with any sign of overload.		Good Practice Statement
R 3.5.2:	Infection	IPNA2020	We suggest that serious bacterial infections associated with nephrotic syndrome be managed as indicated.		Good Practice Statement
			Referral to pediatric nephrologists is crucial.		Good Practice Statement
			Follow-up to prevent Infection with infection control measures and vaccinations.		Good Practice Statement
		IPNA2020	We suggest immune globulins for children with recurrent infections or low serum IgG levels	Very Low	Conditional
		IPNA2020                   IPNA 2020                                   KDIGO 2012/2021	We do not recommend routine antibiotics.  We suggest cotrimoxazole in patients on rituximab (5–10 mg/kg/day 3 times weekly 3–6 m)  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 The diagnosis and treatment of severe infections should follow standard guidelines. Apart from vaccines, there is no evidence of routine antibiotics.     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]. 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 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.	Low                   Low	Conditional                   Conditional
R 3.5.3:	Prevention of thrombosis		We recommend mobilization and avoiding central lines except for specific and transient need strong recommendation.		Good Practice Statement
			Insufficient evidence for routine anticoagulant with no previous history or risk of thrombosis (not graded).		Good Practice Statement
		IPNA 2020	We suggest low molecular weight heparin in those patients with: *previous history of thrombosis, central lines, hereditary thrombophilia predisposition, infection or dehydration	Low	Conditional