Management of idiopathic childhood nephrotic syndrome in sub-Saharan Africa: Ibadan consensus statement

Abstract

In sub-Saharan Africa, glomerular disease, specifically nephrotic syndrome (NS), is the leading cause of chronic kidney disease and end-stage kidney disease in children.1Banh T.H. Hussain-Shamsy N. Patel V. et al.Ethnic differences in incidence and outcomes of childhood nephrotic syndrome.Clin J Am Soc Nephrol. 2016; 11: 1760-1768Crossref PubMed Scopus (54) Google Scholar, 2Esezobor C.I. Ladapo T.A. Osinaike B. et al.Paediatric acute kidney injury in a tertiary hospital in Nigeria: prevalence, causes and mortality rate.PLoS One. 2012; 7e51229Crossref PubMed Scopus (50) Google Scholar, 3Asinobi A.O. Ademola A.D. Ogunkunle O.O. et al.Paediatric end-stage renal disease in a tertiary hospital in South West Nigeria.BMC Nephrol. 2014; 15: 25Crossref PubMed Scopus (24) Google Scholar The prevalence of NS is estimated at 2 to 7 per 100,000 children worldwide,1Banh T.H. Hussain-Shamsy N. Patel V. et al.Ethnic differences in incidence and outcomes of childhood nephrotic syndrome.Clin J Am Soc Nephrol. 2016; 11: 1760-1768Crossref PubMed Scopus (54) Google Scholar and it is one of the more common causes of pediatric kidney disorders in Africa. Despite limited reports from Nigeria and Sudan,2Esezobor C.I. Ladapo T.A. Osinaike B. et al.Paediatric acute kidney injury in a tertiary hospital in Nigeria: prevalence, causes and mortality rate.PLoS One. 2012; 7e51229Crossref PubMed Scopus (50) Google Scholar, 3Asinobi A.O. Ademola A.D. Ogunkunle O.O. et al.Paediatric end-stage renal disease in a tertiary hospital in South West Nigeria.BMC Nephrol. 2014; 15: 25Crossref PubMed Scopus (24) Google Scholar, 4Abdelraheem M.B. Ali el T.M. Mohamed R.M. et al.Pattern of glomerular diseases in Sudanese children: a clinico-pathological study.Saudi J Kidney Dis Transpl. 2010; 21: 778-783PubMed Google Scholar the overall incidence of NS in Africa is unknown. Among the 54 African countries, only 17 have information on the burden of childhood NS, indicating substantial under-reporting.5Olowu W.A. Ademola A. Ajite A.B. et al.Childhood nephrotic syndrome in tropical Africa: then and now.Paediatr Int Child Health. 2017; 37: 259-268Crossref PubMed Scopus (15) Google Scholar The absence of large-scale studies of NS in Africa addressing key questions of incidence and outcomes reflects the limited resources available including medical records, diagnostics, medications, and clinical and research staff. Based on historical data, black children with NS have relatively higher steroid resistance rates than children of other ethnicities throughout Africa,6Bhimma R. Adhikari M. Asharam K. Steroid-resistant nephrotic syndrome: the influence of race on cyclophosphamide sensitivity.Pediatr Nephrol. 2006; 21: 1847-1853Crossref PubMed Scopus (26) Google Scholar, 7Olowu W.A. Adelusola K.A. Adefehinti O. Childhood idiopathic steroid resistant nephrotic syndrome in Southwestern Nigeria.Saudi J Kidney Dis Transpl. 2010; 21: 979-990PubMed Google Scholar, 8Doe J.Y. Funk M. Mengel M. et al.Nephrotic syndrome in African children: lack of evidence for 'tropical nephrotic syndrome'?.Nephrol Dial Transplant. 2006; 21: 672-676Crossref PubMed Scopus (44) Google Scholar and focal segmental glomerulosclerosis is the most common histopathologic diagnosis.9Obiagwu P.N. Aliyu A. Atanda A.T. Nephrotic syndrome among children in Kano: a clinicopathological study.Niger J Clin Pract. 2014; 17: 370-374Crossref PubMed Scopus (10) Google Scholar Recent studies from several regions in Nigeria recently documented high and increasing rates of steroid responsiveness.5Olowu W.A. Ademola A. Ajite A.B. et al.Childhood nephrotic syndrome in tropical Africa: then and now.Paediatr Int Child Health. 2017; 37: 259-268Crossref PubMed Scopus (15) Google Scholar,10Ladapo T.A. Esezobor C.I. Lesi F.E. High steroid sensitivity among children with nephrotic syndrome in southwestern Nigeria.Int J Nephrol. 2014; 2014: 350640Crossref PubMed Scopus (18) Google Scholar,11Asinobi A.O. Gbadegesin R.A. Ogunkunle O.O. Increased steroid responsiveness of young children with nephrotic syndrome in Nigeria.Ann Trop Paediatr. 2005; 25: 199-203Crossref PubMed Scopus (14) Google Scholar Treatment guidelines for NS developed in Western countries are not always applicable to low-resource settings,4Abdelraheem M.B. Ali el T.M. Mohamed R.M. et al.Pattern of glomerular diseases in Sudanese children: a clinico-pathological study.Saudi J Kidney Dis Transpl. 2010; 21: 778-783PubMed Google Scholar often failing to consider economic issues impacting clinical care, such as access to medications, drug level monitoring, and kidney biopsy.5Olowu W.A. Ademola A. Ajite A.B. et al.Childhood nephrotic syndrome in tropical Africa: then and now.Paediatr Int Child Health. 2017; 37: 259-268Crossref PubMed Scopus (15) Google Scholar The Human Hereditary and Health in Africa–Kidney Disease Research Network (H3A-KDRN), was established to conduct genomic studies of kidney disease in sub-Saharan Africa.12H3Africa Kidney Disease Research Network. Available at: https://h3africa.org/index.php/h3africa-kidney-disease-research-network/. Accessed December 10, 2020.Google Scholar The network also provides a platform for capacity building and development of consensus clinical guidelines that address variability in care of those with chronic kidney disease. Our aim was to use the network to assess practice variation in management of NS among centers participating in H3A-KDRN, and generate a consensus statement on the management of childhood NS in sub-Saharan Africa using the modified Delphi approach. The working group included 30 pediatric and/or adult nephrologists from 18 clinical sites across 6 countries who completed a survey on NS management in children/adolescents and participated in the consensus meeting (Supplementary Figure S1). There was significant variation in clinical practice, specifically the hospital policy on age of a child, dose and duration of prednisone, and choice of steroid-sparing agents (Table 1). Most nephrologists were managing children/adolescents using the Kidney Disease: Improving Global Outcomes Guideline (KDIGO) for Glomerulonephritis. Adult nephrologists used adult guidelines for adolescents.4Abdelraheem M.B. Ali el T.M. Mohamed R.M. et al.Pattern of glomerular diseases in Sudanese children: a clinico-pathological study.Saudi J Kidney Dis Transpl. 2010; 21: 778-783PubMed Google Scholar We agreed that the consensus statement would be applicable in the management of children younger than age 18 years.Table 1Variability in clinical practice among 30 practicing nephrologists across sub-Saharan AfricaClinical guidelineKDIGO guidelinesIPNA guidelinesResponses from physiciansConsensusn (%)Mode (minimum–maximum)Age of child, y1830 (100)18 (12–18)18Steroid (prednisone)aAlso may be referred to as prednisolone in some countries. treatmentTreatment at initial presentation Total duration of prednisone, wk121230 (100)12 (8–44)12–16bThis accounts for a 6-week daily duration, a 6-week alternate-day duration, and an additional 4 weeks of tapering.Duration of daily prednisone, wk4–64–630 (100)6 (4–30)6Duration of alternate-day prednisone, wk8–204–630 (100)6 (0–20)6 Maximum daily dose of prednisone, mg606030 (100)60 (40–100)60 Maximum alternate-day dose of prednisone, mg404030 (100)40 (20–100)40Treatment of relapses Maximum daily dose of prednisone, mg60—30 (100)60 (10.0–100)60 Maximum alternate-day dose of prednisone, mg40—30 (100)40 (40.0–40)40Steroid-sparing treatmentcOnly 22 physicians responded to this portion of the survey. However, all percentages listed are based on a denominator of 30. Levamisole (n = 12)dResponses were available only from clinical sites that had access to corresponding steroid-sparing medication.Prescribed dose on alternate days, mg/kg2.5—12 (40)dResponses were available only from clinical sites that had access to corresponding steroid-sparing medication.2.5 (1.5–4)2.5Minimum duration of treatment, mo12—12 (2–24)6Maximum duration of treatment, mo——24 (6–36)24 Cyclophosphamide (n = 17)dResponses were available only from clinical sites that had access to corresponding steroid-sparing medication.,eOne clinical center prescribes cyclophosphamide intravenously. The consensus was to prescribe intravenous cyclophosphamide at 500 mg/m2 per dose, given monthly for 4 months.Prescribed dose, mg/kg per day2N/A17 (57)dResponses were available only from clinical sites that had access to corresponding steroid-sparing medication.2 (2–20)2Minimum duration of treatment, wk88 (8–32)12Maximum duration of treatment, wk1212 (4–72)12Calcineurin inhibitors Cyclosporine (n = 14)dResponses were available only from clinical sites that had access to corresponding steroid-sparing medication.Prescribed dose in mg/kg per day (divided into 2 doses)4–53–514 (47)dResponses were available only from clinical sites that had access to corresponding steroid-sparing medication.3 (0.5–15)3–5Minimum duration of treatment, mo126fCalcineurin inhibitors should be stopped if partial remission is not achieved at 6 months (grade B, moderate recommendation, IPNA guideline).6 (3–24)6Maximum duration of treatment, mo—2424 (6–48)24Monitoring of drug levels during therapy—Weekly, then 1–3 moMinimum target trough level, ng/ml—8010 (33)100 (20–100)50Maximum target trough level, ng/ml—120100 (100–200)100 Tacrolimus (n = 8)dResponses were available only from clinical sites that had access to corresponding steroid-sparing medication.Prescribed dose in mg/kg per day (divided into 2 doses)0.10.1–0.28 (27)dResponses were available only from clinical sites that had access to corresponding steroid-sparing medication.0.1 (0.05–0.5)0.1 – 0.2Minimum duration of treatment, mo126fCalcineurin inhibitors should be stopped if partial remission is not achieved at 6 months (grade B, moderate recommendation, IPNA guideline).12 (3–24)6Maximum duration of treatment, mo—2424 (12–48)24Monitoring of drug levels during therapy—Weekly, then 1–3 moMinimum target trough level, ng/ml—47 (24)5 (3–5)5Maximum target trough level, ng/ml—88 (8–10)8 Mycophenolate (n = 11)dResponses were available only from clinical sites that had access to corresponding steroid-sparing medication.Prescribed dose in mg/m2 per day (divided into 2 doses)1200120011 (37)dResponses were available only from clinical sites that had access to corresponding steroid-sparing medication.1200 (800–1500)600Minimum duration of treatment, mo12126 (3–24)6Maximum duration of treatment, mo—24 (6–60)24Monitoring of white blood cell during treatment—10 (33)Frequency of monitoring white blood cells, wk—4 (1–12)4IPNA, International Pediatric Nephrology Association; KDIGO, Kidney Disease: Improving Global Outcomes; N/A, not available; —, not available in the KDIGO guidelines.a Also may be referred to as prednisolone in some countries.b This accounts for a 6-week daily duration, a 6-week alternate-day duration, and an additional 4 weeks of tapering.c Only 22 physicians responded to this portion of the survey. However, all percentages listed are based on a denominator of 30.d Responses were available only from clinical sites that had access to corresponding steroid-sparing medication.e One clinical center prescribes cyclophosphamide intravenously. The consensus was to prescribe intravenous cyclophosphamide at 500 mg/m2 per dose, given monthly for 4 months.f Calcineurin inhibitors should be stopped if partial remission is not achieved at 6 months (grade B, moderate recommendation, IPNA guideline). Open table in a new tab IPNA, International Pediatric Nephrology Association; KDIGO, Kidney Disease: Improving Global Outcomes; N/A, not available; —, not available in the KDIGO guidelines. The KDIGO recommendation statements on steroid-sensitive and steroid-resistant NS and the agreed upon modifications for low- to middle-income African countries also were compared with the recently published International Pediatric Nephrology Association guidelines (Table 2).13Trautmann A. Vivarelli M. Samuel S. et al.IPNA clinical practice recommendations for the diagnosis and management of children with steroid-resistant nephrotic syndrome.Pediatr Nephrol. 2020; 35: 1529-1561Crossref PubMed Scopus (62) Google ScholarTable 2Summary of the consensus agreement compared with the KDIGO glomerulonephritis and IPNA guidelinesKDIGOIPNAConsensus agreementDefinitions of nephrotic syndrome in children Relapse: uPCR ≥2000 mg/g (≥200 mg/mmol) or ≥3+ protein on urine dipstick for 3 consecutive daysRelapse: urine dipstick ≥3+ protein for 3 consecutive days or uPCR ≥2000 mg/g (≥200 mg/mmol)Relapse: ≥2+ proteinuria for 3 consecutive days on an early morning urine or ≥2+ proteinuria with edema Remission: uPCR <200 mg/g (<20 mg/mmol) or <1+ of protein on urine dipstick for 3 consecutive daysRemission: uPCR <200 mg/g (<20 mg/mmol) or <1+ of protein on urine dipstick for 3 consecutive daysRemission: trace/negative for at least 3 consecutive days on urine dipstick onlyKDIGO guideline numberKDIGO recommendation statementIPNA guidelinesSummary of the consensus agreement3.1.1We recommend that corticosteroid therapy (prednisone or prednisolone) be given for at least 12 wk (1B)Prednisone therapy for 10–12 wkWe agreed on the total duration of prednisone therapy for up to 16 wk to account for tapering of steroids, similar to KDIGO guidelines3.1.1.1We recommend that oral prednisone be administered as a single daily dose (1B) starting at 60 mg/m2 per day or 2 mg/kg per day to a maximum of 60 mg/d (1D)The initial treatment of children with idiopathic NS usually comprises oral prednisone 60 mg/m2 per day or 2 mg/kg per day (maximum, 60 mg/d)We agreed that oral prednisone be administered for the initial episode of NS as a single daily dose at 60 mg/m2 per day, up to a maximum of 60 mg3.1.1.2We recommend that daily oral prednisone be given for 4–6 wk (1C) followed by alternate-day medication as a single daily dose starting at 40 mg/m2 or 1.5 mg/kg (maximum, 40 mg on alternate days) (1D) and continued for 2–5 mo with tapering of the dose (1B)Oral prednisone is given for 4–6 wk followed by 40 mg/m2 or 1.5 mg/kg per dose on alternate days for another 4–6 wkWe agreed on daily oral prednisone at 60 mg/m2 per day up to a maximum of 60 mg as a single daily dose for 6 wk followed by 40 mg/m2 prednisone as a single morning dose on alternate days for another 6 wk and thereafter tapered at the rate of 10 mg/m2 per week to 5 mg on alternate daysThe dose of the prednisone should be discontinued once tapered down to 5 mg on alternate daysTotal duration of therapy will be 16 wk3.2.1.1We suggest that infrequent relapses of SSNS in children be treated with a single-daily dose of prednisone 60 mg/m2 or 2 mg/kg (maximum, 60 mg/d) until the child has been in complete remission for at least 3 days (2D)N/AWe agreed, consistent to KDIGO guidelines, 60 mg/m2 (maximum, 60 mg/d) oral prednisone for relapse daily until remission (urine dipstick trace/negative for at least 3 consecutive days)3.2.2.1We suggest that relapses in children with FR or SD SSNS be treated with daily prednisone until the child has been in remission for at least 3 days, followed by alternate-day prednisone for at least 3 mo (2C)N/AWe agreed for relapse to be treated with oral prednisone 60 mg/m2 (maximum, 60 mg/d) daily until remission (urine dipstick trace/negative for at least 3 consecutive days)Once in remission, decrease prednisone to 40 mg/m2 per day (maximum, 40 mg/d) on alternate days for 1 wk, then taper by 10 mg/m2 per day per week to complete a total of 4 wkSimilar to the initial course, all doses to be rounded up to account for 5-mg tablets3.3.2We recommend that alkylating agents, cyclophosphamide, or chlorambucil be given as corticosteroid-sparing agents for FR SSNS (1B)We suggest alkylating agents, cyclophosphamide, or chlorambucil be given as corticosteroid-sparing agents for SD SSNS (2C)N/AWe agreed to use levamisole as the first-line steroid-sparing agent if available and then cyclophosphamide3.4.1Indications for kidney biopsy in children with SSNS are as follows (not graded): late failure to respond after initial response to corticosteroids; a high index of suspicion for a different underlying pathology; decreasing kidney function in children receiving CNIsQuantification of proteinuria by urine protein/creatinine ratio in either first morning urine or 24-hour urine sample at least once before defining SRNS and/or starting alternate immunosuppressionUse this baseline value for assessing subsequent response (Grade A, strong recommendation)Indications for kidney biopsy in children with SSNS: late-onset steroid resistance; suspicion of a secondary cause of disease; assessment of CNI nephrotoxicity; NS diagnosis before the age of 1 year or older than the age of 12 yr4.1.1We suggest a minimum of 8 wk of treatment with corticosteroids to define steroid resistance (2D)Lack of complete remission within 4 wk of treatment with prednisone at standard doseIf no remission is achieved by 6 wk, the diagnosis of SRNS is confirmedWe agreed to define steroid resistance as lack of response to daily prednisone after 8 wk of therapy consistent with definition in KDIGO guidelines4.1.2The following are required to evaluate the child with SRNS (not graded): a diagnostic kidney biopsy; evaluation of kidney function by GFR or eGFR; quantitation of urine proteinA renal biopsy in all children diagnosed with SRNS, except in known infection or malignancy-associated secondary disease or potentially in patients with familial and/or syndromic cases or genetic causes of SRNS (grade A, strong recommendation)Genetic testing results (grade B, moderate recommendation) as soon as possible, ideally within the 2-wk confirmation periodIn low-resource countries where genetic and/or histopathology assessment is not available, immediate immunosuppressive treatment with CNI may be startedIf CNIs are not available, intravenous or oral cyclophosphamide may be startedWe agreed to evaluate the child with SRNS with the following: percutaneous kidney biopsy to ascertain histopathology and guide treatment (the light microscopy with special immunohistochemistry stains if immunofluorescence and electron microscopy are not available); evaluation of kidney function with serum creatinine measurement to estimate GFR; quantification of uPCR instead of the 24-hour urine collectionPrescribe CNI if biopsy not readily available in the country4.2.1.1We suggest that CNI therapy be continued for a minimum of 6 mo and then stopped if a partial or complete remission of proteinuria is not achieved (2C)We suggest a minimum treatment period of 6 mo to determine the response to CNIs (grade B, weak recommendation)We recommend that CNIs should be stopped if partial remission is not achieved at 6 mo (grade B, moderate recommendation)We agreed to use CNI therapy for SRNS for a minimum of 6 mo to assess response4.2.1.2We suggest CNIs are continued for a minimum of 12 mo when at least a partial remission is achieved by 6 mo (2C)If complete remission is achieved, CNI dosages should be reduced to the lowest dosage required to maintain remissionWe also suggest considering discontinuation of CNIs after 12–24 mo in these patients to reduce the risk of nephrotoxicity (grade C, weak recommendation)We agreed CNI be continued for up to 2 yr when at least partial response is achieved by 6 moCNI, calcineurin inhibitor; eGFR, estimated glomerular filtration rate; FR, frequently relapsing; IPNA, International Pediatric Nephrology Association; KDIGO, Kidney Disease: Improving Global Outcomes; N/A, not available; NS, nephrotic syndrome; SD, steroid-dependent; SRNS, steroid-resistant nephrotic syndrome; SSNS, steroid-sensitive nephrotic syndrome; uPCR, urine protein to creatinine ratio. Open table in a new tab CNI, calcineurin inhibitor; eGFR, estimated glomerular filtration rate; FR, frequently relapsing; IPNA, International Pediatric Nephrology Association; KDIGO, Kidney Disease: Improving Global Outcomes; N/A, not available; NS, nephrotic syndrome; SD, steroid-dependent; SRNS, steroid-resistant nephrotic syndrome; SSNS, steroid-sensitive nephrotic syndrome; uPCR, urine protein to creatinine ratio. The duration of the initial prednisone treatment varied considerably, although most nephrologists followed the recommended duration of 6 weeks daily and 6 weeks alternate-day corticosteroid as a single daily dose (Figure 1a). The majority of nephrologists used 2 mg/kg or 60 mg/m2 per day to a maximum of 60 mg. When switching to alternate-day dosing, the majority chose 1.5 mg/kg or 40 mg/m2 per day, to a maximum daily dose of 40 mg (per day) (Table 1). We agreed to manage the initial episode of NS with oral prednisone at 60 mg/m2 per day (maximum, 60 mg) as a single daily dose for 6 weeks, followed by 40 mg/m2 (maximum, 40 mg) prednisone as a single morning dose on alternate days for another 6 weeks. Prednisone thereafter should be tapered at a rate of 10 mg/m2 per week to 5 mg on alternate days (total cumulative dose, 3595 mg/m2 for a total of 16 weeks). Because the lowest dose available is 5-mg tablets, not suspension, we recommended that all doses be rounded to up to 5 mg accordingly, and, if at the lowest dose of 5 mg, maintain it until the end of the 16th week (different from KDIGO, in which further tapering is specified).4Abdelraheem M.B. Ali el T.M. Mohamed R.M. et al.Pattern of glomerular diseases in Sudanese children: a clinico-pathological study.Saudi J Kidney Dis Transpl. 2010; 21: 778-783PubMed Google Scholar Variations in practice also were noted for treatment of relapses (Table 1). Recommended treatment for relapses should include oral prednisone 60 mg/m2 (maximum, 60 mg/d) daily until remission. Once in remission, we recommend decreasing to 40 mg/m2 per day (maximum, 40 mg [per day]) on alternate days for 1 week, and then taper by 10 mg/m2 per day per week to complete a total of 4 weeks of treatment. For frequently relapsing (FR)/steroid-dependent (SD) steroid-sensitive nephrotic syndrome, approximately 90% of respondents use maintenance alternate-day prednisone for at least 3 months, with most choosing the lowest dose to maintain remission. In line with current KDIGO guidelines, and similar to the protocol described earlier, we recommend prednisone to treat relapses for up to 3 months at the recommended relapse dosing. We agreed to not prescribe prophylactic prednisone for relapse prevention in children with FR/SDNS already on low-dose, alternate-day during episodes of malaria, however, we agreed to use it for upper respiratory infections pending results of clinical trials. Choice of steroid-sparing agent, drug route, and dose varied across the continent, and within each country, as described in Tables 1 and 3 and shown in Figures 1b–d and 2a. Steroid-sparing agents should be initiated once the patient is in remission, using either an alkylating agent (cyclophosphamide, chlorambucil), levamisole, calcineurin inhibitors (cyclosporine, tacrolimus), mycophenolate mofetil, or rituximab, based on availability.Table 3Steroid and steroid-sparing agent cost for treatment of nephrotic syndrome in childrenMedicationUsed to treat FRNSaDefined as 2 or more relapses within the first 6 months of diagnosis or 4 or more relapses within any 12-month period./SDNSbDefined as 2 or more relapses during the steroid taper or 1 relapse within 14 days of steroid cessation.Used to treat SRNScDefined as no response to steroids within 8 weeks of treatment.Medication type/formulationdMultiple medications have different brand names available by country and source of medication; individual names for all countries were not provided. Brand names listed are from Uganda (Prednisolone: Kam Predisol, Kampala Pharmaceuticals Industries 1996 Limited, Kampala, Uganda; Levamisole: Argotrax [Ergamisole], Agog Pharma Ltd, India; Cyclophosphamide: Cytoxan, Baxter Healthcare Corporation, Germany; Cyclosporine: Capimune, Mylan, UK; Neoral, Novartis Pharma Services Inc, Germany; Tacrolimus: Advagraf and Prograf, Astellas Pharma, UK; Mycophenolate Mofetil: Mofilet [Mofetil], Emcure Pharmaceuticals Ltd, India; Cellcept, Roche Pharma, Germany; and Nigeria [Prednisolone: specific brand available; Levamisole: Argotrax, Agog Pharma Ltd, India; Levamisole: Retrax [not mentioned in the manuscript] manufactured by Reals Group located in Lagos, Nigeria; Cyclophosphamide: other brands not mentioned in the manuscript available; Cyclosporine: Neoral, Novartis, Switzerland; Tacrolimus: Prograf, Astellas, Tokyo, Japan; Mycophenolate Mofetil: Teva, Petah Tikva and New Jersey, USA, and Israel; Cellcept, Roche, Basel, Switzerland).Cost (USD)/tabletAverage monthly cost, USDj1 USD is approximately 3650 UGX (Uganda Shilling).,kAverage monthly cost was calculated based on a 4-year-old boy at the 50th percentile for height (103 cm) and weight (16.5 kg) based on World Health Organization guideline growth curves with an estimated surface area of 0.687 m2.Cameroone1 USD is approximately 565 XAF (Central African Franc).Ghanaf1 USD is approximately 4.80 GH¢ (Ghanaian Cedi).Nigeriag1 USD is approximately 360 ₦ (Naira).South Africah1 USD is approximately 15 R (South African Rand).Tanzaniai1 USD is approximately 2285 TZS (Tanzanian Shilling).Ugandaj1 USD is approximately 3650 UGX (Uganda Shilling).SteroidslRoute: oral; dose: 60 mg/m2 per day (maximum daily dose, 60 mg) until remission for 3 days, then 40 mg/m2 per day (maximum daily dose, 40 mg/d), alternate days for 1 week, then taper by 10 mg/m2 per day per week; duration: minimum, 3 days (immediate remission) + 4 weeks, maximum, number of days it takes to achieve remission + 4 weeks; monthly cost was calculated based on a full dose daily for 30 days.(Prednisone/Prednisolone)✓✓Generic5-mg tablets0.30.020.010.010.030.01315.79 ± 28.68LevamisolemRoute: oral; dose: 2.5 mg/kg alternate days; duration: 6 months to determine effectiveness, if effective, 2 years.✓Generic50-mg tablets——0.09——0.1351.39 ± 0.39Brand name50-mg tablets——0.16—0.01—1.05 ± 1.31CyclophosphamidenRoute: oral; dose: 2 mg/kg per day; duration: 3 months; OR route: i.v.; dose: 500 mg/m2 per month; duration: 4 months.✓Generic25-mg capsules———————Brand name50-mg capsules/tablets0.380.310.250.2650.500.416.98 ± 1.89IV500 mg/vial—2.203.005.50—2.802.32 ± 1.001 g/vial—4.004.808.004.604.201.76 ± 0.56CyclosporineoRoute: oral; dose: 3 to 5 mg/kg per day divided twice daily; duration: 6 months to assess response, up to 2 years; monthly cost was calculated based on 5 mg/kg per day.✓✓Generic50 mg——0.83—1.301.4058.24 ± 15.06Brand name25-mg tablets——1.840.2521.750.69140.21 ± 97.2650-mg tablets—1.56——2.60—102.96 ± 36.40100-mg tablets——7.32—2.602.0098.34 ± 72.12TacrolimuspRoute: oral; dose: 0.1 to 0.2 mg/kg per day divided twice daily; duration: 6 months to assess response, up to 2 years; monthly cost was calculated based on 0.2 mg/kg per day.✓✓Generic0.5-mg tablets——1.30——0.55183.15 ± 105.001-mg tablets—2.001.72——0.88151.80 ± 57.703-mg tablets—9.38————309.545-mg tablets—10.00———198.00Brand name0.5-mg tablets———0.562.600.67252.78 ± 227.181-mg tablets——3.452.202.600.93227.20 ± 103.825-mg tablets————3.30—65.34Mycophenolate Mofetil (MMF)qRoute: oral; dose: 600 mg/m2 per dose twice daily; duration: 6 months to determine effectiveness, if effective, 2 years.✓Generic250-mg tablets—0.354————17.51500-mg tablets—0.4162.700.29—1.2028.48 ± 27.40Brand name250-mg tablets———0.167——8.26500-mg tablets—1.87513.50—2.401.33118.13 ± 144.24FRNS, frequently relapsing nephrotic syndrome; IV, intravenously; SDNS, steroid-dependent nephrotic syndrome; SRNS, steroid-resistant nephrotic syndrome.a Defined as 2 or more relapses within the first 6 months of diagnosis or 4 or more relapses within any 12-month period.b Defined as 2 or more relapses during the steroid taper or 1 relapse within 14 days of steroid cessation.c Defined as no response to steroids within 8 weeks of treatment.d Multiple medications have different brand names available by country and source of medication; individual names for all countries were not provided. Brand names listed are from Uganda (Prednisolone: Kam Predisol, Kampala Pharmaceuticals Industries 1996 Limited, Kampala, Uganda; Levamisole: Argotrax [Ergamisole], Agog Pharma Ltd, India; Cyclophosphamide: Cytoxan, Baxter Healthcare Corporation, Germany; Cyclosporine: Capimune, Mylan, UK; Neoral, Novartis Pharma Services Inc, Germany; Tacrolimus: Advagraf and Prograf, Astellas Pharma, UK; Mycophenolate Mofetil: Mofilet [Mofetil], Emcure Pharmaceuticals Ltd, India; Cellcept, Roche Pharma, Germany; and Nigeria [Prednisolone: specific brand available; Levamisole: Argotrax, Agog Pharma Ltd, India; Levamisole: Retrax [not mentioned in the manuscript] manufactured by Reals Group located in Lagos, Nigeria; Cyclophosphamide: other brands not mentioned in the manuscript available; Cyclosporine: Neoral, Novartis, Switzerland; Tacrolimus: Prograf, Astellas, Tokyo, Japan; Mycophenolate Mofetil: Teva, Petah Tikva and New Jersey, USA, and Israel; Cellcept, Roche, Basel, Switzerland).e 1 USD is approximately 565 XAF (Central African Franc).f 1 USD is approximately 4.80 GH¢ (Ghanaian Cedi).g 1 USD is approximately 360 ₦ (Naira).h 1 USD is approximately 15 R (South African Rand).i 1 USD is approximately 2285 TZS (Tanzanian Shilling).j 1 USD is approximately 3650 UGX (Uganda Shilling).k Average monthly cost was calculated based on a 4-year-old boy at the 50th percentile for height (103 cm) and weight (16.5 kg) based on World Health Organization guideline growth curves with an estimated surface area of 0.687 m2.l Route: oral; dose: 60 mg/m2 per day (maximum daily dose, 60 mg) until remission for 3 days, then 40 mg/m2 per day (maximum daily dose, 40 mg/d), alternate days for 1 week, then taper by 10 mg/m2 per day per week; duration: minimum, 3 days (immediate remission) + 4 weeks, maximum, number of days it takes to achieve