Review Management of steroid-resistant nephrotic syndrome in children and adolescents Kjell Tullus, Hazel Webb, Arvind Bagga More than 85% of children and adolescents (majority between 1–12 years old) with idiopathic nephrotic syndrome Lancet Child Adolesc Health 2018 show complete remission of proteinuria following daily treatment with corticosteroids. Patients who do not show Published Online remission after 4 weeks’ treatment with daily prednisolone are considered to have steroid-resistant nephrotic October 17, 2018 syndrome (SRNS). Renal histology in most patients shows presence of focal segmental glomerulosclerosis, minimal http://dx.doi.org/10.1016/ S2352-4642(18)30283-9 change disease, and (rarely) mesangioproliferative glomerulonephritis. A third of patients with SRNS show mutations Nephrology Unit, Great in one of the key podocyte genes. The remaining cases of SRNS are probably caused by an undefined circulating Ormond Street Hospital for factor. Treatment with calcineurin inhibitors (ciclosporin and tacrolimus) is the standard of care for patients with Children, Great Ormond Street, non-genetic SRNS, and approximately 70% of patients achieve a complete or partial remission and show satisfactory London, UK (K Tullus MD, long-term outcome. Additional treatment with drugs that inhibit the renin–angiotensin axis is recommended for H Webb BSc) andDivision of Nephrology, Indian Council of hypertension and for reducing remaining proteinuria. Patients with SRNS who do not respond to treatment with Medical Research Advanced calcineurin inhibitors or other immunosuppressive drugs can show declining kidney function and are at risk for end- Center for Research in stage renal failure. Approximately a third of those who undergo renal transplantation show recurrent focal segmental Nephrology, All India Institute glomerulosclerosis in the allograft and often respond to combined treatment with plasma exchange, rituximab, and of Medical Sciences, New Delhi, India (Prof A Bagga MD) intensified immunosuppression. Correspondence to: Dr Kjell Tullus, Nephrology Unit, Introduction prednisolone at a dose of 60 mg/m² daily for 4 weeks. Great Ormond Street Hospital for Nephrotic syndrome is diagnosed based on a triad of Others recommend treatment for 8 weeks.2–4 Several Children, Great Ormond Street, symptoms: severe proteinuria (>1 g/m² per day), centres, including the Great Ormond Street Hospital for London WC1N 3JH, UK [email protected] hypoalbuminaemia (albumin <2·5 g/dL), and oedema. Children, London, UK, administer three intra venous Most children older than 1 year (generally until 12 years pulses of methylprednisolone (500 mg/m²) before old) are diagnosed with idiopathic nephrotic syndrome regarding patients as resistant.5 Steroid resistance most based on these features and little else. A secondary cause often occurs during initial treatment with prednisolone (eg, systemic lupus erythematosus and Henoch- (initial resistance), but can also occur during treatment Schönlein purpura) is rare. for a relapse, in a patient who had previously responded Idiopathic nephrotic syndrome presents as an acute to treatment with steroids or with a second-line drug disease, with substantial proteinuria and increasing (late resistance). Steroid resistance is an important deter- oedema. A smaller proportion of patients have a slower minant of future risk for end-stage renal disease. and more atypical onset, sometimes over several months or even years. Atypical features include onset in infancy or adolescence, symptoms suggestive of an inflam- Key messages matory kidney disease, renal failure, hypertension, and • About 10–15% of children with idiopathic nephrotic syndrome who do not show macroscopic haematuria. complete remission of proteinuria following 4 weeks’ treatment with corticosteroids More than 85% of patients with idiopathic nephrotic are considered to have steroid-resistant nephrotic syndrome syndrome respond (ie, complete remission of proteinuria • For 30% of patients with steroid-resistant nephrotic syndrome, the condition results and normal serum albumin) following treatment with from a genetic cause; for the remainder, the disease is probably caused by a circulating 1 prednisolone. Response to prednisolone is an important factor prognostic indicator for survival of kidney function. • Renal histology shows minimal change disease and focal segmental glomerulosclerosis Although many patients with steroid-sensitive nephrotic (FSGS) in most patients syndrome have frequent relapses or steroid dependence, • Approximately 50–70% of patients with steroid resistance show complete or partial the long-term outlook for kidney function is favourable. remission following treatment with a calcineurin inhibitor (either ciclosporin or The main long-term problem in these patients is the risk tacrolimus) of side-effects from prolonged treatment with cortico- • Although additional treatment with mycophenolate mofetil or rituximab is steroids and other immuno suppressive medications. considered in children who are resistant to treatment with steroids and calcineurin Patients who do not respond to prednisolone are inhibitors, their efficacy to induce remission is low considered to have steroid-resistant nephrotic syndrome • Patients with a genetic FSGS or those who do not show complete or partial remission (SRNS). The medical community has not yet reached a following treatment with calcineurin inhibitors have high risk of end-stage renal failure consensus regarding the length of time prednisolone • Patients with late resistance and absence of a genetic cause show high risk of recurrent should be given before regarding a patient as steroid FSGS in the renal allograft resistant. We recommend that steroid resistance should • Intensification of treatment with ciclosporin or tacrolimus, and combined treatment be considered in patients who do not show complete with rituximab and plasma exchange might prevent or treat recurrent FSGS effectively remission of proteinuria despite treatment with www.thelancet.com/child-adolescent Published online October 17, 2018 http://dx.doi.org/10.1016/S2352-4642(18)30283-9 1 Review Congenital nephrotic syndrome refers to infants with slit diaphragm (NPHS1, NPHS2, CD2AP, and PLCE1); onset of nephrotic syndrome before 3 months of age. cytoskeleton (ACTN4, MHY9, MYO1E, INF2, and actin Most of these patients have mutations involving the regulatory genes); glomerular basement membrane and podocyte proteins (nephrin, podocin, and WT1) and do matrix proteins (LAMB2, ITGA3, and COL4A3–5); not respond to treatment with steroids and other mitochondrial proteins (COQ2, COQ6, and ADCK4); medications. The course of illness is progressive and nuclear proteins (WT1, LMX1B, NUP93, NUP107, most patients require renal replacement treatment in the NUP205, and SMARCAL1); and other intracellular first decade. We have not included the clinical manage- proteins (TRPC6, SCARB2, APOL1, DGKE, CUBN, ment of these children in this Review. and GAPVD1) with a wide spectrum of illness. Nephrotic syndrome might also be associated with Cause of SRNS syndromic features with mutations in specific genes— Genetic causes eg, Denys-Drash syndrome and Frasier syndrome (WT1); The medical community has learnt much about the Pierson syndrome (LAMB2); nail-patella syndrome genetic causes for SRNS over the past decades. Mutations (LMX1B); Epstein syndrome, Sebastian syndrome, and in more than 70 genes encoding key podocyte proteins related illnesses (MYH9); MELAS syndrome and Leigh are recognised to cause the illness. Despite recognition syndrome (mitochondrial genes); Galloway-Mowat syn- of an increasing number of genetic causes, only drome (WDR73); and Schimke dysplasia (SMARCAL1), 30% of patients with sporadic SRNS show a defined as reviewed by Bierzynska and colleagues6 and Preston mutation.6 and colleagues.7 Genes associated with the occurrence of SRNS are broadly classified as involving: structural elements of the Circulating factor The probable cause for most patients with non-genetic 8,9 A SRNS is thought to be a circulating factor. Circum- stantial evidence exists that makes this theory quite probable, but it has been elusive to define the circulating factors responsible for SRNS.10 A large proportion of children with non-genetic SRNS relapse quickly after kidney transplantation: these patients often respond to plasma exchange or immune adsorption. Small animals infused with patient plasma, whole or its fractions, also develop proteinuria. In 1975, a vascular permeability factor was described.11 Other important suggestions of circulating factors include haemopexin, interleukin-13, cardiotrophin-like cytokine-1, and soluble urokinase-type plasminogen activator receptor.12–15 None of these sug- gested factors have been confirmed by independent research groups so far. B Kidney biopsy Renal histology is an important tool for diagnostic and prognostic categorisation. Biopsies should be examined by light, immunofluorescence, and electron microscopy to define their histological features. An ade quate biopsy should have approximately 25 glomeruli, especially when evaluating lesions that are focal or segmental. Biopsies with fewer glomeruli have low diagnostic accuracy. Common histological diagnoses include focal seg- mental glomerulosclerosis (FSGS) in 35–55% of patients, minimal change disease in 25–40% of patients, and idiopathic mesangioproliferative glomerulonephritis in 10–15% of patients (figure 1).16 In about 20% of patients, the histology shows membranous