Steroid-resistant nephrotic syndrome

CASE PRESENTATION A 5-year-old female was referred for evaluation of steroid-resistant nephrotic syndrome (SRNS). At 3 years of age, her family was concerned about the proteinuria (3+) and hematuria (2+) and brought her to the hospital for evaluation. There was no antecedent infection, fever, or rash. No family history of renal disease was noted, and her parents and her elder brother were negative for urinalysis ( Figure 1a). At the initial visit, laboratory studies revealed hypoproteinemia ( serum albumin 3.1 g/100 ml) and hyperlipidemia ( total cholesterol 282 mg/100 ml), whereas renal function was normal ( serum creatinine 0.2 mg/100 ml, and an estimated glomerular filtration rate 135 ml/min/1.73 m(2), Figure 1b, c and Table 1). On presentation to the hospital, the patient appeared normal. Physical examination was unremarkable with normal growth; the height was 98.2 cm (+0.8 s.d., 68 percentile) and weight was 13.0 kg (-0.5 s.d., 38 percentile). There was no dysmorphic features, edema, joint swelling, or hearing loss. The systemic workup including cardiovascular, neurological, and ophthalmological examination was unremarkable. Renal sonogram demonstrated normal-sized, symmetric kidneys without hydronephrosis or cysts. Urological studies including computed tomography were normal. The renal biopsy obtained at 3 years of age revealed glomeruli of normal size, with most glomeruli only exhibiting mild segmental mesangial cell proliferation ( Figure 2a). There was no glomerulosclerosis, tuft adhesions, or crescent formation affecting glomeruli. There was no cellular infiltrates or fibrosis evident in the tubulointerstitium or arterial vessels. Direct immunofluorescence revealed low-intensity, granular staining of IgG, IgM, and C3 in the mesangium. Electron microscopy demonstrated diffuse foot process effacement, with occasional glomerular basement membrane (GBM) alterations such as thinning, splitting, and some mesangial deposits, there by excluding a primary GBM or an immunocomplex disorder. Following the biopsy, she still had persistent nephrotic-range proteinuria ( urine protein-to-creatinine ratio, 3.8 mg/mg), although maintaining normal renal function. She was treated with oral prednisone (1 mg/kg daily for 4 weeks), but her proteinuria did not respond ( Figure 1b). Because of the unresponsiveness, cyclosporin (5 mg/kg daily) was started in addition to alternate-day predonisone (1 mg/kg). However, the proteinuria had still continued and the immunosuppressants were subsequently tapered off over the next 12 weeks. The patients had been thereafter treated with supportive antiproteinuric therapy. At 5 years of age, she still continued to havenephroticrange proteinuria ( urine protein-to-creatinine ratio, similar to 4.0 mg/mg). To explore the pathological basis of SRNS, a renal biopsy and genetic study was undertaken.