Idiopathic steroid-sensitive nephrotic syndrome (ORPHA:69061)
A rare primary glomerulopathy of unknown cause characterized by edema, nephrotic-range proteinuria and hypoalbuminemia that responds to standard prednisone treatment within 4-6 weeks.
Epidemiology
The annual incidence of idiopathic nephrotic syndrome varies by ethnicity and region ranging from 1/5,900-85,000 children, of which 70-98% are steroid sensitive. The disease is less frequently reported in adults. It has a male predominance (approximately 2:1) in young children.
Clinical description
Disease onset can occur at any age, but mostly between 2 - 6 years, frequently preceded by an upper respiratory tract infection. Patients typically present with edema, mainly periorbital and of lower extremities. Anasarca may develop with pleural and pericardial effusion, ascites, abdominal pain (due to hypoperfusion) and cold extremities with hypotension. Intravascular volume depletion and oliguria are present, and concomitant factors, (sepsis, diarrhea, diuretic use) can lead to acute kidney injury. Proteinuria typically has a relapsing and remitting course of varying frequency, and can be steroid-dependent in certain cases (relapsing during steroid therapy or within 15 days of its discontinuation). Urinalysis reveals nephrotic-range proteinuria and blood chemistry results show reduced serum albumin and total protein, reduced total calcium with ionized calcium usually normal, markedly decreased IgG levels, and hyperlipidemia. Hemoconcentration leads to increased hematocrit levels and thrombocytosis. A state of hypercoagulability (due to hypovolemia, hyperdyslipidemia, thrombocytosis) leads to an increased risk of, usually venous, thrombosis.
Etiology
Etiology is thought to be immune-mediated, although exact mechanism leading to disruption of the glomerular filtration barrier and proteinuria is unknown.
Diagnostic methods
Diagnosis is based on clinical manifestations, laboratory findings, and response to prednisone. Although renal biopsy is usually not performed, it may be advisable in the presence of atypical features (e.g. onset age < 1 or > 12 years, gross hematuria, low serum complement C3, marked hypertension, renal failure without severe hypovolemia), if prolonged therapy with calcineurin inhibitors is required or if the patient's clinical course is particularly difficult. Renal biopsy will most frequently show minimal changes with a negative immunofluorescence (so-called minimal change disease), though occasionally it may show other pictures.
Differential diagnosis
Differential diagnoses include membranous nephropathy, IgA nephropathy, renal vasculitis, C3 glomerulopathy and post-infectious glomerulonephritis.
Management and treatment
At onset, management includes symptomatic care with, in severe cases, albumin infusions. In children, prednisone (60mg/m2/day) is the mainstay of therapy. If the patient presents frequent relapses or steroid-dependent disease, second-line steroid-sparing immunosuppression with various agents, including antiproliferatives, levamisole, calcineurin inhibitors, mycophenolate mofetil and, more recently, rituximab, is prescribed.
Prognosis
Prognosis is variable. After remission of the first episode, the risk of relapse is negligible in 30% of patients. Approximately 20%-30% progress to infrequent relapses (rarely more than 3-4 episodes in total) with prednisone alone. The remaining 40%-50%, mostly children < 5 years of age, have a frequently relapsing or steroid-dependent course. Rarely, patients with initially steroid-sensitive nephrotic syndrome develop secondary steroid resistance, leading to progressive renal failure. In forms that remain steroid-responsive, renal function is typically preserved. Long-term outcome is heavily influenced by side effects of protracted administration of steroids and second-line steroid-sparing agents. The disease tends to resolve following puberty, but a significant percentage, around 10-15% of patients, will continue to present this disease in adulthood.

                            Last update: 
                            June 2020


                            - Expert reviewer(s): 
                            Dr Marina VIVARELLI | ERKNet*


                                * European Reference Network