Idiopathic steroid-resistant nephrotic syndrome (ORPHA:567548)
A rare, idiopathic nephrotic syndrome characterized by the triad of proteinuria, hypoalbuminemia and edema in patients who do not respond, or only partially respond, to the initial trial of corticosteroids. Patients may be multidrug resistant or may be sensitive to second-line immunosuppressive therapy.
Epidemiology
The annual incidence of idiopathic nephrotic syndrome is estimated at 1/34,000 children, although this varies according to ethnicity or the country of origin. Steroid-resistance is described in 2.1-27.3% of children with idiopathic nephrotic syndrome, with annual incidence estimated at 1/390,000. In most regions, there is a male predominance, although reported ratios vary between 1.0 and 3.8.
Clinical description
Children with nephrotic syndrome generally present with signs of edema, for instance with swollen eyes, abdomen, scrotum, and/or ankles. Evaluation by a pediatrician/pediatric nephrologist will confirm the diagnosis of idiopathic nephrotic syndrome. Some criteria may increase the chance of becoming steroid-resistant, such as hematuria, hypertension and/or acute kidney injury at presentation, as well as having a positive family history for kidney disease or signs of extra-renal manifestations. Histologically, children with steroid-resistant nephrotic syndrome (SRNS) present most frequently with focal segmental glomerulosclerosis, less frequently with diffuse mesangial sclerosis, and more rarely with minimal change disease.
Etiology
After exclusion of the genetic forms, SRNS may result from a circulating permeability factor; such a factor is still unidentified, but its presence may result in a relapse of nephrotic syndrome after kidney transplantation. SRNS can also be secondary to an infection (such as CMV or HIV) or an underlying kidney disease (such as IgA nephropathy, membranous nephropathy or a collagenopathy).
Diagnostic methods
SRNS is established when treatment with corticosteroids does not result in a full remission within 4-6 weeks. In such patients, it is essential to search for an underlying genetic cause, underlying kidney disease (by performing a kidney biopsy) and by excluding other causes of the SRNS (laboratory work up for i.e. sickle cell disease, HIV, SLE, HepB, malaria, parvovirus B19).
Differential diagnosis
Genetic forms of SRNS should be excluded, as this has an important impact on subsequent therapies. Underlying kidney disease (membranous nephropathy, membranoproliferative glomerulonephritis, C3 glomerulopathy, IgA nephropathy, lupus nephritis, Alport syndrome/collagen IV glomerulopathy, amyloidosis, thrombotic microangiopathy), circulating permeability factor, infectious causes (cytomegalovirus (CMV), human immunodeficiency virus (HIV), hepatitis B, malaria, parvovirus B19, syphilis), sickle cell disease, and malignancy (mainly lymphoma) should also be excluded.
Management and treatment
Treatment of a child with SRNS is based on reduction of proteinuria, immunosuppressive treatment, and supportive therapy. All children with SRNS should be treated with either an ACE inhibitor or an angiotensin-receptor blocker. Children in whom a genetic diagnosis is disproven and who have a GFR>30 ml/min/1.73m2, should receive immunosuppressive treatment, using calcineurin inhibitors, while corticosteroids are slowly tapered and discontinued. For current treatment schedules, please refer to international guidelines on treatment of SRNS. Supportive therapy consists of salt restriction and, on indication, diuretics to control edema. Albumin infusions are restricted to patients with symptomatic hypovolemia. Standard antibiotic prophylaxis is not recommended. Dysregulation of thyroid function, lipid levels, and calcium, magnesium, and vitamin D levels may occur, and should be treated accordingly. Thromboprophylaxis may be indicated in children with central venous catheters or with a history of thromboembolic events.
Prognosis
Children with SRNS who respond to immunosuppressive treatment and reach complete remission may remain in remission, or exhibit a relapse-remitting course, which is usually steroid-sensitive. Multi-drug resistant SRNS cases generally do continue to kidney failure. There is a high risk of post-renal transplant relapse which may occur within a day after kidney transplantation.

                            Last update: 
                            June 2022


                            - Expert reviewer(s): 
                            Pr M.F. [Michiel] SCHREUDER | ERKNet* - Dr Marina VIVARELLI | ERKNet*


                                * European Reference Network