Treatment of steroid-resistant pediatric nephrotic syndrome

1) SRNS

SRNS is defined as NS that does not respond to one month's treatment with oral prednisolone at a dosage of 60 mg/m²/day. When SRNS is suspected, a meticulous search for the possibility of concurrent infection (e.g., sinusitis and skin infection), drug interaction (e.g., antiepileptic drugs), inappropriate dosage, or compliance problem is necessary. If those possibilities are ruled out, tissue diagnosis from a kidney biopsy is the next step. Histological findings of SRNS are, and occasionally, a secondary glomerulopathy such as amyloidosis is unexpectedly found. At the same time, mutational analysis for genes known to cause SRNS is recommended. Mutations of WT1, INF2, LAMB2, ACTN4, NPHS1, and NPHS2 have been found in Korean children with SRNS by Cheong et al.2-5). While more aggressive treatment is required to achieve remission in the case of SRNS of unknown cause (primary SRNS) to achieve remission, such an aggressive treatment is not effective for those with SRNSthat arises from genetic causes; therefore genetic testing may shield these children from the unnecessary side effects of immunosuppressive medications (Fig. 3).

Fig. 3

Approach of childhood-onset nephrotic syndrome. NS, nephrotic syndrome; GHU, Gross hematuria; BP, blood pressure; FANA, fluorescent antinuclear antibody test; HBV, Hepatitis B virus; HCV, Hepatitis C virus; HIV, Human immunodeficiency virus; PPD, purified protein derivative.

2) Methylprednisolone pulse treatment

When oral prednisolone treatment fails, intravenous methylprednisolone pulse therapy (30 mg/kg, every other day, 6 doses in total) is commonly tried. The original treatment protocol developed by Mendoza et al.6); however, remission rates as high as 70% were reported with this protocol. The current practice involves the administration of 3 to 6 doses of high-dose intravenous methylprednisolone before kidney biopsy, and patients who respond to this treatment are often regarded as responsive to steroid therapy. Commonly encountered side effects of methylprednisolone pulse treatment are infection, Cushing's syndrome, hypertension, glucose intolerance, and arrhythmia during infusion.

3) Calcineurin inhibitors (CNI)

Cyclosporine and tacrolimus (FK-506) were originally introduced as immunosuppressive agents for allograft transplantation due to their inhibitory effect on calcineurin, a key signal transduction molecule activating T lymphocytes. In the past, the anti-proteinuric effect of calcineurin inhibitors (CNIs) was believed to arise from their immunosuppressive effect on lymphocytes7). However, CNI CNIs have recently been found to stabilize the cytoskeleton of glomerular epithelial cells (podocytes) and thereby reduce glomerular proteinuria8). This effect explains why cyclosporine has partial success in some cases of proteinuria of proteinuria arising from genetic causes9). The response rate of SRNS to cyclosporine is roughly 40 to 60. A typical SRNS treatment protocol using cyclosporine involves the administration of cyclosporine (150 to 200 mg/m²/day) and prednisolone (30 mg/m²/day) for 1 month, followed by alternate-day prednisolone for 5 months; this has been shown to result in complete remission in 42% of recipients within the first 6 months10). Cyclosporine has a well-known spectrum of side effects such as nephrotoxicity, infection, hypertension, hyperkalemia, renal tubular acidosis, tremor, glucose intolerance, gum hypertrophy, and hirsutism. The therapeutic drug level (trough) of cyclosporine is <100-200 ng/mL.

Another CNI, tacrolimus, is also used in the treatment of SRNS, although Korean Food and Drug Administration has not approved this medication for treatment of NS11). The dosage of tacrolimus for SRNS is 0.05 to 1 mg/kg/day with a trough level <5 to 10 µg/L. Tacrolimus has a similar spectrum of side effects as cyclosporine but does not cause gum hypertrophy or hirsutism.

4) Alkylating agents and anti-proliferative agents

While cyclophosphamide or chlorambucyl have been used in early reports; however, a recent review by the Children's Nephrotic Syndrome Consensus Conference concluded that these alkylating agents were not superior to steroid mono-therapy12). Additionally, mofetil13) and sirolimus14) have also been tried recently with moderate results.

1) Renal replacement therapy for children with nephrotic syndrome

2) Plasmapheresis

Observations of SRNS recurrence following graft resulted in the introduction of the concept of a 'circulating permeability factor' as a pathogenic mechanism of SRNS19). Thus, the first-line treatment to avoid recurrence is to remove the 'permeability factor' by plasmapheresis therapy. Plasmapheresis replaces patient's plasma containing the 'permeability factor' with 4 to 5% albumin solution or fresh frozen plasma. Immediate initiation of this treatment may induce remission in 50 to 90% of recurrent cases20).

Reports of favorable outcomes of plasmapheresis in patients with recurrent SRNS resulted in the application of this treatment modality in primary SRNS of native kidneys, with success in some cases21). However, it is not yet possible to predict patient responsiveness to this procedure, and the effectiveness of pre-emptive plasmapheresis to prevent SRNS recurrence following transplantation has not yet been established.

3) Rituximab

Rituximab is a monoclonal antibody against CD20, a marker of B cells, which is manufactured as a therapeutic agent for B cell lymphoma. Following the report of a case of post-transplant lymphoproliferative disease where rituximab treatment eradicated both recurrent SRNS and B cell lymphoma after kidney transplantation22), this biological agent has been used for SRNS as a rescue treatment23) with success rate of 20 to 50%. However, treatment indications and an optimal rituximab treatment protocol have not yet been established, and significant adverse effects such as opportunistic infections and rituximab-associated lung injury24) have been reported.