Symptomatic treatment is similarly to that of children who are steroid sensitive. This includes dietary recommendations if no added salt and adequate intake of proteins and vitamins with reduced intake of foods high in cholesterol. Diuretics are used for the treatment of edema. If there is anasarca, salt free albumin with loop diuretics are given for control of edema. In addition, prevention and appropriate treatment of infections and thromboembolic complications, and treatment of hypovolemia, hypertension and hyperlipidemia. If the latter is not controlled by dietary restriction alone, lipid lowering agents are used.

Immunosuppressive therapy

The optimal approach to SRNS is uncertain. The reports of the large number of agents used as specific therapy bears testimony to the lack of a single effective agent for the treatment of this condition.

Alkylating Agents
Cyclophosphamide and chlorambucil have been used either alone, in combination with oral steroids or with high dose pulse steroids. These regimens have met with variable success rates of inducing remission ranging from 10% to 70% [33,34,35,36,37,38]. Many patients exhibit features of steroid toxicity. The use of pulse dose cyclophosphamide over a few months induced remission in 25-60% of children with SRNS [38,39,40].

Cyclosporin
Initial studies evaluating the efficacy of cyclosporin in patients with SRNS showed a relatively small benefit. In eight uncontrolled studies involving 60 patients, complete remission was induced in only 12 (20%) [41]. In the study by the French Society of Pediatric Nephrology involving 65 children with SRNS, complete remission was observed in 42% of children (48% with minimal change disease and 32% with FSGS). Eight of the 27 responders became steroid-sensitive when they subsequently relapsed [42]. Patients who respond to cyclosporin often relapse when the dose is tapered or discontinued [43]. Many reports indicate that the prolonged use of cyclosporin is associated with chronic nephrotoxicity. The most prominent histological feature of chronic cyclosporin nephrotoxicity is the presence of tubulointerstitial lesions, characterised by striped interstitial fibrosis containing groups of atrophic tubules. Cyclosporin associated arteriolopathy is rarely observed. Other side effects include elevation of blood pressure, hyperkalaemia, hypertrichosis, gum hypertrophy, and hypomagnesaemia.

Mycophenolate Mofetil
Mycophenolate Mofetil (MMF) is the prodrug of mycophenolic acid which is formed by hydrolysis. Mycophenolic acid is a potent, selective, uncompetitive, and reversible inhibitor of inosine monophosphate dehydrogenase (IMPDH). The latter is an enzyme required for de novo purine synthesis. Mycophenolic acid inhibits B and T-lymphocyte proliferation, as these cells are critically dependant upon de novo purine synthesis for their proliferation whereas other cell types can utilize salvation pathways for purine synthesis. Mycophenolic acid also prevents glycosylation of lymphocyte and monocyte glycoproteins that are involved in the intracellular adhesion of leucocytes to endothelium [44]. Mycophenolic acid also induces lymphocyte apoptosis and alters cell-surface adhesion molecules and cytokine gene expression [45]. MMF has been used in a few children with SRNS and FSGS [46]. Although in this study it was shown to decrease proteinuria, none of the patients achieved complete remission. In a study by Mendizabal et al [47], MMF was given to 5 children with SRNS. Only one achieved complete remission. Withdrawal of the drug led to relapse with one patient developing chronic renal failure. To date a paucity of data exists concerning the use of MMF in SRNS. The advantage with the use of MMF is its benign side effect profile compared to prednisone and cyclosporine. Its use is not associated with nephrotoxicity, hepatotoxicity, neurotoxicity, hyperglycaemia or abnormalities of lipid metabolism.

Tacrolimus
The main mechanism of action of tacrolimus is through the inhibition of 1L-2 dependant T-cell activation, a process occurring during the early phase of T-cell activation [48]. Tacrolimus also inhibits B-cell activation, in part through its action on T-cells and also directly by blocking TNF- a gene transcription by anti-Ig antibody [48]. The drug only becomes active when complexed with a distinct endogenous intracellular receptor (cystocolic binding protein-FRBP12) known as immunophilin [49]. The immunophilin drug complex interferes with intracellular calcium-dependent signal transduction pathways, processes that are central to T-cell activation [50,51,52,53]. The common biological target for the resulting complex is the calcium and calmodulin-dependent protein phosphatase, calcineurin. Case reports and single centre studies have shown tacrolimus to be effective in treating SR FSGS [54,55,56,57].

Other Agents
Other agents used in steroid dependent or SRNS include inter alia vincristine, azathioprine, sirolimus and mizoribine. Immunoglobulin transfusions have also been used with varying success.

Conclusion
Childhood SRNS continues to pose a major challenge to the attending physician. Although specific genetic factors such as mutations in the NPHS2 and other genes have been identified, suggesting a possible genetic basis for the SRNS with FSGS in a subgroup of patients, in the majority of patients, the pathogenesis remains elusive. The plethora of agents used in the treatment of this condition bears testimony to the lack of an optimal approach in managing this condition. Although data are lacking, use of these drugs, often in combination, is warranted in children with SR idiopathic NS together with adjunctive therapy.

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