Minimal-Change Disease Medication

Diuretics are used to decrease severe edema. NSAIDs also can be used to decrease proteinuria. Patients usually respond to steroids. The response of patients to steroids is used to divide patients into various groups. The following terms are used to categorize the response of patients:

Complete remission: This is defined as complete resolution of proteinuria for at least 3-5 consecutive days.

Partial remission: This is defined as a reduction in the degree of proteinuria without complete clearing.

Relapse: This is defined as a reoccurrence of proteinuria for at least 3-5 consecutive days.

Because MCNS accounts for 90% of all cases of idiopathic nephrotic syndrome in children, steroids are started empirically. A biopsy is performed only in those cases where no remission occurs. In comparison, a biopsy is performed in all adults before the initiation of treatment. Adults tend to respond more slowly, with more than 25% taking as long as 12-16 weeks to undergo complete remission. A typical initial regimen in adults consists of oral prednisone in a daily dosage of 1 mg/kg of body weight for 8-16 weeks (or for 1 wk after remission has been induced). The patient is then placed on an alternate-day single-dose (1 mg/kg) regimen to minimize the incidence of adverse effects. If proteinuria disappears or is reduced to a very low level, high-dose alternate-day therapy is continued for several weeks to 1 month and then slowly tapered over several months in an attempt to reduce the likelihood of relapse.

To prevent relapse, steroids are continued for several weeks after remission. Patients are grouped into the following:

Steroid-sensitive patients: These patients have complete remission within 8-12 weeks with infrequent relapses. Children usually respond within 4-6 weeks, whereas adults respond in up to 15 weeks. Treatment usually is continued for another 6 weeks after complete remission of proteinuria occurs.

Steroid-dependent patients or frequent relapsers: If remission is followed by recurrence, a second course of steroids is given. Those patients who need steroids repeatedly are categorized as frequent relapsers or steroid-dependent patients. Relapse in these patients can occur either during tapering of steroids or after cessation of therapy. In these patients, cytotoxic drugs, such as Cytoxan, chlorambucil, or cyclosporine, can be considered to either induce a remission or decrease the adverse effects of continuous steroid use. Cytotoxic drugs, such as 2 mg/kg/d of cyclophosphamide for 8-12 weeks, can be used in such patients. Cyclosporine (4-6 mg/kg/d) also can be used in patients who continue to relapse or who are steroid-dependent. Because cyclophosphamide is cheaper and has a better response rate, it is preferable over cyclosporine in most patients with steroid-dependent or frequently relapsing MCD.

MMF may also be beneficial to patients with frequent relapses. This was suggested by a small study where 7 patients with MCD and FSGS with multiple relapses were treated with MMF (1 g bid). After 1 year, 5 of the 7 patients were still in remission, and the steroid dose was significantly decreased. In addition, the immunomodulator levamisole also has been used in children.

Steroid-resistant patients: If no reduction in proteinuria occurs by 12-16 weeks, adults are considered steroid-resistant. The most common cause of this is misdiagnosis. Studies in adults and children have shown that both cyclophosphamide and cyclosporine added to steroid treatment may induce remission.^[6] Moreover, if these patients relapse at a later time, they tend to become steroid-sensitive.

Secondary steroid-resistant: Some patients develop secondary steroid resistance after an initial response to steroids.

In children, repeat biopsy can alter the treatment plan in a significant number of patients. Long-term follow-up of patients with MCD persisting post puberty shows that they are at increased risk of osteoporosis, myopia, and hypertension.

In patients who do not respond to treatment, follow-up biopsies have been found to show either IgM nephropathy or FSGS.

A study by Swartz et al of 55 children with steroid-resistant or steroid-dependent MCD determined that 23 of these patients also had mesangial IgM that was visible through immunofluorescence (one of the characteristics of IgM nephropathy).^[7] The investigators also found that the children with MCD and immunofluorescently-visible IgM responded better to treatment with cyclosporine than to therapy with cyclophosphamide.

Adults are particularly prone to the adverse effects of corticosteroids, but they do well on cyclophosphamide.

Cyclosporine may be used as an alternative to cyclophosphamide in order to avoid toxicities associated with the latter.^[8] Keeping the dosage of cyclosporine at a minimum and carefully monitoring the drug’s levels have been shown to be helpful in avoiding cyclosporine-associated nephrotoxicity.

Rituximab has been shown to be effective against minimal-change disease. Relapse has been linked to the reappearance of B19 cells, which rituximab depletes. Rituximab may therefore have a role in the treatment of steroid-dependent and multirelapsing patients. In one trial with immunosuppressant-dependent young adults, a good response was seen with rituximab. It has been shown to be reasonably well tolerated.^{[9, 10]}

In 20% of steroid-resistant patients, a genetic mutation may be responsible. One of these is the NPHS2 mutation; however, heterozygotes respond well to steroids.^[11] The treatment of MCD with tacrolimus has produced varying results.^{[12, 13, 14]}

The choice of immunosuppressants includes cyclophosphamide and chlorambucil. These drugs expose the patient to a wide range of serious adverse effects that include life-threatening infections, gonadal dysfunction, bone marrow dysfunction, and, in the case of chlorambucil, increased risk of leukemia. Pulse cyclophosphamide failed to adequately suppress recurrence of minimal-change nephrotic syndrome in a small group of children who were steroid-dependent. Cyclosporine is considered to be an acceptable drug for maintenance therapy in patients with frequent relapses and steroid dependency. However, it is less efficacious than cyclophosphamide at maintaining sustained remission.

Mycophenolate mofetil (MMF) has been shown in limited studies to be beneficial to patients who are steroid-dependent or with frequent remissions. Unfortunately, the evidence for the benefit of this drug is scant at this time, and it should be considered only when patients develop serious adverse effects to steroid treatment and refuse treatment with cyclophosphamide. Long-term remission with rituximab (an anti-CD20 antibody) in patients who have failed conventional immunosuppressive therapy has been tried with reasonable success and acceptable side effect profile. However, randomized controlled trials need to be conducted before guidelines can be issued.^{[9, 15]}

Class Summary

These agents control volume overload.

Furosemide (Lasix)

Has potent diuretic effects by blocking the sodium reabsorption in the thick ascending limb of the loop of Henle.

Class Summary

For remission of proteinuria.

Prednisone (Sterapred)

Exerts anti-inflammatory effect via the inhibition of inflammatory mediator gene transcription.

Class Summary

For remission of nephrotic syndrome.

Cyclophosphamide (Cytoxan, Neosar)

Interferes with normal function of DNA by alkylation and cross-linking strands of DNA and by possible protein modification.

Class Summary

For remission of nephrotic syndrome.

Cyclosporine A (Sandimmune, Neoral)

Inhibits production and release of IL-2, leading to inhibition of IL-2–mediated activation of T lymphocytes.

Chlorambucil (Leukeran)

To induce remission of proteinuria. Interferes with DNA replication and RNA transcription.

Class Summary

To induce remission of nephrotic syndrome.

Levamisole (Ergamisol)

Stimulates formation of antibodies and enhances T-cell responses. Acts as a biochemical modulator of fluorouracil.

Mycophenolate mofetil (CellCept)

Inhibitor of de novo purine pathway with preferential inhibitory effects on T and B lymphocyte proliferation, has been used to treat steroid-dependent nephrotic syndrome.