Minimal-Change Disease Medication
- Author: Abeera Mansur, MD; Chief Editor: Vecihi Batuman, MD, FACP, FASN more...
Pharmacologic treatment in patients with minimal change disease (MCD) includes the use of diuretics to decrease severe edema. Nonsteroidal anti-inflammatory drugs (NSAIDs) also can be used to decrease proteinuria.
Patients usually respond to steroids. The response is defined in terms of proteinuria, as follows:
Complete remission - Complete resolution of proteinuria for at least 3-5 consecutive days
Partial remission - Reduction in the degree of proteinuria without complete clearing
Relapse - Reoccurrence of proteinuria for at least 3-5 consecutive days
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 falls to a very low level, high-dose alternate-day therapy is continued for several weeks to 1 month and prednisone is then slowly tapered over several months in an attempt to reduce the likelihood of relapse.
Patients with steroid-sensitive MCD have complete remission within 8-12 weeks with infrequent relapses. Children usually respond within 4-6 weeks. Adults tend to respond slowly, with more than 25% taking as long as 12-16 weeks to attain complete remission. Treatment usually is continued for another 6 weeks after complete remission of proteinuria occurs.
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. Relapse in these patients can occur either during tapering of steroids or after cessation of therapy. In these patients, cytotoxic drugs (eg, cyclophosphamide, chlorambucil, or cyclosporine) can be considered to either induce a remission or decrease the adverse effects of continuous steroid use.
Cyclophosphamide may be given in a dosage of 2 mg/kg/d for 8-12 weeks. Cyclosporine is given in a dosage of 4-6 mg/kg/d.) also can be used in patients who continue to relapse or who are steroid-dependent. Because cyclophosphamide is less expensive than cyclosporine and has a better response rate, it is preferable to cyclosporine in most patients with steroid-dependent or frequently relapsing MCD.
Mycophenolate mofetil (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. 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). 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. 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.[10, 11]
Rituximab has also been shown to be very effective in small trials in adults with steroid resistance.
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. The treatment of MCD with tacrolimus has produced varying results.[14, 15, 16]
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. In children with steroid-resistant nephrotic syndrome, those who received tacrolimus (another calcineurin inhibitor) and steroids had a higher complete/partial remission rate and increased chances of sustained remission with fewer adverse effects compared with those who received cyclophosphamide.
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 in patients who are steroid dependent or have 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.[10, 18, 19]
These agents control volume overload.
Has potent diuretic effects by blocking the sodium reabsorption in the thick ascending limb of the loop of Henle.
For remission of proteinuria.
Exerts anti-inflammatory effect via the inhibition of inflammatory mediator gene transcription.
For remission of nephrotic syndrome.
Interferes with normal function of DNA by alkylation and cross-linking strands of DNA and by possible protein modification.
For remission of nephrotic syndrome.
Inhibits production and release of IL-2, leading to inhibition of IL-2–mediated activation of T lymphocytes.
To induce remission of proteinuria. Interferes with DNA replication and RNA transcription.
To induce remission of nephrotic syndrome.
Stimulates formation of antibodies and enhances T-cell responses. Acts as a biochemical modulator of fluorouracil.
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.
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