Minimal-change disease (MCD), also known as lipoid nephrosis or nil disease, is the most common single form of nephrotic syndrome in children. It refers to a histopathologic lesion in the glomerulus that almost always is associated with nephrotic syndrome. It typically is a disease of childhood, but it also can occur in adults.
It is postulated that MCD is a disorder of T cells, which release a cytokine that injures the glomerular epithelial foot processes. This, in turn, leads to a decreased synthesis of polyanions. The polyanions constitute the normal charge barrier to the filtration of macromolecules, such as albumin. When the polyanions are damaged, leakage of albumin follows. The identity of this circulating permeability factor is uncertain, although it is postulated that it may be hemopexin.
Some of the cytokines that have been studied in MCD are interleukin-12 (IL-12) and interleukin-4 (IL-4). IL-12 levels have been found to be elevated in peripheral blood monocytes during the active phase and normalized during remission. Interleukin-18 (IL-18) can synergize with IL-12 to selectively increase the production of vascular permeability factor from T cells. In addition, levels of IL-4 and CD23 (a receptor for immunoglobulin E [IgE] ) have been found to be elevated in peripheral blood lymphocytes.
Synaptopodin is a proline-rich protein intimately associated with actin microfilaments present in the foot processes of podocytes. Greater synaptopodin expression in podocytes is associated with a significantly better response to steroid therapy. On the other hand, the expression of synaptopodin does not predict progression of MCD or diffuse mesangial hypercellularity to focal segmental glomerulosclerosis (FSGS). Thus, this marker could be used in the future to help determine appropriate therapy.
Interleukin-13 (IL-13) has been implicated in the pathogenesis of MCD. In a study on Chinese children in Singapore, it was shown that IL-13 genetic polymorphisms correlate with the long-term outcome of MCD. An animal study by Lai et al suggested that IL-13 overexpression can cause podocyte foot process fusion and proteinuria.
In patients who develop acute renal failure, endothelin 1 expression is greater in the glomeruli, vessels, and tubules than in the nonacute renal failure group. The glomerular epithelial cells (podocytes) and the slit diaphragm connecting the podocyte foot processes play a primary role in the development of proteinuria.
Nephrin is a major component of the slit diaphragm. The slit diaphragm is often missing in MC nephrotic syndrome (MCD) kidneys. The role of nephrin and the slit diaphragm in MCD is not known. However, genetic variants of a glomerular filter protein may play a role in some patients with MCD.
Izzedine et al found a lack of glomerular dysferlin expression associated with minimal-change nephropathy in a patient with limb-girdle muscular dystrophy type 2B. In the same study, 2 of 3 other patients with dysferlinopathy had microalbuminuria.
CD 80, a protein found in B cells and responsible for T-cell activation, is found to be increased in patients with MCD. However, the levels of this protein are not elevated in the urines of patients with FSGS compared with patients with MCD. Thus, this may have clinical applicability in distinguishing these two entities.
In preadolescents, minimal-change nephrotic syndrome (MCNS) makes up 85-95% of all cases of nephrotic syndrome. In adolescents and young adults, the prevalence is 50%, while in adults, MCNS accounts for 10-15% of primary nephrotic syndrome cases. The incidence of nephrotic syndrome is 2-7 new cases annually per 100,000 children, and the prevalence is 15 cases per 100,000 children.
Very few patients progress to end-stage renal disease. These patients are those who have FSGS that has been misdiagnosed as MCD.
Almost all cases are idiopathic, but a small percentage of cases (approximately 10-20%) may have an identifiable cause. Causes may include the following:
Light microscopy: In patients with MCD, the glomerulus is, by definition, normal or nearly so when examined with the light microscope; however, the precise limits of normal are not clearly defined. This creates difficulty in differentiating the appearance of minimal change with mild mesangial proliferation from a mesangial proliferative glomerulonephritis. Diagnosis can be even more difficult because, at the peak age of onset (approximately 3 y), the mesangial and epithelial cells are more prominent. In adult patients, diagnosis is made more challenging by superimposed arterionephrosclerosis secondary to hypertension. In children with frequently relapsing MCD, some involuted glomeruli may be present. These lesions are small and sclerotic but retain their podocyte and parietal epithelial cell constituents. The presence of these glomeruli is related to the duration of the disease.
The most common tubular lesion is protein and lipid droplets in epithelial cells due to increased reabsorption. The presence of areas of tubular atrophy and interstitial fibrosis should raise the suspicion of FSGS.
Immunohistology: These studies usually do not demonstrate significant glomerular deposition of immunoglobulins or complement components in patients with MCD. Some biopsy specimens may be positive for low-level IgM deposits not accompanied by mesangial dense deposits.
Electron microscopy: Retraction of the epithelial foot processes is observed consistently in patients with MCD. This is, at times, erroneously described as foot-process fusion and results from disordered epithelial cell structure with withdrawal of the dendritic process. This finding is not unique to MCD, and the diagnosis is one of exclusion of other diseases based on lack of other processes on light microscopy, immunohistology, or electron microscopy.
Corticosteroids are the treatment of choice, leading to complete remission of proteinuria in most cases. Approximately 90% of children respond within 2 weeks to prednisone at a dose of 60 mg/msq/d. The treatment is continued for another 6 weeks, at lower doses of prednisone, after the remission of proteinuria. In some children, proteinuria fails to clear by 6-8 weeks, and performing a renal biopsy may be useful to determine if another process may be present.
Adults respond more slowly than children. A response in up to 80-90% has been recorded in adolescents and adults. However, the time to remission is up to 16 weeks. If patients are steroid-resistant or they relapse frequently, a trial of immunosuppressants is given.
MCD secondary to Hodgkin lymphoma is frequently resistant to steroids and will remit with cure of the primary disease.
Angiotensin converting enzyme inhibitors and angiotensin II receptor blockers, alone or in combination should be used with a goal of reducing the proteinuria. Blood pressure and renal function should be monitored closely in patients on angiotensin converting enzyme inhibitors and angiotensin II receptor blockers.
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:
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. 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.[9, 10]
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.[13, 14, 15]
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 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, 17]
Clinical Context: Has potent diuretic effects by blocking the sodium reabsorption in the thick ascending limb of the loop of Henle.
These agents control volume overload.
Clinical Context: Exerts anti-inflammatory effect via the inhibition of inflammatory mediator gene transcription.
For remission of proteinuria.
Clinical Context: Interferes with normal function of DNA by alkylation and cross-linking strands of DNA and by possible protein modification.
For remission of nephrotic syndrome.
Clinical Context: Inhibits production and release of IL-2, leading to inhibition of IL-2–mediated activation of T lymphocytes.
Clinical Context: To induce remission of proteinuria. Interferes with DNA replication and RNA transcription.
For remission of nephrotic syndrome.
Clinical Context: Stimulates formation of antibodies and enhances T-cell responses. Acts as a biochemical modulator of fluorouracil.
Clinical Context: 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.
To induce remission of nephrotic syndrome.