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 a study of 37 patients with MCD, 27 patients with FSGS, 30 patients with other glomerulopathies, and 71 healthy controls, Ling and colleagues found that urinary CD80 concentrations were significantly higher in patients with active MCD compared with patients with FSGS or other glomerulopathies and controls. At a cutoff value of 328.98 ng/g creatinine, urinary CD80 had a sensitivity of 81.1 % and a specificity of 94.4 % for diagnosing MCD.
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.
Hypovolemic shock is perhaps the most serious complication of MCD. Hypovolemic shock typically occurs during the edema-forming phase of relapse and may be precipitated by diarrhea, sepsis, drainage of ascitic fluid, or the use of diuretics.
Hypertension, somewhat paradoxically, also may occur in approximately 9-14% of children. Hypertension occurs in approximately 30% of adults, with a greater incidence in older patients (>60 y).
Thromboembolic events are serious complications of nephrotic syndrome. Peripheral thrombosis may result in gangrene, and deep venous thrombosis in the legs or pelvic veins may be a source of pulmonary emboli. Bacterial infections, especially peritonitis, occur with greater frequency, partly because of the loss of immunoglobulin G (IgG) and complement factors B and D in the urine. In fact, the largest reduction in mortality in these patients follows the introduction of antibiotics rather than any specific therapy.
Rates of MCD vary as follows:
Facial edema is noted first. Edema may be preceded by an upper respiratory tract infection, an allergic reaction to a bee sting, the use of certain drugs, or malignancies.
Malaise and easy fatigability can occur. Weight gain often is an additional feature.
The patient also may present with one or more of the following:
Almost all cases are idiopathic, but a small percentage of cases (approximately 10-20%) may have an identifiable cause. Secondary cases may be due to any of the following:
The blood pressure usually is normal in children but may be elevated in adults. (In addition, the plasma creatinine in adults is often slightly elevated at presentation.)
Dependent edema is the most prominent sign. The retina has a wet appearance. Subungual edema with horizontal lines (called Muehrcke lines) also may occur.
Hernias may be found, and the elasticity of the ears may be decreased.
Heavy proteinuria over an extended period of time leads to a state of protein depletion with muscle wasting, thinning of the skin, and growth failure.
Pleural and ascitic fluid can accumulate. Rarely, cellulitis, peritonitis, or pneumonia may be the first indication of an underlying nephrotic syndrome.
Children may have growth failure.
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.
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.
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.
Urinalysis findings are benign in minimal-change disease (MCD), but profound proteinuria and oval fat bodies may be observed. In children, the critical level for diagnosis is proteinuria of more than 40 mg/h/m2. In adults, the threshold is more than 3.5 g/d/1.73 m2.
A random albumin-to-creatinine concentration ratio is in excess of 5. Urine specific gravity is high because of proteinuria. A 24-hour urine measurement should be obtained for protein and creatinine clearance.
Hypoalbuminemia is an important marker of nephrotic syndrome. The level at which edema occurs varies, but it tends to be lower in children than in adults. Nephrotic syndrome in children is defined by a serum albumin of less than 2.5 g/dL. Hyperlipidemia also is a feature of a nephrotic state.
Other laboratory findings are as follows:
Renal sonogram results are normal in patients with MCD.
Because MCD accounts for 90% of all cases of idiopathic nephrotic syndrome in children, renal biopsy is not part of the initial workup for MCD in that age group. Instead, biopsy is performed only in those children who fail to achieve remission with an empiric course of corticosteroids. In contrast, a renal biopsy is performed in all adult patients with nephrotic syndrome, before the initiation of treatment for MCD.
Consultation with a nephrologist generally is needed. The nephrologist has the expertise to perform and interpret the renal biopsy. A renal pathologist has the expertise to interpret biopsy findings under light microscopy, immunofluorescence, and electron microscopy.
Because of the high prevalence of minimal-change disease (MCD) in children with nephrotic syndrome, an empiric trial of corticosteroids commonly is the first step in therapy. 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 2 mg/kg/day (not to exceed 80 mg/day). After the remission of proteinuria, prednisone is continued for another 6 weeks, at lower doses.
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. For example, MCD secondary to Hodgkin lymphoma is frequently resistant to steroids and will remit with cure of the primary disease. Generally, if proteinuria persists after two relapses or courses of steroids, a tissue diagnosis should be made before starting cytotoxic or immunosuppressive therapy.
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.
Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs), 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 ACE inhibitors and ARBs.
The presence of hypovolemia necessitates immediate volume expansion with purified plasma protein fraction and isotonic sodium chloride solution. Parenteral albumin infusions are not appropriate for long-term management of hypoalbuminemia because they have only a transient effect. Such crises should be avoided with recognition of the earlier signs of hypovolemia, including abdominal pain, increase in hematocrit, and response to contributing factors (eg, diarrhea, septicemia, diuretic therapy).
Edema should be controlled by dietary sodium restriction. Small amounts of edema are not of much clinical significance. The use of diuretics should be reserved for patients with severe edema, particularly in the presence of respiratory or gastrointestinal symptoms, and when the condition restricts activity.
Thrombotic episodes should be prevented by mobilization and meticulous attention to venipuncture and intravenous infusion sites. Established episodes should be managed with heparinization.
Infections must be treated aggressively. Cellulitis, peritonitis, otitis, and pneumonia are common infections. Susceptibility to pneumococcal infections warrants the administration of penicillin prophylaxis to patients in relapse. Corticosteroids increase susceptibility to infection.
An adequate dietary protein intake, in accordance with the recommended daily allowance (RDA) is necessary. No evidence suggests that hepatic albumin synthesis is elevated with protein intake that is higher than the RDA.
Dietary sodium restriction helps forestall the progression of edema and also is prudent in the management of hypertension.
Mobilization, rather than bed rest, is indicated to avoid thromboembolic complications.
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:
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]
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.
MCD is treated in the outpatient setting. Followup care includes the following:
The most common complications are the adverse effects of medications. Additional complications may include peritonitis, infections, and acute renal failure. Acute renal failure occurs because of either acute tubular necrosis or acute tubulointerstitial nephritis. In a retrospective review of 95 adult patients with MCD, Waldman et al reported that 24 patients had acute renal failure, with these individuals tending to be older and hypertensive, and to have lower serum albumin and more proteinuria than did patients who did not suffer acute renal failure.
Patients with nephrotic syndrome have an increased incidence of arterial and venous thromboemboli, particularly deep vein and renal vein thrombosis. Renal vein thrombosis is known to occur in patients with MCD, although the incidence is lower than in patients with membranous nephropathy.
Hypercholesterolemia and hypertriglyceridemia can lead to accelerated atherosclerosis and perhaps cause progressive glomerular injury.
Use of antibiotics and glucocorticoids and better-organized schedules of management have substantially reduced the mortality rates associated with MCD. Deaths still occur from disease complications.
Relapses eventually cease. Only approximately 5% of children continue to have steroid-responsive relapses when older than 18 years.
Adults have a similarly good prognosis. Survival rates of 85-90% are observed 10 years or more after disease onset.
Chronic renal failure is extremely rare in patients who are steroid responsive. If chronic renal failure occurs, the possibility that the pathologic lesion is different or has evolved must be considered.