Chapter 24. Minimal Change Disease

Minimal change disease (MCD) is a term used to describe the pathologic findings in a group of patients who present with heavy proteinuria, typically leading to nephrotic syndrome. On renal biopsy the findings include apparently normal glomeruli on light microscopy, negative immunofluorescence, and diffuse podocyte foot process effacement on electron microscopy. While occasionally MCD may be secondary to another condition such as lymphoma, in the majority of cases MCD is one of the idiopathic renal diseases. Because MCD is most likely to be the diagnosis in children presenting with the nephrotic syndrome, the majority of children do not undergo a kidney biopsy, but receive empiric treatment without one. Seventy percent of children with MCD present before age 5 years, and 20–30% of adolescents who present with nephrotic syndrome have MCD. Nevertheless, MCD is the third commonest finding in adults with nephrotic syndrome, after membranous nephropathy and focal, segmental glomerulosclerosis. The typical patient with MCD responds to therapy but experiences recurrent relapses.

• Heavy proteinuria, typically leading to nephrotic syndrome.
• Renal biopsy with minimal changes on light microscopy, negative immunofluorescent microscopy, and podocyte foot process effacement on electron microscopy (Figure 24–1).
• Usually there is no known etiology, although secondary MCD may be associated with neoplastic disease, toxic or allergic reactions to drugs, infections, autoimmune disorders, or other miscellaneous disorders.

MCD is the most common cause of nephrotic syndrome in children and the third most common cause of nephrotic syndrome in adults. In children the incidence of nephrotic syndrome is two to seven cases per 100,000 children and the prevalence is nearly 16 cases per 100,000. While most patients with MCD respond to therapy and have a good long-term prognosis, they are at risk for developing serious complications such as infection and thrombosis, and they are at risk for complications from therapy. The treatment of the MCD patient who is resistant to or dependent on corticosteroid therapy remains a challenge, despite the several therapeutic options available.

Since first postulated by Shaloub in the 1970s, the pathogenesis of MCD has been associated with the presence of a circulating factor capable of inducing proteinuria. Presumably, the circulating factor is secreted by lymphoid cells and functions as a vascular permeability factor or directly affects the function of the podocyte. The induction of remission by immunosuppressive medications further strengthens the argument that the circulating factor is secreted by immune cells whose function is inhibited by these agents. In addition, patients who develop end-stage renal disease from MCD or focal, segmental glomerulosclerosis (FSGS) are at risk for recurrent disease occurring rapidly after transplant. To date, the most promising candidate factors include hemopexin, interleukin (IL)-4, vascular endothelial growth factor (VEGF), low-molecular-weight (<100 kDa) non-Ig permeability factors, and heparanase. The isolation and identification of the pathogenic circulating factors currently remains a “Holy Grail” in nephrotic syndrome research.

Symptoms and Signs

The symptoms of MCD are related to the presence of nephrotic syndrome including peripheral swelling, abdominal discomfort from ascites, occasionally diarrhea from edema of the bowel wall, and, in extreme cases, pain from scrotal swelling and shortness of breath because of pleural effusions. Patients may experience oliguria, rarely leading to acute renal failure because of renal hypoperfusion. Because of an increased susceptibility to infection, especially from encapsulated bacteria, patients may present with signs of peritonitis or septic shock. They are also at an increased risk for thromboembolic phenomena, which may present with signs of deep venous thrombosis, flank pain and hematuria from renal venous thrombosis (rare), or a central nervous system catastrophe from a sagittal sinus thrombosis (also rare). An occasional patient has only minimal swelling.

Laboratory Findings

Urinalysis in patients with MCD shows dipstick positive proteinuria (3+ to 4+); about 15% of patients with MCD also have microscopic hematuria. The urinary protein-to-creatinine ratio (in milligrams/milligram) is ≥3.5 and can be obtained on a random sample, alleviating the need for a 24-hour urine collection. As a consequence of the heavy proteinuria the patient develops hypoalbuminemia. The magnitude of proteinuria in MCD tends to be much greater than that seen in other glomerular diseases, leading to more profound hypoalbuminemia. Hypogammaglobulinemia may also be seen secondary to urinary losses of IgG or due to impaired immunoglobulin G (IgG) production and/or IgG catabolism in MCD. Children with MCD who have low IgG levels also have elevated IgM levels, changes in γ-globulins that may persist during periods of remission.

Renal function is typically normal, although there might be a minor increase in creatinine as a consequence of intravascular volume contraction. In severe cases, the hemoglobin and hematocrit will also be elevated from volume contraction, and platelets may also be elevated. Serum cholesterol and triglycerides are elevated and return to normal slowly after the induction of a remission. It is appropriate to draw a C3 complement level and an antinuclear antibody to rule out other causes of nephrotic syndrome; these will be normal in MCD.

Imaging Studies

Renal ultrasound is not necessarily indicated in nephrotic syndrome, but patients with MCD tend to have enlarged kidneys on ultrasound along with ascites fluid. A chest radiograph will be normal or may show pleural effusions.

Special Tests

Adults with nephrotic syndrome are diagnosed with MCD following a percutaneous renal biopsy that is usually performed with ultrasound or computed tomography (CT) guidance. Since the vast majority of young children with nephrotic syndrome have MCD, they do not undergo a biopsy at presentation unless they have features suggesting a diagnosis other than MCD such as age <1 year, positive family history of nephrotic syndrome, extrarenal disease (eg, arthritis, rash, anemia), symptoms due to intravascular volume expansion, renal failure, or an active urine sediment. Children will undergo a renal biopsy, however, if they follow a steroid-resistant or steroid-dependent course. It is important to have the biopsy tissue studied by immunofluorescent and electron microscopy in addition to light microscopy. The presence of mesangial IgM on biopsy may portend a more therapy-resistant course.

A search for diseases leading to secondary MCD should be considered in adults with MCD (Table 24–1).

The differential diagnosis of a patient with nephrotic syndrome and minimal to no hematuria includes MCD, FSGS, and membranous nephropathy. These lesions are differentiated on renal biopsy, although early FSGS may look like MCD since only some of the glomeruli show segments of sclerosis, and the sclerotic lesions, which tend to appear first in the deep, corticomedullary glomeruli, can be missed in a superficial biopsy.

The complications of MCD are the complications seen with nephrotic syndrome, including infection, thromboembolic phenomenon, and cardiovascular disease, in addition to the potential side effects of therapy. The increased susceptibility to infections, especially infections from encapsulated organisms, is multifactorial. Patients with MCD exhibit defective opsonization of bacteria secondary to low levels of factor B and I, and experience low levels of total IgG, and IgG subclass deficiencies. Treatment with immunosuppressive medications enhances the susceptibility to infections that can be life threatening. The most common infections include peritonitis (especially pneumococcal), cellulitis, and pneumonia. Patients with nephrotic syndrome should receive pneumococcal vaccine, preferably during remission and when they are off immunosuppressive medications. Varicella immune status should be assessed in all patients with MCD, with prompt administration of varicella-zoster immune globulin to nonimmune patients after exposure to an active case of varicella infection. Treatment with acyclovir may be lifesaving in a patient with MCD on immunosuppressive medication who develops a varicella infection. Varicella vaccine given during remission while off steroid therapy appears to be safe and effective in children with MCD. Patients with MCD should also receive yearly influenza vaccine.

Children with MCD appear to be at a lower risk of thrombotic events than adults with MCD, but still may experience life-threatening thrombosis such as sagittal sinus thrombosis, pulmonary artery thrombosis, or inferior vena caval thrombosis, while nephrotic adults are more prone to deep vein or renal vein thrombosis. The hypercoaguable state in nephrotic syndrome is due to several factors including increased clotting factor synthesis (fibrinogen, II, V, VII, IX, X, XIII), urinary losses of anticoagulants (antithrombin III), platelet abnormalities (thrombocytosis, increased aggregability), hyperviscosity, and hyperlipidemia.

Most patients with MCD experience periods of remission during which their lipid profiles eventually return to normal. However, adults with nephrotic syndrome have a higher incidence of coronary heart disease and children with therapy-resistant MCD or steroid dependency may well be at an increased risk of cardiovascular complications. Corticosteroid treatment and hypertension undoubtedly add to the cardiovascular risk.

Other complications include a risk of acute renal failure secondary to renal hypoperfusion during relapse, iron deficiency anemia secondary to loss of iron binding proteins during relapse, and vitamin D deficiency, also due to loss of vitamin D-binding proteins during relapse.

The first line-therapy in MCD is corticosteroids. Children with MCD are highly likely to experience a prompt (75% are in remission by 2 weeks), complete remission with steroid therapy (>95%) while adults seem to be less responsive. Several studies in children have shown that prolonged induction therapy with corticosteroids will lead to a lower incidence of frequent relapses, and once-a-day therapy is equally as effective as divided-dose therapy. A recent randomized, controlled trial of two steroid regimens in children compared the protocol from the Arbeitsgemeinschaft für Pädiatrische Nephrologie consisting of 6 weeks of 60 mg/m2 of prednisone daily for 6 weeks followed by 40 mg/m2 every other day for 6 weeks with a second regimen of 60 mg/m2 daily for 4 weeks followed by 60 mg/m2 every other day for 4 weeks, with tapering by 10 mg/m2 every 4 weeks for an additional 20 weeks. Both regimens were equally as effective in inducing remission, but children under age 4 in the group treated with a longer taper had a lowered incidence of frequent relapses compared to the younger children treated with the 12-week course of therapy.

Adults with MCD require a more prolonged course of steroids to achieve a complete remission. One study from Japan showed that only 45% of adults over 50 years old were in remission after 4 weeks of treatment and many required >8 weeks of treatment to achieve remission. Adults, however, are less likely than children to experience relapses after a steroid-induced remission.

The majority of steroid-sensitive children, and some adults, with MCD experience relapses that typically follow an infection, and remain responsive to treatment with steroids. Relapses are treated with shorter courses of prednisone; prolonged treatment of a relapse does not influence the subsequent frequency of relapses. However, most of these patients with frequent relapses will develop steroid-induced side effects such as hypertension, Cushingoid appearance, hyperactive behavior (in the younger children), and poor growth. Some patients will do well on a prolonged course of low-dose, alternate-day prednisone therapy.

Other therapies should be considered for MCD patients with frequent relapses and steroid toxicity. A course of treatment with alklylating agents such as cyclophosphamide or chlorambucil has been shown to lead to a prolonged remission in children who are frequent relapsers. Cyclophosphamide (2 mg/kg) for 12 weeks is more commonly used and may induce remission lasting several years. Patients must be monitored for bone marrow toxicity with weekly complete blood counts and prompt treatment with varicella-zoster immune globulin if they are not immune to varicella infection. Courses longer than 12 weeks may lead to gonadal toxicity. In practice, many patients begin cyclophosphamide therapy while on alternate day steroids, which are weaned gradually over the course of 3–6 months. If patients resume a frequently relapsing course after receiving a course of cyclophosphamide, alternate day steroid therapy, levamisole (unavailable in the United States) or a course of cyclosporine may be tried. Levamisole has been shown to reduce the incidence of relapses in children with frequent relapses but not in children with steroid dependence. If the patient has not yet had a kidney biopsy, most pediatric nephrologists will perform one prior to using cyclosporine. Cyclosporine has been shown to be useful therapy in the patient with frequent relapsing, steroid- dependent, and probably even steroid-resistant MCD. Because of its toxicity profile, cyclosporine should be prescribed only by physicians who are experienced in its use. Side effects of treatment include hirsuitism, gingival hyperplasia, hypertension, hypomagnesemia, and nephrotoxicity. The usual starting dose is 5–6 mg/kg/day divided in two doses with close monitoring of cyclosporine levels (target trough levels of 50–125 ng/mL), renal function, and magnesium levels. The typical course of therapy is 1–2 years, followed by a slow taper. Many patients experience relapses after discontinuation of cyclosporine; if continued therapy is needed, kidney biopsies should be performed to monitor for nephrotoxicity. Many patients also require alternate day steroid therapy in conjunction with cyclosporine. Tacrolimus, also a calcineurin inhibitor, also shows some promise for therapy of patients with therapy-resistant nephrotic syndrome. Recent reports have suggested that mycophenolate mofetil (MMF), a purine synthesis inhibitor, may be useful in the treatment of children with steroid-dependent nephrotic syndrome.

The majority of patients with steroid resistance are likely to have FSGS. Patients with secondary MCD may experience a remission after successful treatment of the disease inducing the MCD. Angiotensin-converting enzyme (ACE) inhibition or angiotensin receptor blockade is a useful adjunct for patients with steroid resistance even in the absence of hypertension. All patients with MCD should follow a no added salt diet during periods of relapse. Children with marked anasarca, pleural effusions, or signs of renal hypoperfusion associated with sepsis should benefit from the cautious use of intravenous albumin (25%) —1 g/kg given over 2 hours followed by a 1 mg/kg dose of furosemide. The albumin infusion can be repeated up to every 12 hours to achieve a sustained diuresis. However, the patient's urine output must be closely monitored. A patient who has acute tubular necrosis as a complication of renal hypoperfusion may not respond to the albumin and furosemide infusions and is thus at risk for developing pulmonary edema. Intravenous γ-globulin (IVIg) may be useful acutely in a nephrotic patient with hypogammaglobulinemia experiencing sepsis or once monthly in a chronically nephrotic patient to reduce the incidence of sinus infections or bacteremia.

The outcome in MCD is largely based on the patient's response to steroid therapy. In children, prompt remission within 7–9 days of therapy, absence of microhematuria, and age greater than 4 years at presentation predict fewer relapses. By 10 years from diagnosis, only 16% of children are still experiencing relapses. Many children will “outgrow” their disease by or during puberty, although some continue to experience relapses into adulthood. During periods of relapse, patients remain vulnerable to life threatening infections and thrombotic events. The long-term cardiovascular risk in children with MCD who have experienced long periods of steroid therapy and periods of hyperlipidemia and hypertension is largely unknown. Adults with MCD may have an increased risk of coronary artery disease. Patients with MCD who become resistant to steroids later in their course are likely to have FSGS with its high risk for end-stage renal disease.