MINIMAL CHANGE DISEASE
Minimal change disease (MCD, also known as nil disease and lipoid nephrosis) is the leading cause of nephrotic syndrome in children, accounting for 90% of cases in this population, and a major cause of nephrotic syndrome in adults. In addition to its predilection for children, MCD also occurs more frequently in Asians and Caucasians than in African-Americans.
The name of this disease refers to the seemingly normal appearance of glomeruli when visualized using light microscopy. On electron microscopy, however, diffuse foot process effacement can be seen, which is the basis for the proteinuria.
The vast majority (>85%) of MCD cases are primary, idiopathic phenomena. In the remaining cases, MCD occurs secondary to a systemic insult, such as drugs (e.g., NSAIDs, lithium), neoplasms (especially hematologic malignancies), infections (e.g., tuberculosis, syphilis), and allergies to common irritants (i.e., poison ivy, ragweed, poison oak, bee stings, certain foods).
The precise mechanism of MCD is not known. One theory speculates that dysfunctional T-cells produce a cytokine called the glomerular permeability factor, which injures podocytes (visceral epithelial cells) and leads to foot process effacement. Loss of the slit diaphragm architecture, which constitutes the normal barrier to protein ﬁltration, leads to proteinuria. B cells may also play a role, either by producing the glomerular permeability factor or, alternatively, by secreting an antibody that targets a glomerular antigen.
The immune-mediated hypothesis is supported by the efﬁcacy of immunomodulatory treatments, as well as the fact that MCD may occur secondary to allergens, infections, and cancers of the immune system. In cases of idiopathic MCD, it is not clear what would trigger this abnormal immune response. Some have postulated that viral or bacterial infections may be responsible, although at present there is no evidence for this claim. Despite the damage to podocytes, the remainder of the glomerulus remains normal. Thus renal function remains intact or is only slightly impaired.
PRESENTATION AND DIAGNOSIS
The most common presentation of MCD is the sudden onset of nephrotic syndrome (see Plate 4-7). Thus patients typically have substantial edema and the laboratory ﬁndings of nephrotic-range proteinuria, hypoalbuminemia, and hyperlipidemia. In MCD, the proteinuria tends to be more profound than with other causes of nephrotic syndrome (e.g., > 10 to 15 g/day). Serum markers of renal function, such as creatinine concentration, are typically normal or only slightly elevated. In a subset of adults, however, acute kidney injury may occur, possibly because of ischemic acute tubular necrosis resulting from massive loss of intravascular volume. For unclear reasons, adults are also more likely than children to have hypertension and hematuria.
Because patients with MCD tend to have very severe proteinuria, clinicians must be alert for the presence of related complications. As in all cases of nephrotic syndrome, patients are at risk for systemic thromboses. In addition, infection may occur because of multiple factors, including urinary losses of immunoglobulins, alternative complement factor B, and hemolytic factor D. If there is signiﬁcant edema, the risk of cellulitis increases.
The gold standard for diagnosis of MCD is renal biopsy. In children, however, MCD accounts for such an overwhelming majority of nephrotic syndromes that it is often diagnosed on a presumptive basis, with renal biopsy not performed unless empiric treatment fails. In adults, the differential diagnosis for nephrotic syndrome is very broad, and thus in the absence of a clear underlying cause (such as long-standing diabetes mellitus), renal biopsy is essential for optimization of management.
On light microscopy, the glomeruli generally appear normal. Immunoﬂuorescence is usually unremarkable, although occasional mesangial IgM or complement deposits may be seen. Further examination with electron microscopy, however, reveals diffuse foot process effacement. This ﬁnding is not pathognomonic for MCD, however, unless seen in the presence of normal light microscopy ﬁndings in an adequate sample size (typically at least 15 glomeruli).
It is important but sometimes challenging to distinguish MCD from FSGS. In some cases, patients diagnosed with MCD fail to respond to treatment and, on repeat biopsy, are found to have FSGS. It is not clear if these cases indicate missampled FSGS in the original biopsy, or a progression of MCD to FSGS due to prolonged periods of heavy proteinuria. Indeed, the relationship between these two entities is poorly understood and controversial; some experts believe that the two entities are on two ends of a continuum.
Once the diagnosis of MCD is established, patients should be screened for the major causes of secondary MCD. If all of these tests are negative or normal, the MCD can be ruled idiopathic.
The primary, idiopathic form of MCD is very responsive to steroids. Up to 95% of patients achieve complete remission, deﬁned as proteinuria declining to levels below 300 mg/day with stable renal function. Among children, half respond within 2 weeks of treatment, and nearly all of the others respond within 8 weeks. Among adults, half respond within 4 weeks of treatment, but the rest may require several months of additional corticosteroids. For as long as the nephrotic syndrome persists, all patients should adopt a low-salt diet, and diuretics should be used as needed for edema control. ACE inhibitors and statins are generally not required in steroid-responsive patients because their disease is short in duration.
Secondary forms of MCD should be treated by focusing on removal or mitigation of the inciting insult, such as discontinuation of a certain drug or treatment of an underlying malignancy.
Patients who experience total remission have a very good long-term prognosis. In contrast, patients with disease that is unresponsive to treatment may experience progressive scarring of glomeruli, with an associated decline in renal function that ultimately leads to end-stage disease.
More than half of adult MCD patients will have a relapse during their lifetime, and up to one in four will become a frequent relapses, experiencing more than three episodes per year. In general, children and adults who go into remission quickly sometimes within the ﬁrst week of treatment are less likely to have subsequent relapses. Because long-term use of steroids has numerous adverse effects, patients with relapsing disease are often prescribed alternative immunomodulatory therapies, such as calcineurin inhibitors, mycophenolate mofetil, and cyclophosphamide.