Terminology and Histopathology

Minimal change disease (MCD) is a common cause of nephrotic syndrome (NS). Also known as lipoid nephrosis, nil disease, and minimal change nephropathy, kidney histology on light microscopy in MCD is relatively normal, lacking the significant glomerular cell proliferation, infiltration by circulating immunoeffector cells, immune deposits, tubulointerstitial changes, or alterations in the glomerular basement membrane (GBM) that characterize other glomerular diseases. The defining feature of MCD is diffuse effacement and fusion of the majority of podocyte foot processes without electron-dense deposits on electron microscopy. There are variants of MCD that are characterized by diffuse mesangial hypercellularity. Immunofluorescence is typically negative or may show low-level focal staining for C3 and IgM.

MCD can also be diagnosed clinically by exhibiting responsiveness to corticosteroid treatment. In children, because MCD is the cause of 90% of cases of idiopathic NS, a kidney biopsy is only warranted if clinical and laboratory evidence, including disease onset before 6 to 9 months of age or following adolescence, unexpected systemic manifestations, or a low serum C3 level, suggest an alternative diagnosis. Children who do not exhibit these characteristics will typically have MCD and will consequently respond to steroids. The nomenclature steroid-sensitive nephrotic syndrome (SSNS) is also used to describe such children. Steroid responsiveness is a marker of a favorable long-term prognosis. In contrast, children with steroid-resistant nephrotic syndrome (SRNS) are more likely on subsequent kidney biopsies to show focal segmental glomerulosclerosis (FSGS), a disease that is associated with a worse prognosis. The causes of the NS in adults are more varied, including a higher percentage of cases with other histologies such as membranous nephropathy (MN), FSGS, and membranoproliferative glomerulonephritis (MPGN). Because MCD only accounts for approximately 10% to 15% of adult NS cases, a kidney biopsy is usually warranted in adults to establish the etiology of NS and guide management.

MCD can be the cause of significant short-term morbidity and can manifest with a chronic relapsing course with long-term adverse consequences well into adulthood. Both first-line treatment and secondary therapeutic options for more difficult cases can lead to serious toxicity. Therefore, although the long-term prognosis is excellent, optimal management of MCD requires clinical acumen to balance the risks of untreated disease activity against the potential irreversible hazards of available pharmacologic choices.

Pathophysiology

The effacement of podocyte foot processes that is a hallmark of MCD may be mediated by various intracellular signaling pathways. For example, markers of focal adhesion complex–mediated Crk-dependent signaling are enhanced in MCD but not FSGS. Moreover, increased production of proteins such as CD80 and angiopoietin-like protein 4 by podocytes in MCD models supports the central role of podocyte damage in the pathogenesis of MCD. It is thought that proteinuria occurs solely because of a defect in glomerular permselectivity, although alterations in tubular reabsorption may contribute.

MCD is unique in that it predominantly reflects a decrease in the negative charge present in endothelial cells, the GBM, and podocytes, thereby causing selective proteinuria. The reduction in negative charge appears to be a diffuse abnormality that manifests in capillaries throughout the body, with leakage of albumin in the peripheral circulation and accumulation of interstitial fluid. The cause of the diminished negative charge density probably results from immune-mediated defects that inhibit sulfate incorporation into the GBM, rather than a genetic mutation in a podocyte protein.

In addition, immunoeffector cells may elaborate soluble molecules, such as vascular endothelial growth factor, that directly increase GBM permeability to protein. It is likely that the molecular identity of circulating permeability factors that cause proteinuria will differ in patients with MCD and FSGS. A link between abnormal T-cell function and MCD was initially proposed more than 30 years ago by Shalhoub, and many studies since then have documented altered subtype distribution and activity of lymphocytes in children with MCD. The pivotal role of the immune system in MCD pathogenesis is underscored by a study in which albuminuria and podocyte foot process effacement was induced by injection of CD34+ stem cells isolated from patients with MCD or FSGS into immunodeficient NOD/SCID mice. This role is also supported by the finding of a higher Th17/Treg cell ratio in children with MCD. Finally, the genetic linkage between HLA-DQA1 and PLCG2 supports a role for adaptive and autoimmunity in the pathogenesis of MCD.

Although MCD can occur in familial clusters with both vertical (parent-child) and horizontal (sibling) patterns of inheritance, it has not been linked to mutations in any of the well-recognized proteins associated with FSGS, such as Wilms tumor-1, TRPC6, or α-actinin-4. Interestingly, there have been observations linking frequently relapsing childhood MCD to allelic heterogeneity in the gene for nephrin, a key component of the slit diaphragm and a major genetic locus for congenital NS. In addition, in a study of 214 Chinese patients with MCD, variants in the podocin gene were more common than in healthy controls and correlated with proteinuria. Alterations in histone H3 lysine 4 trimethylation in children with MCD raise the possibility that epigenetic changes may contribute to the occurrence of MCD. Polymorphisms in the multidrug resistance-1 gene may influence responsiveness to steroids in patients with MCD.

MCD also is associated with various secondary causes ( Box 17.1 ), including medications, infections, toxins, and malignancies. The pathophysiologic link between these secondary causes and the resulting MCD is not understood.

Incidence

The overall incidence of primary or idiopathic NS, which includes MCD (and its variants), FSGS, MN, and MPGN, is approximately three to five cases/100,000 population/year in children and adults. This rate is fairly constant throughout the world and in most racial and ethnic groups. Recent data suggest that the incidence of MCD is rising in India and Southeast Asia, while FSGS may be increasingly prevalent throughout the world. The contribution of MCD to this general category varies tremendously with the age of the patient. Thus in prepubertal patients more than 6 months of age, MCD accounts for nearly 90% of all cases of idiopathic NS, whereas in adults the percentage of cases attributable to MCD falls to 10% to 15%. Adolescence represents the transition period between the two ends of the spectrum. In a study of 1523 consecutive Chinese patients who underwent biopsy performed during the evaluation of NS, in those aged 14 to 24 years, MCD was documented in 33% of the subgroup. Similarly, in a report of biopsy findings in 538 pediatric patients in Pakistan, among whom 365 were younger children (mean age 7.3 years) and 173 were adolescents (mean age 15.1 years), approximately one-third of the older group had FSGS and only one-fourth had MCD. MN and MPGN also were significantly more common in the older group. These findings suggest that adolescents correspond more closely to adults than they do to younger children.

Clinical Presentation

MCD causes NS, manifesting with nephrotic range proteinuria, edema, hypoalbuminemia, and hypercholesterolemia. Edema is the most common presenting symptom of MCD, and the onset may be acute. The onset of MCD may be associated with an antecedent infection, typically respiratory. Infections may also trigger subsequent relapses of MCD. The rapidity of the appearance of edema is characteristic of MCD compared with other etiologies of NS. In children, edema can occur anywhere in the body, including the periorbital region, scrotum, or abdomen. The pathogenesis of edema in NS is complex and represents an interplay between underfill and overfill mechanisms. Less frequent presenting complaints include infections, such as cellulitis secondary to localized accumulation of fluid and skin breakdown, or bacterial peritonitis in patients with ascites. Hypercholesterolemia arises from alterations in lipoprotein lipase activity, and recent data support an important role for derangements in PCSK9 activity in mediating hypercholesterolemia in MCD. The incidence of thromboembolic events, including renal vein thrombosis and pulmonary emboli, is tenfold higher in adults than in children, and typically these events occur in patients with severe hypoalbuminemia.

Urinalysis reveals microscopic hematuria in 10% to 30% of adults and children with MCD, but gross hematuria is rare. Microscopic examination of the urine may also show waxy casts and oval fat bodies. In one series, acute kidney injury (AKI) occurred in 18% of adult patients who presented with NS and were subsequently diagnosed with MCD. These patients tended to be older, male, and hypertensive and had more severe proteinuria and hypoalbuminemia than patients who did not develop AKI. Kidney biopsies of these patients showed a variety of histologic patterns of injury, including tubular atrophy, interstitial inflammation and fibrosis, and atherosclerotic disease. The cause of the AKI is not entirely clear and may reflect primary changes in glomerular permeability, the reason for which is not entirely clear. Serologic tests are usually negative or normal.