Excerpt from Minimal-Change Disease

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Background

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.

Pathophysiology

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) 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 Singapore Chinese children, it was shown that IL-13 genetic polymorphisms correlate with the long-term outcome of MCD.

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.

Lack of glomerular dysferlin expression has been recently associated with minimal change nephropathy in a patient with limb-girdle muscular dystrophy type 2B. Two of the three patients with this disease had increased microalbuminuria.

Although there have been a multitude of studies recently published, the mechanism by which T cells increase glomerular permeability has remained unproven.

Frequency

United States

In preadolescents, minimal-change nephrotic syndrome (MCNS) makes up 85-95% of all causes of nephrotic syndrome. In adolescents and young adults, the prevalence is 50%. In the population older than 40 years, it is found in 20-25% of cases with nephrotic syndrome. Incidence is 2-7 new cases per 100,000 children, and the prevalence is 15 cases per 100,000 children.

Mortality/Morbidity

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.

Race

• Asians may be at increased risk.

Sex

• It is found twice as frequently in boys than in girls.
• The frequency is the same between the sexes in adults.

Age

• The incidence peaks in children aged 2 years, with approximately 80% being younger than 6 years at the time of diagnosis.
• In adults, the mean age of onset is 40 years.

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