What is the pathophysiology of minimal-change disease (MCD)?

Updated: Jan 05, 2021
  • Author: Abeera Mansur, MD; Chief Editor: Vecihi Batuman, MD, FASN  more...
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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] [3] ) 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. [4] An animal study by Lai et al suggested that IL-13 overexpression can cause podocyte foot process fusion and proteinuria. [5]

In patients who develop acute kidney injury (AKI), endothelin 1 expression is greater in the glomeruli, vessels, and tubules than in the non-AKI 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 and is critical for preserving the glomerular capillary barrier to protein. [6] The slit diaphragm is often missing in MC nephrotic syndrome (MCD) kidneys. 

CD80 is a protein expressed on the surface of several antigen-presenting cells. It is also expressed on podocytes, and increased expression of CD80 has resulted in a reduced expression of nephrin. Urinary levels of CD80 are increased in patients with MCD but not in patients with FSGS. Thus, this may have clinical applicability in distinguishing these two entities. [7]

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. [8]  

A study by Ahmed et al in 36 children with nephrotic syndrome and normal glomerular filtration rate, which included 21 chlidren with MCD, found that urinary CD80 levels were significantly higher in patients with MCD than in those with FSGS (3.5 ± 2.1 versus 1.2 ± 0.5 ng/mg creatinine; P < 0.001). CD80 levels were also higher in patients with MCD than in those with other glomerulopathies or normal controls (n=40).  A urinary CD80 cutoff value of 1.5 ng/gm creatinine showed a sensitivity of 100% and a specificity of 86% for diagnosis of MCD. [9]

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. [10]  In the same study, 2 of 3 other patients with dysferlinopathy had microalbuminuria.

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