Aetiology

Minimal change disease (MCD) accounts for the majority of idiopathic nephrotic syndrome (NS) in children, particularly for the corticosteroid-sensitive forms.[1]​ The aetiology of most corticosteroid-sensitive NS cases is considered to be multifactorial, with likely susceptibility genes.[10]​ In corticosteroid-resistant NS, abnormalities in podocyte-associated genes have been identified in approximately 30% of patients.[10]​ Although typically idiopathic, MCD may be secondary to certain conditions, such as Hodgkin's lymphoma, leukaemia, and, rarely, hepatitis B or C infection.[1]

Pathophysiology

Although the exact pathogenesis of MCD is not known, the pathophysiology of NS indirectly accounts for the mechanisms behind MCD.[10]​

In NS, an increase in glomerular permeability to proteins is the main pathological process resulting in heavy proteinuria. The glomerular permeability in NS is altered either by circulating factors or due to mutations in the podocyte or slit diaphragm proteins.[11]​ Although the exact pathogenesis of primary NS is unclear, evidence suggests that dysregulation of the immune system plays a role in development.[12]​ The observation that a viral illness (with the exception of measles infection) can precede the initial presentation or, in many cases, a relapse in known nephrotic patients, and the association of NS with primary immunological disorders such as lymphoma and leukaemia, supports the hypothesis of systemic T-cell dysregulation.[12]​​​​​ In contrast, measles infection is known to suppress cell-mediated immunity and, in so doing, has been seen to induce remission of NS.[13] A role of B cells in the pathogenesis of idiopathic NS is supported by the therapeutic potential of rituximab, a monoclonal antibody directed against CD20-bearing cells, in the treatment of both childhood and adulthood NS.[14]​ The discovery that circulating autoantibodies against nephrin are present in a subset of patients with MCD further supports an autoimmune aetiology in some patients.[15]​

In genetic studies, corticosteroid-sensitive NS (SSNS) in children is significantly associated with polymorphisms in the human leukocyte antigen class II region in various populations.[14]​ There is no known single causative gene for SSNS; however, NPHS1, which encodes nephrin, is a susceptibility gene.[14]​ Mutations in NPHS1 are known to cause congenital nephrotic syndrome of the Finnish type, a rare monogenic NS, which is corticosteroid resistant, and variants in NPHS1 are associated with susceptibility to SSNS.[16]​ Mutations in single genes KANK 1 or 2, EXT 1, FOXP3 have been reported in cases with SSNS or MCD on histology.[17]​ Other genes identified include MAGI2, TNS2, DLC1, CDK20, ITSN1, and ITSN2.[17]

In MCD, no structural changes are seen in the filtration unit on light microscopy. However, with electron microscopy, effacement of the epithelial foot processes (podocytes) is seen.​​[18]

One review of kidney biopsy data over a 10-year period from a single centre points towards regional and ethnic variations in glomerular diseases with genetic or environmental influence in the pathogenesis.[19]

Classification

Nephrotic syndrome: terminology

There is no specific classification for MCD but, as it is the most common form of NS in children, the classification of NS is deemed important.

Following onset of NS, children are treated with a standard dose of corticosteroid. Response to this standard dosing regimen and the number of relapses in the subsequent 12 months allows classification:[3]

  • Corticosteroid-sensitive NS (SSNS): complete remission after 4 weeks of corticosteroid at standard dose

  • Corticosteroid-resistant NS: lack of complete remission after 4 weeks of corticosteroid at standard dose

  • Infrequent relapsing NS: <2 relapses per 6 months within 6 months of disease onset or <4 relapses per 12 months in any subsequent 12-month period

  • Frequent relapsing NS: ≥2 relapses per 6 months within 6 months of disease onset or ≥4 relapses per 12 months in any subsequent 12-month period

Nephrotic syndrome: pathogenesis[4][5]

Primary (idiopathic): The pathological glomerular injury is limited to the kidney. This group is further divided into those who have benign urine sediment and no glomerular inflammation on biopsy, and those who have active urine sediment and glomerular inflammation on kidney biopsy:

Primary conditions with benign urine sediment

  • MCD

  • Focal segmental glomerulosclerosis (FSGS)

  • Membranous nephropathy

Primary conditions with glomerular inflammation and active urine sediment

  • Membranoproliferative glomerulonephritis

  • IgA nephropathy

Secondary: Associated with systemic diseases or secondary to another process that causes glomerular injury.

Secondary conditions with benign urine sediment

  • Malignancy (membranous nephropathy)

  • Sickle cell disease (FSGS)

  • Kidney scarring or hypoplasia (FSGS)

Secondary conditions with glomerular inflammation and active urine sediment

  • Systemic lupus erythematosus (membranous nephropathy most common)

  • Postinfectious glomerulonephritis

Secondary conditions associated with a vasculitis

  • Henoch-Schonlein purpura

  • Granulomatosis with polyangiitis

  • Microscopic polyangiitis

Secondary causes associated with infections

  • Hepatitis B, C

  • HIV-1 infection

  • Epstein-Barr virus and Parvovirus B19

Secondary causes associated with drugs

  • Non-steroidal anti-inflammatory drugs (NSAIDs)

  • Heroin

  • Interferon alfa

  • Lithium

  • Pamidronate (a bisphosphonate)

Secondary causes associated with malignant disease

  • Lymphoma (MCD)

  • Leukaemia

Genetic: Group of inherited diseases that have defects of the slit diaphragm protein complex within the basement membrane and are therefore associated with NS:

  • Finnish type of congenital NS

  • FSGS

  • Denys-Drash syndrome (diffuse mesangial sclerosis).

Other:

  • Adaptation to nephron reduction with glomerular hyperfiltration

  • Oligomeganephronia

  • Obesity.

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