Minimal change disease

The cause and pathogenesis of the pathology is unclear and it is currently considered idiopathic. However, it does not appear to involve complement or immune complex deposition. Rather, an altered T cell-mediated immunologic response with abnormal secretion of lymphokines by T cells is thought to modify the glomerular basement membrane, specifically the podocytes, increasing permeability.[1] This allows the leakage of albumin and other serum proteins into the urine. Also, the exact cytokine responsible has yet to be elucidated, with IL-12, IL-18 and IL-13 having been most studied in this regard, yet never conclusively implicated.[4] Data from a longitudinal study (Nephrotic Syndrome Study Network – NEPTUNE) published in 2022 suggested that up to 29% of biopsy-confirmed, mixed pediatric and adult minimal change disease cases exhibited serum autoantibodies against nephrin, a structural protein located in the podocyte slit diaphragm.[6]

There has been discussion of B cell involvement in nephrotic syndrome, especially minimal change disease due to the success of immunotherapy that target both B and T cells, increased markers for B cell activation during a relapse of minimal change disease, and alterations in B cell sub-classes during minimal change disease remission.[4] This hypothesis is supported by recent findings of anti-nephrin antibodies isolated in minimal change disease.

When albumin is excreted in the urine, its serum (blood) concentration decreases. Consequently, the plasma oncotic pressure reduces relative to the interstitial tissue. The subsequent movement of fluid from the vascular compartment to the interstitial compartment manifests as the soft tissue swelling referred to as edema. This fluid collects most commonly in the feet and legs, in response to gravity, particularly in those with poorly functioning valves. In severe cases, fluid can shift into the peritoneal cavity (abdomen) and cause ascites. As a result of the excess fluid, individuals with minimal change disease often gain weight, as they are excreting less water in the urine, and experience fatigue.[1]

The first line therapy for minimal change disease is prednisone, a corticosteroid, 60mg/sq.m/day or 2mg/kg/day.[1] For those children who are unable to tolerate corticosteroid treatment, or are unresponsive (usually after a trial of 8 weeks), another immunosuppressant cyclosporin is an alternative; other immunosuppressants have also been used such as a calcineurin inhibitor, mycophenolate mofetil, and rituximab though studies on their effectiveness is fairly limited.[1][4] There is no consensus on how long the corticosteroid therapy should be, with treatment length ranging from 4–12 weeks.[1] Along with corticosteroid therapy, acute symptomatic management involves salt and fluid restriction to control the swelling.[1]

Treatment guidelines for adults are fairly limited, and are largely based on studies done on children.[1] The mainline therapy is also corticosteroid therapy prednisone 1mg/kg/day with other immunosuppressants as possible alternatives, though there is very little data on these alternatives' efficacy.[1] Other medications such as ACE inhibitors to reduce the amount of protein in the urine or statins to decrease high levels of cholesterol seen with nephrotic syndrome are generally unnecessary.[3] ACE inhibitors may be considered in people with MCD who also have high blood pressure.[3]

Minimal change disease usually responds well to initial treatment with the first-line therapy: corticosteroids, with 95% responding.[1] Younger children, who are more likely to develop minimal change disease, usually respond faster than adults with 50% of children having complete remission with 8 days of corticosteroid therapy and most other patients responding by the 4th week.[1] Few do not respond to corticosteroids and have to rely on an alternative therapy. However, despite positive response to corticosteroids, relapses are common, requiring repeat treatment with corticosteroids. About 25% never relapse, another 25% relapse infrequently (one relapse within 6 months of initial response or 1–3 relapses in 12 months), and 50% relapse frequently (>2 relapses within 6 months of initial response or >4 relapses in 12 months).[1] The relapse rate is the reason behind a discussion on continuing prednisone treatment to even beyond 12 weeks to possibly decrease relapse rate; several studies trying this have failed to show significant improvement.[1] A majority of relapses seem to be triggered by respiratory infections.[1] Long term, children can relapse several years after having no symptoms; though after 2 years, the risk is significantly lower.[4]

In most children with minimal change disease, particularly among those who respond typically, there is minimal to no permanent damage observed in their kidneys.[1] Complications primarily arise from the side effects of therapy. Prolonged use of corticosteroids can lead to immunosuppression (leading to infection), growth complications, weight gain.[7]

While most adults diagnosed with minimal change disease respond to corticosteroids, 25% fail to respond after 3–4 months of corticosteroid therapy; it is possible that these patients were incorrectly diagnosed, and do not have minimal change disease.[1] Adults with MCD tend to respond more slowly to corticosteroid treatment, taking up to 3 or 4 months, than children do.[3] Data in adults is less complete than for children, but relapses are fairly frequent with 56–76% of patients relapsing and needing further treatment with immunosuppressants such as ciclosporin, tacrolimus, mycophenolate, and rituximab.[3][4] There is little evidence to support the use of azathioprine for MCD.[3] Complications primarily arise from the side effects of therapy.