Minimal change disease
|Minimal change disease|
|Other names: Minimal change glomerulopathy, minimal change nephrotic syndrome, nil disease, lipoid nephrosis|
|The three hallmarks of minimal change disease seen on electron microscopy: diffuse loss of podocyte foot processes, vacuolation, and the appearance of microvilli.|
|Symptoms||Swelling, foamy urine|
|Complications||Blood clots, infections, high cholesterol|
|Usual onset||2 to 3 years old|
|Diagnostic method||Generally based on symptoms, labs, and urine testing|
|Differential diagnosis||Glomerulonephritis, heart failure, lymphedema|
|Treatment||Corticosteroids, blood pressure medication|
|Frequency||1 in 20,000 children per year|
Minimal change disease (MCD) is a kidney disease with significant protein in the urine but a relatively normal kidney biopsy when examined by a light microscope. Symptoms include swelling and foamy urine. Complications can include blood clots, infections, dehydration, and high cholesterol. Kidney failure is rare.
The cause is generally unknown. It may be triggered by an infection or allergic reaction. The underlying mechanism involves damage to the glomeruli. Diagnosis is generally based on symptoms together with urine and lab tests. If the diagnosis is unclear a kidney biopsy may be useful.
Treatment may include corticosteroids, cyclophosphamide, or cyclosporine. High blood pressure may be managed with an ACE inhibitor or calcium channel blocker. A low salt diet and a diuretic may be used to control swelling. Outcomes are generally good in all age groups. In more than 80% of adults, the disease resolves with treatment.
About 1 in 20,000 children are affected a year. It is most common in those around the age of 2 to 3 years old. In children males are more commonly affected than females. It is uncommon in adults. It is the most common cause of nephrotic syndrome in children, and responsible for 10 to 25% of cases in adults. The disease was first described by Munk in 1913.
Signs and symptoms
The signs of minimal change disease are proteinuria (abnormal excretion of proteins, mainly albumin, into the urine), edema (swelling of soft tissues as a consequence of water retention), weight gain, and hypoalbuminaemia (low serum albumin). These signs are referred to collectively as nephrotic syndrome.
The first clinical sign of minimal change disease is usually edema with an associated increase in weight. The swelling may be mild but patients can present with edema in the lower half of the body, periorbital edema, swelling in the scrotal/labial area and anasarca in more severe cases. In older adults, patients may also present with acute kidney injury (20-25% of affected adults) and high blood pressure. Due to the disease process, patients with minimal change disease are also at risk of blood clots and infections.
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. 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.
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. However, considering that there is no immunoglobulin deposition noted on renal biopsy, it may be that B cells play a more secondary role in activating the T cells that lead to disease, which would explain the effectiveness of immunosuppressants that target B cells.
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.
As minimal change disease is a subset of nephrotic syndrome, diagnosis involves looking for a combination of edema, high amounts of protein in urine, low albumin and high serum cholesterol. Initial workup can include a urinalysis, kidney function tests, serum albumin level and a lipid panel. Microscopic amounts of blood are present in the urine of 10-30% adults with MCD.
As MCD is the most common type of nephrotic syndrome in children, renal biopsy is not usually done in children under the age of 10 unless there are concerning features that are unusual for the disease (high blood pressure, bloody urine, renal dysfunction) and if they fail to respond to corticosteroid therapy. These would suggest that it may not be minimal change disease. In adults, a renal biopsy is required as there is a much wider differential for nephrotic syndrome. As the name suggests, the renal biopsy of a patient with minimal change disease would show minimal or no evidence of disease in light microscopy, which is unique among the causes of nephrotic syndrome.
For years, pathologists found no changes when viewing kidney biopsy specimens under light microscopy, hence the name "minimal change disease." Sometimes, the mesangium may have expanded, but otherwise there is no injury to kidney tissue itself.
With the advent of electron microscopy, the changes now known as the hallmarks of the disease were discovered. These are diffuse loss of visceral epithelial cells' foot processes (i.e., podocyte effacement), vacuolation, and growth of microvilli on the visceral epithelial cells, allowing for excess protein loss in the urine.
The first line therapy to minimal change disease is corticosteroids. For those are who are unable to tolerate corticosteroid treatment, cyclosporine is an alternative; other immunosuppressants have also been used such as calcineurin inhibitor, mycophenolate mofetil, rituximab though studies on their effectiveness is fairly limited. There is no common consensus on how long the corticosteroid therapy should be, with treatment length ranging from 4–12 weeks. Along with corticosteroid therapy, acute symptomatic management involves salt and fluid restriction to control the swelling.
For children who do not respond to corticosteroids (usually after a trial of 8 weeks), a trial of cyclosporine and corticosteroids can be tried.
Treatment guidelines for adults is fairly limited, largely based on studies done on children. The mainline therapy is also corticosteroid therapy with other immunosuppressants as possible alternatives though, there is very little data on the these alternatives' efficacy. 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. ACE inhibitors may be considered in people with MCD who also have high blood pressure.
Minimal change disease usually responds well to initial treatment with the first-line therapy: corticosteroids, with 95% responding. 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. 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). 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. A majority of relapses seem to be triggered by respiratory infections. Long term, children can relapse several years after having no symptoms; though after 2 years, the risk is significantly lower.
In most children with minimal change disease, particularly among those who respond typically, there is minimal to no permanent damage observed in their kidneys. Complications primarily arise from the side effects of therapy. Prolonged use of corticosteroids can lead to immunosuppression (leading to infection), growth complications, weight gain.
While most adults with minimal change disease do respond to corticosteroids, 25% fail to respond after 3–4 months of corticosteroid therapy though it is possible that these patients may not actually have minimal change disease and was incorrectly diagnosed. Adults with MCD tend to also respond more slowly to corticosteroid treatment when compared to children; response is longer, taking up to 3 or 4 months. Data in adults is less complete in comparison to children but relapses are also fairly frequent with 56-76% of patients relapsing and need further treatment with immunosuppressants, such as ciclosporin, tacrolimus, mycophenolate, and rituximab. There is little evidence to support the use of azathioprine for MCD.
Like in children, complications primarily arise from the side effects of therapy. Prolonged use of corticosteroids can lead to immunosuppression (leading to infection), growth complications, weight gain.
Minimal change disease is most common in very young children but can occur in older children and adults.
It is by far the most common cause of nephrotic syndrome in children, accounting for 70-90% of children >1 year of age. After puberty, it is caused by minimal change disease about half the time. Among young children, boys seem to be more likely to develop minimal change disease than girls (about 2:1). Minimal change disease is seen in about 16 in every 100,000 children with it being more common in South Asians and Native Americans, but rarer in African Americans.
In adults, it accounts for less than 15% of adults diagnosed with nephrotic syndrome.
Minimal change disease has been called by many other names in the medical literature, including minimal change nephropathy, minimal change nephrosis, minimal change nephrotic syndrome, minimal change glomerulopathy, foot process disease (referring to the foot processes of the podocytes), nil disease (referring to the lack of pathologic findings on light microscopy), nil lesions, lipid nephrosis, and lipoid nephrosis.
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