Minimal change disease overview
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Minimal change disease (MCD) is a podocytopathy that reveals foot process effacement on electron microscopy. It is the most common cause of nephrotic syndrome in children and less common in adults. Its name refers to the presence of nephrotic syndrome with the absence of any visible glomerular lesions on light microscopy and the absence of any staining on immunofluorescence, appearing similar to completely normal glomeruli on histopathology. Accordingly, it has also been called nil (nothing-in-light microscopy) disease. Other names, such as lipoid nephrosis (due to the presence of lipid-laden macrophages in the tubular epithelial cells and urine) and steroid-responsive/sensitive nephrotic syndrome (due to its generally excellent response to steroid therapy) may also refer to minimal change disease.
Minimal change disease was first described by F. Munk in 1913, when he coined the term “lipoid nephrosis” following the observation of lipid-laden macrophages in the proximal tubular epithelial cells and oval fat bodies in urine. In 1925, Fahr and colleagues noted the resemblance of minimal change disease to focal segmental glomerulosclerosis (FSGS). Ever since its early description, the term “lipoid nephrosis” has been criticized due to the clinical irrelevance of the lipid-laden cells seen on microscopy.
Minimal change disease can be classified based on the underlying clinical etiology of disease into primary and secondary. Minimal change disease currently has no pathological classification system. Based on the proposed Columbia classification, minimal change disease was considered an entity within the spectrum of focal segmental glomerulonephritis (FSGS).
The exact pathogenesis of minimal change disease is not well-understood. T-cell dysfunction may mediate the pathogenesis of minimal change disease. Due to the remarkable observation of disease recurrence after transplantation and the resolution of renal disease in recipients of kidneys from donors with MCD, it has been suggested that the presence of circulatory compounds may be attributable to the disease. Factors associated with the pathophysiology of minimal change disease include glomerular permeability factor (GPF) from T cells, hemopexin, interleukin (IL)13, cardiotrophin-like cytokine (CLC)-1,, and vascular endothelial growth factor (VEGF).
Most cases of minimal change disease occur sporadically with no clear cause. Few cases occur due to genetic mutations.
The differential diagnosis of minimal change disease must always include other renal etiologies of nephrotic syndrome, such as focal segmental glomerulosclerosis (FSGS) and IgM nephropathy, and causes of peripheral edema and hypoalbuminemia, such as congestive heart failure, liver cirrhosis, and protein-losing enteropathy.
Epidemiology and Demographics
Minimal change disease (MCD) is considered a disease of childhood. It is responsible for up to 70-90% of nephrotic syndrome in patients less than 10 years of age, and up to 50% of older children. Among children, several studies have shown a male predominance with approximately 2:1 male to female ratio.
Natural History, Complications and Prognosis
Complications associated with the pathogenesis of the disease as a nephrotic syndrome include thromboembolic events and disorders of hemostasis, hyperlipidemia, vulnerability to infections, and hypertension. Before the steroid era, patients died of renal failure and from infections. Nowadays, patients have excellent renal outcomes when they are still steroid-responsive and virtually all patients survive with a normal creatinine clearance. Although renal outcomes are considered excellent with appropriate therapy, the risk of chronic renal disease cannot be completely ruled out, especially among patients receiving nephrotoxic medications for prolonged periods of time.
History and Symptoms
The hallmark of minimal change disease in children is acute-onset proteinuria that progresses into nephrotic syndrome. Fatigue and subsequent edema develops with symptoms of periorbital edema and weight gain. Children are less likely to present with other clinical features, such as hypertension, renal failure, or hematuria. In contrast, adults are more likely to present with hypertension in approximately 40% of cases, and hematuria in approximately 30% of cases. A reduced estimated glomerular filtration rate (eGFR) at presentation is also not uncommon. Finally, infections, such as pneumonia in an otherwise healthy individual, may be the first sign of nephrotic syndrome in minimal change disease.
On physical examination, symptoms of nephrotic syndrome are most commonly noted. Inspection may include facial, scrotal and vulvar edema. Additionally, subungual edema may be noted showing paradoxically pink lunulae and white nail beds. Finger abnormalities also include Muehrcke lines of the toe and fingernails, which are horizontal white lines. Finally, ascites and pleural effusions due to edema may also be present.
Laboratory findings in minimal change disease include elevated hematocrit, pseudohyponatremia, hypocalcemia, and abnormal lipid panel. Findings of urine analysis include elevated urinary specific gravity, proteinuria that might reach nephrotic range, high urinary protein-creatinine ratio, microscopic hematuria, and lipid-laden cells.
A kidney biopsy is not routinely performed as soon as the nephrotic syndrome is found during lab work-up. According to the National Kidney Foundation (NKF) Kidney Disease – Improve Global Outcomes (KDIGO) guidelines in 2012, an initial attempt using corticosteroids should be performed before a renal biopsy is performed. A renal biopsy of minimal change disease shows no abnormalities on light microscopy. Lipid-laden cells may be seen in proximal tubular epithelium. Renal biopsy is often unremarkable under immunofluorescence, with the exception of few cases that stain positively for IgM antibodies and C3.
A kidney biopsy is not routinely performed as soon as the nephrotic syndrome is found during lab work-up. According to the National Kidney Foundation (NKF) Kidney Disease – Improve Global Outcomes (KDIGO) guidelines in 2012, an initial attempt using corticosteroids should be performed before a renal biopsy is performed. Electron microscopy is required for the diagnosis of minimal change disease. It shows effacement (fusion) of podocytes, which are visceral epithelial cells, with slit-pore membrane obliteration between podocyte foot processes. However, podocyte effacement is not specific and should not be considered pathognomonic of the disease.
Imaging in nephrotic syndrome is usually unremarkable.
Pharmacologic therapy using corticosteroids is considered the mainstay of therapy for minimal change disease. According to the National Kidney Foundation (NKF) Kidney Disease – Improve Global Outcomes (KGIDO) guidelines in 2012, initial empirical treatment using corticosteroids in patients presenting with nephrotic syndrome prior to a kidney biopsy is recommended. Notably also, the use of statins for hyperlipidemia and ACE-I or ARB for proteinuria are both not recommended in patients presenting with the initial episode of MCD.