1. What are the diagnostic criteria for nephrotic syndrome?
Nephrotic syndrome is a syndrome that results from severe proteinuria. Heavy glomerular protein losses (≥3.5 g in an adult or >40 mg/m 2 per hour in a child) lead to the other three criteria for nephrotic syndrome: hypoalbuminemia, hyperlipidemia, and edema. From a practical standpoint, measuring a urine total protein-to-creatinine ratio is preferable to collecting a 24-hour urine for protein. A ratio of ≥3.5 correlates with nephrotic-range proteinuria.
2. What is minimal change disease (MCD; minimal change nephrotic syndrome)?
MCD is a disorder of glomeruli that leads to heavy proteinuria. Kidney biopsy shows normal glomeruli by light microscopy but shows effacement of the podocyte foot processes on electron microscopy. Immunofluorescent microscopy typically is negative, although some patients may show staining for immunoglobulin M (IgM) in the mesangial regions of the glomeruli. Technically, a patient cannot be said to have MCD with certainty without a kidney biopsy. However, so many young children with nephrotic syndrome have MCD that kidney biopsies are performed only in children with atypical findings or after failure of a trial of glucocorticoids. Older adolescents and adults are diagnosed with MCD after a kidney biopsy is performed.
3. How likely is MCD to be the cause of nephrotic syndrome in any individual?
MCD is the cause of nephrotic syndrome in approximately 90% of children younger than age 6, in approximately 65% of older children, and in approximately 20% to 30% of adolescents. In adults with primary glomerular diseases, only 10% to 25% of nephrotic syndrome results from MCD, which puts it third after membranous nephropathy and focal, segmental glomerulosclerosis.
4. What causes MCD?
MCD is an immune-mediated disease, thought to be due to a circulating factor capable of inducing proteinuria. Presumably the circulating factor is secreted by lymphoid cells and functions as a vascular permeability factor and directly affects podocyte function. Although most cases are idiopathic, MCD, particularly in adults, may be associated with neoplastic disease such as lymphoma, toxic or allergic reactions to drugs, certain infections, allergies, or other autoimmune disorders.
6. What is the typical clinical presentation of MCD?
Patients with MCD typically present with mild to severe edema. Because the onset with periorbital edema commonly follows an upper respiratory infection in young children, nephrotic syndrome may sometimes be confused with an allergic reaction until a more thorough evaluation is performed. In the youngest children, there is a 2:1 male to female prevalence, but by adolescence and beyond males and females are equally affected. Other symptoms can include abdominal pain, diarrhea, poor appetite, and decreased urine output. Rarely, a patient may present with sepsis.
7. How is MCD diagnosed?
MCD presents with nephrotic syndrome. However, the child who presents with typical features (see question 1) of nephrotic syndrome is presumed to have MCD and does not undergo a kidney biopsy unless there are unusual factors such as resistance to prednisone therapy, hypertension, decreased kidney function, or hypocomplementemia.
8. What is the standard initial therapy for MCD in children?
The cornerstone of therapy of typical nephrotic syndrome in young children is high-dose glucocorticoids. Children treated with a longer initial course of prednisone may be less likely to experience frequent relapses than those children treated with a more abbreviated course of steroid therapy. Children older than 4 years of age are treated with 60 mg/m 2 daily given early in the morning for 6 weeks followed by 40 mg/m 2 every other morning for an additional 6 weeks. Children younger than age 4 receive the same initial 6-week course of daily prednisone but then should receive a slower taper of 60 mg/m 2 every other morning for 4 weeks, tapering further by 10 mg/m 2 every 4 weeks for an additional 20 weeks. Approximately 95% of young children will experience a complete remission of the nephrotic syndrome within 4 weeks; 75% will respond within 2 weeks.
9. What is the standard initial therapy for MCD in adults?
Prednisone is also the standard initial therapy for adults with MCD. Adults with MCD tend to require a longer course of prednisone before remission is attained. The optimal initial prednisone regimen varies somewhat among nephrologists, but typically a single morning dose of 1 mg/kg per day, maximum of 80 mg, is continued for a minimum of 8 weeks. For patients not in remission at 8 weeks, daily prednisone may be continued for another 2 months until remission is attained. A gradual taper is then recommended on an every-other-day schedule until the patient is tapered off over many months. The slow taper is recommended to sustain the remission and to reduce the likelihood of problems with adrenal insufficiency.
10. How do you define remission in nephrotic syndrome?
Typically, patients with nephrotic syndrome are taught to monitor their urine protein at home using dipsticks. A complete remission is defined in children as a urine dipstick of trace to negative or a urine protein/creatinine ratio of <0.2. In adults, a complete remission is defined as a reduction of proteinuria to ≤300 mg of urinary protein in a 24-hour period; however, a urine protein-to-creatinine ratio of <0.2 is also an appropriate benchmark for adults. A partial remission is defined as a ≥50% reduction in 24-hour protein or a 24-hour urine protein of <3.5 g with a normal serum albumin. Patients with MCD almost always experience a complete, as opposed to a partial, remission. Normalization of serum albumin quickly follows the reduction in proteinuria, but hyperlipidemia may take several months to resolve.
11. What other supportive therapies are useful for MCD?
A no-added-salt diet is always recommended for patients with MCD—it will reduce edema and the tendency to develop hypertension. In addition, angiotensin-converting enzyme (ACE) inhibitors and/or angiotensin receptor blockers (ARBs) are useful in ameliorating proteinuria and are the first choice for the treatment of hypertension in these patients. Oral diuretics may be used with caution in patients with moderate edema. For those patients with severe edema accompanied by ascites, scrotal or labial edema, and/or pleural effusions, intravenous infusions of 25% salt-poor albumin may be helpful. A dose of 1 g/kg, up to a maximum of 50 g, is infused over 2 to 4 hours once or twice a day, followed by intravenous furosemide at a dose of 1 mg/kg. Caution must be observed in the patient with oliguria because that patient could have acute kidney injury, making him or her unresponsive to the diuretic and susceptible to mobilization of peripheral edema, leading to the risk of pulmonary edema with respiratory compromise.
12. What is the typical course for a patient with MCD?
Most children (60% to 75%) with MCD experience relapses of the disease, and sometimes they are frequent—three or more relapses per year. Relapses tend to be precipitated by infections, particularly upper respiratory infections, or allergies. Approximately 50% to 75% of adults who respond to steroids will have a relapse, and 10% to 25% become frequent relapsers. A minority of patients develop steroid dependence of variable severity where the patient cannot be tapered off the prednisone. The steroid dependence can vary from being maintained in remission on low-dose, alternate-day steroids to requiring high-dose, daily steroids to maintain a remission.
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