Nephrotic syndrome overview
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Nephrotic syndrome is group of signs and symptoms resulting from loss of kidney filtration capabilities leading to massive loss of protein in urine, generalized or localized body edema, hyperlipidemia and hypoproteinemia (most importantly, hypoalbuminemia). Causes of Nephrotic Syndrome can be primary (idiopathic) or secondary (from a systemic insult or immune mediated). Nephrotic syndrome (nephrosis) is defined as heavy proteinuria > 3.5 grams per 24 hours in adults. In children, nephrotic syndrome is defined as protein excretion > 40 mg/m2/h. The accurate diagnosis of nephrotic syndrome thus requires 24-hour urine collection. However, in clinical practice, urine dipstick of a qualitative measure of 3+ urinary proteins, or spot urine protein (mg)/creatinine(mg) ratio > 2 may also reflect nephrotic syndrome.
In 1484, Cornelus Roelans of Belgium described a child with “whole body swelling” and nephropathy. In 1905, Müller described the term of "nephrosis" for non-inflammatory kidney diseases.
Nephrotic syndrome can be classified into primary or secondary depending on the underlying etiology. Primary (idiopathic) nephrotic syndrome is defined as nephrotic syndrome due to a primary glomerular disease. Secondary nephrotic syndrome is defined as nephrotic syndrome due to a primary etiology other than glomerular disorders, such as infections, malignancies, systemic conditions, and medications.
The pathophysiology of hypoalbuminemia in nephrotic syndrome is multifactorial. Proteinuria plays an important role in the pathogenesis of hyperlipidemia in nephrotic syndrome. Neurohormonal changes in the renin-angiotensin-aldosterone system, vasopressin, atrial natriuretic peptide (ANP), and sympathetic nervous system are is implicated in edema formation in nephrotic syndrome.
Nephrotic syndrome can occur primarily or due to systemic diseases. The most common cause of nephrotic syndrome in children is minimal change disease. The most common primary causes in adults are focal segmental glomerulosclerosis (FSGS), minimal change disease, and membranous nephropathy. Approximately 30 percent of adults have secondary nephrotic syndrome due to diabetes mellitus, SLE, or amyloidosis. The most common cause of secondary nephrotic syndrome in adults is diabetes mellitus.
Nephrotic syndrome should be differentiate from other causes of glomerular disease such as Fabry's disease, post-streptococcal glomerulonephritis, lupus nephritis, antiglomerular basement membrane disease (goodpasture's syndrome), Cryoglobulinemia, Henoch-Schönlein purpura, amyloidosis, pulmonary-renal syndromes (vasculitis), thin basement membrane disease, Alport's Syndrome, anti-GBM Disease, hypertensive nephrosclerosis, and subacute bacterial endocarditis. The various types of glomerular diseases may be differentiated from each other based on associations, presence of pitting edema, hematuria, hypertension, hemoptysis, oliguria, peri-orbital edema, hyperlipidemia, type of antibodies, light, and electron microscopic features.
Epidemiology and Demographics
Idiopathic nephrotic syndrome has an incidence of 2-7 cases per 100,000 and a prevalence of 16 cases per 100,000. Nephrotic syndrome may affect children and adults alike. There is no age or ethnic predominance. The prevalence of nephrotic syndrome in children has a 2 to 1 male to female ratio.
Natural History, Complications and Prognosis
History and Symptoms
The hallmark of nephrotic syndrome is edema. A positive history of renal disease, systemic diseases such as diabetes mellitus, amyloidosis, or systemic lupus erythematosus, and medication use is suggestive of nephrotic syndrome. The most common symptoms of nephrotic syndrome include volume overload, foamy urine, and fatigue.
A full physical examination should be performed among patients presenting with nephrotic syndrome. Findings on physical examination suggestive of secondary etiologies may be present, such as characteristic rash in systemic lupus erythematosus (SLE), or peripheral neuropathy in diabetes mellitus.
Nephrotic syndrome is characterized by the following laboratory findings: proteinuria > 3.5g/24 hrs on 24-hour urine collection, proteinuria on urine dipstick, and urine protein/creatinine ratio > 3. When nephrotic syndrome is diagnosed (proteinuria > 3.5 g/24 hrs), additional laboratory tests are required such as serum albumin concentration, serum chemistry panel, lipid panel, and serum creatinine concentration.
Chest X-ray may show signs of pleural effusion.
Renal and abdominal doppler ultrasound may be required to investigate for renal etiologies and complications of disease, such as renal vein thrombosis. Kidney size and signs of obstruction during assessment are also important. Doppler ultrasound of the extremities is indicated if patients with nephrotic syndrome present with suspected deep vein thrombosis.
Other Imaging Findings
Ultrasound-guided renal biopsy for visualization under light microscopy, immunofluorescence or immunoperoxidase, and electron microscopy is usually recommended for patients with nephrotic syndrome. Renal biopsy provides diagnostic and prognostic benefit. However, guidelines that define the timing and the circumstances to perform renal biopsy are not present. In minimal change disease, the most common primary cause of nephrotic syndrome in children, and in diabetic nephropathy, the most common secondary cause of nephrotic syndrome in adults, renal biopsy is not generally recommended and is not routinely performed. Nonetheless, patients who present with unknown or unsure etiology of nephrotic syndrome are recommended to undergo renal biopsy for definitive diagnosis.
There are currently no guidelines for the management of edema associated with nephrotic syndrome. The slow reversal of edema is important at a rate of 0.5-1 kg daily to prevent electrolyte disturbances, hypotension, ischemic acute tubular necrosis, and hemoconcentration associated with aggressive diuretic therapy. Since proteinuria is one of the most significant factors for progression of a disease and is associated with outcome, treatment of proteinuria in nephrotic syndrome must always be considered a priority. Angiotensin-converting enzyme inhibitors (ACE-I), with or without angiotensin-II receptor blockers (ARB) have been extensively studied and are well-known to decrease proteinuria and the risk of progression of renal disease in patients with nephrotic syndrome. Pneumococcal vaccines are recommended for all patients with nephrotic syndrome.
The mainstay of treatment for nephrotic syndrome is medical therapy.
Appropriate treatment of conditions that can cause nephrotic syndrome may help prevent the syndrome.