a. Pathophysiologic mechanism. Nephrotic syndrome results from increased glomerular basement membrane (GBM) permeability to serum proteins through changes in either charge-selective or size-selective properties of the GBM. In large part, nephrotic syndrome is mediated by damage to the glomerular podocyte.
b. Clinical manifestations of nephrotic syndrome. Onset is insidious, and renal function as measured by glomerular filtration rate (GFR) may be normal. Clinical findings include proteinuria, hyperlipidemia, and low serum albumin due to increased GBM/podocyte permeability. These changes lead to hypoalbuminemia, edema due to loss of oncotic pressure, and increased sodium retention. Massive proteinuria can cause urine to appear frothy, a clue to the presence of nephrotic syndrome. Glomerular hematuria occurs infrequently but may occur with some diseases that traditionally cause nephrotic syndrome (e.g., diabetic nephropathy). An easy-to-remember mnemonic for nephrotic syndrome is PALE: (These patients may look “PALE” because they’re excreting so much protein—this is not really so, but it makes the following mnemonic easier to remember.)
Proteinuria (>3.5 g/24 hr)
Albumin (<3.0 g/dL)
Lipids (often elevated)
B. Causes of Nephrotic Syndrome
a. Primary glomerular disease. In the absence of underlying diabetes, nephrotic syndrome is caused by primary glomerular disease in most patients. Specific etiologies change frequency by age (i.e., the frequency of minimal change disease decreases while that of membranous nephropathy increases with age). Primary glomerular diseases associated with nephrotic syndrome in adults include:
i. Membranous nephropathy
ii. Minimal change disease
iii. Focal segmental glomerulosclerosis (FSGS)
iv. Membranoproliferative glomerulonephritis
v. Rapidly progressive glomerulonephritis
b. Secondary causes. Often, nephrotic syndrome occurs secondary to systemic disease. Although there is a long list of possible secondary causes, the most common cause is diabetes mellitus. Remember systemic causes for nephrotic syndrome by the mnemonic, “THIS LAD HAS nephrotic syndrome.”
MNEMONIC: (“THIS LAD HAS nephrotic syndrome”)
Tumors and thrombosis
Heroin, Heavy metals, and other toxins/medications (NSAIDs)
Subacute bacterial endocarditis, Syphilis, Schistosomiasis
Hepatitis B and C
Diabetic nephropathy is the most common systemic cause of nephrotic syndrome.
i. Tumors and thrombosis. Many cancers can cause nephrotic syndrome. In older adult patients with unexplained nephrotic syndrome, underlying malignancy should be on the differential diagnosis. Both hematologic malignancies (e.g., lymphoma, leukemia, multiple myeloma) and solid tumors (e.g., cancer of the colon, lung, or breast) can cause nephrotic syndrome. Renal vein thrombosis can also cause acute nephrotic syndrome (or can be a consequence of nephrotic syndrome of another cause).
ii. Heroin, heavy metals, and toxins/medications. Heroin, organic gold, mercury, lithium, bisphosphonates, newer biologics (tyrosine kinase and vascular endothelial growth factor inhibitors) and nonsteroidal antiinflammatory drugs (NSAIDs) can cause nephrotic syndrome.
iii. Infections. There are many infections that can cause nephrotic syndrome. Some important ones are hepatitis B and C, AIDS, subacute bacterial endocarditis, syphilis, and schistosomiasis.
iv. Systemic disorders. Major causes of nephrotic syndrome include systemic lupus erythematosus (SLE), amyloid, and diabetes mellitus. The incidence of diabetes mellitus is increasing dramatically in the general US population; thus, diabetic nephropathy is also increasing and now accounts for about 50% of patients starting hemodialysis.
The incidence of diabetes mellitus is increasing dramatically in the general US population. As a result, diabetic nephropathy now accounts for about 50% of patients starting hemodialysis.
C. Approach to the Patient. After it has been determined that a patient has nephrotic syndrome, the search for the underlying cause begins. A thoughtful history and physical examination should be performed, looking for symptoms and signs of diseases listed previously. Depending on the suspected cause, the following laboratory tests and procedures can be useful:
a. Serum chemistries, including blood urea nitrogen (BUN), creatinine, glucose, hemoglobin A1c, and liver function test measurements
b. Urinalysis and microscopic examination of urine sediment
c. Complete blood count (CBC)
e. Hepatitis serologies
f. Rapid plasma reagin (RPR) or Venereal Disease Research Laboratory (VDRL) test for syphilis
g. HIV test
h. Fat pad or rectal biopsy (to look for amyloidosis)
i. Blood cultures (to rule out endocarditis)
j. Chest radiograph
k. Serum and urine protein electrophoresis (amyloid or myeloma)
l. Renal biopsy
m. Other routine cancer screening appropriate for age and sex (e.g., colorectal cancer screening, Papanicolaou test, mammogram)
D. Treatment. Treatment focuses on the underlying disorder. General management strategies include:
a. Inhibition of the renin-angiotensin-aldosterone axis is central to medical management. Angiotensin-converting enzyme inhibitors slow progression of renal disease, decrease proteinuria, and can help treat hypertension.
b. Specific therapy for hyperlipidemia (e.g., HMG-CoA reductase inhibitors)
c. A diet low in sodium and saturated fat
d. Strict treatment of hypertension with a goal blood pressure of less than 125/75 mm Hg
e. Fluid restriction and diuretics (if hyponatremia and/or edema are present)
f. Adequate protein intake of 0.8–1 g/kg/day with a high-carbohydrate intake to maximize utilization should be encouraged.
g. Anticoagulation can be considered for patients with a serum albumin less than 2 g/dL with risk factors for thromboembolism (e.g., obesity, recent surgeries, personal or family history of thromboembolic disease).
h. Specific treatment of underlying cause (e.g., immunosuppressives for specific glomerulonephritis or antiviral treatment for hepatitis B or C) should be tailored based on the individual clinical scenario.
a. Infections. Patients with nephrotic syndrome are prone to infections due to urinary losses of immunoglobulins and complement.
b. Thrombosis (both arterial and venous) can be caused by loss of antithrombin III, protein C, and protein S in the urine. Thrombosis often occurs in patients with membranous nephropathy.
c. Hypovolemia may be a consequence of overdiuresis or intravascular fluid losses.
d. Weight loss results from protein depletion.
e. Atherosclerosis may result from hyperlipidemia.
Suggested Further Readings
Canetta PAA, Radhakrishnan J. The evidence-based approach to adult-onset idiopathic nephrotic syndrome. Front Pediatr 2015;3.Find this resource:
Hull RP, Goldsmith DJA. Nephrotic syndrome in adults. BMJ 2008;336:1185.Find this resource:
Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury Workgroup. KDIGO clinical practice guideline for glomerulonephritis. Kidney Int Suppl 2012;2:139–274.Find this resource: