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Nephrotic Syndrome
Jeremy D. DeFoe, DO
Karen S. Phelps, MD
image BASICS
DESCRIPTION
  • A clinical syndrome of heavy proteinuria (>3.5 g/1.73 m2/24 hr), hypoalbuminemia, hyperlipidemia, and edema
  • Includes both primary and secondary forms
  • Associated with many types of kidney disease
EPIDEMIOLOGY
Based on definitive diagnosis
  • Diabetic nephropathy: most common cause of secondary nephrotic syndrome (1)
  • Minimal change disease (MCD)
    • Most common nephrotic syndrome in children, peaks at 2 to 8 years
    • Associated with drugs or lymphoma in adults
  • Amyloidosis: rare
  • Lupus nephropathy (LN): Adult women are affected about 10 times more often than men.
  • Focal segmental glomerulosclerosis (FSGS)
    • 25% of nephrotic syndrome in adults
    • Most common primary nephrotic syndrome in African Americans
    • Has both primary and secondary forms
  • Membranous nephropathy
    • Most common primary nephrotic syndrome in Caucasians
    • Associated with malignancy and infection
  • Membranoproliferative glomerulonephritis (MGN)
    • May be primary or secondary
    • May present in the setting of a systemic viral or rheumatic illness
ETIOLOGY AND PATHOPHYSIOLOGY
  • Increased glomerular permeability to protein molecules, especially albumin
  • Edema results primarily from renal salt retention, with arterial underfilling from decreased plasma oncotic pressure playing an additional role.
  • Hyperlipidemia is thought to be a consequence of increased hepatic synthesis resulting from low oncotic pressure and urinary loss of regulatory proteins.
  • The hypercoagulable state that can occur in some nephrotic states is likely due to loss of antithrombin III in urine.
  • Primary renal disease:
    • MCD
    • FSGS
    • MGN
    • IgA nephropathy
  • Secondary renal disease (associated primary renal disease are shown in parentheses):
    • Diabetic nephropathy
    • Amyloidosis
    • LN
    • FSGS
    • Infections (MGN)
    • Cancer (MCD or MGN)
    • Drugs (MCD or MGN)
Genetics
Genetic factors are likely to play a role in susceptibility to the various nephrotic syndromes, although these have not been sufficiently defined to be useful clinically.
RISK FACTORS
  • Drug addiction (e.g., heroin [FSGS])
  • Hepatitis B and C, HIV, other infections
  • Immunosuppression
  • Nephrotoxic drugs
  • Vesicoureteral reflux (FSGS)
  • Cancer (usually MGN, may be MCD)
  • Chronic analgesic use/abuse
  • Preeclampsia
  • Diabetes mellitus
GENERAL PREVENTION
In general, there are few preventive measures, except avoidance of known causative medications.
image DIAGNOSIS
PHYSICAL EXAM
A complete physical exam may discover clues to systemic disease as a potential cause and/or may suggest the severity of disease.
  • Fluid retention: abdominal distention, abdominal fluid shift, extremity edema, puffy eyelids, scrotal swelling, weight gain, shortness of breath. Pericardial rub and decreased breath sounds with pleural effusions may develop.
  • Hypertension
  • Orthostatic hypotension
DIFFERENTIAL DIAGNOSIS
  • Edema and proteinuria: see “Etiology and Pathophysiology.”
  • Edema alone: Other diseases to rule out in patients who have edema without proteinuria include congestive heart failure, cirrhosis, hypothyroidism, nutritional hypoalbuminemia, protein-losing enteropathy.
DIAGNOSTIC TESTS & INTERPRETATION
Initial Tests (lab, imaging)
  • Confirm proteinuria if present: by urine dipstick initially, and then quantitate by 24-hour urine or spot urine protein-to-creatinine ratio.
  • Rule out urine infection with urine culture.
  • Full blood count and coagulation screen
  • Renal function tests: BUN, creatinine with estimated glomerular filtration rate (GFR)
  • Glucose to rule out overt diabetes
  • Consider blood cultures to rule out a postinfectious process.
  • Lipid panel
  • Liver function tests to exclude liver disease or infection
  • Look for autoimmune disease.
    • Antinuclear antibody and/or antidouble-stranded DNA positivity suggest lupus.
    • Complement levels: A low C3 may suggest a postinfectious or membranoproliferative process, whereas both low C3 and C4 point to lupus.
  • Serum protein electrophoresis/urine immune electrophoresis to rule in a paraproteinemia
  • Hepatitis B and C screen
  • HIV and syphilis testing
  • Urinalysis to evaluate for the presence of cellular casts
  • Renal US to verify the presence of 2 kidneys of normal shape and size
  • Chest x-ray to detect presence of pleural effusion or infection
  • If thrombosis is suspected:
    • Doppler US of the legs
    • MRI or venography for renal vein thrombosis
    • Ventilation/perfusion nuclear medicine lung scan and/or CT may be required to rule out pulmonary embolism.
Diagnostic Procedures/Other
Renal biopsy
  • Rarely done in children with first episode of nephrotic syndrome, as MCD is common and empiric steroid therapy is the standard of care.
  • Required to confirm the clinical diagnosis in adults and assist with making a treatment plan (1)
Test Interpretation
  • Light microscopy
    • May see nothing (e.g., MCD)
    • Sclerosis (e.g., FSGS or diabetic nodules in diabetes)
    • Diffuse hypercellularity suggests a proliferative disease such as IgA nephropathy, LN, or postinfectious glomerulonephritis (GN).
  • Immunofluorescence: Mesangial IgA suggests IgA nephropathy, Henoch-Schönlein; other staining patterns are specific for other disease processes.
  • Electron microscopy: The location of immunoglobulin deposits is useful in pointing to a particular diagnosis.
image TREATMENT
MEDICATION
First Line
  • Edema: salt restriction and salt-wasting diuretics (loop and thiazide diuretics):
    • Salt restriction to <2 g sodium per day
    • Restrict fluid intake to <1.5 L/day if hyponatremic.
    • Target weight loss of 0.5 to 1 kg/day (1 to 2 lb/day)
  • Statins have been shown to improve endothelial function (2)[A] and may decrease proteinuria (3)[A], but effect on GFR and preservation of renal function is small. The major role for statin use is in cardiovascular risk reduction.
  • ACE inhibitors or angiotensin II receptor blockers are thought to reduce proteinuria, hyperlipidemia, thrombotic tendencies, progression of renal failure, and to control hypertension, if present (2,4)[A].
  • For steroid-responsive disease (MCD and FSGS), steroids dosed in consultation with nephrologist
P.709

Second Line
  • Many of the nephrotic diseases will require escalation in therapy above steroids. These include rapidly relapsing forms, as well as MGN, LN, and IgA nephropathy. Bolus steroids and other immunosuppressives are required in this circumstance (cyclophosphamide, mycophenolate mofetil, chlorambucil, cyclosporine) (5)[A].
  • Rituximab, combined with steroids or other immunosuppressive agents, has demonstrated early promise in the treatment of refractory nephrotic syndrome (6)[B].
  • Randomized controlled data have been insufficient to determine which patients require prophylactic anticoagulation (7)[A]. Common practice is to anticoagulate with heparin and then warfarin in patients who have persistent nephrotic-range proteinuria. This decision is made based on the patient's history of edema, hypoalbuminemia, thromboembolism, or immobility.
  • Hypocalcemia from vitamin D loss should be treated with oral vitamin D.
ISSUES FOR REFERRAL
Consultation with a nephrologist is often required to assist with renal biopsy to confirm diagnosis and to assist with management of edema. Cytotoxic medications may be called for, depending on the disease process, and this may best be handled by a nephrologist.
ADDITIONAL THERAPIES
Ambulation or range-of-motion exercises to lower risk of deep vein thrombosis (DVT)
INPATIENT CONSIDERATIONS
Admission Criteria/Initial Stabilization
Respiratory distress, sepsis/severe infection, thromboses, renal failure, hypertension, or other complications
Discharge Criteria
Hemodynamically, stable patients without complications may be managed as outpatients.
image ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
Patient Monitoring
  • Frequent monitoring is required for relapse, disease progression, and for detecting signs of toxicity of medical management.
  • Reevaluate for azotemia, urine protein, hypertension, edema, loss of renal function, cholesterol, and weight.
DIET
  • Normal protein (1 g/kg/day)
  • Low fat (cholesterol)
  • Reduced sodium
  • Supplemental multivitamins and minerals, especially vitamin D and iron
  • Fluid restriction if hyponatremic
PATIENT EDUCATION
  • Printed material for patients: National Kidney Foundation, 30 E. 33rd Street, Suite 1100, New York, NY 10016; 800-622-9010
    • Childhood nephrotic syndrome
    • Diabetes and kidney disease
    • Focal glomerulosclerosis
  • Web site: National Institutes of Health: nephrotic syndrome
PROGNOSIS
Nephrotic syndrome in children (MCD) is typically self-limited and carries a good prognosis. In the adult, the prognosis is variable. Complete remission is expected if the basic disease is treatable (infection, malignancy, drug-induced); otherwise, a relapsing and remitting course is possible, with progression to dialysis seen in more aggressive forms (diabetic glomerulosclerosis).
REFERENCES
1. Kodner C. Nephrotic syndrome in adults: diagnosis and management. Am Fam Physician. 2009;80(10): 1129-1134.
2. Gruppo Italíano dí Studí Epídemíologící ín Nefrología. Randomised placebo-controlled trial of effect of ramipril on decline in glomerular filtration rate and risk of terminal renal failure in proteinuric, non-diabetic nephropathy. Lancet. 1997;349(9069):1857-1863.
3. Fried LF, Orchard TJ, Kasiske BL. Effect of lipid reduction on the progression of renal disease: a meta-analysis. Kidney Int. 2001;59(1):260-269.
4. Kunz R, Friedrich C, Wolbers M, et al. Metaanalysis: effect of monotherapy and combination therapy with inhibitors of the renin angiotensin system on proteinuria in renal disease. Ann Intern Med. 2008;148(1):30-48.
5. Hodson EM, Willis NS, Craig JC. Interventions for idiopathic steroid-resistant nephrotic syndrome in children. Cochrane Database Syst Rev. 2010;(11): CD003594.
6. Kamei K, Okada M, Sato M, et al. Rituximab treatment combined with methylprednisolone pulse therapy and immunosuppressants for childhood steroid-resistant nephrotic syndrome. Pediatr Nephrol. 2014;29(7):1181-1187.
7. Kulshrestha S, Grieff M, Navaneethan SD. Interventions for preventing thrombosis in adults and children with nephrotic syndrome (protocol). Cochrane Database Syst Rev. 2006;(2):CD006024.
Additional Reading
&NA;
  • Cadnapaphornchai MA, Tkachenko O, Shchekochikhin D, et al. The nephrotic syndrome: pathogenesis and treatment of edema formation and secondary complications. Pediatr Nephrol. 2014;29(7):1159-1167.
  • Madaio MP, Harrington JT. The diagnosis of glomerular diseases: acute glomerulonephritis and the nephrotic syndrome. Arch Intern Med. 2001;161(1): 25-34.
  • Meyrier A. An update on the treatment options for focal segmental glomerulosclerosis. Expert Opin Pharmacother. 2009;10(4):615-628.
See Also
&NA;
Amyloidosis; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Glomerulonephritis, Acute; HIV/AIDS; Lupus Erythematosus, Discoid; Multiple Myeloma; Acute Kidney Injury (Acute Renal Failure)
Codes
&NA;
ICD10
  • N04.9 Nephrotic syndrome with unspecified morphologic changes
  • N04.1 Nephrotic syndrome w focal and segmental glomerular lesions
  • N04.2 Nephrotic syndrome w diffuse membranous glomerulonephritis
Clinical Pearls
&NA;
  • Nephrotic syndrome is a clinical syndrome of >3.5 g/day proteinuria, hypoalbuminemia, hyperlipidemia, and edema often associated with diabetes and NSAIDs use.
  • Pediatric nephrotic syndrome typically carries a good prognosis and is more easily treated with steroids, although recurrences are common.
  • Nondiabetic adults with nephrotic syndrome will require a renal biopsy to determine cause.
  • Have a high index of suspicion for symptoms that may represent an embolic event in patients with nephrotic syndrome.