Michael Perrotti, MD
BASICS
DESCRIPTION
• Neoprotic syndrome refers to a specific renal disease with a distinct constellation of clinical and laboratory features:
– Proteinuria (>3.5 g/d)
– Hypoalbuminemia (<3 g/dL)
– Peripheral edema
– Hyperlipidemia and thrombotic disease frequently seen
• Nephrotic syndrome (NS) can be caused by specific renal diseases or systemic diseases such as diabetes, lupus and others.
EPIDEMIOLOGY
Incidence
• Uncommon Disease
– Children: 2/100,000 new cases / year
– Adult: 3/100,000 new cases / year
Prevalence
N/A
RISK FACTORS
• Primary renal disease (minimal change disease predominant cause in children)
• Underlying systemic disease in 30% of adults with NS including diabetes mellitus, amyloidosis, systemic lupus erythematosus
• Infection: Streptococcus, hepatitis, mononucleosis, syphilis, tuberculosis, HIV
• Medications: NSAIDs, interferons, bisphosphonates, lithium, gold, captopril, penicillamine, tyrosine kinase inhibitors
• Malignancy
Genetics
• Rare cause
– 2–8% of cases are familial
– Finnish type congenital nephritic syndrome is inherited as autosomal recessive
PATHOPHYSIOLOGY
• Severe proteinuria is due to abnormal permeability of the glomerular basement membrane (GBM) (1).
– GBM normally restricts passage of proteins >70 kd.
• Signs/symptoms of NS worsen as serum albumin falls below 2.5 g/dL.
• Proteinuria can be selective or nonselective.
• Edema results from primary salt retention and secondary decreased plasma oncotic pressure.
• Hyperlipidemia is secondary to increased hepatic synthesis from low oncotic pressure and urinary loss of regulatory proteins.
• Hypercoagulable state is likely due to loss of antithrombin III in urine.
ASSOCIATED CONDITIONS
• Membranous nephropathy (24%)
• Minimal change disease (15%)
• Lupus (14%)
• Focal segmental glomerulosclerosis (12%)
• Membranoproliferative glomerulonephritis (7%)
• Amyloidosis (6%)
• IgA nephropathy (6%)
GENERAL PREVENTION
• Avoidance of risk factors
• Treating conditions that may cause NS
DIAGNOSIS
HISTORY
• Symptoms of fluid/sodium retention:
– Periorbital edema, especially on awakening
– Peripheral edema, especially at end of day
– Dyspnea/orthopnea secondary to pleural effusion
• Anorexia
• Oliguria, foamy urine
• Weight gain
• Foamy appearance of urine
PHYSICAL EXAM
• Along with signs of fluid retention, patients may have signs of systemic disease causing NS
• Vital signs: BP, temperature, weight
• Skin exam: Rash (eg, butterfly rash of SLE), pallor, edema, lymphadenopathy
• Ophthalmic exam: Uveitis in sarcoid, diabetic retinopathy
• Heart/lung exam: Endocarditis, pleural effusion
• Abdominal exam: Masses, ascites
• Neurologic exam: Diabetic neuropathy, CNS lesion, mononeuritis multiplex
DIAGNOSTIC TESTS & INTERPRETATION
Lab
• Blood chemistry: BUN, Cr, comprehensive metabolic panel, CBC
– Hypoalbuminemia (<3 g/dL)
• Serum lipids: Cholesterol, triglycerides often elevated
• Urine analysis and microscopy
– Marked proteinuria causes urine to foam.
– Albuminuria detected by dipstick; all proteinuria detected by SSA; Protein is precipitated in urine by the addition of sulfosalicylic acid (SSA). Performed to confirm positive protein reactions seen on a urine dipstick.
– Positive SSA and negative dipstick: Nonalbumin proteinuria (multiple myeloma)
– Characteristic dipstick reading of 3+ to 4+ in NS patients
– Glycosuria: Suggests diabetes mellitus as possible cause of NS
– Hematuria common (usually microscopic)
– Lipiduria: Maltese crosses seen microscopically
– Microscopic: Oval fat bodies, fatty casts, hyaline casts, cellular casts
• 24-hr urine
– Protein > 3.5 g/24 h, mostly albumin
• Additional testing as needed to rule out other nonrenal causes
– Fasting blood sugar/glucose tolerance
– Hepatitis B and C antibodies
– Antinuclear antibody
– Syphilis serology
– HIV
– Multiple myeloma
Imaging
• Renal ultrasound: Increased echogenicity of renal parenchyma
• Screening for underlying malignancy with CT scan
Diagnostic Procedures/Surgery
Renal biopsy
Pathologic Findings
• Minimal change glomerulopathy
• Membranous glomerulopathy
• Focal segmental glomerulonephritis
• Mesangioproliferative glomerulonephritis
• Membranoproliferative glomerulonephritis
• Diabetic glomerulosclerosis
• Fibrillary glomerulonephritis
• Light chain deposition disease
DIFFERENTIAL DIAGNOSIS
• Congestive heart failure
• Cirrhosis
• Malnutrition
• Protein losing enteropathy
TREATMENT
GENERAL MEASURES
• Sodium restriction (2 g/d)[A]
• Protein restriction
• BP control
• Maintenance of fluid balance
MEDICATION
First Line
• ACE inhibitors (captopril, enalapril, ramipril, others) or Angiotensin II receptor blockers (losartan, olmesartan, telmisartan others) (2)
– Indicated with random protein to creatinine ratio >200 mg/G
– Should not be used concurrently due to risk of hypotension and worsening renal function
– Monitor for hypotension, hypokalemia, or worsening renal function
– Common ACE-I side effects include cough, angioedema, or allergy
• Statin therapy
– Goal LDL <100 and triglyceride <150
– Side effects include myalgia, liver dysfunction, GI disturbance, and rash
• Corticosteroids for primary idiopathic or minimal change disease (3)[A]
Second Line
Cytotoxic agents (cyclophosphamide, chlorambucil, cyclosporine): Minimal change disease unresponsive to steroids, membranous glomerulonephritis with poor prognosis
SURGERY/OTHER PROCEDURES
• Dialysis
• Renal transplantation
ADDITIONAL TREATMENT
Radiation Therapy
N/A
Additional Therapies
Anticoagulation for thrombosis
Complementary & Alternative Therapies
N/A
ONGOING CARE
PROGNOSIS
• Prognosis depends on age, race, pathology, presence of HTN, underlying systemic disease, degree of renal dysfunction, and degree of proteinuria.
• Minimal change disease in children has an excellent prognosis.
• Prognosis of the other glomerulopathies much more variable.
• Prognosis of secondary NS depends on the systemic diseases causing the NS.
COMPLICATIONS
• Acute kidney failure
• Atherosclerosis, hyperlipidemia, cardiovascular disease
• Chronic kidney disease
• Congestive heart failure
• Heart disease
• Malnutrition
• Pneumococcal pneumonia and other infections
• Pulmonary edema
• Arterial and venous thrombosis (particularly deep vein and renal vein thrombosis)
• Pulmonary emboli
FOLLOW-UP
Patient Monitoring
• Assess response to treatment with 24-hr urine protein measurement
• Monitor BP and renal function
• Monitor for treatment toxicity
Patient Resources
• Medline Plus http://www.nlm.nih.gov/medlineplus/ency/article/000490.htm
• www.kidney.diddk.nih.gov
REFERENCES
1. Siddall EC, Radhakrishnan L. The pathophysiology of edema formation in the nephritic syndrome. Kidney Int. 2012;62:635–642.
2. Nakao N, Yoshimura A, Morita H, et al. Combination treatment of angiotensin II receptor blocker and angiotensin converting enzyme inhibitor in non-diabetic renal disease. A randomized controlled trial.Lancet. 2003;361:117–124.
3. Maas R, Hofstra JM, Wetzels JF. An overview of immunosuppressive therapy in idiopathic membranous nephropathy. Minerva Med. 2012;103:253–266.
ADDITIONAL READING
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.
See Also (Topic, Algorithm, Media)
• Chronic Kidney Disease, Adult (Renal Failure, Chronic)
• Chronic Kidney Disease, Pediatric (Renal Failure, Chronic)
• Glomerulonephritis, Acute
• Nephropathy, Membranous
• Nephropathy, Minimal Change
• Proteinuria
CODES
ICD9
• 250.40 Diabetes with renal manifestations, type II or unspecified type, not stated as uncontrolled
• 250.41 Diabetes with renal manifestations, type I [juvenile type], not stated as uncontrolled
• 581.9 Nephrotic syndrome with unspecified pathological lesion in kidney
ICD10
• E10.21 Type 1 diabetes mellitus with diabetic nephropathy
• E11.21 Type 2 diabetes mellitus with diabetic nephropathy
• N04.9 Nephrotic syndrome with unspecified morphologic changes
CLINICAL/SURGICAL PEARLS
• NS is a constellation of signs and symptoms caused by different disorders that damage the kidneys.
• The hallmark of NS is excess protein in the urine and edema.
• The most common cause in children is minimal change disease.
• The most common cause in adults is membranous glomerulonephritis.
• Treatment is directed toward the underlying disorder, symptom reduction, and prevention of complications and preservation of renal function.
• Most patients are given an ACE inhibitor or an angiotensin II receptor blocker to slow the loss of kidney function.