NEPHROTIC SYNDROME

NEPHROTIC SYNDROME - SarithaDhruvakumar, MD
BASICS
DESCRIPTION
A syndrome composed of glomerular proteinuria (3.5 g/1.73 m2 body surface area/day), hypoalbuminemia, hypercholesterolemia, and edema as a result of a primary renal disease or secondary to another disease process
• System(s) Affected: Endocrine/Metabolic; Renal/Urologic
EPIDEMIOLOGY
• Predominant age
- Children: 1.5-6 yearsminimal change disease (MCD)
- Adults: All agesMCD, focal segmental glomerulosclerosis (FGS), membranous nephropathy, membranous glomerulonephritis (MGN) more common in the US; IgG-IgA worldwide
• Predominant sex: Male = Female
Incidence
• Children: 2/100,000 new cases/year
• Adults: 3/100,000 new cases/year
RISK FACTORS
• Any of the disorders listed in Etiology
• Drug addiction (e.g., heroin [FGS])
• Hepatitis B and C, HIV, other infections
• Immunosuppression
• Nephrotoxic drugs
• Vesicoureteral reflux (FGS)
• Cancer (usually MGN, may be MCD)
• Chronic analgesic use/abuse
• Preeclampsia
Genetics
• 2-8% of cases familial
• Finnish type congenital nephrotic syndrome inherited in an autosomal recessive fashion
- Associated with NPHS1 and NPHS2 genes
PATHOPHYSIOLOGY
• Altered permeability of glomerular basement membrane due to primary or secondary renal disease leads to proteinuria and hypoalbuminemia
• Edema likely result of primary renal salt retention in addition to arterial underfilling from decreased plasma oncotic pressure
• Hyperlipidemia thought to be a consequence of increased hepatic synthesis resulting from low oncotic pressure and urinary loss of regulatory proteins
• Hypercoagulable state likely due to loss of antithrombin III in urine
ETIOLOGY
• Primary renal disease
- Fibrillary glomerulopathy (primary)
- Focal glomerulonephritis
- FGS
- IgA nephropathy
- Membranoproliferative glomerulonephritis
- MGN
- Mesangial proliferative glomerulonephritis
- MCD
- Rapidly progressive glomerulonephritis (RPGN)
- Congenital nephrotic syndrome
• Secondary renal disease. Associated primary renal disease shown in brackets
- Allergens (snake venoms, antitoxins, poison ivy, insect stings)
- Amyloidosis
- Carcinoma (bronchogenic, breast, colon, stomach, kidney) (MGN and others)
- Diabetes mellitus (most common)
- Erythema multiforme
- Fibrillary glomerulopathy; secondary: Amyloid, cryoglobulins, multiple myeloma, chronic lymphocytic leukemia
- Henoch-Schonlein purpura
- Heredofamilial (Alport syndrome, Fabry disease)
- Infections: Ventriculoatrial shunt infection, bacterial endocarditis, HIV, hepatitis B and C viruses (HBV, HCV), schistosomiasis, tuberculosis, leprosy, poststreptococcal glomerulonephritis (20% are nephrotic)
- Leukemias
- Lymphoma (Hodgkin [MCD], non-Hodgkin [MGN])
- Focal glomerulosclerosis (reflux nephropathy, heroin abuse, nephron ablation, extensive glomerular scarring in acute glomerulonephritis, chronic renal allograft rejection, end-stage kidney disease, morbid obesity, thromboembolism)
- Malignant hypertension
- Melanoma
- Nephrotoxins and drugs (gold, penicillamine, mercury [MGN], NSAIDs [MCD], and interstitial nephritis)
- Polyarteritis nodosa
- Preeclampsia
- Sarcoid
- Serum sickness
- Sjogren syndrome
- Systemic lupus erythematosus (SLE) [MGN, FGS, focal, mesangial, diffuse, proliferative]
- Preeclampsia
ASSOCIATED CONDITIONS
See "Etiology."


DIAGNOSIS
SIGNS AND SYMPTOMS
• Fluid retention: Abdominal distention, ascites, edema, puffy eyelids, scrotal swelling, weight gain, shortness of breath
• Anorexia
• Hypertension
• Oliguria
• Orthostatic hypotension
• Retinal sheen
• Skin striae
• Foamy urine
History
• Systemic renal disease in 1/3 of patients
• Assess for risk factors
Physical Exam
See "Signs and Symptoms"
TESTS
Lab
• Complement levels
• Antinuclear antibody, anti-double-stranded DNA
• Serum protein electrophoresis
• Urine immune electrophoresis
• Blood cultures
• Diabetic testing
• HBV, HCV, HIV, rapid plasma reagent
• Serum albumin
• Lipid panel
• Serum blood urea nitrogen/Creatinine
• Urinalysis
- Proteinuria (>3 g/24 hours)
 Spot urine protein: Creatinine or 24 hour
- Glycosuria
- Hematuria
- Aminoaciduria
- Granular casts
- Hyaline casts
- Fatty casts
- Foamy appearance
- Lipiduria (may see Maltese Crosses under polarized light)
• Drugs that may alter lab results: See "Etiology"
Imaging
• Radiography
• Ultrasound
• CT
• MRI or venography for renal vein thrombosis
• Fluorescein angiography (for retinopathy)
Diagnostic Procedures/Surgery
• Fat pad biopsy
• Renal biopsy
- Not usually indicated for systemic disease, unless it may affect management
- Controversial in idiopathic cases
Pathological Findings
• Light microscopy
- May see nothing (e.g., MCD)
- Disease specific: Sclerosis (e.g., FGS in diabetes)
• Immunofluorescence: Mesangial IgA (Henoch-Schonlein, IgG-IgA nephropathy; others specific for disease).
• Electron microscopy (specific for disease as in subepithelial deposits of IgG in MGN)
DIFFERENTIAL DIAGNOSIS
• See "Etiology."
• Edema: CHF, cirrhosis, hypothyroidism
TREATMENT
PRE-HOSPITAL
Most patients can be managed as outpatient; inpatient admission for complications
GENERAL MEASURES
• Treatment of underlying disease
• Vigorous treatment of infections (especially bacteriuria, endocarditis, peritonitis)
• Vaccines: Pneumococcal, influenza, and Haemophilus influenzae
• Avoidance of excess sunlight
• Avoidance of nephrotoxic drugs
• Consultation with nephrologist often required
Diet
• Normal protein (1 g/kg/d)
- 0.6 g/kg/d for patients with glomerularfiltration rate 25, prior to dialysis
• Low fat (cholesterol)
• Reduced sodium
• Liberal potassium (unless hyperkalemic)
• Supplemental multivitamins and minerals, especially D and iron
• Fluid restriction if hyponatremic
• Caloric restriction if obese or diabetic
Activity
As tolerated
Nursing
Strict input/output daily weights
MEDICATION (DRUGS)
First Line
• For edema-salt restriction most important, then judicious use of thiazide, loop diuretics
- If resistant, a combination of loop and distal diluting segment diuretics (e.g., metolazone) is synergistic
• Statins have been shown to improve both endothelial function (1)[B] as well as decreasing proteinuria (2)[A]
• Angiotension-converting enzyme inhibitors or angiotensin II receptor blockers thought to reduce proteinuria, hyperlipidemia, and thrombotic tendencies, progression of renal failure (3)[B] and to control hypertension if present.
• For steroid-responsive disease (MCD and FGS), steroids dosed in consultation with nephrologist
• Other nephrotic renal diseases: Frequently relapsing MCD, RPGN, MGN, SLE
- Bolus steroids and/or immune suppression (cyclophosphamide, mycophenolate mofetil, chlorambucil, cyclosporine)
Second Line
• Prescribe anticoagulants for thrombotic events. There are data to suggest prophylactic oral anticoagulation in all cases of membranous glomerulonephritis.
• Hypocalcemia from vitamin D loss should be treated with oral vitamin D (dihydrotachysterol) 0.2 mg/d
• MGN patients with a poor prognosis: Probably benefit from cytotoxic therapy (chlorambucil or cyclophosphamide).
FOLLOW-UP
DISPOSITION
Admission Criteria
Respiratory distress, sepsis/severe infection, thromboses, renal failure, hypertension, or other complications
Discharge Criteria
Hemodynamically stable patients without complications may be managed as outpatients.
Issues for Referral
Consultation with nephrologist for renal biopsy, nephrotic syndrome not caused by systemic renal disease, cytotoxic therapy
PROGNOSIS
Varies with specific causes. Complete remission is expected if the basic disease is treatable (infection, malignancy, drug induced); otherwise, It may progress to dialysis dependence (e.g., diabetic glomerulosclerosis).
COMPLICATIONS
• Hypercoagulability, especially renal vein thrombosis
• Pulmonary emboli
• Pleural effusion
• Ascites
• Hyperlipidemia, cardiovascular disease
• Acute renal failure, progressive renal failure
• Protein malnutrition
• Infection
• Iron deficiency (uncommon)
PATIENT MONITORING
Frequent monitoring for azotemia, hypertension, edema, nephrotoxicity, cholesterol, and weight.
Acute flank pain and hematuria may suggest renal vein thrombosis
REFERENCES
1. Dogra GK, et al. Statin therapy improves brachial artery endothelial function in nephrotic syndrome. Kidney Int. 2002; 62:550-557.
2. Fried LF, et al. Effect of lipid reduction on the progression of renal disease: A meta-analysis. Kidney Int. 2001;59:260-269.
3. Nakao N, et al. Combination treatment of angiotensin II receptor blocker and angiotensin-converting-enzyme inhibitor in non-diabetic renal disease (COOPERATE): A randomized controlled trial. Lancet. 2003;361:117-124.
4. Madaio MP, Harrington JT. The diagnosis of glomerular diseases: Acute glomerulonephritis and the nephrotic syndrome. Arch Intern Med. 2001;161:25-34.
5. Remuzzi G, Schieppati A, Ruggenenti P. Clinical practice. Nephropathy in patients with type 2 diabetes. N Engl J Med. 2002;346:1145-1151.
6. Schwarz A. New aspects of the treatment of nephrotic syndrome. J Am Soc Nephrol. 2001;12(Suppl 17):S44-S47.
MISCELLANEOUS
See also: Amyloidosis; Diabetes mellitus; Glomerulonephritis, acute; HIV infection and AIDS; Multiple myeloma; Renal failure, acute (ARF); Renal failure, chronic; Systemic lupus erythematosus (SLE)