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Nephrotic Syndrome
Aka: Nephrotic Syndrome, Nephrosis
- Definition
- Conditions causing Proteinuria, edema, hypoalbuminemia and Hyperlipidemia
- Epidemiology
- Incidence: 3 per 100,000 per year in U.S.
- Pathophysiology: Edema in Nephrotic Syndrome
- Underfill mechanism (children)
- Significant Proteinuria results in hypoalbuminemia
- Decreased oncotic pressure results in edema
- Overfill mechanism (adults)
- Glomerulus becomes more permeable to albumin and other proteins
- Proteinuria Causes tubulointerstitial inflammation
- Hypoalbuminemia also occurs and results in decreased oncotic pressure
- Sodium retention leads to edema
- Types: Histologic
- Primary glomerulonephropathy progresses to Nephrosis
- Occurs in 20% of cases
- Children
- Minimal Change Disease (NIL Lesion)
- Adults
- Membranous Nephropathy (33%)
- Most common in white patients
- Focal Segmental Glomerulosclerosis (33%)
- Most common in black patients
- Minimal Change Disease (15%)
- Immunoglobulin A Nephropathy (15%)
- Causes: Secondary
- Idiopathic (80-90% of cases)
- Most common
- Systemic Lupus Erythematosus
- Diabetic glomerulosclerosis in Diabetes Mellitus
- Immunologic and metabolic
- Cryoglobulinemia
- Goodpasture's Syndrome (anti-Glomerular Basement Membrane Disease)
- Henoch Schonlein Purpura
- Polyarteritis Nodosa
- Sjogren Syndrome
- Membranoproliferative Glomerulonephritis (MPGN)
- IgA Nephropathy
- Amyloidosis
- Erythema Multiforme
- Microscopic polyangitis
- Viral Infection
- Hepatitis B Infection
- Hepatitis C Infection
- HIV Infection
- Epstein-Barr Virus (Mononucleosis)
- Herpes Zoster (Shingles)
- Bacterial Infection
- Infective Endocarditis
- Syphilis
- Leposy
- Protozoa Infection
- Filariasis
- Helminthiasis
- Malaria
- Schistosomiasis
- Malignancy
- Multiple Myeloma
- Melanoma
- Leukemia or Lymphoma (e.g. Hodgkin's Lymphoma)
- Other cancers (e.g. Lung Cancer, Breast Cancer, Colon Cancer, Renal Cell Carcinoma)
- Medications and drugs
- NSAIDs
- Penicillamine
- Gold
- Lithium
- Heroin
- Pamidronate
- Interferon alfa
- Mercury Poisoning
- Miscellaneous
- Preeclampsia or Eclampsia
- Alport Syndrome
- Allergic Reaction (e.g. Insect stings, Snake Bite, anti-toxins, Poison Ivy)
- Malignant Hypertension
- Sarcoidosis
- Castleman Disease
- Symptoms
- Edema (see signs below) with secondary weight gain
- Foamy urine
- Exertional Dyspnea
- Fatigue
- Signs
- Hypertension
- Edema (most common presenting complaint)
- Initial: Progressive lower extremity edema
- Later: Periorbital edema, Scrotal Edema, Pleural Effusion, Ascites
- May present with acute Congestive Heart Failure
- Labs: Diagnosis
- Diagnostic criteria (in combination with edema)
- Hypoalbuminemia (Serum Albumin <2.5 g/dl)
- Hyperalbuminuria (Proteinuria >3.0 to 3.5 grams per day)
- Other associated lab findings (supportive, but not required for diagnosis)
- Hyperlipidemia (Total Cholesterol often >300 to 350 mg/dl)
- Urinalysis
- Urine Dipstick with 3+ protein suggests nephrotic range Proteinuria
- Use only for initial screening and then confirm with Urine Protein to Creatinine Ratio
- Hematuria or casts suggests Glomerulonephritis
- Urine Protein to Creatinine Ratio
- Ratio >3 to 3.5 suggests nephrotic range Proteinuria
- Correlates with 3 to 3.5 grams protein in 24 Hour Urine Protein
- Efficacy is equivalent to a 24 Hour Urine Protein collection
- Lipid profile
- Total Cholesterol >300 mg/dl (>50% of patients with Nephrotic Syndrome)
- Comprehensive metabolic panel
- Serum Albumin <2.5 g/dl
- Serum Creatinine increase and GFR reduced in some cases
- However Acute Kidney Injury from Nephrotic Syndrome is uncommon
- Other findings
- Increased serum transaminases may suggest underlying Viral Hepatitis
- Renal Biopsy
- Defer decision to biopsy to nephrology
- Indications
- Often not needed if controlled disease or secondary cause is known
- Useful in cases in which biopsy would direct treatment or inform prognosis
- Idiopathic cases or unknown histologic type
- Renal disorders (e.g. SLE)
- Severe disease or Corticosteroid refractory
- Labs: Initial Evaluation of Causes to consider
- HIV Test
- Hepatitis B Serology (HBsAg)
- Hepatitis C Serology (Hepatitis C Antibiody, xHCV)
- Serum Protein Electrophoresis or Urine Protein electrophoresis (Multiple Myeloma, Amyloidosis)
- Rapid Plasma Reagin (Syphilis)
- Connective tissue labs
- Antinuclear Antibody
- Anti-dsDNA
- Complement C3
- Complement C4
- Imaging
- Renal Ultrasound
- Indicated in reduced GFR
- Other imaging to consider in evaluation of complications or differential diagnosis of edema
- Chest XRay
- Echocardiogram
- Abdominal Ultrasound
- Differential Diagnosis
- See Edema
- See Glomerulonephritis
- See Acute Kidney Injury
- Acute Interstitial Nephritis
- Acute Tubular Necrosis
- Renal Vein Thrombosis
- Management
- Consult with nephrology
- Test for underlying cause (often idiopathic)
- Fluids and Electrolytes
- Limit daily Sodium intake to 3 grams/day
- Consider limiting oral fluids to <1.5 Liters daily
- Diuretics
- Precautions
- Initial goal weight loss: 2-4 lb (1 to 2 kg) per day
- Later goal weight loss: 1-2 lb (0.5 to 1 kg) per day (risk of Acute Renal Failure if excessive)
- Loop Diuretics (e.g. Furosemide)
- Diuretic resistance is typical (due to protein-bound nature of Diuretics and hypoalbuminemia)
- Often requires high dose (e.g. Furosemide 80 to 120 mg)
- May require IV dosing as oral absorption may be reduced due to intestinal edema
- Consider human albumin 20% IV before IV Diuretic dose (acute cases only)
- Starting doses
- Furosemide 40 mg orally twice daily OR
- Bumetanide 1 mg twice daily
- Dose titration
- Double dose every 1-3 days until adequate effect
- Adjunctive Diuretics
- Thiazide Diuretics
- Spironolactone
- Metolazone (Zaroxolyn)
- ACE Inhibitor (or Angiotensin Receptor Blocker if ACE Inhibitor intolerant)
- Typically recommended to reduce Proteinuria even if normotensive
- Enalapril (Vasotec) 2.5 to 20 mg per day (dosing used in studies)
- Lisinopril
- Corticosteroids
- Example protocol: 60 mg daily for 4 weeks, then 40 mg every other day for 4 weeks
- Hahn (2015) Cochrane Database Syst Rev (3):CD001533 [PubMed]
- Minimal Change Disease (especially in children)
- Corticosteroid responsive
- Focal Glomerulosclerosis and Membranous Nephropathy
- Variable response to Corticosteroids
- Management per local consultant recommendations
- Immunosuppressants (e.g. Cyclophosphamide, Chlorambucil, Cyclosporine, Rituximab)
- Used alone or in combination with Corticosteroids in some cases (steroids ineffective, intolerable)
- Immunosuppressants may be very effective in some secondary causes (e.g. SLE)
- Other measures
- Avoid Nephrotoxins (e.g. NSAIDs)
- Maintain Blood Pressure less than 130/80
- Control Hyperlipidemia
- Also improves as Proteinuria resolves and underlying secondary cause improves
- Other measures that may be considered in specific cases
- Prophylactic Anticoagulation
- Consider in superimposed Hypercoagulable states (but not used in most cases)
- Avoid unproven strategies
- Avoid intravenous albumin
- Avoid prophylactic antibiotics
- Complications
- Venous Thromboembolism (Deep Vein Thrombosis and Pulmonary Embolism)
- Relative Risk of 1.4 to 1.7
- Deep Vein Thrombosis (occurs in 1.5% of adult Nephrotic Syndrome)
- Renal vein thrombosis (occurs in 0.5% of adult Nephrotic Syndrome)
- Results in part from loss of coagulation regulatory proteins
- Risk factors
- Age 18 to 39 years
- Nephrotic Syndrome onset in last 6 months
- Membranous Nephropathy as the cause of Nephrotic Syndrome (occurs in 7% of cases)
- Serum Albumin <2.0 to 2.5 g/dl
- Infection and Immunodeficiency
- Mechanism
- Serum IgG and complement loss (Proteinuria)
- Nephrotic Syndrome management (Corticosteroids)
- Risk factors
- Children
- Nephrotic Syndrome relapse
- Corticosteroid use
- Most common infections
- Cellulitis
- Peritonitis
- Sepsis
- Acute Renal Failure
- Rare complication
- Appears to be multifactorial
- Sepsis
- Excessive diuresis
- Renal vein thrombosis
- Renal Interstitial Edema
- Prognosis
- Variable based on histology and secondary cause
- Idiopathic Membranous Nephropathy
- One third with benign course
- One third with persistent Proteinuria or edema but normal Renal Function
- One third with progression to End Stage Renal Disease (ESRD) within 10 day
- Chen (2014) Cochrane Database Syst Rev (10):CD004293 [PubMed]
- Primary focal segmental sclerosis
- Moderate Proteinuria (3 g/day): ESRD develops in 50% over 5-10 years
- Severe Proteinuria (>10 g/day): ESRD develops within 3-5 years
- Korbet (2012) J Am Soc Nephrol 23(11): 1769-76 [PubMed]
- References
- Hull (2008) BMJ 336(7654): 1185-9 [PubMed]
- Karnath (2007) Hosp Physician 43(10): 25-30 [PubMed]
- Kodner (2009) Am Fam Physician 80(10): 1129-36 [PubMed]
- Kodner (2016) Am Fam Physician 93(6):479-85 [PubMed]