Nephrotic Syndrome

Aka: Nephrotic Syndrome, Nephrosis

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