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A. Componentsnavigator

  1. Proteinuria (>3gm/day) with hypoalbuminemia
  2. Peripheral edema
  3. Hyperlipidemia and lipiduria
  4. Hypercoagulability is usually present
  5. Incidence ~5/100,000 and prevalence 15/100,000 in children

B. Pathogenesis navigator

  1. Complication of a variety of systemic as well as renal-specific diseases
    1. Damage to glomerular filtration system is common pathology in all cases
    2. Glomerular basement membrane (GBM) damage leads to loss of plasma proteins
    3. Speicific dagamage to GBM podocytes and slit diaphragm causes filtration barrier failure
    4. Nephrotic syndrome eventually progresses to chronic renal failure (CRF) with azotemia
  2. Glomerular basement membrane (GBM) [3]
    1. GBM is kidney's major filtration barrier
    2. GBM has three layers: Lamina rare internal, lamina densa, lamina rare external
    3. High negative charge due mainly to heparan sulfate, also to sialic acid
    4. Filtration barrier effective pore size ~55Å but is negatively charged
    5. Transport of negatively charged molecules is inhibited by negative charges
    6. Serum albumin is ~33Å, but is strongly negatively charged like most proteins
    7. Type IV collagen is a major constituent of GBM
  3. Podocytes [3]
    1. Specialized epithelial cells
    2. Line subepithelial space juxtaposed to Lamina rare external of GBM
    3. Highly differentiated cells with volunious cell body
    4. Have long foot-processes that extend toward GBM
    5. Foot processes separated by 30-40nm thin membrane called slit diaphragm
    6. Nephrin, podocin and CD2 associated protein (CD2AP) are components of slit diaphragm
    7. Mutations in these proteins can lead to congenital (rare) nephrotic syndromes

C. Etiology [1,2]navigator

  1. Primary Causes
    1. Membranous Glomerulonephritis (most common)
    2. Minimal Change Disease (mostly children)
    3. Focal Segmental Glomerulosclerosis (FSGS) ± Hyalinosis (FSGSH)
    4. Membranoproliferative Glomerulonephritis
    5. IgA Nephropathy (mainly adults)
    6. Amyloidosis (mainly >65 years old)
    7. Renal vein thrombosis
    8. Several very uncommon inherited (mutational) syndromes
  2. FSGS
    1. Causes: Idiopathic (primary), secondary: HIV, heroin abuse, renal transplant rejection
    2. Up to 50% of transplanted kidneys in FSGS will have recurrent disease
    3. Plasma factor implicated (see below), possibly an immunoglobulin
  3. Renal Vein Thrombosis (RVT)
    1. High propensity for RVT with nephrotic syndrome due to hypercoagulable state
    2. Note that nephrotic syndrome is also a significant cause of RVT
    3. RVT should be ruled out by magnetic resonance angiography in new nephrotic patients
  4. Amyloidosis
    1. Primary or secondary amyloid may cause nephrotic syndrome
    2. This should be considered in setting of concomitant cardiac and/or neural dysfunction
    3. Consider also in any patient with chronic inflammatory disease or dysglobulinemia
  5. Inherited [3]
    1. Nephrin mutations - 1:8200 livebirths in Finland
    2. Podocin mutations in some cases of sporadic FSGS
    3. CD2 Associated Protein (CD2AP) mutations in uncommon FSGS
    4. Denys-Drash syndrome
    5. Diffuse mesangial sclerosis
    6. Schimke immuno-osseous dysplasia
  6. Secondary Causes
    1. Diabetes Mellitus
    2. Immune Complex Diseases: Systemic Lupus Erythematosus, Systemic Vasculitis
    3. Infection: human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV), malaria, syphilis, schisosomiasis
    4. Malignancy: Leukemia, Lymphoma, Carcinoma, Myeloma
    5. Drugs: gold, NSAIDs, Heavy Metals
    6. Allergic Reactions
    7. Hypothyroidism
    8. Renal Vein Thrombosis
    9. Hypertension: Primary and Scleroderma Renal Crisis
    10. Sickle Cell Anemia
    11. Secondary amyloidosis (such as AL type)
    12. Immunoglobulin (Ig) light or heavy chain deposition diseases
  7. Diabetes Mellitus (DM)
    1. DM is a major risk factor for developing proteinuria and CRF
    2. Cardiovascular risk factors: hypertension, smoking, high cholesterol contribute to microalbuminuria and macroalbuminuria [11]
    3. Moderate proteinuria due to DM is more common than primary true nephrotic syndrome
  8. HIV Related Nephropathy [10]
    1. Much more common prior to highly active antiretroviral therapy (HAART)
    2. Prior to HAART, occurred primarily in black patients with CD4 < 500/µL
    3. Focal segmental glomerulosclerosis with tubulointerstitial lymphocytic infiltrates
    4. Interstitial fibrosis then occurs, but all changes may reverse with HAART
    5. Nephrotic syndrome initially with rapid progression to azotemia
    6. HIV may use the kidney as a reservoir during HAART
    7. Chronic disease may responds to 1mg/kg/d prednisone
    8. Infection prophylaxis should be given if prednisone is used
    9. Including PCP prophylaxis, HSV/HZV prophylaxis if appropriate, MAI prophylaxis
    10. Remains significant cause of end stage renal failure in blacks 20-64 years old
  9. Renal Vascular (Arterial) Disease [16]
    1. Nephrotic range proteinuria is uncommon but not rare in this population
    2. These patients often smoke and have known systemic atherosclerosis
    3. Renal arterial thromboses were present in majority of these patients

D. Symptoms and Signsnavigator

  1. Heavy Proteinuria
    1. >3.5gm/day albuminuria in patients with normal serum albumin
    2. Urinary Protein : Creatinine ratio >0.4mg protein/mmol (3.5mg/dL) creatinine
    3. Proteinuria should be evaluated with urinary protein electrophoresis (UPEP)
    4. This is because urinary dipstick only detects albumin (not globulins or other proteins)
    5. Serum albumin levels <3gm/dL (progressive disease <2gm/dL)
  2. Severe Edema
    [Figure] "Fluid Retention in Nephrotic Syndrome"
    1. Low Serum oncotic pressure
    2. Water and sodium retenetion (usually hyponatremic, total body overloaded)
  3. Hypoalbuminemia
    1. Heavy protein losses in urine
    2. Inadequate hepatic synthesis
  4. Hyperlipidemia
    1. Serum oncotic pressure low causes increased hepatic lipid synthesis
    2. Lipiduria also occurs
  5. Coagulopathy
    1. Cumulative incidence of thromboembolic events is ~50%
    2. Nephrotic syndrome is a hypercoagulable state due to many mechanisms
    3. Loss of anti-thrombin through the kidney
    4. Reduced synthesis of proteins C and S (overall levels generally elevated)
    5. Increased Factor V, VIII, Fibrinogen (Factor I)
    6. Platelet function is augmented - increased platelet factor IV
    7. Altered endothelial cell function
  6. Loss of other plasma proteins
    1. Include thyroid binding globulin (TBG)
    2. Transferrin
    3. Immunoglobulins - leading to IgG deficiency
    4. Metal binding proteins including zinc
    5. Rarely lead to deficiencies, except possibly for Vitamin D
  7. Check vitamin D levels, homocysteine levels, possibly other vitamin levels
  8. Albuminuria of any level in nondiabetic patients is a risk for cordiovascular disease [20]

E. Treatment [1,18]navigator

  1. Treat underlying disease and aggressively treat proteinuria and blood pressure [18]
    1. Goal reduction of proteinuria to <0.3gm/d with ACE inhibitors ± angiotensin II blockers
    2. Blood pressure reduction to 125/75 mm
    3. LDL cholesterol reduction to <100mg/dL (<2.6 mMol)
    4. In diabetics, reduce HbA1c to <7.5%
  2. Glucocorticoids
    1. Prednisone 1-1.5mg/kg/d effective in 80% of minimal change, ~20% of FSGS
    2. Use these high doses for 1-2 months, then slowly taper to alternate day therapy
    3. In children with initially responsive nephrotic syndrome, continue alternating day therapy over 3-7 months [17]
    4. Overall ~60% of glucocorticoid responsive children have at least 5 relapses
    5. Pulse high dose methylprednisolone may also be considered
    6. Long-term, high-dose glucocorticoids in children are not associated with deficits in bone mineral content, or with stunting of growth, but did increase body-mass index [19]
  3. Other Agents
    1. alpha interferon for HCV infection with cryoglobulinemia can improve protein losses
    2. Consider cyclosporine (second line) or alkylating agents (typically third line)
    3. Levamisole 2.5mg/kg on alternating days for children may be beneficial
  4. HIV Nephropathy [4,6]
    1. Prednisone often effective in HIV with FSGS [6]
    2. Decreases creatinine and proteinuria
    3. Dose is 60mg/day for 1 months, with 2-26 week taper
    4. Renal Biopsy must be done to rule out other causes
    5. In HIV nephropathy due to "collapsing" FSGS, prednisone is less or not effective
    6. ACE inhibitors reduce progression of nephrotic syndrome
    7. Antiretroviral therapy may be effective
  5. Dietary Protein Intake
    1. Originally believed that increasing dietary protein intake (DPI) would be beneficial
    2. However, increased DPI actually increases protein catabolism, often lowers albumin
    3. Reduction in protein intake to lower levels increases serum albumin levels
  6. Albumin Infusions
    1. Albumin infusions should be given only for symptomatic hypovolemia
    2. Albumin infusions can cause rapid intravascular fluid accumulation and pulmonary edema
  7. Loop Diuretic
    1. Often with potassium sparing agent such as spironolactone
    2. Caution when initiating therapy as patientts are usually intravascularly depleted
    3. Reverse edema slowly in order to prevent cardiovascular collapse
  8. Conivaptan (Vaprisol®) [9]
    1. Non-selective V1/2 antagonist
    2. Effective in euvolemic and hypervolemic hyponatremia
    3. Includes SIADH, cirrhosis with ascites, nephrotic syndrome, CHF
    4. FDA approved for intravenous infusions for hyponatremia including SIADH
    5. Potent inhibitor of CYP3A4 so oral chronic versions not being developed
    6. Caution with too-rapid correction of hyponatremia, as brain demyelination can occur
  9. Treatment of Hyperlipidemia
    1. Agents currently in use are moderately effective
    2. HMG CoA Reductase inhibitors usually first line
    3. Combination therapy may be needed
    4. Goal is LDL < 100mg/dL
  10. Aspirin for coagulopathy only after an initial clotting event (check bleeding time)
  11. Decreasing Protein Losses [18]
    1. ACE inhibitors (ACE-I) very effective and should always be used first line
    2. Rampiril also shown to reduce progression of renal failure with proteinuria >3gm/d [7]
    3. ACE-I reduce microproteinuria in sickle cell disease [8] and diabetes [9]
    4. Begin with low doses of ACE-I and titrate up to maximal doses
    5. If proteinuria >0.3gm/d on maximal ACE-I, add angiotensin II receptor (AT2R) blockers
    6. Caution with combination ACE-I and AT2R blockers due to hyperkalemia (monitoring)
    7. Pre- and post-ACE-I protein losses should be documented
    8. AT2R blockers should be used alone in patients intolerant of ACE inhibitors
    9. Non-dihydropyridine calcium channel blockers may be added to reduce BP
    10. NSAIDs are no longer considered acceptable for reducing protein losses
  12. Ramipril in Non-Diabetic Proteinuric Nephropathy [13,14,15]
    1. Ramipril is a second generation ACE inhibitor with efficacy in HTN and heart Failure
    2. In patients with non-diabetic proteinuria >3gm/day, ramipril reduced progression
    3. Drug was titrated to a diastolic BP under 90mmHg
    4. Ramipril reduced rate of GFR decline by >20%, more than anti-hypertensive drugs alone
    5. In patients with non-diabetic proteinuria 1-3gm/day, ramipril reduced ESRD progression and reduced proteinuria 13% (versus 15% increased proteinuria in controls)
    6. Ramipril reduced progression to ESRD over 4.5 years from ~70% to ~40%
    7. Ramipril may be preferred agent for treatment of non-diabetic proteinuric nerphropathy
  13. Plasma Adsorption [5]
    1. Serum factor implicated in FSGS, particularly in recurrent disease
    2. Protein adsorption through Protein A (binds primarily Ig) effective in FSGS
    3. Impressive decrease in proteinuria following adsorption
    4. Eluted proteins caused albuminuria in rats (MW was <100,000 making Ig unlikely)

References navigator

  1. Eddy AA and Symons JM. 2003. Lancet. 362(9384):629 abstract
  2. Orth SR and Ritz E. 1998. NEJM. 338(17):1202 abstract
  3. Wolf G and Stahl RAK. 2003. Lancet. 362(9397):1746 abstract
  4. Kimmel PL, Barisoni L, Kopp JB. 2003. Ann Intern Med. 139(3):214 abstract
  5. Savin VJ, Sharma R, Sharma M, et al. 1996. NEJM. 334(14):878 abstract
  6. Smith MC, Austen JL, Carey JT, et al. 1996. Am J Med. 101(1):41 abstract
  7. GISEN Group (Ramipril Efficacy in Nephropathy). 1997. Lancet. 349:1857 abstract
  8. Foucan L, Bourhis V, Bangou J, et al. 1998. Am J Med. 104(4):339 abstract
  9. EUCLID Study Group. 1997. Lancet. 349:1787 abstract
  10. Winston JA, Bruggeman LA, Ross MD, et al. 2001. NEJM. 344(26):1979 abstract
  11. Cirillo M, Senigalliesi L, Laurenzi M, et al. 1998. Arch Intern Med. 158(17):1933 abstract
  12. Dember LM, Shepard JO, Nesta F, Stone JR. 2005. NEJM. 352(20):2111 (Case Record) abstract
  13. GISEN Group (Ramipril Efficacy in Nephropathy). 1997. Lancet. 349:1857 abstract
  14. Ruggenenti P, Perna A, Gherardi G, et al. 1998. Lancet. 352(9136):1252 abstract
  15. Ruggenenti P, Perna A, Gherardi G, et al. 1999. Lancet. 354(9176)359 abstract
  16. Halimi JM, Ribstein J, Du Cailar G, Mimram A. 2000. Am J Med. 108(2):120 abstract
  17. Hodson EM, Knight JF, Willis NS, Craig JC. 2000. Arch Dis Child. 83:45 abstract
  18. Ruggenenti P, Schieppati A, Remuzzi G. 2001. Lancet. 357(9268):1601 abstract
  19. Leonard MB, Feldman HI, Shults J, et al. 2004. NEJM. 351(9):868 abstract
  20. Gerstein HC, Mann JFE, Yi Q, et al. 2001. JAMA. 286(4):421 abstract
  21. 1. Eddy AA and Symons JM. 2003. Lancet. 362(9384):629 abstract
  22. Orth SR and Ritz E. 1998. NEJM. 338(17):1202 abstract
  23. Wolf G and Stahl RAK. 2003. Lancet. 362(9397):1746 abstract
  24. Kimmel PL, Barisoni L, Kopp JB. 2003. Ann Intern Med. 139(3):214 abstract
  25. Savin VJ, Sharma R, Sharma M, et al. 1996. NEJM. 334(14):878 abstract
  26. Smith MC, Austen JL, Carey JT, et al. 1996. Am J Med. 101(1):41 abstract
  27. GISEN Group (Ramipril Efficacy in Nephropathy). 1997. Lancet. 349:1857 abstract
  28. Foucan L, Bourhis V, Bangou J, et al. 1998. Am J Med. 104(4):339 abstract
  29. EUCLID Study Group. 1997. Lancet. 349:1787 abstract
  30. Winston JA, Bruggeman LA, Ross MD, et al. 2001. NEJM. 344(26):1979 abstract
  31. Cirillo M, Senigalliesi L, Laurenzi M, et al. 1998. Arch Intern Med. 158(17):1933 abstract
  32. Dember LM, Shepard JO, Nesta F, Stone JR. 2005. NEJM. 352(20):2111 (Case Record) abstract
  33. GISEN Group (Ramipril Efficacy in Nephropathy). 1997. Lancet. 349:1857 abstract
  34. Ruggenenti P, Perna A, Gherardi G, et al. 1998. Lancet. 352(9136):1252 abstract
  35. Ruggenenti P, Perna A, Gherardi G, et al. 1999. Lancet. 354(9176)359 abstract
  36. Halimi JM, Ribstein J, Du Cailar G, Mimram A. 2000. Am J Med. 108(2):120 abstract
  37. Hodson EM, Knight JF, Willis NS, Craig JC. 2000. Arch Dis Child. 83:45 abstract
  38. Ruggenenti P, Schieppati A, Remuzzi G. 2001. Lancet. 357(9268):1601 abstract
  39. Leonard MB, Feldman HI, Shults J, et al. 2004. NEJM. 351(9):868 abstract
  40. Gerstein HC, Mann JFE, Yi Q, et al. 2001. JAMA. 286(4):421 abstract
  41. 1. Eddy AA and Symons JM. 2003. Lancet. 362(9384):629 abstract
  42. Orth SR and Ritz E. 1998. NEJM. 338(17):1202 abstract
  43. Wolf G and Stahl RAK. 2003. Lancet. 362(9397):1746 abstract
  44. Kimmel PL, Barisoni L, Kopp JB. 2003. Ann Intern Med. 139(3):214 abstract
  45. Savin VJ, Sharma R, Sharma M, et al. 1996. NEJM. 334(14):878 abstract
  46. Smith MC, Austen JL, Carey JT, et al. 1996. Am J Med. 101(1):41 abstract
  47. GISEN Group (Ramipril Efficacy in Nephropathy). 1997. Lancet. 349:1857 abstract
  48. Foucan L, Bourhis V, Bangou J, et al. 1998. Am J Med. 104(4):339 abstract
  49. EUCLID Study Group. 1997. Lancet. 349:1787 abstract
  50. Winston JA, Bruggeman LA, Ross MD, et al. 2001. NEJM. 344(26):1979 abstract
  51. Cirillo M, Senigalliesi L, Laurenzi M, et al. 1998. Arch Intern Med. 158(17):1933 abstract
  52. Dember LM, Shepard JO, Nesta F, Stone JR. 2005. NEJM. 352(20):2111 (Case Record) abstract
  53. GISEN Group (Ramipril Efficacy in Nephropathy). 1997. Lancet. 349:1857 abstract
  54. Ruggenenti P, Perna A, Gherardi G, et al. 1998. Lancet. 352(9136):1252 abstract
  55. Ruggenenti P, Perna A, Gherardi G, et al. 1999. Lancet. 354(9176)359 abstract
  56. Halimi JM, Ribstein J, Du Cailar G, Mimram A. 2000. Am J Med. 108(2):120 abstract
  57. Hodson EM, Knight JF, Willis NS, Craig JC. 2000. Arch Dis Child. 83:45 abstract
  58. Ruggenenti P, Schieppati A, Remuzzi G. 2001. Lancet. 357(9268):1601 abstract
  59. Leonard MB, Feldman HI, Shults J, et al. 2004. NEJM. 351(9):868 abstract
  60. Gerstein HC, Mann JFE, Yi Q, et al. 2001. JAMA. 286(4):421 abstract
  61. Conivaptan. 2006. Med Let. 48(1237):51 abstract