section name header

Info


A. Introductionnavigator

  1. Causes 20-30% of adult nephrotic syndrome cases worldwide
  2. High risk for end-stage renal disease and hypercholesterolemia

B. Pathogenesisnavigator

  1. Idiopathic or secondary to various (apparent) causes
  2. Causes (?) identified in ~35% of cases
    1. Lupus Nephritis (10-20%; usually Type V)
    2. Infection: hepatitis B (HBV) and C viruses (HCV) [2], congenital and secondary syphilis
    3. Neoplasia: particularly cancer of the lung, breast, GI tract and kidney
    4. Drugs: gold, mercury and penicillamine, NSAIDS [3]
    5. Diabetes
  3. Idiopathic - associated with with HLA-DR3 (~12X risk) [4]
  4. Rat model called "Heymann nephritis"
    1. Granular deposits of IgG and C3 similar to that seen in some forms of the human disease
    2. Subepithelial immune deposits
    3. Target antigen in rat is glycoprotein of 330K, but probably not in human
    4. Possible role of TGF-ß1

C. Clinical Course [5]navigator

  1. Variable
  2. Endstage renal failure ~25% within 10 years in adults
  3. Spontaneous remissions ~25% with mean time to remission ~5 years
    1. Patients with idiopathic membranous nephropathy may have better prognosis
    2. High rate of spontaneous remission (complete) for idiopathic variety
    3. Patients with worse prognosis include males and age >50
    4. Hypertension (HTN), high cholesterol, and nephrotic syndrome non-prognostic
  4. Risk for cardiovascular complications from hyperlipidemia
  5. If drugs are implicated, they should be stopped, and glucocorticoids considered [3]

D. Treatmentnavigator

  1. Therapy is difficult and efficacy difficult to prove
    1. Natural history of disease includes frequent spontaneous exacerbations / remissions
    2. Most trials are uncontrolled
    3. Hypertension must always be controlled
  2. Proteinuria
    1. Best controlled by angiotensin II (AT2) converting enzyme (ACE) inhibitors
    2. Reduce glomerular filtration of protein and prevent renal function decline
    3. Further reductions in proteinuria may occur with added AT2 receptor blockers
    4. Caution with combinations of AT2 receptor blockers and ACE inhibitors
  3. Ramipril in Non-Diabetic Proteinuric Nephropathy [6,7]
    1. In non-diabetic proteinuria >3gm/day, ramipril reduced proteinuria progression
    2. Drug titrated to a diastolic BP under 90mmHg
    3. Reduced rate of GFR decline by >20%, more than anti-HTN drugs alone
    4. Ramipril reduced progression to ESRD over 4.5 years from ~70% to ~40%
    5. Ramipril or other ACE inhibitors are first line in any form of nephrotic syndrome
  4. Glucocorticoids
    1. Prednisone (or prednisolone) po or iv 2mg/kg (<120mg) po qod x 8wks
    2. Taper by ~25% per dose each week for 4 weeks
    3. Failed Initial treatment: Pulse methylprednisolone to 7mg/kg (<1000mg) x 3 days
    4. Taper with prednisone as described above; begin ~80mg qod and decrease as previously
    5. High dose pulse (500-1000mg/day) methylprednisolone for 3 days may also be used
    6. Six month course of prednisone may reduce proteinuria but not alter decline in GFR
  5. Cytotoxic Agents
    1. Usually combined with glucocorticoids
    2. Oral Chlorambucil 0.15-0.2mg/kg/d alternating months
    3. Cyclophosphamide (CYC, Cytoxan®) oral 2mg/kg/d more effective than monthly IV [8]
    4. IV CYC on alternate months + glucocorticoids induces durable remissions [9]
    5. Methylprednisolone + chlorambucil x 6 months leads to earlier remission compared with glucocorticoid alone [8]
    6. Oral CYC appears as efficacious as chlorambucil [8]
    7. Both agents show improved responses over glucocorticoids alone
  6. Cyclosporin and Tacrolimus [9]
    1. Alone or in combination with glucocorticoids
    2. Relapses appear more common with stopping cyclosporin than with stopping CYC
  7. Rituximab (Rituxan®) [10]
    1. Monoclonal antibody against CD20, primarily expressed on B lymphocytes
    2. Dosed 375mg/m2 every 4 weeks
    3. Completely and selectively depletes B lymphocytes
    4. Induces reduction in albuminuria and serum cholesterol, increase in serum albumin
    5. Reduces autoantibody (and normal antibody) production
    6. Replacement normal IVIg may be given if long term rituximab is used
  8. HBV Associated Disease
    1. Usually find membranous nephropathy in HBV
    2. Chronic infection is required for development of these complications
    3. Role of cryoglobulins is unclear
    4. Often responds to therapy with interferon (5MU qd sc)
    5. Glucocorticoids or cytotoxic drugs may be combined with interferon in some cases
    6. Careful monitoring of liver and kidney function is essential
    7. Plasmapheresis may be considered in difficult cases
  9. HCV Associated Disease [2]
    1. Usually associated with cryglobulinemia
    2. Pathology usually membranoproliferative glomerulonephropathy
    3. Renal dysfunction may respond to Interferon alpha - ribavirin [2,11]

References navigator

  1. Glassrock RJ. 2003. Semin Nephrol. 23(4):324 abstract
  2. Prasad M, Buller GK, Mena CI, Sofair AN. 2006. NEJM. 355(23):2468 (Case Discussion) abstract
  3. Radford MG Jr, Holley KE, Grande JP, et al. 1996. JAMA. 276(6):466 abstract
  4. Klein J and Sato A. 2000. NEJM. 343(11):782 abstract
  5. Orth SR and Ritz E. 1998. NEJM. 338(17):1202 abstract
  6. GISEN Group. 1997. Lancet. 349:1857 abstract
  7. Ruggenenti P, Perna A, Gherardi G, et al. 1998. Lancet. 352(9136):1252 abstract
  8. Reichert LJM, Huysmans FTM, Assman K, et al. 1994. Ann Intern Med. 121(5):328 abstract
  9. Langford CA, Klippel JH, Balow JE, et al. 1998. Ann Intern Med. 128(12):1021 abstract
  10. Remuzzi G, Chiurchiu C, Abbate M, et al. 2002. Lancet. 360(9337):923 abstract
  11. Loustaud-Ratti V, Liozon E, Karaaslan H, et al. 2002. Am J Med. 113(6):517