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A. Overview of GNnavigator

  1. Components (Definition)
    1. Intraglomerular inflammation
    2. Parenchymal renal cellular proliferation
    3. Hematuria
    4. Nephritic and/or nephrotic presentations may occur
  2. Epidemiology
    1. ~12 per 100,000 per year biopsy proven GN
    2. Increase in crescentic GN over time may be occurring
  3. Types
    1. Acute versus chronic
    2. Acute is a medical emergency as renal failure can occur rapidly
    3. Primary (idiopathic, possibly autoimmune) versus secondary (related to other disease)
    4. Urgent renal biopsy is generally indicated to initiate effective therapy

B. Pathophysiology [1] navigator

  1. Humoral and cell mediated inflammatory mechanisms
  2. Humoral Mechanisms
    1. Direct antibody (Ab) mediated toxicity
    2. Example is anti-collagen IV Abs found in Goodpasture's Syndrome
    3. Anti-collagen IV Abs bind directly to the glomerular basement membrane (GBM)
    4. Another example is histone-DNA complexes which are trapped by the GBM
    5. In systemic lupus, anti-DNA Abs bind to these complexes
    6. The other mechanism is initiation of inflammation by trapped immune complexes (IC)
    7. IC can escape removal by reticuloendothelial (mainly spleen and liver) systems
    8. IC circulate to the kidney and are then trapped on GBM
    9. Abs bound directly or indirectly to glomeruli can initiate inflammation
  3. Cellular Immune Mechanisms
    1. CD4+ T lymphocytes can induce glomerular injury
    2. Expression of CD40 and other accessory molecules in glomeruli activate T cells
    3. This is particularly true in chronic glomerular inflammatory conditions
    4. CD8+ T lymphocytes are often recruited into inflammatory lesions
    5. Macrophages are activated by interferon gamma and other cytokines produced by T cells
    6. Cell trafficking into glomeruli through cell adhesion molecules (CAMs)
    7. Selectins, integrins, and Ig superfamily members play key roles [3]
  4. Mechanisms of Glomerular Injury
    1. Complement deposition and activation on endothelial cells (GBM)
    2. Leukocyte influx and cytokine synthesis
    3. Macrophage and cytotoxic T lymphocyte (CD8+) activation
    4. Release of proteolytic enzymes by neutrophils, eosinophils, and/or macrophages
    5. Damage may be repaired, but nonfunctional fibrotic scar tissue is deposited

C. Symptoms and Signsnavigator

  1. Hematuria - dysmoprhic red blood cells (RBC), possibly RBC casts
  2. Proteinuria - mild to moderate
  3. Hypertension - mild to severe
  4. Uremia - azotemia with symptoms
  5. Oliguria, Anuria

D. Etiologynavigator

  1. IgA (±IgG) Deposition [4]
    1. IgA Nephropathy - most common form
    2. Systemic Lupus Erythematosus
    3. Henoch-Schonlein Purpura (HSP)
    4. Secondary causes of IgA deposition
  2. Concurrent Infection
    1. Usually with immune complexes such as staphylococcus
    2. Bacterial Endocarditis
    3. Shunt Nephritis
    4. Visceral Abscess
  3. Staphylococcal Glomerulonephritis [10]
    1. Two main clinical presentations of Staph with glomerulonephritis:
    2. Immune complex glomerulonephritis and superantigen-associated glomerulonephritis
    3. Immune complex form associated with S. epidermidis infection of CNS shunts and with S. aureus systemic infections
    4. Superantigen form associated with nephrotic range proteinuria, purpura, elevated serum IgA and IgG, and normal complement levels
    5. Superantigen form associated with massive IgA deposition in glomeruli, leading to pathological diagnosis of Henoch-Schonlein purpura (HSP)
  4. Acute Postinfectious Glomerulonephritis
    1. Group A, ß-hemolytic Streptococcus associated disease is most common
    2. Other gram positives: S. viridans; Staph aureus and albus mainly with endocarditis
    3. Gram negatives: Klebsiella pneumoniae, Salmonellla typhosa
    4. Atypicals: Treponema pallidum, Mycobaterium leprae, Actinobacillus, Scrub Typhus
    5. Viral: mainly hepatitis B, CMV, EBV, HIV, Coxsackie, others
    6. Parasites: Plasmodia, Toxoplasma, Schistosoma, Filaria, Trypanosomes, Trichinosis
  5. Vasculitis [5,6]
    1. Anti-GBM Antibody Disease
    2. Wegener's Granulomatosis
    3. ANCA-Associated Glomerulonephritis (Renal Limited Vasculitis)
    4. Cryoglobulinemia [11]
    5. Rare - polyarteritis nodosa, Churg-Strauss Syndrome, Systemic Lupus (SLE)
  6. Membranoproliferative GN
    1. Systemic Immune Complex Disease: Lupus, Henoch-Schonlein Purpura (HSP)
    2. Hereditary Complement Deficiency
    3. Infection: HIV, Chronic Bacteremia (Endocarditis)
    4. Neoplasia: Lymphoma, Myeloma
    5. Chronic Liver DIsease: hepatitis (especially HCV) [11], Cirrhosis, a1-antitrypsin deficiency
    6. Other: Hemolytic Uremic Syndrome (HUS), Sickle Cell Nephropathy, Lipodystrophy
    7. Renal Allograft Rejection
  7. Mesangiocapillary Glomerulonephritis [9]
    1. C3NeF is C3 nephritic factor, an autoantibody that enhances complement activation
    2. C3NeF binds to C3bBb complex leading to prolonged activation of alternative complement
    3. This complex binds to kidneys and mediates complement dependent damage
    4. C3NeF is also associated with acquired partial lipodystrophy
  8. NSAID-associated glomerular injury (exacerbated with dehydration) []

E. Poststreptococcal GN [2]navigator

  1. Most common type of postinfectious GN
  2. Incidence <20/100,000, usually in young persons, 2-12 years old
  3. Pathogenesis
    1. Formation of immune complexes including antibodies and streptococcal antigens
    2. Localization (deposition) on subepithelial portion of glomerular basement membrane
    3. Initiate inflammatory response, including Complement deposition (reduced serum levels)
    4. This leads to localized mesangial and endothelial cell proliferation
    5. Identiy of nephritogenic strep antigen not currently known
  4. Serology
    1. Anti-streptolysin O (ASO) Antibodies rise in ~75% of cases
    2. Titers of ASO rise within 10-14 days; declines over 1-6 months
    3. Anti-DNase B and Anti-hyaluronidase rise more quickly
    4. Elevation in any of the titers will detect ~100% of persons with recent strep infection
    5. Note that ASO titers rise in pharangitis, not in cutaneous disease
    6. Streptococcal antigen M serotypes 12,1, and 4 are especially associated with GN
    7. Anti-Streptokinase, M-protein specific tests, and anti-NADase can also be determined
  5. Symptoms and Signs
    1. Usually follows pharyngitis (10-14 days) after
    2. Many patients will have impetigo
    3. Gross hematuria in ~30%
    4. Edema ~85%
    5. Hypertension ~70%
    6. Usually resolves within 2 weeks of onset
  6. Evaluation
    1. See below for general evaluation
    2. ASO, Anti-DNase B titers should be obtained
    3. Serum complement levels usually depressed
    4. 24 hour urine collection for protein and creatinine
    5. If resolution does not occur within 2 weeks consider other causes
    6. Renal biopsy should be considered for prolonged disease only
  7. Treatment
    1. Aggressive treatment of streptococcal infection
    2. Rest, Fluid and salt restriction
    3. Correction of electrolyte abnormalities and hypertension
    4. Recovery is ~90%, with ~1% mortality in past, and chronic disease in 5-10%

F. Rapidly Progressive Glomerulonephritis (RPGN) [5]navigator

  1. Definition
    1. Creatinine increases 0.5-1.0mg/dL each day with hematuria
    2. RBC casts are usually present
    3. Full laboratory evaluation should be done immediately
    4. Most cases may be pauci-immune necrotizing and crescentic glomerulonephritis
    5. Some of these patients will have associated lung hemorrhage (no granulomas)
    6. This is a medical emergency, is treatable and renal failure can be prevented
  2. Crescent Formation
    1. Glomerulus is ~50% ablated with fibrous connective tissue
    2. Appears crescent shaped
    3. Most common pathological finding in RPGN patients
  3. Underlying Disorders
    1. Linear deposition of immunoglobulins (Anti-GBM Disease) ~20%
    2. Granular immune complex deposition ~30%
    3. Pauci-Immune disease (Perinuclear ANCA or pANCA Associated) ~50%
    4. About 80% of pauci-immune RPGN is ANCA associated
  4. Treatable Causes [7]
    1. Anti-GBM Disease (Goodpasture's)
    2. pANCA Associated RPGN
    3. Wegener's Vasculitis (cANCA-Associated)
    4. Systemic Lupus Erythematosus - Type IV (or III)
    5. Cryoglobulinemia [11]
    6. Henoch-Schonlein Purpura - IgA with IgG and/or IgM deposition
  5. Causes with Marginally Effective Therapy
    1. Idiopathic Nephritic Syndromes (rapidly progressive)
    2. Post-infectious glomerulonephritis
    3. Systemic Sclerosis
    4. HIV Nephropathy - collapsing glomerulonephritis
  6. Renal Biopsy is often indicated to determine cause
  7. Prognosis
    1. Generally poor unless intervention is early and rapid
    2. If treatment is ineffective, dialysis generally required
    3. In some patients on acute dialysis, aggressive therapy can improve renal function

G. Diagnosisnavigator

  1. Urinalysis (including microscopic) and frequent electrolytes are crucial
  2. Anti-streptolysin O (ASO) titer and/or Anti-DNAse B
  3. Anti-Nuclear Antibody (ANA), Anti-Sm, Anti-dsDNA, Anti-U1-RNP should be obtained
  4. Anit-Neutrophil Cytoplastmic (ANCA) and Anti-Basement Membrane (Anti-GBM) Antibodies
  5. Cryoglobulin Levels
  6. Complement (C') Levels
    1. Very helpful to rule out non-immune complex disease
    2. Reduced C' levels are always found in immune complex mediated disease
  7. Biopsy is often indicated
    1. In ANCA or Anti-GBM antibody diseases, Biopsy may not be needed
    2. Special Stains should be done
    3. Indications: No prior infection, negative strep serology, delayed resolution of symptoms

H. Treatment navigator

  1. Treat underlying cause
  2. Renal biopsy usually be obtained early in course if there is any question
  3. High dose prednisone or methylprednisolone pulses unless infection is present
  4. Plasmapheresis or Plasma Exchange
    1. Especially in hemolytic uremic and TTP syndrome patients
    2. Can substantially slow progression in RPGN from Anti-GBM Abs
    3. May be effective in cryoglobulinemia with severe disease [11]
    4. Plasma exchange leads to a higher rate of renal recovery than intravenous methylprednisolone in severe vasculitis patients [12]
  5. Lymphocytapheresis [6]
    1. Studied in rapidly progressive patients, mainly IgA and pauci-immune nephropathy
    2. May be more effective than glucocorticoid pulses
  6. Cyclophosphamide [1,7]
    1. Intravenous pulses are effective in certain diseases, particularly lupus nephritis
    2. Oral daily therapy is more effective in vasculitis
  7. Intravenous Immunoglobulin (IVIg) - may be effective in HUS/TTP
  8. Glucocorticoids + ACE inhibitors and antiogensin receptor blockers in IgA nephropathy
  9. Treatment of fluid overload, electrolyte abnormalities, and hypertension

References navigator

  1. Chadban SJ and Atkins RC. 2005. Lancet. 365:1797 abstract
  2. Hricik DE, Chung-Park M, Sedor JR. 1998. NEJM. 339(13):888 abstract
  3. Adler S and Brady HR. 1999. Am J Med. 107(4):371 abstract
  4. Donadio JV and Grande JP. 2002. NEJM. 347(10):738 abstract
  5. Rabb H and Colvin RB. 2007. NEJM. 357(15):1532
  6. Bazari and Mauiyyedi S. 2002. NEJM. 346(5):353 (Case Record) abstract
  7. Langford CA, Klippel JH, Balow JE, et al. 1998. Ann Intern Med. 128(12):1021 abstract
  8. Furata T, Hotta O, Yusa N, et al. 1998. Lancet. 152(9123):203
  9. Dalbeth N and Callan M. 2002. 360(9342):1300 abstract
  10. Denton MD, Sigumarthy SR, Chua S, Colvin RB. 2006. NEJM. 354(26):2803 (Case Record) abstract
  11. Prasad M, Buller GK, Mena CI, Sofair AN. 2006. NEJM. 355(23):2468 (Case Discussion) abstract
  12. Jayne DR, Gaskin G, Rasmussen N, et al. 2007. J Am Soc Nephrol. 18(7):2180 abstract