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A. Occurrence

  1. Idiopathic IgA nephropathy is most common cause of chronic renal failure (CRF) worldwide
  2. Also the most common cause of glomerulonephritis worldwide
  3. Male : Female ratio of ~2.5:1
  4. Typical onset age 15-30 years
  5. Increased prevalence in Pacific Rim countries; lower in USA and Europe
  6. Common cause of asymptomatic hematuria
  7. CRF develops in ~30% of patients ~10 years after diagnosis of idiopathic IgA nephropathy
  8. Formerly called "Berger's Disease"

B. Pathophysiology

  1. Plasma levels of IgA elevated in ~50% of patients
  2. Circulating Immune complexes with IgA antibodies (Ab) also found
  3. Glomerular increased cellularity, increased pink material in mesangeum
  4. Mesangeal proliferation and inflammation (glomerulonephritis)
  5. Likely has an immune component
    1. No specific antigen has been identified to date
    2. B cell dysfunction leading to pathogenic IgA Abs
    3. IgA1 subtype is exclusively found (IgA2 is not found)
    4. Plasma cells in bone marrow, spleen and lymph nodes produce mainly IgA1
    5. Plasma cells in the gut produce both IgA1 and IgA2
    6. Some T cell subset abnormalities have been observed
  6. Pathology
    1. Diagnosis requires mesangial IgA deposition by immunofluorescence
    2. Deposition of IgM and IgG (with kappa and lambda light chains) usually observed
    3. C3 and terminal complement components usually found
    4. C1 and C4 are uncommon

C. Symptoms and Signs

  1. Early stage disease is usually asymptomatic
  2. Hematuria
    1. Asymptomatic hematuria - very common in patients >25 years old
    2. Episodic gross hematuria occurs in 50-60% of cases at some point
    3. More severe disease with hematuria plus red blood cell (RBC) casts
  3. Hypertension (HTN)
  4. Polyuria of long duration
  5. Proteinuria
    1. Normal filtered protein in urine is 150-200mg/day
    2. About 60% with IgA nephropathy have <990 mg/day; ~40% >1000 mg/day
    3. Over time, incidence of true nephrotic syndrome increases
  6. IgA nephropathy may be increased after respiratory or gastrointestinal infections
  7. Poor Prognostic Findings [3]
    1. Older age
    2. Male sex
    3. HTN
    4. Persistent proteinuria
    5. Renal insufficiency at time of diagnosis
    6. Glomerulosclerosis or interstitial fibrosis on renal biopsy (histologic grade 2 or 3)
  8. Isolated or microscopic hematuria is a good prognostic sign
  9. Chronic lifelong followup is critical in all patients with IgA nephropathy [3]

D. Differential Diagnosis (Table 1 in Ref [1]) [7]

  1. Primary IgA Renal Deposition Diseases
    1. Idiopathic IgA Nephropathy
    2. Henoch-Schonlein Purpura (HSP)
  2. Secondary Causes Commonly Associated with Renal IgA Deposition
    1. Systemic Lupus Erythematosus (SLE)
    2. Multiple myeloma with IgA gammopathy
    3. Spondyloarthropathies
    4. Cryoglobulinemia
    5. Rheumatoid arthritis
    6. Sjogren's syndrome
    7. Behcet's syndrome
    8. Goodpastur's syndrome
  3. Other Conditions Associated with Renal IgA Deposition
    1. Chronic liver disease
    2. Intestinal inflammatory disease: celiac disease, inflammatory bowel disease
    3. Inflammatory skin disease: dermatitis herpetiformis, psoriasis
    4. Inflammatory pulmonary disease: sarcoidosis, cystic fibrosis, bronchiolitis obliterans
    5. Neoplasia: carcinoma of lung, larynx, pancreas; mycosis fungoides
    6. Infection: HIV, leprosy
    7. Other systemic vasculidites
    8. Membranous nephropathy
  4. Diagnosis made by clinical symptoms, signs, laboratory, and renal biopsy analysis

E. Treatment of IgA Nephropathy

  1. Glucocorticoids [9]
    1. High dose glucocorticoids reduce proteinuria levels
    2. Methylprednisolone 1gm IV qd x 3 in months 1, 3 and 5 + 0.5mg/kg oral prednisone on alternate days for 6 months reduces proteinuria and risk of creatinine doubling
    3. Caution with glucocorticoid dependence and nephrotic relapses
    4. Azathioprine is being tested as a "steroid-sparing" agent
  2. ACE Inhibitors [4]
    1. Clearly reduces magnitude of proteinuria
    2. Should be used to treat hypertension
    3. Unclear if overall renal function is preserved long term
    4. First line therapy in all patients with significant proteinuria
    5. Angiotensin II receptor blockers (AT2RB) may be used in ACE intolerant patients
    6. Combinations of AT2RB and ACE inhibitors have been suggested [7]
  3. Cytotoxic Agents [1]
    1. Prednisolone + cyclophosphamide effective in rapidly progressing disease
    2. Azathioprine often used for long-term maintenance therapy
    3. Cyclophosphamide and cyclosporine may reduce proteinuria in nephrotic patients
    4. Mycophenolate mofetil 1gm po bid likely beneficial in some patients [5]
  4. N-3 Polyunsaturated Fatty Acids
    1. Anti-inflammatory fatty acids derived from fish oil
    2. Eicosapentaenoic acid 1.8gm qd + docosahexaenoic acid 1.2gm qd
    3. Risk of death or end-stage renal disease reduced by 67%
    4. Also reduced risk of creatinine elevation
    5. Higher doses (12gm/d) do not appear to be more beneficial than lower doses
    6. Other studies have shown no reduction in risk of creatinine elevation
    7. Overall, likely that fish oils do provide at least some benefit in IgA nephropathy
  5. Intravenous Immune Globulin (IVIg) [8]
    1. Studied in patients with >3gm/day of proteinuria
    2. Dose IVIg 2gm/kg each month x 3 months; showed some efficacy
  6. Lymphocytapheresis [6]
    1. Studied in rapidly progressive patients, mainly IgA and pauci-immune nephropathy
    2. May be more effective than glucocorticoid pulses
  7. Renal Transplantation
    1. Best option for end-stage renal disease
    2. Survival of patients and renal allografts is excellent
    3. Possible that chronic immunosuppression prevents recurrent IgA nephropathy

References

  1. Donadio JV and Grande JP. 2002. NEJM. 347(10):738 abstract
  2. Hricik DE, Chung-Park M, Sedor JR. 1998. NEJM. 339(13):888 abstract
  3. Szeto CC, Lai FMM, To KF, et al. 2001. Ann Intern Med. 110(6):434 abstract
  4. Maschio G, Alberti D, Janin G, et al. 1996. NEJM. 334(15):939 abstract
  5. Nowack R, Birck R, van der Woude FJ. 1997. Lancet. 349:774 abstract
  6. Furata T, Hotta O, Yusa N, et al. 1998. Lancet. 152(9123):203
  7. Chadban SJ and Atkins RC. 2005. Lancet. 365:1797 abstract
  8. Rostoker G, Desvaux-Belghiti D, Pilatte Y, et al. 1994. Ann Intern Med. 120(6):476 abstract
  9. Pozzi C, Bolasco PG, Fogazzi GB, et al. 1999. Lancet. 353:883 abstract