BASICS
DESCRIPTION
- Most common form of glomerulonephritis in the world (particularly high incidence in Asia), resulting from deposition of large amounts of a modified IgA molecule in the glomerular mesangium
- Heterogeneous condition ranging from asymptomatic all the way to end-stage renal disease (ESRD)
EPIDEMIOLOGY
Incidence
30-40% in Asia, 15-20% in Europe, and 5-10% in North America of all renal biopsy performed
Prevalence
- More common in Asians (particularly in Japan and Korea), Caucasians, and American Indians
- Less common in African Americans in the United States and Africa
- Most common in 2nd and 3rd decades of life
- More common in male than female patients
ETIOLOGY AND PATHOPHYSIOLOGY
Autoimmune disease: Underglycated IgA1 deposition within the mesangium leads to an inflammatory reaction (autoantibodies, complement, growth factors) that culminates with glomerular and subsequently renal tubulointerstitial scaring.
Genetics
Rare familial forms of IgA nephropathy exist.
COMMONLY ASSOCIATED CONDITIONS
Diseases associated with glomerular IgA deposition and secondary forms of IgA nephropathy (1)
- Henoch-Sch ¶nlein purpura
- Diseases of the liver (alcoholic, primary biliary, or cryptogenic cirrhosis, etc.)
- Diseases of the intestine (celiac disease, inflammatory bowel disease)
- Diseases of the skin (dermatitis herpetiformis, psoriasis)
- Diseases of the lung (sarcoidosis, idiopathic pulmonary hemosiderosis, cystic fibrosis, etc.)
- Malignancy
- Infection (HIV)
- Other systemic or immunologic disorders (systemic lupus erythematosus, rheumatoid arthritis, cryoglobulinemia, etc.)
DIAGNOSIS
HISTORY
- Classically, it presents with a painless recurrent episodes of macroscopic hematuria concurrent to or immediately after viral upper respiratory infections.
- Wide spectrum from asymptomatic microscopic hematuria to acute renal failure
PHYSICAL EXAM
DIFFERENTIAL DIAGNOSIS
Other conditions associated/presenting with microscopic hematuria:
- Thin basement membrane disease
- Alport syndrome
- Lupus nephritis
- Postinfectious glomerulonephritis
- Nephrolithiasis
- Urinary tract malignancy
- Henoch-Sch ¶nlein purpura (also presenting with IgA deposition)
DIAGNOSTIC TESTS & INTERPRETATION
Initial Tests (lab, imaging)
- Serum BUN and creatinine to evaluate for renal insufficiency
- Complement levels should be normal.
- Urinalysis with microscopy to evaluate for proteinuria, hematuria, dysmorphic RBCs and RBC casts
- Spot urine protein to creatinine ratio or 24-hour urine protein
- Imaging may be indicated to rule out other urologic causes of hematuria.
Diagnostic Procedures/Other
Renal biopsy is the gold standard and the only definitive method for the diagnosis IgA nephropathy.
Test Interpretation
- Light microscopy: variable findings ranging from mesangial cell proliferation and expansion to crescentic or chronic sclerosing glomerulonephritis
- Immunofluorescence staining: pathognomonic finding of IgA deposits in a diffuse pattern within the mesangium
- Electron microscopy: electron-dense deposits in the mesangium
TREATMENT
GENERAL PRINCIPLES
- Therapeutic options are limited to the nonspecific treatment to reduce proteinuria and control blood pressure.
- Monitor low-risk patients with no hypertension, normal GFR, and proteinuria <0.5 g/day.
- Supportive treatment with angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) is the cornerstone of the treatment.
- Strategies to control intrarenal inflammation include the administration of fish oil and for severe disease, the use of immunosuppressive agents such as cyclophosphamide, glucocorticosteroids, and mycophenolate mofetil.
- Good, randomized clinical trials to determine optimal treatments are still lacking.
MEDICATION
First Line
- Antiproteinuric and antihypertensive ACEI or ARB to achieve BP target of 130/80 mm Hg (125/75 mm Hg if proteinuria is >1 g/day) and decrease proteinuria to <0.5 g/day (2)[A]
- 6-Month trial of pulse or oral corticosteroids in addition to RAS blockade in patients with persistent (>3 to 6 months) proteinuria (>1 g/day) (3,4)[B]
- Cyclophosphamide in combination with steroids has been shown to improve renal survival in patients with crescentic forms of IgA nephropathy if estimated GFR is > 30 mL/min (5)[B].
Second Line
Omega-3 fatty acids in large doses (12 g/day) may be beneficial in preserving renal function for persistent proteinuria despite ACEI/ARB use (6)[B].
ISSUES FOR REFERRAL
Any patients with hematuria, proteinuria, or abnormal renal function should be referred to a nephrologist early.
ADDITIONAL THERAPIES
Prevention of chronic kidney disease (CKD) progression and its consequence
- Lipid-lowering therapies with a statin ( ± ezetimibe)
- Low-salt diet ( ± diuretics)
- Antihypertensives
- Smoking cessation and so forth.
SURGERY/OTHER PROCEDURES
Consider referring for kidney transplant evaluation when the patient is reaching CKD stage 5.
INPATIENT CONSIDERATIONS
Admission Criteria/Initial Stabilization
Acute kidney injury or complications related to CKD
ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
- Patients with mild proteinuria (<500 mg/day), normal renal function, and normal BP may be treated conservatively with regular follow-up at 6-month intervals.
- Patients with more aggressive disease characterized by persistent hematuria, high-grade proteinuria, difficult-to-control hypertension, or decreased GFR will require closer monitoring.
Patient Monitoring
- BP
- Serum electrolytes
- Serum creatinine
- Urine microscopy to evaluate disease activity
- Quantification of urine protein
DIET
Low-sodium diet
PATIENT EDUCATION
- Avoid NSAIDs.
- Avoid IV contrast exposure.
- In patients approaching ESRD, educate the patient regarding options for renal replacement therapy (RRT).
PROGNOSIS
- Hypertension, heavy/persistent proteinuria (>1 g/day), decreased GFR, and advanced histologic findings are risk factors for progressing of CKD (7).
- Specific histologic findings also have some prognostic significance.
COMPLICATIONS
- 25-30% of patients will require RRT (e.g., dialysis, transplant) within 20 to 25 years of presentation (8).
- 1.5% of patients reach ESRD each year (8)
- 5% risk of kidney graft failure secondary to a recurrent IgA nephropathy 5 years after renal transplant (8)
REFERENCES
11 Donadio JV, Grande JP. IgA nephropathy. N Engl J Med. 2002;347(10):738-748.22 Cheng J, Zhang W, Zhang XH, et al. ACEI/ARB therapy for IgA nephropathy: a meta analysis of randomised controlled trials. Int J Clin Pract. 2009;63(6):880-888.33 Cheng J, Zhang X, Zhang W, et al. Efficacy and safety of glucocorticoids therapy for IgA nephropathy: a meta-analysis of randomized controlled trials. Am J Nephrol. 2009;30(4):315-322.44 Manno C, Torres DD, Rossini M, et al. Randomized controlled clinical trial of corticosteroids plus ACE-inhibitors with long-term follow-up in proteinuric IgA nephropathy. Nephrol Dial Transplant. 2009;24(12):3694-3701.55 Tumlin J, Lohavichan V, Hennigar R. Crescentic, proliferative IgA nephropathy: clinical and histological response to methylprednisolone and intravenous cyclophosphamide. Nephrol Dial Transplant. 2003;18(7):1321-1329.66 Donadio JVJr, Bergstralh EJ, Offord KP, et al. A controlled trial of fish oil in IgA nephropathy. Mayo Nephrology Collaborative Group. N Engl J Med. 1994;331(18):1194-1199.77 Barbour SJ, Reich HN. Risk stratification of patients with IgA nephropathy. Am J Kidney Dis. 2012;59(6):865-873.88 Barratt J, Feehally J. IgA nephropathy. J Am Soc Nephrol. 2005;16(7):2088-2097.
ADDITIONAL READING
- Floege J, Eitner F. Current therapy for IgA nephropathy. J Am Soc Nephrol. 2011;22(10):1785-1794.
- Kidney Disease: Improving Global Outcomes (KDIGO) Glomerulonephritis Work Group. KDIGO Clinical Practice Guideline for Glomerulonephritis. Kidney Inter Suppl. 2012;2(2):139-274.
CODES
ICD10
N02.8 Recurrent and persistent hematuria with other morphologic changes
ICD9
583.9 Nephritis and nephropathy, not specified as acute or chronic, with unspecified pathological lesion in kidney
SNOMED
- Immunoglobulin A nephropathy (disorder)
- familial immunoglobulin A nephropathy (disorder)
- Immunoglobulin A nephropathy associated with liver disease (disorder)
CLINICAL PEARLS
- IgA nephropathy is the most common cause of glomerulonephritis in the world.
- It has a wide clinical spectrum ranging from asymptomatic microscopic hematuria to ESRD.
- Clinical risk factors for progressive disease are an abnormal GFR, hypertension, and moderate to severe proteinuria.
- Control of proteinuria and hypertension via renin-angiotensin-aldosterone system blockade with ACEIs inhibitors or ARBs is the mainstay of therapy.