Immunoglobulin A Nephropathy

Basics

Description

Primary immune complex–mediated glomerulonephritis

Epidemiology

  • Most common chronic glomerulonephritis worldwide
  • Prevalence varies considerably across countries; more common in Caucasians and Asians compared to African Americans
  • Because reported prevalence is based on biopsy-confirmed diagnosis and therefore does not account for mild or asymptomatic cases, reported data grossly underestimate “true” prevalence.
  • Represents 2–10% of all biopsy-confirmed primary glomerular diseases in adults in the United States
  • No robust epidemiologic data in children

Risk Factors

  • Typically sporadic
  • Familial cases have been described suggesting that genetic factors influence susceptibility to and severity of disease.
  • Reported in children with history of perinatal HIV-1 infection
  • Increased risk of IgA nephropathy in adult patients with celiac disease, cirrhosis, inflammatory bowel disease, and HIV infection

Pathophysiology

  • Etiology and pathogenesis remain uncertain.
  • Substantial evidence that IgA nephropathy is a systemic immune complex–mediated disease as it recurs after transplantation
  • Multiple studies have found abnormal glycosylation patterns of the IgA1 molecule (galactose deficiency), suggesting the following hypotheses:
    • Glycan-specific IgG antibodies form immune complexes with galactose-deficient IgA1.
    • Complexes deposit in the glomerular mesangium
    • Activated mesangial cells proliferate and secrete extracellular matrix, cytokines, and chemokines with resulting renal injury.
  • Majority of patients have elevated galactose-deficient IgA1 in the serum.

Diagnosis

History

  • Clinical presentation varies widely in constellation of signs and symptoms and also in severity.
  • Patients may be completely asymptomatic.
  • In children, the most common presentation is recurrent gross hematuria.
    • Triggered by acute upper respiratory tract infection in about half of the patients
    • In IgA nephropathy, in contrast to postinfectious glomerulonephritis, the hematuria presents at the same time (“synpharyngitic”) or within a few days after the onset of the respiratory illness.
  • Other presentations include the following:
    • Microscopic hematuria found on routine urinalysis (UA)
    • Hematuria (gross or microscopic) and variable levels of proteinuria
    • Acute nephritic syndrome (hematuria, proteinuria, edema, impaired renal function, and hypertension). Rarely, this may be rapidly progressive or accompanied by pulmonary inflammation/hemorrhage.
    • Nephrotic syndrome: edema, hypoalbuminemia, and nephrotic range proteinuria

Physical Exam

  • Hypertension: usually absent in mild disease; variably present depending on severity
  • Edema: found in patients with heavy proteinuria and acute nephritic syndrome

Differential Diagnosis

  • Thin basement membrane disease, Alport syndrome, or idiopathic hypercalciuria in mild cases presenting with hematuria
  • Other forms of glomerulonephritis must be considered in the setting of a more acute presentation, including the following:
    • Postinfectious glomerulonephritis
    • Lupus nephritis
    • Membranoproliferative glomerulonephritis (MPGN)
    • Pauci-immune glomerulonephritis
    • Other vasculitides
    • Henoch-Schönlein purpura nephritis has similar biopsy findings as IgA nephropathy but has additional nonrenal manifestations such as skin rash, abdominal pain, and periarthritis.

Diagnostic Tests and Interpretation

Initial Tests

  • UA: RBCs, RBC casts, and protein
  • Spot urine protein/creatinine ratio or 24-hour urine collection to quantify proteinuria
  • Comprehensive metabolic panel
    • Kidney function tests (blood urea nitrogen and serum creatinine), serum electrolytes, and albumin are normal in mild disease.
    • Variably abnormal based on severity of disease
  • In patients presenting with rapidly progressive glomerulonephritis, check complement levels, antinuclear antibody (ANA), antineutrophil cytoplasmic antibody (ANCA), and anti-glomerular basement membrane (GBM) antibodies to rule out other diseases.
  • Serum IgA levels have very low sensitivity and specificity and are not recommended.
  • Kidney ultrasound findings are nonspecific and either normal or, in more severe cases, may demonstrate increased echogenicity of the renal parenchyma.

Diagnostic Procedures/Other

  • Kidney biopsy is required for a definitive diagnosis.
  • Hallmark of the diagnosis is the presence, on immunofluorescence staining, of IgA deposits in the mesangium, either alone or with C3 (in children), IgM and IgG, or both (in adults).
  • Biopsy is generally not required in mild cases as it does not affect the management or prognosis in the absence of proteinuria.
  • Biopsy findings are variable on light microscopy:
    • Main finding is diffuse or focal mesangial proliferation with mesangial expansion.
    • Other possible findings include segmental or global endocapillary hypercellularity with segmental crescents and segmental necrosis.
    • Glomerulosclerosis in advanced disease
    • Tubulointerstitium is usually normal with varying degree of atrophy and fibrosis in chronic cases.
    • Electron microscopy: immune complex deposits in the mesangium
    • Several histologic classifications have been developed with the purpose of predicting clinical course, prognosticating, and in guiding therapy.
    • The Oxford classification is one such example, based on a constellation of findings such as mesangial cellularity score, segmental glomerulosclerosis, endocapillary hypercellularity, and tubular atrophy/fibrosis.
ALERT
May be progressive and lead to end-stage renal disease (ESRD) in moderate to severe cases. Refer to a nephrologist if persistent proteinuria, abnormal creatinine, gross hematuria, or hypertension.

Treatment

  • Weak evidence base and mostly derived from expert opinion
  • Varies based on severity of renal impairment, amount of proteinuria, and whether or not the course is rapidly progressive with associated crescents on biopsy. Higher amounts and persistence of proteinuria are associated with greater risk of disease progression.

General Measures

  • Clinical presentation: Treat hypercholesterolemia associated with nephrotic syndrome. Address factors that modulate progression of chronic kidney disease (CKD)—obesity, smoking, hypertension.
  • Optimize blood pressure control using angiotensin-converting enzyme inhibitor (ACEI) when possible.

Medication (Drugs)

  • Control of proteinuria and blood pressure
    • Protein excretion 0.5 to 1 g/1.73 m2/24 h: ACEI or angiotensin receptor blockers (ARBs). Increase dose to effect as long as symptomatic hypotension or hyperkalemia do not develop.
    • Protein excretion >1 g/1.73 m2/24 h despite optimum blood pressure control and the use of ACEI or ARB and when GFR is >50 mL/min/1.73 m2: Consider alternate day oral glucocorticoids for 6 months (limited evidence-based).
  • Rapidly progressive glomerulonephritis and/or crescents on biopsy: IV (followed by oral) glucocorticoids and consider additional immunosuppression such as cyclophosphamide or azathioprine or even plasmapheresis (Strength of evidence is poor for immunosuppression other than ACEI/ARB and glucocorticoids.)

Additional Therapies

  • Fish oil suggested when proteinuria is persistent >1 g/1.73 m2/24 h despite optimal supportive care.
  • Mycophenolate mofetil: multiple studies with conflicting conclusions
  • Tonsillectomy: limited and low quality data which currently do not support this as a useful treatment option

Inpatient Consideratons

  • Admission should take place under the care of pediatric nephrologist.
  • Admission maybe needed based on the clinical presentation or complications of IgA nephropathy: such as to establish the diagnosis if the presentation was severe or to treat complications including acute kidney injury (AKI), severe hypertension, CKD, or nephrotic syndrome
  • Nursing considerations vary based on the reason for the admission as the acuity of care would vary: In general, close monitoring of blood pressure, weight, and intake/output are of great importance.

Ongoing Care

Follow-Up Recommendations

IgA nephropathy may be a progressive disease. Patients should be monitored periodically for the following:

  • Kidney function tests
  • Level of proteinuria
  • Blood pressure
  • Intensity and frequency of monitoring depends on severity. Patients presenting with microscopic hematuria and minimal proteinuria should be monitored with UA at least every 6 months to assess for progression of proteinuria.

Prognosis

  • Variable depending on severity of clinical presentation and renal histopathologic score
  • 15–40% of adult patients with IgA nephropathy eventually progress to ESRD.
  • Although some reports suggest that children are more likely to have a benign course and have better prognosis than adults, other studies have reported similar outcomes for adults and children.
  • In one series, renal survival rates in Japanese children were 95% at 10 years and 80% at 20 years.
  • Patients who present with microscopic hematuria and minimal proteinuria have an excellent prognosis.
  • Clinical predictors associated with poor outcome include severe persistent proteinuria, hypertension, and impaired renal function at presentation.
  • The strongest predictive factor is the amount and persistence of proteinuria.
  • Histopathologic features associated with poor outcome include mesangial hypercellularity score, endocapillary hypercellularity, tubular atrophy, and glomerular crescents.

Additional Reading

  1. Edström Halling S, Söderberg MP, Berg UB. Predictors of outcome in paediatric IgA nephropathy with regard to clinical and histopathological variables (Oxford classification). Nephrol Dial Transplant. 2012;27(2):715–722.  [PMID:21750154]
  2. Gutiérrez E, Zamora I, Ballarín JA, et al; for Grupo de Estudio de Enfermedades Glomerulares de la Sociedad Española de Nefrología. Long-term outcomes of IgA nephropathy presenting with minimal or no proteinuria. J Am Soc Nephrol. 2012;23(10):1753–1760.  [PMID:22956820]
  3. Hogg RJ, Fitzgibbons L, Atkins C, et al; for North American IgA Nephropathy Study Group. Efficacy of omega-3 fatty acids in children and adults with IgA nephropathy is dosage- and size-dependent. Clin J Am Soc Nephrol. 2006;1(6):1167–1172.  [PMID:17699343]
  4. Purswani MU, Chernoff MC, Mitchell CD, et al. Chronic kidney disease associated with perinatal HIV infection in children and adolescents. Pediatr Nephrol. 2012;27(6):981–989.  [PMID:22366874]
  5. Radhakrishnan J, Cattran DC. The KDIGO practice guideline on glomerulonephritis: reading between the (guide)lines—application to the individual patient. Kidney Int. 2012;82(8):840–856.  [PMID:22895519]
  6. Rauen T, Eitner F, Fitzner C, et al; for STOP-IgAN Investigators. Intensive supportive care plus immunosuppression in IgA nephropathy. N Engl J Med. 2015;373(23):2225–2236.  [PMID:26630142]
  7. Ronkainen J, Ala-Houhala M, Autio-Harmainen H, et al. Long-term outcome 19 years after childhood IgA nephritis: a retrospective cohort study. Pediatr Nephrol. 2006;21(9):1266–1273.  [PMID:16838184]
  8. Shima Y, Nakanishi K, Hama T, et al. Validity of the Oxford classification of IgA nephropathy in children. Pediatr Nephrol. 2012;27(5):783–792.  [PMID:22134880]
  9. Suzuki H, Kiryluk K, Novak J, et al. The pathophysiology of IgA nephropathy. J Am Soc Nephrol. 2011;22(10):1795–1803.  [PMID:21949093]
  10. Wang T, Ye F, Meng H, et al. Comparison of clinicopathological features between children and adults with IgA nephropathy. Pediatr Nephrol. 2012;27(8):1293–1300.  [PMID:22562475]
  11. Welander A, Sundelin B, Fored M, et al. Increased risk of IgA nephropathy among individuals with celiac disease. J Clin Gastroenterol. 2013;47(8): 678–683.  [PMID:23442839]

Codes

ICD-9

  • 583.9 Nephritis and nephropathy, not specified as acute or chronic, with unspecified pathological lesion in kidney
  • 583.2 Nephritis and nephropathy, not specified as acute or chronic, with lesion of membranoproliferative glomerulonephritis
  • 583.1 Nephritis and nephropathy, not specified as acute or chronic, with lesion of membranous glomerulonephritis

ICD-10

  • N02.8 Recurrent and persistent hematuria w oth morphologic changes
  • N02.5 Recurrent and perst hematur w diffuse mesangiocap glomrlneph
  • N02.2 Recurrent and perst hematur w diffuse membranous glomrlneph

SNOMED

  • 236407003 IgA nephropathy (disorder)
  • 68779003 Primary IgA nephropathy

FAQ

  • Q: Will my child ever outgrow IgA nephropathy?
  • A: No. The etiology and pathogenesis of IgA nephropathy remain uncertain. IgA nephropathy is a chronic condition, but sometimes it can go into spontaneous remission. Spontaneous remission is reported to occur in 59% of children with mild disease. More severe cases can also go into remission with medications.
  • Q: My child has had a kidney transplant. Can IgA nephropathy recur in the graft?
  • A: Yes. Recurrence of the condition can develop in 33% of patients. Depending on the published series, recurrence rates vary between 9% and 66%. However, even if it does come back, it can usually be controlled/treated with medications.
  • Q: My child has microscopic hematuria and proteinuria. He has normal kidney function and blood pressure. His kidney biopsy was consistent with the diagnosis of IgA nephropathy. What is the strongest predictor for progression?
  • A: The amount and persistence of proteinuria. Children with no or mild proteinuria usually have good long-term prognosis, whereas those with high amounts of protein in the urine are more likely to progress and develop long-term kidney damage.

Authors

Maha N. Haddad, MD

Lavjay Butani, MD, MACM


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