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KatiKaartinen

Iga Nephropathy

Essentials

  • An incidental finding of asymptomatic microscopic haematuria and proteinuria should arouse the suspicion of IgA nephropathy (IgAN, also known as IgA glomerulonephritis).
  • Blood pressure is often elevated.
  • ACE inhibitors and ARBs are also the first-line drugs for treating normotensive patients with proteinuria.
  • There is no curative treatment available.

Epidemiology, aetiology and pathogenesis

  • IgAN isthe most common type of primary glomerulonephritis worldwide (see also Glomerulonephrites).
  • According to a study encompassing 10 European countries, the point prevalence of IgAN was found to be about 2.53/10 000 in people of all ages, ranging from 1.14 (Spain) to 5.98 (Lithuania), and the estimated annual incidence across the countries was about 0.76/100 000 http://pubmed.ncbi.nlm.nih.gov/37156519/. The prevalence was considerably lower in children and the elderly.
  • A systematic review of global data found that the incidence of IgAN varied from 0.06 (South Africa) to 4.2 (Japan) per 100 000 http://journals.lww.com/kidney360/fulltext/2023/08000/global_incidence_of_iga_nephropathy_by_race_and.16.aspx. The incidence seemed to be higher in Asians than in non-Asians.
  • The disease is encountered in all age groups, but most commonly diagnosed at the age of 20 to 30 years.
  • It is more common in men than in women
  • The fundamental underlying mechanism is unknown
    • In addition to structurally abnormal IgA immunoglobulin, an external factor (possibly some microbe or dietary antigen, for example) is needed to trigger autoantibody production finally leading to the accumulation of immune complexes in renal corpuscles.
  • Deposits of mainly immunoglobulin IgA1 occur in the renal tissue.
  • Most cases are sporadic. Less than 10% of patients have the familial type of the disease.

Symptoms and findings

  • Microscopic haematuria and various degrees of proteinuria are the usual incidental findings.
    • About 10% of patients have microscopic haematuria as the sole finding and about 5% have nephrotic syndrome Nephrotic Syndrome.
  • About half of the patients have macroscopic haematuria in association with febrile illness.
  • Hypertension is a common finding.
  • Renal failure may be present at diagnosis, already.
  • Rapidly progressive glomerulonephritis or nephrotic syndrome with sudden onset (minimal change type glomerulonephritis) Glomerulonephrites are clinically rare but possible.
  • May present as isolated glomerulonephritis Glomerulonephrites or as part of the Henoch-Schönlein syndrome Henoch-Schönlein Purpura.
  • Secondary disease may be seen in association with conditions such as chronic liver diseases, HIV infection or coeliac disease.

Diagnosis

  • Microscopic haematuria (urinalysis, urine basic particle count) and/or proteinuria (urinalysis, urine albumin/creatinine ratio or 24-hour urinary protein excretion), often associated with high blood pressure, raise suspicion of the disease.
  • Renal biopsy is always needed to confirm the diagnosis.
    • A biopsy is needed if proteinuria is at least 1 g/24 h or eGFR is decreased
    • If the patient has only microscopic or macroscopic haematuria, biopsy should be considered only if it is especially important to confirm the diagnosis.
    • Immunofluorescence testing shows IgA deposits in glomeruli
    • Light microscopic findings may vary.
  • Even mild or suspected IgA nephropathy requires follow-up, since some patients may develop an indication for biopsy or need intensified treatment.
  • The disease cannot be distinguished with certainty from other glomerulonephritides on the basis of clinical features or laboratory tests but the occurrence of macroscopic haematuria soon after (within less than 2 days) the onset of a febrile illness is indicative of IgA nephropathy.
  • Serum IgA is elevated in half of the patients.

Prognosis

  • In 20- to 25-year follow-up, end-stage renal failure develops in about 25 to 30% of patients.
  • The most significant clinical factors at the time of diagnosis or during follow-up suggesting a poor prognosis are:
    • already existing renal failure
    • proteinuria exceeding 1 g/24 h
    • hypertension.
  • Haematuria was previously not considered to be a prognostic factor but in some patients, at least, there is an association between the level and permanence of haematuria and the prognosis.
  • All urinary findings may be spontaneously reversible in a small proportion of the patients (< 10%). Histological regression and disappearance of IgA deposits is rare but possible.
  • Certain histological findings (MEST classification) independently affect the prognosis (mesangial hypercellularity, endocapillary hypercellularity, segmental glomerulosclerosis, tubular atrophy / interstitial fibrosis). The most recent version of the classification (MEST-C) also considers the number of crescents.
  • The disease may also recur in a renal transplant.
  • Risk score calculators can be used for prognostic assessment. Such calculators have been validated for use for adults at the time of biopsy http://qxmd.com/calculate/calculator_499/international-igan-prediction-tool-at-biopsy-adults# and 1 and 2 years http://qxmd.com/calculate/calculator_839/international-igan-prediction-tool-post-biopsy-adults thereafter, and are also available for children for the time of biopsy http://qxmd.com/calculate/calculator_713/international-igan-prediction-tool-at-biopsy-pediatrics.

Treatment and follow-up in primary health care

  • The disease should always be diagnosed in specialized care but mild forms of the disease can be followed up and treated in outpatient care.
  • There is no curative treatment available.
  • Treatment is always based on supportive treatment (i.e. other than immunosuppressive medication).
    1. Antihypertensive treatment with an antiproteinuric ACE inhibitor or ARB at the maximum tolerated dose
      • The blood pressure target is the same as for any patient with chronic renal disease. If the target cannot be reached without adverse effects, a higher blood pressure should be considered acceptable.
      • Systolic blood pressure < 120 mmHg
      • The diastolic blood pressure target has not been separately defined but an appropriate target of < 80 mmHg can probably be reached if systolic blood pressure is at the target level.
      • For organ transplant recipients, the target blood pressure level is < 130/80 mmHg.
    2. An ACE inhibitor or ARB for all patients with urinary protein excretion > 0.5 g/24 h
    3. Assessment and treatment of cardiovascular risks
    4. Other supportive treatment
      • Dapagliflozin prevents aggravation of renal failure and reduces albuminuria in patients with IgA nephropathy.
        • Starting the medication is not recommended if eGFR is < 25 ml/min/1.73 m2 , but medication already started can probably be continued until the beginning of the dialysis stage.
      • Empagliflozin also prevents eGFR reduction in patients with hardly any proteinuria. This probably applies at least partly to IgA nephropathy, as well.
        • Starting the medication is not recommended if eGFR is < 20 ml/min/1.73 m2 , but medication already started can probably be continued until the beginning of the dialysis stage.
  • Patients with mild forms of the disease with a good prognosis can be followed up every 6 to 12 months.
    • Optimal control of blood pressure
    • Plasma creatinine, potassium, sodium, chemical urinalysis and urinary albumin/creatinine ratio or 24-hour urinary protein excretion, urine basic particle count (level of haematuria)
    • If creatinine levels rise progressively or proteinuria increases despite optimal supportive treatment or blood pressure control becomes significantly more difficult, consult specialized care.
  • Chronic renal failure should be treated as in patients with other types of renal disease Treatment of Chronic Renal Failure.

Treatment and follow-up in specialized care

  • A rapidly progressive form of disease should be treated like vasculitis.
  • Minimal change glomerulonephritis-type nephrotic disease of sudden onset should be treated like minimal change glomerulonephritis.
  • Glucocorticoid therapy for 6 months Corticosteroids in Iga Nephropathy should be considered in specialized care:
    • if the level of proteinuria remains at > 0.75-1 g/24 h despite 3-6 months of optimal treatment (with ACE inhibitor or ARB and blood pressure on target) and eGFR is ≥ 50 ml/min.; may be considered even at a lower renal filtration rate but no benefit is likely at GFR levels of < 30 ml/min.
    • if the only problem is decreased eGFR despite optimal treatment of blood pressure and proteinuria, and there is no other evident cause for this.
  • There is no evidence to support repeated glucocorticoid treatment in a slowly progressive form of the disease. New drugs are expected shortly.

    References

    • The EMPA-KIDNEY Collaborative Group, Herrington WG, Staplin N, et al. Empagliflozin in Patients with Chronic Kidney Disease. N Engl J Med 2023;388(2):117-127 [PubMed]
    • EMPA-KIDNEY Collaborative Group. Design, recruitment, and baseline characteristics of the EMPA-KIDNEY trial. Nephrol Dial Transplant 2022;37(7):1317-1329 [PubMed]
    • Barbour SJ, Coppo R, Zhang H, et al. Application of the International IgA Nephropathy Prediction Tool one or two years post-biopsy. Kidney Int 2022;102(1):160-172 [PubMed]
    • Yau K, Dharia A, Alrowiyti I, et al. Prescribing SGLT2 Inhibitors in Patients With CKD: Expanding Indications and Practical Considerations. Kidney Int Rep 2022;7(7):1463-1476 [PubMed]
    • Barbour SJ, Coppo R, Er L, et al. Updating the International IgA Nephropathy Prediction Tool for use in children. Kidney Int 2021;99(6):1439-1450 [PubMed]
    • Kidney Disease: Improving Global Outcomes (KDIGO) Blood Pressure Work Group. KDIGO 2021 Clinical Practice Guideline for the Management of Blood Pressure in Chronic Kidney Disease. Kidney Int 2021;99(3S):S1-S87 [PubMed]
    • Kidney Disease: Improving Global Outcomes (KDIGO) Glomerular Diseases Work Group. KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases. Kidney Int 2021;100(4S):S1-S276 [PubMed]
    • Wheeler DC, Toto RD, Stefánsson BV, et al. A pre-specified analysis of the DAPA-CKD trial demonstrates the effects of dapagliflozin on major adverse kidney events in patients with IgA nephropathy. Kidney Int 2021;100(1):215-224 [PubMed]
    • Floege J, Rauen T, Tang SCW. Current treatment of IgA nephropathy. Semin Immunopathol 2021;43(5):717-728 [PubMed]
    • Heerspink HJL, Stefánsson BV, Correa-Rotter R, et al. Dapagliflozin in Patients with Chronic Kidney Disease. N Engl J Med 2020;383(15):1436-1446 [PubMed]
    • Barbour SJ, Coppo R, Zhang H, et al. Evaluating a New International Risk-Prediction Tool in IgA Nephropathy. JAMA Intern Med 2019;179(7):942-952 [PubMed]
    • Rodrigues JC, Haas M, Reich HN. IgA Nephropathy. Clin J Am Soc Nephrol 2017;12(4):677-686 [PubMed]
    • Sevillano AM, Gutiérrez E, Yuste C, et al. Remission of Hematuria Improves Renal Survival in IgA Nephropathy. J Am Soc Nephrol 2017;28(10):3089-3099 [PubMed]