Guideline sources The following summarized guidelines for the evaluation and management of immunoglobulin A nephropathy (IgAN) are prepared by our editorial team based on guidelines from the Kidney Disease: Improving Global Outcomes Foundation (KDIGO 2021; 2020) and the Japanese Society of Nephrology (JSN 2016). 1 2 3 Guidelines 1. Classification and risk stratification Prognosis: consider using clinical and histologic data at the time of biopsy to risk stratify patients with primary IgA nephropathy. C Show 3 more 2. Diagnostic investigations Serum biomarkers: insufficient evidence to support the use of any serum or urine biomarker other than estimated GFR and proteinuria for diagnosis or prognosis of primary IgA nephropathy. I https://web.pathway.md/diseases/recUhB4iRyv7fSJSB 1/7 6/24/23, 2:28 PM Immunoglobulin A nephropathy Pathway Evaluation for secondary causes: assess all patients with IgA nephropathy for secondary causes, including IgA-associated vasculitis, IgA-dominant infection-related glomerulonephritis, and IgA nephropathy secondary to human immunodeficiency virus, viral hepatitis, IBD, autoimmune disease, or liver cirrhosis. B 3. Diagnostic procedures Kidney biopsy: perform a kidney biopsy for the diagnosis of IgA nephropathy. B Show 2 more 4. Medical management Supportive care: optimize supportive care (including BP management, maximally tolerated dose of ACEIs/ARBs, lifestyle modifications, and addressing cardiovascular risk) as the primary focus of management in patients with IgA nephropathy without a variant form of primary IgA nephropathy (IgA nephropathy with minimal change disease, AKI, or RPGN). B Renin-angiotensin system inhibitors: As per KDIGO 2021 guidelines, initiate ACEIs or ARBs in patients with IgA nephropathy and proteinuria > 0.5 g/day, irrespective of the presence of hypertension. B As per JSN 2016 guidelines, initiate RAAS inhibitors in patients with IgA nephropathy with proteinuria 1.0 g/day and CKD stage G1-3b. A Corticosteroids: As per KDIGO 2021 guidelines, consider administering corticosteroids for 6 months in patients with IgA nephropathy remaining at high risk of progressive CKD despite maximal supportive care. Discuss the risk of treatment-emergent toxicity with patients, particularly having an estimated GFR < 50 mL/min/1.73 m . C Show 4 more As per JSN 2016 guidelines: Administer corticosteroids with any of the following regimens to control the progression of renal dysfunction in patients with IgA nephropathy with urinary protein level 1 g/day and CKD stage G1-2: short course of high-dose oral prednisolone 0.8-1.0 mg/kg for about 2 months followed by gradual tapering over about 6 months pulse therapy with methylprednisolone 1 g for 3 days by infusion or IV every other month for 3 times combined with prednisolone 0.5 mg/kg every other day for 6 months. B Consider administering corticosteroids to reduce proteinuria in patients with IgA nephropathy with a urinary protein level of 0.5-1.0 g/day and CKD stage G1-2. C Updated evidence: TESTING https://web.pathway.md/diseases/recUhB4iRyv7fSJSB 2/7 6/24/23, 2:28 PM Immunoglobulin A nephropathy Pathway In patients with IgA nephropathy and persistent proteinuria > 1 g/d and estimated GFR of 20- 120 mL/min/1.73 m after at least 3 months of BP control and renin-angiotensin system blockade who are at risk of progression, oral methylprednisolone was superior to placebo with respect to a end-stage kidney disease, death due to kidney failure, or a 40% decline in eGFR. Lv J et al. JAMA. 2017 Aug 1. Immunosuppressive agents: As per KDIGO 2021 guidelines, consider initiating immunosuppressive drugs only in patients with IgA nephropathy remaining at high risk of progressive CKD despite maximal supportive care. Offer the opportunity to participate in a clinical trial because of the current uncertainty over the safety and efficacy of existing immunosuppressive treatment choices. C Show 7 more As per JSN 2016 guidelines, consider initiating cyclophosphamide, azathioprine, cyclosporine, mycophenolate mofetil, or mizoribine to improve the renal prognosis in selected patients with IgA nephropathy. C Antithrombotic agents: As per KDIGO 2021 guidelines, do not use antiplatelet or anticoagulant agents in patients with IgA nephropathy. D As per JSN 2016 guidelines, consider administering dipyridamole to reduce proteinuria and control the progression of renal dysfunction in patients with IgA nephropathy. C Management of IgAN with nephrotic syndrome: recognize patients with IgA nephropathy rarely present with nephrotic syndrome (including edema and both hypoalbuminemia and nephrotic- range proteinuria > 3.5 g/day) and mesangial IgA deposition in these cases can be associated with light and electron microscopy features otherwise consistent with a podocytopathy resembling minimal change disease. B Show 4 more Management of IgAN with AKI: Recognize that AKI can occur in patients with IgA nephropathy in the context of severe visible hematuria, commonly in association with an upper respiratory tract infection. Provide supportive care for the immediate management of AKI with visible hematuria. Consider performing a repeat kidney biopsy if kidney function is not improving within 2 weeks following cessation of hematuria. B Recognize that IgA nephropathy may also present with AKI, either de novo or during its natural history, due to RPGN with extensive crescent formation, commonly without visible hematuria. Perform a kidney biopsy as soon as possible in the absence of visible hematuria and when other causes of RPGN (such as antineutrophil cytoplasmic antibody-associated vasculitis, anti- GBM disease) and reversible causes (such as drug toxicity, common pre- and post-renal causes) have been excluded. B Management of IgAN with RPGN: define rapidly progressive IgA nephropathy as a 50% decline in estimated GFR over 3 months, where other causes of RPGN (such as antineutrophil https://web.pathway.md/diseases/recUhB4iRyv7fSJSB 3/7 6/24/23, 2:28 PM Immunoglobulin A nephropathy Pathway cytoplasmic antibody-associated vasculitis, anti-GBM disease) and reversible causes (such as drug toxicity, common pre- and post-renal causes) have been excluded. B Show 4 more 5. Nonpharmacologic interventions Smoking cessation: As per KDIGO 2021 guidelines, advise smoking cessation in patients with IgA nephropathy. B As per JSN 2016 guidelines, advise smoking cessation in patients with IgA nephropathy as it is associated with decreased renal function in patients with IgA nephropathy, in addition to other well-known risks. A Weight loss: As per KDIGO 2021 guidelines, counsel on weight control in patients with IgA nephropathy as appropriate. B As per JSN 2016 guidelines, advise weight loss in patients with IgA nephropathy and obesity (BMI 25 kg/m ). A Physical activity: As per KDIGO 2021 guidelines, provide lifestyle advice including exercise as appropriate in patients with IgA nephropathy. B As per JSN 2016 guidelines, do not advise exercise restriction in patients with IgA nephropathy, even though exercise has been reported to increase proteinuria transiently with return to resting levels after completion of the exercise. D Salt restriction: As per KDIGO 2021 guidelines, advise dietary sodium restriction in patients with IgA nephropathy. B As per JSN 2016 guidelines, advise limiting salt intake to 3-6 g/day (but not < 3 g/day) in patients with IgA nephropathy. B Protein restriction: do not advise protein intake limitation routinely in all patients with IgA nephropathy. Individualize recommendations according to the condition of individual patients and their risk of progressive renal dysfunction. D Omega-3 fatty acids: As per KDIGO 2021 guidelines, do not use fish oil in patients with IgA nephropathy. D As per JSN 2016 guidelines, consider offering omega-3 fatty acids (fish oil) to improve renal prognosis in patients with IgA nephropathy. C 6. Surgical interventions Tonsillectomy: https://web.pathway.md/diseases/recUhB4iRyv7fSJSB 4/7 6/24/23, 2:28 PM Immunoglobulin A nephropathy Pathway As per KDIGO 2021 guidelines: Do not perform tonsillectomy for the treatment of IgA nephropathy in Caucasian patients. Consider performing tonsillectomy in Japanese patients. D Consider performing tonsillectomy for the treatment of recurrent tonsillitis in patients with IgA nephropathy. C As per JSN 2016 guidelines, consider performing tonsillectomy, with or without corticosteroid pulse therapy, to improve urinary findings and slow the progression of renal dysfunction in patients with IgA nephropathy. C Kidney transplantation: do not exclude transplant candidates with IgA nephropathy or IgA vasculitis from kidney transplantation, taking into account the risk of recurrence and discussed with the candidates. D 7. Specific circumstances Female patients: provide preconception counseling when appropriate in all female patients of childbearing potential. B Show 2 more Pediatric patients (diagnosis): recognize that visible hematuria is more frequent in pediatric patients than in adult patients, which may account for earlier diagnosis in pediatric patients. B Show 2 more Pediatric patients, immunosuppressive agents: As per KDIGO 2021 guidelines, consider initiating non-corticosteroid immunosuppressive agents in addition to corticosteroids in patients with more severe disease. C As per JSN 2016 guidelines: Initiate immunosuppressive therapy to reduce urinary protein levels, prevent progression to glomerular sclerosis, and improve the renal prognosis in pediatric patients with severe IgA nephropathy. B Initiate combination therapy with corticosteroids, non-steroidal immunosuppressive agents, anticoagulants, and antiplatelet agents to reduce proteinuria, prevent the progression of glomerular sclerosis, and improve the prognosis of renal function in pediatric patients with severe IgA nephropathy with poor prognosis. B Pediatric patients (RAS inhibitors): initiate ACEIs or ARBs in all pediatric patients with IgA nephropathy and proteinuria > 200 mg/day or protein-to-creatinine ratio > 200 mg/g (> 0.2 g/g; 20 mg/mmol). B Pediatric patients (follow-up): aim for proteinuria 200 mg/day ( 400 mg/1.73 m /day) or protein-to-creatinine ratio 200 mg/g ( 0.2 g/g; 20 mg/mmol). B Show 2 more Patients with IgA vasculitis (diagnosis and evaluation): recognize that there are no internationally agreed criteria for diagnosing IgA vasculitis in adult patients. Consider making a https://web.pathway.md/diseases/recUhB4iRyv7fSJSB 5/7 6/24/23, 2:28 PM Immunoglobulin A nephropathy Pathway clinical diagnosis of IgA vasculitis based on the criteria for children. B Show 3 more Patients with IgA vasculitis (prognosis): recognize that uncontrolled hypertension and the amount of proteinuria at presentation and hypertension and mean proteinuria during follow-up are predictors of poor kidney outcomes in adult patients with IgA vasculitis. B Show 2 more Patients with IgA vasculitis (management): do not use corticosteroids to prevent nephritis in patients with isolated extrarenal IgA vasculitis. D Show 8 more Patients with IgA vasculitis (IgAV-associated RPGN): evaluate the potential risks and benefits of immunosuppression at the individual patient level and discuss them with the patient. B Show 3 more Patients with IgA vasculitis (IgAV-associated nephritis in pediatric patients): recognize that pediatric patients aged > 10 years more often present with non-nephrotic-range proteinuria and impaired kidney function, and they may suffer more chronic histologic lesions with delay in biopsy and delay in treatment > 30 days. B Show 6 more Pediatric patients (lifestyle modifications): advise a low-sodium diet and optimal lifestyle and BP control (systolic BP < 90th percentile for age, sex, and height) in all pediatric patients with IgA nephropathy and proteinuria > 200 mg/day or protein-to-creatinine ratio > 200 mg/g (> 0.2 g/g; 20 mg/mmol). B Pediatric patients (corticosteroids): Consider administering corticosteroids (plus second-line immunosuppression) for improved kidney survival in pediatric patients with IgA nephropathy. C Consider adding corticosteroids to renin-angiotensin system inhibitors from the time of diagnosis in pediatric patients with proteinuria > 1 g/day or protein-to-creatinine ratio > 1 g/g (100 mg/mmol) and/or mesangial hypercellularity. Consider administering oral prednisolone 1-2 mg/kg/day (or equivalent) for 4 weeks followed by alternate-day tapering over 4-6 months, or regimens with IV methylprednisolone. C Pediatric patients (IgAN specific variants): Manage patients with IgA nephropathy with minimal change disease as corticosteroid-sensitive nephrotic syndrome. B Administer corticosteroids (usually methylprednisolone pulses) combined with cyclophosphamide in pediatric patients with rapidly progressive IgA nephropathy. B References 1. Kidney Disease: Improving Global Outcomes KDIGO Glomerular Diseases Work Group. KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases. Kidney Int. 2021 Oct;100 4S S1 S276. Open https://web.pathway.md/diseases/recUhB4iRyv7fSJSB 6/7 6/24/23, 2:28 PM Immunoglobulin A nephropathy Pathway 2. Yuzawa Y, Yamamoto R, Takahashi K et al. Evidence-based clinical practice guidelines for IgA nephropathy 2014. Clin Exp Nephrol. 2016 Aug;20 4 511 535. Open 3. Steven J Chadban, Curie Ahn, David A Axelrod et al. KDIGO Clinical Practice Guideline on the Evaluation and Management of Candidates for Kidney Transplantation. Transplantation. 2020 Apr;104 4S1 Suppl 1 S11 S103. Open 4. Sundararaman Swaminathan, Nelson Leung, Donna J Lager et al. Changing incidence of glomerular disease in Olmsted County, Minnesota: a 30-year renal biopsy study. Clin J Am Soc Nephrol. 2006 May;1 3 483 7. Open 5. Meng-Yu Wu, Chien-Sheng Chen, Giou-Teng Yiang et al. The Emerging Role of Pathogenesis of IgA Nephropathy. J Clin Med. 2018 Aug 20;7 8 225. Open 6. Jennifer C Rodrigues, Mark Haas, Heather N Reich. IgA Nephropathy. Clin J Am Soc Nephrol. 2017 Apr 3;12 4 677 686. Open 7. Simon Jarrick, Sigrid Lundberg, Adina Welander et al. Mortality in IgA Nephropathy: A Nationwide Population-Based Cohort Study. J Am Soc Nephrol. 2019 May;30 5 866 876. Open 8. Anand Padmanabhan, Laura Connelly-Smith, Nicole Aqui et al. Guidelines on the Use of Therapeutic Apheresis in Clinical Practice Evidence-Based Approach from the Writing Committee of the American Society for Apheresis: The Eighth Special Issue. J Clin Apher. 2019 Jun;34 3 171 354. Open 9. Jicheng Lv, Muh Geot Wong, Michelle A Hladunewich et al. Effect of Oral Methylprednisolone on Decline in Kidney Function or Kidney Failure in Patients With IgA Nephropathy: The TESTING Randomized Clinical Trial. JAMA. 2022 May 17;327 19 1888 1898. Open 10. Japanese Society of Nephrology. Essential points from Evidence-based Clinical Practice Guidelines for Chronic Kidney Disease 2018. Clin Exp Nephrol. 2019 Jan;23 1 1 15. Open https://web.pathway.md/diseases/recUhB4iRyv7fSJSB 7/7