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. doi: 10.1016/j.kint.2021.05.021. PMID: 34556256.
Definition, Etiology, PathogenesisTop
IgA nephropathy is the most common primary glomerulopathy. It is characterized by increasing levels of galactose-deficient IgA1, which leads to increased formation of circulating immune complexes and their subsequent deposition in the glomeruli. IgA nephropathy represents 10% to 45% of primary glomerular diseases and is more common in Asian and Caucasian populations.
Secondary causes of IgA nephropathy are most frequently associated with gastrointestinal and liver diseases (such as inflammatory bowel disease [IBD], celiac disease, cirrhosis), autoimmune conditions (ankylosing spondylitis, Sjögren syndrome, rheumatoid arthritis [RA]), pulmonary conditions (sarcoidosis, cystic fibrosis, pulmonary fibrosis), dermatologic conditions (psoriasis, dermatitis herpetiformis), infections (HIV, hepatitis B virus [HBV], hepatitis C virus [HCV], tuberculosis [TB]), and malignancy (lung cancer, renal cell carcinoma [RCC], Hodgkin lymphoma [HL], non-Hodgkin lymphoma [NHL], IgA myeloma). Their treatment and prognosis are related to the underlying condition.
IgA nephropathy is characterized by hematuria that can be microscopic, recurrent macroscopic, or both. Macroscopic hematuria most frequently accompanies viral or bacterial upper respiratory tract infections or gastrointestinal infections. This so-called synpharyngitic hematuria differentiates IgA nephropathy from the longer 10-to-21-day delay of postinfectious glomerulonephritis. Macroscopic hematuria may last from several hours to several days and may be accompanied by flank pain. Non–nephrotic range proteinuria is often present, although nephrotic range proteinuria and nephrotic syndrome occur in 5% to 10% of patients. The degree of proteinuria is the strongest prognostic indicator. Hypertension is present in up to 40% of patients. Acute kidney disease (AKI) is rarely seen, and when it occurs, this may be due to pigment nephropathy during episodes of gross hematuria or crescentic IgA nephropathy. IgA levels are increased in ~50% of patients, but this is neither sensitive nor specific.
There are no validated diagnostic or prognostic serum or urine biomarkers. Kidney biopsy is required for a definitive confirmation.
Diagnosis is based on pathologic findings including predominant mesangial IgA deposition on immunofluorescence.
Hypertension is associated with progression of renal disease and should be controlled (see Renal Parenchymal Hypertension). Renin-angiotensin system (RAS) blockers are the first-line therapy given the usual presence of proteinuria. In patients with proteinuria >0.5 g/d, RAS blockers should be started to reduce proteinuria irrespective of whether they have hypertension or not.
Recently the DAPA-CKD trial demonstrated that adding dapagliflozin in patients with IgA nephropathy treated with an angiotensin-converting enzyme inhibitor (ACEI)/angiotensin receptor blocker (ARB) significantly reduced proteinuria and the risk of chronic kidney disease (CKD) progression.Evidence 1Strong recommendation (benefits clearly outweigh downsides; right action for all or almost all patients). Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to subgroup analysis. Heerspink HJL, Stefánsson BV, Correa-Rotter R, et al; DAPA-CKD Trial Committees and Investigators. Dapagliflozin in Patients with Chronic Kidney Disease. N Engl J Med. 2020 Oct 8;383(15):1436-1446. doi: 10.1056/NEJMoa2024816. Epub 2020 Sep 24. PMID: 32970396.
Patients at high risk of progressive CKD (proteinuria >1 g/d on a maximum dose of RAS blockade and optimal blood pressure control) are candidates for immunosuppressive therapy. The TESTING II trial comparing 0.4 mg to 0.8 mg of oral methylprednisolone with placebo administered over 6 months demonstrated improvement in reducing the risk of CKD progression and end-stage renal disease at the expense of serious adverse events including infections, and our preference is for the lower dose combined with Pneumocystis jiroveci pneumonia prophylaxis.Evidence 2Strong recommendation (benefits clearly outweigh downsides; right action for all or almost all patients). Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to heterogeneity of outcomes. Lv J, Wong MG, Hladunewich MA, et al; TESTING Study Group. 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. doi: 10.1001/jama.2022.5368. PMID: 35579642; PMCID: PMC9115617.
Patients presenting with rapidly progressive glomerulonephritis/crescents on biopsy can be considered for cyclophosphamide and glucocorticoids.
Between 35% to 40% of patients will develop end-stage renal disease by 30 years from diagnosis. The degree of proteinuria is the most significant indicator of poor prognosis, with hypertension and decreased GFR at presentation also associated with worse outcomes.