Immunoglobulin A nephropathy (IgAN) is a proliferative glomerulonephritis associated with predominant mesangial IgA deposition. IgA deposition can occur in isolation or with IgG, IgM, or both, and often with complement protein C3.

Berger disease

IgAN

IgA vasculitis

• Approximately 75% of children and young adults present with macroscopic hematuria often associated with upper respiratory infection or gastrointestinal illness. This is often referred to as “synpharyngitic hematuria.” Older adults present with microscopic hematuria, proteinuria, and hypertension.
• Loin pain may be associated with macroscopic hematuria. This symptom should not be confused with the much rarer disorder, “loin pain hematuria syndrome.”
• Physical findings are usually unremarkable. Hypertension is present in 20% to 30% of patients with chronic kidney disease, and edema is found in the 5% of patients with nephrotic-range proteinuria.
• IgAN presents as acute kidney injury due to hemoglobin toxicity and intratubular obstruction due to red blood cell casts. It can present as macroscopic hematuria in 5% of patients and as chronic kidney disease in 10% to 20% of patients. Another cause for acute kidney injury can be rapidly progressive glomerulonephritis, frequently associated with the histologic finding of crescents in ≥50% of glomeruli.

• Most cases are idiopathic or primary. IgA vasculitis (formerly Henoch-Schönlein purpura) may represent a more systemic, vasculitic form of IgAN.
• Secondary causes of IgAN (Table E1) include hepatitis B; alcoholic cirrhosis; celiac disease; inflammatory bowel disease (IBD); psoriasis; sarcoidosis; cystic fibrosis; cancer of the lungs, larynx, or pancreas; HIV infection; systemic lupus erythematosus; rheumatoid arthritis; diabetic nephropathy; Sjögren syndrome; and Reiter syndrome. Given the role of IgA in the gut, aside from IBD, infections in the gastrointestinal tract have been associated with IgAN or flares of the disease.
• The four-hit pathogenesis model is depicted in Fig. E1. The first hit from disease heritability is abnormal IgA glycosylation that produces polymeric galactose-deficient antibody, Gd-IgA1. The second hit is when Gd-IgA1 becomes auto-antigenic and auto-antibodies and immune complexes form. The third hit occurs when the immune complexes of Gd-IgA1 and antiglycan antibodies deposit in the mesangium leading to enhanced production of growth factors such as PDGF and IGF-1 with mesangial expansion. The fourth hit is intrarenal complement activation with generation of inflammatory cytokines by activated leukocytes.

Figure E1 Pathogenesis of IgA nephropathy.

IgA, Immunoglobulin A; IC, immune complex.

Table E1 Causes of Secondary IgAN

Group		Disease
Gastrointestinal and Liver Disease		Inflammatory bowel disease (Crohn disease, ulcerative colitis), celiac disease, cirrhosis
Infection		HBV, HCV, HIV, tuberculosis, leprosy
Autoimmune Diseases		Ankylosing spondylitis, rheumatoid arthritis, Sjogren syndrome
Malignancy		Lung cancer, renal cell carcinoma, non-Hodgkin and Hodgkin lymphoma, IgA myeloma
Respiratory tract		Sarcoidosis, bronchiolitis obliterans, pulmonary hemosiderosis, cystic fibrosis, pulmonary fibrosis
Skin		Dermatitis herpetiformis, psoriasis

HBV, hepatitis B virus; HCV, hepatitis C virus; HIV, human immunodeficiency virus; IgAN, immunoglobulin A nephropathy.

From Pattrapornpisut P et al: IgA nephropathy: core curriculum 2021, Am J Kidney Dis 78(3):429-441, 2021, https://doi.org/10.1053/j.ajkd.2021.01.024.

The differential diagnosis is the group of glomerular disorders with hematuria.

• IgA vasculitis (Henoch-Schönlein purpura)
• Hereditary nephritis
• Thin glomerular basement membrane disease
• Lupus nephritis
• Vasculitis
• Postinfectious nephritis
• IgA-dominant Staphylococcus-associated postinfectious glomerulonephritis
• Secondary causes associated with IgAN are as discussed previously

While mesangial deposits in IgAN can be triggered by infection, Staphylococcus-associated glomerulonephritis is an immune-mediated glomerulonephritis with sole or dominant presence of IgA within mesangial and subepithelial deposits and hypocomplementemia.

• Diagnosis is based on clinical history and laboratory data. Episodes of gross hematuria with upper respiratory infections and urinalysis with dysmorphic hematuria and/or red blood cell casts and negative serologic tests for other glomerulonephritides (e.g., lupus and vasculitis) are strongly representative of the diagnosis. The diagnosis is confirmed by kidney biopsy revealing predominant or codominant IgA mesangial deposits.
• To standardize diagnosis and provide prognostication, the pathology is scored via the Oxford IgAN (MEST-C) classification that evaluates mesangial hypercellularity, endocapillary hypercellularity, segmental glomerulosclerosis, tubular atrophy/interstitial fibrosis, and crescent formation.
• Prognosis is excellent with normal renal function and low proteinuria; accordingly, kidney biopsy is restricted to patients with sustained proteinuria >1 gram per day or worsening kidney function.

• Urinalysis shows positive blood reaction and variable degrees of proteinuria. Microscopy demonstrates protein, dysmorphic red blood cells, and red blood cell casts.
• Serum creatinine may be elevated.
• Urine protein-to-creatinine ratio may be elevated.
• Serum IgA is elevated in only 50% of patients, but this has little clinical utility and not measured.
• Measurement of Gd-IgA1 and Gd-IgA1-specific IgG antibodies have been proposed as diagnostic biomarkers, but neither has been validated for this purpose.

• Weight reduction in overweight or obese patients
• Smoking cessation
• Low sodium diet

• Antihypertensive therapy, preferably with ACE inhibitors or angiotensin II type 1 receptor blockers (ARB). The goal blood pressure is <125/75 mm Hg if proteinuria is >1 gram per day and <130/80 mm Hg if <1 gram per day. Dual blockade of the renin-angiotensin-aldosterone system (RAAS) is not recommended due to risk of hyperkalemia and/or acute kidney injury.
• Patients with recurrent gross hematuria, isolated microscopic hematuria, no or minimal proteinuria (<1 gram per day), normal blood pressure, and normal kidney function should be monitored every 6 to 12 mo to evaluate disease progression. Fish oil may be considered, but supporting data are limited.
• If recurrent episodes of macroscopic hematuria are associated with tonsillitis, tonsillectomy may benefit these patients; however, this treatment is controversial.
• Patients with persistent proteinuria >1 gram per day with or without hypertension are treated with ACE inhibitors or ARB.
• A 6-mo regimen of glucocorticoid steroids has been recommended for patients with good kidney function and persistent proteinuria of >1 gram per day, despite ACE inhibitor or ARB administration and fish oil after 6 mo. However, a recent, prospective, randomized, controlled trial (STOP-IgAN) showed no difference in decline in GFR with corticosteroids in subnephrotic patients followed for 3 yr. Infections, glucose intolerance, and obesity were more frequent in the steroid-treatment group.⁴ Another recent, multicenter study (TESTING) of 262 subnephrotic patients randomized to steroids vs. placebo showed potential renal benefit of steroid treatment. The trial was terminated early because of excess infections in the steroid group (14.7% vs. 3.2%).⁵ Overall, definitive conclusions regarding steroid treatment are not established. Patients with nephrotic syndrome and relatively preserved kidney function on maximal RAAS blockade can be treated with steroids for a 6-mo course, especially if there is disease progression. Steroid treatment is not indicated if significant chronic disease is demonstrated on renal biopsy or a GFR <20 ml/min per 1.73 m².
• Rapidly progressive glomerulonephritis in the absence of severe fibrosis on kidney biopsy is treated with pulse steroids followed by oral steroids, combined with cyclophosphamide for the first 2 to 3 mo. This initial regimen is followed by oral steroids and azathioprine for 2 yr as a maintenance treatment.
• Patients with acute kidney injury require a kidney biopsy to differentiate acute tubular necrosis due to pigment nephropathy, which requires only supportive therapy, from crescentic IgAN, which requires aggressive medical management.
• Kidney transplantation is the treatment of choice for ESRD. Although the recurrence rate of IgAN in the transplanted kidney is 50%, allograft loss from recurrent IgAN is rare, at 5%.
• Statins are indicated for all IgAN patients with dyslipidemia, hypertension, and other cardiovascular risks.
• The roles of mycophenolate, rituximab, and plasmapheresis are not clearly defined.
• Budesonide delayed release capsules (Tarpeyo) was recently approved for reduction of proteinuria in those at risk for rapid progression.
• A phase 2b clinical trial (NEFIGAN) showed potential benefit of enteric budesonide added to conventional therapy.⁶
• Another randomized phase 2 clinical trial showed antiproteinuric effect of combination therapy with hydroxychloroquine and RAAS inhibitors over 6 mo without significant adverse effects.⁷
• In the DAPA-CKD trial, the SGLT2 inhibitor dapagliflozin was shown to reduce proteinuria and progression of kidney disease in addition to RAAS blockers for patients with eGFR between 25 and 75 ml/min/1.73 m².⁸
• Future treatments may include targeted immunosuppression of the gut and modification of abnormal complement activation.

• Complete remission occurs in <10% of patients.
• ESRD develops in 12% of patients followed for 5 yr, in 15% to 20% within 10 yr, and in 20% to 40% within 20 yr. Prognostic markers for IgAN are described in Box E1.
• Poor prognostic indicators include hypertension, degree of renal insufficiency, greater proteinuria, and particular histologic features on renal biopsy, including crescents, increased mesangial cells, glomerulosclerosis, and tubulointerstitial fibrosis or atrophy.
• Potential future biomarkers include increased serum levels of glycan-specific IgG antibodies that predict progression to ESRD or death, elevated serum levels of galactose-deficient IgA1, factor H-related proteins, and selected urine microRNAs.

The role of fish oil is controversial. One large, randomized, placebo-controlled study showed benefit, although many small, randomized studies have shown no benefit. The recommendation for mild disease is that fish oil is optional for patients. International consensus guidelines recommend fish oil along with ACE inhibitors/ARB if proteinuria is >1 gram per day.

Patients with suspected IgAN are commonly referred to nephrologists for diagnosis and treatment, typically when presenting with gross hematuria and urinalysis with blood and proteinuria.

• Gross hematuria (red urine) is uncommon with intrinsic kidney disease but commonly encountered in IgAN and in cyst rupture from autosomal dominant polycystic kidney disease.
• IgAN is not an entirely benign condition, even when microhematuria is the only clinical presentation. Nearly 40% of patients reach ESRD after 20 yr of illness.
• Episodic gross hematuria that occurs during upper respiratory infections is a classic presentation for IgAN. If present, an ACE inhibitor or ARB should be started.