IgA Nephropathy

Practice Essentials

Immunoglobulin A (IgA) nephropathy is characterized by predominant IgA deposition in the glomerular mesangium.^{[1, 2]}  It is one of the most common causes of glomerulonephritis in the world.^{[3, 4, 5]}  IgA nephropathy was first described by Berger and Hinglais in 1968, and is also known as Berger disease.^{[6, 7]}

Pathologically, a spectrum of glomerular lesions can be seen, but mesangial proliferation with prominent IgA deposition is observed in almost all biopsies. See the images below.

View Image

Light microscopy of a glomerulus from a patient with immunoglobulin A nephropathy showing increased mesangial matrix and cellularity.

View Image

Immunofluorescence microscopy demonstrating large mesangial immunoglobulin A (IgA) deposits diagnostic of IgA nephropathy.

Although IgA nephropathy is a limited nonsystemic kidney disease, many systemic illnesses are sporadically associated with mesangial IgA deposition. Henoch-Schönlein purpura (HSP), a systemic illness, has been closely linked to IgA nephropathy. Other systemic diseases in which mesangial deposits of IgA are regularly observed include systemic lupus erythematosus, hepatitis, dermatitis herpetiformis, and ankylosing spondylitis.

Signs and symptoms

Patients with IgA nephropathy (especially adults) may be asymptomatic, albeit with persistent microscopic hematuria and proteinuria and often hypertension. Symptomatic presentations include the following:

• Episodic gross hematuria
• Rapidly progressive glomerulonephritis
• Proteinuria- less than 3 g/day
• Nephrotic syndrome
• Chronic kidney disease

See Presentation for more detail.

Diagnosis

The workup for IgA nephropathy includes the following:

• Urinalysis of a first-void urine sample, with sediment examination for RBCs and RBC casts
• Proteinuria testing (24-hour measurement of urinary protein or urine protein/creatinine ratio, plus urine protein electrophoresis in patients older than 50 years with proteinuria, to exclude monoclonal light chains)
• Kidney function assessment with 24-hour creatinine clearance test or estimation of glomerular filtration rate
• Kidney biopsy to confirm the diagnosis

See Workup for more detail.

Management

Treatment of IgA nephropathy includes the following:

• All patients should be given supportive therapy to control hypertension and proteinuria, including renin-angiotensin system blockade and dietary sodium restriction.
• Tonsillectomy is appropriate only for patients with recurrent tonsillar infections.
• Immunosuppression has become controversial.^[8] Corticosteroids are the option with the most convincing evidence to support their use, but if used, they should be administered only to carefully selected patients, and preferably should not be given for more than 6 months.
• Cyclophosphamide should be reserved for rapidly progressive crescentic glomerulonephritis.

The US Food and Drug Administration (FDA) has approved the following agents to reduce proteinuria in adults with IgA nephropathy who are at risk of rapid disease progression:

• A targeted-release formulation of the corticosteroid budesonide (Tarpeyo)
• Sparsentan (Filspari), a dual angiotensin II and endothelin-1 receptor antagonist
• Atrasentan, an endothelin type A receptor antagonist 
• Iptacopan (Fabhalta), a complement inhibitor

Kidney transplantation is effective in patients with IgA nephropathy that has progressed to end-stage kidney disease. However, the disorder frequently recurs after transplantation

See Treatment and Medication for more det

For discussion of this disorder in children, see Pediatric IgA Nephropathy.

• References

Pathophysiology

IgA nephropathy appears to result from an ordered sequence of events, starting with galactose-deficient IgA1, which contains less than a full complement of galactose residues on the O-glycans in the hinge region of the heavy chains.^[9]  These may act as auto-antigens that trigger the production of glycan-specific autoantibodies and the formation of circulating immune complexes that are deposited in renal mesangium. These then induce glomerular injury through pro-inflammatory cytokine release, chemokine secretion, and the resultant migration of macrophages into the kidney.^[10]  Immune complexes formed by IgG or IgA antibodies with galactose-deficient IgA lead to deposition in the glomerulus.

Deposited IgA is predominantly polymeric IgA1, which is mainly derived from the mucosal immune system. The association of some cases of IgA nephropathy with syndromes that affect the respiratory tract or gastrointestinal tract, such as celiac disease, led to the suggestion that IgA nephropathy is a disease of the mucosal immune system. This concept is also supported by the clinical observation that hematuria worsens during or after upper respiratory tract or gastrointestinal tract infections. Any bacterial or viral infections can precipitate IgA nephropathy.

An association between IgA nephropathy and inflammatory bowel disease (IBD)—especially Crohn disease, but also ulcerative colitis—has been reported. IBD may be diagnosed before or after onset of IgA nephropathy.^[11] A Swedish population-based cohort study found elevated risk of progression to end-stage kidney disease in patients with comorbid IgA nephropathy and IBD.^[12]

Data strongly suggest that the alternative complement pathway plays a key role in the pathophysiology of IgA nephropathy. Although the formation of immune complexes and their deposition in the glomerular mesangium cannot activate complement through the classic pathway, it may directly activate the alternative complement pathway, which contributes to kidney inflammation and glomerular injury.^[13]

• References

Etiology

Most cases of IgA nephropathy are idiopathic, but the onset or exacerbation of the disease is often preceded by a respiratory tract infection. Association with some bacteria, such as Haemophilus parainfluenzae, has been reported. A variety of other disorders have also been linked with IgA nephropathy, as discussed below.

Cirrhosis and other liver diseases

Glomerular IgA deposition is a common finding in cirrhosis, occurring in more than one-third of patients. Liver disease is accompanied by impaired removal of IgA-containing complexes by the Kupffer cells, predisposing patients to IgA deposition in the kidney.

Glomerular IgA deposits are common in advanced liver disease, but most adults have no clinical signs of glomerular disease, whereas up to 30% of children may have asymptomatic hematuria or proteinuria. Those abnormalities usually resolve after successful liver transplantation.

Gluten enteropathy (celiac disease)

Glomerular IgA deposition occurs in up to a third of patients with gluten enteropathy. Most of these patients have no clinical manifestations of the disease. However, IgA nephropathy and gluten hypersensitivity are associated, and withdrawal of gluten from the diet of these patients has resulted in clinical and immunologic improvement of the renal disease.

HIV infection

IgA nephropathy has been reported in patients with HIV infection, both Whites and Blacks, despite the rarity of typical IgA nephropathy in the Black population.^[14] Clinically, patients have hematuria, proteinuria, and, possibly, kidney insufficiency.

Histologically, findings range from mesangial proliferative glomerulonephritis to collapsing glomerulosclerosis with mesangial IgA deposits. Several patients have had circulating immune complexes containing IgA antibodies against viral proteins.

Familial IgA nephropathy

Although IgA nephropathy is usually a sporadic disease, data suggest that genetic factors are important in susceptibility to development of mesangial glomerulonephritis. Several cases of familial disease have been reported in Italy and the United States, and an autosomal dominant form has been linked to band 6q22-23.^[15] Additionally, increased frequency of specific HLA groups (HLA-DRB1 and HLA-DQB1) has been reported in some populations.^[16] A study of genetic risk for IgA nephropathy in Han Chinese identified three non-HLA gene regions (FBXL21, CCR6, and STAT3) and one HLA gene region (GABBR1) with suggestive significance; further analysis identified five novel susceptibility genes, TGFBI, CCR6, STAT3, GABBR1, and CFB, that may be involved in IgA nephropathy.^[17]

Ai and colleagues reported increased risk for IgA nephropathy in association with low copy number of the α-defensin gene (DEFA1A3). Low total copy numbers also showed significant association with kidney dysfunction in patients with IgA nephropathy.^[18] Single-nucleotide polymorphisms (SNPs) of the enabled homolog gene (ENAH) have been associated with increased susceptibility to childhood IgA nephropathy, as well as to the development of proteinuria and gross hematuria, and pathological progression in children with the disease.^[19]

• References

Epidemiology

Frequency

United States

IgA nephropathy is found in about 10% of biopsies performed for glomerular disease in the United States. Prevalence rates are lower in the United States than in Asian countries. These lower rates may be influenced by a conservative approach by nephrologists in the US, who are reluctant to perform kidney biopsies in asymptomatic patients with only mild abnormalities on urinalyses.

International

Distribution of IgA nephropathy varies in different geographic regions throughout the world. IgA nephropathy is observed in up to 40% of all biopsies performed for glomerular disease in Asia, compared with 20% in Europe and 10% in North America. High prevalence rates are observed in Singapore, Japan, Australia, Hong Kong, Finland, and southern Europe, whereas low prevalence rates are the rule in the United Kingdom, Canada, and the United States.

A study from Scotland found a significant twofold increase in the diagnosis of IgA nephropathy in the patients residing in the most socioeconomically deprived areas compared with the least deprived ones. The variation was not explained by the demographics of the underlying population.^[20]

In a study by Zhou from eastern China utilizing kidney biopsies from 2001-2017, IgA nephropathy was the most common type of primary glomerulonephritis, accounting for 50% of cases. The diagnosis rate of IgA nephropathy remained steady over that 15-year period; however, the prevalence of membranous nephropathy increased, becoming the second most common type.^[21]

In Asia, routine urinalyses are performed for schoolchildren, and kidney biopsies are performed for patients with asymptomatic hematuria, thus raising the reported prevalence of the disease. The estimated annual incidence in Japan is 3.9–4.5 per 100,000 population.^[22]  

The prevalence of IgA nephropathy is highest in geographic areas with large numbers of endemic helminthic species that infest humans, and most of the IgA nephropathy susceptibility loci identified by genome-wide association studies include genes involved in the maintenance of the intestinal epithelial barrier and response to mucosal pathogens, which would confer protection against helminthic infestation. Thus, the increased risk of IgA nephropathy in these populations may be an untoward consequence of a protective adaptation to helminthic infections. It would also explain the association of mucosal infections as a frequent trigger for IgA nephropathy.^[23]

Mortality/morbidity

This disorder is thought to follow a benign course in most cases. However, many patients are at risk for slow progression to end-stage renal disease, which develops in approximately 15% of patients by 10 years and 20% by 20 years, though these percentages depend on how the disease is defined.

Race-, sex-, and age-related demographics

IgA nephropathy is more common in Asians and Whites and is rare in Blacks, both in the United States and in Africa. The condition is frequently observed in Native Americans of the Zuni and Navajo tribes.

IgA nephropathy is more common in males than in females. Virtually all studies show a male predominance of at least 2:1, with reported ratios of up to 6:1.^[24] The higher male predilection is observed in White patients in northern Europe and the United States.

IgA nephropathy can affect all ages but is most common in the second and third decades of life. Eighty percent of patients are aged 16-35 years at the time of diagnosis. The condition is uncommon in children younger than 10 years.

Lifestyle and risk of progression to end-stage renal disease

In a study by Huang et al in Chinese subjects with IgA nephropathy, which compared cases that progressed to end-stage renal disease (ESRD) with controls that did not, the proportion of patients who were males, smokers, alcohol drinkers, and physically inactive was signficantly higher in cases than in controls. Alcohol use proved to be an independent risk factor for progression to ESRD, while regular exercise was associated with decreased risk; males who did not exercise seemed especially likely to progress to ESRD. These authors concluded that physical exercise should be encouraged in IgA nephropathy patients, especially in males, for a better renal outcome, and cessation of alcohol use might help prevent disease progression.^[25]

• References

Prognosis

Although IgA nephropathy usually follows a benign course, end-stage kidney disease (ESKD) develops in 15-20% of patients within 10 years of onset and in about 25-30% of patients by 20 years. Efforts have been made to determine clinical and histologic features associated with progression to ESKD.^{[26, 27]}

The Oxford classification of IgA nephropathy, or MEST score, published in 2009, comprises four histologic features that are independent predictors of clinical outcome.^[4] The IgA Nephropathy Classification Working Group added crescents to the Oxford classification, to form the MEST-C score.^{[28, 29]}  Kidney Disease: Improving Global Outcomes (KDIGO) guidelines recommend preferential use of the MEST-C score, over more general chronic kidney disease models, in patients with an established diagnosis of IgA nephropathy.^{[30, 31]}

The features that determine the MEST-C score are as follows: 

• M – Mesangial cellularity, defined as more than four mesangial cells in any mesangial area of a glomerulus: M0 is mesangial cellularity in <  50% of glomeruli; M1, ≥50%
• E – Endocapillary proliferation, defined as hypercellularity due to an increased number of cells within glomerular capillary lumina: E0 is absence of hypercellularity; E1 is hypercellularity in any glomeruli
• S – Segmental glomerulosclerosis, defined as adhesion or sclerosis (obliteration of capillary lumina by matrix) in part of but not the whole glomerular tuft: S0 is absence of segmental glomerulosclerosis, S1 is presence of segmental glomerulosclerosis in any glomerulus
• T – Tubular atrophy/interstitial fibrosis, defined as the estimated percentage of cortical area showing tubular atrophy or interstitial fibrosis, whichever is greater: T0 is 0-25%; T1 is 25-50%; T2 is > 50%
• C – Crescents: C0 (no crescents), C1 (crescents in less than one-fourth of glomeruli), C2 (crescents in over one-fourth of glomeruli).

The clinical significance of the individual MEST-C features is as follows:

• M1 – Worse outcomes than M0
• E1 – Worse renal survival in patients not on immunosuppression and improved renal survival with immunosuppression
• S1 – Predictive of worse outcomes
• T – Strongest predictor of worse outcomes
• C1 – Predictive of worse outcomes if no immunosuppression is given, but not if immunosuppression is used; C2 is predictive of worse outcomes regardless of immunosuppression

Other predictors of poor renal outcomes include the following:

• High serum creatinine level (> 120 mmol/L) at presentation
• Hypertension (diastolic pressure > 95 mm Hg or need for antihypertensive treatment)
• Proteinuria: Urinary protein excretion < 1 g/24 hr is associated with 56% renal survival and > 3.5 g/24 hr with 7% renal survival^[32]
• Extensive interstitial fibrosis and tubular atrophy on kidney biopsy
• C4d staining on biopsy

Calculators for determining prognosis in patients with IgA nephropathy include the following:

• International IgAN Prediction Tool at biopsy - Adults
• International IgAN Prediction Tool at biopsy - Pediatrics
• International IgAN Prediction Tool post-biopsy - Adults
• International IgAN Prediction Tool post-biopsy – Pediatric

A calculator for estimating the risk of progression to ESRD in patients with IgA nephropathy has been developed by Xie et al, based on a cohort of 619 Chinese patients.^[33] It has yet to be validated in other ethnic groups. The calculator uses four variables:

• Glomerular filtration rate
• Hemoglobin level
• Serum albumin level
• Systolic blood pressure

• References

History

Patients with Iga nephropathy may be asymptomatic, but with persistent microscopic hematuria and proteinuria and often hypertension. This presentation occurs mostly in adults. Impairment of kidney function can occur in such cases, and remission is uncommon. 

Symptomatic presentations in patients with IgA nephropathy include the following:

• Episodic gross hematuria
• Rapidly progressive glomerulonephritis – This is sometimes seen as a late presentation; these patients may rapidly progress to needing renal replacement therapy.
• Proteinuria – Less than 3 g/day (more common)
• Nephrotic syndrome – More than 3.5 g of proteinuria with edema, hypoalbuminemia, hypertension, and hyperlipidemia.
• Chronic kidney disease

Episodic gross hematuria from IgA nephropathy has the following features:

• Eighty percent of these episodes are associated with upper respiratory tract infections, mainly acute pharyngotonsillitis; this synchronous association of pharyngitis and macroscopic hematuria has been dubbed synpharyngitic nephritis.
• Gross hematuria usually appears simultaneously or within the first 48-72 hours after the infection begins; persists less than 3 days; and, in about a third of patients, is accompanied by loin pain, presumably due to renal capsular swelling
• Seen mostly in children and young adults
• These patients have a high likelihood of remission.

• References

Physical

Physical examination findings in patients with IgA nephropathy are usually unremarkable. A minority of patients present with hypertension. More commonly, however, hypertension manifests later in the course of the disease or when patients develop chronic kidney disease and end-stage renal disease (ESRD). Nephrotic syndrome could manifest as edema in the lower extremities.

• References

Approach Considerations

The first step in confirming the diagnosis of IgA nephropathy is a careful urinalysis of a first-void urine sample performed by an experienced urine analyst. Direct examination of the urine sediment is required to identify red blood cells (RBCs) and RBC casts, both of which indicate glomerular injury.

Proteinuria testing can be accomplished quantitatively by a 24-hour measurement of urinary protein or semiquantitatively by measuring a urine protein/creatinine ratio. A normal ratio should be less than approximately 0.1. Also, adults older than 50 years with proteinuria should have urine protein electrophoresis performed to exclude monoclonal light chains as a cause of proteinuria.

Assess kidney function in patients with proteinuria or hematuria by a 24-hour creatinine clearance test. Alternatively, the glomerular filtration rate (GFR) can be estimated using the Modification of Diet in Renal Disease (MDRD) formula or CKD-EPI.

Although the serum IgA level is elevated in up to half of patients, this finding is insensitive, nonspecific, and of no clinical utility

Kidney biopsy is necessary for confirming the diagnosis of IgA nephropathy.^[30]  In addition, biopsy findings are used to determine the MEST-C score (mesangial [M] and endo-capillary [E] hypercellularity, segmental sclerosis [S], interstitial fibrosis/tubular atrophy [T], and crescents [C]), for  predicting risk of progression (see Overview/Prognosis).

In IgA nephropathy, proteinuria rarely occurs without microscopic hematuria. Mild proteinuria is common.

Nephrotic-range proteinuria is uncommon, occurring in only 5% of patients with IgA nephropathy, and is more commonly seen in children and adolescents. Nephrotic-range proteinuria can be seen early in the disease course as well as in patients with advanced disease

Patients with heavy proteinuria and nephrotic syndrome are likely to have IgA deposition with diffuse proliferative glomerular lesions or minimal-change light microscopic findings

Acute kidney injury

Acute kidney injury, with edema, hypertension, and oliguria, occurs in fewer than 5% of patients. It can develop from either of the following two distinct mechanisms:

• Acute severe immune injury can manifest as necrotizing glomerulonephritis and crescent formation
• Alternatively, only mild glomerular injury is observed with gross hematuria, and kidney injury is presumably due to tubular occlusion by RBCs; this is reversible, and kidney function recovers with supportive measures

• References

Histologic Findings

Light microscopy

On kidney biopsy, the most common light microscopy findings are focal or, more often, diffuse mesangial proliferation and extracellular matrix expansion (as seen in the image below). Morphology can range from normal to moderate or severe intracapillary or extracapillary proliferative lesions. Some patients with little or no change by light microscopy have IgA deposits on immunofluorescence.

View Image

Light microscopy of a glomerulus from a patient with immunoglobulin A nephropathy showing increased mesangial matrix and cellularity.

Occasionally, patients have focal glomerular sclerosis indistinguishable from focal segmental glomerulosclerosis on light microscopy. A number of other findings can be observed in advanced disease, including interstitial fibrosis, tubular atrophy, and vascular sclerosis. A few patients have segmental necrotizing lesions with crescent formation due to extensive disruption of the capillaries. These findings can be helpful prognostic tools in patients with IgA nephropathy (see Overview/Prognosis).

Electron microscopy

Electron microscopy shows mesangial hypercellularity and increased mesangial matrix. The important finding is electron-dense deposits of IgA in the mesangium, such as those in the image below, but deposits in the subendothelial and subepithelial region of the glomerular capillary wall are found in a minority of patients, especially those with more severe disease. Subendothelial deposits are often present when there is endocapillary hypercellularity.

View Image

Electron microscopy showing large dark mesangial deposits.

Immunofluorescence

Immunofluorescence findings are the pathologic hallmark of this disease. IgA is deposited in a diffuse granular pattern in the mesangium (as seen in the image below) and occasionally in the capillary wall. The deposits are predominantly polymeric IgA of the IgA1 subclass; in addition, IgG is found in 43% of cases, and IgM in 54%.^[23] C3 is often present. Polyclonal deposits, often with more lambda than kappa light chains, are seen. Presence of C4d indicates a worse prognosis.

View Image

Immunofluorescence microscopy demonstrating large mesangial immunoglobulin A (IgA) deposits diagnostic of IgA nephropathy.

• References

Approach Considerations

Because the clinical presentation and prognosis in IgA nephropathy varies widely, treatment must be individualized.^[34] All patients should be given supportive therapy to control hypertension and proteinuria, including renin-angiotensin system blockade and dietary sodium restriction. Tonsillectomy is appropriate only for patients with recurrent tonsillar infections.

Control of proteinuria is prudent, since there is a mostly linear association between the severity of proteinuria and decline in estimated glomerular filtration rate (GFR). Use of immunosuppression should be determined by considering the rate of progression, comorbidities, and whether alarming features are present on biopsy. However, immunosuppression has become controversial.^[8] Currently, corticosteroids are the option with the most convincing evidence to support their use, but if used, they should be administered only to carefully selected patients, and preferably should not be given for more than 6 months. Sodium–glucose transporter 2 (SGLT2) inhibitors, which have an established role in chronic kidney disease generally, have also demonstrated benefit in IgA nephropathy.^[35]

The US Food and Drug Administration (FDA) has approved several agents to reduce proteinuria in adults with IgA nephropathy who are at risk of rapid disease progression: a targeted-release formulation of the corticosteroid budesonide (Tarpeyo); sparsentan (Filspari), a dual angiotensin II and endothelin-1 receptor antagonist; atrasentan (Vanrafia), an endothelin-1 receptor antagonist; and iptacopan (Fabhalta), a complement inhibitor.

Cyclophosphamide should be reserved for rapidly progressive crescentic glomerulonephritis. Most nephrologists agree with not using immunosuppression when the GFR is less than 30 mL/min/1.73 m², although others would suggest a different GFR threshold. Regardless, the lower the GFR, the higher the risk of adverse events and the lower the likelihood of benefiting from immunosuppressants. Immunosuppression should definitely be avoided when the biopsy shows large amounts of interstitial fibrosis and tubular atrophy.

Additional supportive care measures, to be used as appropriate, include the following^[30] :

• Address cardiovascular risk
• Dietary sodium restriction
• Smoking cessation
• Weight control
• Exercise

• References

Medical Care

IgA nephropathy is a common cause of glomerulonephritis. Although it is a benign disease in most patients, chronic kidney disease and end-stage kidney disease (ESKD) occur in about 20-40% of patients within 20 years of presentation. Currently, multiple treatment options are available; no one therapy is appropriate for all patients. No randomized controlled trial has verified the value of the MEST-C score (see Overview/Prognosis) in making treatment decisions, but proteinuria seems to be the biggest prognostic factor. There are no trials in patients with a urinary protein-to-creatinine ratio (UPCR) of < 0.5 g/day.

General recommendations include the following:

• In patients with isolated hematuria (ie, without proteinuria or hypertension) monitor with urinalysis, kidney function testing, and blood pressure measurement.
• Treat hypertension early and aggressively with renin-angiotensin blockade; a reasonable goal is a blood pressure of 130/80 mm Hg if proteinuria is < 1g/day.^[36]  If proteinuria is > 1 g/day, then 125/75 mm Hg should be the goal.^[30]
• Steroids are most beneficial if more than 1 g of proteinuria is present in a 24-hour urine specimen.^[37]
• Goal UPCR is < 0.5-0.75 g/day with renin-angiotensin blockade.
• If UPCR is > 1.5 g/day despite maximum renin-angiotensin blockade for 4-6 months, steroids can be added, but not if the GFR is < 25 mL/min/1.73m².^[38]
•  If UPCR is persistently 0.75-1.5 g/day, the short-term benefits of steroid use remains uncertain.
• The presence of crescents on biopsy in a sample with more than 10 glomeruli is an indication for treatment with cyclophosphamide.
• The role of direct renin inhibitors and mineralocorticoid receptor antagonists have not been evaluated in a randomized controlled trial.
• If GFR > 25 mL/min/1.73 m² and UPCR is > 0.6 g/day there is a benefit to treatment.^[39]

Renin-angiotensin blockade

Angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) are the preferred agents for lowering blood pressure and decreasing proteinuria.^[30]  In a randomized, controlled trial in 44 patients with biopsy-proven IgA nephropathy who had proteinuria and normal or moderately reduced kidney function, Kaplan-Meier renal survival after 7 years was 92% in patients treated with enalapril versus 55% in the control group (P < 0.05).^[40]  

Results of a prospective, open-label, multicenter, centrally randomized, controlled trial in 97 patients suggested that the combination of the ACEI ramipril with prednisone was more effective than ramipril alone in discouraging progression of kidney disease associated with IgA nephropathy.^[41]  The combination of an ACEI with an ARB is used by some clinicians, especially if serum creatinine is monitored cautiously, but this approach is not supported by randomized controlled trial data; although it decreases proteinuria, it is associated with greater risk of acute kidney injury and hyperkalemia. 

Dual angiotensin II and endothelin-1 receptor blockade

Sparsentan (Filspari), a dual angiotensin II and endothelin-1 receptor antagonist, gained accelerated approval from the US Food and Drug Administration (FDA) in February 2023. It is indicated to reduce proteinuria in adults with IgA nephropathy who are at risk of rapid disease progression, generally a urine protein-to-creatinine ratio (UPCR) 1.5 g/g or greater. Endothelin-1 and angiotensin II are thought to contribute to the pathogenesis of IgA nephropathy via the endothelin A receptor and the angiotensin II type 1 receptor respectively. 

Approval was supported by interim data from the phase 3 PROTECT clinical trial (n = 404). After 36 weeks of treatment, reduction of proteinuria from baseline was 49.8% with sparsentan compared with 15.1% with the ARB irbesartan (P  < 0.0001).^[42]  Final analysis at 110 weeks confirmed the interim results, with UPCR reduction of 42.8% with sparsentan versus 4.4% with irbesartan.^[43]  

Owing to risks of hepatotoxicity and birth defects, sparsentan is available only through a restricted program called the FILSPARI REMS (Risk Evaluation Mitigation Strategy program).

Endothelin-1 blockade

Atrasentan (Vanrafia), an endothelin type A (ET_A) receptor antagonist, received accelerated FDA approval in April 2025 for the reduction of proteinuria in adults with primary IgA nephropathy who are at risk of rapid disease progression (UPCR ≥1.5 g/g). Atrasentan can be added to supportive care, including use of a renin-angiotensin sysem (RAS) inhibitor and/or a sodium-glucose co-transporter-2 (SGLT2) inhibitor. Atrasentan does not require a REMS program.

Approval was based on results from the the ongoing phase 3 ALIGN study, in which patients receiving atrasentan in combination with a RAS inhibitor achieved clinically meaningful and statistically significant 36.1% reduction in proteinuria compared with placebo (P < 0.0001), with results seen as early as week 6 and sustained through week 36. Patients treated with atrasentan plus both a RAS inhibitor and an SGLT2 inhibitor demonstrated a 37.4% reduction in UPCR compared with placebo.^[44]

Complement inhibition

Iptacopan (Fabhalta) gained accelerated approval from the FDA in August 2024 to reduce proteinuria in adults with primary IgA nephropathy who are at risk for rapid disease progression.^[45] In IgA nephropathy, deposition of immune complexes containing galactose-deficient IgA1 (Gd-IgA1) activates the alternative complement pathway, and this is thought to contribute to the pathogenesis of IgA. Iptacopan binds to complement factor B and thus inhibits the effect of the alternative pathway.^[13]

Approval of iptacopan for this indication was based on interim analysis of the first 250 patients that reached Month 9 in the phase 3 APPLAUSE-IgAN study. Iptacopan achieved a 44% reduction of proteinuria from baseline compared with 9% for placebo (P< 0.0001).^[45]

Corticosteroids and other immunosuppressive agents

Some trials of corticosteroid therapy for IgA nephropathy have shown positive outcomes. However, the possible benefit from corticosteroids should be weighed against the risks of immunosuppression for the individual patient.^[46]  

In general there is no benefit gained by adding corticosteroids to renin-angiotensin blockade when proteinuria < 1 g/day. When proteinuria is 1-3 g/day, steroids can be added, but benefits take 6-8 years to become manifest. If proteinuria is > 3 g/day, the benefit of steroids with renin-angiotensin blockade takes 2-3 years to manifest.

Guidelines for IgA nephropathy from Kidney Disease: Improving Global Outcomes (KDIGO) suggest that a 6-month course of corticosteroid therapy may be given to patients who have persistent proteinuria ≥1 g/d despite 3–6 months of optimized supportive care (including ACEI or ARB treatment and blood pressure control), and a glomerular filtration rate (GFR) > 50 mL/min/1.73m².^[30]  

Corticosteroid regimens studied have included the following^[47] :

• Intravenous methylprednisolone ,1 g/day for 3 consecutive days at months 1,3, and 5; plus oral prednisone for 6 months at 0.5 mg/kg every other day^[48]
• Oral prednisone for 6 months at 1 mg/kg/day for 2 months followed by 0.2 mg/kg/day^[41]
• Oral prednisone for 6-8 months at 0.8-1 mg/kg/day for 2 months, then reduced to 5-10 mg every 2 weeks^[49]

Clinical guidelines for managment of IgA nephropathy developed by the Japan Ministry of Health Labour and Welfare (MHLW) and the Japanese Society of Nephrology (JSN) include the following recommendations for corticosteroid use in patients with urinary protein level ≥1 g/day and chronic kidney disease (CKD) stage G1-2^[22] :

• High-dose oral steroid therapy: Prednisolone at 0.8–1.0 mg/kg for about 2 months, followed by gradual tapering over about 6 months (grade B)
• Steroid pulse therapy: Methylprednisolone 1 g for 3 days by infusion (or IV) every other month, 3 times plus prednisolone 0.5 mg/kg, every other day, for 6 months (grade B) 

A retrospective study of 1147 patients from the European Validation Study of the Oxford Classification of IgAN (VALIGA) cohort classified according to the Oxford-MEST classification (see Overview/Prognosis) showed a significant reduction in proteinuria, a slower rate of kidney function decline, and greater renal survival with corticosteroid therapy. In contrast to KDIGO recommendations, corticosteroids reduced the risk of progression even in patients with an initial estimated GFR ≤50 mL/min/1.73 m² and in direct proportion to the extent of proteinuria. Over median follow-up of 4.7 years, the annual decline in kidney function with corticosteroid therapy versus no steroid use was 1.0 versus 3.2 mL/min/1.73 m², respectively (P = 0.004).^[50]  

In contrast, the TESTING trial (Therapeutic Evaluation of STeroids in IgA Nephropathy Global study), which enrolled patients with proteinuria > 1 g/d and estimated GFR (eGFR) of 20 to 120 mL/min/1.73 m², showed that high-dose oral methylprednisone was associated with significantly increased rates of serious adverse outcomes in participants with >1 g/day proteinuria. Patients were randomized 1:1 to oral methylprednisolone (0.6-0.8 mg/kg/d; maximum, 48 mg/d) or placebo for 2 months, with subsequent weaning over 4-6 months. While proteinuria and eGFR levels were improved in the methylprednisone arm, the trial was stopped after 1.5 years due to serious adverse events.^[51]  The TESTING-2 trial is in progress in Asian countries and Australia and Canada.

The KDIGO guidelines suggest not treating with corticosteroids combined with cyclophosphamide or azathioprine unless the patient has crescentic IgA nephropathy with rapidly deteriorating kidney function.^[30]  Use of mycophenolate mofetil has been controversial, as studies have been small in size and studies have reported negative results.^{[36, 52]}  The KDIGO guidelines do not recommend use of mycophenolate mofetil.^[30]

The Supportive Versus Immunosuppressive Therapy for the Treatment of Progressive IgA Nephropathy (STOP-IgAN) trial showed that after 3 years, full clinical remission had occurred in 5% of patients in the supportive-care group, as compared with 17% of patients who received immunosuppression with steroids plus cyclophosphamide followed by azathioprine. STOP-IgAN enrolled patients 18-70 years of age with proteinuria > 0.75 g/day with hypertension and GFR of 30-90 mL/min/1.73 m². Patients with crescentic lesions were excluded.^[53]

The primary end point was UPCR < 0.2 g/day and a decrease in eGFR < 5 mL/min/1.73 m² from baseline at 3 years. There was no significant difference in the annual decline in eGFR between the two groups, and patients in the immunosuppression arm were more likely to experience significant adverse effects (severe infections, impaired glucose tolerance, and weight gain of more than 5 kg in the first year of treatment).^[53]

The STOP-IgAN authors note that the study results do not apply to patients who have proteinuria > 3.5 g/day, as such patients have a very high risk of progression and have been reported to have a particularly good response to corticosteroids.^[53]  Thus, use of immunosuppression should be considered only for patients with active disease and rapid progression.

A 2015 Cochrane review of immunosuppressive therapy for IgA nephropathy concluded that corticosteroid therapy may lower risks of kidney disease progression, proteinuria, doubling of serum creatinine, and need for dialysis or transplantation. However, the review concluded that the optimal management of IgA nephropathy remains uncertain, and larger controlled trials are needed.^[54]  

Targeted-release budesonide

The phase 2b NEFIGAN trial demonstrated a 24% decrease in mean UPCR in patients receiving a novel targeted-release formulation of oral budesonide that delivers the drug to the distal ileum, thus targeting the Peyer patches; this agent is twice as potent as prednisone. Mean UPCR of participants was 1.2 g/day and mean eGFR was 78 mL/min/1.73 m². Budesonide 16 mg/day, added to optimized renin-angiotensin system blockade, reduced proteinuria by around 25-30% compared with placebo. Patients in the treatment group experienced an increased rate of steroid-related events including acne, hypertension, cushingoid features, mood swings, and hirsutism. The authors conclude that the results support the hypothesis that mucosal immune dysfunction has a significant role in the pathogenesis of IgA nephropathy.^[55]  

The phase 3 NefigArd trial showed a statistically significant treatment benefit with targeted-release budesonide versus placebo; the time-weighted average decrease in eGFR over 2 years was 2.47 mL/min/1.73 m² with budesonide versus 7.52 mL/min/1.73 m² with placebo.^[56]  The FDA has approved targeted-release budesonide (Tarpeyo) for proteinuria reduction in adults with primary IgA nephropathy who are at risk for rapid disease progression; the FDA issued accelerated approval for this indication in 2021 and converted it to full approval in December 2023.^[57]

Sodium–glucose transporter 2 (SGLT2) inhibitors

The Dapagliflozin and Prevention of Adverse outcomes in Chronic Kidney Disease (DAPA-CKD) and the Study of Heart and Kidney Protection With Empagliflozin trials confirmed that the SGLT2 inhibitors dapagliflozin and empagliflozin have nephroprotective effects in nondiabetic patients with albuminuric chronic kidney disease, and that the benefit extended to patients with eGFR < 30 mL/min/1.73 m².^[34] Both trials included large numbers of participants with IgA nephropathy, and a pre-specified analysis of the DAPA-CKD trial affirmed that dapagliflozin reduced the risk of chronic kidney disease progression in the patients with IgA nephropathy, with a favorable safety profile.^[58]

Fish oil

Fish oil (omega-3 fatty acids) at a dose of 12 g/d has been used, with controversial and conflicting results, but it is frequently administered to patients with declining kidney function.^{[59, 22]} Deficiencies of essential fatty acids have been detected in IgA nephropathy, and fish oil is rich in long-chain omega-3 polyunsaturated fatty acids. These produce altered and less biologically effective prostaglandins and leukotrienes, as well as reduced platelet aggregation. Current evidence does not support the use of fish oil as monotherapy, but some physicians combine fish oil with other therapies. KDIGO guidelines suggest that fish oil may be given to patients who have persistent proteinuria ≥1 g/d despite 3–6 months of optimized supportive care (including ACEI or ARB treatment and blood pressure control) (grade 2D).

Calcitriol

A study by Liu examined the effect of calcitriol on urinary protein excretion in patients with IgA nephropathy. The study found that adding calcitriol to a renin-angiotensin system inhibitor resulted in a safe decrease in proteinuria.^[60]

Rituximab

CD19 B-cells are increased in IgA nephropathy. However, in a randomized controlled trial in 34 patients with proteinuria and kidney dysfunction, treatment with rituximab did not significantly improve kidney function or proteinuria over the course of 1 year. Rituximab had no significant effect on GFR, proteinuria, galactose-deficient IgA1 levels, or IgG autoantibodies. Consequently, the authors do not recommend the use of rituximab in these patients.^[61]

Miscellaneous drugs

See the list below:

• Mycophenolate mofetil: Not effective in Americans or Europeans; possibly useful in Asians.
• Azathioprine: Ineffective and possibly even harmful
• Calcineurin Inhibitors: Possibly effective; nephrotoxic and not studied in randomized controlled trials
• Adrenocorticotropic hormone (ACTH) gel (Acthar gel): A prospective pilot study of ACTH gel in a dose of 80 units subcutaneously twice weekly for 6 months reported that patients with  urinary protein >1 g/24-hour and eGFR > 30 ml/min had a significant reduction in 24-hour urinary protein with stable eGFR at 12-month follow-up^[62]
• Hydroxychloroquine: A randomized controlled study with 30 patients in each arm demonstrated that when added to optimized renin-angiotensin-aldosterone system inhibition, hydroxychloroquine significantly reduced proteinuria in patients with IgA nephropathy over 6 months without evidence of adverse events; however, the short treatment period and lack of post-withdrawal observations limit conclusions about long-term efficacy and safety.^[63]
• Cyclophosphamide: Effective in 1 small controlled study in patients with crescentic disease^[64] ; efficacy not confirmed in the STOP-IgAN trial, which excluded crescentic disease

Drug trials

Trials of the following agents are in progress or completed:

• Atacicept: Atacicept blocks the effects of BAFF (B-cell activating factor) and APRIL (a proliferation-inducing ligand), both of which are increased in IgA nephropathy and correlate with disease activity.
• OMS721: OMS721 (narsoplimab) is a human monoclonal antibody that targets mannan-binding lectin-associated serine protease–2 (MASP-2), the effector enzyme of the lectin pathway of the complement system. 

• References

Diet

A low-antigen diet, which consists of restricting dietary gluten and avoiding meats and dairy products, has been recommended to decrease mucosal antigen exposure. However, it has not been shown to preserve kidney function.

Low-protein diets have been recommended to slow the rate of progression of many nephropathies. No large trial explicitly addresses the role of low-protein diets in slowing the decline in kidney function in IgA nephropathy. The MDRD Study Group trial is the largest trial of low-protein diets to date, but it included patients with a variety of renal diseases. This trial was unable to determine whether a low-protein diet was beneficial. Although the meta-analysis of studies of low-protein diets suggests some benefits, the effects are subtle and difficult to apply to a given patient.^{[65, 66]}

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Tonsillectomy

Tonsillectomy is a controversial treatment for IgA nephropathy. Tonsillectomy may limit the production of degalactosylated IgA1 by reducing mucosal-associated lymphoid tissue (MALT). However, an Italian study found that other markers of innate immunity activation (eg, toll-like receptors) were not affected by tonsillectomy, possibly because of extra-tonsillar MALT.^[67]

A study in White patients in which 98 of 264 patients underwent tonsillectomy found that tonsillectomy may slow the progression of IgA nephropathy, but mainly in patients with macroscopic hematuria.^[68] A Japanese study in which 70 of 200 patients underwent tonsillectomy concluded that the procedure was associated with a favorable renal outcome of IgA nephropathy in terms of clinical remission and delayed renal deterioration, even in non-steroid–treated patients.^[69]

Especially in Japan, tonsillectomy has been combined with steroid pulse administration for clinical remission.^[70] Japanese guidelines from 2014 note that evidence supporting the benefit of tonsillectomy is weak, but recommend that tonsillectomy, by itself or combined with steroid pulse therapy, may be considered a treatment option.^[22]  In contrast, Kidney Disease: Improving Global Outcomes (KDIGO) guidelines suggest that tonsillectomy not be used for IgA nephropathy.^[30]  Currently, most experts reserve tonsillectomy for patients who have tonsillar infection or tonsillitis.

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Kidney Transplantation

Kidney transplantation is effective in patients with IgA nephropathy, but the disorder frequently recurs after transplantation (20-60%). The higher recurrence rates in transplantation from living related donors suggest genetic susceptibility to the disease.^[71]  

Some patients with post-transplantation IgA nephropathy present with microscopic hematuria and proteinuria, while others have only positive histologic findings. The disease usually progresses slowly, similarly to the disease in the native kidneys, and graft loss due to recurrent disease occurs in fewer than 10% of patients. There is little evidence that any specific immunosuppressive regimen decreases recurrence, but analysis of the Australia and New Zealand Dialysis and Transplant Registry (ANZDATA) suggests increased risk with steroid withdrawal.^[72]

Baek et al have reported reasonably good long-term results in patients receiving a second kidney transplant for IgA nephropathy. Recurrent disease was identified in only 2 of 28 patients during follow-up of 61.61 ± 47.23 months.^[73]

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Medication Summary

Currently, no cure exists for IgA nephropathy. However, therapies that can delay the onset of need for dialysis and transplantation are available. Hypertension should be treated early and aggressively. ACE inhibitors are the antihypertensives of choice. 

The US Food and Drug Administration (FDA) has approved the following agents to reduce proteinuria in adults with IgA nephropathy who are at risk of rapid disease progression:

• A targeted-release formulation of the corticosteroid budesonide (Tarpeyo)
• Sparsentan (Filspari), a dual angiotensin II and endothelin-1 receptor antagonist
• Atrasentan (Vanrafia), an endothelin type A receptor antagonist
• Iptacopan (Fabhalta), a complement inhibitor

• References

Iptacopan (Fabhalta)

• Dosing, Interactions, etc.

Clinical Context:  Indicated to reduce proteinuria in adults with primary IgA nephropathy who are at risk of rapid disease progression, generally a urine protein-to-creatinine ratio (UPCR) at least 1.5 g/g. 

• References

Class Summary

In immunoglobulin A (IgA) nephropathy, kidney deposition of galactose deficient IgA1-containing immune complexes locally activates the alternative complement pathway, which is thought to contribute to the pathogenesis of IgA. By binding to Factor B, iptacopan inhibits the effect of the alternative pathway.   

• References

Budesonide (Tarpeyo)

• Dosing, Interactions, etc.

Clinical Context:  Modulates numbers and activities of mucosal B-cells in the ileum, including the Peyer patches, which express glucocorticoid receptors and are responsible for the production of galactose-deficient IgA1 antibodies causing IgA nephropathy. Indicated to reduce loss of kidney function in adults with primary immunoglobulin A nephropathy who are at risk of disease progression.

• References

Prednisone (Sterapred)

• Dosing, Interactions, etc.

Clinical Context:  Immunosuppressant for treating autoimmune disorders. Decreases inflammation by reducing capillary permeability and suppressing PMN activity. Stabilizes lysosomal membranes and suppresses lymphocyte and antibody production.

• References

Class Summary

Prednisone should be used in patients with nephrotic syndrome and minimal histologic findings. When treated with corticosteroids, patients with proteinuria and preserved kidney function (ie, CrCl >70 mL/min) have shown significant delay of disease progression compared with patients not receiving corticosteroids.

• References

Benazepril (Lotensin)

• Dosing, Interactions, etc.

Clinical Context:  Prevents conversion of angiotensin I to angiotensin II, which is a potent vasoconstrictor. Also causes lower aldosterone secretion, thus reducing systemic and glomerular capillary pressure.

• References

Class Summary

Comparative studies show ACE inhibitors are more effective than other antihypertensives (ie, beta blockers, calcium channel blockers) in reducing blood pressure and proteinuria, protecting renal function, and delaying onset of ESRD.

• References

Losartan (Cozaar)

• Dosing, Interactions, etc.

Clinical Context:  Nonpeptide angiotensin II receptor antagonist that blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II. May induce a more complete inhibition of the renin-angiotensin system than ACE inhibitors, do not affect the response to bradykinin, and are less likely to be associated with cough and angioedema. For patients unable to tolerate ACE inhibitors.

• References

Class Summary

Reduce blood pressure and proteinuria, protect renal function, and delay onset of ESRD.

• References

Omega-3 polyunsaturated fatty acid (Fish oil)

• Dosing, Interactions, etc.

Clinical Context:  May be of benefit by decreasing mediators of glomerular injury and decreasing platelet aggregation.

• References

Class Summary

Orphan drug indicated for treatment of IgA nephropathy. Used in patients with proteinuria and decreased renal function.

• References

Cyclophosphamide (Neosar, Cytoxan)

• Dosing, Interactions, etc.

Clinical Context:  Cyclic polypeptide that suppresses some humoral activity. Chemically related to nitrogen mustards. Activated in the liver to its active metabolite, 4-hydroxycyclophosphamide, which alkylates the target sites in susceptible cells in an all-or-none type reaction. As an alkylating agent, the mechanism of action of the active metabolites may involve cross-linking of DNA, which may interfere with growth of normal and neoplastic cells.

Biotransformed by cytochrome P-450 system to hydroxylated intermediates that break down to active phosphoramide mustard and acrolein. Interaction of phosphoramide mustard with DNA considered cytotoxic.

When used in autoimmune diseases, mechanism of action is thought to involve immunosuppression due to destruction of immune cells via DNA cross-linking.

In high doses, affects B cells by inhibiting clonal expansion and suppression of production of immunoglobulins. With long-term low-dose therapy, affects T cell functions.

• References

Class Summary

Cyclophosphamide is used in nonmalignant renal diseases for its immunosuppressive effects.

• References

Atrasentan (Vanrafia)

• Dosing, Interactions, etc.

Clinical Context:  Endothelin type A (ET_A) receptor antagonist. Indicated to reduce proteinuria in adults with primary immunoglobulin A nephropathy (IgAN) at risk of rapid disease progression, generally a urine protein-to-creatinine ratio (UPCR) ≥1.5 g/g 

• References