IgA nephropathy is a chronic kidney disease in which an antibody called immunoglobulin A (IgA) deposits in the tiny filters of the kidneys, triggering inflammation and progressive damage. It is the most common form of primary glomerulonephritis worldwide, and it was first described by the Parisian pathologist Jean Berger in 1968, which is why older medical literature sometimes calls it Berger’s disease. The condition ranges from benign in some people to relentlessly progressive in others, and roughly a quarter to a third of those diagnosed will eventually develop kidney failure over the span of two to three decades.
How the Disease Develops
The prevailing explanation for how IgA nephropathy arises is known as the multi-hit hypothesis, a four-step chain of events. In the first step, a person produces abnormally high levels of a particular form of IgA1, one where certain sugar molecules (galactose) are missing from the antibody’s structure. This galactose-deficient IgA1 circulates in the bloodstream and acts as a kind of accidental target. In the second step, the immune system produces autoantibodies, usually IgG, that recognize and bind to this abnormal IgA1. The third step is the formation of immune complexes as these autoantibodies latch onto the galactose-deficient IgA1. In the fourth step, some of those immune complexes get trapped in the kidney’s filtering units (the glomeruli), where they activate cells in the tissue and set off inflammation that gradually scars the kidney.1PubMed Central. Pathogenesis of IgA Nephropathy: Current Understanding and Implications for Development of Disease-Specific Treatment2PubMed Central. Biomarkers for IgA nephropathy on the basis of multi-hit pathogenesis
This model has been widely supported by research, but it raises the obvious question: why do some people produce so much galactose-deficient IgA1 in the first place? That answer increasingly points to the gut.
The Gut-Kidney Connection
Most IgA in the human body is produced in the mucosal lining of the gut. A growing body of research frames IgA nephropathy as a disease driven in part by a “gut-kidney axis,” where disruptions to the intestinal immune system spill over into kidney damage. Studies in animal models have shown that gut bacteria play a pivotal role; mice genetically predisposed to produce high levels of IgA develop the disease only when their intestinal microbiome is present, not when their gut is germ-free.3PubMed. The gut-kidney axis in IgA nephropathy: role of microbiota and diet on genetic predisposition In humans, imbalances in gut bacteria appear to shift how the mucosal immune system handles IgA production, favoring the galactose-deficient forms that kick off the disease chain.4PubMed Central. Gut Microbiota and Immunoglobulin A Nephropathy: Exploration of Dietary Intervention and Treatment Strategies
This connection between the intestinal lining and the kidneys has become a central framework for understanding the disease and, as discussed later, has directly inspired new drug designs that target the gut immune response rather than just suppressing the immune system broadly.5PubMed Central. Precision targeting of gut-kidney axis: mucosal immunomodulation in IgA nephropathy-a perspective
Who Gets It and Why Geography Matters
IgA nephropathy can appear at any age but is most commonly diagnosed between the ages of 15 and 30, with men affected more often than women in most populations. One of its most striking features is geographic variation. The disease is far more common in East Asian and Pacific Rim populations than in people of European descent, and it is relatively uncommon in people of African ancestry. This gradient is not just about diagnostic practices or biopsy rates; it tracks with genetic susceptibility. Large genome-wide association studies have identified dozens of gene regions linked to IgA nephropathy risk. A genetic risk score built from these regions is highest in Asian populations, intermediate in Europeans, and lowest in Africans, mirroring the prevalence pattern closely.6Clinical Kidney Journal. Ethnicity and IgA nephropathy: worldwide differences in epidemiology, timing of diagnosis, clinical manifestations, management and prognosis
Some of the susceptibility genes make biological sense. One risk locus sits near a gene called ST6GAL1, which is involved in modifying sugar groups on proteins, a process directly relevant to how galactose-deficient IgA1 is produced. Another cluster is in the DEFA gene region, which encodes defensins, antimicrobial proteins active in the gut lining. Risk variants at both of these loci show frequency differences across global populations that correlate with geographic differences in disease prevalence.7Nature Communications. Identification of new susceptibility loci for IgA nephropathy in Han Chinese A separate genome-wide meta-analysis identified additional loci implicating immune-regulation genes and confirmed significant genetic heterogeneity between Asian and European populations.8PubMed Central. Genome-Wide Meta-Analysis Identifies Three Novel Susceptibility Loci and Reveals Ethnic Heterogeneity of Genetic Susceptibility for IgA Nephropathy
Symptoms and How the Disease Shows Up
IgA nephropathy often announces itself during or shortly after a throat or upper respiratory infection. The hallmark presentation is visible blood in the urine occurring alongside acute pharyngitis, sometimes called “synpharyngitic hematuria.”9PubMed. The epipharynx-kidney axis triggers glomerular vasculitis in immunoglobulin A nephropathy The urine can look pink, brown, or tea-colored, and the episode often resolves within days. Many people dismiss it as a one-off event and never seek evaluation, which is one reason the disease can go undetected for years.
Outside of these dramatic flares, the disease frequently produces no noticeable symptoms at all. Microscopic blood in the urine and protein leaking into the urine (proteinuria) are the two most common findings on routine urinalysis, and they are often discovered incidentally during checkups. Proteinuria in particular is both a marker and a driver of kidney damage: the more protein spills into the urine, the faster kidney function tends to decline.
Diagnosis Still Requires a Biopsy
There is no blood test that can definitively diagnose IgA nephropathy. The gold standard remains a kidney biopsy, in which a small sample of tissue is examined under a microscope with special staining. The defining feature is the presence of IgA deposits in the mesangium, the tissue between the capillary loops in the kidney’s filtering units.
Once a biopsy is obtained, pathologists score the tissue using the Oxford Classification, which grades four (sometimes five) types of lesions: mesangial hypercellularity (M), endocapillary hypercellularity (E), segmental sclerosis (S), tubular atrophy and interstitial fibrosis (T), and crescents (C). Among these, T and S have the strongest and most consistent association with long-term outcomes. In one multivariate analysis, S and T lesions carried hazard ratios of roughly 3.8 and 6.4, respectively, for progression to kidney failure.10PubMed Central. Utilizing the MEST score for prognostic staging in IgA nephropathy A systematic review of the Oxford Classification found that while T scores were reproducible across pathologists, agreement on M, S, E, and C was more variable, and in about a quarter of studied outcomes none of the scores predicted progression at all.11PubMed Central. Systematic Review of the Oxford Classification of IgA Nephropathy: Reproducibility and Prognostic Value
Researchers are actively pursuing blood and urine tests that could supplement or eventually replace biopsies for diagnosis. Galactose-deficient IgA1 levels in the blood are elevated in many patients, but the test is not specific enough on its own. Newer candidates include VLA-4 and VEGFD, serum proteins that in one comparative study distinguished IgA nephropathy from other kidney diseases with about 85% accuracy and outperformed galactose-deficient IgA1 measurement.12PubMed Central. Novel Biomarkers as Non-Invasive Diagnostic Tools in IgA Nephropathy: A Comparative Study with Lupus Nephritis and Membranous Nephropathy Urinary biomarkers such as TYROBP and HCK have also shown promise in early validation.13PubMed Central. Urinary TYROBP and HCK as genetic biomarkers for non-invasive diagnosis and therapeutic targeting in IgA nephropathy None of these are ready for clinical use yet, but the field is moving steadily toward non-invasive diagnosis.14PubMed. New biomarkers in IgA nephropathy
Predicting Who Will Progress
One of the most frustrating aspects of IgA nephropathy for patients and doctors alike is its unpredictability. Some people live decades with stable kidney function and only microscopic blood in the urine. Others progress to kidney failure within a few years. The International IgA Nephropathy Prediction Tool, endorsed by the 2021 KDIGO guidelines, was developed in a cohort of nearly 2,800 adults and combines clinical data (kidney function, blood pressure, proteinuria at biopsy), biopsy findings, age, and medications to estimate the risk of losing half of kidney function or reaching kidney failure.15JAMA Internal Medicine. Evaluating a New International Risk-Prediction Tool in IgA Nephropathy It performs well at the time of biopsy, with a concordance statistic (a measure of prediction accuracy) around 0.82 on external validation.
The tool was originally designed for use at the moment of biopsy, which left a gap for patients already under observation. An updated version re-calibrated for use one or two years after biopsy showed improved prediction performance, with concordance statistics reaching 0.85–0.87 in validation cohorts.16PubMed. Application of the International IgA Nephropathy Prediction Tool one or two years post-biopsy Machine learning approaches have also shown comparable accuracy and flagged urine protein excretion, global sclerosis, and tubular atrophy as the strongest individual predictors.17PubMed. Prediction and Risk Stratification of Kidney Outcomes in IgA Nephropathy
Foundational Treatment and SGLT2 Inhibitors
The first-line management of IgA nephropathy revolves around controlling blood pressure and reducing proteinuria. Drugs that block the renin-angiotensin system (RAS), such as ACE inhibitors and angiotensin receptor blockers (ARBs), have been the backbone of treatment for years. Dietary sodium restriction (below 2 grams per day) and avoidance of high-protein diets are standard recommendations. Fish oil supplements have been studied repeatedly, but the evidence remains conflicting, and a gluten-free diet, while it may reduce IgA immune complexes, has not demonstrated lasting kidney benefit in patients without celiac disease.18American Journal of Kidney Diseases. Current and Emerging Therapies for IgA Nephropathy: A Comprehensive Review – Section: Conservative/Supportive Care
A significant recent addition to supportive care is SGLT2 inhibitors, a class of drugs originally developed for diabetes that turned out to protect kidneys across a wide range of diseases. Two large randomized trials, DAPA-CKD and EMPA-KIDNEY, included patients with IgA nephropathy and showed that these drugs reduced proteinuria, stabilized kidney function trajectories, and lowered the risk of progression.19PubMed Central. Efficacy of SGLT2 inhibitors in preventing end-stage kidney disease in patients with IgA nephropathy: a scoping review A subanalysis of the DAPA-CKD trial, which included 270 patients with IgA nephropathy, provided early evidence that dapagliflozin is safe and effective as an add-on to existing care.20PubMed. SGLT-2 inhibition in IgA nephropathy: the new standard of care? Many nephrologists now consider SGLT2 inhibitors part of the standard package for managing the disease.
Corticosteroids and the Risk-Benefit Calculation
For patients whose proteinuria stays above a gram per day despite optimal supportive care, the question of immunosuppression comes up. The TESTING trial, a large randomized study, showed that a 6- to 9-month course of oral methylprednisolone significantly reduced the risk of kidney function decline, kidney failure, or death from kidney disease compared with placebo. The kidney benefits were consistent whether patients received the original full dose or a reduced-dose protocol, but adverse events, including serious infections, were higher in the steroid groups. The reduced-dose regimen carried fewer side effects than the full dose while preserving the protective effect on kidneys.21JAMA. Effect of Oral Methylprednisolone on Decline in Kidney Function or Kidney Failure in Patients With IgA Nephropathy: The TESTING Randomized Clinical Trial22PubMed Central. The Efficacy and Safety of Reduced-Dose Oral Methylprednisolone in High-Risk Immunoglobulin A Nephropathy
A meta-analysis of steroid trials confirmed that low-dose glucocorticoids reduce both proteinuria and the risk of reaching end-stage kidney disease, but also noted that newer targeted approaches may achieve similar benefits with fewer systemic side effects.23PubMed Central. Efficacy and safety of steroids glucocorticoids compared with supportive therapy for IgA nephropathy: a systematic review and meta-analysis That observation has pushed the field toward disease-specific drugs rather than broad immunosuppression.
Disease-Specific Drugs Now Reaching Patients
Two drugs have emerged from clinical trials with strong enough data to reshape how IgA nephropathy is treated. The first is targeted-release budesonide (marketed as Nefecon), a formulation of a corticosteroid designed to release specifically in the lower part of the small intestine, where much of the IgA-producing immune tissue sits. In the phase 2b NEFIGAN trial, 16 mg per day of this formulation reduced proteinuria by about 24% compared with placebo over 9 months, on top of existing blood-pressure-lowering therapy.24The Lancet. Targeted-release budesonide versus placebo in patients with IgA nephropathy (NEFIGAN): a double-blind, randomised, placebo-controlled phase 2b trial The phase 3 NefIgArd trial confirmed these benefits over a two-year follow-up, and the drug became the first therapy approved specifically for IgA nephropathy, targeting the gut mucosal immune system upstream of kidney damage.25The Lancet. Targeted-release budesonide versus placebo in patients with primary IgA nephropathy (NefIgArd): a 2-year, randomised, double-blind, placebo-controlled phase 3 trial
The second drug is sparsentan, a single molecule that blocks two receptor systems at once: the endothelin A receptor and the angiotensin II receptor. In the phase 3 PROTECT trial, sparsentan reduced proteinuria by about 40% more than maximally dosed irbesartan (a standard ARB) over 110 weeks, while also preserving kidney function better than the comparator.26PubMed. Efficacy and safety of sparsentan versus irbesartan in patients with IgA nephropathy (PROTECT): 2-year results from a randomised, active-controlled, phase 3 trial Unlike budesonide, sparsentan does not suppress the immune system; it works by reducing pressure and permeability in the kidney’s filtering units.
Complement and APRIL Inhibitors on the Horizon
Beyond the drugs already approved, the pipeline for IgA nephropathy has expanded dramatically. Two major biological pathways have attracted the most attention. The first is the complement system, a part of the immune system’s inflammatory cascade that amplifies damage once immune complexes deposit in the kidney. The alternative pathway appears to be the dominant route of complement activation in IgA nephropathy.27PubMed Central. Advances in Complement-Targeted Therapy for IgA Nephropathy Iptacopan, an oral inhibitor of complement Factor B, showed sustained proteinuria reduction and strong complement pathway suppression in a phase 2 trial, with no reports of serious infections or treatment-related serious adverse events.28PubMed. Results of a randomized double-blind placebo-controlled Phase 2 study propose iptacopan as an alternative complement pathway inhibitor for IgA nephropathy Sefaxersen, an antisense inhibitor also targeting Factor B, has shown promising phase 2 results including reduced proteinuria and improved hematuria.29PubMed. The expanding role of complement inhibitors in the treatment of IgA nephropathy
The second pathway involves APRIL and BAFF, two signaling molecules that keep B cells alive and drive IgA production. APRIL in particular has been directly linked to the production of galactose-deficient IgA1.30Frontiers in Nephrology. The role of BAFF and APRIL in IgA nephropathy: pathogenic mechanisms and targeted therapies Sibeprenlimab, a monoclonal antibody that neutralizes APRIL, showed encouraging results in a phase 2 trial and is now in phase 3 testing.31PubMed Central. A Phase 2 Trial of Sibeprenlimab in Patients with IgA Nephropathy If complement and APRIL-targeted drugs prove effective in phase 3, the treatment landscape for IgA nephropathy could look radically different within a few years, with multiple mechanism-specific options layered on top of supportive care.
IgA Nephropathy After Kidney Transplant
Kidney transplantation cures the kidney failure but does not fix the underlying immune abnormality. The disease can recur in a transplanted kidney because the recipient’s immune system continues producing the pathogenic IgA1 and autoantibodies. In one large study of 504 transplant recipients, the cumulative incidence of biopsy-confirmed IgA recurrence was about 23% at 15 years. Patients with recurrence had nearly four times the risk of graft loss compared with those without, and roughly a third lost their transplant within 8 years of the recurrence diagnosis.32PubMed Central. Recurrence of IgA Nephropathy after Kidney Transplantation in Adults Smaller single-center analyses report recurrence rates in a similar range, around 15–21%, though some do not reach statistical significance for worse graft outcomes due to limited sample size.33PubMed Central. Early post-transplant serum IgA level is associated with IgA nephropathy recurrence after kidney transplantation34Renal Replacement Therapy. IgA nephropathy recurrence after living donor kidney transplantation: a retrospective analysis of postoperative outcomes at a single high-volume transplant center
Recurrence does not always mean graft loss; many recurrences are detected early and managed with intensified supportive therapy. But the possibility underscores why so much research energy is being directed at upstream immune targets: a drug that truly reduced galactose-deficient IgA1 production could protect both native and transplanted kidneys.
The Relationship With IgA Vasculitis
IgA vasculitis (formerly called Henoch-Schönlein purpura, or HSP) is a condition mainly seen in children that involves IgA deposits not just in the kidneys but in the walls of small blood vessels throughout the body, causing a distinctive skin rash, joint pain, and abdominal symptoms. The kidney involvement in IgA vasculitis looks nearly identical to IgA nephropathy under the microscope, and the two conditions share many biological abnormalities. They have even been reported in twins and in the same patient at different times.35PubMed. What is the difference between IgA nephropathy and Henoch-Schönlein purpura nephritis?
Whether the two are truly the same disease at different points on a spectrum or two separate diseases that share a final common pathway remains debated. IgA nephropathy typically appears in young adults and presents with isolated kidney findings, while IgA vasculitis peaks in childhood and involves multiple organs. Some research suggests the conditions may differ in their developmental mechanisms; one cross-sectional study found that patients with IgA vasculitis nephritis had significantly more inflammation inside the glomerular capillaries and different patterns of IgA deposition compared with IgA nephropathy patients, and the factors driving galactose-deficient IgA1 were not consistent between the two diseases.36PLOS ONE. A cross-sectional analysis of clinicopathologic similarities and differences between Henoch-Schönlein purpura nephritis and IgA nephropathy Other reviews conclude they likely represent different ends of a continuous disease spectrum.37PubMed Central. IgA Vasculitis and IgA Nephropathy: Same Disease? For patients, the practical difference matters most: if you had IgA vasculitis as a child, you carry some elevated risk of kidney involvement later, and long-term follow-up of urine tests is worthwhile.
How the Disease Differs in Children
IgA nephropathy in children tends to look different than in adults, both in how it presents and in what the biopsy shows. Children more commonly arrive at diagnosis after an episode of visible blood in the urine triggered by a throat infection. Their biopsies tend to show more acute inflammatory changes and less chronic scarring, which makes sense given that they have had less time living with the disease before someone investigates.38PubMed Central. IPNA clinical practice recommendations for the diagnosis and management of children with IgA nephropathy and IgA vasculitis nephritis
The natural history across ages is not identical either. While some children have a benign course with proteinuria and hematuria that resolves or stabilizes, others follow trajectories that differ from adult patterns, and the predictors of progression may not be the same. Recent clinical practice recommendations from the International Pediatric Nephrology Association now provide guidance specifically tailored to children, acknowledging that adult treatment protocols cannot simply be transplanted to younger patients.39PubMed. IgAN Across the Age Spectrum: The Pediatric Perspective For families, the reassuring piece is that many children diagnosed with IgA nephropathy do well long-term, though lifelong monitoring of kidney function and urine protein is still recommended.
Secondary IgA Nephropathy
Not every case of IgA deposits in the kidneys is “primary” IgA nephropathy. IgA deposition can also occur alongside other diseases, including liver cirrhosis, celiac disease, inflammatory bowel disease, certain infections, and some cancers. Whether these secondary forms arise through the same galactose-deficient IgA1 pathway or through entirely separate mechanisms remains an open question.40PubMed Central. Secondary IgA nephropathy In some cases, treating the underlying condition (for example, a gluten-free diet in celiac disease or antiviral therapy in hepatitis) can reduce or eliminate the kidney deposits. Distinguishing primary from secondary forms matters because the treatment strategy depends on it, and a biopsy showing IgA deposits should always prompt a clinical search for possible underlying causes before labeling the disease as primary.