Kidney transplants can free patients of IgA nephropathy in their own kidneys, but the disease often comes back in the donated organ, and the powerful drugs that now tame the native illness were never tested in these recipients. A new review published in Transplant International argues that recurrent IgA nephropathy has become an underrecognized cause of allograft loss precisely as transplant survival improves, leaving clinicians to manage it with case reports, small series and registry data rather than evidence from dedicated trials.
The authors, a group of transplant nephrologists led by Paolo Cravedi of the Icahn School of Medicine at Mount Sinai, describe a widening gap between native and post-transplant care. Over the past decade, IgA nephropathy has attracted more targeted therapies than any other primary glomerular disease. In 2021 the United States Food and Drug Administration granted accelerated approval to targeted-release budesonide, the first drug approved for the condition, and at least five additional molecules have since followed. In 2025, the Kidney Disease: Improving Global Outcomes initiative updated its IgA nephropathy guidelines and then, only six months later, issued a further commentary adding B-cell modulators to the treatment algorithm. Kidney transplant recipients were excluded from the pivotal trials behind these advances, so none of this momentum has translated into approved options for recurrent disease.
How often the disease returns depends heavily on how hard doctors look. Jean Berger, the physician credited with identifying IgA nephropathy, described recurrence in 17 of 32 transplant patients, or 53.1 percent, all of whom underwent serial protocol biopsies. Modern registries report more conservative figures, typically 20 to 30 percent at 10 to 15 years after transplantation. One registry within the Post-Transplant Glomerular Diseases, or TANGO, consortium followed 504 recipients with biopsy-proven native IgA nephropathy across 16 centers in Europe, North America and South America and found a cumulative recurrence incidence of 23 percent at 15 years; 95 percent of the recurrences were detected on for-cause rather than protocol biopsies. By contrast, the Australia and New Zealand Dialysis and Transplant registry reported an incidence of only 10.8 percent at 10 years, a difference the review attributes to variation in biopsy ascertainment, diagnostic classification, population homogeneity and sample size.
Histologically, recurrence spans a spectrum from isolated mesangial IgA deposition without light-microscopic changes, often found incidentally on protocol biopsies in stable recipients, to mesangioproliferative, endocapillary proliferative and crescentic glomerulonephritis. Mesangial deposits alone do not invariably predict progressive allograft dysfunction, and patients presenting with proteinuria and declining graft function frequently turn out to have concurrent problems such as chronic antibody-mediated rejection, transplant glomerulopathy, calcineurin inhibitor toxicity or interstitial fibrosis and tubular atrophy. Because IgA deposits carry limited prognostic weight on their own, clinicians increasingly apply the Oxford MEST-C classification, developed and validated in native disease, to allograft biopsies. In 57 North American recipients with recurrent IgA nephropathy, a higher total MEST-C score was associated with death-censored graft failure, with an adjusted hazard ratio of 8.57 for scores of 2 to 3 and 61.32 for scores of 4 to 5 compared with a score of zero; the individual E, T and C components were each also significant.
The most consistent risk factors for recurrence point to a native disease that was either aggressive or had not yet quieted when the transplant took place: younger age at transplantation, a shorter interval from IgA nephropathy diagnosis to kidney failure, preemptive transplantation and a shorter time on dialysis. Preformed donor-specific antibodies at transplantation were associated with recurrence in the TANGO cohort, with a hazard ratio of 2.74, and de novo donor-specific antibodies after transplantation carried an even larger hazard ratio of 6.05. The authors propose inadequate immunosuppression as a shared driver of both antibody formation and recurrence, but they caution that these estimates rest on small numbers of antibody-positive patients who experienced recurrence.
Whether maintenance corticosteroids protect against recurrence remains contested, and much of the argument traces to two large but methodologically similar registry analyses. An ANZDATA survival analysis of 1,521 first-transplant recipients with IgA-related kidney failure, modeling steroid use as a time-varying covariate, found steroid use associated with a markedly reduced risk of recurrence-related graft loss, with a subhazard ratio of 0.50. An analysis of 9,690 United Network for Organ Sharing and Organ Procurement and Transplantation Network recipients similarly reported higher recurrence-attributable graft loss with early steroid withdrawal, with a subhazard ratio of 0.666, though overall patient and death-censored graft survival did not differ between groups. Neither study adjusted for induction immunosuppression, a structural limitation the review stresses, since steroid-avoidance protocols are rarely implemented in isolation; notably, in the ANZDATA cohort only 26 percent of patients received induction therapy, and none of those who did lost the graft to IgA nephropathy. More rigorous designs, including a propensity-matched United States Renal Data System analysis, a single-center steroid-free protocol with a 13.6 percent recurrence rate comparable to national benchmarks, and the TANGO multivariable analysis, found no significant association between steroid withdrawal and recurrence.
When recurrence does occur, the allograft pays a substantial price. In an ANZDATA cohort of 2,501 IgA nephropathy transplant recipients, five-year death-censored graft survival after recurrence was only 58 percent, comparable to focal segmental glomerulosclerosis and membranous nephropathy but considerably better than membranoproliferative glomerulonephritis at 30 percent. TANGO data showed 10-year death-censored graft survival of 76 percent among patients with recurrence versus 89 percent among those without. Because recurrence can only be diagnosed after transplantation, a naive comparison of survival curves favors the recurrence group through immortal time bias; when the TANGO investigators modeled recurrence as a time-varying covariate to correct for this, the adjusted hazard ratio for graft loss reached 3.7, suggesting the true impact of recurrence is considerably greater than simple survival curves imply.
The review also reframes why the disease returns despite immunosuppression that successfully prevents rejection. IgA nephropathy is now understood through a four-hit cascade that begins with overproduction of a galactose-deficient IgA1 variant, which is recognized by anti-glycan autoantibodies to form circulating immune complexes that deposit in the mesangium and drive injury. Central to the first two hits are B cells and plasma cells regulated by two cytokines of the tumor necrosis factor superfamily, B-cell-activating factor and a proliferation-inducing ligand. Translational studies have correlated elevated levels of these cytokines with elevated galactose-deficient IgA1, and murine models support their mechanistic roles: mice overexpressing BAFF develop an IgA-dominant glomerulonephritis with abnormally glycosylated circulating IgA, while APRIL-deficient and TACI-deficient mice show reduced IgA levels. Conventional transplant immunosuppression suppresses T-cell activation and indirectly inhibits B-cell responses but has relatively limited effects on long-lived plasma cells and the mucosal immune compartments responsible for ongoing production of the pathogenic IgA, a biological mismatch that plausibly explains why recurrent disease develops despite adequate rejection prevention.
Biomarker evidence mirrors this biology but remains immature. A recent meta-analysis pooling eight studies found serum galactose-deficient IgA1 levels significantly higher overall in patients who developed recurrence than in those who did not, with a standardized mean difference of 0.50, while pretransplant levels did not differ significantly between groups. In a cohort of 33 patients with biopsy-proven native IgA nephropathy undergoing transplantation, pretransplant serum APRIL levels did not differ between those who later developed recurrence and those who did not, but mean post-transplant APRIL levels remained persistently elevated in the recurrence group for up to three years. These findings suggest both markers may hold more value as post-transplant indicators of active disease than as pretransplant risk-stratification tools, though the evidence comes from small cohorts with variable follow-up and non-standardized assays.
Treatment experience after transplantation is early and mixed. Case reports and small series of targeted-release budesonide showed slowed eGFR decline and significant proteinuria reduction with reasonable tolerability, though the largest reported experience, a 10-patient cohort in Parma, Italy, observed no meaningful benefit, and the investigators note that cohort used a controlled-release inflammatory bowel disease formulation rather than the one studied in the NEFIGARD trial. Iptacopan, a complement factor B inhibitor approved for native disease after the APPLAUSE-IgAN trial showed an annualized eGFR slope of minus 3.10 versus minus 6.12 milliliters per minute per 1.73 square meters with placebo, has produced striking histologic responses in isolated cases, including resolution of active inflammatory activity in a patient with refractory crescentic recurrence, but a five-patient series found reduced glomerular complement deposition was not consistently accompanied by proteinuria improvement. The most substantial post-transplant data belong to telitacicept, a TACI-Ig fusion protein blocking both BAFF and APRIL: a retrospective series of 10 Chinese patients achieved complete or partial remission in four, with proteinuria reductions exceeding 30 percent in 60 percent overall and stable renal function in nine of ten through 12 months, though one patient developed antibody-mediated rejection, and a larger prospective single-arm cohort of 25 recipients reported reductions in 24-hour urinary protein and urine albumin-to-creatinine ratio of 51.6 percent and 62.7 percent by week 28. The authors conclude that progress will require harmonized registries, validated biomarkers, industry collaboration and dedicated randomized trials in transplant recipients, so that kidney transplant patients no longer remain therapeutic orphans in an era of targeted IgA nephropathy therapy.
Subject of Research: Recurrence of IgA nephropathy after kidney transplantation and the lack of transplant-specific evidence for targeted therapies
Article Title: Recurrence of immunoglobulin A nephropathy after kidney transplantation: a therapeutic gap in the era of targeted therapies
Article References: Sanchez-Russo, L., Vasquez-Rios, G., Riella, L. V., & Cravedi, P. (2026). Recurrence of immunoglobulin A nephropathy after kidney transplantation: a therapeutic gap in the era of targeted therapies. Transplant International, 39, Article 17469. https://doi.org/10.3389/ti.2026.17469
Image Credits: AI Generated
Keywords: IgA nephropathy, kidney transplantation, graft survival, recurrence, BAFF, APRIL, complement inhibition, targeted-release budesonide, telitacicept, biomarkers, TANGO consortium, immunosuppression
News Source: Ophelia Keating. (November 5, 2026). Kidney transplant patients with IgA nephropathy still lack proven treatments as recurrence erodes graft survival. Scienmag.
