The previous decade has seen substantial advancement in the treatment of immunoglobulin A nephropathy (IgAN), with more targeted therapies developed than for any other primary glomerulonephritis (GN). The recognition of IgAN as a more aggressive condition than previously believed, even in patients with only moderate proteinuria [1, 2], combined with the acceptance of proteinuria as a surrogate endpoint for clinical trials [3], has attracted investment and driven innovation in a field where only repurposed therapies from other diseases had previously been explored. In 2021, the United States Food and Drug Administration (FDA) granted accelerated approval for targeted-release budesonide for the treatment of IgAN, the first medication approved for this disease [4]. Since then, the FDA has not only granted full approval to this molecule, but has also granted accelerated or full approval to at least five additional molecules for the treatment of IgAN as of this writing. In 2025, the Kidney Disease: Improving Global Outcomes (KDIGO) updated its guidelines on IgAN, only to release a commentary 6 months later updating the treatment algorithm to include B-cell modulators [5, 6], a testament to the rapidly evolving landscape of IgAN.

The advancements in the treatment of recurrent IgAN following kidney transplantation do not parallel those seen in native disease. This is due, in part, to the exclusion of kidney transplant recipients from clinical trials on IgAN [7]. As long-term allograft survival improves, recurrent IgAN is becoming an increasingly important contributor to late graft dysfunction, yet management remains guided by isolated case reports, small case series, and expert opinion. Herein, we review the epidemiology, pathogenesis, and clinical impact of recurrent IgAN, summarize lessons from available registries, and discuss the emerging role of disease-specific therapies in the transplant setting.

In IgAN, a sequence of pathogenic events culminates in the deposition of immune complexes within the renal mesangium, triggering mesangial cell activation and proliferation, release of pro-inflammatory cytokines, and complement activation, ultimately manifesting as glomerular injury and fibrosis. This cascade is conceptualized as the “four-hit hypothesis,” which begins with the overproduction and increased circulation of a pathogenic IgA variant deficient in galactose (Gd-IgA1) within the O-glycans of the hinge region [26–30]. The exposed N-acetylgalactosamine residues on Gd-IgA1 are recognized by anti-glycan autoantibodies, predominantly immunoglobulin G (IgG) and, to a lesser extent, IgA, and this interaction generates circulating immune complexes that deposit in the mesangium, driving renal injury (Figure 1) [31].

Although circulating Gd-IgA1 levels are higher on average in IgAN, substantial overlap with healthy individuals limits the diagnostic and prognostic performance of current assays and suggests that Gd-IgA1 concentration alone is insufficient to explain disease expression [32–36]. Mass spectrometry can provide more detailed, site-specific characterization of IgA1 glycoforms, but its analytical complexity and limited throughput currently constrain large-scale clinical implementation [37]. Some studies also identified Gd-IgA1 directly targeting mesangial antigens, which would not require the formation of immune complexes for disease initiation and progression [38–40].

Central to the first two hits of this cascade are B-cells and plasma cells. Over the past decade, a substantial body of evidence has shifted attention away from the immune complexes themselves and toward the aberrant B-cell biology responsible for generating Gd-IgA1 in the first place, implicating dysregulated cytokine signaling in B-cell maturation, class-switching, and survival [41–43]. Two cytokines of the tumor necrosis factor (TNF) superfamily, B-cell-activating factor (BAFF) and a proliferation-inducing ligand (APRIL), have emerged as particularly important regulators of IgA biology and IgAN pathogenesis, positioning them as candidate upstream therapeutic targets. BAFF acts primarily through the BAFF receptor (BAFF-R) and is critical to the maturation of transitional B-cells, while APRIL binds with high affinity to transmembrane activator and calcium-modulating cyclophilin ligand interactor (TACI) and B-cell maturation antigen (BCMA), both more highly expressed at later stages of B-cell maturation; APRIL signaling through these receptors drives class-switch recombination and supports the long-term survival of memory B-cells and plasma cells [44].

Both cytokines have been implicated in IgAN pathogenesis through translational studies correlating elevated BAFF and APRIL levels with elevated Gd-IgA1, and through murine models that illustrate their mechanistic roles: BAFF-transgenic mice overexpressing BAFF develop an IgA-dominant GN with abnormally glycosylated circulating IgA, while APRIL-deficient and TACI-deficient mice show reduced IgA levels [42, 45–50].

The growing recognition that Gd-IgA1 production by B-cells and plasma cells is affected by BAFF/APRIL axis, has provided the rationale for BAFF and APRIL targeted therapies in IgAN. Sibeprenlimab, an APRIL inhibitor, received FDA accelerated approval in November 2025 based on proteinuria reduction in phase 3 data [51], and atacicept, a TACI-Ig fusion protein that blocks both BAFF and APRIL, followed with its own FDA accelerated approval in July 2026 [52, 53]. Taken together, this evidence reframes IgAN less as a disease of immune complex deposition per se, and more fundamentally as one of dysregulated B-cell and plasma cell biology, a framing directly relevant to the question of why disease recurs after transplantation despite immunosuppressive regimens.

The persistence of disease despite successful transplantation highlights a fundamental distinction between alloimmunity and autoimmunity. Conventional immunosuppressive regimens effectively suppress T-cell activation and indirectly inhibit B-cell responses but have relatively limited effects on long-lived plasma cells and mucosal immune compartments responsible for ongoing Gd-IgA1 production. This biological mismatch provides a plausible explanation for why recurrent IgAN develops despite adequate prevention of rejection and further supports targeting upstream B-cell and plasma-cell pathways.

Biomarkers of post-transplant IgAN recurrence largely mirror those implicated in native disease. Elevated levels of Gd-IgA1 and APRIL have both been reported in patients with recurrent IgAN following kidney transplantation; however, their association with recurrence risk has so far been reported only in small cohorts with variable follow-up periods and non-standardized assay measurements [9, 54]. Notably, Gd-IgA1 deposition has been detected in renal allografts biopsied as early as 1 hour post-transplantation [55]. A recent meta-analysis pooling eight studies found that serum Gd-IgA1 levels were significantly higher overall in patients who developed recurrence than in those who did not (standardized mean difference 0.50, 95% CI 0.15–0.85, p = 0.005). Pretransplant levels, by contrast, did not differ significantly between groups [56]. Together, these findings suggest Gd-IgA1 may hold more value as a post-transplant marker of active recurrence than as a pretransplant risk-stratification tool.

APRIL has similarly been investigated as a candidate biomarker. In a cohort of 33 patients with biopsy-proven native IgAN undergoing kidney transplantation, pretransplant serum APRIL levels did not differ significantly between patients who would later develop recurrence and those who would not (15.6 ± 15.7 pg/mL vs. 16.8 ± 10.8 pg/mL, p = 0.611); however, mean post-transplant APRIL levels remained persistently elevated in the recurrence group for up to 3 years [57]. As with Gd-IgA1, this suggests that serial post-transplant monitoring, rather than a single pretransplant measurement, may ultimately prove more clinically useful once a validated, commercially available assay is developed.

Future biomarker development will likely extend beyond circulating Gd-IgA1 and APRIL measurements. Integration of donor-derived cell-free DNA, urinary immune biomarkers, complement activation products, tissue immune phenotyping, multiplex imaging, and spatial transcriptomic approaches may allow improved discrimination between active recurrent disease, concomitant alloimmune injury, and irreversible chronic scarring. Incorporation of these biomarkers into prospective transplant cohorts will be essential for biomarker qualification and treatment-response monitoring.

As understanding of the key upstream drivers of IgAN pathogenesis and downstream mechanisms of injury continues to grow, the therapeutic portfolio for native IgAN has expanded considerably, with an array of B-cell and plasma cell modulators either approved or in advanced stages of study [51, 58–61].

Systemic steroids remain an option for IgAN, but their safety profile continues to weigh the balance toward targeted-release budesonide for many patients. This concern is well illustrated by the TESTING trial, in which the original methylprednisolone dosing regimen (0.6–0.8 mg/kg/day) had to be reduced partway through the study (to 0.4 mg/kg/day) after an excess of serious infections, including deaths, emerged in the treatment arm. Even at the reduced dose, methylprednisolone significantly lowered the risk of the composite outcome of kidney function decline, kidney failure, or death due to kidney disease compared with placebo [62], and significantly reduced Gd-IgA1 levels [63]. A substantial component of pathogenic IgA production is thought to arise from dysregulated mucosal immune responses, particularly in the gut-associated lymphoid compartment, although circulating and bone-marrow plasma cells may also contribute. Therefore, a targeted-release steroid formulation, budesonide, has been developed to reduce systemic toxicity. Targeted-release budesonide was the first medication to receive FDA approval for the treatment of IgAN and is displacing the use of systemic steroids given its efficacy in proteinuria reduction, Gd-IgA1 reduction, and eGFR decline, alongside a more favorable safety profile compared to systemic corticosteroids [64].

The growing recognition of the importance of the complement system as an effector mechanism of injury in IgAN [65], has driven the use of complement directed therapy in IgAN. Iptacopan, a complement factor B inhibitor, significantly slowed kidney function decline in the APPLAUSE-IgAN trial, with an annualized total eGFR slope of −3.10 mL/min/1.73 m² with iptacopan compared with −6.12 mL/min/1.73 m² with placebo [66].

Notably, all of these pivotal trials excluded patients with recurrent post-transplant IgAN. As a result, no established guidelines exist for treating recurrence, and experience with both newer agents and older immunosuppressants such as cyclophosphamide remains largely anecdotal. Registry data indicate that most patients diagnosed with recurrence are managed with supportive care directed at non-specific drivers of nephron loss, such as angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs), with only a minority started on additional immunosuppression [12]. It is worth noting that this registry data predate the modern treatment paradigm for native IgAN, which now favors earlier initiation of disease-specific therapy alongside supportive care with ACE inhibitors, ARBs, or sodium-glucose cotransporter 2 (SGLT2) inhibitors.

Experience in using targeted-release budesonide in treating post-transplant IgAN is largely limited to case reports and small case series [67, 68]. In these reports, targeted-release budesonide slowed eGFR decline and significantly reduced proteinuria, and appeared reasonably well tolerated; hyperglycemia and fluid overload were reported but did not lead to treatment discontinuation. Notably, none of these patients had changes made to their maintenance immunosuppression, and low-dose systemic prednisone was continued alongside targeted-release budesonide. To our knowledge, the largest reported experience comes from a cohort of 10 patients treated at the University of Parma, Italy. In this cohort, investigators observed no meaningful reduction in proteinuria or improvement in eGFR; it is important to note, however, that the formulation used differed from that studied in the NEFIGARD trial, employing a controlled-release budesonide formulation typically used to treat inflammatory bowel disease [69].

Experience with iptacopan in post-transplant IgAN recurrence is similarly confined to case reports and small case series. In one report, iptacopan was used in a patient with recurrence refractory to aggressive immunosuppression, including rituximab, cyclophosphamide, and systemic steroids; after this therapeutic failure, with active crescentic IgAN on biopsy, the patient was started on iptacopan with penicillin prophylaxis, and a follow-up biopsy at 48 months post-transplant showed features of chronic injury but resolution of active inflammatory activity [70]. A separate case series of three patients treated with iptacopan alongside a short course of high-dose prednisone showed significant proteinuria reduction in two of the three [71]. A larger case series of five patients offered a more tempered picture: iptacopan produced a marked reduction in glomerular C5b-9 and C3 deposition on repeat biopsy within 6–12 months, but this histologic response was not consistently accompanied by proteinuria improvement, suggesting complement blockade may attenuate ongoing immune-mediated injury without necessarily producing an early clinical response [72]. Across these reports, no patients underwent changes to their maintenance immunosuppression, and all received meningococcal vaccination with penicillin prophylaxis during treatment given the risk of attenuated vaccine responses; no infections were observed during follow-up, though follow-up duration was short at the time of publication.

Telitacicept, a TACI-Ig fusion protein targeting both BAFF and APRIL, has generated the most substantial post-transplant recurrence data among B-cell/plasma cell-directed therapies to date, from two recent cohorts in China. In a retrospective series of 10 patients with biopsy-proven recurrent IgAN treated with telitacicept (160–240 mg weekly, subcutaneously), 6 months of therapy produced complete remission in two patients and partial remission in two more, with a proteinuria reduction exceeding 30% in 60% of patients overall; renal function remained stable in nine of ten patients through 12 months. Safety was reassuring on the whole, with no deaths, no serious adverse events, and no progression to graft failure or ESKD, though one patient (10%) developed antibody-mediated rejection after 12 months of treatment [73]. A larger, prospective single-arm cohort of 25 transplant recipients with biopsy confirmed recurring IgAN receiving add-on telitacicept reported substantial reductions in 24-h urinary protein and urine albumin-to-creatinine ratio by week 28 (51.6% and 62.7%, respectively; both p < 0.001) [74]. Together, these early data position telitacicept as a promising approach to the B-cell/plasma cell-driven biology underlying IgAN recurrence, though controlled trials and longer safety follow-up, particularly around alloimmune risk, are still needed. List of available therapies for IgAN, along with the corresponding evidence for their use in post-transplant recurrence, are summarized in Table 2.

In current clinical practice, treatment decisions should remain individualized. Before escalation of disease-specific therapy, clinicians should exclude competing causes of proteinuria, optimize supportive measures including blood pressure control, renin-angiotensin system blockade and SGLT2 inhibition when appropriate, and carefully assess concomitant alloimmune injury on biopsy. Disease-specific therapies should ideally be administered within prospective clinical studies whenever feasible.

Recurrent IgAN after kidney transplantation is an important cause of late allograft injury. Its impact is underestimated because recurrence may be histologically silent, diagnosed years after transplantation, and confounded by other causes of late graft dysfunction, including chronic antibody-mediated rejection, calcineurin inhibitor toxicity, and chronic scarring. As allograft survival improves, progressive recurrent IgAN may increasingly contribute to late graft loss.

Progress in this area will require a transplant-specific evidence base. Harmonized multicenter registries should capture not only recurrence rates, but also biopsy indication, time from transplant to recurrence, proteinuria and eGFR trajectories, DSA status, rejection history, induction and maintenance immunosuppression, steroid exposure, and standardized histologic features of activity and chronicity. The TANGO consortium [80] already provides a model for this type of collaborative effort; the next step is to expand and standardize such registries so that clinically meaningful recurrence can be distinguished from incidental mesangial IgA deposition.

Trials of newer IgAN therapies have consistently excluded transplant recipients: potential drug-drug interactions with calcineurin inhibitors, concerns about compounding infection risk on top of maintenance immunosuppression, and the practical difficulty of powering a trial against a hard endpoint like graft loss that may take a decade or more to accrue have all made this a difficult population to study. Future studies should be designed around the realities of transplant nephrology. Graft loss is an important outcome, but it is impractical as the primary endpoint for most trials of recurrent IgAN. More feasible studies should use enrichment strategies and short-to intermediate-term endpoints, including change in proteinuria, eGFR slope, histologic activity and chronicity, complement deposition, and patient-centered safety outcomes. Trials should stratify by DSA and antibody-mediated rejection status, induction and maintenance immunosuppression, steroid exposure, time from transplant to recurrence, and the presence of active versus chronic lesions. Basket or platform designs that include transplant recipients alongside native IgAN cohorts may be an efficient first step, but dedicated transplant cohorts will ultimately be needed to define dosing, safety, and efficacy.

Biomarker development should be embedded in these studies rather than pursued separately. Serial assessment of Gd-IgA1, anti-glycan antibodies, BAFF/APRIL levels, complement biomarkers, urine markers, and tissue readouts may help identify patients at risk, monitor response, and separate active recurrence from irreversible chronic injury. At present, none of these tools is sufficiently validated to guide routine post-transplant management, but they should be incorporated prospectively into registries and trials.

In the era of targeted IgAN therapies, kidney transplant recipients should not remain therapeutic orphans. The next step is a transplant-specific evidence base that moves beyond anecdotal add-on therapy and defines rational, safe, and measurable treatment strategies for recurrent IgAN before irreversible allograft injury develops.