IVIG IN CHRONIC ANTIBODY MEDIATED REJECTION : SLOWING THE DECLINE OF KIDNEY ALLOGRAFT FUNCTION

Kidney transplantation (KT) remains the treatment of choice for patients with end-stage renal disease, surpassing chronic dialysis in cost-effectiveness, patient survival, and quality of life(1-3). Advances in immunosuppression have dramatically reduced acute rejection, yielding excellent short-term outcomes. For example, recent trials report 1-year graft survival of 89–92%. However, long-term graft attrition remains problematic: by 10 years post-transplant, patient survival falls to ~34–57%, and many grafts fail.(5,6) Chronic active antibody-mediated rejection (c-aABMR) is a leading driver of late kidney allograft failure(4). It is characterized histologically by transplant glomerulopathy and inflammation of the microvasculature, and clinically by new or worsening hypertension, proteinuria, and progressive decline in renal function. In fact, median graft survival after a diagnosis of c-aABMR is less than two years.(7,8)

Despite its importance, no consensus treatment for c-aABMR exists.(4)The U.S. Food and Drug Administration has approved no therapies specifically for chronic AMR(4), and expert guidelines currently recommend only supportive care and optimization of baseline immunosuppression(9). At many centers, treatment protocols for c-aABMR are adapted from desensitization regimens, typically combining plasmapheresis, high-dose steroids, intravenous immunoglobulin (IVIG), and sometimes rituximab.(10)To date, published trials of these interventions have been small and inconclusive. A recent consensus review noted that plasmapheresis or high-dose IVIG are “standard of care” for antibody-mediated rejection, but stressed the lack of “conclusive evidence to support any specific therapy” in chronic ABMR.(4) Consequently, patient outcomes remain poor: one analysis found that more than half of patients diagnosed with c-aABMR lose their graft within two years.(4)

Among salvage therapies, IVIG has been used empirically to neutralize donor-specific antibodies and modulate the immune response. A small randomized trial (the VIPAR study) recently reported that monthly IVIG stabilized allograft histology and eGFR in c-aABMR, whereas graft function continued to decline without IVIG.(11) Editorial commentary on VIPAR also noted preliminary evidence of histologic and functional benefit with high-dose IVIG.(12) These findings suggest IVIG could be a valuable adjunct in c-aABMR, but data are still limited. We therefore performed a retrospective case series to evaluate the efficacy of IVIG therapy (2 g/kg in four split doses) in KT patients with biopsy-proven c-aABMR. Our goal was to determine whether IVIG could slow eGFR loss and reduce proteinuria over six months, thereby potentially prolonging graft survival.

We conducted a retrospective analysis of all adult kidney transplant recipients treated for biopsy-proven c-aABMR at our center between January 2024 and June 2025. c-aABMR was diagnosed by renal biopsy according to Banff criteria, requiring evidence of chronic active lesions (e.g. transplant glomerulopathy, peritubular capillaritis) in the presence of donor-specific anti-HLA antibodies. Six patients met inclusion criteria (see Table 1 for baseline demographics). All patients had persistent or de novo HLA donor-specific antibodies (DSA) at diagnosis. The IVIG regimen consisted of total dose 2 g/kg, divided into four equal infusions (0.5 g/kg each) administered at 3-week intervals. Concomitant immunosuppression (calcineurin inhibitor, antiproliferative agent, steroids) was maintained unchanged during the course of IVIG. No other desensitizing therapy (plasmapheresis or rituximab) was given during the study period.

Primary outcomes were changes in kidney function (estimated glomerular filtration rate, eGFR) and proteinuria at 6 months post-IVIG. We calculated the rate of eGFR decline over the 6 months prior to therapy (using the CKD-EPI equation) and compared it to the decline over the 6 months following IVIG. Proteinuria was quantified by spot urine protein-to-creatinine ratio (UPCR). Patients were classified as “responders” if their eGFR stabilized (decline slowed to <10% of baseline per our criteria) and UPCR decreased by ≥25% at 6 months. Secondary outcomes included graft survival and treatment-related adverse events.

Statistical analysis was performed using paired t-tests to compare pre- and post-treatment eGFR decline and proteinuria. Continuous variables are presented as means ± standard deviation. A two-sided p-value < 0.05 was considered statistically significant. This retrospective study was approved by our institutional review board.

The cohort included six patients . The mean age at IVIG treatment was forty six (±9) years; five were male. The median time from transplant to c-aABMR diagnosis was 8.75 years. Baseline immunosuppression was tacrolimus plus mycophenolate and prednisone in 4 cases whereas it was prednisolone plus  mycophenolate and everolimus in 2 cases. Prior to IVIG, all patients exhibited progressive graft dysfunction; mean eGFR fell from 52.9 ± 21.5 to 33.71 ± 13.77 mL/min/1.73 m² over the 6 months before treatment (mean decline 19.24 mL/min/1.73 m² ). The mean UPCR six months before treatment was 1.74mg/g .It increased to 3.58 ± 2.58 mg/g at the time of diagnosis of c ABMR.

After IVIG therapy, the decline in eGFR was markedly attenuated: mean eGFR went from 33.7 +_13.77 at time of diagnosis of chronic ABMR to avg 35.97 ± 16.87 mL/min/1.73 m² at 6 months, representing an increase in egfr of 2.25L/min (p<0.001 vs. pre-treatment decline). In other words, the rate of eGFR loss slowed from  19.24 and increased to 2.7 mL/min per 6 months (Fig. 1). Likewise, mean proteinuria improved: the mean UPCR fell from 3.58 ± 2.58 to 3.07 ± 3.38 at 6 months .Median percent reduction in UPCR at 6 months was 28.3%.

 By our response criteria, four patients (66.7%) were classified as responders, showing both stabilization of eGFR slope and ≥25% reduction in UPCR. Two patients (33.3%) continued to show moderate graft function decline and persistent proteinuria and were deemed non-responders. At 6-month follow-up, 1 patient had returned to dialysis. IVIG was generally well tolerated; no infusion-related reactions or serious infections were reported during the study period.

In summary, we report that high-dose IVIG therapy in six patients with biopsy-proven chronic active ABMR was associated with significantly slower eGFR decline and reduced proteinuria over 6 months. Two-thirds of the patients met predefined criteria for therapeutic response. These data suggest that IVIG can meaningfully attenuate graft injury in chronic ABMR and may help prolong graft survival. While preliminary, our findings underscore the need for further research on IVIG and other novel treatments for this challenging condition.