Treatment for c-aABMR May Improve Long-Term Allograft Survival

The introduction of calcineurin inhibition (CNI), and induction therapy with T cell depleting agents has significantly improved short-term outcomes of kidney transplantation; however, improvement in long-term renal allograft survival remains a considerable clinical challenge. Recent studies have suggested that chronic-active antibody mediated rejection (c-aABMR) is one of the major barriers for long-term renal allograft survival. Advanced c-aABMR often presents as progressive loss of allograft function and progressive proteinuria and hypertension. Most patients diagnosed with c-aABMR develop allograft failure within 2 years.

Based on favorable results, in the past decade a renal transplant center in The Netherlands (Erasmus Medical Center, Department of Nephrology & Transplantation, Rotterdam) began treating patients with c-aABMR with a single course of intravenous immunoglobulin (IVIG) therapy and pulse intravenous methylprednisolone (MP). Kasia A. Sablik, MD, and colleagues recently conducted a retrospective analysis to examine the efficacy of that treatment in patients with c-aABMR. Results of the analysis were reported online in BMC Nephrology [doi.org/10.1186/s12882-019-1385-z].

Inclusion criteria were biopsy proven c-aABMR, treatment with three doses of 1 g intravenous MP over a 3-day period combined with a single dose of IVIG (1g/kg body weight), sufficient data on allograft function, and no further treatment. All biopsies were for cause and were evaluated at the time of biopsy by an experienced renal pathologist based on the then current Banff classification. Of the 167 patients potentially eligible for inclusion, 69 met inclusion criteria. In addition, the researchers identified a historical patient group (n=27) who did not receive any additional treatment on diagnosis of c-aABMR. Most of the patients in the historical group were diagnosed prior to 2008 when the local treatment guideline for c-aABMR was adopted.

Among the 69 patients analyzed, average age was 53 years, and 75% received a living donor kidney transplant. The maintenance immunosuppressive regimen consisted of double immunosuppression with a combination of tacrolimus and mycophenolate mofetil. Forty-six percent of the patients used steroids.

Time to biopsy from time of transplantation was a median of 6.3 years; median estimated glomerular filtration rate (eGFR) was 34 mL/min/1.73 m², and median proteinuria was 230 mg/mmol at the time of renal biopsy. There were no deaths in the first year of follow-up.

Among the 69 patients treated with IVIG-MP, renal allograft function declined from an average eGFR of 44 mL/min/1.73 m² at 1 year prior to therapy to 34 mL/min/1.73 m² at time to treatment. Allograft function further declined to 28 mL/min/1.73 m² the year after treatment. The calculated average decline in eGFR of 6.3 mL/min/1.73 m² in the year after IVIG-MP treatment was significantly less than the average decline of 9.8 mL/min/1.73 m² in the year prior to treatment (multilevel analysis, P<.001).

One year after treatment, 43 of the 69 patients (62%) had an eGFR of at least 25% above the projected eGFR and were categorized as responders. There were two frequent patterns of response: (1) significant slowing of progressive eGFR loss and (2) stabilization of renal function after treatment. Improvement of eGFR within the year after treatment was not usually seen.

Decline in allograft function among the responders as a group was from 43 mL/min/1.73 m² 1 year prior to treatment to 33 mL/min/1.73 m² at time of treatment (eGFR decline: 10.3 mL/min/1.73 m²). After IVIG-MP treatment, the calculated average decline in eGFR was 2.0 mL/min/1.73 m².

In the untreated historic group, the average decline in eGFR was 11.3 mL/min/1.73 m² prior to the diagnosis of c-aABMR and 9.7 mL/min/1.73 m² following the diagnosis. There was no significant change in graft function.

Three patients in the treatment group (non-responders) had relentless progression of disease to graft failure and returned to dialysis within the first year after IVIG-MP administration. Responders had significantly improved graft survival; mean survival was 5.9 years versus 3.1 years for non-responders P=.003).

At 1, 3, and 5 years following diagnosis of c-aABMR, graft survival among responders was 100%, 75%, and 59%, respectively, compared with 89%, 57%, and 20% for the non-responders. Graft survival among the untreated patients was similar to that of the non-responders (74%, 38%, and 33%, respectively).

Of all clinical variables, the only significant difference between responders and non-responders was age of donor. Responders had, on average, slightly older donors compared with non-responders (53 vs 47 years; P=.046). Responders more often had a living donor compared with non-responders, a difference that did not reach statistical significance (81% vs 65%; P=.14).

An analysis of data of 41 patients on the effects of treatment on proteinuria was conducted (the remaining 28 patients had insufficient data for the analysis). There was, on average, an association between IVIG-MP treatment and a decrease in proteinuria level the first year after treatment administration. Initially, proteinuria increased in the 41 patients from 75 mg/mmol 1 year before treatment to 229 mg/mmol at time of treatment. In the year after treatment with IVIG-MP, proteinuria decreased from 229 mg/mmol to 190 mg/mmol.

There were some limitations to the study, according to the authors. The retrospective design allowed for unknown bias due to selection of patients with a for-cause biopsy; the design also excluded the possibility of a uniform schedule of maintenance immunosuppression.

In conclusion, the researchers said, “Immunosuppressive therapy with IVIG-MP may significantly slow eGFR loss in a substantial proportion of patients with c-aABMR, leading to improved graft survival. As c-aABMR is now recognized as a major cause of long-term renal allograft loss, the efficacy of IVIG-MP treatment is an important and hopeful finding.”

Takeaway Points

1. Long-term kidney allograft loss is associated with chronic-active antibody mediated rejection (c-aABMR). Researchers conducted a retrospective analysis to examine the efficacy of treatment with intravenous immunoglobulins and methylprednisolone (IVIG-MP) in patients with c-aABMR.
2. Sixty-nine patients at a center in The Netherlands were treated with IVIG-MP; after 1 year of treatment, 43 patients were considered responders, showing slowing of deterioration of graft function.
3. There was also a significant improvement in proteinuria upon treatment.