Allograft and patient survival after sequential HSCT and kidney transplantation from the same donor-A multicenter analysis

Abstract

Tolerance induction through simultaneous hematopoietic stem cell and renal transplantation has shown promising results, but it is hampered by the toxicity of preconditioning therapies and graft-versus-host disease (GVHD). Moreover, renal function has never been compared to conventionally transplanted patients, thus, whether donor-specific tolerance results in improved outcomes remains unanswered. We collected follow-up data of published cases of renal transplantations after hematopoietic stem cell transplantation from the same donor and compared patient and transplant kidney survival as well as function with caliper-matched living-donor renal transplantations from the Austrian dialysis and transplant registry. Overall, 22 tolerant and 20 control patients were included (median observation period 10 years [range 11 months to 26 years]). In the tolerant group, no renal allograft loss was reported, whereas 3 were lost in the control group. Median creatinine levels were 85 μmol/l (interquartile range [IQR] 72-99) in the tolerant cohort and 118 μmol/l (IQR 99-143) in the control group. Mixed linear-model showed around 29% lower average creatinine levels throughout follow-up in the tolerant group (P < .01). Our data clearly show stable renal graft function without long-term immunosuppression for many years, suggesting permanent donor-specific tolerance. Thus sequential transplantation might be an alternative approach for future studies targeting tolerance induction in renal allograft recipients.

Keywords: bone marrow/hematopoietic stem cell transplantation; clinical research/practice; kidney (allograft) function/dysfunction; kidney transplantation/nephrology; tolerance: clinical.

Figure 1

Flow chart illustrating data retrieval and further patient selection for the matching procedure

Figure 2

Kaplan‐Meier plot of transplant kidney survival; shaded areas and dashed lines represent 95% confidence intervals. No transplanted kidney was lost in the group of sequentially transplanted patients. RT, renal transplantation [Color figure can be viewed at wileyonlinelibrary.com]

Figure 3

Comparison of serum creatinine levels (on log2 scaled axis) after RT between groups; the mean is indicated as diamond shape in the boxplots [Color figure can be viewed at wileyonlinelibrary.com]

Figure 4

Mixed model for log2‐transformed serum creatinine levels modeling time using natural splines with 3 knots. Estimates were transformed to original scale. The shaded areas around the model estimates constitute 95% confidence intervals. The overall difference between the 2 groups was significant. No relevant difference in the change of creatinine levels over time between the 2 groups was found. Four patients from the control group had to be excluded due to missing longitudinal serum creatinine measurements. We restricted the analysis to the first 14 years after RT due to lack of serum creatinine measurements for most OEDTR patients thereafter. RT, renal transplantation [Color figure can be viewed at wileyonlinelibrary.com]

Figure 5

(A) Clinical course of the 2 tolerant patients transplanted at our center (pat. N18 and N19). Both patients underwent transplantation with only a short steroid taper to reduce ischemia‐reperfusion injury. No further immunosuppression was administered. (B) Humoral immune activation was assessed by measuring donor‐ and recipient‐specific antibodies. There were no signs of humoral immune activation. (C) Chimerism was assessed via real‐time PCR in separated T cells before and 1 year after RT in both patients. The proportion of recipient‐derived T cells was low and virtually didn't change over the time. (D) Protocol biopsies performed 1 month and 12 months after RT showed structurally regular renal tissue with no signs of cell‐ or antibody‐mediated rejection. Data from patient N18 have been shown previously (Schwarz 2016) with a shorter follow‐up19 [Color figure can be viewed at wileyonlinelibrary.com]

Figure 6

Kaplan‐Meier plot of overall patient survival; shaded areas and dashed lines represent 95% confidence intervals. Overall there were 4 deaths in the sequential group but one was treated as censored at the last follow‐up visit as the exact time of death is unknown. RT, renal transplantation [Color figure can be viewed at wileyonlinelibrary.com]