Barbara Voss

The effect of donor age, recipient age, and HLA match on immunologic graft survival in cadaver renal transplant recipients.

We retrospectively analyzed 526 primary cadaver recipients transplanted at a single center to identify pre-transplant variables that predict long-term survival with multivariate analysis. All recipients received atleast three random blood transfusions and were treated under a quadruple-therapy protocol consisting of ALG, azathioprine, prednisone, and cyclosporine. Of 526 consecutive transplants, 86 grafts were lost from acute or chronic rejection. Thirteen grafts were lost for nonimmunologic reasons and 35 recipients died with a functioning graft. A total of 273 patients (52%) experienced at least one episode of acute rejection. Donor age ranged from 3 to 64 years, with 62% of donors less than 30 years of age and 9% of donors over 50 years of age. Donor age was not predictive of long-term graft survival and neither was the difference be-

Pretransplant donor-specific antibodies detected by single-antigen bead flow cytometry are associated with inferior kidney transplant outcomes.

Background. The clinical significance of pretransplant donor-specific antibodies (pre-Tx DSAs) detected by single-antigen bead flow cytometry (SAB-FC) remains unclear. Methods. To investigate the impact that pre-Tx DSAs detected by SAB-FC have on early clinical outcomes, we tested pre-Tx sera from all consecutive deceased-donor kidney transplants performed between January 2005 and July 2006 (n=237). Results. In the study population of which 66% had a high-immunologic risk, mean fluorescence intensity (MFI) more than or equal to 100 for class I and more than or equal to 200 for class II were the lowest DSA thresholds associated with inferior antibody-mediated rejection-free graft survival (75% vs. 90%, P=0.004 and 76% vs. 87%, P=0.017, respectively). The hazard ratio for antibody-mediated rejection increased linearly with higher class II DSA from MFI 100 to 800 (1.7[0.8–3.2], P=0.1 for MFI≥100 vs. 4.7[2.4–8.8], P<0.001 for MFI ≥800). Differences in graft function were only evident in patients with class II MFI more than or equal to 500 (estimated glomerular filtration rate: 47.6 vs. 54.3, P=0.02 and proteinuria: 0.6±0.6 vs. 0.4±0.3, P=0.03). A difference in death-censored graft survival was detected in patients with class II MFI more than or equal to 1000 (75% vs. 91.9%, P=0.055). Conclusion. High-pre-Tx DSAs detected by SAB-FC are associated with incrementally poor graft outcomes in deceased-donor kidney transplant with high-immunologic risk.

Orthotopic liver transplantation in patients 60 years of age and older.

Cyclosporine appears to have abrogated age as a contraindication to kidney transplantation in the elderly, although it is unclear whether this is true for other types of solid organ transplantation. We performed a retrospective analysis of liver transplant recipients who were 60 years of age and older (n = 23) versus recipients of primary transplants who were 18 to 59 years of age (n = 84). Indications in recipients over 60 included alcoholism (6), postnecrotic cirrhosis (6), cancer (4), primary biliary cirrhosis (3), sclerosing cholangitis (2), and one patient with polycystic liver disease. There were no important differences in the initial transplant hospitalization or the incidence of infection and rejection between the two groups. No patient in the over-60 population required retransplantation. Actuarial patient survival is 83% at 2 years for recipients 60 years of age and above compared to 76% patient survival in adult recipients who are under the age of 60. Liver transplant recipients over the age of 60 years have excellent patient and graft survival and the same postoperative morbidity as recipients who are under 60 years of age. Therefore, advanced age does not appear to be a contraindication to orthotopic liver transplantation.

Chronic allograft nephropathy uniformly affects recipients of cadaveric, nonidentical living-related, and living-unrelated grafts.

Background. Chronic allograft nephropathy (CAN) remains a major barrier to long-term allograft survival. The authors retrospectively compared the development of CAN in recipients of cadaveric (CAD), living-related donor (LRD), and living-unrelated donor (LURD) transplants at their center. Methods. The authors retrospectively examined the impact of various factors on the incidence of CAN using univariate and multivariate proportional hazards analysis in a single-center kidney transplant population. Results. Between 1 January 1990 and 31 May 2000, 2,140 kidney-alone transplants were performed at the authors’ center. The overall 5-year incidence of biopsy-proven CAN was 12.2% (n=203). Risk factors for CAN included the number of transplants (P =0.0001), acute rejection (P =0.0001), panel reactive antibody (P =0.0001), discharge creatinine (P =0.0001), 1-year creatinine (P =0.0015), delayed graft function (P =0.007), total human leukocyte antigen (HLA)-B and -DR mismatches (P =0.0005), recipient age (P =0.003), black donor race (P =0.001), black recipient race (0.0457), donor age (P =0.0053), cold storage time (P =0.019), and cytomegalovirus infections (P =0.002). Interestingly, although the LRD HLA-identical recipients had a significantly lower incidence of CAN (P =0.0015), the incidence of CAN in CAD and HLA-nonidentical LRD recipients did not differ. Graft survival was significantly worse in CAD recipients compared with all other groups (P <0.001). Conclusions. These results demonstrate the importance of immunologic and nonimmunologic factors on the development of CAN. The disparities in overall graft survival, despite the similarities in CAN rates, suggests that other factors, in addition to CAN, influence the increase in graft loss in CAD transplant recipients.

Mycophenolate Mofetil Versus Enteric-Coated Mycophenolate Sodium: A Large, Single-Center Comparison of Dose Adjustments and Outcomes in Kidney Transplant Recipients

Background. Although enteric-coated mycophenolate sodium (EC-MPS) was developed to reduce gastrointestinal (GI) side effects in kidney transplantation, a multicenter clinical trial of patients undergoing de novo renal transplantation found that efficacy failure and adverse GI event rates for EC-MPS were comparable with mycophenolate mofetil (MMF). A common strategy to mitigate mycophenolic acid-related GI adverse events includes dose manipulations such as split dosing, dose reduction, and discontinuation. Several studies have demonstrated that dose alterations with MMF are associated with poorer graft outcomes. Methods. To determine whether there was a clinically significant difference in dose alterations and outcomes with EC-MPS compared with MMF, we conducted a retrospective study comparing MMF and EC-MPS in all consecutive kidney transplants (n=1709) between 2000 and 2006. Results. Graft survival between MMF and EC-MPS patients was not different during the study period (P=0.9928). The incidence of biopsy-proven acute rejection at 2 years was higher in the MMF group (30.2% MMF vs. 21.9% EC-MPS, P=0.0004). The adjusted risk of dose reductions was significantly higher in MMF-treated patients (hazard ratio=1.703, P<0.0001). Similarly, the adjusted risk of drug discontinuation was higher in the MMF group (hazard ratio=1.507, P=0.0002). EC-MPS patients also demonstrated a trend toward a lower incidence of infections and a significantly lower incidence of fungal infections. Conclusion. EC-MPS was associated with fewer dose reductions or discontinuations, which may have translated into the observed significantly lower incidence of biopsy-proven rejection. EC-MPS has become the mycophenolic acid agent of choice at this large center.

Alemtuzumab Induction and Antibody-mediated Kidney Rejection After Simultaneous Pancreas-kidney Transplantation

Background. The best induction agent for simultaneous pancreas-kidney transplantation (SPKT) remains the subject of debate. Alemtuzumab is effective in preventing acute cellular rejection (ACR) in SPK recipients and has been used to prevent antibody-mediated rejection (AMR) in sensitized kidney transplant candidates. Methods. A retrospective cohort study was performed including 136 SPK recipients receiving maintenance immunosuppression with tacrolimus, mycophenolic acid prodrugs, and prednisone. Two groups were compared: those who received induction with alemtuzumab (n=97) and those induced with basiliximab (n=39). Results. Kidney ACR was more frequent in SPKT induced with basiliximab (2-year 12.8% vs. 3.1%, P=0.04), but the incidence of AMR was similar (2-year 18% with basiliximab vs. 13.8% with alemtuzumab, P=NS). Kidney rejection was associated with clinical pancreas rejection in 70% of cases, without differences between the groups. Postrejection kidney graft survival was similar in both groups (2-year basiliximab/alemtuzumab 94.7%/91.2%), but death-censored kidney graft survival was lower with alemtuzumab (100%/91.2%, P=0.056). In the basiliximab group, the predominant cause of kidney loss was death-with-function, whereas in the alemtuzumab group AMR accounted for all losses. Pancreas graft survival was similar in both groups, yet more pancreas losses due to acute rejection occurred in alemtuzumab-treated patients (4 vs. 1). Conclusions. Kidney AMR is more common than ACR in SPKT recipients treated with alemtuzumab, tacrolimus, mycophenolic acid, and steroids. ACR is better prevented by alemtuzumab than basiliximab, but no relevant difference is found in prevention of AMR. Despite the high incidence of AMR, survival rates are excellent in both groups.

Bisphosphonates and bone fractures in long-term kidney transplant recipients.

Background. There is little information on the role of bisphosphonates and bone mineral density (BMD) measurements for the follow-up and management of bone loss and fractures in long-term kidney transplant recipients. Methods. To address this question, we retrospectively studied 554 patients who had two BMD measurements after the first year posttransplant and compared outcomes in patients treated, or not with bisphosphonates between the two BMD assessments. Kaplan-Meier survival and stepwise Cox regression analyses were performed to examine fracture-free survival rates and the risk-factors associated with fractures. Results. The average time (±SE) between transplant and the first BMD was 1.2±0.05 years. The time interval between the two BMD measurements was 2.5±0.05 years. There were 239 and 315 patients in the no-bisphosphonate and bisphosphonate groups, respectively. Treatment was associated with significant preservation of bone loss at the femoral neck (HR 1.56, 95% CI 1.21–2.06, P=0.0007). However, there was no association between bone loss at the femoral neck and fractures regardless of bisphosphonate therapy. Stepwise Cox regression analyses showed that type-1 diabetes, baseline femoral neck T-score, interleukin-2 receptor blockade, and proteinuria (HR 2.02, 0.69, 0.4, 1.23 respectively, P<0.01), but not bisphosphonates, were associated with the risk of fracture. Conclusions. Bisphosphonates may prevent bone loss in long-term kidney transplant recipients. However, these data suggest a limited role for the initiation of therapy after the first posttransplant year to prevent fractures.

Alemtuzumab induction and recurrence of glomerular disease after kidney transplantation.

Background. An increase in the incidence of autoimmune diseases has been described in patients receiving alemtuzumab. Methods. To determine whether induction with alemtuzumab increases recurrence of glomerular disease, we performed a retrospective study in 443 patients with biopsy-proven glomerular diseases undergoing kidney transplantation. Patients receiving alemtuzumab (n=161) were compared with those receiving interleukin (IL)-2-receptor antagonists (n=217) or antithymocyte globulin (n=64). Results. Biopsy-proven glomerular disease recurrence was similar in patients induced with alemtuzumab or IL-2 receptor antagonists. Patients receiving antithymocyte antibody had a lower recurrence rate than patients treated with other induction agents, with borderline significance (hazard ratio [HR] 0.13, 95% confidence interval [95% CI] 0.02−0.98, P=0.047). Patients with systemic lupus treated with alemtuzumab had a similar re-emergence of autoreactive antibodies to patients treated with other agents. Recurrent disease increased the risk of allograft failure (HR 2.36, 95% CI 1.28−4.32, P=0.0056). The development of acute rejection and the use of deceased (vs. living) donor kidneys were also significant factors influencing graft survival. A greater risk of mortality was detected in those patients with recurrent glomerular disease (HR 3.76, 95% CI 1.37−10.35, P=0.01), whereas increased age at transplantation (HR 1.05) and the use of deceased (vs. living) donor kidneys (HR 3.20) also increased mortality. No specific induction agent significantly affected graft loss or mortality when using adjusted or unadjusted hazard ratios. Conclusions. In this retrospective analysis, induction with alemtuzumab did not increase the rate of re-emergence of autoantibodies or biopsy-proven recurrence of glomerular disease. A slight reduction in the incidence of recurrence was observed in patients treated with thymoglobulin, yet this observation can only be validated in a prospective randomized trial.

Antibody-Mediated Rejection of the Kidney after Simultaneous Pancreas-Kidney Transplantation

The prevalence, risk factors, and outcome of antibody-mediated rejection (AMR) of the kidney after simultaneous pancreas-kidney transplantation are unknown. In 136 simultaneous pancreas-kidney recipients who were followed for an average of 3.1 yr, 21 episodes of AMR of the kidney allograft were identified. Eight episodes occurred early (</=90 d) after transplantation, and 13 occurred later. Histologic evidence of concomitant acute cellular rejection was noted in 12 cases; the other nine had evidence only of humoral rejection. In 13 cases, clinical rejection of the pancreas was diagnosed simultaneously, and two of these were biopsy proven and were positive for C4d immunostaining. Multivariate analysis identified only one significant risk factor: Female patients were three times more likely to experience AMR. Nearly all early episodes resolved with treatment and did not predict graft loss, but multivariate Cox models revealed that late AMR episodes more than tripled the risk for kidney and pancreas graft loss; therefore, new strategies are needed to prevent and to treat late AMR in simultaneous pancreas-kidney transplant recipients.

The impact of hepatitis C virus donor and recipient status on long-term kidney transplant outcomes: University of Wisconsin experience

Singh N, Neidlinger N, Djamali A, Leverson G, Voss B, Sollinger HW, Pirsch JD. The impact of hepatitis C virus donor and recipient status on long‐term kidney transplant outcomes: University of Wisconsin experience.