Transplant outcomes and economic costs associated with patient noncompliance to immunosuppression.

We describe factors associated with immunosuppression compliance after kidney transplantation and examine relationships between compliance with allograft outcomes and costs. Medicare claims for immunosuppression in 15 525 renal transplant recipients with at least 1 year of graft function were used to calculate compliance as medication possession ratio. Compliance was categorized by quartiles as poor, fair, good and excellent. We modeled adjusted associations of clinical factors with the likelihood of persistent compliance by multiple logistic regressions (aOR), and estimated associations of compliance with subsequent graft and patient survival with Cox proportional hazards (aHR). Adolescent recipients aged 19-24 years were more likely to be persistently noncompliant compared to patients aged 24-44 years (aOR 1.49 [1.06-2.10]). Poor (aHR 1.80 [1.52-2.13]) and fair (aHR 1.63[1.37-1.93]) compliant recipients were associated with increased risks of allograft loss compared to the excellent compliant recipients. Persistent low compliance was associated with a $12 840 increase in individual 3-year medical costs. Immunosuppression medication possession ratios indicative of less than the highest quartile of compliance predicted increased risk of graft loss and elevated costs. These findings suggest that interventions to improve medication compliance among kidney transplant recipients should emphasize the benefits of maximal compliance, rather than discourage low compliance.

Outcomes of simultaneous heart-kidney transplant in the US: a retrospective analysis using OPTN/UNOS data.

Simultaneous heart-kidney transplantation (SHK) remains uncommon in the US. We examined outcomes of SHK compared to heart transplant alone (HTA) and deceased donor kidney transplant (DDKT). Data from OPTN/UNOS heart and kidney data bases were used to identify 16,710 HTA, 263 SHK transplants and 68,833 DDK transplants between 1998 and 2007. Outcomes included patient survival (PS), acute cardiac and renal rejection and renal graft survival (rGS). The adjusted risk of death was 44% lower with SHK compared to HTA. Over half of SHK were performed in cases where pretransplant dialysis was not initiated. In these cases, there was no significant difference in the risk of death between SHK and HTA (HR 1.01; 95% CI 0.67-1.50). Recipients of SHK had worse 1-year rGS and PS and had a higher relative risk of overall renal graft loss compared to DDKT recipients. One-year rates of cardiac (14.5%) and renal (6.5%) rejection were lower in SHK compared to HTA and DDKT, respectively. Recipients of SHK had a lower adjusted risk of death compared to HTA recipients, particularly in patients who required pretransplant dialysis. These data suggest that SHK should be considered in heart transplant candidates with renal failure requiring dialysis, whereas the utility of SHK in cases of renal failure not requiring dialysis warrants further study.

A retrospective analysis of immunosuppression compliance, dose reduction and discontinuation in kidney transplant recipients.

We describe factors associated with poor compliance and dose reductions and examine the relative impact of compliance, dose reduction and discontinuation on graft outcome. Medicare claims for MMF in 7062 deceased donor renal recipients with at least 1 year of graft function were used to calculate compliance and dose reductions. Compliance was modeled using medication possession ratio to define quartiles for poor, low, medium and high compliance. The relative impact of compliance, dose reduction and discontinuation on graft outcome was assessed with Cox proportional hazards. Pediatric (Age 0-18, Odds ratio = 1.71, 95% CI 1.11-2.63, p = 0.014) and adolescent recipients (19-24, 1.57, 1.23-2.00, p < 0.001) were more likely poorly compliant compared to adults age 25-44. Poor compliance was also associated with physical limitations, hypertension, delayed graft function, rejection, infection and GI conditions. Poor (1.43, 1.11-1.84, p = 0.005) and low (1.46, 1.13-1.88, p = 0.004) compliance was associated with an increased hazard of graft loss as was >50% dose reduction (1.69, 1.15-2.50, p = 0.008) and discontinuation (8.34, 6.85-10.2, p < 0.001). Medication possession ratios lower than the 3-year mean were associated with an increased risk of graft loss. These results may indicate that interventions to improve compliance among kidney transplant recipients should strive for high rather than discourage low compliance.

Patient and graft survival implications of simultaneous pancreas kidney transplantation from old donors.

We investigated graft and patient survival implications of simultaneous pancreas kidney (SPK) transplant from old donors. Data describing patients with type 1 diabetes mellitus listed for an SPK transplant from 1994 to 2005 were drawn from Organ Procurement and Transplant Network registries. Allograft survival, patient survival and long-term survival expectations among SPK recipients from young (age <45 years) and old (age >/=45 years) donors were modeled by multivariate regression. We also examined predictors of reduced early access to young donor transplants. Of 16 496 eligible SPK candidates, 8850 patients (53.6%) received an SPK transplant and 776 (8.8%) of these transplants were from old donors. Reasonable 5-year, death-censored kidney (77.8 %) and pancreas (71.3%) survivals were achieved with old donors. SPK transplantation from both young and old donors predicted lower mortality compared to continued waiting. An additional expected wait of 1.5 years for a young donor equalized long-term survival expectations to that achieved with use of old donors. Early allocation of young donor transplants declined in the more recent era and varied by region, candidate age, blood type and sensitization. We conclude that old SPK donors should be considered for patients with decreased access to young donor transplants. Prospective evaluation of this practice is needed.

Multivariate analysis of the effectiveness of using antibody induction therapy according to the degree of HLA mismatches.

OBJECTIVE: HLA mismatches have a strong impact on acute rejection and renal allograft survival. The objective of this study was to evaluate the effectiveness of antibody induction according to the degree of HLA mismatches. METHODS: Of 20,429 deceased donor (DD) transplantations and 12,859 living donor (LD) transplantations reported to the United Network for Organ Sharing (UNOS) between 1999 and 2001, 51% of DD and 45% of LD transplant recipients received induction therapy. Propensity scores (PS) were calculated to indicate independent factors associated with the use of induction. Levels of HLA match examined for DD transplant recipients were 0 ABDR (n = 3239), 0 DR (n = 4210), and DR mismatched transplants (n = 12,980), and 0 (n = 1133), 1 (n = 3836), and 2 (n = 7890) haplotype mismatches for LD transplant recipients. Outcome parameters were reported as hazard ratios (HR) for graft loss and odds ratios (OR) for first-year acute rejection. RESULTS: Recipients with HLA mismatches were more likely to receive induction antibody for DR mismatch in DDs (PS = 1.11, 95% confidence interval [CI] 1.04-1.19) and for haplotype mismatch in LDs (PS = 1.36, 95% CI 1.22-1.52). Induction reduced the likelihood of acute rejection for DD transplant recipients regardless of the level of HLA mismatch (OR = 0.70; 95% CI 0.57-0.85 in 0 ABDR MM; OR = 0.76, 95% CI 0.64-0.89 in 0 DR MM; and OR = 0.69, 95% CI 0.62-0.77 in DR MM), and for 2 haplotype mismatched LD transplant recipients (OR = 0.82, 95% CI 0.70-0.96); in other LD transplant recipients, reductions in acute rejection rates were observed but not statistically significant. Induction reduced the risk of graft loss for DR mismatched DD transplant recipients by about 12% (HR = 0.88; 95% CI 0.80-0.97). CONCLUSIONS: Antibody induction resulted in a significant reduction of acute rejection and graft loss for patients with HLA mismatch.

Multivariate analysis of antibody induction therapy and their associated outcomes in deceased donor transplants.

AIMS: The aims of this study were to describe factors associated with the use of overall induction, classes of induction agents, and to evaluate the incidence of acute rejection, short-term graft survival, and patient survival. METHODS: Of 24,901 transplants reported to the United Network for Organ Sharing (UNOS) between 1999 and 2001, 51% received induction therapy including Thymoglobulin (T; n = 3090), Simulect (S; n = 6063), or Zenapax (Z; n = 3755). Propensity scores (PS) were calculated to indicate factors associated with use of induction and for each induction agent. Outcome parameters included graft survival (GS), hazard ratio (HR) for graft loss (GL), and odds ratio (OR) for first-year acute rejection (AR). RESULTS: Pediatric (PS = 1.29; 95% confidence interval [CI] 1.12-1.49, vs adults) and retransplanted recipients (PS = 1.36; 1.23-1.49, vs first) were more likely to receive induction. One-year GS (90.1 vs 88.0%; P < .001), GL = 0.92% (0.86-0.98; P = .01), and AR free = 0.74 (P < .001) were superior in patients receiving induction. Using multivariate analysis, the odds of rejection 0.73 (0.68-0.78), GL 0.91 (0.85-0.97), and death 0.90 (0.82-0.98) were lower in those receiving induction. Among patients given induction, those receiving T were more likely sensitized (PS = 1.50%; 1.31-1.71), retransplanted (PS = 1.51; 1.31-1.75), or had delayed graft function (PS = 1.75; 1.58-1.93). T decreased the odds of rejection compared with S or Z (OR = 0.74; 0.69-0.79), but the type of induction agent did not have an impact on graft outcome HR for T = 1.07 (0.96-1.19). CONCLUSIONS: The use of antibody induction was associated with lower risk of rejection and better GS. There were no differences in GS among individual regimens. Comparative safety data were not analyzed but should be taken into consideration when choosing antibody preparations.

Controlling treatment allocation bias in a registry analysis when comparing calcineurin inhibitors.

Previous analyses of outcomes between immunosuppressive regimens included data from the early years of tacrolimus use and frequently included all Tacrolimus- or cyclosporine-based regimens. We now evaluate clinical outcomes associated with only the two most commonly prescribed regimens--Tacrolimus (Tac)-mycophenylate mofetil (MMF) and cyclosporine (CsA)-MMF--using recent data reported to the UNOS Scientific Renal Transplant Registry. Data from living donor kidney transplants was chosen to minimize selection bias between treatment groups. Outcomes are reported only for recent years (1998 to 1999 with 3-year follow-up) because acute rejection rates were markedly higher in 1995 to 1997 compared to 1998 to 2000 (38% to 68% vs 21% to 32%) and clinical practice has evolved since 1995, which would have biased results in favor of more recent immunosuppressive regimens. Three-year graft survival for patients transplanted from 1998 to 1999 was significantly higher in living donor kidney transplant patients receiving CsA-MMF (91.1%, n = 4686) versus Tac-MMF (88.1%, n = 2393) (P =.0006). After adjustment for potential confounding variables, risk of graft failure at 3 years was significantly higher in patients receiving Tac-MMF versus CsA-MMF for both all-cause graft failure (hazard ratio 1.28, 95%CI 1.09 to 1.49, P =.002) and death-censored graft failure (hazard ratio 1.25, 95%CI 1.05 to 1.49, P =.013). In view of the reduced rejection rate that has been reported using Tac-MMF versus CsA-MMF in clinical trials, it is possible that the nonimmunologic effects of calcineurin inhibitors may now play an increasingly important role in determining graft survival rates. In conclusion, this large-scale registry analysis demonstrates that graft survival in living donor kidney transplant patients is significantly improved using CsA-MMF compared to Tac-MMF.

Maintenance immunosuppression.

An "intent-to-treat" analysis was developed to examine the administration of primary and adjunctive immunosuppressive agents by year of transplant for unsensitized, sensitized, multi-organ and living donor transplant recipients by centers reporting to the UNOS Registry of Renal Transplant Recipients. Based on these analyses, several trends were noted: Tacrolimus became the dominant primary agent for multi-organ transplant recipients in 1998, sensitized recipients in 2000, and unsensitized and living-donor transplant recipients in 2001. MMF became the dominant adjunctive agent for all transplants studied in 1996. The combination of CsA-MMF was most often administered to unsensitized and living donor recipients while Tac-MMF was most often used for multi-organ transplants. The trend of decreasing rejection rates from 60% in 1996 to 20% in 2001 was similar for each type of transplant studied. Rejection rates were highest with the Csa-Aza combination and lowest with the Tac-MMF combination. Combinations with the lowest rates of rejection did not necessarily have the highest graft outcome. HLA matching decreased rejection rates and improved graft outcome for each type of transplant and immunosuppression combination. Graft outcome in HLA-matched living donor transplants was highest with the less potent CsA-Aza combination and lowest with the Tac-MMF combination. Treatment crossover from CsA to Tac or Aza to MMF was least frequent among HLA-matched recipients. Crossover from MMF to Aza was highest in HLA-matched living donor transplants.

Twelve years' experience with national sharing of HLA-matched cadaveric kidneys for transplantation.

BACKGROUND: In October 1987, the United Network for Organ Sharing (UNOS) established a national kidney-sharing program to increase the number of HLA-matched transplantations. Since then, over 7500 cadaveric kidneys have been shipped to centers in 48 states for transplantation to HLA-matched patients. We evaluated the efficacy of the program during its first 12 years of operation. METHODS: We compared the rates of rejection and actuarial graft survival for 7614 HLA-matched and 81,364 HLA-mismatched cadaveric kidney transplantations reported to the UNOS Scientific Registry between October 1987 and September 1999. To assess the effects of the extended period of ischemia associated with shipping HLA-matched kidneys, we identified 3562 pairs of cadaveric kidneys in which one kidney went to an HLA-matched recipient and the other went to an HLA-mismatched recipient. RESULTS: The estimated 10-year rate of graft survival was 52 percent for HLA-matched transplants, as compared with 37 percent for HLA-mismatched transplants. The estimated half-lives of the transplants were 12.5 years and 8.6 years, respectively, and the mean duration of cold ischemia was 23 hours and 22 hours, respectively. After adjustment for the effects of demographic characteristics, at 10 years the overall rates of graft survival and the rates of functional-graft survival (with data censored on patients who died with a functioning graft) were 10 percent and 11 percent higher, respectively, for HLA-matched transplants than for HLA-mismatched transplants. Among 3562 pairs of kidneys, HLA-matched transplants had higher rates of survival, a lower incidence of episodes of rejection, and a lower risk of loss as a result of rejection. CONCLUSIONS: A superior graft outcome with little increase in the duration of cold ischemia justifies national sharing of HLA-matched kidney transplants.

Flow cytometric detection of HLA-specific antibodies as a predictor of heart allograft rejection.

BACKGROUND: Historically, panel reactive antibody (PRA) analysis to detect HLA antibodies has been performed using cell-based complement-dependent cytotoxicity (CDC) techniques. Recently, a flow cytometric procedure (FlowPRA) was introduced as an alternative approach to detect HLA antibodies. The flow methodology, using a solid phase matrix to which soluble HLA class I or class II antigens are attached is significantly more sensitive than CDC assays. However, the clinical relevance of antibodies detected exclusively by FlowPRAhas not been established. In this study of cardiac allograft recipients, FlowPRA was performed on pretransplant sera with no detectable PRA activity as assessed by CDC assays. FlowPRA antibody activity was then correlated with clinical outcome. METHODS: PRA analysis by anti-human globulin enhanced (AHG) CDC and FlowPRA was performed on sera corresponding to final cross-match specimens from 219 cardiac allograft recipients. In addition, sera collected 3-6 months posttransplant from 91 patients were evaluated. The presence or absence of antibodies was correlated with episodes of rejection and patient survival. A rejection episode was considered to have occurred based on treatment with antirejection medication and/or histology. RESULTS: By CDC, 12 patients (5.5%) had pretransplant PRA >10%. In contrast, 72 patients (32.9%) had pretransplant anti-HLA antibodies detectable by FlowPRA (34 patients with only class I antibodies; 7 patients with only class II antibodies; 31 patients with both class I and class II antibodies). A highly significant association (P<0.001) was observed between pretransplant HLA antibodies detected by FlowPRA and episodes of rejection that occurred during the first posttransplant year. Fifteen patients died within the first year posttransplant. Of nine retrospective flow cytometric cross-matches that were performed, two were in recipients who had no pretransplant antibodies detectable by FlowPRA. Both of these cross-matches were negative. In contrast, five of seven cross-matches were positive among recipients who had FlowPRA detectable pretransplant antibodies. Posttransplant serum specimens from 91 patients were also assessed for antibodies by FlowPRA. Among this group, 58 patients had FlowPRA antibodies and there was a trend (although not statistically significant) for a biopsy documented episode of rejection to have occurred among patients with these antibodies. CONCLUSIONS: Collectively, our data suggest that pre- and posttransplant HLA antibodies detectable by FlowPRA and not AHG-CDC identify cardiac allograft recipients at risk for rejection. Furthermore, a positive donor reactive flow cytometric cross-match is significantly associated with graft loss. Thus, we believe that detection and identification of HLA-specific antibodies can be used to stratify patients into high and low risk categories. An important observation of this study is that in the majority of donor:recipient pairs, pretransplant HLA antibodies were not directed against donor antigens. We speculate that these non-donor-directed antibodies are surrogate markers that correspond to previous T cell activation. Thus, the rejection episodes that occur in these patients are in response to donor-derived MHC peptides that share cryptic determinants with the HLA antigens that initially sensitized the patient.

Anti-HLA antibodies after solid organ transplantation.

We have cited more than 23 studies showing that de novo development of anti-HLA antibodies is associated with increased acute and chronic rejection and decreased graft survival in kidney, heart, lung, liver, and corneal transplants. Antibodies to both HLA class I and class II antigens seem to be detrimental. Antibodies of the IgG isotype and possibly the IgM isotype were clinically relevant. Most studies showed that donor-specific antibodies were associated with rejection and graft loss. Therefore, HLA antibodies provide a clinical readout for patient alloreactivity that may have the ability to distinguish graft dysfunction due to immunologic and nonimmunologic causes. Antibody may act as a critical trigger for rejection of allografts and may serve as an early indicator of a slowly smoldering chronic rejection that is not manifested at a given time by biochemical measures such as serum creatinine levels. The effectiveness of various drugs on chronic rejection should be evaluable by their effects on HLA antibody production. We predict that recently developed ELISA and flow cytometry techniques using purified HLA antigen will increase the clinical relevance of posttransplantation HLA antibody monitoring by (1) allowing the detection of low levels of donor antibody; (2) easily distinguishing the isotype and target (HLA class I or class II) of the antibodies; and (3) correlating the antibody with specific graft pathology.

Maintenance immunosuppression.

1. The increased utilization of Neoral, Tacrolimus and mycophenolate mofetil correlated with the dramatic decrease in rejection rates in the 1990s. 2. The 4% difference in the incidence of rejection noted for recipients treated with Tacrolimus (20%) compared with Neoral (16%) corresponded to a 34% increased odds ratio in the multivariate analysis. The risk of graft loss and patient death were similar for the 2 calcineurin inhibitors. 3. Almost every renal transplant recipient received mycophenolate mofetil in 1999. This agent reduced the risk of 3-year graft loss by 60% and halved the risk of death compared with azathioprine. 4. Use of solumedrol as a corticosteriod increased from 26-67% in the 1990s, but this change in practice did not significantly impact outcome. 5. Although recipients given induction ATG or OKT3 had increased risk of graft failure, these recipients more likely were sensitized or required early dialysis. 6. The risk of rejection was 90% higher for recipients with 5-6 HLA mismatches than those with 0 A,B,DR mismatches. Recipients with a poorly HLA-matched kidney had 50% increased risk of graft loss within 3 years compared with HLA-matched transplants.

Transplant risks.

1. Changes in serum creatinine is a potentially useful predictor of chronic rejection. Patients with 2 10% increases in creatinine values in 3 consecutive years between 1-5 years had 4 times the risk of chronic rejection graft loss than patients with stable creatinine. 2. Formation of HLA antibody may correlate with graft rejection since losing a kidney increased the risk of broad sensitization 5-fold and losing multiple kidneys increased the risk ten-fold. 3. Sensitization increased the risk of acute and chronic rejection while pregnancies decreased the risk of acute and chronic rejection suggesting that pregnancy may result in "beneficial" sensitization. 4. HLA matching was the most potent factor decreasing the risk of acute rejection 2-fold and chronic rejection by 62%. 5. The incidence of acute and chronic rejection have both decreased significantly since 1994.

Evaluation of the transplant recipient and donor: molecular approach to tissue typing, flow cytometry and alternative approaches to distributing organs.

An enzyme-linked immunosorbent assay test for measuring and characterizing anti-human leukocyte antigen antibodies in recipient sera received mixed evaluations. Enzyme-linked immunosorbent assay and flow cytometry crossmatch tests using solubulized donor human leukocyte antigens were introduced New methods for allocating kidneys included permissible human leukocyte antigen mismatch, human leukocyte antigen amino acid residue match, and kidney size/human leukocyte antigen match algorithms.