Mark I. Aeder

Changes in Deceased Donor Kidney Transplantation One Year After KAS Implementation

After over a decade of discussion, analysis, and consensus‐building, a new kidney allocation system (KAS) was implemented on December 4, 2014. Key goals included improving longevity matching between donor kidneys and recipients and broadening access for historically disadvantaged subpopulations, in particular highly sensitized patients and those with an extended duration on dialysis but delayed referral for transplantation. To evaluate the early impact of KAS, we compared Organ Procurement and Transplantation Network data 1 year before versus after implementation. The distribution of transplants across many recipient characteristics has changed markedly and suggests that in many ways the new policy is achieving its goals. Transplants in which the donor and recipient age differed by more than 30 years declined by 23%. Initial, sharp increases in transplants were observed for Calculated Panel‐Reactive Antibody 99–100% recipients and recipients with at least 10 years on dialysis, with a subsequent tapering of transplants to these groups suggesting bolus effects. Although KAS has arguably increased fairness in allocation, the potential costs of broadening access must be considered. Kidneys are more often being shipped over long distances, leading to increased cold ischemic times. Delayed graft function rates have increased, but 6‐month graft survival rates have not changed significantly.

Ten-year experience in transplantation of A2 kidneys into B and O recipients

BACKGROUND This article summarizes our 10-year multicenter experience with transplantation of 50 blood group A2 and A2B kidneys into B and O patients. METHODS Since 1986, we have transplanted kidneys from 46 cadaver donors and 4 living donors who were blood group A2 (47 donors) or A2B (3 donors) into 19 B and 31 O patients. In 1991, we began allocating these kidneys preferentially to B and O recipients who were selected based on a history of low (< or =4) anti-A IgG isoagglutinin titers. Immunosuppression was no different from that used in ABO-compatible grafts. RESULTS The 1-month function rate before thus selecting the patients was 68% (19/28), but is now 94% (17/18). Two-year cadaver-donor graft survival with this selection method is 94%, compared with 88% for 640 concurrent and consecutive ABO-compatible transplants (log-rank, 0.15). All four living-related transplants are still functioning, with a mean follow-up of 71 months. Since we began allocating A2 kidneys preferentially to B and O recipients, the percentage of the B patients who received A2 or A2B kidneys has increased from 29% (8/28) to 55% (10/18). CONCLUSIONS Transplantation of A2 or A2B kidneys into B and O patients is clinically equivalent to that of ABO-compatible transplantation when recipients are selected by low pretransplant anti-A titer histories. This approach increases access of blood group B recipients to kidneys.

Long-term graft survival is improved in cadaveric renal retransplantation by flow cytometric crossmatching.

BACKGROUND Cadaveric renal retransplantation is associated with a higher risk of early graft failure than primary grafts. A large proportion of those graft losses is likely attributable to donor-directed HLA class I antibodies, detectable by flow cytometry cross-matching but not by conventional crossmatching techniques. METHODS Long-term graft survival in a group of 106 recipients of consecutive cadaveric renal regrafts between 1990 and 1997, in whom a negative flow T-cell IgG crossmatch was required for transplantation, was compared with two other groups of cadaveric transplant recipients. The first group consisted of 174 cadaveric regrafts transplanted between 1985 and 1995 using only a negative anti-human globulin (AHG) T-cell IgG crossmatch. The second group was primary cadaveric transplants done concurrently with the flow group (1990 to 1997) using only the AHG T-cell IgG crossmatch. RESULTS The long-term (7 year) graft survival rate of flow crossmatch-selected regraft recipients (68%; n= 106) was significantly improved over that of regraft recipients who were selected for transplantation by only the AHG crossmatch technique (45%; n=174; log-rank=0.001; censored for patients dying with a functioning graft). Graft outcome for the flow cross-matched regraft recipients was not significantly different from that of primary cadaveric patients (72%; n=889; log-rank=0.2; censored for patients dying with a functioning graft). Finally, a positive B-cell IgG flow cytometric crossmatch had no influence on long-term regraft outcome. CONCLUSIONS The use of the flow T-cell IgG cross-match as the exclusion criterion for cadaveric renal retransplantation yields an improved long-term graft outcome over that obtained when only the AHG cross-match is used and has improved survival of regraft recipients to the level of our primary cadaveric renal transplant population.

Hemodialysis Vintage, Black Ethnicity, and Pretransplantation Antidonor Cellular Immunity in Kidney Transplant Recipients

Prolonged exposure to dialysis before transplantation and black ethnicity are known risk factors for acute rejection and graft loss in kidney transplant recipients. Because the strength of the primed antidonor T cell repertoire before transplantation also is associated with rejection and graft dysfunction, this study sought to determine whether hemodialysis (HD) vintage and/or black ethnicity affected donor-directed T cell immunity. An enzyme-linked immunosorbent spot (ELISPOT) assay was used to measure the frequency of peripheral T cells that expressed IFN-gamma in response to donor stimulator cells before transplantation in 100 kidney recipients. Acute rejection occurred in 38% of ELISPOT (+) patients versus 14% of ELISPOT (-) patients (P = 0.008). The median (HD) vintage was 46 mo (0 to 125 mo) in ELISPOT (+) patients versus 24 mo (0 to 276 mo) in ELISPOT (-) patients (P = 0.009). Black recipients had a greater median HD vintage (55 versus 14 mo in nonblack recipients; P < 0.001). Black recipients with less HD exposure had a low incidence of an ELISPOT (+) test, similar to nonblack recipients. Among variables examined, only HD vintage remained a significant positive correlate with an ELISPOT (+) result (odds ratio per year of HD 1.3; P = 0.003). These data suggest that the risk for developing cross-reactive antidonor T cell immunity increases with longer HD vintage, providing an explanation for the previously observed relationship between increased dialysis exposure and worse posttransplantation outcome. Longer HD vintage may also explain the increased T cell alloreactivity that previously was observed in black kidney recipients.

Cold ischemia time: An independent predictor of increased HLA class I antibody production after rejection of a primary cadaveric renal allograft

Background. Cadaveric kidneys experiencing longer cold ischemia time (CIT) are associated with higher levels of delayed graft function, acute rejection, and early graft loss. One mechanism to explain these results is that ischemia/reperfusion (I/R) injury makes the allograft more immunogenic by upregulating molecules involved in the immune response (e.g., HLA Class I/II). Methods. We evaluated the influence of CIT on the production of HLA Class I antibody level, measured by an antihuman globulin panel reactive antibody (AHG PRA) level, in 90 unsensitized recipients of primary cadaveric renal transplants (from a total of 1442 between 1985 and 1997) who rejected their kidneys. Results. By multivariate analysis, a CIT of 15 hr or more (vs.<15 hr) independently increased the risk of the AHG Class I PRA level being ≥20% after unsensitized patients rejected their first kidneys (relative risk=3.57; 95% confidence interval=1.26 to 10.14;P =0.01), despite the same degree of Class I/II mismatch between the two CIT groups. The overall mean peak PRA level after primary kidney rejection was significantly lower for the CIT<15 hr group (25.9%±33.9; n=24) compared with the CIT≥15 hr group (46.3%±36.5; n=66) (P <0.001). Conclusion. Longer CIT induces a humorally more immunogenic kidney.

Ethical Considerations for Participation of Nondirected Living Donors in Kidney Exchange Programs

Kidneys from nondirected donors (NDDs) have historically been allocated directly to the deceased donor wait list (DDWL). Recently, however, NDDs have participated in kidney exchange (KE) procedures, including KE ‘chains’, which have received considerable media attention. This increasing application of KE chains with NDD participation has occurred with limited ethical analysis and without ethical guidelines. This article aims to provide a rigorous ethical evaluation of NDDs and chain KEs. NDDs and bridge donors (BDs) (i.e. living donors who link KE procedures within KE chains) raise several ethical concerns including coercion, privacy, confidentiality, exploitation and commercialization. In addition, although NDD participation in KE procedures may increase transplant numbers, it may also reduce NDD kidney allocation to the DDWL, and disadvantage vulnerable populations, particularly O blood group candidates. Open KE chains (also termed ‘never‐ending’ chains) result in a permanent diversion of NDD kidneys from the DDWL. The concept of limited KE chains is discussed as an ethically preferable means for protecting NDDs and BDs from coercion and minimizing ‘backing out’, whereas ‘honor systems’ are rejected because they are coercive and override autonomy. Recent occurrences of BDs backing out argue for adoption of ethically based protective measures for NDD participation in KE.

Simultaneous Liver–Kidney Allocation Policy: A Proposal to Optimize Appropriate Utilization of Scarce Resources

The introduction of the Mayo End‐Stage Liver Disease score into the Organ Procurement and Transplantation Network (OPTN) deceased donor liver allocation policy in 2002 has led to a significant increase in the number of simultaneous liver–kidney transplants in the United States. Despite multiple attempts, clinical science has not been able to reliably predict which liver candidates with renal insufficiency will recover renal function or need a concurrent kidney transplant. The problem facing the transplant community is that currently there are almost no medical criteria for candidacy for simultaneous liver–kidney allocation in the United States, and this lack of standardized rules and medical eligibility criteria for kidney allocation with a liver is counter to OPTNs Final Rule. Moreover, almost 50% of simultaneous liver–kidney organs come from a donor with a kidney donor profile index of ≤0.35. The kidneys from these donors could otherwise be allocated to pediatric recipients, young adults or prior organ donors. This paper presents the new OPTN and United Network of Organ Sharing simultaneous liver–kidney allocation policy, provides the supporting evidence and explains the rationale on which the policy was based.

Differences in patient and transplant professional perceptions of immunosuppression-induced cosmetic side effects

Background. A two-part study was initiated to compare kidney transplant patient and transplant professional perceptions regarding immunosuppression-related physical changes and their impact on transplant recipients. Methods. Parallel surveys were developed and administered to transplant patients and active transplant clinicians. Results. Eighty percent of surveyed patients reported immunosuppression-induced hirsutism, gingival hyperplasia, acne, alopecia, or cushingoid facies. Hirsutism (94%) and gingival hyperplasia (51%) occurred more frequently in cyclosporine patients (p < 0.01); alopecia (30%) occurred more frequently in tacrolimus patients (p < 0.01). Patient reported incidence of physical changes significantly exceeded observations by professionals for every condition (p < 0.01), however 84.4% of affected patients reported feeling “happy to endure” changes “for the sake of having a transplant.” Patients also reported emotional and social effects due to physical changes, an outcome underestimated by transplant professionals (p < 0.01). Patients and professionals communicated about physical changes; however, more than half of affected patients believed communication occurred “rarely/never” while over half of the professionals believed communication occurred “every visit/most of the time.” Although most physicians believed changes could be addressed, doctors recommended treatment for less than half of the affected patients. When recommended therapy changes were pursued, treatments were effective in the majority of cases. Conclusions. Incidence of immunosuppression-related physical changes is high and somewhat dependent on drug regimen. Although patients seem willing to accept cosmetic changes for the sake of having a transplant, physical changes have a psychosocial impact that is underestimated by clinicians. Immunosuppression-related physical changes remain underaddressed; effective interventions offer opportunities for improved care.

Long-term graft outcomes after steroid withdrawal in African American kidney transplant recipients receiving sirolimus and tacrolimus

Background. We previously reported excellent short-term outcomes in African American kidney transplant patients receiving tacrolimus/sirolimus and withdrawn from corticosteroid therapy three months after transplantation. We now report the long-term outcomes of patients subjected to this protocol. Methods. In all, 47 African American kidney transplant recipients were enrolled in an uncontrolled trial in which they were initially treated with sirolimus, tacrolimus, and corticosteroids, without antibody induction therapy. Eligible patients were withdrawn from prednisone between three and five months posttransplant, and followed for acute rejection and changes in renal function. Outcomes (group 1, n=32) were compared to those of patients deemed not to be candidates for steroid withdrawal (group 2, n=15). Results. After a mean follow-up of 48.5 months, 13 of 32 patients (41%) in group 1 developed acute rejection; only 13 patients (41%) remain steroid-free. Nine of 13 rejection episodes were associated with noncompliance. Graft loss occurred in 8 of 32 patients (25%) in group 1 and in 5 of 15 patients (33%) in group 2 (P=NS). Serum creatinine rose from 1.4±0.41 to 2.45±1.7 mg/dL in group 1 (P=0.004) and from 2.1±0.45 to 2.62±1.2 mg/dL (P=NS) in group 2. Among 13 patients in group 1 who remain steroid-free, creatinine concentration has risen from 1.28±.0.37 prior to steroid withdrawal to 1.64+0.54 at last follow-up (P=0.027). Conclusions. Late noncompliance and/or rejection in African Americans withdrawn from steroids have a negative impact on long-term graft function and survival. Steroid withdrawal may be associated with long-term deterioration of renal function, even in the absence of overt acute rejection.

Technical limitations in the rapid infusion of intravenous fluids

We compared fluid delivery, both in vitro and in vivo, using various combinations of fluid sets and intravenous catheters. Administration sets were a minidrip, a maxidrip, and a blood infusion set. The catheters included 14-, 16-, 18-, and 20-gauge short catheters, 16- and 19-gauge long catheters, and an 8 French catheter introducer for flow-directed pulmonary arterial lines. Blood infusion tubing alone delivered fluid at 3.12 +/- .07 mL/second, significantly faster than either the maxidrip (2.59 +/- .06, P less than .01) or the minidrip (0.56 +/- .02, P less than .001). The 8 French introducer provided no additional resistance to the flow of the maxidrip or blood infusion set when used in combination with an anesthesia extension. All the other catheters slowed flow significantly. Percutaneous insertion of an 8 French catheter introducer connected to blood administration tubing allows for rapid delivery of fluids and for subsequent insertion of a Swan-Ganz catheter, which is often necessary in critically ill patients.