J. Michael Cecka

Deleterious effects of delayed graft function in cadaveric renal transplant recipients independent of acute rejection

BACKGROUND In cadaveric renal transplantation, delayed graft function (DGF) correlates with poor long-term graft survival; however, whether its effects are independent of acute rejection is controversial. We wished to study the effect of DGF on graft survival, controlling for acute rejection, discharge creatinine, and human leukocyte antigen match. METHODS We analyzed 27,096 first cadaveric donor renal transplants reported to the UNOS Scientific Renal Transplant Registry between January 1994 and November 1997. DGF was defined as dialysis need in the first week. Acute rejection was recorded for initial hospitalization and within 6 months. Kaplan Meier survival curves were analyzed with the log rank test. RESULTS DGF increased the incidence of acute rejection before discharge (8% without DGF; 25% with DGF, P<0.01) and any acute rejections by 6 months (25% without DGF, 42% with DGF, P<0.01). Without early rejection, DGF reduced 1-year graft survival from 91 to 75% (P<0.0001) and graft half-life from 12.9 to 8.0 years. In kidneys with acute rejection within 6 months, DGF decreased 3-year graft survival from 77 to 60% and graft half-life from 9.4 to 6.2 years (P<0.001). With a discharge creatinine of less than 2.5 mg/dl, the difference in graft half-life between no DGF and no rejection (13.4 years) and DGF with rejection (9.8 years) was significant (P<0.001). Increased donor age and cold ischemia time additionally decreased graft survival, whereas a good human leukocyte antigen match could not overcome the deleterious effects of DGF or acute rejection. CONCLUSIONS DGF is an important independent predictor of poor graft survival. Newer immunosuppressive strategies must minimize nonimmune and immune renal injury if long-term graft survival is to improve.

Evidence for antibody-mediated injury as a Major determinant of late kidney allograft failure

Background. Late graft failure (LGF) is believed to be the consequence of immunologic and nonimmunologic insults leading to progressive deterioration in kidney function. We studied recipients with new onset late kidney graft dysfunction (n=173) to determine the importance of C4d staining and circulating donor-specific antibody (DSA) in subsequent LGF. Methods. One hundred seventy-three subjects transplanted before October 1, 2005 (mean time after transplant 7.3±6.0 years) had a baseline serum creatinine level of 1.4±0.3 mg/dL before January 1, 2006 and underwent biopsy for new onset graft dysfunction after that date (mean creatinine at biopsy 2.7±1.6 mg/dL). Statistical analysis was based on central DSA and blinded pathology determinations. Results. Subjects were divided into four groups based on C4d and DSA: no C4d, no DSA (group A; n=74); only DSA (group B; n=31); only C4d (group C; n=28); and both C4d and DSA (group D; n=40). Among DSA+ recipients (groups B and D), group D had broader reactivity and a stronger DSA response. After 2 years, groups C and D (C4d+) were at significantly greater risk for LGF than groups A and B. Adjusting for inflammation (Banff i, t, g, and ptc scores) did not change the outcome. Local diagnosis of calcineurin inhibitor nephrotoxicity was spread across all four subgroups and did not impact risk of LGF. Conclusions. Evidence of antibody-mediated injury (DSA or C4d) is common (57%) in patients with new onset late kidney allograft dysfunction. The risk of subsequent graft failure is significantly worse in the presence of C4d+ staining.

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.

The Report of a National Conference on the Wait List for Kidney Transplantation

In March, 2002, over 100 members of the transplant community assembled in Philadelphia for a meeting designed to address problems associated with the growing number of patients seeking kidney transplantation and added to the waiting list each year. The meeting included representatives of nine US organizations with interests in these issues. Participants divided into work groups addressing access to the waiting list, assigning priority on the list, list management, and identifying appropriate candidates for expanded criteria donor kidneys. Each work group outlined problems and potential remedies within each area. This report summarized the issues and recommendations regarding the waiting list for kidney transplantation addressed in the Philadelphia meeting.

Kidney Allograft and Patient Survival in Type I Diabetic Recipients of Cadaveric Kidney Alone Versus Simultaneous Pancreas/Kidney Transplants: A Multivariate Analysis of the UNOS Database

Simultaneous pancreas-kidney transplant (SPK) is now a common treatment for insulin-dependent diabetic patients with end-stage renal disease. Renal graft survival rates after SPK have been less well studied. This study compared the kidney survival results for 3642 SPK and 2374 cadaveric renal transplants (CRT) in type I diabetic patients at 112 US transplant centers reported to UNOS during 1994 through 1997. The analysis included follow-up information through September 2000. The kidney graft survival rates were significantly lower among recipients of CRT compared with SPK recipients (P < 0.001). Patients who received SPK were younger, less often sensitized, transplanted after shorter periods on dialysis, and less often black. The donors of SPK organs were younger, more often died from head trauma, were less often female, and more often black. SPK renal grafts were transplanted with a shorter cold ischemia time to more poorly HLA-matched recipients. After adjustment of these and other factors, whether a patient was recipient of CRT or SPK was not associated with increased risk of kidney graft failure or patient death. SPK recipients experienced half the rate of delayed kidney function (11% versus 23%) but nearly double the rate of rejections during the initial hospitalization (15% versus 9%) compared with CRT recipients. SPK was associated with better renal allograft survival compared with CRT, despite a higher rate of renal allograft rejection. This observation was explained by favorable donor and recipient factors in the SPK group. After controlling for these factors, SPK provided no protective or detrimental effect on short-term renal allograft or patient survival.

Determinants of long‐term survival of pediatric kidney grafts reported to the United Network for Organ Sharing kidney transplant registry*

Abstract: Pediatric 1‐yr kidney graft survival rates have steadily improved in the US so that, by 1998, over 90% of hospital‐discharged young recipients had survived the first year post‐transplantation (Tx). However, 25% of the early surviving kidney grafts failed at 5 yr, yielding a projected half‐life of 10 yr. Given a median age at transplant of 13 yr (range 0–20 yr), 50% of all current pediatric kidney recipients will need a second graft before the age of 25 years. We examined 8422 pediatric renal transplants reported to the United Network for Organ Sharing (UNOS) Kidney Transplant Registry and, by using a log‐linear multifactorial analysis, determined the relative influence of 26 major transplant factors on long‐term graft survival. Results are reported as percentages of assignable variation (totaling 100% for all 26 factors combined) in pediatric outcomes beyond 1 yr and as adjusted graft survival rates. Transplant center, recipient race and age, transplant year, and panel‐reactive antibody (PRA) had assignable variation percentages of 25, 24, 16, 12, and 4, respectively. When combined, they accounted for 81% of changes in long‐term survival. Besides center effects, Blacks, teenagers, and transplants performed before 1994 exhibited significantly (p < 0.0001) lower adjusted 5‐yr graft survival rates as did the few sensitized (PRA > 40%) pediatric patients (p = 0.02). Patients transplanted with a living donor kidney demonstrated a 5% point advantage at 5 yr post‐Tx over cadaver donor kidneys (p = 0.001). Although the survival rate of pediatric kidney transplants has improved steadily, the long‐term outcomes for teenagers and for Black recipients lag significantly behind those of younger patients and non‐Blacks.

Adult-size kidneys without acute tubular necrosis provide exceedingly superior long-term graft outcomes for infants and small children: a single center and UNOS analysis. United Network for Organ Sharing.

BACKGROUND Infants with end-stage renal disease are at highest risk for early graft loss and mortality of any subgroup undergoing renal transplantation. This study evaluates the influence of donor tissue mass and acute tubular necrosis (ATN) on graft survival and incidence of acute rejection episodes in infant and small child recipients of living donor (LD) and cadaver (CAD) adult-size kidneys (ASKs), pediatric CAD kidneys and combined kidney-liver transplants. Methods. Kidney transplants in infants and small children at a single center and those reported to the UNOS Scientific Renal Transplant Registry were analyzed. At Stanford, multi-variate analysis was conducted on 45 consecutive renal allograft recipients weighing < or = 15 kg, mean weight 11.2 +/- 2.6 kg. The UNOS Registry results in age groups 0-2.5 (n=548) and 2.5-5 years (n=743) were compared with age groups 6-12, 13-18, and the lowest risk adult group of 19-45 years. STANFORD RESULTS. Graft survival was 97.8 +/- 0.0 at 2 years and 84.6 +/- 0.1% at 8 years. The incidence of biopsy proven rejection was 8.8% in the first 3 months and 15.5% over the 8-year follow-up. None of the pediatric CAD kidneys had ATN. Rejection episodes were restricted to the pediatric CAD kidneys alone (3/3), with no kidney rejections in the combined pediatric CAD kidney-liver transplants (0/6; P=0.003). Four ASK transplants had ATN (1 postoperative and 3 late), and all predisposed to subsequent acute rejection episodes (4/4), whereas there were no rejection episodes in ASK transplants without ATN (0/32; P<0.001). At 3 years posttransplantation, mean serum creatinines were worse in ASKs with ATN (1.5 vs. 0.9 mg/dL; P<0.001) and in all grafts with rejection episodes (1.2 vs. 0.9 mg/dL; P<0.05). UNOS RESULTS: Among the 5 age groups studied, significantly better (P<0.001) long-term graft survival rates were observed in allograft recipients in the 2 youngest age groups with ASKs without ATN: 82 +/- 3% and 81 +/- 3% for LD and 70 +/- 7% and 78 +/- 4% for CAD recipients in the 0-2.5 and 2.5- to 5-year age groups, respectively, at 6 years after transplantation. Moreover, the projected graft half-lives after the 1st year in the LD groups without ATN were at least equivalent to those of HLA-identical sibling recipients ages 19-45 years: 26.3 +/- 5 and 29.3 +/- 6 years for the 0- to 2.5- and 2.5- to 5-year age groups, respectively, and 23.3 +/- 1 years for HLA-identical transplants. The graft half-lives for CAD recipients without ATN ages 0-2.5 and 2.5-5 yearswere equivalent or better than those for LD transplants without ATN in recipients aged 19-45 years: 15.4+/- 7 and 23.7 +/- 8 years versus 15.0 +/- 0.3 years. Mean serum creatinines were superior in the 2 younger recipient age groups compared with older age groups. CONCLUSIONS Increased donor tissue mass of the ASK or kidney-liver transplants, in the absence of ATN, seems to confer a protective effect to infant and small child recipients of these allografts. This is manifested by a prolonged rejection-free state in the single center experience and enhanced graft survival and function in the UNOS analysis, comparable to HLA identical sibling transplants for LD infant and small child recipients and to LD adult results for CAD infant and small child recipients. To optimize this protective effect by whatever mechanism, absolute avoidance of ATN is essential in infant recipients of ASK or combined kidney-liver transplants.

Selecting donors of platelets for refractory patientson the basis of HLA antibody specificity

BACKGROUND: Patients who are refractory to platelet transfusion as a result of HLA alloimmunization are generally given HLA‐matched or crossmatched platelets. However, HLA‐matched platelets that are matched at HLA‐A and ‐B loci (A‐matched) or those without any mismatched or cross‐reactive antigens (BU‐matched) are frequently unavailable. A disadvantage of crossmatching is that crossmatched platelets have a shelf life of only 5 days, so that crossmatch tests must be performed frequently for patients requiring long‐term platelet transfusions. An alternative method is the selection of platelets according to the patients HLA antibody specificity, called the antibody specificity prediction (ASP) method.

HLA and MICA: targets of antibody-mediated rejection in heart transplantation.

Background. The goal of this study was to determine whether antidonor antibodies directed against human leukocyte antigen (HLA) or endothelial cells (ECs) expressed antigens, including major histocompatibility complex class I chain-related antigens A (MICA) are associated with the diagnosis of antibody-mediated rejection (AMR) in heart transplant recipients. Methods. We studied posttransplant antidonor HLA antibodies in 168 heart allograft recipients transplanted from October 2001 to December 2005. Among them, there were 37 AMR+ patients and 131 age- and sex- matched AMR− controls. Sera were collected at the time of protocol biopsies and tested for the presence of HLA antibodies. Seventy-two of the 168 patients were genotyped for donor and recipient MICA alleles and were tested for the presence of anti-MICA antibodies. Thirty-one patients who never developed antibodies to HLA or MICA were further tested for anti-EC antibodies. Results and Conclusions. Of 37 AMR+ patients, 22 (60%) developed donor-specific antibodies (DSA) to HLA compared with 6 of 131(4%) AMR− patients (P<0.0001). Of the remaining 15 AMR+ patients, 5 had anti-HLA antibodies that were not donor specific and 10 did not show any HLA antibodies. In the subgroup of 72 patients, all 19 AMR+ patients had clearly demonstrable antibodies reactive with donor HLA, MICA or with nondonor-derived ECs, with 30% of them showed antibodies directed to non-HLA antigens. The incidence of transplant coronary artery disease was significantly higher in patients who had DSA to HLA and MICA compared with patients without DSA.

Could more effective use of kidneys recovered from older deceased donors result in more kidney transplants for older patients

In the face of a severe shortage of kidneys from deceased organ donors that limits access to transplantation for many patients, about one of every seven kidneys (more than 1,500 each year) recovered from deceased donors in the United States are not transplanted. Eurotransplant, which coordinates organ distribution for six countries and a population of about 118 million, discards only one of every 20 kidneys procured for transplantation. We compared kidney procurement, transplants, and discards between January 2000 and June 2003 in the United States and in the Eurotransplant region using the Organ Procurement and Transplantation Network/United Network for Organ Sharing and Eurotransplant databases to examine differences that might account for this wide disparity.