Paul I. Terasaki, PhD, 1929-2016.

Paul Terasaki was a pioneer of transplantation and had a global following. His career, which spanned >50 years, included accomplishments and discoveries that revolutionized the field of transplantation and that advanced the care of transplant patients. Paul is survived by his wife Hisako, his brother, four children and six grandchildren as well as legions of close friends and colleagues around the world who will continue to build on his successes.

Kidney paired donation in the presence of donor-specific antibodies.

Incompatible donor/recipient pairs with broadly sensitized recipients have difficulty finding a crossmatch-compatible match, despite a large kidney paired donation pool. One approach to this problem is to combine kidney paired donation with lower-risk crossmatch-incompatible transplantation with intravenous immunoglobulin. Whether this strategy is non-inferior compared with transplantation of sensitized patients without donor-specific antibody (DSA) is unknown. Here we used a protocol including a virtual crossmatch to identify acceptable crossmatch-incompatible donors and the administration of intravenous immunoglobulin to transplant 12 HLA-sensitized patients (median calculated panel reactive antibody 98%) with allografts from our kidney paired donation program. This group constituted the DSA(+) kidney paired donation group. We compared rates of rejection and survival between the DSA(+) kidney paired donation group with a similar group of 10 highly sensitized patients (median calculated panel reactive antibody 85%) that underwent DSA(-) kidney paired donation transplantation without intravenous immunoglobulin. At median follow-up of 22 months, the DSA(+) kidney paired donation group had patient and graft survival of 100%. Three patients in the DSA(+) kidney paired donation group experienced antibody-mediated rejection. Patient and graft survival in the DSA(-) kidney paired donation recipients was 100% at median follow-up of 18 months. No rejection occurred in the DSA(-) kidney paired donation group. Thus, our study provides a clinical framework through which kidney paired donation can be performed with acceptable outcomes across a crossmatch-incompatible transplant.

Calculated PRA: initial results show benefits for sensitized patients and a reduction in positive crossmatches.

The calculated panel reactive antibody (CPRA), which is based upon unacceptable HLA antigens listed on the waitlist form for renal transplant candidates, replaced PRA as the measure of sensitization among US renal transplant candidates on October 1, 2009. An analysis of the impact of this change 6 months after its implementation shows an 83% reduction in the number of kidney offers declined nationwide because of a positive crossmatch. The increasing acceptance and utilization of unacceptable HLA antigens to avoid offers of predictably crossmatch-positive donor kidneys has increased the efficiency of kidney allocation, resulting in a significant increase in the percentage of transplants to broadly sensitized (80+% PRA/CPRA) patients from 7.3% during the period 07/01/2001-6/30/2002 to 15.8% of transplants between 10/1/09-3/31/10. The transplant rates per 1000 active patient-years on the waitlist also increased significantly for broadly sensitized patients after October 1, 2009. These preliminary results suggest that 'virtual' positive crossmatch prediction based on contemporary tools for identifying antibodies directed against HLA antigens is effective, increases allocation efficiency and improves access to transplants for sensitized patients awaiting kidney transplantation.

Calculated PRA (CPRA): the new measure of sensitization for transplant candidates.

The ways we measure whether a patient is sensitized to HLA antigens and to what extent sensitization affects access to transplantation have changed remarkably during the past decade. What we mean by sensitized and broadly sensitized today is heavily dependent upon the sensitivity of the test that is used to measure antibodies. Because we provide additional allocation points for broadly sensitized patients in the United States kidney allocation system in an effort to compensate for their biological disadvantage, some consistency and accountability are required. The calculated panel-reactive antibody, which provides an estimate of the percentage of deceased organ donors that will be crossmatch incompatible for a candidate provides both consistency and accountability.

Inflammation in areas of tubular atrophy in kidney allograft biopsies: a potent predictor of allograft failure.

The Banff scoring schema provides a common ground to analyze kidney transplant biopsies. Interstitial inflammation (i) and tubulitis (t) in areas of viable tissue are features in scoring acute rejection, but are excluded in areas of tubular atrophy (TA). We studied inflammation and tubulitis in a cohort of kidney transplant recipients undergoing allograft biopsy for new-onset late graft dysfunction (N = 337). We found inflammation ('iatr') and tubulitis ('tatr') in regions of fibrosis and atrophy to be strongly correlated with each other (p < 0.0001). Moreover, iatr was strongly associated with death-censored graft failure when compared to recipients whose biopsies had no inflammation, even after adjusting for the presence of interstitial fibrosis (Hazard Ratio = 2.31, [1.10-4.83]; p = 0.0262) or TA (hazard ratio = 2.42, [1.16-5.08]; p = 0.191), serum creatinine at the time of biopsy, time to biopsy and i score. Further, these results did not qualitatively change after additional adjustments for C4d staining or donor specific antibody. Stepwise regression identified the most significant markers of graft failure which include iatr score. We propose that a more global assessment of inflammation in kidney allograft biopsies to include inflammation in atrophic areas may provide better prognostic information. Phenotypic characterization of these inflammatory cells and appropriate treatment may ameliorate late allograft failure.

Histopathologic clusters differentiate subgroups within the nonspecific diagnoses of CAN or CR: preliminary data from the DeKAF study.

The nonspecific diagnoses 'chronic rejection''CAN', or 'IF/TA' suggest neither identifiable pathophysiologic mechanisms nor possible treatments. As a first step to developing a more useful taxonomy for causes of new-onset late kidney allograft dysfunction, we used cluster analysis of individual Banff score components to define subgroups. In this multicenter study, eligibility included being transplanted prior to October 1, 2005, having a 'baseline' serum creatinine < or =2.0 mg/dL before January 1, 2006, and subsequently developing deterioration of graft function leading to a biopsy. Mean time from transplant to biopsy was 7.5 +/- 6.1 years. Of the 265 biopsies (all with blinded central pathology interpretation), 240 grouped into six large (n > 13) clusters. There were no major differences between clusters in recipient demographics. The actuarial postbiopsy graft survival varied by cluster (p = 0.002). CAN and CNI toxicity were common diagnoses in each cluster (and did not differentiate clusters). Similarly, C4d and presence of donor specific antibody were frequently observed across clusters. We conclude that for recipients with new-onset late graft dysfunction, cluster analysis of Banff scores distinguishes meaningful subgroups with differing outcomes.

Pathological and clinical characterization of the 'troubled transplant': data from the DeKAF study.

We are studying two cohorts of kidney transplant recipients, with the goal of defining specific clinicopathologic entities that cause late graft dysfunction: (1) prevalent patients with new onset late graft dysfunction (cross-sectional cohort); and (2) newly transplanted patients (prospective cohort). For the cross-sectional cohort (n = 440), mean time from transplant to biopsy was 7.5 +/- 6.1 years. Local pathology diagnoses included CAN (48%), CNI toxicity (30%), and perhaps surprisingly, acute rejection (cellular- or Ab-mediated) (23%). Actuarial rate of death-censored graft loss at 1 year postbiopsy was 17.7%; at 2 years, 29.8%. There was no difference in postbiopsy graft survival for recipients with versus without CAN (p = 0.9). Prospective cohort patients (n = 2427) developing graft dysfunction >3 months posttransplant undergo 'index' biopsy. The rate of index biopsy was 8.8% between 3 and 12 months, and 18.2% by 2 years. Mean time from transplant to index biopsy was 1.0 +/- 0.6 years. Local pathology diagnoses included CAN (27%), and acute rejection (39%). Intervention to halt late graft deterioration cannot be developed in the absence of meaningful diagnostic entities. We found CAN in late posttransplant biopsies to be of no prognostic value. The DeKAF study will provide broadly applicable diagnostic information to serve as the basis for future trials.

Should pediatric patients wait for HLA-DR-matched renal transplants?

Graft survival rates from deceased donors aged 35 years or less among all primary pediatric kidney transplant recipients in the United States between 1996 and 2004 were retrospectively examined to determine the effect of HLA-DR mismatches on graft survival. Zero HLA-DR-mismatched kidneys had statistically comparable 5-year graft survival (71%), to 1-DR-mismatched kidneys (69%) and 2-DR-mismatched kidneys (71%). When compared to donors less than 35 years of age, the relative rate of allograft failure was 1.32 (p = 0.0326) for donor age greater than or equal to age 35. There was no statistical increase in the odds of developing a panel-reactive antibody (PRA) greater than 30% at the time of second waitlisting, based upon the degree of HLA-A, -B or -DR mismatch of the first transplant, nor was there a 'dose effect' when more HLA antigens were mismatched between the donor and recipient. Therefore, pediatric transplant programs should utilize the recently implemented Organ Procurement and Transplantation Network's (OPTN)allocation policy, which prioritizes pediatric recipients to receive kidneys from deceased donors less than 35 years of age, and should not turn down such kidney offers to wait for a better HLA-DR-matched kidney.

The liver neither protects the kidney from rejection nor improves kidney graft survival after combined liver and kidney transplantation from the same donor.

It has been proposed that the liver protects a simultaneously transplanted kidney from acute rejection. Using the United Network for Organ Sharing database, we compared the kidney allograft data from 248 combined liver and kidney transplants (LKT) with a control group comprising 206 contralateral kidney alone transplants (KAT) from the same donor. The LKT and KAT groups were identical with respect to most baseline parameters, save a greater degree of HLA matching in the KAT group. The overall 3-year graft survival rate was higher in the KAT group compared with the LKT group (80% vs 68%, P < 0.01). When these data were censored to remove death as a cause of graft loss and to minimize the matching effect, the 3-year survival rates were not statistically different (78% for KAT and 81% for LKT, P = NS). We conclude that the liver neither protects the kidney from rejection nor improves kidney allograft function or survival after LKT.

Repeating HLA antigen mismatches in renal retransplants--a second class mistake?

Should HLA antigens that were mismatched in a renal transplant that failed be avoided in subsequent transplants? There were 890 retransplantations reported to the UCLA International Kidney Transplant Registry between 1985 and 1993 that had been performed in the face of a repeat HLA incompatibility. The 1- and 3-year regraft survival rates were 67% and 55%, respectively, for these retransplants, compared with 73% and 60% for 3220 regrafts with no HLA-A, -B, or -DR antigens mismatched twice (P = 0.030). When the repeat HLA-mismatched antigens were examined by locus, there was no difference in regraft survival comparing patients with no repeat HLA incompatibilities with those mismatched twice for HLA-A or -B antigens only, but there was a significant long-term decrease in survival of patients mismatched twice for HLA-DR antigens. The 377 patients mismatched twice only for HLA-A or -B antigens had 1- and 3-year regraft survival rates of 67% and 59%, respectively, compared with 65% (P = 0.289) and 50% (P = 0.025) for 281 patients with HLA-DR repeat mismatches only. Repeat mismatches for a combination of HLA-A or -B and -DR antigens resulted in 65% and 44% 1- and 3-year regraft survival in 129 patients. The half-lives for retransplants with repeat HLA class I, II, and I and II incompatibilities were 8, 6, and 4 years, respectively (P = 0.005). The data do not support preemptive avoidance of repeat HLA-A or -B incompatibilities. The crossmatch test excludes relevant mismatches. Repeated HLA-DR incompatibilities are not excluded by crossmatch tests and have a deleterious effect on long-term regraft survival. HLA-DR antigens mismatched in a previous failed transplant should be avoided.

Improvement of kidney transplant regraft results by using trauma death donors.

Patients who have lost a transplanted kidney are widely recognized as high-risk patients for retransplantation. We have found a profound difference in cadaver kidney regraft survival associated with the age and sex of the donor. Kidneys from male cadaver donors yielded significantly higher graft survival rates than kidneys from female donors. The difference in graft survival at one year was 7% for all first transplants (n = 2974), 14% if the recipient was sensitized, and 18% in 688 patients being regrafted. The difference was even more striking in regraft recipients of kidneys from young male donors (72% one-year graft survival) as compared with recipients of kidneys from older female donors (44% one-year graft survival). The donor age and sex effects correlated well with the cause of donor death. Young male donors accounted for 59% of trauma deaths whereas older female donors made up only 7%. Nontrauma donors, on the other hand, were 38% older female and 14% younger male. The survival of trauma-death donor kidneys in regrafted patients was 69% at one year and 37% for nontrauma donor kidneys, a 32% difference (P less than 0.001). These results indicate that regraft survival could be significantly increased through the use of cadaver kidneys from trauma death donors.

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.

The great success of Asian kidney transplant recipients.

BACKGROUND: Little has been written about allograft survival in non-African-American minority groups. We examine the success of kidney transplantation in 1900 Asian recipients. METHODS: Data from 42,252 cadaveric and 16,115 live donor kidney transplant recipients were monitored from the United Network for Organ Sharing Scientific Renal Transplant Registry from 1991 through 1996. RESULTS: Asian recipients exhibited the highest cadaveric allograft survival rates (89% 1-year and 83% 3-year survival) and the longest mean allograft half-life (18 years). Asian women had the highest mean graft half-life (23 years). Asians were less likely to be broadly sensitized and had a high incidence of IgA nephropathy causing end-stage renal disease. Although it has been suggested that their low body weights may help explain the excellent allograft outcome, Asians exhibited superior graft survival rates even when compared with low body weight recipients of other races. CONCLUSION: Asian renal allograft recipients, particularly Asian females, have the highest allograft survival rates of all racial groups.

The transfusion effect in cadaver kidney transplants--yes or no.

The transfusion effect in first cadaver kidney transplants was re-examined at the UCLA Transplant Registry. One-year graft survival rates were 71% for non-transfused patients, which improved to 75% (P less than 0.05) with a single transfusion, 77% (P less than 0.01) with 2, and 78% (P less than 0.01) with 3 and 4 transfusions. One-year graft survival rates did not improve further with additional transfusions but remained at the same level. Thus, the transfusion effect clearly does exist, and 2 to 4 transfusions are sufficient to obtain the maximum beneficial transfusion effect. Patients with zero HLA-DR mismatched transplants had no blood transfusion effect. Transfusions improved the 1-year graft survival rate by 8% for transplant recipients with 1 DR-mismatched grafts (P less than 0.01) and by 10% with 2 DR-mismatched grafts (P less than 0.01). The transfusion effect was greater in Black than White recipients; however, the 77% 1-year graft survival rate for transfused Black recipients of zero DR-mismatched kidneys did not differ from that of transfused comparably matched Whites. We conclude that transfusion protocols should not be abandoned unless patients receive zero DR-mismatched kidneys.

Kidney transplants in black recipients. HLA matching and other factors affecting long-term graft survival.

Primary kidney transplants from living related and cadaveric donors to black recipients failed twice as rapidly as those to white recipients in data reported to the United Network for Organ Sharing Scientific Renal Transplant Registry between 1987 and 1991. The projected half-life for 132 HLA-identical sibling donor transplants in blacks was 15 years versus 29 years for 1,033 whites (P < 0.001). For recipients of cadaveric grafts, the half-lives were 5 years for blacks (n = 5,282) and 10 years for whites (n = 14,917). The 1-year graft survival rates and half-lives improved with HLA matching in both blacks and whites, but the 2-fold difference in long-term survival rates persisted even among recipients of well-matched grafts. With a zero HLA-A,B-mismatched donor, blacks had an 8-year half-life, compared with 17 years for whites (P < 0.001). The racial difference was most marked in young adults, with a 15-20% disparity at 3 years between blacks and whites aged 16-30. Pediatric and older black patients had 3-year graft survival rates similar to those of whites. Antilymphocyte globulin or OKT3 prophylaxis improved graft survival by 2% at 1 year and 5% at 2 years among blacks, but the half-life remained 5.6 years. In contrast to these findings in the United States, 63 blacks transplanted in Canada had the same short- and long-term graft survival as whites, suggesting an important long-term influence of the health care system and socioeconomic factors. In addition to improved access to health care and improved HLA typing of blacks, more black donors are needed to provide better matched transplants for blacks awaiting transplants.

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.

Six-antigen-matched transplants. Causes of failure.

The causes of failure were studied for 1386 cadaver kidney transplants shared through the UNOS 6-antigen match program from November 1987 to February 1992. The one-year graft survival for 1004 HLA-matched first cadaver transplants was 88% compared with 90% for parent donor and 78% for 22,188 HLA-mismatched first cadaveric donors reported to the UNOS Scientific Renal Transplant Registry. The cause of graft loss was immunological in 55% of HLA-mismatched cadaver kidney failures, whereas only 39% of the HLA-matched graft failures were immunological. The fraction of immunological failures in HLA-matched first transplant recipients younger than age 17 was 57% and decreased with increasing age to 14% for recipients older than age 60. Death with a functioning graft accounted for 50% of failures in the older age group. Sensitization was associated with an increased incidence of immunological failures in matched first graft recipients from 36% in nonsensitized to 53% in broadly sensitized patients, and 55% of failures were immunological in second graft recipients compared with 39% in first transplants. Some immunological failures may have been due to tissue typing, since only 18% of failures in kidneys with well-defined HLA antigens were immunological, whereas 44% of kidneys matched with more difficult HLA antigens were lost due to immunological causes. The results indicate that phenotypically identical cadaver renal transplants have a reduced rate of immunological failures. As the accuracy of this tissue typing for the more difficult HLA antigens improves, immunological failures in this group of transplants will decline even further.

Patient death after renal transplantation--an analysis of its role in graft outcome.

Whether patient deaths among renal transplant recipients should be counted as transplant failures when they occur while the transplant is still functioning is a controversial issue. Analyses of more than 45,000 first cadaver transplants reported to the UNOS Scientific Renal Transplant Registry between October 1987 and March 1995 showed that deaths among transplant recipients were strongly associated with the patient's age and presence of insulin-dependent diabetes. Other factors associated with poor early graft function were also associated with a significantly increased risk of death. Deaths within the first 5 years increased from 9% of recipients aged 2-15 to 30% of those over age 45 (P < 0.001). Deaths with a functioning graft occurred in 2% of the youngest patients and 13% in the older age group (P < 0.001). Among diabetics, 32% died within 5 years (12% with a functioning graft) compared with 10% (6% with graft function) of patients with glomerulonephritis (P < 0.001). When the transplanted kidney failed to function immediately or the patient required dialysis during the first week after transplant, 30% of patients died within 5 years compared with 20% when the graft functioned (P < 0.001). There was no difference in the percentage of deaths with a functioning graft. We conclude that deaths among renal transplant recipients follow an expected pattern in which the likelihood of death increases with age and diabetes.