Subsequent Graft Function Research Articles

Predicting the viability of liver allografts procured from non-heart-beating donors: The role of histopathology

Predicting the viability of liver allografts procured from non-heart-beating donors: The role of histopathology

Donor Postextubation Hypotension and Age Correlate With Outcome After Donation After Cardiac Death Transplantation

Compared with standard donors, kidneys recovered from donors after cardiac death (DCD) exhibit higher rates of delayed graft function (DGF), and DCD livers demonstrate higher rates of biliary ischemia, graft loss, and worse patient survival. Current practice limits the use of these organs based on time from donor extubation to asystole, but data to support this is incomplete. We hypothesized that donor postextubation parameters, including duration and severity of hemodynamic instability or hypoxia might be a better predictor of subsequent graft function. We performed a retrospective examination of the New England Organ Bank DCD database, concentrating on donor factors including vital signs after withdrawal of support. Prolonged, severe hypotension in the postextubation period was a better predictor of subsequent organ function that time from extubation to asystole. For DCD kidneys, this manifested as a trend toward increased DGF. For DCD livers, this manifested as increased rates of poor outcomes. Maximizing the predictive value of this test in the liver cohort suggested that greater than 15 min between the time when the donor systolic blood pressure drops below 50 mm Hg and flush correlates with increased rates of diffuse biliary ischemia, graft loss, or death. Donor age also correlated with worse outcome. Time between profound instability and cold perfusion is a better predictor of outcome than time from extubation to asystole. If validated, this information could be used to predict DGF after DCD renal transplant and improve outcomes after DCD liver transplant.

Arteriosclerosis in Kidneys From Healthy Live Donors: Comparison of Wedge and Needle Core Perioperative Biopsies

Abstract Context.—Although risks associated with live kidney donation are low, there are few pathologic studies of kidneys from live donors, and possible risk factors for development of hypertension or renal insufficiency remain unknown. There are many studies of histopathologic changes in deceased donor kidneys and how these changes affect subsequent graft function; most are based on wedge rather than needle core biopsies. Objective.—To examine the frequency and severity of arterial fibrointimal thickening and other pathologic lesions in kidneys from healthy live donors and compare wedge and needle core biopsies as methods for evaluating these changes. Design.—For 36 of 332 live donor renal transplantations performed from January 2004 through November 2006, a wedge biopsy of the transplanted kidney was done prior to and/or after implantation, and a needle core biopsy was done postimplantation or during the ensuing 7 days. For these 36 allografts, we compared pathologic features of the wedge and core peri...

Arteriosclerosis in Kidneys From Healthy Live Donors: Comparison of Wedge and Needle Core Perioperative Biopsies

Although risks associated with live kidney donation are low, there are few pathologic studies of kidneys from live donors, and possible risk factors for development of hypertension or renal insufficiency remain unknown. There are many studies of histopathologic changes in deceased donor kidneys and how these changes affect subsequent graft function; most are based on wedge rather than needle core biopsies. To examine the frequency and severity of arterial fibrointimal thickening and other pathologic lesions in kidneys from healthy live donors and compare wedge and needle core biopsies as methods for evaluating these changes. For 36 of 332 live donor renal transplantations performed from January 2004 through November 2006, a wedge biopsy of the transplanted kidney was done prior to and/or after implantation, and a needle core biopsy was done postimplantation or during the ensuing 7 days. For these 36 allografts, we compared pathologic features of the wedge and core perioperative biopsies. Findings on core and wedge biopsies were similar, except for arterial fibrointimal thickening. Moderate thickening (Banff cv2) was present on 13 core biopsies, and mild thickening (cv1) was present on another 10; by contrast, no wedge biopsies showed cv2 lesions, and only 8 showed cv1. Arterial thickening on core but not wedge biopsies correlated significantly with increasing patient age. The findings indicate that needle core biopsies are superior to wedge biopsies for evaluating vascular changes in donor kidneys, and they suggest a need for studies correlating such changes with long-term outcomes of live donors, particularly older donors.

Experience with deceased donor kidney transplantation in 114 patients over age 60

In the recent past, advanced age was a contraindication to kidney transplantation (KT). The purpose of this study was to review retrospectively our single center experience in deceased donor (DD) KT with respect to recipient age. From 10/1/01 to 9/1/06, we performed 356 adult DD KTs. Patients received antibody induction in combination with tacrolimus, mycophenolate mofetil, and tapered steroids. A total of 114 (32%) patients were greater than 60 (including 25 >70 years), 186 (52%) were 40-59 years of age, and 56 (16%) were 19-39 years of age. Of the 114 older patients, 61 (54%) received KTs from expanded criteria DDs (ECD), more than the younger age groups (39% ECDs in patients 40-59 years versus 18% ECDs in patients 19-39 years, P < .0001). Mean waiting time (21 mo) was less for patients greater than 60 years compared with the other 2 groups combined (29 mo, P = .06). Patient survival was 91% in recipients greater than 60 years compared with 95% in those less than 60 years of age (P = NS) with a mean follow-up of 27 mo. Graft survival was similar for all 3 age groups (82% >60 years vs 83% in patients 40-59 years vs 87% in patients 19-39 years, P = NS). Initial and subsequent graft function, morbidity, and resource use were similar among groups. Patient survival [93% ECD vs 89% standard criteria DDs (SCD), P = NS) and graft survival (82% ECD vs 81% SCD, P = NS) rates were similar, whereas mean waiting times (18 mo ECD vs 25 mo SCD, P = .04) were less in patients greater than 60 years who received ECD KTs compared with patients greater than 60 years who received SCD KTs. Patients greater than 60 years account currently for one third of DD KTs performed at our center, and more than half receive kidneys from ECDs. By preferentially directing ECD kidneys to appropriately selected elderly patients, waiting times can be decreased and survival is similar compared with SCD KTs in the elderly. In addition, short-term outcomes can be achieved in patients greater than 60 years that are comparable with those in younger patients.

428: Lipopolysaccharide preconditioning is protective in lung ischemia reperfusion injury

Purpose: In lung transplantation, donor lungs are procured from ventilated patients who are frequently colonized with bacteria. How bacterial colonization influences subsequent ischemia-reperfusion injury and graft function is poorly understood. Exposure to bacterial products at sufficient levels can cause lung injury. However, recent work in other organ systems suggests that low-dose lipopolysaccharide (LPS) pretreatment may confer protection in ischemia-reperfusion injury through replication of ischemic preconditioning responses.

Optimal use of older donors and recipients in kidney transplantation

The aging donor and recipient population have led to new challenges in kidney transplantation. The purpose of this study was to review retrospectively our single center experience in deceased-donor kidney transplantation, with respect to donor and recipient age. From October 1, 2001, through February 20, 2004, we performed 144 deceased-donor kidney transplantations, which included 37 procedures (26%) in recipients > or =60 years old and 107 procedures (74%) in recipients 19 to 59 years old. The deceased-donor pool included 57 expanded criteria donors (ECD) and 87 standard criteria donors (defined as not ECD). ECD kidneys were used by matching estimated renal functional mass to recipient size (body mass index, <25 kg/m(2)), which included the use of dual kidney transplantations (n = 9). ECD kidney recipients were further selected on the basis of age >40 years and low immunologic risk. Recipients received rabbit antithymocyte globulin or alemtuzumab induction in combination with tacrolimus, mycophenolate mofetil, and steroids. The mean age differed between recipient groups (65 vs 46 years; P < .001). In recipients > or =60 years old, 23 recipients (62%) received kidney transplants from ECDs compared with 34 kidney transplants from ECDs (32%; P < .001) in recipients who were <60 years old. Patient survival was 89% in recipients who were > or =60 years old, compared with 95% in recipients who were <60 years old (P = .11), with a mean follow-up time of 27 months. Kidney graft survival rates were 84% in both recipient groups. Initial and subsequent graft function, rejection, infection, reoperation, length of stay, readmission, and resource use were similar among groups. By the matching of nephron mass with recipient size and avoiding the use of ECD kidneys in recipients with a high immunologic risk, short-term outcomes that are comparable with standard criteria donor kidneys in younger patients can be achieved with either older donors or recipients, regardless of age.

Graft size assessment by preoperative computed tomography in living related partial liver transplantation.

The size of segmental liver grafts assessed by preoperative computed tomography (CT) volumetry was evaluated in relation to surgical outcome in 14 living related partial liver transplantations (LRLTs). The aim was to show that graft size can be accurately assessed before operation and to estimate the lower safety limit of graft size in assessing subsequent graft function and survival. The relationship between calculated CT volume and weight of the liver was linear in the recipient (r = 0.97) and donor (r = 0.98). The mean(s.e.m.) modified liver weight ratio (MLWR; ratio of graft weight to recipient's expected liver weight based on body-weight) was 0.59(0.07) (range 0.27-1.09). Surgical complications related to an oversized graft and primary graft failure caused by a small-for-size graft were not observed. The lowest MLWR of any survivor was 0.27. These results suggest that a partial liver graft reduced to about 30 per cent of the recipient's expected liver weight can tolerate LRLT well.

Protocol Transplant Biopsies

Studies suggest that surveillance or protocol biopsies that are performed during the first year after kidney transplantation may be clinically useful in identifying early acute rejection or chronic allograft nephropathy at a point when they may be amenable to treatment. Although the benefit of this approach has yet to be evaluated in large, multicenter, prospective trials, numerous studies suggest that implementation of protocol biopsies may improve long-term graft function. In particular, a number of reports suggest that detection of chronic allograft nephropathy in early protocol biopsies is predictive of subsequent graft function and loss and that early treatment may have a dramatic effect on the outcome of the graft. Protocol biopsies also have the potential to be of great value in high-risk patients, such as those with delayed graft function, by allowing for early intervention for acute rejection. Furthermore, the procedure seems to be relatively straightforward and safe. Nevertheless, paucity of data has meant that clear proof of a benefit of early treatment of subclinical rejection and chronic allograft nephropathy detected by protocol biopsy is lacking. Moreover, the optimal timing of protocol biopsies and reliable methods to quantify the histologic changes observed in biopsy specimens have yet to be determined. This review discusses the pros and cons of protocol biopsies and considers the place of this procedure in the routine treatment of kidney transplant patients.

Ex Vivo Gene Transfer for Improvement of Transplanted Pancreatic Islet Viability and Function

Human pancreatic islet transplantation has recently been shown to be successful in replacing pancreatic endocrine function into type 1 diabetic recipients. A major drawback, however, is the high amount of pancreatic ss cells required to render one single patient insulin-independent. Given the shortage of human beta cell donors, the majority of type 1 diabetic patients remain excluded from this therapeutic option. High number of islets are requested since substantial islet cell death and dysfunction occur within the first few hours and days after islet transplantation. Impaired vascularization of the engraft, the non-specific inflammatory reaction at the site of transplantation, together with the presence of active or memory autoimmune responses to islet autoantigens and allogeneic recognition contribute to apoptosis of ss cells and subsequent early graft function loss. This review will focus on ex vivo engineering of the islet graft by gene transfer to improve islet engraftment. An overview of currently used gene transfer techniques will be given and their potential will be discussed.

Donor Kidney Glomerular Filtration Rate and Post-Transplant Graft Function

This study aimed to estimate the relationship between the single kidney glomerular filtration rate (SKGFR) of a planned kidney transplant and the subsequent graft function and survival of living related kidney recipients (LKRs). Of 180 LKRs with the graft functioning for more than a year, 70 patients without delayed graft function (DGF) or acute rejection (AR) were selected for the study. According to SKGFR, assessed by 99mTcDTPA, the patients were allocated into Group 1, receiving kidney with SKGFR < 50 mL/min (32 patients), and Group 2, with SKGFR > 50 mL/min (38 patients). The database included donor, recipient and transplant variables. No significant difference was found between the patient and graft survival rate, creatinine clearance (CCr) and the rate of CCr change between the groups. Additional evaluation revealed no significant influence of the ratio of SKGFR and the recipient's body weight/size on patient and graft outcome. The analysis of factors of influence on patient and graft survival and function revealed the major influence of nonimmunological factors but not of SKGFR of the transplanted kidney. Our study did not confirm the influence of SKGFR on graft function and survival in the LKRs without DGF and AR but the limited number of patients must not be disregarded.

KIDNEY TRANSPLANTATION IN THE ELDERLY: VARIATIONS OF THE “MATCH-GAME”

P99 Aims: Introduction: The aging donor (D) and recipient (R) population has led to new challenges in kidney transplantation (KT). Controversy exists regarding the optimal approach to the elderly D or R. A number of strategies have been proposed including matching by age, medical risk, serology, HLA, size, or nephron mass. The purpose of this study was to retrospectively review our single center experience in deceased donor (DD) KT with respect to age. Methods: From 10/1/01 through 11/15/03, we performed a total of 129 DD KTs, including 33 (26%) in Rs ≥60 years and 96 (74%) in Rs 19-59 years of age. The DD pool included 51 expanded criteria donors (ECD; defined and allocated according to UNOS policy) and 78 standard criteria donors (SCD; defined as non-ECD). ECD kidneys were utilized by matching estimated renal functional mass to recipient size (BMI <25 kg/m2), including the use of dual KTs (N=8). ECD kidney Rs were further selected based on age >40 and low immunologic risk. Rs received rATG or alemtuzumab induction in combination with tacrolimus, MMF, and steroids; those ≥60 had lower tacrolimus targets and MMF doses. Results: The mean age differed significantly between R groups (65 vs 46 years, p<.001), including 7 patients >70. In Rs ≥60, 22 (67%) received KTs from ECDs compared to 29 from ECDs (30%, p<.001) in Rs <60. Other demographic and transplant characteristics were similar among groups. Patient survival is 97% in Rs ≥60 compared to 99% in Rs <60 (p=NS) with a mean follow-up of 12 months. Kidney graft survival rates are 94% in Rs ≥60 vs 89% in Rs <60, p=NS. Initial and subsequent graft function, rejection, infection, re-operations, length of stay, re-admissions, and resource utilization were similar among groups. Nine patients had opportunistic viral infections (5 CMV, 3 polyomavirus nephropathy, 1 EBV-associated PTLD), including 4 (12.5%) in Rs ≥60 compared to 5 (5%, p=NS) in Rs <60. However, all 9 cases occurred in ECD Rs (18% ECD vs 0 SCD Rs, p<.001). Conclusions: By matching nephron mass with R size and avoiding the use of ECD kidneys in high immunologic risk Rs, short-term outcomes that are comparable to SCD kidneys in younger patients can be achieved with either older Ds or Rs, regardless of age. However, the risk of viral infection is higher in ECD Rs, and long-term follow-up is needed to ultimately determine the risks and benefits of KT in this setting.

Seizure frequency is associated with age at menopause in women with epilepsy

To determine whether the age at menopause in women with epilepsy is associated with seizure frequency. Women with epilepsy ages 45 and older from urban epilepsy centers were surveyed by interview and chart review for reproductive and general health characteristics, as well as seizure history, including frequency and treatment. Women who were not menopausal (> or = 1 year since last menses) were excluded. Subjects were divided into low, high, and intermediate seizure frequency groups. Statistical analyses included a one-way analysis of variance along with post hoc analysis (Bonferroni approach) to calculate pairwise comparisons. Sixty-eight subjects had a mean age at last menses (menopause) of 47.8 years (SD +/- 4.1, range 37 to 59 years). The age at menopause was 49.9 years in the low seizure frequency group (n = 15), 47.7 years in the intermediate seizure frequency group (n = 25), and 46.7 in the high seizure frequency group (n = 28). The difference in age at menopause in the three groups spanned approximately 3 years (p = 0.042). There was a negative correlation between the age at menopause and seizure group based on estimated lifetime seizures (p = 0.014, r = -0.310). No confounding influences such as history of cigarette smoking, number of pregnancies, or use of enzyme-inducing antiepileptic drugs were present. Seizure frequency or lifetime number of seizures is associated with the timing of cessation of reproductive cycling. Seizures may disrupt hypothalamic and pituitary function or alter neurally mediated trophic effects on the ovary.

Serine proteinase inhibitor-9, an endogenous blocker of granzyme B/perforin lytic pathway, is hyperexpressed during acute rejection of renal allografts.

Serine proteinase inhibitor (PI)-9 with a reactive center P1 (Glu)-P1' is a natural antagonist of granzyme B and is expressed in high levels in cytotoxic T lymphocytes (CTL). In view of the role of CTL in acute rejection, we explored the hypothesis that PI-9 would be hyperexpressed during acute rejection. Because PI-9 can protect CTL from its own fatal arsenal and potentially enhance the vitality of CTL, we examined whether PI-9 levels correlate with the severity of rejection as well as predict subsequent graft function. We obtained 95 urine specimens from 87 renal allograft recipients. RNA was isolated from the urinary cells and mRNA encoding PI-9, granzyme B, or perforin and a constitutively expressed 18S rRNA was measured with the use of real-time quantitative polymerase chain reaction assay, and the level of expression was correlated with allograft status. The levels of PI-9 (P=0.001), granzyme B (P<0.0001), and perforin mRNAs (P<0.0001), but not the levels of 18S rRNA (P=0.54), were higher in the urinary cells from the 29 patients with a biopsy-confirmed acute rejection than in the 58 recipients without acute rejection. PI-9 levels were significantly higher in patients with type II or higher acute rejection changes compared with those with less than type II changes (P=0.01). Furthermore, PI-9 levels predicted subsequent graft function (r=0.43, P=0.01). PI-9 mRNA levels in urinary cells are diagnostic of acute rejection, predict renal allograft histology grade, and predict functional outcome following an acute rejection episode.

Transfer of “infectious” cardiac allograft tolerance induced by donor-specific transfusion

Background. “Infectious tolerance” has been defined as the tolerance induced in a new recipient by the adoptive transfer of cells from a recipient accepting an allograft after anti-CD4 and anti-CD8 monoclonal antibody treatment. A clear understanding of the mechanisms responsible for graft acceptance after donor-specific blood transfusion (DST) has remained elusive. We examined the development and “infectious” nature of immunologic changes resulting in indefinite survival of LEW to DA rat cardiac allografts after DST alone without the need for antibody. Methods. One hundred × 106 LEW splenocytes (SC) as DST were injected intravenously into DA recipients 7 days before LEW cardiac transplantation. Subsequently, 100 × 106 SC harvested from a DA recipient 30, 60, or 100 days after graft acceptance were adoptively transferred into lightly γ-irradiated (450 rad) naïve DA recipients 24 hours before a second LEW cardiac allograft. Subsequent graft function was determined. Results. Adoptive transfer of SC from the DST-treated DA rats 30 days after LEW heart transplant acceptance into naïve γ-irradiated DA rats failed to transfer tolerance to LEW cardiac allografts. However, SC from DA rats bearing LEW hearts for more than 60 days induced indefinite tolerance to all LEW hearts. This infectious tolerance could be adoptively transferred again to a second DA recipient. Conclusions. DST-generated regulatory cells can downregulate naïve lymphocytes to promote allograft acceptance. This tolerance can be expanded and serially transferred to a subsequent naïve cardiac recipient. (Surgery 2002;132:167-72.)

Invited commentary

Despite significant advances in organ procurement and preservation techniques, transplanted lungs are unusually sensitive to ischemia-reperfusion injury. Severe early graft dysfunction has been reported in up to 20% of lung recipients, and this early dysfunction can lead to an increase in early and late morbidity and mortality. Although ischemia plays an important role in initiating early post-transplant lung injury, reperfusion mechanisms are equally important. Pulmonary ischemia-reperfusion (I/R) injury is a complex process involving many cell types and inflammatory biochemical mediators. The study by Sunose and colleagues has utilized a popular dog model of lung transplantation to evaluate the effect of a COX-2 inhibitor on subsequent graft function after 12 hours of ischemia and varying times of up to 4 hours of reperfusion. The hilum of the contralateral non-transplanted lung was ligated in order to evaluate the function of the transplanted organ and its ability to support the animal. The COX-2 inhibitor was administered to both the donor animal 15 minutes prior to lung ischemia, and to the recipient animal 15 minutes prior to reperfusion. COX-2 is an inducible protein that catalyzes arachidonic acid to several active metabolites, including pro-inflammatory thromboxane A2 (TxA2). The authors point out that COX-2 is temporarily induced in monocytes and tissue macrophages during inflammatory conditions, such as might be encountered during ischemia and reperfusion. Therefore, the authors imply that donor pulmonary macrophages may play an important early role in ischemia-reperfusion injury.

Modulation of fluid-phase complement activation inhibits hyperacute rejection in a porcine-to-human xenograft model

YPERACUTE rejection (HAR) of porcine organs is due to classical complement activation by naturally occurring human antibodies to the endothelium. Pigs that are transgenic for human regulators of complement (RCA) seem promising with respect to avoiding HAR, and their use in various studies has brought xenotransplantation closer to clinical reality. However, RCAs are usually expressed on the endothelial cells as clusters and the activation of complement may take place at some distance from RCA localisation. Thus, it should be emphasised that, although RCA pig xenografts may be protected against HAR, a certain degree of complement activation may still contribute to an inflammatory reaction with subsequent impaired graft function. Therefore, efforts should be taken to control the fluid-phase activation of complement, which was the main topic of our studies. We have established an ex vivo perfusion model 1 to investigate the effect of complement manipulation by intravenous immunoglobulin (IVIG), a C3-binding peptide (Compstatin) and C1-inhibitor (C1-INH) on HAR.

Organ preservation: The profit and loss account of using hypothermia to maintain viability

Hypothermia is an integral component of current ex vivo organ storage procedures, and it is intuitive to expect cooling to have a preservative effect on biological tissues. Whereas this is true for simple systems such as enzymes in solution, hypothermia can have many conflicting effects on the structure and function of cells within a graft that will combine to affect subsequent graft function. This is becoming more important as the potential donor criteria are expanded to meet the growing organ shortage. This review outlines what is currently understood about cooling-induced changes in the molecular and physiological processes within cells and how these can alter vital homeostatic processes. The roles of oxidative versus anaerobic metabolism at low temperatures are considered and how these affect ongoing changes in the stored organ. Finally, some ideas are put forward on ways to harness this residual hypothermic metabolism to improve graft preservation techniques.

Histopathological findings in renal allografts at time of transplantation and correlation with onset of graft function.

Histopathological changes quantified using the chronic allograft damage index (CADI) have been shown to predict subsequent graft outcome and developing chronic rejection. The aim of the study reported here was to investigate the extent to which cadaveric renal allografts exhibit histopathological changes at time of transplantation, focusing on changes covered by the CADI. We also analysed whether any histopathological change predicts delayed graft function. One hundred and twenty-eight cadaveric kidney allografts with adequate protocol biopsy were studied. Tubular epithelial anisometric vacuolization was the commonest change, found in 62% of grafts and scored moderate or severe in 28% of these cases. Other prevalent changes were interstitial fibrosis, vascular hyalinosis, glomerular sclerosis and tubular basement-membrane thickening in 40%, 37%, 28% and 22% of biopsies, respectively. Intensities were, however, scored as mild in over 95% of specimens. The mean CADI for all grafts was 0.74. A significant difference in CADIs was seen between grafts from donors under and over 40 years of age. Grafts with early, delayed and no function had a similar incidence of histopathological changes. Histopathological changes in renal allografts were mostly uncommon and mild at time of transplantation, but some grafts exhibited changes which were quantified using the CADI. Though histopathological changes quantified with the CADI are predictive of subsequent graft function, they did not affect onset of graft function.

Tubular antithrombin at transplantation determines subsequent renal allograft function.

Antithrombin is found in the microvasculature and tubules of normal and transplanted human kidneys. Although depletion of vascular antithrombin is associated with renal allograft dysfunction, neither the distribution nor clinical significance of tubular antithrombin is known. Changes in tubular antithrombin in biopsy specimens (n=41) obtained from donor kidneys at transplantation were studied immunohistochemically. The relationship between these changes and subsequent graft function was analyzed. Granular intracellular antithrombin was found only within the proximal tubular epithelium. Allografts with depleted tubular antithrombin at transplantation (n=20) had significantly greater plasma creatinine concentrations at posttransplant days 3 (P < 0.001) and 5 (P < 0.03) than allografts with normal tubular antithrombin (n=21). Indeed, depletion of tubular antithrombin at transplantation correlated with the degree of graft dysfunction at 3 days after transplantation. Depleted tubular antithrombin at transplantation is associated with reduced early graft function, and this may identify patients at risk of a complicated follow-up.