Renal Graft Survival Research Articles

Outcome of liver transplantation in hispanics versus non-hispanics: is there a difference?

IN THE PAST DECADE 10% of orthotopic liver transplant (OLT) recipients in the United States have been of Hispanic origin. Little has been reported regarding OLT outcomes in reference to recipient ethnic origin. Differences in outcome have been shown in renal transplant graft survival of African-American recipients when compared to Caucasians. Differences in outcome of other organ transplants relative to ethnicity have never been clearly proven. At our center more than 50% of OLT recipients are from Hispanic origin, and it is of our particular interest to establish any ethnic difference in graft or patient survival if present. To determine the differences in outcome of the Hispanic (H) group versus the non-Hispanic group (NH), we analyzed our experience for the past 5 years.

Decreased short-term renal graft survival in Maghrebian recipients

Decreased short-term renal graft survival in Maghrebian recipients

Estimated and Measured Donor Creatinine Clearance are Poor Predictors of Long-Term Renal Graft Function and Survival

The objective of this study was to evaluate estimated and measured donor renal function in predicting graft function long-term and to identify donor criteria associated with nonacceptable graft prognosis. In 200 consecutive cadaver donors creatinine clearance was measured at explantation and estimated using the Cockcroft formula on admission serum creatinine. Graft function was evaluated in recipients (n = 387) by 24-h creatinine clearance regularly during 3 years after transplantation. Measured creatinine clearance correlated to some extent with long-term graft function, while Cockcroft estimation was slightly superior and similar to using donor age only. Kidneys from donors with intra-operative creatinine clearance < or = 55 mL/min (median 50 mL/min) produced acceptable recipient graft function of 48 mL/min at 3 years and 76% 3-year graft survival. Donor age > or =60 years resulted in clearance at 3 years of 29 mL/min and 78% 3-year graft survival; adding the criteria of admission Cockcroft < or =60 mL/min, graft function at 3 years (28 mL/min) and 3-year graft survival (76%) were similar. In conclusion, creatinine-based estimates of the functional capacity of the donor kidney, calculated or intra-operatively measured, do little to improve the ability of donor age alone to predict long-term allograft function after renal transplantation, and nonacceptable donors are not discriminated.

Prevalence of transfusion transmitted virus infection and its effect on renal graft survival in renal transplant recipients.

Little is known about the prevalence of transfusion transmitted virus (TTV) infection in renal transplant recipients (RTxs) and its effects on allograft survival. We investigated the prevalence of TTV and its effects on liver injury and graft survival in RTxs. The study was performed in 33 consecutive RTxs (8 females, 25 males) and 100 blood donors (35 females, 65 males). A nested polymerase chain reaction was used to detect TTV DNA in serum. Serum creatinine and alanine aminotransferase (ALT) levels and 24-h protein excretion were determined in both TTV-positive and-negative patients. The total number of blood transfusions, the duration of hemodialysis and the total duration after transplantation were recorded in RTxs. In addition, hepatitis B surface antigen (HbsAg), anti-hepatitis C virus (HCV) and hepatitis G virus DNA antibodies were determined in all patients. TTV DNA was detected in 51.5% of RTxs and in 7% of the control group and this difference was statistically significant (p < 0.01). In the RTx group, 64.7% of TTV-positive and 56.2% of TTV-negative patients had undergone a previous blood transfusion. However, the blood transfusion replacement rate, total duration of dialysis therapy and posttransplant period did not differ between these two groups. Five (15.1%) patients in the RTx group had abnormal liver function tests (ALT >40 IU/l). Of these patients, 2 were anti-HCV-positive, 1 was HBsAg-positive and anti-HCV- plus TTV DNA-positive and the serologic tests of the remaining 2 patients were all negative. Among the TTV-positive patients, 2 (11.7%) were anti-HCV-positive, 1 (5.8%) was HBsAg-positive and 3 (17.6%) were HGV DNA-positive. The baseline serum creatinine levels did not differ significantly between the TTV-positive and-negative patients, being 1.5 +/- 0.6 and 1.4 +/- 0.6 mg/dl, respectively ( p > 0.05). Two of the TTV-positive patients and 1 of the TTV-negative patients had proteinuria. A 1-year follow-up of TTV-positive and-negative patients demonstrated neither acute nor chronic graft rejection. In RTxs, TTV infection was more prevalent than in the normal population. In our patients the virus did not have an important effect on renal graft rejection and did not cause liver injury. However, the question of whether TTV infection may affect graft survival requires further long-term investigation in larger groups.

Impediments to successful gene transfer to the kidney in the context of transplantation and how to overcome them

Manipulation of the graft with immunosuppressive genes represents a novel approach to overcome the toxicity of immunosuppressants currently used to prevent acute rejection. Here we compared the efficiency of a non-viral versus a viral technique of gene transfer to the kidney in the setting of isotransplantation and evaluated whether transfection with adenovirus encoding CTLA4Ig prolonged allograft survival. Donor rat kidneys were perfused with a medium containing the cationic polymer polyethylenimine PEI 25k complexed to a vector coding for the beta-galactosidase (beta-gal) gene or with a replication-deficient adenovirus encoding the beta-gal gene (AdCMVbeta-gal; 1 x 10(9) pfu) before isotransplantation. In another set of experiments, donor kidneys were perfused with an adenovirus encoding the murine CTLA4Ig gene (AdmCTLA4Ig; 1 x 10(9) pfu) before allotransplantation. Perfusion with PEI/DNA complexes resulted in large areas of hypoperfusion, histology showed glomerular and tubular injury, capillary thrombosis, and complement activation. Reperfusion with lower PEI/DNA ratio was possible but no detectable transfection observed. In animals receiving adenovirus, beta-gal activity increased with time and localized mainly in proximal and distal tubular cells as documented by beta-gal histochemistry and in situ hybridization. Adenovirus-mediated transduction of CTLA4Ig, a recombinant fusion protein that blocks T cell activation, resulted in a prolonged allograft survival. The toxic effects observed in kidneys exposed to PEI 25k prevent any future possibility of their use in clinical transplantation. By contrast, adenovirus-mediated gene transfer to the kidney offers exciting perspectives for the future of transplant medicine. Transducing the graft with a gene encoding CTLA4Ig effectively prolongs renal graft survival and induces sustained unresponsiveness to the donor antigens without the need of immunosuppression.

Predictors of Pregnancy Outcome in Renal transplant Recipients

Objective: To identify preconceptional risk predictors specific to renal transplant patients.Methods: Preconception selection criteria which influenced the perinatal outcome in 23 pregnancies in 20 renal transplant patients at British Columbia’s Women’s and Children’s Hospital in the period 1989 to 1999 were retrospectively analyzed. Successful pregnancy outcome in this series was defined as delivery after 34 weeks, birth weight appropriate for gestational age, stable renal graft function, and no evidence of rejection within at least two years after the pregnancy.Results: Seventy-five percent of patients with preconceptional serum creatinine of less than 125 µmol/L had successful pregnancy outcomes compared to 25 percent of those with serum creatinine greater than 125 µmol/L (p = 0.11). Fifteen percent of patients with pre-existing proteinuria of one to three g per day had worsening proteinuria, renal graft function, and hypertension, and subsequently had graft rejection (p = 0.0006). Seventy-two percent of patients with poorly controlled hypertension delivered prior to 34 weeks (p = 0.008). Renal graft rejection was strongly associated with prepregnancy creatinine more than 125 µmol/L (p = 0.004), preexisting proteinuria more than one g per day (p = 0.001), and poorly controlled chronic hypertension (p = 0.04). Prematurity due to obstetric intervention with worsening maternal or fetal condition (28%) was the major contributor to perinatal morbidity and mortality. Intrauterine growth restriction was observed in 23 percent of these pregnancies.Conclusion: Pregnancy does not have a detrimental effect on renal graft survival, provided that renal graft function is normal at the time of conception.

Cohort study of the prognostic significance of acute transplant glomerulitis in acutely rejecting renal allografts.

Acute transplant glomerulitis is a unique lesion in renal allografts, the prognostic significance of which is controversial. We conducted this retrospective cohort study to examine the independent prognostic significance of moderate-to-severe transplant glomerulitis in acute rejection. Renal allograft survival for patients with acute rejection were studied, comparing one group with significant glomerulitis (G, n=28) with those with no glomerulitis (NG, n=35). Clinical, biopsy, and demographic data and renal graft survival were compared, and the association of G with graft failure was examined. In the G versus NG group, a greater percentage of patients were highly sensitized (peak panel reactive antibody value >80%; P=0.009), had had a previous renal transplant (40% vs. 11%; P=0.02), or had suffered from delayed graft function (P=0.03). The G group had a trend toward earlier rejection episodes (P=0.07), a significantly higher serum creatinine at the time of index biopsy (P=0.01), a higher prevalence of vascular rejection (P=0.02), and less improvement in mean reciprocal serum creatinine at 1-2 weeks after biopsy (P=0.02). Although there was a trend toward shorter allograft survival in the G group (P=0.09), the level of significance of which increased with adjustment for transplantation time period and the duration of the transplant-biopsy interval (P=0.06), the relative risk for graft loss was no longer significant when additionally adjusted for index biopsy Banff score (relative risk, 0.97; P=0.97). In this study, G was significantly more common in highly sensitized patients and was strongly associated with vascular rejection biopsies but was not an independent predictor of graft survival.

Current immunosuppressant regimens: considerations for critical care

While current immunosuppressive drug regimens have significantly increased the rate of successful transplantation outcomes, they convey potentially serious and overlapping adverse effects. Cyclosporine and tacrolimus are the cornerstones of current immunosuppression, achieving excellent one-year renal graft survival rates. Other promising new drugs include sirolimus, which has been demonstrated to reduce efficacy failure rates among renal transplant recipients, and everolimus, which is currently undergoing clinical trials. Agents targeting novel sites in the immune response or disrupting the ischemia-reperfusion cascades are currently under development. Among them, only FTY720 is undergoing large-scale human clinical trials. With its unique mechanism of action and synergistic interactions with cyclosporine and sirolimus, it may provide the foundation for a new era in immunosuppression.

Sobrevida del injerto en los primeros 100 trasplantes renales del Hospital Carlos van Buren

Renal transplant is the best therapeutic alternative for chronic renal failure, although it is not exempt of risks. To report the survival of renal transplant recipients and grafts and the main complications at a public hospital in Chile. This is a non experimental, open historical cohort study, with reposition of the first 100 transplants in 94 patients, performed at the Carlos van Buren Hospital between 1984 and 1998. Seventy grafts came from cadaveric donors and 30 from live donors. As immunosuppressive therapy, prednisone + azathioprine was used in 48 transplants and the same regimen plus cyclosporine in 52. Mean age of recipients was 36 +/- 23 years old. Ten years actuarial survival of patients was 80.5% in transplants from cadaveric donors and 86% in transplants from live donors. Ten years graft survival was 57.5% in transplants from cadaveric donors and 42% in transplants from live donors. The period in which the transplant was performed (first or second half of the observation period), type of donor, HLA B-DR compatibility and sensitization (% PRA) had no effect on survival. Twenty five subjects lost their graft, 12 due to acute steroid resistant rejection, 10 due to chronic graft nephropathy and three due to renal artery thrombosis. Fifteen subjects died with a functioning graft, 10 due to infections, two due to an acute myocardial infarction, two due to an acute pancreatitis and one due to a brain tumor. Survival of grafts and renal transplant recipients was not influenced by the type of donor, period of transplantation and immune variables. Main causes of recipient death were infections and the main cause of graft failure was acute rejection.

Influence of aspirin on early allograft thrombosis and chronic allograft nephropathy following renal transplantation.

Primary thrombosis and chronic allograft nephropathy are important causes of early and late graft loss, respectively, following renal transplantation. This study examined the potential for aspirin therapy to reduce these complications. A consecutive series of 105 cadaveric renal transplants treated with aspirin 150 mg daily for the first 3 months after transplantation was compared with an untreated historical control group (n = 121). Protocol needle-core biopsies were performed on all transplants in both groups at 1 week and 12 months after transplantation. Needle-core allograft biopsies were performed at 3, 6 and 12 months after transplantation, and serum creatinine was measured at each outpatient attendance for the duration of follow-up. There was a significantly lower rate of primary allograft thrombosis in patients treated with aspirin (none of 105) compared with that in the control group (six (5 per cent) of 121; P = 0.03). There were no differences in renal function or 2-year allograft survival between the two groups. Aspirin-treated patients had a lower incidence of chronic allograft nephropathy at 1 year than controls although this did not reach statistical significance (16 versus 26 per cent; P = 0.075). There were no major bleeding complications in either group in association with peptic ulcer disease or following renal transplant biopsy. Aspirin reduced the rate of early graft thrombosis of renal transplants in this series but did not improve renal function or graft survival. A trend towards a lower rate of chronic allograft nephropathy was noted with aspirin treatment. These findings require confirmation in a prospective randomized trial.

Impact of humoral alloreactivity early after transplantation on the long-term survival of renal allografts

The contribution of humoral alloreactivity to the rejection of renal allografts is not well defined because humoral antigraft reactions are not easily detectable in transplant biopsies, and serial measurements of circulating allo-antibodies in the post-transplantation period are not routinely performed. We have developed diagnostic techniques that improve the assessment of humoral alloreactivity in vivo and in vitro. Humoral alloreactivity in transplant biopsies derived from 218 single kidney grafts was detected by assessing the deposition of complement fragment C4d in interstitial capillaries. Circulating alloantibodies were determined in corresponding serum samples by flow cytometry using lymphoblastoid cell lines of donor DR-type as target cells and by a conventional microcytotoxicity test. The impact of capillary C4d and other selected variables on renal graft survival was calculated by univariate and multivariate analysis. Capillary C4d, present in 46% of biopsies from first grafts and 72% of regrafts, is related to circulating alloantibodies. Grafts with capillary C4d have a markedly shorter survival than grafts without capillary C4d (50% graft survival, 4 vs. 8 years, P = 0.0001). Among several risk factors, capillary C4d is the strongest predictor of subsequent graft loss in a multivariate analysis (relative risk, 2.1, 95% CI, 1.4 to 3.1). Humoral alloreactivity detectable within six months after transplantation has a much stronger impact on graft survival than alloreactivity detected beyond this period. Humoral alloreactivity, manifested by the capillary deposition of complement C4d in about 50% of biopsied renal grafts, exerts a strong impact on graft survival when it operates within six months after transplantation.

Outcome of renal transplant recipients and graft survival in the ICU

Outcome of renal transplant recipients and graft survival in the ICU

Influence of protective genes in the HLA system on renal graft survival

IMMUNE resistance of an individual is genetically determined. Recognition of self-antigens from non–self-antigens is under the tight control of the major histocompatibility complex (MHC) and depends on the genotype inherited from the parents. From the point of view of species survival, recognition of antigens by the immune system is a biologic function of utmost importance, protecting the organism against foreign pathogens. However, detection of donor antigens by the immune system of the host, followed by graft rejection, is an unwanted outcome. It is believed that the so-called protective genes have played an important role in species preservation of homosapiens in the course of evolution. These genes are closely associated with gene products of the MHC/HLA class I and II system, participating in the recognition and presentation of foreign antigens to some lymphocyte classes Humoral and cellular reaction to pathogens develops at a faster pace in individuals with protective genes. Unfortunately, the price for a more active immune reactivity is paid by a small percentage of the population in the form of various autoimmunologic diseases. Correlation between these diseases and antigens associated with protective genes HLA-B5, -B35, -B7, -B27, -B8, -B18, -DR2, -DR3, and -DR4 has been reported. The purpose of this work was to study the presence of protective genes in renal graft recipients and their influence on survival of the graft.

Permanent detrimental effect of nonimmunological factors on long-term renal graft survival: a parsimonious model of time-dependency.

We attempted to model and test the pattern of effects of prognostic factors on renal graft survival during the posttransplantation time course. Patients who received a cadaveric kidney-only transplant between January 1990 and December 1995 in Eurotransplant, who received cyclosporine as induction therapy, and who had a complete follow-up at the time of analysis were included in the study (n= 10614). An index summarizing all covariate information was calculated and used for modeling the time-dependent effects with relation to graft failure. The immunological factors (HLA mismatch and % panel-reactive antibody) were seen to have a slowly decreasing negative effect on renal graft survival. The cold ischemic trauma (>24 hr) exerted a permanent detrimental effect on the grafts. The use of organs obtained from old donors was associated with a constant higher risk of graft loss. An analysis of determinants of human allograft dysfunction should also study the interaction between the effects and time. Nonimmunological factors had a constant detrimental effect on graft failure, whereas the impact of the immunological factors--although remaining important for late graft loss--very slowly decreased. In the context of marginal transplants, clustering of unfavorable factors should be avoided to prevent late graft losses.

Impact of pre-existing donor hypertension and diabetes mellitus on cadaveric renal transplant outcomes

Hypertension (HTN) and diabetes mellitus (DM) predispose to systemic atherosclerosis with renal involvement. The prevalence of HTN and DM in cadaveric renal donors (affected donors) and the results of transplantation are unknown. We investigated these issues with national data from the US Renal Data System. A total of 4,035 transplants from affected donors were matched 1:1 with unaffected controls according to donor age and race, recipient race, and year of transplantation. Graft and patient survival were estimated. Among the 25,039 solitary renal transplantations performed between July 1, 1994, and June 30, 1997, cadaveric renal transplants from donors with HTN accounted for 15%, and donors with DM, 2%. Programs with 1-year cadaveric renal graft survival rates greater than 90% had 50% less affected donors compared with programs having 1-year cadaveric renal graft survival rates of 85% or less. Compared with donor-age–matched controls, transplants from affected donors were at minimally increased risk for primary nonfunction, delayed graft function, and acute rejection. Three-year graft survival rates were 71% in affected donor organs and 75% in controls (P = 0.001). Compared with controls, duration of HTN was an independent risk factor for graft survival (3-year graft survival rates, 75% versus 65%; relative risk = 1.36 for HTN >10 years; P < 0.001). A substantial fraction of cadaveric renal donors have preexisting HTN. Programs transplanting fewer affected donor kidneys had better than average results. Because the negative impact of donor HTN and DM on transplant outcome was of moderate degree except when the duration of donor HTN was greater than 10 years, use of affected donors should not be discouraged, but graft and patient survival analyses should account for their presence.

Effect of tacrolimus (FK506) and sirolimus (rapamycin) mono- and combination therapy in prolongation of renal allograft survival in the monkey.

Our previous studies confirmed that tacrolimus (FK506) and sirolimus [rapamycin (RAPA)], in combination, are not antagonistic but are synergistic in the prolongation of heart and small bowel grafts in the rodent. The aim of this study was to confirm further the synergistic effect of combined FK506 and RAPA in the more clinically relevant model, kidney transplantation in monkeys. A total of 60 male Vervet monkeys were randomly assigned to 10 groups (n> or =5). Monkeys with renal allografts were treated with different doses of FK506 and/or RAPA orally for 60 days. Graft survival, body weight, clinical biochemistry determinations, oral glucose tolerance test, trough levels of the two drugs, and histopathology were investigated. Low doses of FK506 (1 or 4 mg/kg) combined with RAPA (0.5 mg/kg) produced synergistic effect in the prolongation of renal graft survival [combination index (CI) = 0.292, 0.565]. There were no additive or synergistic drug-associated toxicities such as hyperglycemia, nephrotoxicity, and hyperlipidemia. There also was no pharmacological antagonism. Concomitant therapy of low-dose (drug-optimal) FK506 and RAPA produced a synergistic effect in the prolongation of kidney allograft survival in Vervet monkeys without additive drug-associated toxicities.

The impact of donor age on renal graft survival

The impact of donor age on renal graft survival

The effect of body mass index on long-term renal allograft survival.

A number of factors have been implicated in decreasing long-term renal graft survival. Factors such as living versus cadaveric donor status, acute rejection, and HLA matching have been studied in detail. Mild obesity defined as a body mass index (BMI) of >25 has been found to have a deleterious effect on a number of physiologic processes. We studied the effect of a BMI >25 on long-term renal transplantation outcome. A total of 405 patients who underwent transplantation at Saint Barnabas Medical Center from 1990 to 1997 were evaluated. All known variables impacting on long-term graft function were collected. Multivariate analysis utilizing the Cox-proportional hazard model and Kaplan-Meier actuarial survival were applied to these risk factors. BMI >25 was isolated as an independent risk factor for both decreased graft survival and patient survival (relative risk 2.0 for each). Cadaveric donor status, acute rejection, and use of azathioprine versus mycophenolate mofetil were the only other significant risk factors. Mild obesity before transplantation has a negative impact on long-term renal graft and patient survival.

Renal allograft survival following acute rejection correlates with blood pressure levels and histopathology

Acute rejection (AR) is a strong predictor of renal graft survival, but the negative impact of AR on survival is variable, suggesting that other factors modulate this relationship. In this study, we examined the variables that correlate with graft survival after AR, particularly the impact of blood pressure (BP), graft function, and histopathology. The study population included patients with no AR (N = 942) and patients with one (N = 407) or two (N = 156) AR during the first year post-transplant. Patients were adults who were recipients of living related (LRD, N = 410) or cadaveric grafts (CAD, N = 1095) and who were transplanted in a single institution and followed for 5.8 +/- 4 years. Compared with patients without AR, those with AR were significantly younger, had more human lymphocyte antigen mismatches, and included more CAD recipients. Graft survival was analyzed beyond six-months post-transplant. In patients with AR, reduced survival correlated (multivariate) with (a) younger recipients (P = 0.01), (b) AR occurring later during the first-year post-transplant (P = 0.0006), (c) elevated serum creatinine (Cr) before (P = 0.05), at the time (P = 0.0001) of, or after AR (P = 0.0004), and (d) average BP levels after AR [systolic BP (P = 0.003 logistic, P < 0.0001 by Cox), diastolic BP (P = 0.007), mean arterial pressure (P < 0.0001)]. This latter correlation was independent of graft function and recipient race. Thus, post-AR BP levels correlated with graft survival in patients with post-AR creatinine </=2 mg/dl (N = 408, P = 0.0009), in Caucasian recipients (P = 0.001), and in African American recipients (P = 0.01). In contrast, there was no significant correlation between BP levels and graft survival in patients without AR. AR histopathology, analyzed in patients with one AR episode, correlated with graft survival only the first six months after AR but not thereafter. Graft survival after AR can be predicted independently by graft function and BP levels after the event. Patients with elevated BP post-AR have poor graft survival even if they have excellent graft function.

Renal transplantation and graft survival and its influencing factors

AT THE PRESENT time, one of the objectives of renal transplantation is to prolong and maximize survival of the implant. Chronic nephropathy (CN) and patient death with functioning implant are the predominant causes of loss of implant. Numerous studies have demonstrated that immunologic and nonimmunologic factors influence implant survival. In this work we present a retrospective study of the most frequent causes in graft loss and its influencing factors in a group of kidney transplant patients.