Occurrence Of Rejection Episodes Research Articles

MO950: Living Donor Kidney Transplantation—Does Donor Sex Modify Recipient Outcomes?

Abstract BACKGROUND AND AIMS Living donor kidney transplantation (LDKT) provides the best outcomes of all renal replacement modalities, including survival and quality of life. Studies on the association between pre-donation estimated glomerular filtration rate (eGFR) and graft outcomes have yielded inconsistent results. Two eGFR thresholds are generally used to accept or deny a donor (respectively, ≥90 and <60 mL/min/1.73 m2), with 60–89 mL/min/1.73 m2 as an intermediate range in which the decision is based on other factors. In this study, we aimed to evaluate how donor's pre-donation eGFR, particularly when <90 mL/min/1.73 m2 impacts the recipient's kidney function and graft survival, and if these outcomes are modified by donor's sex. METHOD This is a unicentric retrospective observational study that included the LDKT pairs submitted to transplant between 2008 and 2017. We gathered clinical data, including donor's comorbidities, immunological features of the transplant, the occurrence of acute rejection episodes in the first year, and graft eGFR during the follow-up period. For statistical purposes, we split the donors in three groups: group 1, with eGFR ≥90 mL/min/1.73 m2; group 2, eGFR < 90mL/min/1.73 m2 and female sex; and group 3, eGFR <90 mL/min/1.73 m2 and male sex. The Kaplan–Meier curves and Cox proportional hazards multivariable regression were used for survival analysis, and linear mixed regression was used to evaluate the annual slope of the recipient's eGFR. RESULTS We studied 210 donor-recipient pairs. The average age at the time of transplant was 48.0 ± 10.6 years for donors and 41.3 ± 13.3 years for recipients. Pre-donation eGFR was 100.1 ± 14.2 mL/min/1.73 m2 and most donors (78%) were in group 1 (eGFR 105.9 ± 9.4 mL/min/1.73 m2). We found two independent predictors of death censored graft failure: the occurrence of rejection episode(s) during the first year (HR: 4.99, CI: 1.44–17.26, P = 0.011) and having a donor from group 3 (HR: 5.14, CI: 1.49–17.75, P < 0.010). The independent predictors of global graft loss were rejection episode(s) during the first year (HR: 4.002, CI: 1.224–13.086, P = 0.022), calculated PRA > 0% (HR: 3.802, CI: 1.387–10.489, P = 0.010) and donor from group 3 (HR: 3.514, CI: 1.087–11.355, P = 0.036). At 1-year after transplant, the recipients from group 1 had a significantly higher eGFR than patients from group 2, but did not differ from group 3 (respectively, 60.8 versus 54.4 [P < 0.05], versus 55.2 mL/min/1.73 m2 [P = 0.328]). However, when analyzing the slope of annual decline in the recipients’ eGFR beyond 1-year post-transplant, the groups 1 and 2 did not differ (decline rate of -1.0 mL/min/1.73 m2 in both groups, P = 0.978), but there was a statistical difference between groups 1 and 3 (decline rates of, respectively, −1.0 versus −2.7 mL/min/1.73 m2 P = 0.003). CONCLUSION This study suggests that in LDKT, when donors’ eGFR is borderline (<90 mL/min/1.73 m2), donors’ sex has an important impact on recipient outcomes. In fact, we observed that having a male donor is a strong predictor of graft failure (both death-censored and global) and that there is a steeper decline in the annual kidney function of these recipients after the first year. Thus, we suggest that donors’ eGFR should be clinically balanced with other determinants of kidney function, particularly in the presence of a male donor, with careful selection of both donors and recipients.

B-cell activating factor BAFF as a novel alert marker for the immunological risk stratification after kidney transplantation

The B cell activating factor BAFF has gained importance in the context of kidney transplantation due to its role in B cell survival. Studies have shown that BAFF correlates with an increased incidence of antibody-mediated rejection and the development of donor-specific antibodies. In this study, we analyzed a defined cohort of kidney transplant recipients who were treated with standardized immunosuppressive regimens according to their immunological risk profile. The aim was to add BAFF as an awareness marker in the course after transplantation to consider patient’s individual immunological risk profile. Included patients were transplanted between 2016 and 2018. Baseline data, graft function, the occurrence of rejection episodes, signs of microvascular infiltration, and DSA kinetics were recorded over 3 years. BAFF levels were determined 14 d, 3 and 12 months post transplantation. Although no difference in graft function could be observed, medium-risk patients showed a clear dynamic in their BAFF levels with low levels shortly after transplantation and an increase in values of 123% over the course of 1 year. Patients with high BAFF values were more susceptible to rejection, especially antibody-mediated rejection and displayed intensified microvascular inflammation; the combination of high BAFF + DSA puts patients at risk. The changing BAFF kinetics of the medium risk group as well as the increased occurrence of rejections at high BAFF values enables BAFF to be seen as an awareness factor. To compensate the changing immunological risk, a switch from a weaker induction therapy to an intensified maintenance therapy is required.

Livers from brain dead donors with chronic active alcohol abuse for liver transplantation

Background: Liver grafts from donors with chronic and active history of alcohol abuse are usually discarded for liver transplantation (LT). Our aim is to report our results with those grafts. Methods: We performed a case control study on 113 LT from 2015 to 2016. Inclusion criteria for the study group were adult patients transplanted with livers from donors with chronic active alcohol abuse. The control group consisted in randomly matched LTs with similar recipient (R) and donor (D) age, sex and ischemia time, performed in those two years with standard livers. The ratio of case-to-control was 1:2. Short term results, biochemical data from day 0 to 30 after LT, complications and survival are reported. Data were compared. P≤0.5 was considered statistically significant. Results: The study group consisted of 4 LT whereas 8 patients transplanted with standard grafts served as control group. Mean micro-macro steatosis percentage in livers from donors with alcohol abuse was 36±16%. Laboratory exams showed statistically significant worse values for Aspartate Aminotransferase and International Normalized Ratio at Day 0, and Total Bilirubin at day 8, for livers from donors with alcohol abuse. No statistical difference was found in the occurrence of rejection episodes. All patients of both groups are alive after 347±264 days (range 24-725) from LT. Conclusion: May be it’s time to reconsider the use for LT of livers from donors with chronic and active alcohol abuse.

Polymorphisms in IMPDH2, UGT2B7, and CES2 genes influence the risk of graft rejection in kidney transplant recipients taking mycophenolate mofetil

The immunosuppressant mycophenolic acid (MPA), derived from the prodrug mycophenolate mofetil (MMF), is a drug used widely by kidney transplant recipients. This drug selectively inhibits inosine monophosphate dehydrogenase that controls the proliferation of lymphocytes, aiding in the prevention of rejection of the transplanted organ. Polymorphisms in key genes involved in MMF metabolism may alter the function of the enzymes encoded by them and contribute to interindividual variability in the response to the drug and its efficacy. The aim of this study was to investigate the association of nine polymorphic variants of eight genes involved in MMF pharmacokinetics, with rejection and adverse effects exhibited by kidney transplant recipients who use this drug. Our sample comprised 145 kidney transplant recipients undergoing post-transplant treatment whose immunosuppressive therapy consisted of MMF and corticosteroid combined or not with a calcineurin inhibitor or mTOR inhibitor. The average age of the patients was 46.9 ± 12.5 years, and they underwent transplantation 7 ± 5.71 years ago. The combination of the T/C and C/C genotypes of the polymorphism rs11706052 (IMPDH2) was associated with a 4.2-fold protection, and the combination of the genotypes A/G and G/G of the polymorphism rs7438135 (UGT2B7) showed a 2.4-fold protection, against rejection. The association of T/C and C/C genotypes in the SNP rs11706052 (IMPDH2) with the occurrence of rejection episodes considering only patients who received immunosuppressive drug MMF associated with cyclosporine or tacrolimus and corticoids, demonstrated association with a protection against rejection 15.6-fold. The T/T genotype of the polymorphism rs2241409 (CES2) was associated with a 7.2-fold increased risk of rejection. Therefore, these polymorphisms that showed a strong association with rejection episodes should be considered in future studies on new prognostic markers for rejection in patients treated with MMF.

Significance of Donor HLA Antibodies in Small Bowel Transplantation

Introduction: Donor Specific Antibodies (DSA) is known to be an indicator of poor prognosis in most organ transplants but for small bowel transplant (SBTx) there is a paucity of studies. We have evaluated the outcomes of SBTx patients correlating the DSA samples collected with the occurrence of rejection episodes and graft failure. Method: SBTx from April 1993 to October 2015 were reviewed, on all its modalities. The data comprise donor and recipient demographics, indications, DSA status, biopsies, immunosuppression, patient and graft survival. 318 DSA samples were collected from 51 patients over the period but not following a monitoring protocol. DSA samples were correlated with rejection episodes in SBTx and its impact on outcome. HLA antibodies were detected and measured in a single antigen bead assay. Results: 94 SBTx were performed in 87 patients. Regarding to the type of transplant, 59.6% were Liver + SBTx, 31.9% Isolated SBTx, Multivisceral and Modified Multivisceral were 4.35% each. Sixty-nine patients had SB rejection at some point. 14 of these had at least one DSA positive sample. In 16 no rejection cases tested for DSA one was positive, 2 patients had only liver rejection. Despite the trend we do not see a significant association between DSA and rejection (Fisher’s p=0.24). Forty-one SBTx with acute rejection (AR) had HLA antibody tests undertaken and DSA was found in 10 cases (3 with antibodies against HLA class I, 4 against HLA DR, and 10 against HLA DQ). Graft loss was seen in 5/10 with DSA positive compared with 1/31 in the DSA negative cases (Fisher’s p=0.0018). In the 5 DSA positive graft loss cases, 4 of the antibodies are HLA DQ-specific and were persistent while in the remaining case the antibody was against donor HLA DR and this became undetectable before graft failure. There were 5 DSA (2 HLA Class I, 1 HLA DR, 5 HLA DQ) positive cases without graft loss to date and in all but one of these the antibodies were transient. Conclusion: Rejection is not significantly associated with DSA in our analysis. However, we have found a significant association of graft loss with DSA and this seems to relate to antibody persistence. Antibodies against donor HLA DQ dominate this association and this is consistent with other forms of transplantation where these antibodies correlate with chronic rejection. A protocol of routine DSA testing therefore seems warranted, particularly in patients having experienced AR.

The recipient's heme oxygenase-1 promoter region polymorphism is associated with cardiac allograft vasculopathy.

Heme oxygenase-1 (HO-1) catalyses the degradation of heme to biliverdin, free iron, and carbon monoxide. The promoter region contains a highly polymorphic (GT)n repeat, where shorter (GT)n repeat sequences are linked to higher transcriptional activity, which was shown to correlate with a cytoprotective effect. Higher HO-1 levels may protect from cardiac allograft vasculopathy. Cardiac allograft recipients transplanted between 1988 and 2012 were analyzed for the HO-1 (GT)n repeat polymorphism using PCR and DNA fragment analysis with capillary electrophoresis. A relation to cardiac allograft vasculopathy (CAV) was analyzed using Cox regression including common risk factors for CAV and the occurrence of rejection episodes as explanatory variables. A total of 344 patients were analyzed, of which 127 patients were positive for CAV (36.9%). In our multivariable Cox regression analysis, the short homozygous HO-1 (GT)n genotype with <27 repeats (S/S) revealed a higher risk for CAV (P = 0.032). Donor age (P = 0.001) and donor weight (P = 0.005) were significant predictors for CAV. A potential risk for CAV was associated with rejection episodes (P = 0.058) and history of smoking (P = 0.06). The recipient HO-1 (GT)n genotype may contribute to CAV development. This finding has to be evaluated in larger series including studies targeting the underlying disease mechanism.

Humoral Responses to Collagen-V and Vimentin Are Associated with Renal Graft Failure

Background: Following the primary endothelial injury caused by cellular or humoral immunities against donor antigens, some non-polymorphic tissue antigens of allograft, which are not normally exposed to immune system, become accessible. Autoimmunities against these antigens may be involved in further tissue injury. Autoimmunities to collagen-V and vimentin have been found to be associated with graft dysfunction in lung and heart transplantation respectively. Since both collagen-V and vimentin are widely expressed in most connective tissues, we hypothesize that autoimmunities against collagen-V and vimentin are also associated with failure of other allografts. Methods: 121 kidney recipients who either had biopsy-proved graft injury or experienced rejection episodes were included in this study. Serum samples selected before occurrence of rejection episodes or biopsy-proven graft injury were tested for collagen-V and vimentin antibodies using Luminex technique. Donor specific antibody (DSA) against HLA A, B, or DR were tested using Labscreen Single Antigen Beads. The association between graft outcome and allo- or auto-antibodies were analyzed retrospectively. Results: The percentages of patients with collagen-V, vimentin, and donor-HLA antibodies were 21%, 45%, and 35% respectively. Mean fluorescence intensity of antibodies against collagen-V (962±710), vimentin (849±642) were significantly lower than that of HLA antibodies (7273±5407). 64% of HLA DSA+ patients had collagen-V and/or vimentin antibodies, while 46% of autoantibodies positive patients had HLA-DSAs. Presence of autoantibodies seemed to be significantly associated with HLA-DSAs (p< 0.05). Graft survival analysis demonstrated that DSA and autoantibody double negative patients had the highest 5-yr graft survival rate (61%, ref.), followed by those with only HLA-DSA (55%, p>0.05%), only autoantibody (47%, p>0.05), and double positive patients (12%, p< 0.01).[Figure 1]After adjustment for other predictors of graft failure, multivariate Cox analysis confirmed that the difference of graft survival rates between double negative and double positive patients was statistically significant. Conclusion: Collagen-V & vimentin antibodies were detected at low titers but high frequencies in renal graft recipients. Survival analysis suggested a synergistic effect of HLA-DSA and autoantibodies. HLA-A, B, or DR DSA were only detected in 46% of autoantibody+ patients, which suggested that these DSAs were not the only cause of primary endothelial injury resulting in secondary autoantibody responses. Cellular immunities or other alloantibodies (HLA-C, DP, DQ, or MICA- specific) might be also involved. Further studies are required to determine: 1) the time course of autoantibody development and its association with allospecific humoral and/or cellular immunities; 2) whether collagen-V and vimentin antibodies exist in failed or rejected allografts (elution of antibody from biopsy tissue); 3) the association of autoantibodies with biopsy-proven graft injury, especially chronic injury such as interstitial fibrosis.

Humoral Responses to Collagen-V and Vimentin Are Associated with Renal Graft Failure

Background: Following the primary endothelial injury caused by cellular or humoral immunities against donor antigens, some non-polymorphic tissue antigens of allograft, which are not normally exposed to immune system, become accessible. Autoimmunities against these antigens may be involved in further tissue injury. Autoimmunities to collagen-V and vimentin have been found to be associated with graft dysfunction in lung and heart transplantation respectively. Since both collagen-V and vimentin are widely expressed in most connective tissues, we hypothesize that autoimmunities against collagen-V and vimentin are also associated with failure of other allografts. Methods: 121 kidney recipients who either had biopsy-proved graft injury or experienced rejection episodes were included in this study. Serum samples selected before occurrence of rejection episodes or biopsy-proven graft injury were tested for collagen-V and vimentin antibodies using Luminex technique. Donor specific antibody (DSA) against HLA A, B, or DR were tested using Labscreen Single Antigen Beads. The association between graft outcome and allo- or auto-antibodies were analyzed retrospectively. Results: The percentages of patients with collagen-V, vimentin, and donor-HLA antibodies were 21%, 45%, and 35% respectively. Mean fluorescence intensity of antibodies against collagen-V (962±710), vimentin (849±642) were significantly lower than that of HLA antibodies (7273±5407). 64% of HLA DSA+ patients had collagen-V and/or vimentin antibodies, while 46% of autoantibodies positive patients had HLA-DSAs. Presence of autoantibodies seemed to be significantly associated with HLA-DSAs (p< 0.05). Graft survival analysis demonstrated that DSA and autoantibody double negative patients had the highest 5-yr graft survival rate (61%, ref.), followed by those with only HLA-DSA (55%, p>0.05%), only autoantibody (47%, p>0.05), and double positive patients (12%, p< 0.01).[Figure 1]After adjustment for other predictors of graft failure, multivariate Cox analysis confirmed that the difference of graft survival rates between double negative and double positive patients was statistically significant. Conclusion: Collagen-V & vimentin antibodies were detected at low titers but high frequencies in renal graft recipients. Survival analysis suggested a synergistic effect of HLA-DSA and autoantibodies. HLA-A, B, or DR DSA were only detected in 46% of autoantibody+ patients, which suggested that these DSAs were not the only cause of primary endothelial injury resulting in secondary autoantibody responses. Cellular immunities or other alloantibodies (HLA-C, DP, DQ, or MICA- specific) might be also involved. Further studies are required to determine: 1) the time course of autoantibody development and its association with allospecific humoral and/or cellular immunities; 2) whether collagen-V and vimentin antibodies exist in failed or rejected allografts (elution of antibody from biopsy tissue); 3) the association of autoantibodies with biopsy-proven graft injury, especially chronic injury such as interstitial fibrosis.

Repeat Penetrating Corneal Transplantation in Patients with Keratoconus

To determine factors influencing penetrating corneal graft survival in patients receiving repeat grafts in the same eye after a failed first graft for keratoconus. Large cohort study from a national register of corneal grafts, in which data were recorded prospectively and analyzed retrospectively. Follow-up extended to 23 years. Follow-up was available for 229 regrafts performed in 177 eyes of 173 patients. Regrafts were performed more than once in 16 eyes. Corneal graft survival was analyzed using Kaplan-Meier survival plots and Cox proportional hazards regression, clustered by patient. Graft survival. Graft survival was significantly worse (P<0.001) for second (n = 176) and third or greater grafts (n = 20), compared with first grafts for keratoconus (n = 4871). Kaplan-Meier survivals at 1, 5, and 15 years postgrafting were 88%, 69%, and 46% for second grafts, and 65%, 49%, and 33% for third and subsequent grafts, respectively (P<0.001). Risk factors associated with graft failure of repeat grafts in multivariate analysis were the geographic location of surgery ("center"; P = 0.04), failure of the previous graft within 10 years of surgery (P = 0.02), recipient age at graft ≥60 years (P = 0.04), occurrence of rejection episodes (P = 0.007), and corneal neovascularization postoperatively (P = 0.007). Repeat corneal grafts in eyes originally grafted for keratoconus showed better survival when the previous graft had survived ≥10 years, surgery was performed at a favorable location, the recipient was <60 years old at grafting, and graft rejection and neovascularization were circumvented. The authors have no proprietary or commercial interest in any of the materials discussed in this article.

Corneal Transplantation for Keratoconus

To determine factors influencing long-term graft survival and visual acuity in 4834 eyes of 4060 patients receiving their first penetrating corneal graft for keratoconus. A large cohort study was performed from a national register of corneal grafts in which data were recorded prospectively and analyzed retrospectively. Main outcome measures were graft survival and Snellen visual acuity. Follow-up extended up to 23 years. Kaplan-Meier survival rates of first grafts for keratoconus were 89%, 49%, and 17% at 10, 20, and 23 years, respectively. After 15 years, the graft survival rate was no better than that of all other penetrating grafts (P=.36). Multivariate risk factors influencing failure of first grafts for keratoconus included time to suture removal, postgraft uveitis or microbial keratitis, corneal vascularization prior to or after graft, geographic location of surgery and follow-up (center effect), recipient age at graft, occurrence of rejection episodes, graft size, and surgeon workload. The timing of bilateral grafts made no difference to the risk of rejection. A Snellen visual acuity of 20/40 or better at the most recent follow-up was recorded in 74% of grafts. Penetrating grafts performed for keratoconus exhibited better visual outcome and graft survival than grafts performed for other indications. However, the Kaplan-Meier survival rate of first penetrating grafts for keratoconus was 17% at 23 years after graft and had not plateaued at this time, indicating that young patients are likely to need 1 or more repeated grafts during their lifetime.

Multidimensional Adherence Classification System: Initial development with adolescent transplant recipients

As transplantation has progressively become a more viable option for children with life-threatening illness, ensuring that adolescents do not lose their new organ secondary to medication non-adherence is paramount. The first step to addressing non-adherence is adequate assessment of this construct. In this investigation, we introduce the MACS. The MACS includes self-report and drug assay levels. Self-report is a subjective measure with a low false-positive rate, but is vulnerable to social desirability. Drug assays are an objective measure of drug ingestion, but values suggestive of non-adherence may be influenced by medical complications and timing. The MACS builds on the strengths of both methods and attempts to contain their weaknesses. The sample in this study consisted of 82 adolescent solid organ transplant recipients. The non-adherence rate using the MACS in this sample was 61%. Initial data to support this system are promising. The occurrence of rejection episodes and mortality were significantly related to membership in the Genuinely Non-adherent category. Beyond providing initial support for the MACS, we discuss the clinical implications of this adherence classification system.

Influence of HLA disparity, immunosuppressive regimen used, and type of kidney allograft on production of anti-HLA class-I antibodies after transplant and occurrence of rejection

We studied the effects of HLA disparity, immunosuppressive regimen used, and the type of kidney allograft on production of anti-HLA antibodies after transplant and the occurrence of rejection episodes.Five living-unrelated donors and 4 living-related donors kidney recipients received quadruple therapy (including sirolimus and mycophenolate mofetil). Fifteen living-unrelated donors and 19 living-related donors received triple therapy (excluding sirolimus). A single bolus of 4 to 6 mg/kg rabbit anti-human T-lymphocyte immune serum was included with both regimens. Recipients were studied over a 3-year period. Human leukocyte antigen profiles were determined by DNA (SSP) typing, and anti-HLA class-I antibodies were determined by the complement-dependent microcytotoxicity assay and an enzyme-linked immunosorbent assay.The degree of HLA disparity did not appear to affect anti-HLA antibody production or the occurrences of rejection episodes. None of the patients who received quadruple therapy developed anti-HLA class-I antibodies. Two living-unrelated donors and 2 living-related donors recipients who received triple therapy developed anti-HLA class-I antibodies. One of the 2 living-unrelated donors antibody-positive patients rejected the kidney and returned to dialysis, and the other patient has normal graft function 3 years after the transplant. The 2 living-related donors patients with normal graft function were antibody-positive 1 year after the transplant but were antibody-negative at 2 and 3 years after transplant.Sirolimus appeared to inhibit production of antibodies after transplant. Moreover, use of present day immunosuppressive agents diminishes the role of HLA matching in relation to the occurrence of rejection episodes.

A study of HLA-G polymorphism and linkage disequilibrium in renal transplant patients and their donors

The role of the Major Histocompatibility Complex (MHC) in transplantation immunology is widely known. Incompatibilities associated with Human Leukocyte Antigens (HLA) between donors and recipients are related to poorer prognosis in allograft acceptance and survival, often resulting in rejection episodes. HLA-A, HLA-B, HLA-DR and HLA-DQ compatibility are widely studied in clinical transplants but few studies investigated the influence of non-classical HLA loci, such as HLA-G, a non-classical class I HLA gene located at 6p21.31 in the MHC region, i.e. 300 kb telomeric to HLA-A. MHC region genes are characterized by extreme polymorphism as well as strong positive linkage disequilibrium (LD) between HLA loci (alleles). LD studies related to MHC region provide investigators with a tool to assess candidate genes with an at-risk HLA haplotype, with implications for allograft transplants, human reproduction and disease susceptibility. Many studies reported striking LD between HLA-G and HLAA alleles and also between HLA-G and HLA Class II alleles, but the biologicalimplications for these findings are not clear yet. DNA sequencing methodology was used to determine HLA-G (exons 2 and 3) polymorphisms from 52 patients who underwent kidney transplantation and their donors. It is the purpose of this study to investigate the influence of HLA-G polymorphism in a set of kidney transplants and the occurrence of rejection episodes. It was observed that pairs with 2 HLA-G matches presented a lower risk of rejection occurrence than those pairs with 0 or 1 match. It was also observed that subjects whose genotype presented one synonymous substitution (S) in one HLA-G allele in the HLA-G⁎0101 group of alleles and another allele with a non-synonymous substitution (N/S) on HLA-G⁎0103, HLA-G⁎010401, HLA-G⁎010403 or HLA-G⁎0105N alleles, apparently had a greater chance of rejection episodes. Additionally, HLA-G, as well as HLA-A, -B e -DR, compatibility may also be important for allograft acceptance (rejection probability lower than 0.09%). Besides, heterozygous S/NS patients had a five times greater chance of rejection than S/S and NS/NS patients. Some haplotypes found in the present study were already described in literature: A⁎01-G⁎01B (⁎010102 or ⁎0106), A⁎03-G⁎0101A, A⁎23-G⁎010401, A⁎26-G⁎01B, A⁎31-G⁎0103, A⁎02-G⁎0101A, A⁎24-G⁎0101A, A⁎33-G⁎0103, A⁎68-G⁎01B. We have also described LD between HLA-G alleles and HLA class II DRB1⁎ allelic groups and found significant LD between DRB1⁎04-G⁎01B, DRB1⁎13-G⁎010401, DRB1⁎14-G⁎010108, DRB1⁎15-G⁎0103, DRB1⁎03-G⁎0101A and DRB1⁎03-G⁎01B.

Surgical Aspects of Third and Subsequent Renal Transplants Performed by the Extraperitoneal Access

We reviewed our experience with third, fourth, and fifth renal transplants performed by the extraperitoneal access. The charts of 21 third and subsequent transplants performed extraperitoneally were reviewed. Surgical aspects, the occurrence of rejection episodes, delayed graft function (DGF), graft and patient survival were evaluated and compared with 1560 first transplants in adults with nonmanipulated fossa performed in the same period. Transfusion was necessary in 52% of the retransplants and in 5.7% of the first transplants (P<0.0001). Mean operative time was 327 min for retransplants and 212 min for first transplants (P<0.0001). Surgical complications occurred in 4 patients (19%): two arterial thrombosis and two ureteral obstructions. DGF occurred in 11 patients (52%) among retransplants and in 453 (29%) among first transplants (P=0.028). Acute rejection occurred in 7 (33.3%) retransplants and in 530 first transplant patients (33.9%). The mean serum creatinine among retransplant patients 30 days and one year after transplantation was 2.5 mg/dl and 1.8 mg/dl. One-year graft survival was 57.1% (75% for live and 46% for cadaver donors) for retransplants and 86% for first transplant patients (P<0.0001). Third and subsequent transplants performed extraperitoneally are more time-consuming and require more transfusions in the perioperative period. A higher but acceptable incidence of arterial thrombosis and urinary obstruction were observed. One-year graft survival was better with live donor grafts, but was still lower when compared with first transplants using the same surgical technique.

Simultaneous Pancreas–Kidney Transplantation: Analysis of Rejection

The 3-year data concerning the occurrence of rejection episodes (RE) are reported herein. Patients and methods Two hundred five simultaneous pancreas–kidney (SPK) transplantations were performed from May 1998 to September 2000, including 103 patients randomly assigned to tacrolimus (Tac) and 102 to cyclosporine microemulsion (CsA-ME). All patients received concomitant rATG induction therapy, mycophenolate mofetil (MMF), and short-term corticosteroids. Results After a follow-up of 3 years, acute rejection episodes occurred in 41 patients receiving tacrolimus and in 51 patients receiving CsA ME. The majority of first rejection episodes in both groups occurred during the first 6 months (93% and 90%, respectively) and in most cases were treated with corticosteroids (88% and 90%). Actuarial rejection-free graft survival was not significantly different between the two groups (54% and 44% at 3 years posttransplant). In a multivariate analysis, HLA compatibility ( P = .003) and graft vessel extension ( P = .0005) had a significant influence on rejection-free survival. Rejection influenced pancreatic graft survival ( P = .01) and pancreatic graft loss owing to rejection influenced patient survival ( P = .02). In the intent-to-treat analysis of early rejection, first moderate-to-severe episodes (1 of 40 versus 12 of 47; P = .004) and refractory episodes (2 of 40 versus 10 of 47; P = .03) were significantly lower with tacrolimus than with CsA ME. Pancreatic graft survival was worse among late rejectors (53%) than nonrejectors (86%; P = .002). In addition, serum creatinine was highest in late rejectors. In conclusion, Tac-based immunosuppressive therapy shows advantages over CsA ME in terms of the severity of acute rejection episodes among patients undergoing SPK transplantation.

Independent Predictors of Renal Dysfunction After Heart Transplantation in Patients With Normal Pretransplant Renal Function

Renal dysfunction (RD) is a common complication after heart transplantation (HT), but predictors of post-HT RD have not been clearly identified. We studied 262 HT patients (mean age 54 years, 221 men) with normal baseline renal function. Potential risk factors examined were age, sex, pre-HT ischemic cardiomyopathy, pre- and post-HT diabetes mellitus, pre- and post-HT arterial hypertension, initial immunosuppressive protocol (before 1998 [high cyclosporine, azathioprine, and prednisone] vs after 1998 [low cyclosporine, mycophenolate mofetil, and prednisone]), occurrence of rejection episodes > or =ISHLT Grade 3A, and creatinine level 1 month after HT. RD was considered mild if creatinine level was 1.5 to 2.5 mg/dl, moderate if creatinine level was >2.5 mg/dl, and severe if dialysis or kidney transplant was required. The cumulative incidence of RD (creatinine >1.5 mg/dl) was 35% at 12 months, 42% at 24 months, and 47% at 60 months (mean follow-up 59 +/- 31 months). Only 1% of patients had severe RD 60 months after HT. Independent predictors of RD 24 months after HT were older age (odds ratio [OR] 1.1 [95% confidence interval (95% CI) 1.0-1.1]; p = 0.001), male sex (OR 3.3 [95% CI 1.3-8.1]; p = 0.008), pre-1998 immunosuppressive protocol (OR 2.8 [95% CI 1.4-5.4]; p = 0.003), and creatinine level 1 month after HT (OR 3.2 [95% CI 1.0-5.4]; p < 0.0001). The cumulative incidence of RD in HT patients treated with calcineurin inhibitors increased with time after HT. Age, male sex, an immunosuppressive protocol with relatively high cyclosporine levels and creatinine level 1 month after HT were independent predictors of the presence of RD 24 months after HT.

Late cytomegalovirus disease following liver transplantation

The widespread use of antiviral prophylaxis or preemptive therapy among orthotopic liver transplantation (OLT) recipients has reduced the occurrence of early cytomegalovirus (CMV) disease. Late disease is increasingly reported. Little is known about CMV disease occurring beyond the first year after transplantation. The aim of this study was to evaluate the occurrence of CMV disease two or more years after OLT and to determine its risk factors and clinical features. Eightyone consecutive OLT recipients followed for 2 years or longer after transplantation were included in the study. Data were collected on demographic and clinical variables, clinical presentation, treatment, and outcome of late CMV disease. Late CMV disease occurred in 7/81 liver recipients (8.5%) at a mean time of 5.9 years after OLT (range: 3.5–9.3, median: 6.3 years). All seven patients were women, with a mean age of 47.7 years (range: 26–60, median: 59 years). There was no association between the developemnt of late CMV disease and the occurrence of rejection episodes, treatment with corticosteroids, or the early use of antiviral prophylaxis. Clinical presentation included fever and disturbed liver functions in all patients, one patient had concurrent CMV pneumonitis and one CMV retinitis. Though all patients responded to ganciclovir. two had recurrent disease episodes and one patient died of secondary bacterial sepsis. Late-onset CMV disease can occur several years after OLT. Although it manifests classic clinical features of early disease, it is not associated with traditional risk factors and its pathogenesis may differ from that of early disease.

Switching cyclosporine blood concentration monitoring from C 0 to C 2 in children late after liver transplantation

Background Measurement of cyclospoprine (CsA) blood levels at 2 hours after oral administration (C 2) has been proposed as a better measurement of trough level (C 0) due to reduced intrapatient variability, acute rejection rate and renal toxicity. The aim of the present study was to assess whether there was any advantage to conversion from C 0 to C 2 CsA blood level monitoring in children late after liver transplantation. We reviewed the data from 44 children more than 1 year after liver transplantation. We measured the daily dose of CsA and the C 0 level before switching versus the daily dose and C 2 level at 6 months after conversion, in addition to the alanine aminotransferase (ALT) activity, creatinine blood concentration, and episodes of acute rejection. Results Conversion from C 0 to C 2 monitoring was not associated with a significant change in mean daily dose of CsA, mean concentration of creatinine, ALT activity or occurrence of rejection episodes. Conclusion Switching from C 0 to C 2 monitoring did not seem to proffer any benefits for children late after liver transplantation.

The role of graft-resident Kupffer cells and lymphocytes of donor type during the time course after liver transplantation?a clinico-pathological study

Although graft-resident passenger leukocytes are known to mediate acute rejection by triggering direct allorecognition, they may also act in an immunomodulatory fashion and play an important role in tolerance induction. The present study evaluated by non-isotopic in situ hybridization and immunohistochemistry if and during which time period after transplantation Kupffer cells (KC) and lymphocytes of the liver were replaced by recipient cells and if there is any correlation with the occurrence of rejection episodes and the clinical course. A successive re-population of the liver by recipient lymphocytes and KC was observed after transplantation but a smaller portion of lymphocytes and KC with donor genotype was detectable during the whole time course studied. There was no correlation between the portion of recipient-derived KC and donor-derived lymphocytes and histopathological alterations of the liver tissue. The biopsy content of KC with recipient origin has had no prognostic significance for the probability of survival, but patients with a low portion of donor lymphocytes in the liver biopsy obtained during the first week after transplantation have had a better prognosis for survival. The present results indicate that graft-resident KC and lymphocytes are potentially not the main cell types involved in tolerance induction after liver transplantation.

Late cytomegalovirus disease following liver transplantation.

The widespread use of antiviral prophylaxis or preemptive therapy among orthotopic liver transplantation (OLT) recipients has reduced the occurrence of early cytomegalovirus (CMV) disease. Late disease is increasingly reported. Little is known about CMV disease occurring beyond the first year after transplantation. The aim of this study was to evaluate the occurrence of CMV disease two or more years after OLT and to determine its risk factors and clinical features. Eighty-one consecutive OLT recipients followed for 2 years or longer after transplantation were included in the study. Data were collected on demographic and clinical variables, clinical presentation, treatment, and outcome of late CMV disease. Late CMV disease occurred in 7/81 liver recipients (8.5%) at a mean time of 5.9 years after OLT (range: 3.5--9.3, median: 6.3 years). All seven patients were women, with a mean age of 47.7 years (range: 26--60, median: 59 years). There was no association between the development of late CMV disease and the occurrence of rejection episodes, treatment with corticosteroids, or the early use of antiviral prophylaxis. Clinical presentation included fever and disturbed liver functions in all patients, one patient had concurrent CMV pneumonitis and one CMV retinitis. Though all patients responded to ganciclovir, two had recurrent disease episodes and one patient died of secondary bacterial sepsis. Late-onset CMV disease can occur several years after OLT. Although it manifests classic clinical features of early disease, it is not associated with traditional risk factors and its pathogenesis may differ from that of early disease.