Experienced Rejection Episodes Research Articles

Association between CYP3A5 Gene Polymorphism and Post-Transplant Acute Immune Rejection in Renal Transplant Recipients Receiving Tacrolimus Therapy: A Correlation Study.

Acute immune rejection remains a challenge in the post-transplant period, with approximately 7.8% of renal transplant recipients experiencing rejection episodes within the first year. Genetic polymorphisms in the CYP3A5 gene, which influences tacrolimus metabolism, have garnered interest regarding their association with clinical outcomes in renal transplantation. This retrospective correlation study analysed clinical data from kidney transplant patients who received tacrolimus treatment at our hospital from June 2015 to June 2023. The presence of CYP3A5 gene polymorphisms, tacrolimus trough levels, and demographic and clinical data were collected and analysed. A total of 105 kidney transplant patients were included. Patients were divided into acute immune rejection (n = 56) and non-acute immune rejection (n = 49) groups. The distribution of CYP3A5 gene polymorphisms differed significantly between the acute rejection and non-acute rejection groups (p = 0.037). The acute rejection group exhibited a higher frequency of CYP3A5 *1/*1 or *1/*3 genotypes than the non-acute rejection group. No statistically significant differences were found in the tacrolimus trough levels between the two groups. Correlation analysis revealed a statistically significant correlation between CYP3A5 gene polymorphism and post-transplant acute immune rejection (r = 0.223, p < 0.05). This study demonstrated a significant association between CYP3A5 gene polymorphism and the risk of post-transplant acute immune rejection in renal transplant recipients receiving tacrolimus therapy. These findings highlighted the importance of genetic variability in tacrolimus metabolism when managing immunosuppressive therapy in transplant recipients.

Donor antigen-specific regulatory T cell administration to recipients of live donor kidneys: A ONE Study consortium pilot trial

Regulatory T cells (Tregs) can inhibit cellular immunity in diverse experimental models and have entered early phase clinical trials in autoimmunity and transplantation to assess safety and efficacy. As part of the ONE Study consortium, we conducted a phase I-II clinical trial in which purified donor antigen reactive (dar)-Tregs (CD4+CD25+CD127lo) were administered to 3 patients, 7 to 11 days after live donor renal transplant. Recipients received a modified immunosuppression regimen, without induction therapy, consisting of maintenance tacrolimus, mycophenolate mofetil, and steroids. Steroids were weaned off over 14 weeks. No rejection was seen on any protocol biopsy. Therefore, all patients discontinued mycophenolate mofetil 11 to 13 months posttransplant, per protocol. An early for-cause biopsy in 1 patient, 5 days after dar-Treg infusion, revealed absence of rejection and accumulation of Tregs in the kidney allograft. All patients had Treg-containing lymphoid aggregates evident on protocol biopsies performed 8 months posttransplant. The patients are now all >6 years posttransplant on tacrolimus monotherapy with excellent graft function. None experienced rejection episodes. No serious adverse events were attributable to Treg administration. These results support a favorable safety profile of dar-Tregs administered early after renal transplant, suggest early biopsy might be an instructive research endpoint and provide preliminary evidence of potential immunomodulatory activity.

Impact of the immunotherapy induction on allograft outcome and survival in kidney transplant patients with donor-specific antibodies to HLA-DQB1

BackgroundThe presence of donor-specific antibodies (DSAs) against HLA-DQB1 is considered a significant barrier to good outcome and allograft survival in kidney transplantation (KT). This study aimed to assess the impact of induction immunotherapy on the outcome and allograft survival in KT patients with HLA-DQB1-DSA. MethodologyThirty-two patients who had undergone KT and found to be positive for HLA-DQB1-DSA were monitored at least one to 10 years. They were allocated into two groups of patients: G1 received induction immunotherapy (n = 14 patients; 43.75%), and G2 did not (n = 18 patients; 56.25%). ResultsIn G1, 6 (42.86%) patients experienced rejection episodes (RE), 2 (14.29%) due to antibody-mediated rejection (ABMR) and 4 (28.57%) due to T-cell-mediated rejection (TCMR). In G2, 13 (72.22%) patients experienced RE, 3 (16.67%) due to ABMR, and 10 (55.56%) due to TCMR. Graft loss occurred in 4 patients from G1, 2 (14.29%) due to ABMR and 2 (14.29%) due to non-immunological causes. In G2, 9 (50.00%) patients lost their grafts, 2 (11.11%) due to TCMR, 2 (11.11%) due to ABMR, and 5 (27.78%) due to non-immunological causes. The graft survival rate was 64.29% in G1 and 45.83% in G2. Glomerulitis and peritubular capillaritis were observed in 3 and C4d-positive patients with/or without induction who lost their grafts by ABMR by HLA-DQ DSA. Two patients from G2 lost their graft by TCMR due to interstitial lymphocytic infiltrate (i1), foci of mild tubulitis (t2), interstitial edema, moderate interstitial fibrosis and tubular atrophy. Better graft survival rates were shown in patients from G1 who received induction immunotherapy. ConclusionOur study suggests that patients with an immunological profile of HLA-DQ+ DSA+ treated by immunotherapy induction have a decreased risk of ABMR and increased allograft survival, and the presence of anti-HLA-DQB1 DSA+ detected before and after KT were associated with ABMR episodes and failure.

OR14 Relevance of MICA-129 dimorphism in live donor renal transplantation

Aim Strong or weak NK/T cell activation by NKG2D-MICA-129 met or val allele respectively can lead to different allograft outcomes by influencing the degree of NK cell activation. The aim was to understand the role of MICA-129 dimorphism in allograft rejection in live donor renal transplantation. Methods A total of 176 live donor renal transplant patients were genotyped for MICA-129 dimorphism using TaqMan technique and were followed up for a minimum period of 1.5 years post-transplant. Serum samples of all recipients were evaluated at the pre and post-transplant periods, 1–2 week, 3 months, 6 months and at time of rejection (if applicable) for the presence of HLA specific antibodies using Luminex technology. The biopsy proven rejection episodes were recorded and correlated with MICA-129 dimorphism for the presence of met or val alleles and the respective genotypes met/met, met/val and val/val. Results MICA-129 met allelic as well as met/met genotypic frequencies dominated in recipients experiencing rejection episodes, particularly those with antibody mediated rejection (AMR) as compared with the no rejection episode group (NRE) (61% vs 32%; p > 0.0006 and 43% vs 13%; p > 0.01 respectively). Five of the six met/met AMR cases developed denovo high titer (Mean MFI > 5000) HLA-DSA for HLA class II molecules, 3–6 months post transplantation. This is in contrast to the met/val and val/val groups who maintained low titer antibodies till the time of biopsy. Presence of met allele also correlated with serum creatinine levels and C4d positivity and the data revealed an allele dose dependent increase in intensity towards AMR progression. Conclusions These results point towards an important role of MICA-129 dimorphism in renal allograft rejection and suggest that recipients with MICA-129 met allele may warrant special post-transplant intervention/management.

Study the Cross-talk Between Hepatitis B Virus Infection and Interferon Regulatory Factors in Liver Transplant Patients

Background: Interferon regulatory factors (IRFs) as immunoregulatory molecules have a determinative antiviral role in liver transplantation outcomes and graft rejection. Hepatitis B virus (HBV) and its antigen derivatives also choose some strategies to escape from innate immune responses. Objectives: The current study aimed at evaluating inflammatory cross-talks between pattern recognition receptors (PRRs) signaling components such as IRF3 and IRF7 with HBV infection in mRNA levels in patients undergoing liver transplantation. Methods: The 46 HBV infected liver recipients were divided into rejection experienced (20) and not experienced (26) groups and a healthy control group was also considered. Peripheral mononuclear cells (PBMCs) were isolated form each studied patient on the days 1, 4, and 7 in post-transplant period. After RNA extraction and cDNA synthesis from each collected sample, the expression levels of IRF3 and IRF7 genes were evaluated using in-house SYBER Green based the real-time polymerase chain reaction (PCR) protocols. Results: The overexpression of mRNA levels of IRF3 (3.37 folds) and IRF7 (1.74 folds) on the day 1 were found in patients experiencing rejection, compared with non-rejected ones, based on initial ischemia/reperfusion (I/R) injuries. But, the mRNA levels of IRF3 (0.53 folds) and IRF7 (0.74 folds) on the day 4 were downregulated in patients with rejected transplantation, compared with non-rejected ones. Finally, reducing the expression of IRF3 (0.54 fold) on the day 7 and upregulation of IRF7 (2.38 fold) on the day 7 were found in rejected liver recipients, compared with non-rejected ones in post-transplant period. Conclusions: Downregulation of IRF3 expression in patients with HBV infection, who experienced rejection episodes in the first week post-liver transplantation indicated that they may be at higher risk for acute rejection; the hypothesis, which should be investigated in further studies.

Early post-transplant immune monitoring can predict long-term kidney graft survival: Soluble CD30 levels, anti-HLA antibodies and IgA-anti-Fab autoantibodies

This study aimed to investigate the predictive power of anti-HLA antibodies, sCD30 levels and IgA-anti-Fab autoantibody before and early after transplantation in relation to long-term kidney allograft survival. Pre- and post-transplant sera samples of 59 living-unrelated donor kidney recipients were tested for above risk factors by enzyme-linked immunoabsorbent assay. 15 out of 59 cases experienced rejection episodes (failure group). Pre- and post-transplant high sCD30 levels were significantly associated with graft failure (P=0.02 and P=0.004) and decreased 4year graft survival (P=0.009 and P=0.001). Higher frequency of post-transplant HLA class-II antibody in the absence of class-I antibody was observed in failure group (P=0.007). Patients with post-transplant HLA class-I and class-II antibodies either alone or in combination showed significant lower 4year graft survival. Recipients with high sCD30 levels in the presence of HLA class-I or class-II antibodies within 2 weeks post-transplant had poor graft survival (P=0.004 and P=0.002, respectively). High levels of post-transplant IgA-anti-Fab antibody was more frequent in functioning-graft patients (P=0.00001), correlated with decreased serum creatinine levels (P=0.01) and associated with improved graft survival (P=0.008). Our findings indicate the deleterious effect of early post-transplant HLA antibodies and increased sCD30 levels dependently and protective effect of IgA-anti-Fab antibodies on long-term renal graft outcomes.

Five-year clinical effects of donor bone marrow cells infusions in kidney allograft recipients

Augmentation of microchimerism in solid organ transplant recipients by donor bone marrow cells (DBMC) infusion may promote immune hyporesponsiveness and consequently improve long-term allograft survival. Between March 2005 and July 2007, outcomes for 20 living unrelated donor (LURD) primary kidney recipients with concurrent DBMC infusion (an average of 2.19 ± 1.13 x 10⁹ donor cells consisting of 2.66 ± 1.70 x 10⁷ CD34⁺ cells) were prospectively compared with 20 non-infused control allograft recipients given similar conventional immunosuppressive regimens. With five years of clinical follow up, a total of 11 cases experienced rejection episodes (3 DBMI patients vs. 8 controls, p = 0.15). One DBMC-infused patient experienced chronic rejection vs. two episodes (1 biopsy-confirmed) in the control patients. Actuarial and death-censored 5-y graft survival was significantly higher in infused patients compared with controls (p = 0.01 and p = 0.03, respectively). Long-term graft survival was significantly associated with pre-transplant anti-HLA antibodies (p = 0.01), slightly with peripheral microchimerism (p = 0.09) and CD4⁺CD25⁺FoxP3⁺ T cells (p = 0.09). Immunosuppressant dosing was lower in infused patients than controls, particularly for mycophenolate mofetil (p = 0.001). The current findings as well as our previous reports on these patients indicates clinical improvement in long-term graft survival of renal transplant patients resulting from low-dose DBMC infusion given without induction therapy.

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.

Restored Kidney Transplant Using Kidneys Affected by Small Tumors: Outcomes and Lessons Learned

Objectives: The use of kidneys with small tumors has been focused as a potential source for solving the organ donor shortage. Buell, Mannami, and Nicol respectively reported 14, 8, and 31 transplants using kidneys after excision of renal cell carcinoma (RCC). Nalesnik et al. recently collected data to clarify the risk of cancer transmission to optimize organ usage. Based on Mannami's published series, we initiated a prospective open clinical trial and then extended the series after completion of the first stage. Methods: At first, our trial that utilized resected kidneys for transplant into unrelated recipients after restoration had an estimated enrollment of 5 patients with one year of follow-up and was approved by Tokushukai Joint Ethics Committee and registered with U.S. ClinicalTrials.gov. Donors were selected from among patients who opted to undergo nephrectomy for small tumors after extensive discussion of other possible treatment modalities. After nephrectomy, the tumor was removed from each kidney, which was restored and transplanted into an unrelated recipient who was selected by a third-party selection committee based on the blood group match, high clinical evaluation score, and negative cross-match test. The trial was extended to enroll another 5 patients after the fifth transplant because of requests from other waiting patients. In addition to these 9 cases, we have reviewed the eight cases reported by Mannami. Results: In the initial trial, five men aged 51-79 years were the kidney donors. The nephrometry RENAL scores for their renal tumors (Kutikov-Uzzo) were 5-7, suggestive of low-moderate complexity. A total of 56 dialysis patients aged 31-83 years (mean: 58.7 years) were enrolled as candidate recipients. Two recipients had a history of kidney transplant. All patients received triple immunosuppression and 4 are steroid-free. Four recipients have experienced rejection episodes so far and the latest serum creatinine levels range from 1.22 to 1.67 mg/dl after 15 to 23 months of follow-up. There has not been any recurrence of RCC. In the extended trial, 4 patients aged 46-65 years have undergone restored kidney transplant so far and their recent creatinine levels range from 1.06 to 1.80 mg/ml without tumor recurrence. Two patients from Mannami's series are surviving with functioning graft and without tumor at 62 and 118 months after transplant. Conclusions: Selected candidates can benefit from restored kidney transplant, achieving good renal function without cancer. In full understanding of cancer-transmission possibility, transplant candidates may benefit from accepting these marginal kidneys (discarded kidneys with small tumors) in exchange for a shorter waiting time on dialysis. Source of Funding: None

Restored Kidney Transplant Using Kidneys Affected by Small Tumors: Outcomes and Lessons Learned

Objectives: The use of kidneys with small tumors has been focused as a potential source for solving the organ donor shortage. Buell, Mannami, and Nicol respectively reported 14, 8, and 31 transplants using kidneys after excision of renal cell carcinoma (RCC). Nalesnik et al. recently collected data to clarify the risk of cancer transmission to optimize organ usage. Based on Mannami's published series, we initiated a prospective open clinical trial and then extended the series after completion of the first stage. Methods: At first, our trial that utilized resected kidneys for transplant into unrelated recipients after restoration had an estimated enrollment of 5 patients with one year of follow-up and was approved by Tokushukai Joint Ethics Committee and registered with U.S. ClinicalTrials.gov. Donors were selected from among patients who opted to undergo nephrectomy for small tumors after extensive discussion of other possible treatment modalities. After nephrectomy, the tumor was removed from each kidney, which was restored and transplanted into an unrelated recipient who was selected by a third-party selection committee based on the blood group match, high clinical evaluation score, and negative cross-match test. The trial was extended to enroll another 5 patients after the fifth transplant because of requests from other waiting patients. In addition to these 9 cases, we have reviewed the eight cases reported by Mannami. Results: In the initial trial, five men aged 51-79 years were the kidney donors. The nephrometry RENAL scores for their renal tumors (Kutikov- Uzzo) were 5-7, suggestive of low-moderate complexity. A total of 56 dialysis patients aged 31-83 years (mean: 58.7 years) were enrolled as candidate recipients. Two recipients had a history of kidney transplant. All patients received triple immunosuppression and 4 are steroid-free. Four recipients have experienced rejection episodes so far and the latest serum creatinine levels range from 1.22 to 1.67 mg/dl after 15 to 23 months of follow-up. There has not been any recurrence of RCC. In the extended trial, 4 patients aged 46-65 years have undergone restored kidney transplant so far and their recent creatinine levels range from 1.06 to 1.80 mg/ml without tumor recurrence. Two patients from Mannami's series are surviving with functioning graft and without tumor at 62 and 118 months after transplant. Conclusions: Selected candidates can benefit from restored kidney transplant, achieving good renal function without cancer. In full understanding of cancer-transmission possibility, transplant candidates may benefit from accepting these marginal kidneys (discarded kidneys with small tumors) in exchange for a shorter waiting time on dialysis.

Safety and Efficacy of Peginterferon Alfa-2a Plus Ribavirin Combination Treatment in Chronic Hepatitis C Post-Renal Transplant Patients; Prospective Cohort

Background: Chronic liver disease has a significant impact on the survival of renal transplant recipients. At present, there is no safe and efficacious therapy of chronic hepatitis C (HCV) after renal transplantation. Interferon-based therapy in renal transplant recipients remains a controversial issue, as it has been associated with a high risk of rejection and poor efficacy. Aim: To assess the safety and efficacy of PEG-IFN and ribavirin combination therapy in post-renal transplant HCV-infected patients. Methods: Thirty two adult renal transplant recipients at two centers in Saudi Arabia, >12 months after transplant surgery with confirmed HCV and evidence of histological disease (METAVIR >A2/F2; >F3=17) were recruited in a pilot open-label trial with PEGIFN-alpha-2a (135-180 μg/week, based on GFR [MDRD equation]) plus ribavirin (200-1200 mg/day, based on GFR). Safety and laboratory assessments were performed weekly for 4 weeks, then 2-weekly for 8 weeks, and then 6-weekly for 36 weeks. Subjects were more male (57%), mean age 47 ± 13(years±SD), BMI 26.4±5.2, genotype (G1=21, G4=11) and mean HCV RNA 6.4± 0.9 log10 IU/mL. Early (EVR) and sustained virologic response (SVR) were defined as a 2-log10 reduction from baseline or undetectable HCV RNA (< 50 IU/mL) at treatment week 12, and undetectable HCV RNA at 24 weeks of off-treatment follow-up, respectively. Renal biopsy was performed in patients with a 20% increase in serum creatinine from pretreatment levels. Results: All patients completed the treatment periods and 21 completed all study assessments. Dose reductions of PEGIFN and ribavirin were required in 36% and 54%, respectively for hematological side effects. EVR was similar between G1 (58.8%) and G4 (45.4%) patients (P = 0.08). Overall, 62.5%, 47 % and 37.5% achieved EVR, end-of-treatment response and SVR, respectively. No patient experienced rejection episodes during or after therapy from the 9 (28%) who required renal biopsy. There was no difference in the pre-treatment and end of assessment serum creatinine (110 ± 41 vs. 125 ± 52 μmol/L, P = 0.16). Three of the non responder patients developed liver decompensation. Conclusions: PEGIFN/ribavirin therapy in renal recipients is safe in low risk for rejection patients, with good efficacy in the treatment of chronic HCV. Treatment-related non-renal side effects are common and may contribute to sub-optimal virologic response.

Detection of Cytomegalovirus and Human Herpesvirus-6 DNA in Liver Biopsy Specimens and Their Correlation With Rejection After Liver Transplantation

Cytomegalovirus (CMV) and human herpesvirus-6 (HHV-6) reactivation after transplantation put patients at an increased risk of graft rejection mainly among those who receive organs that are positive in their donor biopsies. The aim of this study was to investigate the presence of CMV and HHV-6 DNA in liver biopsy specimens from the donors and from their grafts for correlation with rejection after transplantation. We followed 41 liver transplantation patients whose samples were evaluated using nested-polymerase chain reactions (N-PCR). Twenty-one (51%) of the 41 studied patients experienced rejection; 4/21 (19%) were CMV positive in the donor biopsy specimens and remained positive; another 5 subjects became positive. The patients who received organs from donors with biopsies positive for CMV demonstrated a trend to develop graft rejection after transplantation (Fisher's exact test [P = .0591] with significant results on univariate and multivariate analysis [P = .042]). Eight of the 21 who experienced rejection episodes were HHV-6 positive in the donor biopsy but there was no statistical significance CMV DNA diagnosed in liver donor biopsies remained positive posttransplantation in liver biopsy recipients; it was considered a tendency to develop acute cellular rejection after transplantation.

2274 CLINICAL TRIAL OF RESTORED KIDNEY TRANSPLANT AFTER RESECTION OF RENAL CELL CARCINOMA: RESULTS OF THE INITIAL AND EXTENDED STUDIES

You have accessJournal of UrologyTransplantation & Vascular Surgery: Renal Transplantation, Vascular Surgery II1 Apr 20122274 CLINICAL TRIAL OF RESTORED KIDNEY TRANSPLANT AFTER RESECTION OF RENAL CELL CARCINOMA: RESULTS OF THE INITIAL AND EXTENDED STUDIES Yoshihide Ogawa, Tomoharu Kobayashi, Shinyu Shiroma, Keimei Kojima, Rensuke Mannami, Makoto Mannami, Keiichi Kitajima, Mitsuo Nishi, Seiichi Ito, and Naoki Mitsuhata Yoshihide OgawaYoshihide Ogawa Akishima, Japan More articles by this author , Tomoharu KobayashiTomoharu Kobayashi Akishima, Japan More articles by this author , Shinyu ShiromaShinyu Shiroma Uwajima, Japan More articles by this author , Keimei KojimaKeimei Kojima Uwajima, Japan More articles by this author , Rensuke MannamiRensuke Mannami Uwajima, Japan More articles by this author , Makoto MannamiMakoto Mannami Uwajima, Japan More articles by this author , Keiichi KitajimaKeiichi Kitajima Kagoshima, Japan More articles by this author , Mitsuo NishiMitsuo Nishi Marugame, Japan More articles by this author , Seiichi ItoSeiichi Ito Kure, Japan More articles by this author , and Naoki MitsuhataNaoki Mitsuhata Kure, Japan More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2012.02.2452AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Kidneys from patients with small renal cell carcinomas (RCC) have been considered as a potential source for solving the organ donor crisis. Buell, Mannami, and Nicol respectively reported 14, 8, and 31 transplant procedures using kidneys after resection of RCC. Nalesnik et al. recently performed the first step towards evaluating the risk of cancer transmission to optimize organ usage. However, no prospective data are available on the transmission risk for RCC. To address this issue and raise awareness, we performed a prospective open trial that utilized resected kidneys for transplant into third-party recipients after restoration. METHODS Our study of restored kidney transplant had an estimated enrollment of 5 patients with one year of follow-up and was approved by Tokushukai Joint Ethics Committee and registered with U.S. ClinicalTrials.gov. Donors were selected from among patients who opted to undergo nephrectomy for small RCC after extensive discussion of other possible treatment modalities. After nephrectomy, the tumor was removed from each resected kidney, which was restored and transplanted into an unrelated recipient who was selected by a third-party selection committee based on the blood group match, high clinical evaluation score, and negative cross-match test. The trial was extended to enroll another 5 patients after the fifth transplant because of strong requests from other patients. RESULTS In the initial study, five male patients aged 51-79 years were the kidney donors. The nephrometry RENAL scores for their renal tumors (Kutikov-Uzzo) were 6 or 7, suggestive of moderate complexity. A total of 56 dialysis patients aged 31-83 years (mean: 58.7 years) were enrolled as candidate recipients. Two recipients had a history of kidney transplant. All patients received triple immunosuppression. Four recipients have experienced rejection episodes so far and the latest serum creatinine levels range from 1.22 to 1.67 mg/dl after 15 to 23 months of follow-up. There has not been any recurrence of RCC. In the extended study, 4 patients aged 46-65 years have undergone restored kidney transplant so far and their recent creatinine levels range from 1.06 to 1.80 mg/ml without tumor recurrence. CONCLUSIONS Selected candidates can benefit from restored kidney transplant, achieving good renal function without recurrence of RCC. Urologists should bridge the growing gap between the number of donor kidneys needed and the available supply by employing discarded kidneys with small RCC for renal transplantation. © 2012 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 187Issue 4SApril 2012Page: e917-e918 Advertisement Copyright & Permissions© 2012 by American Urological Association Education and Research, Inc.MetricsAuthor Information Yoshihide Ogawa Akishima, Japan More articles by this author Tomoharu Kobayashi Akishima, Japan More articles by this author Shinyu Shiroma Uwajima, Japan More articles by this author Keimei Kojima Uwajima, Japan More articles by this author Rensuke Mannami Uwajima, Japan More articles by this author Makoto Mannami Uwajima, Japan More articles by this author Keiichi Kitajima Kagoshima, Japan More articles by this author Mitsuo Nishi Marugame, Japan More articles by this author Seiichi Ito Kure, Japan More articles by this author Naoki Mitsuhata Kure, Japan More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Stool Calprotectin Monitoring After Small Intestine Transplantation

Small intestine transplantation is the only life-saving therapy available for patients with intestinal failure and life-threatening complications of parenteral nutrition, but it is still plagued by high levels of early acute rejection. The ability to diagnose rejection noninvasively, ideally before pathologic manifestations, would be a major advance in the care of intestinal transplant patients. We measured calprotectin levels in 732 stool samples collected, analyzed over from 72 patients having undergone 74 total transplants, and correlated them with clinical indications, ostomy output, and pathologic findings. We found that overall patients with rejection have higher mean levels of stool calprotectin than those without, but because of significant interpatient variability, defining an effective general "cutoff" for the test is difficult. Each patient, in effect, has to act as their own control. Patients experiencing rejection episodes have greater fluctuations in calprotectin levels than those without, suggesting increased "reactivity" within the graft. Our most frequent clinical indicator for biopsy, an increase in ostomy output, had no real relationship to the discovery of rejection. Although more frequent prospective sampling could perhaps demonstrate an advantage in early indication of rejection, based on these data, routine stool calprotectin monitoring is not strongly supported.

Interleukin 8 −251T>A and Interferon gamma +874A>T polymorphism: Potential predictors of allograft outcome in renal transplant recipients from north India

Background Episodes of acute rejection represent an important risk factor for the development of chronic allograft nephropathy. We explored whether certain cytokine gene polymorphisms in renal transplant recipients may be useful markers for susceptibility to allograft rejection. Interleukin 8 ( IL8) −251 T>A and interferon gamma ( IFNG) +874A>T gene polymorphisms were correlated with allograft outcome in renal transplant recipients. Methods Genotyping was done by amplification refractory mutational system-polymerase chain reaction (ARMS-PCR) in 264 healthy controls and 296 renal transplant recipients categorized into 235 non-rejecters and 61 rejecters. Results IL8 −251AA genotype was associated with 2.7-folds increased risk for allograft rejection in recipients experiencing rejection episodes as compared to non-rejecters (OR = 2.70, P = 0.032). Cox proportional analysis revealed > 2-folds increased susceptibility for allograft rejection (HR = 2.38, P = 0.010) in IL8 −251AA recipients. Kaplan–Meier analysis also demonstrated lower mean time to first rejection episode for IL8 −251AA recipients (23 months) as compared to TT recipients (30 months) (log rank P = 0.022). No association of IFNG +874A>T was observed with allograft rejection, however, an increasing trend towards immunosuppressant toxicity was observed in patients with +874TT genotype at one month post transplantation. Conclusion Thus, IL8 −251AA genotype may serve as potential predictor of allograft outcome in our North Indian cohort of renal transplant recipients.

Pegylated interferon-α-based treatment for chronic hepatitis C in renal transplant recipients: an open pilot study

Treatment of hepatitis C in renal transplant recipients remains a controversial issue, as interferon therapy has been associated with a high risk of rejection and poor efficacy. We report here the use of pegylated interferon-alpha, alone or in combination with ribavirin, in renal transplant recipients with chronic hepatitis C. Eight renal transplant recipients with chronic hepatitis C were recruited. The mean delay between renal transplantation and antiviral therapy was 198.8 months. Sustained virological response was observed in four of out eight patients. Three patients with sustained virological response were genotype 2, one was genotype 1; fibrosis stages were F1 for one patient, F2 for 2, F3 for one. At baseline, renal dysfunction was moderate in seven patients and severe in one patient. No patient experienced rejection episodes during or after pegylated interferon-alpha therapy. One patient developed haemolytic uraemic syndrome, which eventually resulted in graft loss and return to dialysis. In conclusion, for renal transplant recipients treated with pegylated interferon-alpha-based therapy, we observed a low risk of renal dysfunction, acceptable tolerance and significant virological efficacy. This is therefore the first study to suggest that pegylated interferon-alpha could be proposed late after transplantation to renal transplant recipients.

Corneal transplant rejection

The purpose of this article is to review the clinical findings of different types of corneal graft rejection and examine the different options of therapy, including well-established and new treatment modalities. A PubMed literature review search was performed, targeting recent articles on the subject of corneal graft rejection and therapies over the past 40 years. The conclusions of the review were that there are many types of corneal graft rejection, including epithelial, stromal, endothelial, or any combination thereof; 30% of patients will experience rejection episodes within the first year. Different therapies exist for the treatment of corneal transplant rejection. Corticosteroids can be administered by many routes and are the established standard for the treatment of corneal graft rejection. Cytotoxic agents, such as azathioprine can also be used for treatment, however, side effects and toxicity may limit its use. Cyclosporine is an increasingly used therapy for the treatment and prevention of corneal graft rejection, especially in patients at high risk of rejection, and can be produced to be taken orally or made into different strength topical formulations. Tacrolimus and rapamycin are the newest pharmaceuticals used to treat corneal graft rejection.

Composite Tissue Allotransplantation: Classification of Clinical Acute Skin Rejection

Composite tissue allotransplantation (CTA) is a recently introduced option for limb replacement and reconstruction of other nonreconstructible tissue defects. As with recipients of other allotransplants, CTA recipients can experience rejection episodes that are presumed to be mediated by immune mechanisms similar to those affecting solid organ grafts. However, a systematic examination of this process has not been performed, and there are no standardized criteria for the description of severity or type of rejection We collected biopsies from human limb allografts and abdominal walls in various stages of rejection for histological and immunohistochemical analysis to formulate a CTA rejection scheme. Biopsies were ranked by severity and reproducibility of the system was tested using a second set of biopsies. Tissue slides were examined blindly by three pathologists and the nonparametric Kendall coefficient of concordance (W) was used to assess the amount of agreement among the pathologists in their classification grades. Rejection initially appeared as a perivascular infiltrate progressing to involve the dermis. Arteritis was observed only in the medium to large size arteries of the subcutis. Myositis was seen occasionally. Perineural involvement without frank neuritis was present in advanced rejection. The infiltrate was predominantly CD4+ in milder cases and CD8+ in advanced cases. HLA-DR was minimally expressed in keratinocytes even in severe rejection. Kendall's W was 0.9375 (p<or=0.0001). Based on this survey, we proposed an initial classification system for acute rejection in the skin of a CTA and demonstrated that this system is easily reproduced by independent pathologists.

A technique for detecting rejection episodes in human transplant recipients using radioactive fibrinogen.

Abstract Radioactive 125I-labelled human fibrinogen was given to 32 patients who had received renal transplants. In each case radioactivity was measured over the transplant and expressed as a percentage of the value recorded over the heart. Recipients that were experiencing rejection episodes had higher levels of radioactivity over their transplants when compared with patients who were free of rejection at the time. It is suggested that this technique could be of value in the diagnosis of rejection episodes, particularly in those recipients who remain oliguric after transplantation.