Consistent survival in consecutive cases of life-supporting porcine kidney xenotransplantation using 10GE source pigs.

Xenotransplantation represents a possible solution to the organ shortage crisis and is an imminent clinical reality with long-term xenograft survival in pig-to-nonhuman primate (NHP) heart and kidney large animal models, and short-term success in recent human decedent and clinical studies. However, concerns remain about safe clinical translation of these results, given the inconsistency in published survival as well as key differences between preclinical procurement and immunosuppression and clinical standards-of-care. Notably, no studies of solid organ pig-to-NHP transplantation have achieved xenograft survival longer than one month without CD40/CD154 costimulatory blockade, which is not currently an FDA-approved immunosuppression strategy. We now present consistent survival in consecutive cases of pig-to-NHP kidney xenotransplantation, including long-term survival after >3 hours of xenograft cold preservation time as well as long-term survival using FDA-approved immunosuppression. These data provide critical supporting evidence for the safety and feasibility of clinical kidney xenotransplantation. Moreover, long-term survival without CD40/CD154 costimulatory blockade may provide important insights for immunosuppression regimens to be considered for first-in-human clinical trials.

Combined islet and kidney xenotransplantation for diabetic nephropathy: an update in ongoing research for a clinically relevant application of porcine islet transplantation.

Combined islet and kidney xenotransplantation for the treatment of diabetic nephropathy represents a compelling and increasingly relevant therapeutic possibility for an ever-growing number of patients who would benefit from both durable renal replacement and cure of the underlying cause of their renal insufficiency: diabetes. Here we briefly review immune barriers to islet transplantation, highlight preclinical progress in the field, and summarize our experience with combined islet and kidney xenotransplantation, including both challenges with islet-kidney composite grafts as well as our recent success with sequential kidney followed by islet xenotransplantation in a pig-to-baboon model.

Pretransplant Screening for Prevention of Hyperacute Graft Loss in Pig-to-primate Kidney Xenotransplantation.

BACKGROUND: Xenotransplantation using pig organs is now a clinical reality. However, the process for xenograft recipient screening lacks clarity and scientific rigor: no established thresholds exist to determine which levels of preformed antipig natural antibodies (Nabs) will be safe for clinical xenograft transplantation, and hyperacute rejection (HAR) or acute humoral xenograft rejection (AHXR), which still impacts pig-to-primate kidney xenograft survivals, may impede broader application of pig-to-human clinical xenograft transplantation. METHODS: We retrospectively examined 28 cases of pig-to-baboon kidney xenotransplantation using GalTKO±human complement regulatory protein (hCRP)-transgenic (Tg) pig donors, as well as 6 cases of triple-KO multi-Tg (10GE) pig donors, and developed screening algorithms to predict risk of HAR/AHXR based on recipient antipig Nab levels. Preformed Nabs were evaluated using both complement-dependent cytotoxicity and antibody (IgM and IgG) binding flow-cytometry assays. RESULTS: High complement-dependent cytotoxicity was associated with HAR/AHXR as expected. However, we also found that high levels of IgG were independently associated with HAR/AHXR, and we developed 2 indices to interpret and predict the risk of IgG-mediated HAR/AHXR. CONCLUSIONS: Based on the data in this study, we have established a new 2-step screening, which will be used for future clinical kidney xenotransplantation trials.

Progress in Xenotransplantation: Immunologic Barriers, Advances in Gene Editing, and Successful Tolerance Induction Strategies in Pig-To-Primate Transplantation.

Organ transplantation is the most effective treatment for end stage organ failure, but there are not enough organs to meet burgeoning demand. One potential solution to this organ shortage is xenotransplantation using pig tissues. Decades of progress in xenotransplantation, accelerated by the development of rapid genome editing tools, particularly the advent of CRISPR-Cas9 gene editing technologies, have enabled remarkable advances in kidney and heart xenotransplantation in pig-to-nonhuman primates. These breakthroughs in large animal preclinical models laid the foundation for three recent pig-to-human transplants by three different groups: two kidney xenografts in brain dead recipients deemed ineligible for transplant, and one heart xenograft in the first clinical grade study of pig-to-human transplantation. However, despite tremendous progress, recent data including the first clinical case suggest that gene-modification alone will not overcome all xenogeneic immunologic barriers, and thus an active and innovative immunologic strategy is required for successful xenotransplantation. This review highlights xenogeneic immunologic barriers, advances in gene editing, and tolerance-inducing strategies in pig-to-human xenotransplantation.

Effective Technique for Pancreas Transplantation by Iliac Vascular Transposition, Without Heparin-Based Anticoagulation Therapy.

BACKGROUND: To evaluate patients undergoing a new procedure, iliac vascular transposition, in pancreas transplantation regarding the risk of thrombosis and graft survival without heparin-based anticoagulation therapy. METHODS: Iliac vascular transposition (IVT) involves changing the positions of the external iliac artery and vein relative to each other. In this study, this technique was evaluated in patients undergoing the procedure compared with patients not undergoing the procedure (iliac vascular parallel (IVP) group). RESULTS: No patients received prophylactic heparin therapy. Two patients in the IVP group (n = 26) developed complete thrombosis and six developed partial thrombosis, compared with no patients with complete thrombosis and one with partial thrombosis in the IVT group (n = 29). The cumulative incidence of thrombosis was significantly higher in the IVP group (p < 0.01). Cox regression revealed that not receiving iliac vascular transposition was the only significant risk factor for thrombosis (odds ratio: 10.1, 95% confidence interval: 1.27-81.2; p = 0.03). One-year graft survival was significantly better in the IVT group vs IVP group (p = 0.03). CONCLUSIONS: IVT in pancreas transplantation is a simple technique that results in a lower thrombosis risk and better graft survival rates without heparin-based anticoagulation therapy.

Progress in islet xenotransplantation: Immunologic barriers, advances in gene editing, and tolerance induction strategies for xenogeneic islets in pig-to-primate transplantation.

Islet transplantation has emerged as a curative therapy for diabetes in select patients but remains rare due to shortage of suitable donor pancreases. Islet transplantation using porcine islets has long been proposed as a solution to this organ shortage. There have already been several small clinical trials using porcine islets in humans, but results have been mixed and further trials limited by calls for more rigorous pre-clinical data. Recent progress in heart and kidney xenograft transplant, including three studies of pig-to-human xenograft transplant, have recaptured popular imagination and renewed interest in clinical islet xenotransplantation. This review outlines immunologic barriers to islet transplantation, summarizes current strategies to overcome these barriers with a particular focus on approaches to induce tolerance, and describes an innovative strategy for treatment of diabetic nephropathy with composite islet-kidney transplantation.

Safety and Efficacy of Sodium-glucose Cotransporter 2 Inhibitors in Kidney Transplant Recipients With Pretransplant Type 2 Diabetes Mellitus: A Retrospective, Single-center, Inverse Probability of Treatment Weighting Analysis of 85 Transplant Patients.

Whether sodium-glucose cotransporter 2 (SGLT2) inhibitors can be used effectively and safely in kidney transplant (KT) recipients with pretransplant type 2 diabetes as the primary cause of end-stage renal disease (ESRD) remains unclear. In this study, we retrospectively analyzed the efficacy and safety of SGLT2 inhibitors compared with other oral hypoglycemic agents (OHAs) in KT recipients with pretransplant type 2 diabetes as the primary cause of ESRD. METHODS: In this retrospective, observational, single-center, inverse probability of treatment weighting (IPTW) analysis study, we compared the outcomes of SGLT2 inhibitors (SGLT2 group) and other OHAs (control group) following KT. A total of 85 recipients with type 2 diabetic nephropathy as the major cause of ESRD before KT who were treated at our institute between October 2003 and October 2019 were screened and included. The variables considered for IPTW were recipient age, sex, body mass index, history of cardiovascular disease, ABO incompatibility, insulin therapy, estimated glomerular filtration rate (eGFR), and hemoglobin A1c (HbA1c) at the initiation of additional OHAs. Primary endpoints were changes in HbA1c, body weight, and eGFR 1 y after the initiation of additional OHAs. RESULTS: After IPTW analysis, there were 26 patients in the SGLT2 group and 59 patients in the control group (n = 85 overall). The body weights were significantly reduced in the SGLT2 group. There was no statistical difference in changes in HbA1c and eGFR. Similarly, there was no significant difference in the incidence of urinary infection, acute rejection, or other side effects between the groups. CONCLUSIONS: Our findings suggested that SGLT2 inhibitors reduced the body weight of KT recipients and were used safely without increasing side effects.

Impact of Recipient Age on Outcomes After Pancreas Transplantation.

BACKGROUND: Few reports have provided the ages of pancreas transplant recipients. The aim of this study was to determine whether recipient age affects survival of pancreatic grafts after transplantation. METHODS: We analyzed 73 patients who had undergone pancreas transplantation at our institution from August 2001 to March 2020 and assessed the effects of recipient age on pancreas graft survival within 5 years after pancreas transplantation. RESULTS: The cutoff value for recipient age established by receiver operating characteristic curve was 35 years. The pancreas graft survival rate of recipients aged 35 years or younger (1, 3, and 5 years: 72.9%, 41.7%, and 41.7%, respectively) was significantly lower than that of recipients aged over 35 years (1, 3, and 5 years: 93.2%, 88.4%, and 88.4%, respectively). Multivariate Cox hazard regression analysis showed that recipient age 35 years or younger (hazard ratio = 3.60; 95% confidence interval, 1.04-12.50; P = .044) and solitary pancreas transplantation (hazard ratio = 10.72; 95% confidence interval, 2.72-42.28; P < .001) were significant risk factors for pancreas graft loss within 5 years. CONCLUSION: Our data suggest that younger recipient age is a risk factor for pancreas graft loss after transplantation.

Predicting Operation Time and Creating a Difficulty Scoring System in Donor Nephrectomy.

Background: To determine predictive formulas for operation time and surgical difficulty in laparoscopic living-donor kidney transplantation. Methods: We retrospectively analyzed data for 222 living donors aged >20 years and recorded factors affecting operation time from patients' CT images and medical records. We used the factors significantly affecting operation time to create a formula to predict operation time and designed a model to predict surgical difficulty based on the standardized partial regression coefficient, ß. We also analyzed the relationship between surgical difficulty (high vs low) and operation time. Results: This study involved 111 pure retroperitoneoscopic donor nephrectomies (PRDN) and 111 hand-assisted laparoscopic donor nephrectomies (HALDN). Patients' mean age was 55.7 years, and 59.5% were women; 5.0% underwent right nephrectomy, and 77.0% vs 23.0% had single- vs multiple renal arteries. The average estimated kidney graft weight was 160.0 g, and actual average graft weight was 155.3 g. The following factors were significantly correlated with operation time in the regression analysis: number of renal arteries, Mayo adhesive probability score, estimated kidney graft weight, right nephrectomy, and operation type (PRDN). These five factors were used to create the operation time prediction equation and difficulty scoring system. The multiple r2 value was 0.40 for the operation time prediction equation. Receiver operating characteristic curve analysis of the difficulty scoring system revealed the following: sensitivity: 78.0%, specificity: 64.9%, and c-statistic: 0.76 (95% confidence interval: 0.70 to 0.83). Conclusions: The equation to predict operation time and the surgical difficulty prediction model created in this study are easy to calculate and are accurate. Both may help in selecting an appropriately skilled surgeon and in improving safety in living-donor kidney transplantation.

Risk Factors and Optimal Methods for Incisional Hernias After Kidney Transplantation: A Single-Center Experience From Asia.

BACKGROUND: For kidney transplant patients, incisional hernia (IH) is a major complication resulting from prolonged pretransplant dialysis, immunosuppressive drugs, and the high prevalence of diabetes. However, there have been relatively few studies of IH after kidney transplantation (KT) in Japan and in the greater Asian population. Additionally, operative methods for IH repair have not been established. METHODS: We retrospectively analyzed 465 consecutive patients who underwent KT at our hospital from April 2013 to March 2019. Patients who underwent incisional hernia repair were included in this study, and the follow-up time was extended to September 2020. We defined severe IH as an IH requiring surgical repair. We examine the risk factors for severe IH among KT patients and also discuss the operative methods of IH repair. RESULTS: During the study period, 7 patients developed severe IH after KT. The cumulative occurrence rate for severe IH was 1.1% 1 year postoperatively. Multivariate logistic regression analyses showed that age at KT and dialysis duration (hazard ratio = 1.112, P = .016; hazard ratio = 1.106, respectively; P = .038) were independent risk factors for severe IH. We used polypropylene mesh for IH repair in all cases, with onlay repair performed in 5 of 7 cases. There was no recurrence or infection after mesh repair during follow-up. CONCLUSIONS: In this study, age at KT and dialysis duration were independent risk factors for severe IH in the Japanese population. Onlay repair with a polypropylene mesh appeared to be a safe and acceptable operation for IH repair after KT.

Impact of the introduction of pure retroperitoneoscopic living-donor nephrectomy on perioperative donor outcomes: A propensity score matching comparison with hand-assisted laparoscopic living-donor nephrectomy.

INTRODUCTION: We previously reported that the outcomes of pure retroperitoneoscopic donor nephrectomy are superior to those of hand-assisted retroperitoneoscopic donor nephrectomy. Consequently, we introduced pure retroperitoneoscopic donor nephrectomy in our hospital. Here, we compared perioperative outcomes between hand-assisted intra-abdominal laparoscopic donor nephrectomy and pure retroperitoneoscopic donor nephrectomy. METHODS: We retrospectively reviewed data from 315 living-donor kidney transplantation procedures performed between October 2015 and December 2020 (213 involving hand-assisted intra-abdominal laparoscopic donor nephrectomy, October 2015 to June 2019; 102 involving pure retroperitoneoscopic donor nephrectomy, May 2019 to December 2020). After propensity score matching, 90 transplantations were included in each group (n = 180 overall). RESULTS: Donors in the pure retroperitoneoscopic donor nephrectomy group had longer warm ischemia times (P < .001), lower serum C-reactive protein concentrations and white blood cell counts on postoperative day 1 (P < .001 and P < .001, respectively), and shorter postoperative stays (P < .001) than donors in the hand-assisted intra-abdominal laparoscopic donor nephrectomy group. Five (5.6%) modified Clavien-classifiable complications occurred in the hand-assisted intra-abdominal laparoscopic donor nephrectomy group; no complications occurred in the pure retroperitoneoscopic donor nephrectomy group (P = 0.008). One recipient in the hand-assisted intra-abdominal laparoscopic donor nephrectomy group had donor-related delayed graft function. There were no significant differences between groups in recipient estimated glomerular filtration on postoperative day 7. CONCLUSION: The introduction of pure retroperitoneoscopic donor nephrectomy was safe and effective. Moreover, it was less invasive and less harmful for donors, compared with hand-assisted intra-abdominal laparoscopic donor nephrectomy; recipient outcomes were equivalent.

Serum pancreatic enzymes in the early postoperative period predict complications associated with pancreatic fluid after pancreas transplantation: A retrospective, single-center, observational cohort study.

BACKGROUND: Pancreas transplantation (PT) is a radical treatment for diabetes mellitus (DM). Although the results of PT have been improving, surgical complications remain. Few reports have focused on complications associated with pancreatic fluid (CAPF) after PT. We aimed to investigate the risk factors and predictors for CAPF after PT. METHODS: Sixty-nine patients, who underwent deceased-donor PT for type 1 DM at our institution from August 2001 to May 2020, were retrospectively studied. We identified CAPF from those with Clavien-Dindo Classification ≥grade III and assessed risk factors by univariate and multivariate analyses using logistic regression. RESULTS: Twenty-one (30.4%) patients had complications with Clavien-Dindo Classification ≥grade III. Eleven (16.0%) patients were diagnosed with CAPF. Median serum pancreatic amylase (P-AMY) levels with CAPF on postoperative day (POD)1 and POD2 were significantly higher than those without CAPF (P = .019 and P = .027, respectively). In multivariable analysis, serum P-AMY levels on POD1 were an independent predictive factor for CAPF (odds ratio 1.83, 95% confidence interval 1.07-3.14, P = .008). CONCLUSIONS: Complications associated with pancreatic fluid after PT is associated with high serum P-AMY in the early postoperative period. Serum pancreatic enzymes in the first few postoperative days after PT may be a significant predictive factor for CAPF.

Effects of Concomitant Administration of Vonoprazan Fumarate on the Tacrolimus Blood Concentration in Kidney Transplant Recipients.

Vonoprazan fumarate (vonoprazan) is a new kind of acid suppressant with potent acid inhibitory effects. Therefore, it has been administered to kidney transplant recipients for treatment or prophylaxis of steroid ulcers, refractory peptic ulcers, and gastroesophageal reflux disease. Because tacrolimus, which is a well-established immunosuppressant for kidney transplantation, and vonoprazan share the CYP3A4 system for metabolism, drug interactions are anticipated upon simultaneous administration. We retrospectively analyzed 52 kidney transplant recipients who were converted from rabeprazole, which has a small effect on the tacrolimus trough blood concentration (C0), to vonoprazan between August 2016 and July 2019. We compared the tacrolimus C0/tacrolimus dose (C0/D) before and after conversion and serum liver enzymes, serum total bilirubin, and the estimated glomerular filtration rate (eGFR). As a result, mean tacrolimus C0/D before and after conversion was 1.98 ± 1.02 and 2.19 ± 1.15 (ng/mL)/(mg/d), respectively, (p < 0.001). Additionally, mean aspartate transaminase (AST) before and after conversion was 18.6 ± 4.2 and 19.6 ± 5.2 IU/L, respectively, (p = 0.037). Mean alanine transaminase (ALT) before and after conversion was 15.8 ± 5.5 and 17.6 ± 7.1 IU/L, respectively, (p = 0.007). Mean eGFR before and after conversion was 50.6 ± 14.4 and 51.4 ± 14.7 mL/min/1.73 m2, respectively (p = 0.021). Mean AST, ALT, and eGFR were slightly but significantly elevated within normal ranges after conversion. In conclusion, our study suggests that the mean tacrolimus C0/D was elevated significantly by converting from rabeprazole to vonoprazan, but it had little clinical significance. Vonoprazan can be administered safely to kidney transplant recipients receiving tacrolimus.

Association of Pretransplant BK Polyomavirus Antibody Status with BK Polyomavirus Infection After Kidney Transplantation: A Prospective Cohort Pilot Study of 47 Transplant Recipients.

BACKGROUND: Prevention and early detection of BK polyomavirus (BKV) infection is important for long-term kidney graft survival; hence, pretransplant screening methods are essential to identify recipients at high risk for BKV infection. This study investigated the association of pretransplant donor and recipient BKV antibody status with the occurrence of post-transplant BKV infection. METHODS: We prospectively enrolled 47 adult living donor kidney transplant pairs from December 2014 to January 2016. Recipient and donor pretransplant BKV antibody titer was measured by hemagglutination inhibition (HI) test. Donor and recipient median HI titer of 1:20 was used as a cutoff to define seropositivity. Recipients were divided into 2 groups (BKV antibody donor-seropositive/recipient-seronegative (D+/R-) and non-D+/R-). Urinary cytology was used to screen for BKV infection. Plasma polymerase chain reaction testing for BKV DNA was used when decoy cells in urine were persistently detected. RESULTS: Nine (19.2%) of 47 patients belonged to the D+/R- group. Decoy cells were observed in 32 recipients (68.1%) during follow-up. BK viremia occurred in 3 (6.4%) cases. The maximum decoy cell count was significantly higher in the D+/R- group than in the non-D+/R- group (P = .0002). Decoy-cell-free survival was significantly shorter in the D+/R- group (P = .0220). Multivariate analysis identified only BKV antibody serostatus as an independent risk factor for decoy cell appearance (P = .0491). CONCLUSIONS: Pretransplant donor and recipient BKV antibody status was associated with higher maximum decoy cell count and shorter decoy-cell-free survival after kidney transplantation.

Hepatitis B virus reactivation in kidney transplant patients with resolved hepatitis B virus infection: Risk factors and the safety and efficacy of preemptive therapy.

BACKGROUND: Hepatitis B virus (HBV) reactivation is associated with complications and adverse outcomes in patients with clinically resolved HBV infection who are seronegative for hepatitis B surface antigen (HBs Ag), and seropositive for hepatitis B core antibody (HBc Ab) and/or hepatitis B surface antibody (HBs Ab) before kidney transplantation (KT). METHODS: We retrospectively analyzed 52 patients with resolved HBV infection who were HBV-DNA negative. HBV-DNA after KT was evaluated, and the occurrence of HBV reactivation and outcomes were monitored. We defined HBV reactivation as seropositivity for HBV-DNA at or above the minimal detection level of 1.0 log IU/mL and treated preemptively (using entecavir) when the HBV-DNA level was at or above 1.3 log IU/mL, in accordance with the Japanese Guidelines for HBV treatment. RESULTS: Among the 52 patients, the mean age was 57.2 ± 10.8 years. The median HBc Ab titer was 12.8 (interquartile range, 4.6-42.6) cutoff index, and five (9.6%) cases of HBV reactivation occurred. No patients developed graft loss and died due to HBV reactivation. Statistical analysis showed that age and HBc Ab titer were significant risk factors for HBV reactivation (P = .037 and P = .042, respectively). No significant differences were found between graft survival and the presence or absence of HBV reactivation. CONCLUSION: These results suggest that HBc Ab titer and age could be significant risk factors for HBV reactivation. Resolution of HBV infection did not appear to be associated with patient or graft survival, regardless of whether HBV reactivation occurred, when following our preemptive strategy.