Pancreas after kidney transplantation, is it the time to overcome the stigma?

BACKGROUND: Pancreas transplantation is the most effective treatment to improve quality of life and overcome complications in patients with end-stage renal disease and diabetes mellitus. One of the main approaches for concurrent renal disease and diabetes mellitus which has been underutilized during the past decade is a pancreas transplant after kidney transplantation. Our study aimed to quantify outcomes following pancreas after kidney transplants (PAKs) in the United States from 2001 to 2020 with an emphasis on graft and patient survival. METHODS AND MATERIALS: A retrospective registry analysis was performed by accessing the OPTN/UNOS database for PAKs that were performed in the United States from January 2001 to April 2020. The study population was divided into two subgroups: patients receiving a pancreas transplant between 2001 and 2010 and those receiving a pancreas transplant between 2011 and 2020. RESULTS: The study examined a total number of 3706 PAK recipients; patients who received a PAK from January 2001 through December 2010 (n = 2892) and those who received a PAK from January 2011 to April 2020 (n = 814). The selection process of transplant recipients did not drastically change throughout the 2001-2010 and 2011-2020 periods. Length of stay at the hospital after the transplantation improved significantly in the 2011-2020 group relative to the 2001-2010 group (8.48 vs. 10.08 days, mean, p < 0.01). Additionally, more transplantation with 4-6 human leukocyte antigen mismatch occurred in the 2011-2020 group than in the 2001-2010 group (80.6% vs. 71.4%, p < 0.01). The pancreas preservation time of 13.35 h in the 2001-2010 group decreased significantly to 11.17 h in the 2011-2020 group (p < 0.001). The mean donor's amylase and lipase also decreased significantly in the 2011-2020 cohort. Significant graft survival improvement was observed in the 2011-2020 group compared to the 2001-2010 group after a long-term follow-up (p < 0.001). The mean Calculated Pancreas Donor Risk Index was 1.08 for the 2001-2010 group and 0.99 for the 2011-2020 group with a significant difference (p < 0.001). CONCLUSION: The beneficial results and improved outcomes observed in PAK patients demonstrate the effectiveness of the operation for individuals in need of a pancreas transplant. PAKs can prove to be a meaningful solution to overcome long waiting times, decrease the donor-recipient imbalance, expand the donor pool, and overcome the current underutilization in order to improve the short- and long-term quality of life in the groups of interest.

Early conversion to belatacept-based immunosuppression regimen promotes improved long-term renal graft function in kidney transplant recipients.

BACKGROUND: Belatacept has been demonstrated as an effective alternative immunosuppressant in kidney transplant recipients. This study focuses on outcomes of early and late conversion to Belatacept-based immunosuppression after kidney transplant. MATERIALS AND METHODS: This retrospective analysis of a prospectively collected database included all adult kidney transplants patients at SUNY Upstate Medical Hospital from 1 January 2014 to 30 December 2022. Early conversion was defined as all conversions done at <6 months after kidney transplantation, and late conversion to belatacept was defined as conversion at >6 months after kidney transplantation. RESULTS: Out of 61 patients included in this study, 33 patients (54%) were in the early conversion group, and 28 patients (46%) were in the late conversion group. The mean eGFR in the early conversion group was 26.73 ± 16.26 ml/min/1.73 m2 before conversion to belatacept, which improved to 45.3 ± 21.01 ml/min/1.73 m2 at one-year post-conversion (p = 0.0006). Furthermore, eGFR changes in the late conversion group were insignificant, with 46.30 ± 15.65 ml/min/1.73 m2 before conversion to belatacept, and 44.76 ± 22.91 ml/min/1.73 m2 after one year of follow-up (p = 0.72). All four biopsy-proven allograft rejections in the early conversion group were acute T-cell-mediated rejections (ATMR). In the late conversion group, out of three biopsy-proven rejections, one was chronic antibody-mediated rejection (CAMR), one was ATMR, and one was mixed ATMR/CAMR. All four patients with ATMR rejection received mycophenolic acid (MPA) as part of their immunosuppressive regimen, and none received tacrolimus. The one-year post-conversion allograft survival rate in early and late conversion groups was 100%. However, the one-year post-conversion patient survival rate was 90.9% in the early conversion group and 100% in the late conversion group (P = 0.11). CONCLUSIONS: Early post-transplant conversion to belatacept can improve the eGFR more meaningful when compared to late conversion. Patients who receive belatacept and MPA rather than tacrolimus may have increased rates of T-cell-mediated rejection.

Immunosuppression regimen modification during COVID-19 infection in kidney transplant recipients.

BACKGROUND: COVID-19 pandemic had tremendously affected all the aspects of human life during the past 3 years. In this study, we focused on kidney transplant patients' course from the COVID-19 diagnosis, immunosuppressive medication modification, hospitalization, and COVID-19 complications and how the COVID-19 infection affected the kidney and patients' quality of life during the hospitalization and after the discharge. MATERIAL AND METHOD: A retrospective analysis of a prospectively collected database of all kidney transplants adult patients who had a positive COVID-19 PCR from 1 January 2020 to 30 December 2022, and had a history of kidney transplant at the SUNY Upstate Medical Hospital was done to identify the cases. RESULTS: 188 patients met the inclusion criteria and were included in the study. Based on the immunosuppressive regimen modification during COVID-19 infection, patients divided into two groups; in 143 (76%) patients, the immunosuppressive medication was reduced, and in 45 (24%) of patients, the immunosuppressive regimen continued as before during the COVID-19 infection. The mean time from the transplant to the diagnosis of COVID-19 was 67 months in the group we reduced the IM regimen, and 77 months in the group without changes in IM regimen. The mean recipients' age was 50.7 ± 12.9 years in the group we reduced the IM regimen, and 51.8 ± 16.4 years in the group without changes in IM regimen (P = 0.64). The vaccination rate against COVID-19 with at least 2 doses of either the CDC recommended Moderna or Pfizer vaccines was 80.2% in the group we reduced the IM regimen, and 84.8% in the group without changes in IM regimen (P = 0.55). The hospitalization rate due to COVID-19 related symptoms was 22.4% % in the group we reduced the IM regimen, and 35.5% in the group without changes in IM regimen (P = 0.12). However, the ICU admission rate was higher in the group we reduced the IM regimen, but the difference was not significant (26.5% Vs.6.25%, P = 0.12). 6 episodes of biopsy-proven rejection in the group with IM reduction was observed, which were 3 episodes of acute antibody-mediated rejections (ABMR) and 3 episodes of acute T-Cell-mediated rejections (TCMR), and 3 episodes in the group without any change in IM regimen, which were 2 episodes of ABMR and 1 episode of TCMR (P = 0.51). No significant difference was mentioned in the eGFR and serum creatinine after the comparison between the groups after 12 months of follow up. 124 patients responded to the post-COVID-19 questionnaires and were included in the data analysis. The response rate was 66%. Fatigue and exertion were the most reported symptom with a 43.9% prevalence. CONCLUSIONS: We found that immunosuppressive regimen minimization did not impact the kidney function in the long-term and it might be a helpful strategy to minimize the effect of COVID-19 infection on patients' condition during the hospital stay. With all the treatments, vaccinations, and precautions, still some patients did not achieve the complete recovery compared to their pre-COVID-19 health status. Fatigue was the main reported symptom amongst all the reported symptoms.

Deceased Donor Kidney Transplantation From Donors With Acute Kidney Injury: Realities and Costs.

OBJECTIVES: Transplant of kidneys from donors with acute kidney injury has shown favorable outcomes. We investigated the outcomes of kidney transplant recipients with deceased donors who developed acute kidney injury before organ procurement. MATERIALS AND METHODS: We retrospectively reviewed the medical records of recipients from January 2016 to December 2021 in a single center. Outcomes in recipients of kidney grafts from donors with and without acute kidney injury were compared. RESULTS: The mean follow-up time was 40 months. Our study included 129 (34%) kidneys transplanted from donors with acute kidney injury and 251 (66%) kidneys from donors without acute kidney injury. Delayed graft function rate in recipients was 33% in the acute kidney injury group and 25.5% in the group without acute kidney injury (P = .099). Readmission rate at 30 days was significantly higher among recipients of kidneys with acute kidney injury compared with recipients of kidneys without acute kidney injury (45% vs 33.5%; P = .02). The mean overall costs of transplant in the acute kidney injury group were comparable to the group without acute kidney injury ($253 865 vs $253 611; P = .97). The acute rejection rate was comparable between the 2 groups (4% in both groups; P = .96). Delayed graft function rate was increased with increased stage of acute kidney injury (18% stage 1, 45% stage 2, 36% stage 3; P = .03). However, the overall length of hospital stay and costs were comparable among recipients of different stages of acute kidney injury. CONCLUSIONS: Our study showed that kidney transplants from donors with acute kidney injury have early and late outcomes comparable to kidney transplants from donors without acute kidney injury. Allografts from donors with acute kidney injury can be used safely and can expand the donor pool in kidney transplant without increasing perioperative resource utilization.

Conversion to Belatacept in kidney transplant recipients with chronic antibody-mediated rejection (CAMR).

BACKGROUND: The costimulatory inhibitor Belatacept (Bela) has been shown to be an effective alternative in several clinical situations, including chronic antibody-mediated rejection, calcineurin toxicity, and de novo alloantibody formation. To further explore the usefulness of Belatacept under various clinical scenarios, we performed a retrospective analysis of a prospective database of all recipients who had a BPAR diagnosis of CAMR and were converted to a Belatacept maintenance immunosuppression regimen after kidney transplantation. MATERIAL AND METHOD: We conducted a retrospective analysis of a prospectively collected database of all kidney transplants adult patients at SUNY Upstate Medical Hospital from 1 January 2013 to 31 December 2021. Our inclusion criteria were the patients who have been diagnosed with CAMR according to their renal biopsy based on the 2013 Banff criteria. The primary objective was to compare the kidney viability and function using GFR between the two interest groups and finally compare the outcomes. RESULTS: A total of 48 patients met our inclusion criteria based on the kidney biopsy result, which showed chronic antibody-mediated graft rejection (CAMR). Nineteen patients (39.6%) were converted to the Belatacept, and we continued the previous immunosuppression regimen in 29 patients (60.4%). The mean time from the transplant date to the diagnosis of CAMR was 1385 days in the Belatacept group and 914 days for the non-Belatacept group (P = 0.15). The mean GFR comparison at each time point between the groups did not show a significant difference, and Belatacept did not show superiority compared to the standard immunosuppression regimen in terms of kidney function preservation. 1 (5.2%) patient from the Belatacept group and 1 (3.4%) patient from the non-Belatacept group had a biopsy-proven acute rejection (BPAR) after CAMR confirmation, and it was comparable (P = 0.76). De novo synthesis of the DSA rate was 12.5% in the Belatacept group and 15% In the non-Belatacept group, which was comparable. (P = 0.90). The patient survival rate was 100% in both groups. CONCLUSIONS: We conclude that compared to the standard Tacrolimus/MMF/Prednisone regimen, Belatacept did not significantly benefit in preserving the GFR in long-term follow-ups and stabilizing the DSA production, which is one of the main factors resulting in chronic graft failure.

Piperacillin/Tazobactam and Meropenem Use Increases the Risks for Acute Graft Rejection Following First Kidney Transplantation.

Many broad-spectrum antibiotics (BSA) alter the intestinal microbiome that regulates adaptive immune responses. We hypothesized that BSA use before and early after kidney transplant may affect acute graft rejection (AGR). We carried out a retrospective cohort study on all patients who underwent kidney transplants in our institution. Patient demographics, clinical data, diagnosis, and treatment history were collected. Antibiotic use within 2 months prior to transplant and during the hospital admissions for transplant, as well as antibiotic types were recorded. A total of 357 consecutive first transplants were included for analysis. Median age was 52 years (range 7-76). A total of 67 patients received living donor and 290 deceased donor kidneys. A total of 19 patients received BSA within two months prior to transplant and 55 patients during the hospital admission for the transplant. With a median follow-up of 1270 days, 38 episodes of biopsy-proven AGR were recorded. There was no difference in the AGR rates during the first year between patients who received BSA and those who did not. However, the use of piperacillin/tazobactam or meropenem (PM) was associated with increased risks for the development of AGR, irrespective of the source of the donor grafts. Time to development of AGR was also shorter. Our data, therefore, suggest that the use of PM BSA prior to and immediately after kidney transplant increases the risks for AGR.

Utilization of Treg Cells in Solid Organ Transplantation.

Organ transplants have been a life-saving form of treatment for many patients who are facing end stage organ failure due to conditions such as diabetes, hypertension, various congenital diseases, idiopathic diseases, traumas, and other end-organ failure. While organ transplants have been monumental in treatment for these conditions, the ten year survival and long-term outcome for these patients is poor. After receiving the transplant, patients receive a multi-drug regimen of immunosuppressants. These drugs include cyclosporine, mTOR inhibitors, corticosteroids, and antibodies. Polyclonal antibodies, which inhibit the recipient's B lymphocytes, and antibodies targeting host cytokine inhibitors which prevent activation of B cells by T cells. Use of these drugs suppresses the immune system and increases the risk of opportunistic pathogen infections, tumors, and further damage to the transplanted organs and vasculature. Many regulatory mechanisms are present in organs to prevent the development of autoimmune disease, and Tregs are central to these mechanisms. Tregs secrete suppressive cytokines such as IL-10, TGF-B, and IL-35 to suppress T cells. Additionally, Tregs can bind to target cells to induce cell cycle arrest and apoptosis and can inhibit induction of IL-2 mRNA in target T cells. Tregs also interact with CTLA-4 and CD80/CD86 on antigen presenting cells (APCs) to prevent their binding to CD28 present on T cells. Due to their various immunosuppressive capabilities, Tregs are being examined as a possible treatment for patients that receive organ transplants to minimize rejection and prevent the negative outcomes. Several studies in which participants were given Tregs after undergoing organ transplantations were reviewed to determine the efficacy and safety of using Tregs in solid organ transplantation to prevent adverse outcomes.

Changes in immune profile affect disease progression in hepatocellular carcinoma.

Objective: Hepatocellular carcinoma (HCC) as a chronic liver condition is largely associated with immune responses. Previous studies have revealed that different subsets of lymphocytes play fundamental roles in controlling or improving the development and outcome of solid tumors like HCC. Hence, this study aimed to investigate whether immune system changes were related to disease development in HCC patients. Methods: Peripheral blood mononuclear cells were isolated from 30 HCC patients and 30 healthy volunteers using Ficoll density centrifugation. The isolated cells were stained with different primary antibodies and percentages of different immune cells were determined by flow cytometry. Results: HCC patients indicated significant reductions in the numbers of CD4+ cells, Tbet+IFNγ+cells, and GATA+IL-4+cells in peripheral blood in comparison with healthy individuals (p < 0.05). There was no significant change in IL-17+RORγt+cells between patient and healthy groups. In contrast, Foxp3+CD127lowcell frequency was significantly higher in patients than healthy subjects (p < 0.0001). The numbers of Th1, Th2, and Th17 cells were significantly lower in HCC patients than healthy control (p < 0.0001), although the reduction in Th2 cell numbers was not statistically significant. On the contrary, Treg percentage showed a significant increase in patients compared to healthy subjects (p < 0.0001). Other data revealed that Th1, Th2, and Th17 cell frequencies were significantly higher in healthy individuals than patients with different TNM stages of HCC, with the exception of Th2 in patients with stage II HCC (p < 0.01-0.05). Treg percentage was significantly increased in patients with different TNM stages (p < 0.0001). Among all CD4+ T cells, the frequency of Th2 cell was significantly associated with TNM stages of HCC (p < 0.05). Conclusion: Our data provide further evidence to show that immune changes may participate in determining HCC progression and disease outcome. However, it should be mentioned that more investigations are needed to clarify our results and explain possible impacts of other immune cells on the pathogenesis of HCC.

Liver Resection Promotes (Regulates) Proinflammatory Cytokines in Patients with Hepatocellular Carcinoma.

Background: Several animal studies have shown the roles of cytokines in regulating liver regeneration following liver resection (LR), which is a type of surgery designed to remove cancerous tumors from the liver. This study investigated how the expressions and serum levels of some pro- and anti-inflammatory cytokines in patients with hepatocellular carcinoma (HCC) were changed during LR. Methods: Liver tissues from 15 patients with HCC were collected and the levels of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), IL-1α, IL-1 ß, IL-10, and transforming growth factor-beta1 (TGF-ß1) were assessed using real-time PCR assay at different times before and after LR. The serum values of TNF-α and IL-6 were also measured by ELISA. Results: After 60 and 90 minutes of LR, IL-6 gene expression was significantly increased (P < 0.001 - 0.05). The same trend was also observed in TNF-α expression after 90 minutes of LR (P < 0.01). No significant changes were observed in the expressions of IL-1α, IL-1ß, IL-10, and TGF-ß1 before and after LR. In addition, LR had significant effects on TNF-α and IL-6 serum levels (P < 0.05 - 0.0001). Conclusion: Our data provided further evidence to reveal that IL-6 and TNF-α cytokines are critical to improve liver regeneration.

Utilization of Mesenchymal Stem Cells in Kidney Transplantation: From Bench to Bedside.

There has been ample of preclinical and animal studies whichshowed efficacy and safety of using mesenchymal stem cells (MSCs)after transplantation for tissue repair, immunosuppression ortolerance induction. However, there has been a significant progressrecently using MSCs in small clinical trials after transplantation. Recent results using MSCs after transplantation seem to befeasible and safe. However, there are some limitations to show theeffectiveness of these cells including source, dose, timing and routeof infusions. Currently, live donor kidney transplantation has beenespecially considered and development of recent regimes includingimmunosuppression drugs and MSCs administration to kidney andother organs and deceased donor transplantation would be crucial.Therefore, in this review we focused on immunomodulatory effectsof MSCs that have been extensively studied to suppress variousinflammatory responses in kidney transplantation.

Liver Transplantation: What Every Gastroenterologist Should Know about It.

Liver Transplantation (LT) is the treatment of choice for patients with end-stage liver disease. Improvement in outcomes (allograft and patient survival) has led to widespread use of LT worldwide. This success is due to improvement in patient selection, transplantation surgery, anesthesia/postoperative care, and immunosuppression management. This review will focus on different aspects of LT, which every physician should know to provide better patient care.

Current Challenges of Kidney Transplantation in Iran: Moving Beyond The "Iranian Model".

Organ Transplantation in Iran has come a long way with many different policies and approaches addressing demand and supply. The first successfully kidney transplantation was performed at Namazi Hospital in Shiraz from a living donor in 1967. However, there had been only limited transplant activities in Iran until mid-1970. Previously, patients compensated the lack of organ transplants in Iran by travelling outside the country including the United Kingdom for living related transplants or to India, taking advantage of commercially available organs, usually with poor outcomes. There have also been attempts in the past to import allografts from Europe and the United States. After 1979 revolution, kidney transplantation was activated in Iran by using living donors which was know as Iranian model. Recently, there has been emphasis to expand deceased donor kidney transplantation. However, there are several challenges to expand transplant care in Iran.

Current Challenges of Liver Transplantation in Iran.

Liver transplantation (LT) is a lifesaving procedure and the treatment of choice for patients suffering from end-stage liver disease (ESLD). There is increasing number of patients with ESLD in Iran. There is a need to expand and develop new centers to provide better access to LT for patients with ESLD in Iran. This review will address current and future challenges for LT in Iran.

Competition in liver transplantation: helpful or harmful?

Improved outcomes of liver transplantation have led to increases in the numbers of US transplant centers and candidates on the list. The resultant and ever-expanding organ shortage has created competition among centers, especially in regions with multiple liver transplant programs. Multiple reports now document that competition among the country's transplant centers has led to the listing of increasingly high-risk patients and the utilization of more marginal liver allografts. The transplant and medical communities at large should carefully re-evaluate these practices and promote innovative approaches to restoring trust in the allocation of donor organs and confirming that there is nationwide conformity in the guidelines used for evaluating and listing potential candidates for this scarce resource.

Current state of the art in management of vascular complications after pediatric liver transplantation.

Vascular complications by compromising the blood flow to the allograft can have significant and sometimes life-threatening consequences after pediatric liver transplantation. High level of suspicion and aggressive utilization of diagnostic modalities can lead to early diagnosis and salvage of the allograft. This review will summarize the current trends in management of vascular complications after pediatric liver transplantation.

Effect of staff migration on kidney transplant activity in United Network for Organ Sharing region 1 transplant centers.

Organ shortage is unquestionably the greatest challenge facing the field of transplantation today. Transplant centers are constantly competing with one another for limited numbers of organs for their recipients. Recruitment of specialized transplant surgical expertise and leadership is thought to enable a center to grow in volume and thus profitability in the increasingly difficult world of health care reimbursement. In this study, the pattern of kidney transplants at 13 different centers in the United Network for Organ Sharing's region 1 is examined: the comparison is between transplant volume before and after changes in the centers' leadership between 2000 and 2011. Each center's kidney transplant volume showed a significant increase after a leadership change that ultimately regressed to the center's baseline. This study is the first to show that behavioral changes in transplant center competition cause transient increases in transplant volume that quickly regress back to mean levels.

Human adipose-derived mesenchymal stem cells attenuate liver ischemia-reperfusion injury and promote liver regeneration.

BACKGROUND: Ischemia-reperfusion injury (IRI) of the liver is a well-known cause of morbidity and mortality after liver transplantation. Effective treatment strategies aimed at decreasing hepatic IRI injury and accelerating liver regeneration could offer major benefits in liver transplantation, especially in the case of partial allografts. Human adipose-derived mesenchymal stem cells (HADMSCs) are an attractive source for regenerative medicine because of their anti-inflammatory and regenerative properties. We hypothesized that HADMSCs attenuate IRI and promote liver regeneration. METHODS: Mice were subjected to 60 minutes of partial IRI with or without 70% partial hepatectomy. Animals were treated with HADMSCs. Liver IRI was evaluated with serum levels of alanine aminotransferase, serum interleukin-6, and histopathology. Liver samples were stained for specific markers of liver regeneration. RESULTS: Histology, serum interleukin-6, and alanine aminotransferase release revealed that treatment with HADMSCs attenuated liver injury compared with control patients. Improved animal survival and increased number of regenerating cells were observed in HADMSC-treated animals who underwent IRI and partial hepatectomy compared with the control group. CONCLUSION: HADMSC represents a potential therapeutic strategy to decrease IRI and promote regeneration in liver transplantation.

Liver ischemia/reperfusion injury: an overview.

The present review discusses strategies for minimizing the ischemia/reperfusion injury (IRI) experienced during liver surgery and transplantation. We present the experimental models used to study the complexity of hepatic IRI and new surgical and pharmacologic strategies for manipulating and improving liver function after liver surgery and transplantation. This would be of clinical interest to reduce the prevalence of IRI and improve patient management and outcomes. The ongoing effort to expand the pool of usable liver grafts has made it clear that a better understanding of the mechanisms of IRI and other consequences of using expanded criteria donor (ECD) liver allografts are critical to improving results with these grafts.

Pediatric transplantation and tolerance: past, present, and future.

Solid organ transplantation is the treatment of choice in children with end-stage organ failure. With improving methods of transplant surgery and post-transplant care, transplantation is more frequently performed worldwide. However, lifelong and non-specific suppression of the recipient's immune system is a cause of significant morbidity in children, including infection, diabetes, and cancer. There is a great need to develop IS minimization/withdrawal and tolerance induction approaches.