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Background. The COVID-19 pandemic has led to an increase in SARS-CoV-2–test positive potential organ donors. The benefits of life-saving liver transplantation (LT) must be balanced against the potential risk of donor-derived viral transmission. Although emerging evidence suggests that the use of COVID-19–positive donor organs may be safe, granular series thoroughly evaluating safety are still needed. Results of 29 consecutive LTs from COVID-19–positive donors at a single center are presented here. Methods. A retrospective cohort study of LT recipients between April 2020 and December 2022 was conducted. Differences between recipients of COVID-19–positive (n = 29 total; 25 index, 4 redo) and COVID-19–negative (n = 472 total; 454 index, 18 redo) deceased donor liver grafts were compared. Results. COVID-19–positive donors were significantly younger (P = 0.04) and had lower kidney donor profile indices (P = 0.04) than COVID-19–negative donors. Recipients of COVID-19–positive donor grafts were older (P = 0.04) but otherwise similar to recipients of negative donors. Donor SARS-CoV-2 infection status was not associated with a overall survival of recipients (hazard ratio, 1.11; 95% confidence interval, 0.24-5.04; P = 0.89). There were 3 deaths among recipients of liver grafts from COVID-19–positive donors. No death seemed virally mediated because there was no qualitative association with peri-LT antispike antibody titers, post-LT prophylaxis, or SARS-CoV-2 variants. Conclusions. The utilization of liver grafts from COVID-19–positive donors was not associated with a decreased overall survival of recipients. There was no suggestion of viral transmission from donor to recipient. The results from this large single-center study suggest that COVID-19–positive donors may be used safely to expand the deceased donor pool.

Islet transplantation for type 1 diabetes management is hindered by the life-long need for immunosuppressive medications. Here, the authors report an islet encapsulation device with local anti-rejection drug release that achieves long-term diabetes reversal in male rats and reduces drug-related toxicity.

Background. Combined liver–lung transplantation is an uncommon, although vital, procedure for patients with simultaneous end-stage lung and liver disease. The utility of lung–liver transplant has been questioned because of initial poor survival outcomes, particularly when compared with liver-alone transplant recipients. Methods. A single-center, retrospective review of the medical records of 19 adult lung–liver transplant recipients was conducted, comparing early recipients (2009–2014) with a recent cohort (2015–2021). Patients were also compared with the center’s single lung or liver transplant recipients. Results. Recent lung–liver recipients were older (P = 0.004), had a higher body mass index (P = 0.03), and were less likely to have ascites (P = 0.02), reflecting changes in the etiologies of lung and liver disease. Liver cold ischemia time was longer in the modern cohort (P = 0.004), and patients had a longer posttransplant length of hospitalization (P = 0.048). Overall survival was not statistically different between the 2 eras studied (P = 0.61), although 1-y survival was higher in the more recent group (90.9% versus 62.5%). Overall survival after lung–liver transplant was equivalent to lung-alone recipients and was significantly lower than liver-alone recipients (5-y survival: 52%, 51%, and 75%, respectively). Lung–liver recipient mortality was primarily driven by deaths within 6 mo of transplant due to infection and sepsis. Graft failure was not significantly different (liver: P = 0.06; lung: P = 0.74). Conclusions. The severity of illness in lung–liver recipients combined with the infrequency of the procedure supports its continued use. However, particular attention should be paid to patient selection, immunosuppression, and prophylaxis against infection to ensure proper utilization of scarce donor organs.

Background. Islet and β-cell function is intrinsic to glucose homeostasis. Pancreatectomy and islet autotransplantation (PIAT) for chronic pancreatitis (CP) treatment is a useful model for assessing islet function in the absence of immune-suppression and to perform extensive presurgical metabolic evaluations not possible from deceased donors. We recently showed that in CP-PIAT patients, preoperative islet identity loss presented with postoperative glycemic loss. Here, we examine presurgical islet function using Homeostatic Model Assessment-Beta Cell Function (%) (HOMA-β) and glycemic variables and compared them with postsurgical insulin independence and their predicted alignment with Secretory Unit of Islet Transplant Objects (SUITO) and beta cell score after transplantation (BETA-2) scores. Methods. Seven CP-PIAT patients were assessed for β-cell function metrics, including pretransplant and 6-mo posttransplant HOMA-β using insulin and C-peptide and evaluations of proposed insulin independence by SUITO and BETA-2 graft function equations. These were compared with oral glucose tolerance tests and pancreas histological samples taken at the time of transplant, examined for β-cell maturity markers. Results. Pre-PIAT, HOMA-β (60%−100%) associated with post-PIAT insulin independence. This association was only moderately supported by post-PIAT SUITO threshold scores (≥26) but robustly by BETA-2 scores (≥16.2). Appropriate posttransplant oral glucose tolerance test curves were found in those patients with normal pretransplant HOMA-β values. Preoperative low serological β-cell function was displayed by concurrent evidence of β-cell identity alterations including colocalization of insulin and glucagon, loss of urocortin-3, and increased intra-islet vimentin in patients who were insulin-dependent post-PIAT. Conclusions. These data encourage HOMA-β assessment before PIAT for estimating posttransplant insulin independence.

Background. Data about vaccine efficacy in solid organ transplant patients are limited. We previously reported our initial observation of a 6.2% immunogenicity rate in kidney transplant recipients (KTRs) after administration of 1 dose of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccine. We sought to report our observations of anti-SARS-CoV-2 antibody in KTRs after 2 doses of the SARS-CoV-2 mRNA vaccine. Methods. We identified 105 KTRs who received 2 doses of the Pfizer-BioNTech or Moderna mRNA-1273 vaccine per availability and had anti-SARS-CoV-2 labs obtained at least 2 wk following administration of the second dose. Antibody testing was performed using 3 clinically validated qualitative and semiquantitative assays. Results. KTRs had a 36.2% antibody response rate, whereas an age ≥68 years and a longer time from transplant were factors associated with antibody response. Conclusions. The low antibody response in KTRs may be associated with the immunosuppressive state. More data are needed to evaluate if KTRs may require higher vaccine doses or an additional booster dose to increase their ability to mount an immune response to the SARS-CoV-2 vaccine.

Background. Orthostatic hypotension (OH) is a poorly understood complication of simultaneous pancreas–kidney (SPK) transplantation. We sought to determine the incidence, timing, and relationship of OH to rapid glycemic control in the early posttransplant period. Methods. This was a nonrandomized retrospective single-center review of 75 SPK and 19 kidney-alone (KA) recipients with type 1 diabetes (DM). Results. OH occurred in 57 (76%) SPK versus 2 (10%) KA recipients (odds ratio [OR] 61.72, 95% confidence interval [CI], 9.69-393.01; P < 0.001). The median onset of OH was 12 (interquartile range [IQR] 9–18) days posttransplant and resolved in 85% of SPK recipients after a median of 2.5 (IQR 1.2–6.3) months. Among SPK recipients, independent risk factors for OH were a shorter duration of DM (OR 0.85, 95% CI, 0.73-0.98; P = 0.03) and rapid glycemic control in the early posttransplant period (OR 1.13, 95% CI, 1.01-1.27; P = 0.04), as evidenced by a larger percent change in hemoglobin A1c (HbA1c) from transplant to month 3. OH patients had a higher median baseline HbA1c [8.3% (IQR 7.2–10.0) versus 7.1% (IQR 6.8–8.3); P = 0.07], lower median 3-month HbA1c [4.8% (IQR 4.6–5.2) versus 5.2% (IQR 5.0–5.4); P = 0.02], and a larger reduction in HbA1c over time as compared to recipients without OH (P < 0.01). Conclusions. Our results show that OH is more likely to occur following SPK versus KA transplantation and is strongly associated with rapid glucose normalization within the early posttransplant period.

Abstract Background Checkpoint inhibitors (CPIs) have revolutionized the treatment of cancer, but their use remains limited by off-target inflammatory and immune-related adverse events. Solid organ transplantation (SOT) recipients have been excluded from clinical trials owing to concerns about alloimmunity, organ rejection, and immunosuppressive therapy. Thus, we conducted a retrospective study and literature review to evaluate the safety of CPIs in patients with cancer and prior SOT. Methods Data were collected from the medical records of patients with cancer and prior SOT who received CPIs at The University of Texas MD Anderson Cancer Center from January 1, 2004, through March 31, 2018. Additionally, we systematically reviewed five databases through April 2018 to identify studies reporting CPIs to treat cancer in SOT recipients. We evaluated the safety of CPIs in terms of alloimmunity, immune-related adverse events, and mortality. We also evaluated tumor response to CPIs. Results Thirty-nine patients with allograft transplantation were identified. The median age was 63 years (range 14–79 years), 74% were male, 62% had metastatic melanoma, 77% received anti-PD-1 agents, and 59% had prior renal transplantation, 28% hepatic transplantation, and 13% cardiac transplantation. Median time to CPI initiation after SOT was 9 years (range 0.92–32 years). Allograft rejection occurred in 41% of patients (11/23 renal, 4/11 hepatic, and 1/5 cardiac transplantations), at similar rates for anti-CTLA-4 and anti-PD-1 therapy. The median time to rejection was 21 days (95% confidence interval 19.3–22.8 days). There were no associations between time since SOT and frequency, timing, or type of rejection. Overall, 31% of patients permanently discontinued CPIs because of allograft rejection. Graft loss occurred in 81%, and death was reported in 46%. Of the 12 patients with transplantation biopsies, nine (75%) had acute rejection, and five of these rejections were T cell-mediated. In melanoma patients, 36% responded to CPIs. Conclusions SOT recipients had a high allograft rejection rate that was observed shortly after CPI initiation, with high mortality rates. Further studies are needed to optimize the anticancer treatment approach in these patients.

Abstract Background We explored the association of C‐peptide (marker of secreted insulin), proinsulin and proinsulin ⁄C‐peptide ratio (PI/C) (markers of beta‐cell endoplasmic reticulum [ER] stress) with undercarboxylated (uOC) and carboxylated osteocalcin (cOC) and their ratio (uOC/cOC) in children with recently diagnosed type 1 (T1D) or type 2 diabetes (T2D), and the correlation of these variables with partial remission (PR) in children with T1D. Methods Demographic and clinical data of children with new‐onset diabetes (n = 68; median age = 12.2 years; 33.8% non‐Hispanic White, 45.6% Hispanic/Latino, 16.2% African American and 4.4% other) were collected at diagnosis and during the first (V1), second (V2) and third clinical visits at 9.0, 32.0 and 175.7 weeks, respectively. Serum proinsulin, C‐peptide, uOC and cOC values were measured 7.0 weeks after diagnosis. PR was defined as insulin dose–adjusted HbA1c (IDAA1c) ≤9. Results In children with new‐onset T1D with DKA (33.3%) or T2D (29.4%), Spearman's correlation coefficient revealed a positive association between the C‐peptide levels and both uOC and uOC/cOC ratio. In T1D (n = 48), both higher serum C‐peptide levels and low PI:C ratio were associated with higher BMI percentile (β = 0.02, P = .001; β = −0.01, P = .02, respectively) and older age at diagnosis (β = 0.13, P = .001; β = −0.12, P = .001, respectively). Furthermore, in children with T1D, C‐peptide levels at V1 correlated with IDAA1c ≤ 9 at V1 (P = .04). Conclusion C‐peptide levels are associated with a higher uOC and uOC/cOC ratio in paediatric diabetes. In new‐onset T1D children, older age and higher BMI were associated with lower beta‐cell stress and higher preserved function, which was predictive of PR on follow‐up.

Following publication of the original article [1], the authors reported an error in the Acknowledgments section. It should be read: ‘We are grateful to Mohsin Shah from the Department of Emergency Medicine at The University of Texas MD Anderson Cancer Center for assisting in study selection, and to Gregory F. Pratt from the Research Medical Library and Erica Goodoff, from the Department of Scientific Publications at The University of Texas MD Anderson Cancer Center for their valuable contributions.

Background. Acceptance of dual kidney transplantation (DKT) has proven difficult, due to surgical complexity and concerns regarding long-term outcomes. We herein present a standard technique for ipsilateral DKT and compare outcomes to single-kidney transplant (SKT) recipients. Methods. A retrospective single-center comparison of DKT and SKT performed between February 2007 and July 2013. Results. Of 516 deceased donor kidney transplants, 29 were DKT and 487 were SKT. Mean follow-up was 43 ± 67 months. DKT recipients were older and more likely than SKT recipients to receive an extended criteria graft (p

Ganciclovir-resistant cytomegalovirus (CMV) is associated with significant morbidity in solid organ transplant recipients. Management of ganciclovir-resistant CMV may be complicated by nephrotoxicity which is commonly observed with recommended therapies and/or rejection induced by “indirect” viral effects or reduction of immunosuppression. Herein, we report a series of four high serologic risk (donor CMV positive/recipient CMV negative) kidney transplant patients diagnosed with ganciclovir-resistant CMV disease. All patients initially developed “breakthrough” viremia while still receiving valganciclovir prophylaxis after transplant and were later confirmed to exhibit UL97 mutations after failing to eradicate virus on adequate dosages of valganciclovir. The patients were subsequently and successfully treated with reduced-dose (1-2 mg/kg) cidofovir and CMV-hyperimmune globulin, given in 2-week intervals. In addition, all patients exhibited stable renal function after completion of therapy, and none experienced acute rejection. The combination of reduced-dose cidofovir and CMV-hyperimmune globulin appeared to be a safe and effective regimen in patients with mild disease due to ganciclovir-resistant CMV.

The pharmacokinetics of tacrolimus are influenced by many factors, including genetic variability, acute infections, liver dysfunction, and interacting medications, which can result in elevated concentrations. The most appropriate management of acute tacrolimus toxicity has not been defined though case reports exist describing the therapeutic use of enzyme inducers to increase tacrolimus metabolism and decrease concentrations. We are reporting on the utilization of phenytoin to assist in decreasing tacrolimus concentrations in a case series of four solid organ transplant recipients with acute, symptomatic tacrolimus toxicity presenting with elevated serum creatinine, potassium, and tacrolimus trough concentrations greater than 30 ng/mL. All four patients had the potential causative agents stopped or temporarily held and were given 300 to 400 mg/day of phenytoin for two to three days. Within three days of beginning phenytoin, all four patients had a decrease in tacrolimus concentration to less than 15 ng/mL, a return to or near baseline creatinine concentration, and lack of phenytoin-related side effects. Therefore, phenytoin appears to be a safe and potentially beneficial treatment option in patients with symptomatic tacrolimus toxicity.

Although current therapies for pretransplant desensitization and treatment of antibody-mediated rejection (AMR) have had some success, they do not specifically deplete plasma cells that produce antihuman leukocyte antigen (HLA) antibodies. Bortezomib, a proteasome inhibitor approved for the treatment of multiple myeloma (a plasma cell neoplasm), induces plasma cell apoptosis. In this paper we review the current body of literature regarding the use of this biological agent in the field of transplantation. Although limited experience with bortezomib may seem to show promise in the realm of transplant recipients desensitization and treatment of AMR, there is also experience that may suggest otherwise. Bortezomib's role in desensitization protocols and treatment of AMR will be defined better as more clinical data and trials become available.

The ability to isolate high-yield pure and viable islets from human cadaver pancreas donors is dependent on donor factor as well as isolation factors. The aim of this study was to examine factors influencing islets recovery and in vivo function with an emphasis on donor and isolation methods as well as to compare the effectiveness of Liberase, widely used in clinical islet isolation, with Serva for the isolation of pure functional islets. The results of 123 islet isolations using Liberase for digestion were compared with those of 113 isolations with Serva. Islet equivalents per gram of tissue were similar between Liberase and Serva (3620 ± 1858 vs. 4132 ± 2104, p < 0.2) as well as the percent purity (75 ± 16 vs. 74 ± 15, p < 0.9). In vivo function of islets from 71 isolations (Liberase = 45, Serva = 26) were further tested by transplantation into NOD-SCID mice following short-term culture (

Transforming growth factor-β1 (TGF-β1) is a pleotropic cytokine that promotes angiogenesis and extracellular matrix protein synthesis in addition to its immunosuppressive effects. The purpose of this study is to identify optimal conditions for in vivo expression of TGF-β1 by human islets to exploit the possible beneficial effects and minimize undesirable side effects. We transduced human islets with adenoviral vectors encoding the active form of Ad-TGF-β1 or Ad-LacZ to test the effects of TGF-β1 gene expression on islet in vivo function following their transplantation into a NOD-SCID mouse model. Islets were transduced with multiplicity of infection (MOI) of 20, 10, 5, and 2.5 per islet cell. At a MOI ranging from 2.5 to 20, expression of TGF-β1 in islet supernatant persisted for 1–2 months and ranged from 153 ± 5 to 2574 ± 1299 pg/ml, respectively. Transduction with the lowest MOI (2.5) did not compromise the in vivo production of human C-peptide. We conclude that TGF-β1 expression in transplanted islets does not compromise viability and that adenoviral transduction with the TGF-β1 gene has a dose-dependent effect, with larger MOIs being deleterious. The data also indicate that in vitro culture system and the in vivo NOD-SCID model could be used successfully to evaluate the nonimmune effects of gene transduction.

Kidney–pancreas (KP) transplantation has been shown to improve left ventricular (LV) geometry and function 6–24 months after the procedure, yet whether these improvements are sustained in long-term survivors has not been demonstrated. This study examined whether early improvements in LV geometry and function were sustained 3–5 years after KP transplantation. Left ventricular function and geometry were prospectively evaluated prior to, and at 1, 2, and 3–5 years posttransplant using two-dimensional, M-mode, echocardiography with Doppler interrogation in the parasternal and apical views. The sample included 21 KP and a comparison group of 12 diabetic kidney-alone (KA) recipients. Long-term (3–5 years) data were obtained for KP recipients only. Although KA recipients had a longer duration of dialysis and worse diastolic function pretransplant, the groups were similar on other baseline measures. KA recipients experienced minimal improvements while KP recipients had significant improvements in cardiac function and geometry, both in terms of mean values and the percentage of KP recipients who experienced normalization posttransplant (p < 0.05). KP recipient improvements were also sustained at 3–5 years posttransplant on three of five measures, with 75% of long-term KP recipients achieving normal LV mass posttransplant compared with 31% pretransplant. Data indicate that significant impairments in cardiac geometry and function occur in diabetic KA and KP recipients. Though both groups experienced early improvements posttransplant, KP recipients achieved more dramatic and clinically significant improvements at 1, 2, and 3–5 years posttransplant. Additional studies are needed to examine the relevance of these findings with regard to the cardiac morbidity and mortality of these patients.

The objective of this study was to determine whether transfection of human islets with an adenovirus construct encoding an inhibitor of tumor necrosis factor (TNFi) was effective at limiting damage to beta cells induced by human peripheral blood leukocytes (huPBL). Human islets transfected with TNFi or control islets were transplanted under the kidney capsule of NOD-scid mice. After a 15-day engraftment period, half of the mice received injections of activated huPBL and half received buffer injections. Islet graft function was assessed by two different methods, both of which use a species-specific radioimmunoassay to determine human insulin. In some mice, insulin production following intraperitoneal glucose injection was determined in serum. In other mice, total graft insulin content was determined by acid ethanol extraction. Histochemical stains were performed on some kidneys at the termination of the experiment to evaluate graft presence, transgene expression, and huPBL infiltration. In huPBL injected mice, graft performance was maintained in mice whose grafts were transfected with TNFi but declined substantially in control groups with sham transfected or β-galactosidase transfected islet grafts. Similar results were obtained using either glucose-stimulated insulin release or graft insulin content as a measure of graft survival. There was no significant difference in graft function between control groups receiving buffer injections, regardless of whether the islets had been transfected. Human leukocytes were found in all huPBL groups regardless of islet transfection status. We conclude that transfection of human islets with an adenovirus encoding TNFi protects beta cells from destruction induced by human leukocytes. The local production of TNFi does not prevent graft infiltration by leukocytes, only the destruction of grafts by the infiltrating leukocytes. These results raise the possibility that local expression of an inhibitor of the proinflammatory cytokine TNF-α may also prevent graft failure in clinical islet transplantation.

Background The natural history of de novo donor-specific antibodies ( dn DSA) after lung transplantation is not well-described. We sought to determine the incidence and risk factors associated with dn DSA and compare outcomes between recipients with transient (or isolated) vs persistent dn DSA after transplantation. Methods A single-center review of all lung transplants from 1/2009-7/2013. DSAs were tested eight times in the first year and every 4 months thereafter. Outcomes examined included acute rejection and graft failure. Results Median follow-up was 18 months (range: 1-61 months), and 24.6% of 333 first-time lung-only transplant recipients developed a dn DSA. Ethnicity, HLA- DQ mismatches, post-transplantation platelet transfusion and Lung Allocation Score >60 were associated with dn DSA ( P<.05). Overall graft survival was worse for dn DSA-positive vs negative recipients ( P=.025). Of 323 recipients with 1-year follow-up, 72 (22.2%) developed dn DSA, and in 25 (34.7%), the dn DSA was transient and cleared. Recipients with transient dn DSA were less likely to develop acute rejection than those with persistent dn DSA ( P=.007). Conclusions Early post-lung transplantation, dn DSA occurred in 1/4 of recipients, was associated with peri-transplant risk factors and resulted in decreased survival. Spontaneous clearance of dn DSA, seen in one-third of recipients, was associated with a lower risk of acute rejection. [ABSTRACT FROM AUTHOR]

Cheadle C, Watkins T, Ehrlich E, Barnes K, Gaber AO, Hemmerich S, Rabb H. Effects of anti-adhesive therapy on kidney biomarkers of ischemia reperfusion injury in human deceased donor kidney allografts. Clin Transplant 2011: 25: 766-775. © 2010 John Wiley & Sons A/S. Abstract: Introduction: Molecular biomarkers validated previously in animal models are increasingly being studied in conjunction with traditional clinical endpoints in therapeutic trials. Patient and Methods: We hypothesized that human kidneys would exhibit a brisk, gene-specific inflammatory response during ischemia reperfusion injury (IRI), which would be modified by anti-adhesive therapy. Forty deceased-donor kidneys were biopsied prior to implantation and ∼1 h after reperfusion during an intervention trial with the selectin antagonist YSPSL (recombinant P-selectin glycoprotein ligand Ig). Ten inflammatory genes were measured by RT-PCR and normalized to three housekeeping genes. Results: Pre-implantation kidney biopsies were already significantly inflamed relative to healthy tissue, with transcripts encoding IL-6, IL-8, and CD25 > 10-fold elevated. After reperfusion, IL-6 and IL-8 increased additional 60- and 120-fold (p < 0.05), while already elevated CD25-levels remained stable. Furthermore, transcripts encoding MCP-1, E-selectin, and TNFα were also induced significantly upon reperfusion (p < 0.0005). Systemic treatment of the recipient with YSPSL pre-reperfusion, with or without pre-implantation YSPSL flush of the donor organ, attenuated the post-reperfusion increase in MCP-1 and TGFβ (p < 0.05), E-selectin and hemoxygenase 1 transcripts (p < 0.1). Conclusions: Our data in humans demonstrate a robust increase in inflammatory gene transcript levels during kidney transplantation IRI and reduction thereof by inhibition of leukocyte adhesion. [ABSTRACT FROM AUTHOR]

In an effort to ameliorate the problem of orthostatic hypotension in pancreas transplant patients, current medical management consists of maximizing the patient's hydration, altering antihypertensives, increasing sodium intake, initiation of fludrocortisone, compression stockings, and behavioral modifications. Despite these medical interventions, a subset of patients remains symptomatic. Midodrine (ProAmatine®), an alpha-adrenergic agonist, was approved for the treatment of symptomatic orthostatic hypotension in the US. This preliminary report attempts to assess the safety and efficacy of midodrine use in kidney/pancreas (KP) or pancreas alone (PA) transplant recipients. A retrospective review was performed of 7 KP and 1 PA recipient experiencing symptomatic postural hypotension after maximizing other medical treatments. Blood pressure, serum creatinine (SrCr), and objective responses to postural hypotension were assessed at routine intervals. Pre-midodrine monitoring revealed a mean orthostatic change in systolic blood pressure from sitting to standing of 43 mmHg (range 20–100 mmHg). Patients received a mean starting midodrine dose of 18 mg/d, which was titrated to a maximum dose of 30 mg/d. Systolic blood pressure monitoring revealed a mean orthostatic change of 27 mmHg (range 0–81 mmHg) after initiation of treatment with midodrine and a mean follow-up of 3.2 months. All study patients reported improvement in symptoms of orthostatic hypotension. SrCr was not affected based upon comparison of pre-treatment and current SrCr values of 1.4 and 1.3 mg/dL, respectively. The most common side effect experienced was supine hypertension. These preliminary results suggest that midodrine is safe and effective in transplant recipients; however, the dosage should be titrated to symptomatic relief or a maximum dose of 30 mg. Careful monitoring for supine hypertension is necessary. [ABSTRACT FROM AUTHOR]

From 1989 to 1997, we performed 159 pancreas transplantations (PTXs), including 117 simultaneous kidney–PTX (SKPT), 25 PTXs alone (PTA), and 17 sequential PTXs after kidney transplantations (PAKT). A total of 73 PTXs were performed with systemic-bladder (S-B) and 86 with portal-enteric (P-E) drainage. The need for allograft pancreatectomy (PCTY) may be considered as an index of technical morbidity after PTX. A total of 37 PCTYs (23%) were performed at a mean of 4.7 months after PTX. Twenty-seven PCTYs were performed within 1 month, 30 (81%) within 3 months, and the remaining seven more than 6 months after PTX. The incidence of PCTY did not differ according to type of transplantation: simultaneous kidney–PTX (SKPT) (23%), PTA (24%), and PAKT (23.5%). Indications for PCTY were thrombosis (23), rejection (9), infection (3), and pancreatitis (2). During the study, a total of 70 pancreas grafts were lost, with PCTY performed in 37 (53%). PCTY was directly related to the timing of graft loss; 77% of grafts lost within 3 months of PTX required PCTY, while 25% of grafts lost after 3 months resulted in PCTY (p<0.01). The incidence of graft failure resulting in PCTY was similar according to type of transplantation: SKPT (55%), PTA (46%), and PAKT (50%). The incidence of PCTY was also similar according to technique of transplantation: 26% S-B versus 21% P-E, p=NS. However, the incidence of graft failure resulting in PCTY was higher in P-E (69%) versus S-B (43%) (p<0.05) PTX recipients. Patient and kidney graft survival and pancreas retransplant graft survival rates were higher in PTX recipients with P-E drainage.Conclusions: PCTY is performed in over half of cases of pancreas allograft loss and is directly related to the timing and cause of graft loss. The incidence of PCTY is neither related to the type nor technique of PTX. The lower overall incidence of graft loss after PTX with P-E drainage is offset by a higher incidence of PCTY in these grafts that... [ABSTRACT FROM AUTHOR]

Deceased diabetic kidneys are increasingly utilized in transplantation. The relationship of donor's history of diabetes to clinical and histological outcomes was examined. Forty‐nine diabetic deceased donor kidneys (D‐DM) were transplanted into 26 normal (R‐N/D‐DM) and 23 diabetic recipients (R‐DM/D‐DM) and compared to 211 diabetic recipients of normal kidneys(R‐DM/D‐N) and 466 normal recipients of normal kidneys (R‐N/D‐N). Patient survival at 5 years was 89.7% in R‐N/D‐N, 96.2% in R‐N/D‐DM, 80.1% in R‐DM/D‐N, and a 71.6% in R‐DM/D‐DM (P =.008). Death‐censored graft survival at 5 years was 86.3% in R‐N/D‐N, 87.4% in R‐N/D‐DM, 93.5% in R‐DM/D‐N, and 87.5% in R‐DM/D‐DM (P =.24). Multivariable regression analysis showed that compared to non‐diabetic recipients, diabetic recipients had a 2‐ to 3‐fold increased risk of mortality. In this cohort, there was no impact on death‐censored graft survival of diabetic donor status. Only 6 of 26 post‐perfusion biopsies showed evidence of diabetic nephropathy (

Abstract Kidney transplantation is the preferred treatment for individuals with end‐stage kidney disease. From a modeling perspective, our understanding of kidney function trajectories after transplantation remains limited. Current modeling of kidney function post‐transplantation is focused on linear slopes or percent decline and often excludes the highly variable early timepoints post‐transplantation, where kidney function recovers and then stabilizes. Using estimated glomerular filtration rate (eGFR), a well‐known biomarker of kidney function, from an aggregated dataset of 4904 kidney transplant patients including both observational studies and clinical trials, we developed a longitudinal model of kidney function trajectories from time of transplant to 6 years post‐transplant. Our model is a nonlinear, mixed‐effects model built in NONMEM that captured both the recovery phase after kidney transplantation, where the graft recovers function, and the long‐term phase of stabilization and slow decline. Model fit was assessed using diagnostic plots and individual fits. Model performance, assessed via visual predictive checks, suggests accurate model predictions of eGFR at the median and lower 95% quantiles of eGFR, ranges which are of critical clinical importance for assessing loss of kidney function. Various clinically relevant covariates were also explored and found to improve the model. For example, transplant recipients of deceased donors recover function more slowly after transplantation and calcineurin inhibitor use promotes faster long‐term decay. Our work provides a generalizable, nonlinear model of kidney allograft function that will be useful for estimating eGFR up to 6 years post‐transplant in various clinically relevant populations.

New immunosuppressive therapies that improve long-term graft survival are needed in kidney transplant. Critical Path Institute’s Transplant Therapeutics Consortium received a qualification opinion for the iBOX Scoring System as a novel secondary efficacy endpoint for kidney transplant clinical trials through European Medicines Agency’s qualification of novel methodologies for drug development. This is the first qualified endpoint for any transplant indication and is now available for use in kidney transplant clinical trials. Although the current efficacy failure endpoint has typically shown the noninferiority of therapeutic regimens, the iBOX Scoring System can be used to demonstrate the superiority of a new immunosuppressive therapy compared to the standard of care from 6 months to 24 months posttransplant in pivotal or exploratory drug therapeutic studies.

BackgroundLiver retransplantation (reLT) has historically had inferior survival relative to primary liver transplant (LT). To improve outcomes after reLT, researchers have identified factors predicting overall (OS) and/or graft survival (GS) after reLT. This systematic review and random effects meta-analysis sought to summarize this literature to elucidate the strongest independent predictors of post-reLT.MethodsA systematic review was conducted to identify manuscripts reporting factors affecting survival in multivariable Cox proportional hazards analyses. Papers with overlapping cohorts were excluded.ResultsAll 25 included studies were retrospective, and 15 (60%) were single-center studies. Patients on pre-transplant ventilation (HR, 3.11; 95% CI, 1.56–6.20; p = 0.001) and with high serum creatinine (HR, 1.46; 95% CI, 1.15–1.87; p = 0.002) had the highest mortality risk after reLT. Recipient age, Model for End-Stage Liver Disease score, donor age, and cold ischemia time >12 h also conferred a significant risk of post-reLT death (all p

The transcriptional regulation of B-cell response to antigen stimulation is complex and involves an intricate network of dynamic signals from cytokines and transcription factors propagated from T-cell interaction. Long-term alloimmunity, in the setting of organ transplantation, is dependent on this B-cell response, which does not appear to be halted by current immunosuppressive regimens which are targeted at T cells. There is emerging evidence that shows that B cells have a diverse response to solid organ transplantation that extends beyond plasma cell antibody production. In this review, we discuss the mechanistic pathways of B-cell activation and differentiation as they relate to the transcriptional regulation of germinal center B cells, plasma cells, and memory B cells in the setting of solid organ transplantation.

BackgroundSolid organ transplant (SOT) recipients are at increased risk for morbidity and mortality from COVID-19 due to their immunosuppressed state and reduced immunogenicity from COVID-19 mRNA vaccines. This investigation examined the association between COVID-19 mRNA vaccination status and mortality among SOT recipients diagnosed with COVID-19.Methods & findingsA retrospective, registry-based chart review was conducted investigating COVID-19 mortality among immunosuppressed solid organ transplant (SOT) recipients in a large metropolitan healthcare system in Houston, Texas, USA. Electronic health record data was collected from consecutive SOT recipients who received a diagnostic SARS-CoV-2 test between March 1, 2020, and October 1, 2021. The primary exposure was COVID-19 vaccination status at time of COVID-19 diagnosis. Patients were considered 'fully vaccinated' at fourteen days after completing their vaccine course. COVID-19 mortality within 60 days and intensive care unit admission within 30 days were primary and secondary endpoints, respectively. Among 646 SOT recipients who were diagnosed with COVID-19 at Houston Methodist Hospital between March 2020, and October 2021, 70 (10.8%) expired from COVID-19 within 60 days. Transplanted organs included 63 (9.8%) heart, 355 (55.0%) kidney, 108 (16.7%) liver, 70 (10.8%) lung, and 50 (7.7%) multi-organ. Increasing age was a risk factor for COVID-19 mortality, while vaccination within 180 days of COVID-19 diagnosis was protective in Cox proportional hazard models with hazard ratio 1.04 (95% CI: 1.01-1.06) and 0.31 (0.11-0.90), respectively). These findings were confirmed in the propensity score matched cohort between vaccinated and unvaccinated patients.ConclusionsThis investigation found COVID-19 mortality may be significantly reduced among immunosuppressed SOT recipients within 6 months following vaccination. These findings can inform vaccination policies targeting immunosuppressed populations worldwide.

BackgroundSolid organ transplant (SOT) recipients are predicted to have worse COVID-19 outcomes due to their compromised immunity. However, this association remains uncertain because published studies have had small sample sizes and variability in chronic comorbidity adjustment.MethodsIn this retrospective cohort study conducted at a multihospital health system, we compared COVID-19 outcomes and survival up to 60 days following hospital admission in SOT recipients taking baseline immunosuppressants versus hospitalized control patients.ResultsThe study included 4,562 patients who were hospitalized with COVID-19 (108 SOT recipients and 4,454 controls) from 03/2020 to 08/2020. Mortality at 60 days was higher for SOT recipients (17% SOT vs 10% control; unadjusted odds ratio (OR) = 1.74, 95% confidence interval (CI) 1.04-2.91, P = 0.04). We then conducted a 1:5 propensity matched cohort analysis (100 SOT recipients; 500 controls) using age, sex, race, body mass index, hypertension, diabetes, chronic kidney disease, liver disease, admission month, and area deprivation index. Within 28 days of admission, SOT recipients had fewer hospital-free days (median; 17 SOT vs 21 control; OR = 0.64, 95%CI 0.46-0.90, P = 0.01) but had similar ICU-free days (OR = 1.20, 95%CI 0.72-2.00, P = 0.49) and ventilator-free days (OR = 0.91, 95%CI 0.53-1.57, P = 0.75). There was no statistically significant difference in 28-day mortality (9% SOT vs 12% control; OR = 0.76, 95%CI 0.36-1.57, P = 0.46) or 60-day mortality (16% SOT vs 14% control; OR = 1.15, 95%CI 0.64-2.08, P = 0.64).ConclusionsHospitalized SOT recipients appear to need additional days of hospital care but can achieve short-term mortality outcomes from COVID-19 that are similar to non-SOT recipients in a propensity matched cohort study.

Abstract The post 3 kidney transplant course of pretransplant echocardiographically‐defined pulmonary hypertension (PH) was reviewed in 115 patients. Of these 61 patients (the largest cohort reported to date), underwent 160 “for indication” echocardiograms posttransplant (mean echocardiograms per patient: 2.6 ± 2.3). Patients undergoing posttransplant echocardiograms demonstrated greater risks for worse outcomes than those without posttransplant echocardiograms; however, there was no difference in mortality, death‐censored graft failure or the composite of death or graft failure between these two groups. Of patients tested, 36 (59%) showed resolution of PH at a median of 37.5 months. Six patients (16.7%) in whom PH resolved (at a median of 29 months), experienced recurrence of PH after an interval of 48 months. No pretransplant demographic or echocardiographic characteristics distinguished those in whom PH persisted versus resolved. Though there was no difference in the risk for mortality or death‐censored graft loss between the two groups at 3 and 5 years, there was a higher risk for the composite of mortality or graft loss at three but not at five years in the group with persistent PH. In conclusion, echocardiographically defined PH resolved in 59% of patients following kidney transplantation; but irrespective of resolution there was no clear association with worse outcome.

Introduction: We describe a technique we call “Meso-transjugular intrahepatic portosystemic shunt (MTIPS)” for relief of portal hypertension secondary to portal vein thrombosis (PVT) using combined surgical and endovascular technique. Materials and Methods: Nine adult patients with PVT underwent transjugular intrahepatic portosystemic shunt through a combined transjugular and mesenteric approach (MTIPS), in which a peripheral mesenteric vein was exposed through a minilaparotomy approach. The right hepatic vein was accessed through a transjugular approach. Mechanical thrombectomy, thrombolysis, and angioplasty were performed when feasible to clear PVT. Results: All patients had technically successful procedures. Patients were followed up for a mean time of 13.3 months (range: 8 days to 3 years). All patients are still alive and asymptomatic. Conclusion: We conclude that MTIPS is effective for the relief of portal hypertension secondary to PVT.

Immunosuppressant agents are essential in every transplant recipient’s care yet walking the fine line of over- or under-immunosuppression is a constant struggle for both patients and transplant providers alike. Optimization and personalization of immunosuppression has been limited by the need for non-invasive graft surveillance methods that are specific enough to identify organ injury in real time. With this in mind, we propose a pilot study protocol utilizing both donor derived cell free DNA (dd-cfDNA, gene expression profiling (GEP), and machine learning (iBox), called KidneyCare, to assess the feasibility and safety in reducing immunosuppressant exposure without increasing the risk of clinical rejection, graft injury, or allograft loss. Patients randomized to the immunominimization arm will be enrolled in one of two protocols designed to eliminate one immunosuppressant and optimize the dose of the Calcineurin Inhibitors (CNIs) using the KidneyCare platform. All patients will be maintained on dual therapy of either steroids and a low dose CNI, or mycophenolate mofetil (MMF) and low dose CNI. Their outcomes will be compared to patients who have their immunosuppressants managed using standard clinical assessment and treatment protocols to determine the impact of immuno-optimization on graft function, complications, and patient reported outcomes.

Diabetes is one of the most prevalent, costly, and debilitating diseases in the world. Pancreas and islet transplants have shown success in re-establishing glucose control and reversing diabetic complications. However, both are limited by donor availability, need for continuous immunosuppression, loss of transplanted tissue due to dispersion, and lack of vascularization. To overcome the limitations of poor islet availability, here, we investigate the potential of bone marrow–derived mesenchymal stem cells differentiated into islet-like insulin-producing aggregates. Islet-like insulin-producing aggregates, characterized by gene expression, are shown to be similar to pancreatic islets and display positive immunostaining for insulin and glucagon. To address the limits of current encapsulation systems, we developed a novel three-dimensional printed, scalable, and potentially refillable polymeric construct (nanogland) to support islet-like insulin-producing aggregates’ survival and function in the host body. In vitro studies showed that encapsulated islet-like insulin-producing aggregates maintained viability and function, producing steady levels of insulin for at least 4 weeks. Nanogland—islet-like insulin-producing aggregate technology here investigated as a proof of concept holds potential as an effective and innovative approach for diabetes cell therapy.

Background: Significant morbidity is associated with standard open flank living donor nephrectomy. Laparoscopicdonor nephrectomy is criticized for a steep learning curve and a tendency to avoid the right kidney. The anterior muscle-splitting technique uses principles or advantages of an open extraperitoneal approach with minimal morbidity and the advantageous muscle-splitting (instead of cutting) procedure.Objective: To compare mini-incision laparoscopic instrument-assisted (MILIA) live donor nephrectomy using a muscle-splitting technique to the standard open-flank donor nephrectomy (ODN) approach for efficacy and safety.Methods: MILIA living donor nephrectomies were performed in 119 donors and compared to a cohort of open-flank nephrectomy donors (n=38) from the same center. Both donor groups were matched for body mass index as well as other personal characteristics.Results: The mean donor age was 35 (range: 18–60) years. The right kidney was procured in 28% of cases. The majority of donors were female (58%) and Caucasian (60%). No differences were observed between MILIA and ODN donors for the age, gender and ethnicity. However, MILIA donors experienced a longer mean±SD operative time (234±47 vs. 197±33 min, p

The actual dietary protein intake of adults without and with different stages of chronic kidney disease is not known. To evaluate this we performed cross-sectional analyses of 16,872 adults (20 years of age and older) participating in the National Health and Nutrition Examination Survey 2001-2008 who completed a dietary interview by stage of kidney disease. Dietary protein intake was assessed from 24-h recall systematically collected using the Automated Multiple Pass Method. Complex survey analyses were used to derive population estimates of dietary protein intake at each stage of chronic kidney disease. Using dietary protein intake of adults without chronic kidney disease as the comparator, and after adjusting for age, the mean dietary protein intake was 1.30 g/kg ideal body weight/day (g/kgIBW/d) and was not different from stage 1 or stage 2 (1.28 and 1.25 g/kgIBW/d, respectively), but was significantly different in stage 3 and stage 4 (1.22 and 1.13 g/kgIBW/d, respectively). These mean values appear to be above the Institute of Medicine requirements for healthy adults and the NKF-KDOQI guidelines for stages 3 and 4 chronic kidney disease. Thus, the mean dietary protein intake is higher than current guidelines, even after adjusting for age. [ABSTRACT FROM AUTHOR]