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Background: Cytomegalovirus (CMV) donor-positive/recipient-negative (D+R-) serostatus is independently associated with worse allograft and patient survival across solid organ transplant (SOT) types. We characterized trends in CMV D+R- serostatus among adult SOT recipients performed in the United States., Methods: Donor (D) and recipient (R) CMV serostatus and demographic factors were obtained from the Scientific Registry of Transplant Recipients for persons ≥18 y undergoing a first SOT between January 1, 2000, and December 31, 2020. The proportions of D+R- SOTs over time were assessed using Chi square for trend and modeled through 2040. Factors associated with D/R seropositivity were assessed using logistic models., Results: Among 472 549 SOTs, the average proportion of D+R- SOTs increased significantly among kidney, liver, heart, and lung between 2000 to 2009 and 2010 to 2020: 18.0% to 18.3% ( P  = 0.034), 19.4% to 21.8% ( P  < 0.001), 22.2% to 25.5% ( P  < 0.001), and 23.6% to 27.0% ( P  < 0.001), respectively. The increased proportion over time resulted from a disproportionate increase in R- (34.9% to 37.0% for all organ types, P  < 0.001) and a smaller corresponding change in D+ (60.8% to 60.3%, P  < 0.001)., Conclusions: The proportion of high-risk CMV D+R- SOTs increased significantly across all organs and is projected to continue to increase. These findings inform population-level strategies to mitigate the negative impact of CMV D+R- in SOT., Competing Interests: A.P.L. has received consulting fees, research support, contracted research, or consulting fees from: Amplyx Pharmaceuticals, Novartis, Merck, J&J, NovoNordisc, GSK, NobelPharma, Hologic, and Allovir. The other authors declare no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Renal biopsy has been proposed to determine the cause or reversibility of renal failure for patients with end-stage liver disease and may be useful in the kidney allocation. Nevertheless, little data exist to validate the usefulness of kidney biopsies in this patient population., Methods: We evaluated the utility of renal biopsies in a cohort of 59 consecutive liver transplant candidates with renal impairment of unclear etiology referred to determine the need for simultaneous liver kidney transplantation (SLK) versus liver alone transplantation (LAT). Pathological diagnoses, patient outcomes and the usefulness of biopsy results in predicting renal recovery were analyzed., Results: Our biopsy complication rate was relatively low with only 2.9% and 4.2% serious complications occurring with transjugular and percutaneous renal biopsies, respectively. The most common pathological diagnoses on renal biopsies were membranoproliferative glomerulonephritis (23%) followed by IgA nephropathy (19%) and acute tubular injury (19%). Simultaneous liver kidney transplantation was recommended for patients with greater than 40% global glomerular sclerosis, or with interstitial fibrosis greater than 30% or for patients on hemodialysis for 2 months or longer. The best histological predictor for posttransplant glomerular filtration rate in the LAT group was the extent of global glomerulosclerosis (P = 0.0001). Based on biopsy criteria, we were able to avoid kidney allocation to 70% of our patients with renal dysfunction. Over the first year posttransplant, SLK and LAT patients had comparable estimated glomerular filtration rates. Kaplan-Meier survival analysis did not demonstrate a difference in patient survival between patients who underwent LAT versus SLK., Conclusions: Renal biopsy can be relatively safe in this population, may help elucidate the etiology of renal failure, may predict post-LAT kidney function, and may be helpful in kidney allocation for liver transplant candidates.

Background: PD-L1, a ligand for programmed death 1 (PD-1), delivers a negative costimulatory signal to T cells and plays a critical role in the regulation of peripheral tolerance., Methods: We used PD-L1(-/-) mice to evaluate the role of the PD-L1 signal on allogeneic immune responses in vivo and the underlying mechanisms. Heart transplantation was performed from PD-L1(-/-) donors or recipients in major histocompatibility complex fully mismatched mouse combinations. The immunologic function of allograft recipients was evaluated ex vivo by enzyme-linked immunospot, mixed lymphocytes reaction, cytotoxic T lymphocyte, and flow cytometry., Results: Our results demonstrated that PD-L1(-/-) T cells proliferated vigorously under alloantigen stimulation, and also that the antigen-presenting cells (APCs) from PD-L1(-/-) mice exhibited a stronger allostimulatory activity compared with that in wild-type mice. Heart allografts were rejected at an accelerated rate in both PD-L1(-/-) donors and recipients. This was associated with significantly augmented donor specific T-cell proliferation and antidonor cytotoxic T lymphocyte activities, and enhanced Th1- or Th2-type immune responses of heart allograft recipients., Conclusions: Absence of PD-L1 input triggers a stimulatory signal to effector T cells and APCs, accelerating heart allograft rejection. Engagement of the PD-L1 signal on T cells or APCs may be necessary to induce transplant tolerance.

Background: Historically, antibody induction has been used because of the higher immunologic risk of graft loss or rejection observed in simultaneous pancreas and kidney (SPK) transplantation compared with kidney transplantation alone. This trial was designed to assess the effect of antibody induction in SPK transplant recipients receiving tacrolimus, mycophenolate mofetil, and corticosteroids. Induction agents included T-cell-depleting and interleukin-2 receptor antibodies., Methods: A total of 174 SPK transplant recipients were enrolled in a prospective, open-label, multi-center study. They were randomized to induction (n=87) or non-induction (n=87) groups and followed for 3 years., Results: At 3 years, actual patient (94.3% and 89.7%) and pancreas (75.9% and 75.9%) survivals were similar between the induction and non-induction groups, respectively. Actual kidney survival was similar at 1 and 2 years, but at 3 years, it was significantly better in the induction group compared with the non-induction group (92% vs. 81.6%; P =0.04). At 3 years, median serum creatinine and hemoglobin A1C were similar between the induction and non-induction groups (1.35 mg/dL and 1.20 mg/dL, 5.4% and 5.5%, respectively). Three-year cumulative incidence of biopsy-confirmed, treated acute kidney rejection in the induction and non-induction groups was 19.5% and 27.5% (P =0.14), respectively, with odds 4.6 times greater in African Americans regardless of treatment (P =0.004). Significantly higher rates of cytomegalovirus (CMV) viremia and CMV syndrome occurred in those receiving T-cell-depleting antibody induction (36.1%) when compared with those receiving anti-interleukin-2 receptor antibodies (2%) and non-induction (8.1%) (P <0.0001)., Conclusions: Tacrolimus, mycophenolate mofetil, and corticosteroids resulted in excellent safety and efficacy in SPK transplant recipients. Actual 3-year kidney survival was significantly better in the induction group; however, CMV viremia and CMV syndrome rates were significantly higher in the T-cell-depleting antibody group. African Americans demonstrated a significantly greater risk of acute rejection despite antibody induction. Decisions regarding the use of induction therapy must weigh the risk of kidney graft loss or rejection against the risk of infection.

Background: Initial doses of OKT3 are associated with a cytokine-induced acute clinical syndrome (ACS). This study assessed the safety of a recombinant human tumor necrosis factor receptor fusion protein (TNFR:Fc) given to minimize OKT3-ACS symptoms in renal allograft recipients undergoing induction therapy., Methods: Sixteen patients were randomized into treatment or control groups. Treated patients received TNFR:Fc 1 hr before OKT3 on days 0 and 3. Patients were monitored after transplant for OKT3-ACS symptoms. Levels of cytokines, serum creatinine, and C-reactive protein were followed., Results: Patients receiving TNFR:Fc had lower OKT3-ACS symptoms as measured by a scoring system. There was a higher incidence of infection in treated patients (10/12) compared to controls (1/4) in the 3 months after transplant, but the etiology of this difference was unclear. There were no significant differences in cytokine profiles., Conclusions: TNFR:Fc is well tolerated by renal transplant patients receiving OKT3 induction therapy and modestly decreases the symptoms associated with OKT3-ACS.

Glomerular abnormalities are frequent in patients undergoing liver transplantation; however, renal dysfunction following transplantation is mainly attributed to cyclosporine toxicity. Membranoproliferative glomerulonephritis (MPGN) is seen in patients infected with hepatitis C virus (HCV), the virus responsible for 30% of the end-stage liver disease leading to liver transplantation. To determine the incidence of renal abnormalities in liver transplant recipients and the association with HCV, we undertook a longitudinal study in HCV-positive (n=91) and HCV-negative (n=106) liver transplant recipients. Mean creatinine clearance before transplantation was 94 ml/min/1.73 m2 in HCV+ patients and 88 ml/min/1.73 m2 in HCV- patients. By 3 months after transplantation, the mean creatinine clearance decreased by approximately one third in both groups. A greater proportion of HCV+ patients excreted >2 g protein/day after transplantation (P=0.05) and had renal biopsies showing MPGN than did HCV- recipients (4/10 HCV+ patients vs. 0/7 HCV- patients; P=0.1). In the HCV+ group, proteinuria was not associated with recurrent HCV hepatitis, DQ matching, posttransplant diabetes, or hypertension. Treatment of HCV-related MPGN with interferon-alpha2b appeared to stabilize proteinuria and renal function but did not reverse renal dysfunction nor cause liver allograft rejection. After transplantation, HCV+ patients had similar renal function over 3 years after transplantation, compared with HCV- patients, but they had an increased risk of proteinuria and occurrence of MPGN that was only partially responsive to interferon.

Obstruction of the IVC occurs in only 1-2% of patients after liver transplantation. The mortality of this complication can be as high as 66%. This case report describes the use of a Wallstent for an IVC obstruction that was unresponsive to conventional balloon angioplasty.

Although surgical proficiency is essential to the immediate outcome of transplantation, long-term success depends upon how adequately the transplantation recipient is managed. Immunosuppression, the most critical aspect of after care, is subject to wide variation. In January 1990, a survey was sent to the directors of all transplant programs in the United States performing one or more kidney, heart, liver, heart-lung, or pancreas transplant in 1988. Detailed data were obtained on both the drugs and methods used for induction and maintenance immunosuppression, as well as the treatment of rejection. Each program director was asked to rank each immunosuppressive approach according to its perceived impact on patient outcomes. Over 85% of all eligible program directors completed the survey. There is no evidence of survey respondent bias. The use of polyclonal and monoclonal agents for induction immunosuppression was favored most by pancreas program directors (72-76%). These agents were least preferred by liver transplant programs (35-37%). About half of kidney, heart, and heart-lung program directors preferred these agents. Triple-drug therapy consisting of CsA, PRED, and AZA was considered the most preferable maintenance protocol for all transplants (i.e., kidney, 89%; heart, 94%; liver, 88%; heart-lung, 86%; pancreas, 96%). Either i.v. steroids or OKT3 were regarded as the preferred approaches for the treatment of acute or resistant rejection. Finally, the acceptability of outpatient treatment of rejection varied by transplant type (i.e., kidney, 9%; heart, 58%; liver, 5%; heart-lung, 29%; pancreas, 8%). Although there are similarities in the ratings of various aspects of immunosuppressive therapy, there are important differences. This information is critical to anticipate the implications of new immunosuppressive agents and to evaluate changes in the use of existing drugs and therapeutic approaches.

This study was undertaken to determine the effects of somatostatin 201-995 (SMS) on the maintenance dose of intravenous cyclosporine and on graft blood flow, exocrine secretion, and rejection after porcine pancreaticoduodenal allotransplantation (PDA). For seven days, 12 pigs (6 control, 6 SMS-treated) were studied to determine the effects of SMS on serum CsA concentrations. Twenty-six pigs (14 control, 12 SMS) with streptozocin-induced diabetes underwent PDA. Blood flow was measured through graft celiac and superior mesenteric arteries 15 and 60 min after reperfusion. SMS (75 micrograms s.c.) was given after the 15-min blood-flow measurement in the SMS group. Sixteen pigs (8 control, 8 SMS) were followed postoperatively with daily measurements of serum glucose and amylase concentrations, and urine amylase and trypsin activities. All pigs were immunosuppressed with azathioprine, prednisone, and i.v. CsA. SMS pigs also received SMS (75 micrograms s.c.) every 8 hr. SMS had no effect on maintenance dose of CsA or on serum amylase, urine amylase, or urine trypsin activities. Mean days to rejection were also not affected. Intraoperative graft blood flow was significantly decreased by SMS, but incidence of graft thrombosis was unchanged. These results suggest that in the porcine PDA model, SMS does not appear to inhibit exocrine secretion and potentially may adversely affect the early course of PDA by decreasing graft blood flow.

In 18 consecutive pancreaticoduodenal allograft recipients (15 combined kidney/pancreas and 3 pancreas only after a prior successful kidney transplantation) operated on between December 1987 and February 1989, we studied the soluble interleukin 2 receptor (SIL-2R) level over time. All pancreaticoduodenal allografts were transplanted with exocrine drainage via a duodenocystostomy that allowed for cystoscopically directed needle biopsies of the pancreas. Of these 18 recipients, at 6 weeks after transplantation, 6 had had no rejection episodes or cytomegalovirus disease (control group), an acute allograft rejection had developed in 7, CMV disease developed in 4, and both rejection and CMV disease developed in 1 by 12 days after transplantation. SIL-2R level increased in all patients during immunosuppressive induction therapy (preoperative mean +/- SE, 1637 +/- 284 U/mL; maximum, 4367 +/- 687 U/mL). After induction therapy, the mean was 2768 +/- 432 U/mL. In all 6 recipients in the control group, SIL-2R level continued to decrease. However, SIL-2R level was significantly higher compared with controls, in those who had CMV disease (levels were increased at a mean of 7 days before diagnosis of CMV disease) and in those who had acute rejection episodes (levels were increased a mean of 7 days before the clinical diagnosis of rejection). Factors that did not cause an increase in SIL-2R level included acute pancreatitis, wound infection, operative procedures, and CsA nephrotoxicity. SIL-2R level can be useful for monitoring pancreaticoduodenal allograft recipients. Increases predict impending rejection or CMV disease, prior to the onset of organ dysfunction. When SIL-2R level increases, we recommend cultures of blood and urine to exclude CMV and pancreaticoduodenal allograft biopsy to confirm early rejection prior to the initiation of potentially dangerous antirejection therapy.

We have studied the histopathologic correlates of a significantly decreased urinary amylase excretion rate (UAER) to determine its reliability in predicting the presence of cellular rejection within pancreas allografts drained via a duodenocystostomy. Significant hypoamylasuria in pancreas allograft recipients was defined as a diminution of greater than 50% in UAER sustained for greater than 36 hr and not associated with a decrease in serum amylase activity. We observed 18 such episodes of hypoamylasuria in 13 of 18 patients receiving pancreas allografts. Pancreaticoduodenal material was obtained during 11 of these episodes, one attempt failed, and for the remaining 6 episodes we obtained 3 renal allograft biopsy specimens. Histopathologic examination of the 14 specimens revealed cellular rejection in 9 (64%), fibrosis in 2 (14%), enzymatic necrosis in 1 (7%), cytomegaloviral pancreatitis in 1 (7%), and no abnormal features in 1 (7%). During these 14 episodes, a genetically identical renal allograft was present for 11 and showed signs of dysfunction in 9; however, the pancreatic histologic features suggested rejection in only 7 of the 9. Thus even the combination of hypoamylasuria and renal dysfunction in recipients of genetically identical organs was not fully reliable in predicting pancreas allograft rejection. In addition, the interval between organ implantation and onset of hypoamylasuria did not predict the histologic diagnosis. As with other solid-organ allografts, biopsy is a useful adjuvant for determining patient management in the presence of organ dysfunction.

Conventional staining techniques to determine the presence of tissue eosinophils underestimate their number and do not usually detect eosinophil degranulation. We have studied the involvement of eosinophils in acute renal allograft rejection by immunofluorescence localization of eosinophil granule major basic protein (MBP) in the kidney and by measurement of MBP in the plasma and urine by radioimmunoassay. Tissue eosinophilia and extracellular deposition of MBP indicative of eosinophil degranulation were observed in 94% and 87%, respectively, of patients with acute rejection as compared with 17% and 17%, respectively, of patients with cyclosporine nephrotoxicity. The urine levels of MBP were significantly elevated in acute rejection but not in cyclosporine nephrotoxicity. Plasma MBP concentrations were within the normal range in both acute rejection and cyclosporine nephrotoxicity. The presence of marked tissue eosinophilia and eosinophil degranulation did not always indicate irreversible rejection. Interleukin-2 and IL-2 receptors were also elevated in the urine during acute rejection. These results support a role for the eosinophil as an effector of tissue damage during rejection and suggest the potential usefulness of urine MBP determinations for the immunologic monitoring of transplanted patients.

We studied the serum levels of soluble interleukin-2 receptors (SIL-2R) in liver allograft recipients: a control group without rejection or CMV disease, a group with only rejection episodes, and a group with only cytomegalovirus disease. Rejection was diagnosed by the presence of compatible laboratory and histologic abnormalities and absence of other causes of graft dysfunction. CMV disease was diagnosed by isolation of CMV in blood or liver specimen cultures or identification of cytomegalic inclusions in the liver biopsy specimen. Of 82 consecutive recipients treated with cyclosporine and prednisone, 12 were in the control group, 20 in the rejection group, and 5 in the CMV disease group. The remaining 45 had other or multiple complications. In the control group the SIL-2R levels (determined by an ELISA) decreased by a mean of 4% per day after transplantation; in the rejection group the levels increased by a mean of 17% per day in the 10 days prior to the diagnosis of rejection; in the CMV disease group the levels tended to increase prior to the diagnosis of CMV disease. The rejection group had significantly higher SIL-2R levels than the control group at comparable times. Thus, SIL-2R levels were significantly increased at the time of allograft rejection compared with levels in a control group, and recipients with CMV disease had increased levels of SIL-2R but they were not as high as in recipients with rejection episodes.

Monoclonal antibodies were used to identify T-helper cells (TH) and T-suppressor/cytotoxic cells (TS/C) in biopsy specimens obtained 7, 21, 90, 180, and 365 days postoperatively, and during episodes of graft dysfunction, from 34 consecutive liver transplant patients treated with cyclosporine and steroids. Rejection was diagnosed by the presence of appropriate laboratory and light microscopic findings and at least 8 weeks of follow-up to exclude other causes of graft dysfunction. Four immunohistologic patterns were seen--no labeled cells (No), only lobular TS/C, only portal TH, and a portal mixture of TH and TS/C (mix). Of 36 specimens with the No or only lobular TS/C pattern, 29 were not associated with rejection. Of the 39 specimens with the portal TH or portal Mix pattern, 33 were associated with a rejection episode. In addition, in nine specimens from patients with no biochemical or routine histologic evidence of rejection, the presence of portal TH or a portal mix indicated immunologic rejection 5 days to 5 weeks before biochemical and routine histologic evidence of it was manifested. Immunohistologic labeling appears to be an early indicator of liver allograft rejection.

We found splenic artery aneurysms in 6 of 71 consecutive patients who underwent orthotopic liver transplantation at the Mayo Clinic. The incidence of splenic artery aneurysms in cirrhotic patients with portal hypertension was 10%. Five of the aneurysms were found in patients suffering from chronic active hepatitis, whereas no aneurysms were encountered in patients with primary sclerosing cholangitis or primary biliary cirrhosis. One patient ruptured a splenic artery aneurysm shortly after liver transplantation, and 1 patient developed an aneurysm 3 months after transplantation. We recommend coeliac angiography to be performed prior to liver transplantation, and if splenic artery aneurysms are found, ligation of the splenic artery should be performed at the time of transplantation to prevent possible rupture.

Among the first 52 recipients of primary liver allografts with follow-up of 2 weeks or greater, 6 patients had biopsy-confirmed vanishing bile duct syndrome (VBDS) and required retransplantation. Five of these six patients had positive lymphocyte crossmatches. Of the 46 remaining liver transplant recipients, 11 had positive crossmatches. Thus, the incidence of VBDS was 5/16 in recipients with a positive crossmatch and 1/36 in recipients with a negative crossmatch. The positive-crossmatch group was significantly more likely to develop VBDS than the negative-crossmatch group (P less than 0.004, log rank test). Additional HLA studies comparing degree of donor-recipient mismatch at the various HLA loci showed no significant difference between the groups for class I disparity. However, class II mismatch was of borderline significance (P less than 0.056). When evaluated individually, the DQ mismatch (P less than 0.04) appeared to be more important than the DR mismatch (P = NS). Our data suggest that a positive lymphocyte crossmatch and a class II mismatch, in particular HLA DQ disparity, may play an important role in the pathogenesis of VBDS.

To determine the nature and sequence of the histologic changes in the early rejection of pancreaticoduodenal allografts and to assess the correlation between pancreaticoduodenal biopsy findings and the pathologic changes in the graft, we performed serial cystoscopically directed needle biopsies of pancreaticoduodenal allografts in 18 dogs and compared the findings with the histologic changes in 16 autografts as controls. Tissue adequate for evaluation was obtained by the biopsy technique in 70% of instances. The earliest and most characteristic manifestation of rejection was diffuse mixed inflammatory infiltrates involving the pancreatic acinar tissue and duodenum. The biopsy findings correlated well with the changes in the resected pancreatic specimens. Cellular rejection in the duodenum correlated with rejection in the pancreatic graft. There were no changes in the autografts that resembled cellular rejection. We conclude that, in the canine model, cystoscopically directed needle biopsy of pancreaticoduodenal allografts consistently provides adequate tissue for the diagnosis of rejection; the status of the graft can be monitored by serial biopsies of pancreatic acinar tissue and, possibly, by serial biopsies of the duodenal wall alone.

Gram-negative bacterial and fungal infections are a major cause of morbidity and mortality following liver transplantation. We therefore used selective bowel decontamination (SBD) to eliminate the endogenous source of gram-negative aerobic bacteria and Candida pathogens in an attempt to reduce the high incidence of infection related to these organisms. Thirty consecutive patients undergoing liver transplantation were treated with SBD starting 3 days prior to donor search and continuing for 21 days postliver transplantation. Selective bowel decontamination consisted of administering nonabsorbable antibiotics (Polymixin E, gentamicin, Nystatin) and a low bacterial diet. Surveillance cultures of the throat and rectum were obtained to monitor efficacy of selective bowel decontamination. In addition, in the posttransplant period, tracheal, wound, blood, and bile cultures were obtained to screen for gram-negative bacterial and Candida colonization and infection. Our baseline surveillance culture revealed that 29/30 (97%) of recipients were colonized with gram-negative aerobic bacteria and 16/30 (53%) with Candida. Three days after selective bowel decontamination was started, 26/30 (87%) were free of gram-negative bacteria, and 100% were free of Candida colonization of the gastrointestinal tract. There was a similar reduction in the oropharyngeal gram-negative aerobic bacteria and Candida colonization. In the first 30 days following liver transplantation, gram-negative infections were not diagnosed in any of our patients. Following discontinuation of SBD, recolonization of the gastrointestinal tract with gram-negative aerobic bacteria and Candida occurred within 5 days in 26/28 (90%) and 11/28 (35%), respectively. Our study suggests that prophylactive administration of nonabsorbable antibiotics will markedly reduce gram-negative aerobic bacterial and Candida colonization and appears to reduce the high incidence of infection related to these organisms in the early posttransplant period.