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A recent study concluded that SARS-CoV-2 mRNA vaccine responses were improved among transplant patients taking mTOR inhibitors (mTORi). This could have profound implications for vaccine strategies in transplant patients; however, limitations in the study design raise concerns about the conclusions. To address this issue more robustly, in a large cohort with appropriate adjustment for confounders, we conducted various regression- and machine learning-based analyses to compare antibody responses by immunosuppressive agents in a national cohort (n= 1037). MMF was associated with significantly lower odds of positive antibody response (aOR = 0.090.130.18). Consistent with the recent mTORi study, the odds tended to be higher with mTORi (aOR = 1.001.452.13); however, importantly, this seemingly protective tendency disappeared (aOR = 0.470.731.12) after adjusting for MMF. We repeated this comparison by combinations of immunosuppression agents. Compared to MMF + tacrolimus, MMF-free regimens were associated with higher odds of positive antibody response (aOR = 2.394.267.92for mTORi+tacrolimus; 2.345.5415.32for mTORi-only; and 6.7810.2515.93for tacrolimus-only), whereas MMF-including regimens were not, regardless of mTORi use (aOR = 0.811.542.98for MMF + mTORi; and 0.811.512.87for MMF-only). We repeated these analyses in an independent cohort (n= 512) and found similar results. Our study demonstrates that the recently reported findings were confounded by MMF, and that mTORi is not independently associated with improved vaccine responses.

In kidney transplantation, BKvirus infection has historically resulted in high rates of graft dysfunction and graft loss. Unlike other opportunistic infections, no therapies have been shown to prevent BK. The purpose of the current study was to evaluate the safety and efficacy of ciprofloxacin for the prevention of BKviremia in kidney transplant recipients. Two hundred kidney transplant recipients were enrolled in a prospective, randomized, double‐blind, placebo‐controlled trial comparing a 3‐month course of ciprofloxacin (n = 133) vs placebo (n = 67) for the prevention of BKviremia. The primary endpoint of BKviremia at month 6 posttransplant occurred in 25 (18.8%) patients in the ciprofloxacin group and 5 (7.5%) in the placebo group (P= .03). Higher rates of BKviremia (23.3% vs 11.9%; P= .06) and BKnephropathy (5.8% vs 1.5%; P= .26) remained at 12 months in the ciprofloxacin group. Ciprofloxacin use was associated with a significantly higher rate of fluoroquinolone‐resistant gram‐negative infections (83.3% vs 50%; P= .04). A 3‐month course of ciprofloxacin was ineffective at preventing BKviremia in kidney transplant recipients and was associated with an increased risk of fluoroquinolone‐resistant infections. Clinical trial registration number: NCT01789203. A 3‐month course of ciprofloxacin beginning within 1 week of transplantation is ineffective for the prevention of BK viremia in kidney transplant recipients and is associated with a significantly higher rate of fluoroquinolone‐resistant gram‐negative infections.

In kidney transplantation, BK virus infection has historically resulted in high rates of graft dysfunction and graft loss. Unlike other opportunistic infections, no therapies have been shown to prevent BK. The purpose of the current study was to evaluate the safety and efficacy of ciprofloxacin for the prevention of BK viremia in kidney transplant recipients. Two hundred kidney transplant recipients were enrolled in a prospective, randomized, double-blind, placebo-controlled trial comparing a 3-month course of ciprofloxacin (n = 133) vs placebo (n = 67) for the prevention of BK viremia. The primary endpoint of BK viremia at month 6 posttransplant occurred in 25 (18.8%) patients in the ciprofloxacin group and 5 (7.5%) in the placebo group (P= .03). Higher rates of BK viremia (23.3% vs 11.9%; P= .06) and BK nephropathy (5.8% vs 1.5%; P= .26) remained at 12 months in the ciprofloxacin group. Ciprofloxacin use was associated with a significantly higher rate of fluoroquinolone-resistant gram-negative infections (83.3% vs 50%; P= .04). A 3-month course of ciprofloxacin was ineffective at preventing BK viremia in kidney transplant recipients and was associated with an increased risk of fluoroquinolone-resistant infections. Clinical trial registration number: NCT01789203.

1-year data from this trial showed the noninferiority of a novel once-daily extended-release tacrolimus (LCPT; Envarsus XR) to immediate-release tacrolimus (IR-Tac) twice daily after kidney transplantation.

Preemptive transplantation results in excellent patient and graft survival yet most transplant candidates are referred for transplantation after initiation of dialysis. The goal of this study was to determine barriers to preemptive renal transplantation.

Renal transplant recipients with de novo DSA (dDSA) experience higher rates of rejection and worse graft survival than dDSA-free recipients. This study presents a single-center review of dDSA monitoring in a large, multi-ethnic cohort of renal transplant recipients.

This study reviewed the outcomes of a screening protocol for BK viremia to determine if early diagnosis, followed by immunosuppression minimization, would prevent progression to nephropathy and graft loss.

Previously transplanted patients are more likely to be sensitized, leading to prolonged waitlist times and decreased graft survival. This analysis of the United Network for Organ Sharing kidney/pancreas transplant database investigates factors at the time of first transplant associated with increased sensitization in patients undergoing second transplantation.

A prednisone and calcineurin inhibitor (CNI)-free protocol was compared with a sirolimus, cyclosporine A (CsA), and prednisone-based immunosuppressive regimen for simultaneous pancreas-kidney transplantation (SPK).

Sirolimus is an antiproliferative immunosuppressive agent that inhibits the mammalian target of rapamycin. It is highly effective in preventing acute renal allograft rejection and can be used with either calcineurin inhibitors, antimetabolites or corticosteroids. Early studies in renal transplantation have provided insight into optimal dosing strategies of sirolimus and of concomitant immunosuppressive agents. Familiarity with the adverse effect profile of sirolimus and pharmacokinetic and dynamic interactions with other immunosuppressive agents allows for earlier recognition and better management of sirolimus-related complications. The role of sirolimus in preserving long-term renal function, post-transplant malignancies and in prevention of atherosclerosis is currently being considered.

This study aims to determine the impact of thymoglobulin-sirolimus-cyclosporine immunosuppression on the alloimune response of pancreas-kidney transplant recipients.

Malignancies, a well-known complication of immunosuppressive therapy in renal transplant recipients, represent an important cause of long-term morbidity and mortality. One approach to addressing this problem is identifying agents that display antineoplastic properties concomitant with their immunosuppressive effects.

We previously reported that the use of basiliximab together with sirolimus permits a window of recovery from delayed graft function before the introduction of reduced-dose cyclosporine. The present study reviews our experience with the substitution of thymoglobulin for basiliximab as induction therapy for recipients at increased risk for early acute rejection episodes.

We investigated a novel immunosuppressive protocol including thymoglobulin induction in combination with sirolimus and corticosteroids, followed by introduction of markedly reduced exposures to cyclosporine to prevent pancreas-transplant rejection.

Elevations of interleukin 6 (IL-6) have been described in drug-induced anaphylaxis. Although IL-6 is well known to stimulate an acute phase response, profiling acute phase protein levels, such as C-reactive protein (CRP), has, to our knowledge, never been performed in patients with acute allergic reactions.

We investigated whether recipients of living donor grafts who suffer an acute rejection progress to graft loss because of chronic rejection at a slower rate than recipients of cadaveric grafts.

Background:Emergency department visits for acute allergic reactions are common. Although the diagnosis and classification of these allergic reactions is primarily empiric, it is not always clear whether certain signs and symptoms constitute systemic mediator release syndromes, such as anaphylaxis, and thus may warrant more aggressive therapy or follow-up. Objective:We sought to determine associations between various clinical signs and symptoms with both plasma histamine levels and serum tryptase levels in adult patients presenting to an emergency department with acute allergic syndromes. The clinical correlates of raised β-tryptase levels were also investigated. Methods:Ninety-seven adult emergency department patients were prospectively studied by using a questionnaire, physical examination, and serum-plasma sampling. Plasma histamine and serum total and β-tryptase levels were determined. Clinical groupings were compared for mediator levels by using simple and multivariate analysis. Results:Elevated levels of plasma histamine (10 nmol/L) and serum total tryptase (15 ng/mL) were observed in 42 and 20 patients, respectively. Detectable β-tryptase (≥1 ng/mL) was observed in 23 patients, including 15 of the patients with elevated total tryptase levels. Suspected food allergy incidences and the duration of reaction were similar in patients with increased histamine levels and in patients with increased tryptase levels. Increased total tryptase levels, histamine levels, or both were observed in some patients who did not have airway, cardiovascular, or abdominal signs. Histamine levels correlated better with clinical signs than tryptase levels. Histamine elevations (10 nmol/L) were observed more frequently in patients characterized by the following clinical signs in univariate analysis: the presence of urticaria, more extensive erythema, abnormal abdominal findings, and wheezing. Total tryptase increases were observed more frequently only in patients with urticaria. Histamine levels correlated with initial heart rates. In multivariate analysis the extent of urticaria was the best single predictor of plasma histamine levels and of either an elevated histamine or tryptase level. Detectable β-tryptase levels were observed in some patients who had neither elevated total tryptase nor elevated histamine levels. Unlike patients without detectable β-tryptase levels, patients who had detectable β-tryptase levels had a significant correlation between total tryptase and histamine levels (P< .05). Conclusions:Raised histamine and, less commonly, raised tryptase levels are observed in almost 50% of patients presenting to emergency departments with acute allergic reactions. Some cases associated with systemic mediator release do not have classical features of severe anaphylaxis, such as hypotension or tachycardia. The lack of total tryptase elevations in many patients with elevated plasma histamine levels suggests basophil involvement. The clinical utility of β-tryptase determinations in the evaluation of acute allergic reactions needs further study. (J Allergy Clin Immunol 2000;106:65-71.)

Hydrophobic chromatography on phenyl–Sepharose has revealed the decidedly hydrophobic character of several members of the group of cytolytic proteins termed ‘thiol-activated’. Pneumolysin, alveolysin, cereolysin, and streptolysin O were found to be equally hydrophobic, as were the oxidized and reduced forms of alveolysin. Hydrophobic chromatography has been utilized in the development of an improved procedure for the purification of pneumolysin.

<$O_ST_ABS>Objective<$C_ST_ABS>Myocardial reperfusion following brief periods of ischaemia is associated with prolonged, reversible periods of metabolic dysfunction. As the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is inhibited in vitro by reactive oxygen species, we hypothesized that production of reactive oxygen species during reperfusion would lead to inhibition of GAPDH in post-ischaemic myocardium. Methods: Anaesthetized closed-chest dogs were subjected to 20 min balloon occlusion of the left anterior descending coronary artery. Biopsy samples were taken after 3 and 24 h of reperfusion, to determine the activity of GAPDH and the concentrations of glycolytic intermediates in post-ischaemic and remote, non-ischaemic territories. Results: A significant reduction in GAPDH activity was observed in post-ischaemic relative to remote tissue after 3 h reperfusion (4.8 ± 0.5 vs. 2.9 ± 0.2 µmol/min/mg protein; P < 0.01). Western blotting revealed no reduction in the levels of GAPDH protein. Analysis of enzyme kinetics showed the loss of activity to be associated with decreased V_max (5.9 ± 0.5 vs. 3.2 ± 0.2 µmol/min/mg protein; P < 0.01) with no significant change in the K_m for glyceraldehyde-3-phosphate (GAP). Incubation of the inhibited enzyme under both mild and strong reducing conditions failed to reactivate the enzyme. The acute reduction in enzyme activity in post-ischaemic tissue was accompanied by regional differences in glycolytic intermediates, notably a twofold accumulation of GAP (P < 0.05), and a reduction in the glucose metabolic rate (GMR) determined by positron emission tomography and [18F]2-fluorodeoxyglucose. By 24 h reperfusion, no regional differences in GAPDH activity, reaction V_max or K_m, GAP concentrations or GMR were detectable. Conclusions: These results suggest that inhibition of GAPDH activity may represent an important point at which glycolysis is limited during reperfusion, and further, that the mechanisms of enzyme inhibition do not involve simple oxidation or S-thiolation of critical active site thiol groups.

Ischemia and reperfusion lead to the rapid induction of proto-oncogenes in the heart and subsequent induction of genes with cardioprotective functions. The activity of the transcription factors c-Jun and ATF-2 can be stimulated by activation of c-Jun amino-terminal kinase (JNK) in response to a variety of stresses. Here we show that ischemia and reperfusion led to the activation of JNK and also of the distantly-related mitogen activated protein kinase (MAPK). Activation of JNK, but not (MAPK), was abolished by removal of calcium from the perfusate immediately prior to ischemia. In contrast, infusion of the hydrogen peroxide scavenger catalase abolished activation of MAPK in response to ischemia and reperfusion, but activation of JNK was inhibited significantly by catalase only when superoxide dismutase was also present. Hydrogen peroxide infusion activated MAPK but not JNK, supporting a role for hydrogen peroxide produced during reperfusion in MAPK activation. We conclude that while ischemia and reperfusion activate both JNK and MAPK, the mechanisms of activation are different for the 2 kinases. Activation of these kinases is likely to contribute to altered gene expression in response to ischemia and reperfusion.

The effects of a subtherapeutic regimen of rapamycin (RAPA) combined with CsA and donor-specific blood transfusions (DST) were investigated in the ACI to LEW cardiac allograft model. Three protocols were studied. In protocol 1, recipients received a DST (day −1), RAPA intravenously at 0.08 mg/kg/day (day −1 to 5), and CsA intramuscularly at 5 mg/kg/day (day −1 to 1). In protocol 2, the course of CsA was extended to day 5, and in protocol 3 the treatment was further modified to include a second DST on day 3. Control groups received drug treatments alone or combined with DST or third-party blood transfusions. In all protocols, RAPA, CsA, or DSTs alone had little or no effect on graft survival. RAPA-DST or CsA-DST also had no effects beyond the ones induced by the drugs alone. In the RAPA-CsA groups, graft survivals were similar to the ones obtained with CsA alone. In contrast, in each of the protocols, the RAPA-CsA-DST treatment resulted in significant prolongation of graft survival as compared with all controls (P<0.05). The administration of a second DST (CsA-RAPA-DST×2) provided no additional benefits over a single DST. Lymph node cells from CsA-RAPA-DST subjects were hyporesponsive in MLR against donor cells and suppressed the proliferation of normal LEW cells in an MLR coculture assay, suggesting the presence of suppressor cells. Furthermore, in the CsA-RAPA-DST group, the antidonor antibody response was suppressed. These data demonstrate that RAPA, CsA, and DST interact positively by inducing a clear-cut and significant prolongation of allograft survival in the rat model under conditions in which the individual components of the treatment are essentially ineffectual.

Mouse mAbs directed against the α/β-TCR were tested in clinical phase II and in triple-blind, randomized phase III studies. A clinical phase II trial administered 50 mg of murine anti-human α/β-TCR mAb (BMA 031) intravenously on the day of, as well as 2 and 4 days after, cadaveric donor renal transplantation in combination with a CsA/prednisone regimen. None of 12 patients showed even moderately adverse side effects. A phase III, triple-blind randomized trial enrolled 24 patients in the BMA 031 group and 22 patients in a placebo control group. BMA 031 treatment significantly reduced the incidence of rejection events within the first 10 posttransplant days to 1 patient versus 9 episodes in the placebo group (P0.01). By the end of 30 days, 6 rejection episodes had occurred in the BMA 031 group and 11 in the control cohort (P=NS). After a minimum of 30 months follow-up, the actual allograft survival rate was 87 in the BMA-treated group compared with 68 in the control cohort.

A mouse IgG1mAb (R73) directed against the rat α/β-TCR was documented not only to prolong the survival of allografts across major RT1 plus non-RT1 antigenic disparities, but also to display a synergistic immuno-suppressive interaction with CsA. Heterotopic cardiac transplants from Buffalo (RT1b) rats survived significantly longer in Wistar-Furth (RT1u) hosts treated immediately after the operation with 0.25 mg/kg R73 i.v., with a mean survival time of 11.0\pm5.5 versus 6.8\pm1.2 days in the untreated group (P0.01). Administration of 0.5 or 5.0 mg/kg R73 displayed dose-dependent prolongation of survival to 17.0\pm8.3 days (P0.05) or 28.6\pm 14.0 days (P0.01), respectively. One 0.5 mg/kg i.v. dose of R73 delivered to normal Wistar-Furth hosts produced peripheral T cell depletion that reversed after 16 days. Three injections of 0.5 mg/kg R73 on days 0, 2, and 4 prolonged allograft survival to 52.5\pm38.6 days compared with 17.0\pm8.3 days with a single dose (P0.01). Addition of 3 daily doses of 5 or 10 mg/kg CsA administered per oral gavage to a single dose of 0.05, 0.25, or 0.5 mg/kg R73 injected on day 0 produced a synergistic effect to prolong allograft survival, as determined by the rigorous median-effect analysis. The synergistic interaction, which may be explained by the inhibitory effect of CsA on Ca2+-dependent pathways triggered after activation of TCR, the target of R73, warrants clinical investigation in order to assess the potential impact of anti-α/β-TCR mAb on CsA-based immunosuppressive regimens.

The induction of donor-specific unresponsiveness in allograft recipients would lessen the need for chronic immunosuppression and its concomitant morbidities. In view of recognized interactions between the immune and neuroendocrine systems, we hypothesized that manipulating prolactin (PRL) levels might enhance the immunosuppressive effects of donor-specific blood transfusions. Bromocriptine (BR) and domperidone (DOM), administered via osmotic pumps, were used to inhibit or increase pituitary PRL secretion, respectively, in male LEW rats treated with donor-specific transfusions (DST, Day −1), cyclosporine (CsA, 5 mg/kg, Days −1 to +1), and receiving ACI heart allografts. Neither compound had direct effects on lymphoid cellsin vitro.BR had no effects on graft survival in rats treated with either BT or CsA (BR–DST, 7.0 ± 0.7; BR–CsA, 9.2 ± 3.1; CsA, 11.3 ± 3.9 days). DOM–DST–CsA also did not affect graft survival (8.7 ± 3.1 days). BR and CsA, similarly, had no effects in rats receiving a nonspecific transfusion (8.8 ± 1.1 days). In contrast, BR administration in rats treated with DST and CsA unequivocally prolonged graft survival (17.0 ± 1.4 days;P< 0.01 vs all controls), suggesting that hypoprolactinemia increased the tolerogenic effects of DST. Spleen and lymph node cells harvested from BR–DST–CsA rats on Postoperative Day 8 showed impaired responses to mitogenic or allogeneic challenges. Cytotoxic antibody levels at Day 5 were low in all groups receiving CsA. Possible mechanisms are discussed.

Although the introduction of cyclosporine-prednisone immunosuppression has improved early renal graft survival, chronic rejection remains a major cause of long-term graft dysfunction. This study retrospectively examined 69 cases of chronic rejection among 643 primary renal allograft recipients treated with cyclosporine-prednisone immunosuppression from July 1981 to October 1989. Chronic rejection was defined as a rejection episode diagnosed >90 days posttransplantation with characteristics of progressive nonacute renal function deterioration, confirmed, in most cases, by renal biopsy. This group was compared with an equal-sized matched cohort. Among cadaveric recipients, 61 of 456 patients (13.4) displayed chronic rejection, whereas among living-related recipients, 8 of 187 patients (4.3) developed chronic rejection. The average time from the date of transplantation to diagnosis of chronic rejection was 15±14 months. One- and three-year graft survivals following diagnosis of chronic rejection were 51 (30/59) and 25 (13/51), respectively, compared with the cohort one- and three-year graft survivals of 98 (58/59) and 86 (32/37) at similar periods posttransplantation. HLA mismatch, PRA status, blood transfusion history, lipid levels, cyclosporine trough levels, incidence of prior acute rejection, and initial graft dysfunction were not significantly different between the chronic rejection group and the matched cohort. Hypertension and proteinuria were significantly associated with chronic rejection (P<0.001). Of 58 biopsies performed, findings solely consistent with chronic rejection were observed in 9 cases (15) and "acute upon chronic" rejection in 49 cases (83). Treatment of acute concomitants improved the renal function in 43 (27/63) by the time of hospital discharge. Nonetheless, at 12 months the incidence of improved renal function eroded to 22 (13/59), suggesting that the benefit was relatively shortlived. Although the overall incidence of chronic rejec-

Several letters to the editor are presented in response to articles in previous issues including "A New Maginot Line?" in the May 2015 issue, "49 Wisconsin Law Blogs: Attorneys Writing Their Way to New Business" in the March 4, 2015 issue and one on current membership of Wisconsin Supreme Court.

Objective: [2-18F] 2-fluorodeoxyglucose (FDG) is widely used to trace glucose metabolism for cardiac imaging with positron emission tomography. Because the transport and phosphorylation rates differ for glucose and FDG, a lumped constant (LC) is used to correct for these differences. The effects of ischemia and reperfusion on the LC in vivo are unknown. To determine the validity of FDG as a tracer of glucose metabolism in post-ischemic myocardium in vivo, the relationship between glucose uptake (GU) and FDG metabolic rate (FDG-MR) was assessed early post-reperfusion following a transient ischemic event. Methods: FDG metabolic rate, measured with FDG and PET, was compared to invasive measurements of substrate metabolism in reperfused and global myocardium of dogs subjected to 25 min ischemia and 2 h reperfusion. Results: The FDG metabolic rate was decreased 20±4% in reperfused relative to remote myocardium. Glucose oxidation and lactate uptake were also decreased in reperfused relative to global myocardium, by 26±6% and 60±8% respectively. Glucose uptake did not differ significantly between reperfused and global myocardium. A linear correlation between FDG metabolic rate and glucose uptake was found in both reperfused and remote myocardium. Estimates of the LC from the slopes of the regression lines were similar in reperfused and remote myocardium, 1.25 and 1.44 respectively, and did not differ significantly from the LC determined in control dogs, 1.1. Conclusions: We conclude that the FDG metabolic rate continues to correlate well with glucose metabolism in reperfused myocardium. While FDG metabolic rate was modestly decreased in the absence of a significant change in glucose uptake, large alterations in the LC are not found 2 h post-reperfusion in vivo.