Ex vivo delivery of Mirococept: A dose-finding study in pig kidney after showing a low dose is insufficient to reduce delayed graft function in human kidney.

The complement system plays a pivotal role in the pathogenesis of ischemia-reperfusion injury in solid organ transplantation. Mirococept is a potent membrane-localizing complement inhibitor that can be administered ex vivo to the donor kidney prior to transplantation. To evaluate the efficacy of Mirococept in reducing delayed graft function (DGF) in deceased donor renal transplantation, we undertook the efficacy of mirococept (APT070) for preventing ischaemia-reperfusion injury in the kidney allograft (EMPIRIKAL) trial (ISRCTN49958194). A dose range of 5-25 mg would be tested, starting with 10 mg in cohort 1. No significant difference between Mirococept at 10 mg and control was detected; hence the study was stopped to enable a further dose saturation study in a porcine kidney model. The optimal dose of Mirococept in pig kidney was 80 mg. This dose did not induce any additional histological damage compared to controls or after a subsequent 3 hours of normothermic machine perfusion. The amount of unbound Mirococept postperfusion was found to be within the systemic dose range considered safe in the Phase I trial. The ex vivo administration of Mirococept is a safe and feasible approach to treat DGF in deceased donor kidney transplantation. The porcine kidney study identified an optimal dose of 80 mg (equivalent to 120 mg in human kidney) that provides a basis for further clinical development.

Daratumumab for delayed RBC engraftment following major ABO mismatched haploidentical bone marrow transplantation.

BACKGROUND: Recent case reports have described the efficacy of daratumumab to treat refractory pure red cell aplasia (PRCA) following major ABO mismatched allogeneic hematopoietic stem cell transplantation (HSCT). In this report, we describe the use of daratumumab as a first-line agent for treatment of delayed red blood cell (RBC) engraftment following a major ABO mismatched pediatric HSCT and provide a review of the literature. STUDY DESIGN AND MATERIALS: We report on a 14-year-old with DOCK8 deficiency who underwent a myeloablative, haploidentical bone marrow transplant from her major ABO mismatched sister (recipient O+, donor A+) for treatment of her primary immunodeficiency. Despite achieving full donor chimerism, she had delayed RBC engraftment requiring ongoing transfusions. Due to iron deposition, symptomatic anemia, and persistence of anti-A iso-hemagglutinins despite discontinuation of immunosuppression, treatment for delayed RBC engraftment with the CD38-targeted monoclonal antibody daratumumab was selected as a less immunosuppressive agent that could more selectively target iso-hemagglutinin producing plasma cells without causing broad B-cell aplasia. RESULTS: Clinical effect with daratumumab was demonstrated by reduced iso-hemagglutinin titer, increased reticulocytosis, normalization of her hemoglobin, and transfusion independence. In the 11-month follow-up period to date, no additional transfusions or immunosuppression have been necessary, despite persistence of low-level anti-A iso-hemagglutinin. CONCLUSION: Our experience suggests that daratumumab was an effective first-line therapy for delayed RBC engraftment and that earlier consideration for daratumumab in treatment of delayed RBC engraftment may be warranted.

A phase I/II, double-blind, placebo-controlled study assessing safety and efficacy of C1 esterase inhibitor for prevention of delayed graft function in deceased donor kidney transplant recipients.

Delayed graft function (DGF) is defined as need for dialysis early posttransplant. DGF is related to ischemia-reperfusion injury (IRI) that diminishes allograft function and may be complement dependent. Here, we investigate the ability of C1 esterase inhibitor (C1INH) to prevent IRI/DGF in kidney transplant recipients. Seventy patients receiving deceased donor kidney transplants at risk for DGF were randomized to receive C1INH 50 U/kg (#35) or placebo (#35) intraoperatively and at 24 hours. The primary end point was need for hemodialysis during the first week posttransplant. Assessments of glomerular filtration rate and dialysis dependence were accomplished. Complications and safety of therapy were recorded. Similar characteristics with no significant differences in cold-ischemia time or risk factors for DGF were seen. C1INH did not result in reduction of dialysis sessions at 1 week posttransplant, but significantly fewer dialysis sessions (P = .0232) were required 2 to 4 weeks posttransplant. Patients at highest risk for DGF (Kidney Donor Profile Index ≥85) benefited most from C1INH therapy. Significantly better renal function was seen at 1 year in C1INH patients (P = .006). No significant adverse events were noted with C1INH. Although the primary end point was not met, significant reductions in need for dialysis and improvements in long-term allograft function were seen with C1INH treatment.

The role of complement inhibition in kidney transplantation.

INTRODUCTION AND BACKGROUND: The complement system which belongs to the innate immune system acts both as a first line of defence against various pathogens and as a guardian of host homeostasis. The role of complement has been recently highlighted in several aspects of kidney transplantation: ischaemia-reperfusion, antibody-mediated rejection and native kidney disease recurrence. SOURCES OF DATA: Experimental data, availability of complement-blocking molecules (mainly the anti-C5 monoclonal antibody, eculizumab) and several trials in human kidney transplant recipients has led to some areas of agreement and some disappointment. AREAS OF AGREEMENT AND CONTROVERSIES: So far, eculizumab has shown great efficacy in treatment and prevention of atypical haemolytic and uraemic syndrome, some efficacy in the prevention of antibody-mediated and so far no efficacy in the prevention of delayed graft function. GROWING POINTS: Among the numerous potentially available drugs potentially interfering with complement, recent focus has been made on C1 blockers in the setting of antibody-mediated rejection with promising results. AREAS TIMELY FOR DEVELOPING RESEARCH: Complement is now recognized as a major player in transplant immunology, several targets are going to be tested to define precisely which ones may be potentially useful in clinical practice.

Early post-transplant conversion from tacrolimus to belatacept for prolonged delayed graft function improves renal function in kidney transplant recipients.

Prolonged delayed graft function (DGF) in kidney transplant recipients imparts a risk of poor allograft function; tacrolimus may be detrimental in this setting. We conducted a retrospective single center analysis of the first 20 patients converted to belatacept for prolonged DGF as part of a clinical protocol as a novel treatment strategy to treat prolonged DGF. Prior to conversion, patients underwent an allograft biopsy to rule out rejection and confirm tubular injury. The primary outcome was the estimated glomerular filtration rate (eGFR) at 12 months post-transplant; secondary outcome was the change in eGFR 30 days post-belatacept conversion. At 1 year post-transplant, the mean eGFR was 54.2 (SD 19.2) mL/min/1.73 m2 . The mean eGFR on the day of belatacept conversion was 16 (SD 12.7) mL/min/1.73 m2 and rose to 43.1 (SD 15.8) mL/min/1.73 m2 30 days post-conversion (P<.0001). The acute rejection rate was 20% with 100% patient survival at 12 months post-transplant. There was one graft loss in the setting of an invasive Aspergillus infection that resulted in withdrawal of immunosuppression and transplant nephrectomy. Belatacept conversion for prolonged DGF is a novel treatment strategy that resulted in an improvement in eGFR. Additional follow-up is warranted to confirm the long-term benefits of this strategy.

SANGUINATE (PEGylated Carboxyhemoglobin Bovine): Mechanism of Action and Clinical Update.

Historically, blood substitutes were under development that would provide oxygen carrying capacity as well as fluid replacement for both trauma and surgical indications. Their development was halted by the inability of the products to deliver therapeutic amounts of oxygen targeted to hypoxic tissue as well as from the inherent toxicity of the molecules. This led to the concept of an oxygen therapeutic that would be targeted for indications caused by anemia/ischemia/hypoxia but would not exhibit the toxicity that plagued earlier products. The complex pathophysiology of diseases such as sickle cell and hemorrhagic stroke not only has hypoxia as a pivotal event but also includes inflammation and vasoconstriction that perpetuate the oxygen deprivation. There is a need for an effective therapeutic that addresses the multiple events of inflammation and oxygen deprivation. SANGUINATE acts as a dual mode carbon monoxide (CO) and oxygen delivery therapeutic. SANGUINATE is designed not only to treat hypoxia but also to act on concurrent pathologies such as inflammation and reperfusion injury. This expands the potential therapeutic utility of SANGUINATE beyond anemia into indications such as early brain injury and delayed kidney graft function, where inflammation plays a pivotal pathological role as well as in indications such as sickle cell disease where the inflammation and hypoxia contribute to the development of comorbidities such as vaso-occlusive crisis. Clinical trials in multiple indications are underway.

Protective Effects of L-Carnitine Against Delayed Graft Function in Kidney Transplant Recipients: A Pilot, Randomized, Double-Blinded, Placebo-Controlled Clinical Trial.

OBJECTIVE: Delayed graft function (DGF) is an early complication after deceased donor kidney transplantation with significant adverse effects on graft outcomes. Ischemia-reperfusion injury during transplantation is a major cause of DGF. Tissue concentrations of carnitine, an antioxidant and regulator of cellular energy supply, decrease in the kidney following ischemia-reperfusion insult. Based on promising animal data, this study evaluated the possible protective effect of L-carnitine against DGF. DESIGN: This study is a pilot, randomized, double-blind, placebo-controlled clinical trial that was conducted on kidney transplantation patients in kidney transplant ward of Imam Khomeini hospital complex affiliated to Tehran University of Medical Sciences, Tehran, Iran. SUBJECTS: Patients older than 14 years old undergoing their first kidney transplantation from a deceased donor were evaluated for eligibility to take part in this study. Fifty-six patients were randomly assigned to L-carnitine or placebo groups. INTERVENTION: During this trial, 3 g of oral L-carnitine or placebo was administered in 3 divided doses each day for 4 consecutive days starting the day before kidney transplantation (i.e., days -1, 0, 1, and 2). MAIN OUTCOME MEASURE: The need for dialysis within the first week after transplantation, serum creatinine and urine output were assessed daily. After hospital discharge, patients were followed for 3 months regarding organ function. RESULTS: DGF incidence did not differ between the L-carnitine and placebo groups (18.51% vs. 23.8%, respectively; P = .68). Total allograft failure within 3 months after kidney transplantation happened in 6 patients in the placebo and 1 patient in the L-carnitine group (P = .05). CONCLUSION: This study showed no protective effects of oral L-carnitine supplementation against DGF occurrence recipients; however, 3-month graft loss was lower in the L-carnitine supplemented group.

Belatacept Conversion in an HIV-Positive Kidney Transplant Recipient With Prolonged Delayed Graft Function.

We report an HIV-positive renal transplant recipient with delayed graft function who was converted from tacrolimus to belatacept in an attempt to improve renal function. The patient had kidney biopsies at 4 and 8 weeks posttransplant that revealed acute tubular necrosis and mild fibrosis. After 14 weeks of delayed function, belatacept was initiated and tacrolimus was weaned off. Shortly after discontinuing tacrolimus, renal function began to improve. The patient was able to discontinue dialysis 21 weeks posttransplant. HIV viral load was undetectable at last follow-up. To our knowledge, this is the first report of belatacept use in a patient with HIV.

Effect of an Early Switch to Belatacept Among Calcineurin Inhibitor-Intolerant Graft Recipients of Kidneys From Extended-Criteria Donors.

Transplant recipients receiving a kidney from an extended-criteria donor (ECD) are exposed to calcineurin inhibitor (CNI) nephrotoxicity, as demonstrated by severe delayed graft function and/or a low GFR. Belatacept is a nonnephrotoxic drug that is indicated as an alternative to CNIs. We reported 25 cases of conversion from a CNI to belatacept due to CNI intolerance within the first 6 mo after transplantation. The mean age of the recipients was 59 years, and 24 of 25 patients received ECD kidneys. At the date of the medication switch, 12 of 25 patients displayed a calculated GFR (cGFR) <15 mL/min, six patients remained on dialysis, and the biopsies showed evidence of acute tubular damage associated with severe vascular or tubulointerstitial chronic lesions. Three patients did not recover renal function, and three patients died during the follow-up period. Among the remaining patients, renal function improved: The cGFR was 18.28 ± 12.3 mL/min before the medication switch compared with 34.9 ± 14.5 mL/min at 1 year after conversion to belatacept (p = 0.002). Tolerance of and compliance with belatacept were good, and only one patient experienced acute rejection. Belatacept is an effective therapy that preserves renal function in kidney transplant patients who are intolerant of CNIs.

Eltrombopag after allogeneic haematopoietic cell transplantation in a case of poor graft function and systematic review of the literature.

BACKGROUND: Late graft failure after allogeneic haematopoietic cell transplantation (HCT) can result from the failed engraftment of long-term engrafting cells. The use of thrombopoietin (TPO) receptor agonists (TRA) has been extensively studied and remains an important component of experimental ex vivo stem cell expansion protocols, but its use in allogeneic transplantation is still evolving. METHODS: We describe the use of eltrombopag, a TRA, to stimulate the rescue of late graft failure in a patient following allogeneic HCT, and we performed a systematic review of published studies describing the use of TRAs following allogeneic transplantation. RESULTS: A total of eight publications were identified from our systematic search and included observational case studies (five studies, total of seven patients) that primarily addressed ITP or isolated thrombocytopenia at various time points after allogeneic HCT and prospective clinical trials (three studies, total of 177 patients with 95 patients receiving TRAs). No studies reported specifically on the use of TRAs for the treatment of trilineage graft failure as a means of in vivo stem cell expansion. The use of TRAs following allogeneic HCT appears safe and promising. CONCLUSION: The use of eltrombopag or other TRAs to treat poor graft function after allogeneic HCT is intriguing and warrants further study.

Thrombin may modulate dendritic cell activation in kidney transplant recipients with delayed graft function.

BACKGROUND: Coagulation and complement activation represent key events in ischaemia-reperfusion-induced renal injury leading to delayed graft function (DGF). It is still unclear whether the coagulation cascade may also influence the acquired immunity. The aim of the present study was to investigate the expression of protease-activated receptor 1 (PAR-1), the main thrombin receptor, by graft-infiltrating dendritic cells (DCs), and to evaluate whether thrombin may influence DCs complement production and T-cell response. METHODS: PAR-1, BDCA1, CD11c, BDCA4, fibrin, C3c and C3d protein expression were evaluated by confocal microscopy. Cultured DCs were obtained incubating monocytes (Ms) with IL-4 and GM-CSF. DC maturation was obtained with IFN-g+sCD40L or with a cytokine cocktail (IL-1b, TNF-a, PGE2, IL-6). PAR1 protein expression on cultured DC was evaluated by flow-cytometry. Complement receptors, C3, IL12/IL17p40 and IL10 gene expression was evaluated by qPCR. T cell phenotype was evaluated by ELISPOT. IFN-g protein presence was evaluated by ELISA. RESULTS: PAR-1 was expressed by infiltrating myeloid DCs in pre-transplant and in DGF biopsies. In DGF grafts, myeloid DCs localized within fibrin and C3d deposits and expressed C3c. In vitro, PAR-1 protein expression was increased in monocyte-derived immature DCs and in cytokine-induced mature DCs compared to monocytes. PAR-1 activation caused a time-dependent increase in C3 and complement receptors expression. Moreover, thrombin stimulation, while reducing interleukin-10 mRNA abundance, induced interleukin-12/IL-17 p40 gene expression, and promoted C3a ability to increase interleukin-12/IL17 mRNA abundance. These changes in the DCs' cytokine pattern influenced their ability to induce interferon-g production by T cells, suggesting the activation of a T helper-1 bias. CONCLUSION: Our data suggest that PAR-1 is expressed by DCs in DGF grafts and its activation may induce complement production and a Th1 bias. This observation suggests a potential pathogenic link between DGF and acquired allo-response leading to graft damage.

Outcomes of standard dose EC-MPS with low exposure to CsA in DCD renal transplantation recipients with DGF.

AIMS: The lower limit of exposure to cyclosporine A (CsA) has not yet been established in donation after cardiac death (DCD) renal transplantation recipients with delayed graft function (DGF) receiving enteric-coated mycophenolate sodium (EC-MPS) therapy. Stable and adequate mycophenolic acid (MPA) dosing may facilitate lower CsA exposure after DCD renal transplantation in recipients with DGF without compromising safety. METHODS: A 12-month, single-centre open-label prospective trial was performed in our centre. According to their DGF risk index using the previous DGF prediction models, we divided up the patients on oral CsA into either a DGF group (n = 26) and no DGF group (n = 48). All of the patients initially received the standard EC-MPS dosing (1440 mg/day). The initial dose of CsA in the low risk of DGF group was 4.5 mg/kg/day and in the high risk of DGF group was 2.5 mg/kg/day. Efficacy parameters, safety and tolerability were assessed over a 12-month study period. RESULTS: The incidence of DGF was 18.5% in the 162 DCD recipients. Between the DGF group and the no DGF group, the 1-year patient survival and graft survival were not significantly different. The incidence of BPAR was higher in the DGF group (26.9% vs. 8.3%, p = 0.032). Most patients in the DGF group had recovery of renal function after 1 month. The adverse events between the two groups were not significantly different. The daily EC-MPS doses of the DGF group were significantly higher than the no DGF group before the 6-month follow-up period. There were no significant differences between the two groups regarding the mean AUC levels during the follow-up period. CONCLUSIONS: These results show that low expose CsA with standard dosing of EC-MPS and thymoglobulin was efficacious, safe and well-tolerated in DCD renal transplant recipients with DGF in China. Furthermore, stable and adequate MPA exposure helped to reduce the dose of and exposure to CsA. Thus, this may lead to less-induced nephrotoxicity and better renal function recovery.

Tauroursodeoxycholic acid and 4-phenyl butyric acid alleviate endoplasmic reticulum stress and improve prognosis of donation after cardiac death liver transplantation in rats.

BACKGROUND: Inevitable warm ischemia time before organ procurement aggravates posttransplantation ischemia-reperfusion injury. Endoplasmic reticulum (ER) stress is involved in ischemia-reperfusion injury, but its role in donation after cardiac death (DCD) liver transplantation is not clear and the effect of ER stress inhibitors, tauroursodeoxycholic acid (TUDCA) and 4-phenyl butyric acid (PBA), on the prognosis of recipient of DCD liver transplantation remains unclear. METHODS: Male Sprague-Dawley rats (8-10 weeks) were randomly divided into the control group: liver grafts without warm ischemia were implanted; DCD group: warm ischemia time of the liver grafts was 60 minutes; TUDCA and PBA groups: based on the DCD group, donors were intraperitoneally injected with TUDCA or PBA 30 minutes before the organ procurements. Serum aminotransferase levels, oxidative stress activation and expression of ER stress signal molecules were evaluated. Pathological examinations were performed. The survivals of the recipients in each group were compared for 14 days. RESULTS: Compared with the control group, DCD rats had significantly higher levels of serum aminotransferase at 6 hours, 1 day and 3 days after operation (P<0.01, 0.01 and 0.05, respectively) and oxidative indices (P<0.01 for both malondialdehyde and 8-hydroxy deoxyguanosine), more severe liver damage (P<0.01) and up-regulated ER stress signal expressions (P<0.01 for GRP78, phos-eIF2alpha1, CHOP, ATF-4, ATF-6, PERK, XBP-1 and pro-caspase-12). All recipients died within 3 days after liver transplantation. Administration of TUDCA or PBA significantly decreased aminotransferase levels (P<0.05), increased superoxide dismutase activities (P<0.01), alleviated liver damage (P<0.01), down-regulated ER stress signal expressions (P<0.01) and improved postoperative survivals (P<0.01). CONCLUSIONS: ER stress was involved with DCD liver transplantation in rats. Preoperative intraperitoneally injection of TUDCA or PBA protected ER stress and improved prognosis.

The positive efficacy of dexmedetomidine on the clinical outcomes of patients undergoing renal transplantation: evidence from meta-analysis.

INTRODUCTION: Whether dexmedetomidine (DEX), an anesthetic adjuvant, can improve renal transplant outcomes is not clear. METHODS: We systematically identified clinical trials in which DEX was administered in renal transplantation (RT). On November 1, 2022, we searched The Cochrane Library, MEDLINE, EMBASE and https://www. CLINICALTRIALS: gov/. The main outcomes were delayed graft function and acute rejection. RESULTS: A total of seven studies were included in the meta-analysis. The results showed that compared with the control, DEX significantly reduced the occurrence of delayed graft function (RR 0.76; 95% CI 0.60-0.98), short-term serum creatinine [postoperative day (POD) 2: (MD -22.82; 95% CI -42.01 - -3.64)] and blood urea nitrogen [POD 2: (MD -2.90; 95% CI -5.10 - -0.70); POD 3: (MD 2.07; 95% CI -4.12 - -0.02)] levels, postoperative morphine consumption (MD -4.27; 95% CI -5.92 - -2.61) and the length of hospital stay (MD -0.85; 95% CI-1.47 - -0.23). However, DEX did not reduce the risk of postoperative acute rejection (RR 0.75; 95% CI 0.45-1.23). The results of the subgroup analysis showed that country type, donor type, and average age had a certain impact on the role of DEX. CONCLUSIONS: DEX may improve the short-term clinical outcome of RT and shorten the length of hospital stay of patients.

Increased CMV disease and "severe" BK viremia with belatacept vs. sirolimus three-drug maintenance immunosuppression.

OBJECTIVES: Belatacept may provide benefit in delayed graft function, but its association with infectious complications is understudied. We aim to assess the incidence of CMV and BK viremia in patients treated with sirolimus or belatacept as part of a three-drug immunosuppression regimen after kidney transplantation. MATERIALS AND METHODS: Kidney transplant recipients from 01/01/2015 to 10/01/2021 were retrospectively reviewed. Maintenance immunosuppression was either tacrolimus, mycophenolate and sirolimus (B0) or tacrolimus, mycophenolate, and belatacept (5.0 mg/kg monthly) (B1). Primary outcomes of interest were BK and CMV viremia which were followed until the end of the study period. Secondary outcomes included graft function (serum creatinine, eGFR) and acute rejection through 12 months. RESULTS: Belatacept was initiated in patients with a higher mean kidney donor profile index (B0:0.36 vs. B1:0.44, p = .02) with more delayed graft function (B0:6.1% vs. B1:26.1%, p < .001). Belatacept therapy was associated with more "severe" CMV viremia >25,000 copies/mL (B0:1.2% vs. B1:5.9%, p = .016) and CMV disease (B0:0.41% vs. B1:4.2%, p = .015). However, there was no difference in the overall incidence of CMV viremia >200 IU/mL (B0:9.4% vs. B1:13.5%, p = .28). There was no difference in the incidence of BK viremia >200 IU/mL (B0:29.7% vs. B1:31.1%, p = .78) or BK-associated nephropathy (B0:2.4% vs. B1:1.7%, p = .58), but belatacept was associated with "severe" BK viremia, defined as >10,000 IU/mL (B0:13.0% vs. B1:21.8%, p = .03). The mean serum Cr was significantly higher with belatacept therapy at 1-year follow up (B0:1.24 mg/dL vs. B1:1.43 mg/dL, p = .003). Biopsy-proven acute rejection (B0:1.2% vs. B1:2.6%, p = .35) and graft loss (B0:1.2% vs. B1:0.84%, p = .81) were comparable at 12 months. CONCLUSIONS: Belatacept therapy was associated with an increased risk of CMV disease and "severe" CMV and BK viremia. However, this regimen did not increase the overall incidence of infection and facilitated comparable acute rejection and graft loss at 12-month follow up.

Tetrahydrobiopterin ameliorates hepatic ischemia-reperfusion Injury by coupling with eNOS in mice.

BACKGROUND: In the liver, eNOS appears to have a central role in protecting against ischemia/reperfusion (I/R) injury. We hypothesized that tetrahydrobiopterin (BH4) would protect livers subjected to I/R injury by coupling with eNOS. METHODS: Chinese Kun Ming (KM) mice were subjected to 60 min of 70% hepatic ischemia 30 min after the administration of BH4 or saline. After reperfusion, survival was evaluated. The histologic appearance and ALT, BH4, nitrite/nitrate, 8-isoprostane, and eNOS protein expression levels were measured. RESULTS: The 1-wk survival rate was 66.67% in the BH4 group and 33.33% in the saline group. The serum ALT values in the BH4 group 1, 3, 6, 12, and 24 h after reperfusion were significantly lower than those of the saline group. A histologic examination of the liver revealed only a small necrotic area in the BH4 group as opposed to massive necrosis in the saline group. The percentage values of the hepatic necrotic area 24 h after reperfusion were significantly less for the BH4 group than for the saline group. The nitrite/nitrate levels in the liver tissue were significantly increased by ~2-fold in the BH4 group compared with the saline group. The free radical indicator 8-isoprostane was reduced approximately 50% in the BH4 group compared with the saline group. Western blotting showed that the level of eNOS protein between the groups was not significantly different. CONCLUSIONS: BH4 significantly improved the survival rate by reducing liver failure. This was supported by the histologic findings, and the mechanism was explored. According to the results, we suggest that BH4 prevents liver damage from I/R injury by attenuating reactive oxygen species and increasing NO synthesis, and might provide a novel and promising therapeutic option for preventing I/R injury.

Kidney transplant outcomes are related to tacrolimus, mycophenolic acid and prednisolone exposure in the first week.

This study analysed associations between tacrolimus, mycophenolic acid (MPA) and prednisolone exposures on day 4 and month 1 post kidney transplant and clinical outcomes. Area under the concentration-time curve (AUC) for each drug was estimated using validated multiple regression-derived limited sampling strategies. Multivariate logistic regression was used to associate drug exposure with clinical outcomes. One hundred and twenty subjects were studied. Between-subject variability in dose-adjusted exposure to each medication was high. Both day 4 tacrolimus and MPA exposures were independently predictive of delayed graft function (2.6 change in odds for a standard deviation (SD) increase in tacrolimus AUC(0-12) , P = 0.02; 0.23 change in odds for a SD increase in MPA AUC(0-12) , P = 0.02). Both day 4 MPA and total prednisolone exposures were independently predictive of rejection (0.20 change in odds for a SD increase in MPA AUC(0-12) , P = 0.04; 0.40 change in odds for a SD increase in total prednisolone AUC(0-6) , P = 0.03). Lowest tertile exposure to all three immunosuppressant medications imposed significantly higher odds of rejection [adjusted odds ratio 34.2 (95% CI 4.1, 284.4), P = 0.001]. This study highlights the importance of achieving early target exposure and suggests a potential role for individualized initial dosing or early therapeutic monitoring of all three immunosuppressive agents.

[Vitamin D in the treatment of cardiorenal syndrome in patients with chronic nephropathy].

AIM: To determine place of vitamin D in prevention and treatment of cardiorenal syndrome (CRS) and chronic allograft nephropathy (CAN) in the aspect of myocardial and renal reparation. METHODS AND MATERIAL: In Russia and the Netherlands we included in a randomized placebo controlled study 120 vitamin D deficient [25(OH) vitamin D<40 mol/l] recipients of asystolic and cadaveric donors. Patients were divided in 4 groups: paricalcitol (2-4 g/day) group (n=28), calcitriol (1-6 g/day orally) group (n=28), diet (1200-1800 IU/day of vitamin D with multivitamins and from foodstuffs) group (n=26), placebo with diet control group (n=27). RESULTS: After 180 days degree of CAN according to the Banff classification was 1.24 and 1.22 in paricalcitol and calcitriol groups, respectively, compared with 1.43 and 1.68 in diet and placebo groups, respectively (p<0.05). Glomerular filtration rate (GFR) changed from 46.7 to 84.4, 81.4, 76.8, and 54.5 ml/min/1.73 m3 in paricalcitol, calcitriol, diet and placebo groups, respectively. Fluorescence activated cell scanning (FACS) analysis allowed to detect quantitative induction of SP+ cells amounting 7.4, 2.9 and 1.2%; 7.2, 2.7; and 1.1%; 6.1, 2.9 and 1.2%; 9.3, 1.3 and 0.7% of peripheral blood progenitors, renal epithelial cells, and cardiomyocytes in paricalcitol, calcitriol, diet and placebo groups, respectively. Levels of CD133, CD34, CD73, and CD105 were significantly elevated in patients of paricalcitol (median 161, range 0-834 copies), calcitriol (163, 0-721), and diet (119, 0-401) groups, compared with the placebo group (0,0-41), p<0.01. Level of nuclear vitamin D receptor (VDR) protein in renal tissue homogenizate and myocardium achieved 584, 599, 478, and 333 mole VRD/mg and 801, 715, 654, and 389 Φmole VRD/mg of protein in paricalcitol, calcitriol, diet and placebo groups, respectively (p<0.01). Circulating progenitor stem cells demonstrated comparatively high level of VDR expression--529, 526, 401, and 211 mole VRD/mg in CD133, CD34 cells; 432, 414, 303, and 290 mole VRD/mg in CD73, CD105 cells; 549, 558, 442, and 302 φmole VRD/mg in SP+ cells in paricalcitol, calcitriol, diet and placebo groups, respectively (p<0.05). Hypercalcemia was detected in 4(14%) patients in calcitriol group (p<0.001). Under influence of antihypertensive therapy arterial pressure decreased after transplantation from 180/101 to 143/87, 141/94, 147,102, and 165/101 mm Hg in paricalcitol, calcitriol, diet and placebo groups, respectively (p<0.01). NYHA heart failure functional class changed from 2.3 to 1.8, 1.9, 1.9, and 2.5 in paricalcitol, calcitriol, diet and placebo groups, respectively (p<0.01). In 6 months after transplantation average CCS scores were 533 (0-998), 611 (0-1712), 524 (122-1278) and 990 (120-1800) cells in paricalcitol, calcitriol, diet and placebo groups, respectively (p<0.05). CONCLUSIONS: Vitamin D is an effective mean of prevention and treatment of CRS and CAN, stimulator of reparation of renal and myocardial tissues. Optimal for wide clinical practice is the use of active vitamin D analog paricalcitol (2-4 g/day) as well as special diet with multivitamins (up to 1800 IU of cholecalciferol).

A pilot study evaluating GSK1070806 inhibition of interleukin-18 in renal transplant delayed graft function.

INTRODUCTION: Delayed graft function (DGF) following renal transplantation is a manifestation of acute kidney injury (AKI) leading to poor long-term outcome. Current treatments have limited effectiveness in preventing DGF. Interleukin-18 (IL18), a biomarker of AKI, induces interferon-γ expression and immune activation. GSK1070806, an anti-IL18 monoclonal antibody, neutralizes activated (mature) IL18 released from damaged cells following inflammasome activation. This phase IIa, single-arm trial assessed the effect of a single dose of GSK1070806 on DGF occurrence post donation after circulatory death (DCD) kidney transplantation. METHODS: The 3 mg/kg intravenous dose was selected based on prior studies and physiologically based pharmacokinetic (PBPK) modeling, indicating the high likelihood of a rapid and high level of IL18 target engagement when administered prior to kidney allograft reperfusion. Utilization of a Bayesian sequential design with a background standard-of-care DGF rate of 50% based on literature, and confirmed via extensive registry data analyses, enabled a statistical efficacy assessment with a minimal sample size. The primary endpoint was DGF frequency, defined as dialysis requirement ≤7 days post transplantation (except for hyperkalemia). Secondary endpoints included safety, pharmacokinetics and pharmacodynamic biomarkers. RESULTS: GSK1070806 administration was associated with IL18-GSK1070806 complex detection and increased total serum IL18 levels due to IL18 half-life prolongation induced by GSK1070806 binding. Interferon-γ-induced chemokine levels declined or remained unchanged in most patients. Although the study was concluded prior to the Bayesian-defined stopping point, 4/7 enrolled patients (57%) had DGF, exceeding the 50% standard-of-care rate, and an additional two patients, although not reaching the protocol-defined DGF definition, demonstrated poor graft function. Six of seven patients experienced serious adverse events (SAEs), including two treatment-related SAEs. CONCLUSION: Overall, using a Bayesian design and extensive PBPK dose modeling with only a small sample size, it was deemed unlikely that GSK1070806 would be efficacious in preventing DGF in the enrolled DCD transplant population. TRIAL REGISTRATION: NCT02723786.

Recombinant apoptosis inhibitor of macrophage protein reduces delayed graft function in a murine model of kidney transplantation.

Reperfusion injury following cold and warm ischemia (IRI) is unavoidable during kidney transplantation and contributes to delayed graft function (DGF) and premature graft loss. Death of tubular epithelial cells (TECs) by necrosis during IRI releases pro-inflammatory mediators (e.g. HMGB1), propagating further inflammation (necroinflammation) and tissue damage. Kidney Injury Molecule-1 (KIM-1) is a phagocytic receptor upregulated on proximal TECs during acute kidney injury. We have previously shown that renal KIM-1 protects the graft against transplant associated IRI by enabling TECs to clear apoptotic and necrotic cells, and that recognition of necrotic cells by KIM-1 is augmented in the presence of the opsonin, apoptosis inhibitor of macrophages (AIM). Here, we tested whether recombinant AIM (rAIM) could be used to mitigate transplant associated IRI. We administered rAIM or vehicle control to nephrectomised B6 mice transplanted with a single B6 donor kidney. Compared to grafts in vehicle-treated recipients, grafts from rAIM-treated mice exhibited significantly less renal dysfunction, tubular cell death, tissue damage, tubular obstruction, as well as local and systemic inflammation. Both mouse and human rAIM enhanced the clearance of necrotic cells by murine and human TECs, respectively in vitro. These data support testing of rAIM as a potential therapeutic agent to reduce DGF following kidney transplantation.