BackgroundDelayed graft function (DGF) is traditionally defined as the requirement for dialysis during the first week after transplantation. DGF is a common complication of renal transplantation, and it negatively affects short- and long-term graft outcomes. Ischaemia reperfusion injury (IRI) is a prime contributor to the development of DGF. It is well established that complement system activation plays a pivotal role in the pathogenesis of IRI. Mirococept is a highly effective complement inhibitor that can be administered ex vivo to the donor kidney just before transplantation. Preclinical and clinical evidence suggests that Mirococept inhibits inflammatory responses that follow IRI. The EMPIRIKAL trial (REC 12/LO/1334) aims to evaluate the efficacy of Mirococept in reducing the incidence of DGF in cadaveric renal transplantation.Methods/designEMPIRIKAL is a multicentre double-blind randomised case-control trial designed to test the superiority of Mirococept in the prevention of DGF in cadaveric renal allografts, as compared to standard cold perfusion fluid (Soltran®). Patients will be randomised to Mirococept or placebo (Pbo) and will be enrolled in cohorts of N = 80 with a maximum number of 7 cohorts. The first cohort will be randomised to 10 mg of Mirococept or Pbo. After the completion of each cohort, an interim analysis will be carried out in order to evaluate the dose allocation for the next cohort (possible doses: 5–25 mg). Immunosuppression therapy, antibiotic and antiviral prophylaxis will be administered as per local centre protocols. The enrolment will take approximately 24 months, and patients will be followed for 12 months. The primary endpoint is DGF, defined as the requirement for dialysis during the first week after transplantation. Secondary endpoints include duration of DGF, functional DGF, renal function at 12 months, acute rejection episodes at 6 and 12 months, primary non-function and time of hospital stay on first admission and in the first year following transplant. Safety evaluation will include the monitoring of laboratory data and the recording of all adverse events.DiscussionThe EMPIRIKAL trial is the first study to evaluate the efficacy of an ex vivo administered complement inhibitor (Mirococept) in preventing DGF in cadaveric human renal transplantation. Mirococept has a unique ‘cytotopic’ property that permits its retention in the organ microvasculature.Trial registrationISRCTN registry, ISRCTN49958194. Registered on 3 August 2012.Electronic supplementary materialThe online version of this article (doi:10.1186/s13063-017-1972-x) contains supplementary material, which is available to authorized users.
Acute kidney injury (AKI) is a common complication in cirrhotic patients. Serum creatinine is a poor biomarker for detection of renal impairment in cirrhotic patients. This study aimed to evaluate urinary neutrophil gelatinase-associated lipocalin (NGAL) and urinary interleukin-18 (IL-18) as early biomarkers of acute kidney injury in cirrhotic patients. 160 patients with cirrhosis admitted to the Liver Units at Zagazig University Hospitals were classified into three groups: (I) nonascitic patients, (II) ascitic patients without renal impairment, and (III) ascitic patients with renal impairment. Patients with renal impairment were further divided into four subgroups: [A] prerenal azotemia, [B] chronic kidney disease (CKD), [C] hepatorenal syndrome (HRS), and [D] acute tubular necrosis (ATN). Significant elevation of both urinary NGAL and urinary IL-18 in cirrhotic patients with renal impairment especially in patients with ATN was observed. Urinary NGAL and urinary IL-18 have the ability to differentiate between AKI types in patients with cirrhosis. This could improve risk stratification for patients admitted to the hospital with cirrhosis, perhaps leading to early ICU admission, transplant evaluation, and prompt initiation of HRS therapy and early management of AKI.
Cardiovascular disease is the leading cause of morbidity and mortality in patients with chronic kidney disease (CKD). The carotid intima-media thickness (CIMT) and arterial stiffness are useful markers of subclinical atherosclerosis and significantly correlate with various metabolic risk factors. Chemerin is one of the adipokines that may represent a link between obesity and inflammation and may be a potential candidate playing a role in the pathogenesis of atherosclerosis and cardiovascular complications. Therefore, we studied the relationship of chemerin levels with atherosclerosis as measured by CIMT in diabetic CKD patients, either predialysis or on hemodialysis (HD). In addition, we studied its correlation with other cardiovascular risk factors such as interleukin-6 (IL-6) and insulin resistance (IR). Fifty-eight patients were enrolled in the study; 23 patients with CKD (11 are diabetic) on conservative treatment and 35 (18 are diabetic) on maintenance HD. Serum concentrations of chemerin and IL-6 were determined by ELISA. All participants underwent measurements of CIMT by highresolution ultrasonography. A stepwise increase in serum chemerin levels was found depending on the glomerular filtration rate: 286.6 ± 10.02 ng/mL in the control group, 332.1 ± 21.54 ng/mL in the predialysis group, and 355.7 ± 20 ng/mL in the HD group. A significant rise of serum chemerin level was observed in diabetic CKD patients either on conservative therapy or on HD when compared with nondiabetic CKD patients. Moreover, there was a significant difference in serum levels of chemerin, IL-6, CIMT, serum insulin, and homeostasis model assessment of IR (HOMA-IR) between diabetic and nondiabetic patients in both groups. Chemerin showed a significant positive correlation with HOMA-IR, serum insulin, and C-reactive protein. In conclusion, serum chemerin level was found to be an independent predictive marker of the presence of atherosclerosis in patients with CKD either on conservative treatment or on HD.
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.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.