Delayed Graft Dysfunction Research Articles

ClinCirc identifies alterations of the circadian peripheral oscillator in critical care patients.

BackgroundAssessing circadian rhythmicity from infrequently sampled data is challenging; however, these types of data are often encountered when measuring circadian transcripts in hospitalized patients.MethodsWe present ClinCirc. This method combines 2 existing mathematical methods (Lomb-Scargle periodogram and cosinor) sequentially and is designed to measure circadian oscillations from infrequently sampled clinical data. The accuracy of this method was compared against 9 other methods using simulated and frequently sampled biological data. ClinCirc was then evaluated in 13 intensive care unit (ICU) patients as well as in a separate cohort of 29 kidney-transplant recipients. Finally, the consequences of circadian alterations were investigated in a retrospective cohort of 726 kidney-transplant recipients.ResultsClinCirc had comparable performance to existing methods for analyzing simulated data or clock transcript expression of healthy volunteers. It had improved accuracy compared with the cosinor method in evaluating circadian parameters in PER2:luc cell lines. In ICU patients, it was the only method investigated to suggest that loss of circadian oscillations in the peripheral oscillator was associated with inflammation, a feature widely reported in animal models. Additionally, ClinCirc was able to detect other circadian alterations, including a phase shift following kidney transplantation that was associated with the administration of glucocorticoids. This phase shift could explain why a significant complication of kidney transplantation (delayed graft dysfunction) oscillates according to the time of day kidney transplantation is performed.ConclusionClinCirc analysis of the peripheral oscillator reveals important clinical associations in hospitalized patients.FundingUK Research and Innovation (UKRI), National Institute of Health Research (NIHR), Engineering and Physical Sciences Research Council (EPSRC), National Institute on Academic Anaesthesia (NIAA), Asthma+Lung UK, Kidneys for Life.

The Role of Platelet-Lymphocyte Ratio and Neutrophil-Lymphocyte Ratio in Predicting the Delayed Graft Function in Pediatric Renal Transplant Patients.

Delayed graft function is a common adverse outcome after renal transplant. Attempts for early prediction and prevention of delayed graft function are often challenging and misleading. Herein, we investigated for the first time the correlation between delayed graft function and preoperative noninvasive hematologic parameters to predict the possible adverse outcomes for renal transplant in pediatric patients. In this study, preoperative hematologic parameters of 51 pediatric renal transplant recipients followed between 2015 and 2021 were analyzed retrospectively. The selected 16 renal transplant patients with delayed graft function and 35 patients without delayed graft function had no concomitant comorbidities. The cutoff values for platelet-to-lymphocyte ratio of <5 and neutrophilto- lymphocyte ratio of <175 were considered low. We retrospectively evaluated a total of 51 (male/female, 33/18) pediatric kidney transplant recipients with a median age of 12 (interquartile range, 8-18) years. Median level of circulating lymphocytes was significantly higher in patients with delayed graft function compared with patients without delayed graft function (2 vs 1, P = .040). The preoperative low values for platelet-to-lymphocyte ratio and neutrophil-to-lymphocyte ratio were more prevalent in recipients who developed delayed graft function versus those who did not develop delayed graft function (68.8% vs 31.4% [P = .014] and 68.8% vs 34.3% [P = .023], respectively). Pretransplant low platelet-to-lymphocyte ratio and neutrophil-to-lymphocyte were associated with increased number of delayed graft dysfunction. These novels and noninvasive inflammatory biomarkers may contribute to an early prediction of delayed graft function in pediatric kidney transplant recipients.

Robotic-assisted kidney transplant: a single center experience with median follow-up of 2.8years.

The main aim of the paper is to report a single-centre experience with RAKT, focusing on surgical, perioperative and functional outcomes at a median follow-up of 2.8years. Data of 26 RAKT patients was prospectively collected from December 2014 to February 2019 with follow-up of up to 55months. All donors were done laparoscopically. We followed Vattikuti-Medanta technique with modification of using pfannenstiel incision instead of Gelpoint and patient positioned in steep Trendelenburg position (30°) with leg split position. Hypothermia was maintained using a "modified graft hypothermia jacket". The engrafted kidney is oriented with the vessels being tagged with Prolene sutures. The mean BMI was 26.1 ± 4.7. The mean warm, cold and total ischemia times were 4.8 ± 1.1, 113.8 ± 20.9 and 118.7 ± 21.2min, respectively. Mean rewarming time was 62.5 ± 10min. The mean post-operative day (POD) 1, 3, 7, 30, 6months, 1 year and most recent creatinine was 3.4, 2.4, 1.8, 1.4,1.2, 1.2 and 1.69mg/dl. There was no case of delayed graft dysfunction (DGF) with graft survival of 1.8-55months. The mean GFR at POD 1, 1month and 1year was 24, 53.16 and 64.6. We had two intraoperative complications-one topsy turvy graft placement with anastomosis of donor ureter to native ureter and other had to be converted to open technique after anastomosis to control graft surface bleeding. Three postoperative complications-one patient has graft pyelonephritis which was managed conservatively with antibiotics. Two patients had lymphocele. One patient was managed with just aspiration while the other required laparoscopic de-roofing of the lymphocele. The mean hospital stay was 13.5 ± 3days. RAKT is feasible and safe only if performed by surgeons with appropriate background in robotic surgery and kidney transplantation after proper surgical training at experienced centres in the mid-term follow-up. Further studies need to confirm the long-term safety of RAKT.

DRAM is Involved in Hypoxia/Ischemia-Induced Autophagic Apoptosis in Hepatocytes.

Liver hypoxia/ischemia injury leads to acute liver injury, delayed graft dysfunction, and failure during liver transplantation. Previous studies showed that autophagy is involved in liver hypoxia/ischemia injury. Our and others’ studies have found that the damage-regulated autophagy modulator (DRAM) could induce the autophagic apoptosis. However, the role of DRAM regulating autophagy in liver hypoxia/ischemia injury remains unclear. The aim of this study was to determine whether DRAM is involved in oxygen-glucose deprivation (OGD)-induced hepatocyte autophagic apoptosis. Normal hepatocytes (HL-7702) were treated with OGD while Balb/c mice underwent surgery to induce 70% liver ischemia. To evaluate the role of DRAM in hypoxia/ischemia-induced hepatic injury, DRAM siRNA was used to knockdown DRAM expression in cultured hepatocytes and a recombinant adenovirus vector expressing DRAM was used to overexpress DRAM in cultured hepatocytes in vitro and in the liver in vivo. Hepatic injury was analyzed by histopathological methods and measurement of hepatocyte enzyme release. Cell apoptosis was analyzed by flow cytometry and TUNEL staining. Several autophagic biomarkers were observed by western blot analysis. OGD and 70% hepatic ischemia significantly induced cell autophagy, apoptosis and DRAM expression in hepatocytes in vitro and in vivo. OGD-induced autophagic apoptosis was inhibited by 3-Methyladenine (3-MA). OGD-induced injury and autophagy in HL-7702 cells were significantly attenuated by DRAM knockdown but aggravated by DRAM overexpression in vitro. Similarly, DRAM overexpression increased ischemia-induced liver injury and hepatic apoptosis in vivo. Our data demonstrate that hypoxia/ischemia induces hepatic injury through a DRAM-dependent autophagic apoptosis pathway. These data also suggest that DRAM plays an important role in ischemia-induced liver injury and hepatocyte apoptosis.

Static Cold Storage vs Ex Vivo Machine Perfusion: Results From a Comparative Study on Renal Transplant Outcome in a Controlled Donation After Circulatory Death Program

IntroductionWe aimed to evaluate if ex vivo machine perfusion could minimize the negative impact of cold ischemia on those renal grafts obtained from controlled donation after circulatory death (cDCD). Material and methodsProspective observational paired study of kidney transplants from cDCD performed in our center. The kidney from each pair preserved on ice was transplanted first within the first few hours following procurement, while the contralateral kidney was machine-perfused with a LifePort device (Organ Recovery Systems, Brussels, Belgium) and transplanted the following day. ResultsA total of 12 cDCDs were included. No differences were observed in delayed graft dysfunction or graft survival between the 2 groups. ConclusionThe use of ex vivo perfusion devices is simple and they do not require any large infrastructural or high economic investments, considering the fact that it allows a better selection of recipients and viable organs no longer need to be discarded because of prolonged warm ischemia times.

Impact of renal allograft nephrectomy on graft and patient survival following retransplantation: a systematic review and meta-analysis.

It is not clear whether renal allograft removal affects the outcome of renal retransplantation. This study aimed to determine the effect of allograft nephrectomy (AN) and no-AN (No AN) on renal retransplantation. A systematic review and meta-analysis were conducted using MEDLINE, Embase and the Cochrane Library. Observational studies or randomized controlled trials including renal retransplantation recipients with AN or No-AN were included. The primary outcomes were graft survival, patient survival, acute rejection (AR) and delayed graft dysfunction; the secondary outcomes were positive panel reactive antibody rate and serum creatinine level at 1 year after retransplantation, cold ischemia time and time of hemodialysis before recent transplantation. Pooled estimates of odds ratios (ORs) and the weighted mean difference for outcomes were calculated. A total of 13 studies divided into 20 trials including 1923 patients were analyzed. The No-AN group had a significantly higher 3-year graft survival rate {OR 0.48 [95% confidence interval (CI) 0.34-0.69], 10 studies, n = 1030} and 5-year graft survival rate [OR 0.65 (95% CI 0.44-0.97), 16 studies, n = 1878] than the AN group. The rates of 5-year patient survival [OR 1.82 (95% CI 1.14-2.90), 5 studies, n = 749], positive panel reactive antibody [OR 3.08 (95% CI 2.08-4.56), 12 studies, n = 1225], AR [OR 1.59 (95% CI 1.21-2.09), 15 studies, n = 1388] and delayed graft dysfunction [OR 1.66 (95% CI 1.20-2.03), 8 studies, n = 879] were all significantly higher in the AN group. Compared with the No-AN group, cold ischemia time was longer in the AN group [weighted mean difference 1.84 (95% CI 0.90-2.79), 7 studies, n = 919]. The rate of 1-year graft survival and 10-year graft survival, serum creatinine levels at 1 year after retransplantation and the time of hemodialysis before recent transplantation were similar between the AN and No-AN groups. We recommend allowing the failed graft to remain unless symptoms dictate the need for surgery. We also suggest donor-specific antibody dynamic monitoring and better human leukocyte antigen matching for improved long-term outcome of retransplantation.

Incidence and outcome of transplant renal artery stenosis: A single-center experience

Introduction: Transplant renal artery stenosis (TRAS) is a recognized, potentially curable cause of posttransplant arterial hypertension, allograft dysfunction, and graft loss. Aim: This study aims to study the incidence, clinical presentation, and outcome of TRAS in renal allograft recipients. Materials and Methods: This is a retrospective study done at the Institute of Nephrology, Madras Medical College, from January 2009 to November 2016. Demographic data, type of renal donor, and posttransplant evaluation including delayed graft dysfunction, acute rejection, cytomegalovirus status, blood pressure profile, and graft function were studied. Laboratory and investigation data including serum potassium, lipid profile, Doppler transplant renal artery, and angiogram were analyzed. Results: Five hundred and twenty-six renal allograft recipients were studied; 7 patients had TRAS (1.3%). The timeline of TRAS ranged from 3 to 30 months (median: 5 months) after transplant. Three patients (42%) presented with refractory hypertension, six (85%) patients developed allograft dysfunction, and three (42%) patients presented with anuria. All patients were treated with percutaneous transluminal angioplasty with stenting, and one patient had recurrent TRAS after 1 year and treated with balloon angioplasty and stenting. Among seven patients, three patients have normal graft function, three had chronic graft dysfunction, and one patient had graft loss. Conclusion: The incidence of TRAS in the study was 1.3%. Early detection and correction reduce patients morbidity and allograft dysfunction.

A Clinical Algorithm to Guide the Need for ERCP for Evaluation of Early Post Liver Transplant Cholestasis.

Introduction: Severe cholestasis after liver transplant can be due to delayed graft dysfunction, reperfusion injury or biliary complications. ERCP in the immediate post-transplant period has significant risks and limitations. Our aim was to develop a criteria using a combination of HIDA and clinical information to further guide biliary intervention in these patients. Methods: Among 806 liver transplants, 62 patients required further evaluation of biliary complications within 30 days of transplant by HIDA scan. 57 patients (5 excluded as they had bile leak), were included in the study. Serum total bilirubin levels within 48 hours of ERCP were used to determine the success of ERCP intervention. If there was a > 50% reduction in bilirubin levels within 48 hours of ERCP intervention, biliary duct obstruction was established and ERCP was considered successful. Results: 25 patients had normal HIDA, 32 patients had delayed uptake suggesting hepatocellular dysfunction. Among the 25 patients with normal HIDA, 12 had ERCP, 6 required stent. Among the 6 patients with stent only 2 had >50% decrease in serum bilirubin within 48 hours (true biliary duct obstruction =8%). Out of 32 patients with delayed uptake on HIDA scan, 22 had ERCP, and 14 required stents. 4 patients had >50% decrease in bilirubin within 48 hours ( true biliary obstruction =12.5%). 3 patients had >50% decrease in bilirubin 48 hours after ERCP even when no stent was placed. Hence, among the 57 patients with severe hyperbilirubinemia in the immediate post-operative period, only 11% had large duct obstruction as the etiology of the hyperbilirubinemia. More importantly, of the 34 ERCPs performed only 17% had biliary obstruction. The peak AST among patients with biliary obstruction was lower at 1005±364 IU/L (vs. 2522±3177 IU/L p value 0.035) and the peak bilirubin among patients with biliary obstruction was 24±11mg/ (vs. 18±10 mg/dl p value 0.02). On multivariate analysis, we found that patients having both AST < 1500 IU/L, a bilirubin >15 mg/dl have an odds ratio of 25.1 (p value 0.002, 95% CI 6-37) in predicting biliary obstruction and benefiting from ERCP. Conclusion: Normal HIDA scan along with combination of peak AST and peak bilirubin levels offer a valuable tool in identifying patients who will NOT benefit from ERCP. By using these parameters large number of ERCPs could be avoided in the immediate post-transplant period.

Trasplante renal en mayores de 60 años en un hospital de Colombia

IntroductionKidney transplantation is the treatment of choice in patients with end- stage renal disease. Renal transplantation in without fear of ethical conflicts is the best treatment option in the elderly. The objective is to describe the demographic and clinical characteristics of patients over 60 years old with at least one year of renal transplantation in a single center of Colombia. MethodsThis is a cohort study of patients over 60 years old from a single center in Bogota, Colombia. About 28 patients were analyzed between June 2004 and March 2012. ResultsThe mean age was 65 years old, with 89% males. The main cause of chronic kidney disease was diabetic nephropathy, followed by hypertensive nephrosclerosis. Most of them (96.4%) were deceased donor transplants with a mean age of 40 years old, cold ischemia time was 12hours and there was a mismatch of 3.25 (±1.29). Major comorbidities were hypertension, diabetes, dyslipidemia, and coronary arterial disease. Almost 17% had delayed graft dysfunction. Serum creatinine at 6 and 12 months was 1.27mg/dl (±0.31) and 1.25mg/dl (±0.33), respectively. Only 10% of patients had acute cellular rejection. Humoral rejections were not documented. The patient survival at 1 year was 89.7%, and death-censored graft survival was 96.4%. The most frequent cause of death was acute myocardial infarction. ConclusionsProper selection of kidney transplant recipients shows satisfactory results in survival, with low morbidity in patients older than 60 years.

Experiencia inicial de nefrectomía derecha de donante vivo por laparoscopia

Live donor nephrectomy laparoscopic technique is now standard. However, the right side is controversial because of the short length of the renal vein and the incidence of venous thrombosis. methodsA prospective study of patients live donors since May 2006 to September 2008 in which right nephrectomy was performed by laparoscopic live donor. The placement of trocares was usual and the transperitoneal approach. Incision was used for the extraction of Gibson. ResultsOf the 10 selected patients, 1 was excluded due to conversion to open technique. The criteria for lateralization were sex, renal volume and complex vascular anatomy. 6 patients had made back-table reconstruction surgery with prosthetic vascular due to the length of the renal vein. The average operative time was 158.3 minutes and the bleeding averaged 272 cc. Warm ischemia time averaged 3.2 minutes. The average hospital stay was 1.6 days. 1 recipient presenting delayed graft dysfunction ConclusionsLaparoscopic live donor right nephrectomy offers an excellent quality of graft, being a technique feasible and safe, maintaining the principle of leaving the best kidney donor.

Renal Apoptosis Following Carbon Dioxide Pneumoperitoneum in a Rat Model

Laparoscopically recruited kidneys regain normal function more slowly than laparotomy harvested organs for several possible reasons. We investigated the effects of CO(2) induced pneumoperitoneum on kidney function, as reflected by blood and urine creatinine levels, and its relation with renal cell apoptosis. CO(2) pneumoperitoneum was established in anesthetized Wistar male rats that were randomly allocated at 6 per group into 1 of 6 groups with an intraperitoneal pressure of 0 (control), 5, 8, 12, 15 or 18 mm Hg. Pressure was maintained for 60 minutes in all groups. Three additional groups were subjected to 30-minute pneumoperitoneum at 0, 12 and 18 mm Hg, respectively. The rats were kept alive for the ensuing 24 hours, after which blood and urine creatinine were analyzed and the abdominal organs were harvested. Various areas of the organs were analyzed for apoptotic cells using the TUNEL method. Cells were randomly counted in 10 eyeshots in 3 sections each using an ocular micrometer. Creatinine levels in blood and urine changed as pressure and pneumoperitoneum duration progressed. Isolated TUNEL positive nuclei were detected in the outer medulla and the cortex of control kidneys. There was a significantly higher number of TUNEL positive nuclei in the cortex and the medulla of all pressurized kidneys (p <0.05), which increased in parallel with increasing intraperitoneal pressure and pneumoperitoneum exposure time. The CO(2) pneumoperitoneum gradient and its duration affect renal function and induce apoptosis. This could be a mechanism involved in renal delayed graft dysfunction in recipients of laparoscopically harvested kidneys.

A primary screening of porcine endogenous retrovirus in some Chinese pigs

THE CONTINUING shortage of human organs for human transplantation has prompted consideration of animal organs and cells as an alternative tissue source, among which pigs are promising source of xenografts, including fetal pig pancreatic islet cells for insulin-dependent diabetes and neural cells for refractory parkinsonism, as well as extracorporeal pig kidney perfusion as a bridging strategy for kidney failure. Pig-to-human transplantation represents a distant xenotransplantation, that is associated with the immunological barriers of hyperacute rejection, acute vascular rejection, and delayed graft dysfunction. Xenozoonoses is also one of the major problems. Pig-tohuman zoonotic pathogens include bacteria, epiphytes, leptospira, viruses and parasites. Porcine endogenous retrovirus (PERV) is becoming a crucial obstacle for clinical trials. The risks of xenoinfection can be reduced or eliminated by using specific pathogen-free animal colonies, but this approach will not work for PERV because the genome of these viruses is in the germline of all pigs. The retroviral elements of PERV are inherited in Mendelian fashion after infection of germ cells during evolution. Some scientists warn that xenotransplantation would open a Pandora’s box that brings new disasters to humans. They call for a moratorium on clinical trials. They are worried that when porcine and human retroviruses coinfect a cell, they may recombine to form a chimeric virus, because recombination is common among cells infected by retroviruses, as shown by analysis of sequence data from a number of mammalian retroviruses. So, the existence of PERV and whether it can be communicated between pig and human to cause community infection are becoming hot topics. China has the richest sources of pig species in the world; it is able to provide limitless xenografts once pig-to-human xenotransplantation becomes possible. But first, we must screen for PERV infection among these pigs, which was the purpose of this study in three species.