Prospective Assessment of the Prevalence of Enter Hyperoxalosis in Kidney Transplant Candidates.

Enteric hyperoxalosis (EH) is an emerging cause of kidney transplantation (KT) dysfunction. We sought to determine the prevalence of EH and factors that affect plasma oxalate (POx) among at-risk KT candidates. Methods: We prospectively measured POx among KT candidates evaluated at our center from 2017 to 2020 with risk factors for EH namely bariatric surgery, inflammatory bowel disease, or cystic fibrosis. EH was defined by a POx ≥10 µmol/L. Period-prevalence of EH was calculated. We compared mean POx across 5 factors: underlying condition, chronic kidney disease (CKD) stage, dialysis modality, phosphate binder type, and body mass index. Results: Of 40 KT candidates screened, 23 had EH for a 4-y period prevalence of 58%. Mean POx was 21.6 ± 23.5 µmol/L ranging from 0 to 109.6 µmol/L. 40% of screened had POx >20 µmol/L. Sleeve gastrectomy was the most common underlying condition associated with EH. Mean POx did not differ by underlying condition (P = 0.27), CKD stage (P = 0.17), dialysis modality (P = 0.68), phosphate binder (P = 0.58), and body mass index (P = 0.56). Conclusions: Bariatric surgery and inflammatory bowel disease were associated with a high prevalence of EH among KT candidates. Contrary to prior studies, sleeve gastrectomy was also associated with hyperoxalosis in advanced CKD. POx concentrations observed in EH reached levels associated with tissue and potentially allograft deposition. Concentrations can be as high as that seen in primary hyperoxaluria. More studies are needed to assess if POx is indeed a modifiable factor affecting allograft function in patients with EH.

Thymol mitigates cadmium-induced behavioral and cognitive deficits by up-regulating hippocampal BDNF levels in rats.

Cadmium is a potent neurotoxin and induces adverse impact on brain function. Protective effects of monoterpenes on the CNS have been reported previously. The present study was designed to investigate the beneficial effect of thymol on cadmium-induced neurotoxicity. Rats were initially divided into 2 groups, vehicle control and thymol. Thymol (40mg/kg) was given orally for 14 days. Each group was subdivided into two groups (Vehicle control and Cadmium, Thymol and Thymol+Cadmium). Cadmium Chloride (5mg/kg) was given for last 3 days only to the groups assigned as Cadmium and Thymol+Cadmium. Behavioral parameters were assessed after 24h of last dose of cadmium. Brain sample were collected and BDNF was measured in hippocampus. The present study suggests that pre-administration of thymol provides a protective therapy against cadmium-induced intoxication by enhancing the brain BDNF levels and plasticity. Results further suggest that thymol not only ameliorates cadmium-induced learning and memory impairment but also reduced anxiety, motor incoordination and depression assessed by various behavioral tests. The study may provide a better apprehension of the neuroprotective role of thymol and highlighting its significance in the diet for human health particularly in cadmium intoxication.

Quercetin exhibits potent antioxidant activity, restores motor and non-motor deficits induced by rotenone toxicity.

The rotenone-induced animal model of Parkinson's disease (PD) has been used to investigate the pathogenesis of PD. Oxidative stress is one of the main contributors of neurodegeneration in PD. Flavonoids have the potential to modulate neuronal function and combat various neurodegenerative diseases. The pre- and post-supplementation of quercetin (50 mg/kg, p.o) was done in rats injected with rotenone (1.5 mg/kg, s.c). After the treatment, behavioral activities were monitored for motor activity, depression-like behavior, and cognitive changes. Rats were decapitated after behavioral analysis and the brain samples were dissected out for neurochemical and biochemical estimation. Results showed that supplementation of quercetin significantly (p<0.01) restored rotenone-induced motor and non-motor deficits (depression and cognitive impairments), enhanced antioxidant enzyme activities (p<0.01), and attenuated neurotransmitter alterations (p<0.01). It is suggested that quercetin supplementation improves neurotransmitter levels by mitigating oxidative stress via increasing antioxidant enzyme activity and hence improves motor activity, cognitive functions, and reduces depressive behavior. The results of the present study showed that quercetin pre-supplementation produced more significant results as compared to post-supplementation. These findings show that quercetin can be a potential therapeutic agent to reduce the risk and progression of PD.

Neuroprotective role of a monoterpene (thymol) on diazepam induced withdrawal symptoms in rats.

Benzodiazepine administration is known to be related to tolerance and a withdrawal syndrome on sudden cessation. Thymol possesses multiple biological properties especially in the pathogenesis of different brain disorders. However, to the best of our knowledge there is no study that relates the use of thymol to benzodiazepine induced withdrawal symptoms. Therefore the aim of the current study was to investigate the usefulness of thymol in the treatment of benzodiazepine withdrawal syndrome in rats. Animals were divided into four groups, thymol (40mg/kg/ml), diazepam (4 mg/kg), thymol + diazepam and vehicle control group. The treatment was given for 14 days and then suddenly ceased. After 24 h animals were tested in different behavioral paradigms such as physical signs for withdrawal, marble burying test, inverted screen test, elevated plus maze, passive avoidance test and open field activity. The results of the present study revealed that co-administration of thymol significantly reduced the withdrawal symptoms induced by diazepam. Our results further suggest that administration of thymol not only ameliorates rebound anxiety associated with diazepam withdrawal but also improves motor and memory impairment in rats.

A prospective multicenter pilot study of HIV-positive deceased donor to HIV-positive recipient kidney transplantation: HOPE in action.

HIV-positive donor to HIV-positive recipient (HIV D+/R+) transplantation is permitted in the United States under the HIV Organ Policy Equity Act. To explore safety and the risk attributable to an HIV+ donor, we performed a prospective multicenter pilot study comparing HIV D+/R+ vs HIV-negative donor to HIV+ recipient (HIV D-/R+) kidney transplantation (KT). From 3/2016 to 7/2019 at 14 centers, there were 75 HIV+ KTs: 25 D+ and 50 D- (22 recipients from D- with false positive HIV tests). Median follow-up was 1.7 years. There were no deaths nor differences in 1-year graft survival (91% D+ vs 92% D-, P = .9), 1-year mean estimated glomerular filtration rate (63 mL/min D+ vs 57 mL/min D-, P = .31), HIV breakthrough (4% D+ vs 6% D-, P > .99), infectious hospitalizations (28% vs 26%, P = .85), or opportunistic infections (16% vs 12%, P = .72). One-year rejection was higher for D+ recipients (50% vs 29%, HR: 1.83, 95% CI 0.84-3.95, P = .13) but did not reach statistical significance; rejection was lower with lymphocyte-depleting induction (21% vs 44%, HR: 0.33, 95% CI 0.21-0.87, P = .03). In this multicenter pilot study directly comparing HIV D+/R+ with HIV D-/R+ KT, overall transplant and HIV outcomes were excellent; a trend toward higher rejection with D+ raises concerns that merit further investigation.

Steroid-sparing maintenance immunosuppression is safe and effective after simultaneous liver-kidney transplantation.

Optimization of maintenance immunosuppression (mIS) regimens in the transplant recipient requires a balance between sufficient potency to prevent rejection and avoidance of excessive immunosuppression to prevent toxicities and complications. The optimal regimen after simultaneous liver-kidney (SLK) transplantation remains unclear, but small single-center reports have shown success with steroid-sparing regimens. We studied 4184 adult SLK recipients using the Scientific Registry of Transplant Recipients, from March 1, 2002, to February 28, 2017, on tacrolimus-based regimens at 1 year post-transplant. We determined the association between mIS regimen and mortality and graft failure using Cox proportional hazard models. The use of steroid-sparing regimens increased post-transplant, from 16.1% at discharge to 88.0% at 5 years. Using multi-level logistic regression modeling, we found center-level variation to be the major contributor to choice of mIS regimen (ICC 44.5%; 95% CI: 36.2%-53.0%). In multivariate analysis, use of a steroid-sparing regimen at 1 year was associated with a 21% decreased risk of mortality compared to steroid-containing regimens (aHR 0.79, P = .01) and 20% decreased risk of liver graft failure (aHR 0.80, P = .01), without differences in kidney graft loss risk (aHR 0.92, P = .6). Among SLK recipients, the use of a steroid-sparing regimen appears to be safe and effective without adverse effects on patient or graft survival.

Kidney retransplantation after anti-programmed cell death-1 (PD-1)-related allograft rejection.

In this report, we describe the first kidney retransplantation performed after anti-programmed cell death-1 (PD-1)-related allograft rejection. In 2014, we administered pembrolizumab (anti-PD-1) for ~9 months to a 57-year-old kidney transplant recipient with metastatic cutaneous squamous cell carcinoma (CSCC). The patient experienced both a complete antitumor response and T cell-mediated allograft rejection requiring reinitiation of hemodialysis. Four-and-a-half years after initiating pembrolizumab, the patient remained without evidence of CSCC relapse and received a kidney transplant from a living-unrelated donor. Ten-and-a-half months after kidney retransplantation, the allograft is functioning well and the patient's CSCC remains in remission. This case illustrates the potential for PD-1 blockade to bring about durable immune-mediated tumor control in chronically immunosuppressed patients, and begins to address the feasibility of kidney retransplantation in patients who have previously received immune checkpoint inhibitor therapy for cancer. Results from this and future cases may help elucidate mechanisms of antitumor immunity and allograft tolerance, and inform updates to transplant decision models. Our report also underscores the need for clinical trials testing novel immunotherapy combinations in solid organ transplant recipients designed to uncouple antitumor and anti-allograft immunity.

Delayed Graft Function in Simultaneous Liver Kidney Transplantation.

BACKGROUND: Delayed graft function (DGF) is associated with inferior posttransplant outcomes in kidney transplantation. Given these adverse outcomes, we sought to determine the incidence, unique risk factors, and posttransplant outcomes for simultaneous liver kidney (SLK) transplant recipients developing DGF. METHODS: We studied 6214 adult SLK recipients from March 2002 to February 2017 using the Scientific Registry of Transplant Recipients. We determined associations between risk factors and DGF using Poisson multivariate regression and between DGF and graft failure and mortality using Cox proportional hazard analysis. RESULTS: The overall rate of DGF was 21.8%. Risk factors for DGF in the hepatitis C virus (HCV)-negative recipient population included pretransplant dialysis (adjusted incident rate ratio [aIRR] 3.26, P = 0.004), donor body mass index (aIRR 1.25 per 5 kg/m, P = 0.01), and transplantation with a donation after circulatory death (aIRR 5.38, P = 0.001) or imported donor organ (regional share aIRR 1.69, P = 0.03; national share aIRR 4.82, P < 0.001). DGF was associated with a 2.6-fold increase in kidney graft failure (adjusted hazard ratio [aHR] 2.63, P < 0.001), 1.6-fold increase in liver graft failure (aHR 1.62, P < 0.001), and 1.6-fold increase in mortality (aHR 1.62, P < 0.001). CONCLUSIONS: In HCV-negative SLK recipients, recipient pretransplant dialysis and components of kidney graft quality comprise significant risk factors for DGF. Regardless of HCV status, DGF is associated with inferior posttransplant outcomes. Understanding these risk factors during clinical decision-making may improve prevention of DGF and may represent an opportunity to improve posttransplant outcomes.

Tree nuts supplementation instigates the oxidative status and improves brain performance in male rats.

Exposure to cadmium has been extensively increased due to its usage in modern daily life. Inside the human body it induces deteriorating effects in every vital organ including brain. Oxidative stress has been widely implicated in neurotoxicity induced by cadmium exposure. Consumption of dietary source of exogenous antioxidants is one of the recommended ways to extenuate heavy metal-induced oxidative stress. The potential of nuts against heavy-metal induced neurotoxicity has not been investigated earlier. This study was, therefore, conducted to find out the antioxidant ability of almond and walnut in the prevention of cadmium-induced oxidative stress. Rats were treated with nuts (400 mg/kg) daily for 28 days whereas, cadmium (50 mg/kg) was given once in a week. Brain function was monitored in terms of memory performance using Morris water maze and elevated plus maze. Moreover, oxidative stress status was also evaluated. Results showed that weekly exposure of cadmium significantly reduced %memory retention, increased lipid per oxidation and inhibited antioxidant enzymes activity. When nuts supplemented rats were monitored for these parameters, it was observed that almond and walnut have a great potential to reduce cadmium-induced neurotoxicity as evident by decreased oxidative stress and improved memory function in cadmium intoxicated rats.

Curcumin lessens unpredictable chronic mild stress-induced depression and memory deficits by modulating oxidative stress and cholinergic activity.

Unpredictable chronic mild stress (UCMS) model is the most established method to study neurobiological mechanisms of depression. This work was intended to explore the efficacy of curcumin to revert the UCMS-induced oxidative burden and associated depression as well as potential of curcumin as an acetyl cholinesterase (AchE) inhibitor. Animals were initially grouped into control and curcumin (200mg/kg, p.o) and further subdivided into unstressed and stressed groups. Depression and anxiety were evaluated by forced swim test (FST) and light/dark transition (LDT) while memory function was assessed by passive avoidance test (PAT). Effect of curcumin on oxidative stress following UCMS was determined by measuring peroxidation of lipid (LPO) and antioxidant enzyme activities. AchE activity was also determined. Findings showed that curcumin supplementation significantly attenuated the UCMS-induced depression and anxiety like symptoms, decreased the load of UCMS propagated oxidative stress by improving antioxidant enzymes activities. Curcumin also improved the memory function and exhibited inhibitory effect on AchE activity. In conclusion it can be suggested that supplementation of curcumin in daily life can help in combating the stress-induced depression and ever increasing load of oxidative stress. Study also highlights the anti-acetylcholinesterase potential of curcumin which may be responsible for improved memory function following UCMS.

A comparative study showing greater effects of curcumin compared to donepezil on memory function in rats.

Curcumin possesses wide spectrum of biological actions, on that account the current study was aimed to investigate the beneficial effectiveness of curcumin on memory and oxidative stress if any, over synthetic drug donepezil approved for the treatment of memory disorders. Eighteen Albino wistar (male) rats were divided into 3 groups namely vehicle control which received neutral oil orally and 0.9% saline intraperitoneally, curcumin which received curcumin orally dissolved in neutral oil at the dose of 100mg/ml/kg for seven days, donepezil which received donepezil intraperitoneally at the dose of 1mg/ml/kg for seven days. To assess memory and cognition Elevated Plus Maze and Morris Water Maze tests were performed. Rats were sacrificed after behavioral analysis and their brains were removed for biochemical assays including lipid peroxidation and antioxidant enzymes such as catalase, superoxide dismutase, glutathione peroxidase. Acetylcholine esterase activity and acetylcholine levels were also determined. Our results showed that both curcumin and donepezil improved memory and inhibited acetylcholinesterase, however curcumin inhibited AchE with more potency than donepezil when compared to vehicle control rats. Moreover curcumin exhibited greater antioxidant potential to decrease the load of oxidative stress in brain cells than donepezil as compared to vehicle control rats. In conclusion present study proposed that increased antioxidant potential of curcumin may be responsible for its increased acetylcholine levels and associated enhanced memory performance.

The Impact of "Mom/Dad of the Day" Cards, Newborn Heart Auscultation, and Father Skin-to-Skin Care on Parent-Newborn Bonding.

Texas Tech Pediatrics at Northwest Texas Hospital System in Amarillo, Texas, currently practices giving "Mom/Dad of the Day" cards to all new parents, offering the opportunity for fathers to auscultate the newborn heart sound, and encouraging maternal and paternal skin-to-skin contact. New parents were asked to fill out 2 anonymous surveys regarding these practices. Survey results showed statistically significant positive responses by the parents for subjective improvement in fetal sleep and feeding as well as parental confidence and preparedness for taking care of their newborn. Additionally, these practices are desired by parents, with 96% fathers recommending that the hospital routinely offering opportunities for heart auscultation and 94% parents recommending "Mom/Dad of the Day" cards for all future parents in the hospital. Small, nonmedical initiatives such as these are well received and can be feasibly adopted in more hospitals to improve patient quality of care.

Anticholinergic drug atropine diminishes newly formed fear memory in male rats.

Post-traumatic stress disorder (PTSD) is a condition which is triggered shortly after experiencing traumatic events. PTSD is complicated by the fact that people with PTSD often develop additional disorders such as phobias, addiction, depression, panic disorder and obsessive-compulsive disorder. Beta-adrenergic and cholinergic system both are involved in memory formation as well as in emotional response associated with memory. It is reported that the administration of beta-adrenergic and cholinergic antagonist results in the impairment in memory formation. Here, we examined the potential of beta-adrenergic antagonist propranolol and muscarinic cholinergic antagonist atropine for impairing the recently formed fear memory associated with PTSD. Reconsolidation is the memory process during which labile memory converts into permanent memory. In this study it is hypothesized that if recently formed fear memory is disturbed during reconsolidation phase by pharmacological intervention then it could be possible to impair well-consolidated fear memory. Atropine and propranolol were injected in separate set of rats (n=6) just after the reactivation of fear memory. Short term memory and long term memory were monitored after 2 h and 24 h of reactivation respectively. Results of current study demonstrated that only atropine showed significant impairment of reconsolidation of newly formed fear memory whereas propranolol did not show fear memory disrupting effects. The results emphasize the significance of pharmacological intervention to impair reconsolidation of newly formed fear memory.

Preoperative Echocardiographic Differences and Transplant Outcomes Among Patients Receiving Simultaneous Liver-Kidney Versus Liver Transplant Alone.

OBJECTIVES: Liver transplant and simultaneous liver-kidney transplant are major surgeries performed on high-risk individuals with end-stage liver disease and end-stage renal disease. We sought to examine the relationship between pretransplant echocardiographic parameters and outcomes in our simultaneous liver-kidney transplant and liver transplant-alone populations. MATERIALS AND METHODS: In our retrospective analysis, we included adult patients who underwent index transplant from January 1, 2010 to December 31, 2015 at Johns Hopkins Comprehensive Transplant Center. RESULTS: Our study included 312 patients, 266 who underwent liver transplant alone and 46 who underwent simultaneous liver-kidney transplant. Baseline population demographics were similar in both groups of patients. Primary diagnosis at transplant was similar in both groups except that patients undergoing liver transplant were more likely to have a diagnosis of hepatocellular carcinoma, whereas those undergoing simultaneous liver-kidney transplant were more likely to have polycystic kidney disease. Within the liver transplant-alone group, the strongest demographic predictor of poor outcome was age at transplant. The strongest echocar diographic predictors were related to elevated left ventricular ejection fraction and right ventricular systolic pressure. CONCLUSIONS: In our investigation regarding whether the pretransplant cardiovascular evaluation predicted outcomes for patients undergoing liver transplant alone and patients undergoing simultaneous liver-kidney transplant, we found that elevations in right ventricular systolic pressure and left ventricular ejection fraction may be associated with poor outcomes in the posttransplant period.

Direct-Acting Antiviral Prophylaxis in Kidney Transplantation From Hepatitis C Virus-Infected Donors to Noninfected Recipients: An Open-Label Nonrandomized Trial.

Background: Given the high mortality rate for patients with end-stage kidney disease receiving dialysis and the efficacy and safety of hepatitis C virus (HCV) treatments, discarded kidneys from HCV-infected donors may be a neglected public health resource. Objective: To determine the tolerability and feasibility of using direct-acting antivirals (DAAs) as prophylaxis before and after kidney transplantation from HCV-infected donors to non-HCV-infected recipients (that is, HCV D+/R- transplantation). Design: Open-label nonrandomized trial. (ClinicalTrials.gov: NCT02781649). Setting: Single center. Participants: 10 HCV D+/R- kidney transplant candidates older than 50 years with no available living donors. Intervention: Transplantation of kidneys from deceased donors aged 13 to 50 years with positive HCV RNA and HCV antibody test results. All recipients received a dose of grazoprevir (GZR), 100 mg, and elbasvir (EBR), 50 mg, immediately before transplantation. Recipients of kidneys from donors with genotype 1 infection continued receiving GZR-EBR for 12 weeks after transplantation; those receiving organs from donors with genotype 2 or 3 infection had sofosbuvir, 400 mg, added to GZR-EBR for 12 weeks of triple therapy. Measurements: The primary safety outcome was the incidence of adverse events related to GZR-EBR treatment. The primary efficacy outcome was the proportion of recipients with an HCV RNA level below the lower limit of quantification 12 weeks after prophylaxis. Results: Among 10 HCV D+/R- transplant recipients, no treatment-related adverse events occurred, and HCV RNA was not detected in any recipient 12 weeks after treatment. Limitation: Nonrandomized study design and a small number of patients. Conclusion: Pre- and posttransplantation HCV treatment was safe and prevented chronic HCV infection in HCV D+/R- kidney transplant recipients. If confirmed in larger studies, this strategy should markedly expand organ options and reduce mortality for kidney transplant candidates without HCV infection. Primary Funding Source: Merck Sharp & Dohme.

Enriched environment palliates nicotine-induced addiction and associated neurobehavioral deficits in rats.

This study was designed to investigate the role of enriched environment in preventing and/or reducing the neurobehavioral deficits produced after nicotine administration in albino Wistar rats. Equal numbers of rat in two groups were either placed in social environment (control group) or social along with physically enriched environment for four weeks before the administration of nicotine. Exposure to different environmental conditions was followed by the intraperitoneal injection of nicotine at the dose of 0.6 mg/kg for seven consecutive days during which addictive behavior was monitored using conditioned placed preference paradigm. Behavioral responses to locomotor activity, anxiety and retention of short term memory were investigated in control and nicotine injected groups exposed to different environments. Results of this study showed that the rats pre-exposed to physical along with social enrichment exhibited a decrease in drug seeking behavior, hyper locomotion, anxiogenic effects along with improvement of working memory as compared to control and nicotine injected groups that were kept in social environment alone. This behavioral study suggests that the exposure to physical enrichment along with socialization in young age can later reduce the chances of compulsive dependence on nicotine and related neurobehavioral deficits.

Outcomes and risk stratification for late antibody-mediated rejection in recipients of ABO-incompatible kidney transplants: a retrospective study.

The required intensity of monitoring for antibody-mediated rejection (AMR) after of ABO-incompatible (ABOi) kidney transplantation is not clearly formulized. We retrospectively evaluated a single-center cohort of 115 ABO-incompatible (ABOi) kidney transplant recipients, of which 32% were also HLA incompatible (ABOi/HLAi) with their donors. We used an adjusted negative binomial model to evaluate risk factors for late AMR. Using this model, we risk-stratified patients into high- and low-risk groups for the development of late AMR; 26% of patients had at least one AMR episode; 49% of AMR episodes occurred within 30-days after transplant and were considered early AMR. Patients with an early AMR episode had a 5.5-fold greater incidence of developing late AMR [IRR = 5.5, (95% CI: 1.5-19.3), P = 0.01]. ABOi/HLAi recipients trended toward increased late AMR risk [IRR = 1.9, (95% CI: 0.5-6.6), P = 0.3]. High-risk recipients (those with an early AMR or those who were ABOi/HLAi) had a sixfold increased incidence of late AMR [IRR = 6.3, (95% CI: 1.6-24.6), P = 0.008] versus low-risk recipients. The overall incidence of late AMR was 20.8% vs. 1.5% in low-risk recipients. Changes in anti-A/B titer did not correlate with late AMR (IRR = 0.9 per log titer increase, P = 0.7). This risk-stratification scheme uses information available within 30 days of ABOi transplantation to determine risk for late AMR and can help direct longitudinal follow-up for individual patients.

Successful Renal Transplantation of Deceased Donor Kidneys With 100% Glomerular Fibrin Thrombi and Acute Renal Failure Due to Disseminated Intravascular Coagulation.

BACKGROUND: Disseminated intravascular coagulation (DIC)-positive kidneys have historically been turned down for fear of poor outcomes. Higher severity injuries, which are prone to DIC, are typically seen in younger, otherwise healthy potential donors. The continued kidney allograft shortage has generated interest in the use of these DIC-positive grafts. There have been some reports of acceptable outcomes of renal transplantation using kidneys from donors with DIC. There are multiple clinical series demonstrating good outcomes from DIC-positive kidneys when the extent of glomeruli containing fibrin thrombi is less than 50% and donor renal function is preserved. These grafts are frequently associated with a period of delayed graft function. METHODS: We report 2 transplants with kidneys from brain dead donors with known DIC. RESULTS: Both donors had renal failure and pretransplant renal biopsies showing 100% of the glomeruli containing fibrin thrombi. The recipients experienced delayed graft function requiring hemodialysis which was discontinued on postoperative days 18 and 39 for cases 1 and 2, respectively. Both patients are now over 14 months posttransplant with stable allograft function. CONCLUSIONS: Until clearer organ selection criteria are established, caution should be exercised when considering the use of kidneys with a similar phenotype and allocation decisions made by a multidisciplinary transplant team on a case-by-case basis.