Poly[ADP-Ribose] Polymerase-1 Expression Is Related To Cold Ischemia, Acute Tubular Necrosis, and Delayed Renal Function In Kidney Transplantation

Cold ischemia time especially impacts on outcomes of expanded-criteria donor (ECD) transplantation. Ischemia-reperfusion (IR) injury produces excessive poly[ADP-Ribose] Polymerase-1 (PARP-1) activation. The present study explored the hypothesis that increased tubular expression of PARP-1 contributes to delayed renal function in suboptimal ECD kidney allografts and in non-ECD allografts that develop posttransplant acute tubular necrosis (ATN)

Impact of Normothermic Preservation with Extracellular Type Solution Containing Trehalose on Rat Kidney Grafting from a Cardiac Death Donor

BACKGROUND: The aim of this study was to investigate factors that may improve the condition of a marginal kidney preserved with a normothermic solution following cardiac death (CD) in a model of rat kidney transplantation (RTx). METHODS: Post-euthanasia, Lewis (LEW) donor rats were left for 1 h in a 23°C room. These critical kidney grafts were preserved in University of Wisconsin (UW), lactate Ringer's (LR), or extracellular-trehalose-Kyoto (ETK) solution, followed by intracellular-trehalose-Kyoto (ITK) solution at 4, 23, or 37°C for another 1 h, and finally transplanted into bilaterally nephrectomized LEW recipient rats (n = 4-6). Grafts of rats surviving to day 14 after RTx were evaluated by histopathological examination. The energy activity of these marginal rat kidneys was measured by high-performance liquid chromatography (HPLC; n = 4 per group) and fluorescence intensity assay (n = 6 per group) after preservation with UW or ETK solutions at each temperature. Finally, the transplanted kidney was assessed by an in vivo luciferase imaging system (n = 2). RESULTS: Using the 1-h normothermic preservation of post-CD kidneys, five out of six recipients in the ETK group survived until 14 days, in contrast to zero out of six in the UW group (p<0.01). Preservation with ITK rather than ETK at 23°C tended to have an inferior effect on recipient survival (p = 0.12). Energy activities of the fresh donor kidneys decreased in a temperature-dependent manner, while those of post-CD kidneys remained at the lower level. ETK was superior to UW in protecting against edema of the post-CD kidneys at the higher temperature. Luminescence intensity of successful grafts recovered within 1 h, while the intensity of grafts of deceased recipients did not change at 1 h post-reperfusion. CONCLUSIONS: Normothermic storage with extracellular-type solution containing trehalose might prevent reperfusion injury due to temperature-dependent tissue edema

Anthropomorphic Measurements That Include Central Fat Distribution Are More Closely Related with Key Risk Factors than BMI in CKD Stage 3

Background: Body Mass Index (BMI) as a marker of obesity is an established risk factor for chronic kidney disease (CKD) and cardiovascular disease (CVD). However, BMI can overestimate obesity. Anthropomorphic measurements that include central fat deposition are emerging as a more important risk factor. We studied BMI, waist circumference (WC), waist-to-height ratio (WHtR), waist-to-hip ratio (WHR) and conicity index (CI) in a cohort of patients with CKD stage 3 and compared the associations with other known risk factors for CKD progression and CVD. Methods: 1740 patients with CKD stage 3 were recruited from primary care for the Renal Risk in Derby study. Each participant underwent clinical assessment, including anthropomorphic measurements and pulse wave velocity (PWV), as well as urine and serum biochemistry tests. Results: The mean age of the cohort was 72.969 years with 60 % females. The mean eGFR was 52.5610.4 ml/min/1.73 m 2 and 16.9 % of the cohort had diabetes. With the cohort divided into normal and increased risk of morbidity and mortality using each anthropomorphic measurement, those measurements that included increased central fat distribution were significantly associated with more risk factors for CKD progression and CVD than increased BMI. Univariable analysis demonstrated central fat distribution was correlated with more risk factors than BMI. Subgroup analyses using recognised BMI cut-offs to define obesity and quartiles of WHR and CI demonstrated that increasing central fat distribution wa

Mouse Studies to Shape Clinical Trials for Mitochondrial Diseases: High Fat Diet in Harlequin Mice

BACKGROUND: Therapeutic options in human mitochondrial oxidative phosphorylation (OXPHOS) diseases have been poorly evaluated mostly because of the scarcity of cohorts and the inter-individual variability of disease progression. Thus, while a high fat diet (HFD) is often recommended, data regarding efficacy are limited. Our objectives were 1) to determine our ability to evaluate therapeutic options in the Harlequin OXPHOS complex I (CI)-deficient mice, in the context of a mitochondrial disease with human hallmarks and 2) to assess the effects of a HFD. METHODS AND FINDINGS: Before launching long and expensive animal studies, we showed that palmitate afforded long-term death-protection in 3 CI-mutant human fibroblasts cell lines. We next demonstrated that using the Harlequin mouse, it was possible to draw solid conclusions on the efficacy of a 5-month-HFD on neurodegenerative symptoms. Moreover, we could identify a group of highly responsive animals, echoing the high variability of the disease progression in Harlequin mice. CONCLUSIONS: These results suggest that a reduced number of patients with identical genetic disease should be sufficient to reach firm conclusions as far as the potential existence of responders and non responders is recognized. They also positively prefigure HFD-trials in OXPHOS-deficient patients

Role of tolvaptan in the management of hyponatremia in patients with lung and other cancers: current data and future perspectives

Bijin Thajudeen,1 Abdulla K Salahudeen1,2 1Department of Nephrology, Banner University of Arizona Medical Center, 2Department of Nephrology, Southern Arizona Veterans Health Care System, Tucson, AZ, USA Abstract: Hyponatremia is the most frequently observed electrolyte abnormality in clinical practice, and its frequency is almost double in hospitalized cancer patients. As a subset of cancer, hyponatremia is quite common in lung cancer patients, and it is often coupled with the diagnosis of syndrome of inappropriate antidiuretic hormone secretion. The presence of hyponatremia is consequential in that its presence adversely affects cancer patients&rsquo; prognosis and outcomes. Limited data suggest that correcting hyponatremia in lung cancer patients can increase response to anticancer treatment, may help reduce length of hospital stay and cost, and reduce morbidity and mortality. The type of treatment for hyponatremia depends on several factors; the key factors are the duration and severity of neurological symptoms of hyponatremia and the status of extracellular volume. When hyponatremia is caused by syndrome of inappropriate antidiuretic hormone, hypertonic saline is indicated for acute symptomatic cases, whereas fluid restriction is recommended in chronic asymptomatic hyponatremia. The latter allows a slower rate of correction, thus avoiding the dreaded complication of osmotic demyelination syndrome. Fluid restriction is, however, insufficient or impractical, and often the use of pharmacological therapy such as antidiuretic hormone receptor antagonists becomes necessary. Availability of these antagonists as an effective treatment in the management of hyponatremia has been a major breakthrough, and furthermore, its clinical or investigational use in cancer-related hyponatremia may offer a potential opportunity to gain further insights into the prognostic impact of hyponatremia correction on cancer patients&rsquo; outcomes. Tolvaptan is a prototype of ADH receptor antagonists that acts at renal tubular levels to increase free water excretion without inducing major systemic electrolyte abnormalities such as hypokalemia or alkalosis. The aim of this paper is to provide a brief review while focusing on cancer hyponatremia; (1) of the epidemiology of hyponatremia and its pathophysiology and diagnostic approaches and (2) of the pharmacokinetics of tolvaptan and its clinical efficacy, safety, and compliance. Keywords: treatment, pharmacology, safety, tolerability, efficacy, adherenc