Search

Kidney disease, a common complication of diabetes, associates with poor prognosis. Our previous animal model studies linked aquaporin (AQP)11 to acute kidney injury, hyperglycemia-induced renal impairment, and kidney disease in diabetes. Here, we report the AQP11 rs2276415 variant as a genetic factor placing type 2 diabetic patients at greater risk for the development of kidney disease. We performed two independent retrospective case-control studies in 1,075 diabetic and 1,619 nondiabetic individuals who were identified in the Synthetic Derivative Database with DNA samples in the BioVU DNA repository at Vanderbilt University (Nashville, TN). A χ(2)-test and multivariable logistic regression analysis with adjustments for age, sex, baseline serum creatinine, and underlying comorbid disease covariates showed a significant association between rs2276415 and the prevalence of any event of acute kidney injury and chronic kidney disease (CKD) in diabetic patients but not in patients without diabetes. This result was replicated in the second independent study. Diabetic CKD patients over 55 yrs old with the minor AQP11 allele had a significantly faster progression of estimated glomerular filtration rate decline than patients with the wild-type genotype. Three-dimensional structural analysis suggested a functional impairment of AQP11 with rs2276415, which could place diabetic patients at a higher risk for kidney disease. These studies identified rs2276415 as a candidate genetic factor predisposing patients with type 2 diabetes to CKD., (Copyright © 2016 the American Physiological Society.)

Aquaporin 11 (AQP11) is a newly described member of the protein family of transport channels. AQP11 associates with the endoplasmic reticulum (ER) and is highly expressed in proximal tubular epithelial cells in the kidney. Previously, we identified and characterized a recessive mutation of the highly conserved Cys227 to Ser227 in mouse AQP11 that caused proximal tubule (PT) injury and kidney failure in mutant mice. The current study revealed induction of ER stress, unfolded protein response, and apoptosis as molecular mechanisms of this PT injury. Cys227Ser mutation interfered with maintenance of AQP11 oligomeric structure. AQP11 is abundantly expressed in the S1 PT segment, a site of major renal glucose flux, and Aqp11 mutant mice developed PT-specific mitochondrial injury. Glucose increased AQP11 protein expression in wild-type kidney and upregulation of AQP11 expression by glucose in vitro was prevented by phlorizin, an inhibitor of sodium-dependent glucose transport across PT. Total AQP11 levels in heterozygotes were higher than in wild-type mice but were not further increased in response to glucose. In Aqp11 insufficient PT cells, glucose potentiated increases in reactive oxygen species (ROS) production. ROS production was also elevated in Aqp11 mutation carriers. Phenotypically normal mice heterozygous for the Aqp11 mutation repeatedly treated with glucose showed increased blood urea nitrogen levels that were prevented by the antioxidant sulforaphane or by phlorizin. Our results indicate an important role for AQP11 to prevent glucose-induced oxidative stress in proximal tubules.

Background & Aims: Capsule endoscopy has been shown to be useful in diagnosing small bowel Crohn's disease. Faecal lactoferrin has been shown to have a high sensitivity and specificity in discriminating between inflammatory bowel disease and irritable bowel syndrome. There have been no studies on the use of faecal lactoferrin in the setting of suspected Crohn's disease using capsule endoscopy. Our aim was to investigate the clinical utility of lactoferrin in patients with suspected Crohn's disease using capsule endoscopy., Methods: Data was collected prospectively on patient symptoms, family history and blood parameters. Patients were requested to return a stool sample and quantitative analysis using sandwich ELISA was performed for faecal lactoferrin., Results: Seventeen patients were recruited with all patients having had more than one criterion for referral. The diagnostic yield for capsule endoscopy was 41%, of which 71% of patients had an elevated faecal lactoferrin (correlation coefficient 0.56, p=0.01). The sensitivity, specificity, positive predictive value and negative predictive value of faecal lactoferrin were 71%, 100%, 100% and 83%, respectively., Conclusion: Faecal lactoferrin has a high positive and negative predictive value for the diagnosis of small bowel Crohn's disease, detected by capsule endoscopy. Faecal lactoferrin is a useful marker (in conjunction with clinical parameters) to determine which patients should be referred for capsule endoscopy.

A preliminary study of the response of various inoperable malignant diseases to simultaneously administered 5-fluoro-uracil and orthovolt x-ray was performed. The 5-fluoro-uracil was given intravenously at a relatively nontoxic dosage level. The x-ray tumor dose was limited to 2,000 roentgens in every patient. Pronounced and rapid tumor regression occurred in 12 of 18 evaluable patients. Significant objective response was obtained in each of eight patients with epidermoid carcinoma of the lung. Toxicity occurred in half of the patients, manifested by pharyngitis, esophagitis, proctitis, leukopenia and thrombocytopenia.