Levels of retinol and retinyl esters in plasma and urine of dogs with urolithiasis

Vitamin A (VA) deficiency and Tamm-Horsfall glycoprotein (THP), a protein that binds retinol and retinyl esters in canine urine, might be involved in the pathogenesis of urolithiasis in dogs. In the present study, we assessed levels of retinol, retinyl esters, retinol-binding protein (RBP) and THP in plasma and urine of dogs with a history of urolithiasis (n = 25) compared with clinically healthy controls (n = 18). Plasma retinol concentrations were higher in dogs with uroliths of struvit (P < 0.01), calcium oxalate (P < 0.05), urate (P < 0.01) and cysteine, but there were no differences in the concentrations of plasma RBP and retinyl esters. Excretion of urinary retinol and retinyl esters were tentatively, but not significantly higher in the stone-forming groups, which was accompanied by increased levels of urinary RBP (P < 0.01) and lower excretions in THP (P < 0.01). The results show that VA deficiency may be excluded as a potential cause for canine urolithiasis. However, the occurrence of RBP and a concomitant reduction of THP in urine indicates a disturbed kidney function as cause or consequence of stone formation in dogs.

Perioperative use of crystalloids in patients undergoing open radical cystectomy: balanced Ringer's maleate versus a glucose 5%/potassium-based balanced solution: study protocol for a randomized controlled trial

BACKGROUND The optimal crystalloid solution to use perioperatively in patients undergoing open radical cystectomy remains unclear. Many of the fluids used for intravenous hydration contain supraphysiologic concentrations of chloride, which can induce hyperchloremia and metabolic acidosis, resulting in renal vasoconstriction and decreased renal function. In addition, patients receiving less fluid and less sodium show faster recovery of gastrointestinal (GI) function after colonic surgery. METHODS AND DESIGN This is an investigator-initiated, single-center, randomized, controlled, parallel group trial with assessor-blinded outcome assessment, in the Department of Urology, University Hospital Bern, Switzerland. The study will involve 44 patients with bladder cancer scheduled for radical cystectomy and urinary diversion. The primary outcome is the duration between the end of surgery and the return of the GI function (first defecation). Secondary outcomes are fluid balance (body weight difference postoperatively versus preoperatively) and the incidence of kidney function disorders according to the Risk-Injury-Failure-Loss-End Stage Renal Disease (RIFLE classification). An equal number of patients are allocated to receive Ringerfundin® solution or a glucose/potassium-based balanced crystalloid solution as baseline infusion during the entire time that intravenous administration of fluid is necessary during the perioperative period. The randomized crystalloid solution is infused at a rate of 1 ml/kg/h until the bladder has been removed, followed by 3 ml/kg/h until the end of surgery. Postoperative hydration is identical in both groups and consists of 1,500 ml of the randomized crystalloid solution per 24 hours. Postoperative patient care is identical in both groups; patients are allowed to drink clear fluids immediately after surgery, and liquid diet is started on postoperative day 1, as well as active mobilization and the use of chewing gum. Body weight is measured daily in the morning. Time of first flatus and first defecation are recorded. DISCUSSION This trial assesses the benefits and harms of two different balanced crystalloid solutions for perioperative fluid management in patients undergoing open radical cystectomy with urinary diversion, with regard to return of GI function and effects on postoperative renal function. TRIAL REGISTRATION Current Controlled Trials ISRCTN32976792 (registered on November 21 2013).

Direct in vitro and in vivo comparison of 161Tb and 177Lu using a tumour-targeting folate conjugate

Purpose The radiolanthanide 161Tb (T 1/2 = 6.90 days, Eβ− av = 154 keV) was recently proposed as a potential alternative to 177Lu (T 1/2 = 6.71 days, Eβ− av = 134 keV) due to similar physical decay characteristics but additional conversion and Auger electrons that may enhance the therapeutic efficacy. The goal of this study was to compare 161Tb and 177Lu in vitro and in vivo using a tumour-targeted DOTA-folate conjugate (cm09). Methods 161Tb-cm09 and 177Lu-cm09 were tested in vitro on folate receptor (FR)-positive KB and IGROV-1 cancer cells using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) viability assay. In vivo 161Tb-cm09 and 177Lu-cm09 (10 MBq, 0.5 nmol) were investigated in two different tumour mouse models with regard to the biodistribution, the possibility for single photon emission computed tomography (SPECT) imaging and the antitumour efficacy. Potentially undesired side effects were monitored over 6 months by determination of plasma parameters and examination of kidney function with quantitative SPECT using 99mTc-dimercaptosuccinic acid (DMSA). Results To obtain half-maximal inhibition of tumour cell viability a 4.5-fold (KB) and 1.7-fold (IGROV-1) lower radioactivity concentration was required for 161Tb-cm09 (IC50 ~0.014 MBq/ml and ~2.53 MBq/ml) compared to 177Lu-cm09 (IC50 ~0.063 MBq/ml and ~4.52 MBq/ml). SPECT imaging visualized tumours of mice with both radioconjugates. However, in therapy studies 161Tb-cm09 reduced tumour growth more efficiently than 177Lu-cm09. These findings were in line with the higher absorbed tumour dose for 161Tb-cm09 (3.3 Gy/MBq) compared to 177Lu-cm09 (2.4 Gy/MBq). None of the monitored parameters indicated signs of impaired kidney function over the whole time period of investigation after injection of the radiofolates. Conclusion Compared to 177Lu-cm09 we demonstrated equal imaging features for 161Tb-cm09 but an increased therapeutic efficacy for 161Tb-cm09 in both tumour cell lines in vitro and in vivo. Further preclinical studies using other tumour-targeting radioconjugates are clearly necessary to draw final conclusions about the future clinical perspectives of 161Tb.

Cross-sectional study of 168 patients with hepatorenal tyrosinaemia and implications for clinical practice

BackgroundHepatorenal tyrosinaemia (Tyr 1) is a rare inborn error of tyrosine metabolism. Without treatment, patients are at high risk of developing acute liver failure, renal dysfunction and in the long run hepatocellular carcinoma. The aim of our study was to collect cross-sectional data.MethodsVia questionnaires we collected retrospective data of 168 patients with Tyr 1 from 21 centres (Europe, Turkey and Israel) about diagnosis, treatment, monitoring and outcome. In a subsequent consensus workshop, we discussed data and clinical implications.ResultsEarly treatment by NTBC accompanied by diet is essential to prevent serious complications such as liver failure, hepatocellular carcinoma and renal disease. As patients may remain initially asymptomatic or develop uncharacteristic clinical symptoms in the first months of life newborn mass screening using succinylacetone (SA) as a screening parameter in dried blood is mandatory for early diagnosis. NTBC-treatment has to be combined with natural protein restriction supplemented with essential amino acids. NTBC dosage should be reduced to the minimal dose allowing metabolic control, once daily dosing may be an option in older children and adults in order to increase compliance. Metabolic control is judged by SA (below detection limit) in dried blood or urine, plasma tyrosine (<400 ¿M) and NTBC-levels in the therapeutic range (20¿40 ¿M). Side effects of NTBC are mild and often transient.Indications for liver transplantation are hepatocellular carcinoma or failure to respond to NTBC. Follow-up procedures should include liver and kidney function tests, tumor markers and imaging, ophthalmological examination, blood count, psychomotor and intelligence testing as well as therapeutic monitoring (SA, tyrosine, NTBC in blood).ConclusionBased on the data from 21 centres treating 168 patients we were able to characterize current practice and clinical experience in Tyr 1. This information could form the basis for clinical practice recommendations, however further prospective data are required to underpin some of the recommendations.

Hyperphosphatemia Is an Independent Risk Factor for Mortality in Critically Ill Patients: Results from a Cross-Sectional Study.

BACKGROUND Phosphate imbalances or disorders have a high risk of morbidity and mortality in patients with chronic kidney disease. It is unknown if this finding extends to mortality in patients presenting at an emergency room with or without normal kidney function. METHODS AND PATIENTS This cross sectional analysis included all emergency room patients between 2010 and 2011 at the Inselspital Bern, Switzerland. A multivariable cox regression model was applied to assess the association between phosphate levels and in-hospital mortality up to 28 days. RESULTS 22,239 subjects were screened for the study. Plasma phosphate concentrations were measured in 2,390 patients on hospital admission and were included in the analysis. 3.5% of the 480 patients with hypophosphatemia and 10.7% of the 215 patients with hyperphosphatemia died. In univariate analysis, phosphate levels were associated with mortality, age, diuretic therapy and kidney function (all p<0.001). In a multivariate Cox regression model, hyperphosphatemia (OR 3.29, p<0.001) was a strong independent risk factor for mortality. Hypophosphatemia was not associated with mortality (p>0.05). CONCLUSION Hyperphosphatemia is associated with 28-day in-hospital mortality in an unselected cohort of patients presenting in an emergency room.

Reduced serum chemerin in patients with more severe liver cirrhosis

Chemerin is a well-established modulator of immune cell function and its serum levels are induced in inflammatory diseases. Liver cirrhosis is associated with inflammation which is aggravated by portal hypertension. The objective of this study was to evaluate whether chemerin is induced in patients with more severe liver cirrhosis and portal hypertension. Chemerin has been measured by ELISA in the portal venous serum (PVS), systemic venous serum (SVS) and hepatic venous serum (HVS) of 45 patients with liver cirrhosis. Chemerin is higher in HVS compared to PVS in accordance with our recently published finding. SVS, HVS and PVS chemerin decline in patients with more advanced liver injury defined by the CHILD-PUGH score. Hepatic chemerin has been determined in a small cohort and is similarly expressed in normal and cirrhotic liver. MELD score and serum markers of liver and kidney function do not correlate with chemerin. There is a positive correlation of chemerin in all compartments with Quick prothrombin time and of SVS chemerin with systolic blood pressure. PVS chemerin is induced in patients with modest/massive ascites but this does not translate into higher HVS and SVS levels. Chemerin is not associated with variceal size. Reduction of portal pressure by transjugular intrahepatic portosystemic shunt does not affect chemerin levels. These data show that low chemerin in patients with more severe liver cirrhosis is associated with reduced Quick prothrombin time.

1D.03: Inactive Matrix Gla Protein is Assocated with Renal Resistive Index in a Population-Based Study

OBJECTIVE Renal resistive index (RRI) varies directly with renal vascular stiffness and pulse pressure. RRI correlates positively with arteriolosclerosis in damaged kidneys and predicts progressive renal dysfunction. Matrix Gla-protein (MGP) is a vascular calcification inhibitor that needs vitamin K to be activated. Inactive MGP, known as desphospho-uncarboxylated MGP (dp-ucMGP), can be measured in plasma and has been associated with various cardiovascular (CV) markers, CV outcomes and mortality. In this study we hypothesize that increased RRI is associated with high levels of dp-ucMGP. DESIGN AND METHOD We recruited participants via a multi-center family-based cross-sectional study in Switzerland exploring the role of genes and kidney hemodynamics in blood pressure regulation. Dp-ucMGP was quantified in plasma samples by sandwich ELISA. Renal doppler sonography was performed using a standardized protocol to measure RRIs on 3 segmental arteries in each kidney. The mean of the 6 measures was reported. Multiple regression analysis was performed to estimate associations between RRI and dp-ucMGP adjusting for sex, age, pulse pressure, mean pressure, renal function and other CV risk factors. RESULTS We included 1035 participants in our analyses. Mean values were 0.64 ± 0.06 for RRI and 0.44 ± 0.21 (nmol/L) for dp-ucMGP. RRI was positively associated with dp-ucMGP both before and after adjustment for sex, age, body mass index, pulse pressure, mean pressure, heart rate, renal function, low and high density lipoprotein, smoking status, diabetes, blood pressure and cholesterol lowering drugs, and history of CV disease (P < 0.001). CONCLUSIONS RRI is independently and positively associated with high levels of dp-ucMGP after adjustment for pulse pressure and common CV risk factors. Further studies are needed to determine if vitamin K supplementation can have a positive effect on renal vascular stiffness and kidney function.

PCSK9 Plasma Concentrations Are Independent of GFR and Do Not Predict Cardiovascular Events in Patients with Decreased GFR.

BACKGROUND Impaired renal function causes dyslipidemia that contributes to elevated cardiovascular risk in patients with chronic kidney disease (CKD). The proprotein convertase subtilisin/kexin type 9 (PCSK9) is a regulator of the LDL receptor and plasma cholesterol concentrations. Its relationship to kidney function and cardiovascular events in patients with reduced glomerular filtration rate (GFR) has not been explored. METHODS Lipid parameters including PCSK9 were measured in two independent cohorts. CARE FOR HOMe (Cardiovascular and Renal Outcome in CKD 2-4 Patients-The Forth Homburg evaluation) enrolled 443 patients with reduced GFR (between 90 and 15 ml/min/1.73 m2) referred for nephrological care that were prospectively followed for the occurrence of a composite cardiovascular endpoint. As a replication cohort, PCSK9 was quantitated in 1450 patients with GFR between 90 and 15 ml/min/1.73 m2 enrolled in the Ludwigshafen Risk and Cardiovascular Health Study (LURIC) that were prospectively followed for cardiovascular deaths. RESULTS PCSK9 concentrations did not correlate with baseline GFR (CARE FOR HOMe: r = -0.034; p = 0.479; LURIC: r = -0.017; p = 0.512). 91 patients in CARE FOR HOMe and 335 patients in LURIC reached an endpoint during a median follow-up of 3.0 [1.8-4.1] years and 10.0 [7.3-10.6] years, respectively. Kaplan-Meier analyses showed that PCSK9 concentrations did not predict cardiovascular events in either cohort [CARE FOR HOMe (p = 0.622); LURIC (p = 0.729)]. Sensitivity analyses according to statin intake yielded similar results. CONCLUSION In two well characterized independent cohort studies, PCSK9 plasma levels did not correlate with kidney function. Furthermore, PCSK9 plasma concentrations were not associated with cardiovascular events in patients with reduced renal function.

Physician's adherence to the standard protocol for diabetes treatment in Brooke Army Medical Center (BAMC)

The level of compliance with clinical practice guidelines for patients with Type II Diabetes Mellitus was evaluated in 157 patients treated at BAMC from 1 January 2006 to 1 January 2007. This retrospective analysis was conducted reviewing data from medical records and following the VA/DOD protocols that health care providers are expected to follow at this facility. Data collected included patient’s age and gender, presence or absence of complications of diabetes, physical examination findings, glycemic and lipid control, eye care, foot care, kidney function, and self-management and education. Subjects were selected performing systematic random sampling, and included both male and female patients, from a variety of ages and ethnic groups. The Diabetes complications screened for included glycemic and lipid complications, retinopathy, cardiovascular complications, peripheral circulation complications, and nephropathy. The results revealed that 19.10% had no complications and that the most common complications were: cardiovascular (49.68%), glycemic and lipid control (10.82%), retinopathy and peripheral circulation (8.28% each), and nephropathy (2.54%). Only 2.54% of the records reviewed did not include information on complications. Strictly following the Department of Defense guidelines, six treatment modules were evaluated independently and together to get a final percentage of adherence to the clinical practice guidelines. It was established that the level of adherence was going to be graded as follows: Extremely deficient: 0-15%; very poor: 16-30%; Poor and in need of improvement: 31-45%. Acceptable: 46-60%; Good: 61-80%, and Excellent: 81-100%. The results indicated that the percentage of physicians' adherence to each protocol was as follows: 88.31%, 89.93%, 90.63%, 89.42%, 89.42% and 89.64%. When the results were pooled, the level of adherence to the clinical practice guidelines was 89.55%, proving my hypothesis that Brooke Army Medical Center physicians have excellent adherence to the standard protocols for Diabetes Type II to treat their patients. ^

Transferrina e colagénio tipo IV : novos marcadores glomerulares de lesão renal

Trabalho Final do Curso de Mestrado Integrado em Medicina, Faculdade de Medicina, Universidade de Lisboa, 2014

Safety of oral tenofovir disoproxil fumarate-based pre-exposure prophylaxis for HIV prevention: prospective studies in HIV-uninfected men and women

Thesis (Ph.D.)--University of Washington, 2016-06

Short-term peaks in glucose promote renal fibrogenesis independently of total glucose exposure

Postprandial hyperglycemia is implicated as a risk factor predisposing to vascular complications. This study was designed to assess recurrent short-term increases in glucose on markers of renal fibrogenesis. Human renal cortical fibroblasts were exposed to fluctuating short-term (2 h) increases to 15 mM D-glucose, three times a day over 72 h, on a background of 5 mM D-glucose. To determine whether observed changes were due to fluctuating osmolality, identical experiments were undertaken with cells exposed to L-glucose. Parallel experiments were performed in cells exposed to 5 mM D-glucose and constant exposure to either 15 or 7.5 mM D-glucose. Fluctuating D-glucose increased extracellular matrix, as measured by proline incorporation ( P < 0.05), collagen IV ( P < 0.005), and fibronectin production ( P < 0.001), in association with increased tissue inhibitor of matrix metalloproteinase (MMP) ( P < 0.05). Sustained exposure to 15 mM D-glucose increased fibronectin ( P < 0.001), in association with increased MMP-2 ( P = 0.01) and MMP-9 activity ( P < 0.05), suggestive of a protective effect on collagen matrix accumulation. Transforming growth factor-beta(1) (TGF-beta(1)) mRNA was increased after short-term (90 min) exposure to 15 mM glucose (P < 0.05) and after 24-h exposure to 7.5 mM ? ( P < 0.05). Normalization of TGF-beta(1) secretion occurred within 48 h of constant exposure to an elevated glucose. Fluctuating L-glucose also induced TGF-beta(1) mRNA and a profibrotic profile, however, to a lesser extent than observed with exposure to fluctuating D-glucose. The results suggest that exposure to fluctuating glucose concentrations increases renal interstitial fibrosis compared with stable elevations in D-glucose. The effects are, in part, due to the inherent osmotic changes.

Generalized, pruritic, ulcerating maculopapular rash necessitating cessation of sirolimus in a liver transplantation patient

The use of sirolimus as an alternative to calcineurin antagonists has enabled the continuation of immunosuppression in patients with renal impairment with preservation of kidney function. Sirolimus is generally well tolerated, with the main causes of cessation of therapy related to its effect on blood lipid profile as well as leukopenia and thrombocytopenia. We report a case of a debilitating ulcerating maculopapular rash necessitating cessation of the drug in a liver transplantation patient. A 56-year-old Caucasian liver transplantation patient presented with a diffuse, debilitating rash attributed to sirolimus use. This ultimately necessitated cessation of the immunosuppressant with subsequent resolution of her symptoms. From a review of the current literature, this is a highly unusual adverse reaction to sirolimus.

Cardiovascular risk factors in Turkish immigrants with type 2 diabetes living in the Netherlands

The cross sectional study investigated the association of tobacco smoke, vitamin D status, anthropometric parameters, and kidney function in Turkish immigrants with type 2 diabetes (T2D) living in the Netherlands. Study sample included a total of 110 participants aged 30 years and older (males= 46; females= 64). Serum cotinine, a biomarker for smoke exposure, was measured with a solid-phase competitive chemiluminescent immunoassay. Serum 25-hydroxyvitamin D [25(OH)D] was determined by electrochemiluminescence immunoassay (ECLIA). Measures of obesity including: body weight, body mass index (BMI), waist circumference (WC), and hip circumference (HC) were measured. Waist-to-hip ratio (WHR) and waist-to-height ratio (WHtR) were calculated. Urine albumin was measured by immunoturbidimetric assay. Urine creatinine was determined using the Jaffe method. All statistical analyses were performed using SPSS, version 19.0 (SPSS Inc., Chicago, IL, USA). Independent samples t-test, chi-squared tests, multiple linear regression and logistic regression analysis were used. Cotinine levels were positively associated with cholesterol to HDL ratio and atherosclerosis-index. Serum 25(OH)D levels were negatively associated with diastolic blood pressure. Gender-specific associations between anthropometric measures and high sensitivity C-reactive protein (hs-CRP) levels were observed. Hs-CRP was positively associated with WC and WHR in males and WHtR in females. Microalbuminuria (MAU), as determined by albumin-to-creatinine ratio, was present in 21% of the Turkish immigrants with T2D. Participants with hypertension were 6.58 times more likely (adjusted odds ratio) to have positive MAU as compared to normotensive participants. Our findings indicate that serum cotinine, 25(OH)D, hs-CRP, and MAU may be assessed as a standard of care for T2D management in the Turkish immigrant population. Further research should be conducted following cohorts to determine the effects of these biomarkers on CVD morbidity and mortality.

Hypertension, poor glycemic control, and microalbuminuria in Cuban Americans with type 2 diabetes

Purpose: To investigate to what degree the presence of hypertension (HTN) and poor glycemic control (GC) influences the likelihood of having microalbuminuria (MAU) among Cuban Americans with type 2 diabetes (T2D).Methods: A cross-sectional study conducted in Cuban Americans (n = 179) with T2D. Participants were recruited from a randomly generated mailing list purchased from KnowledgeBase Marketing, Inc. Blood pressure (BP) was measured twice and averaged using an adult size cuff. Glycosylated hemoglobin (A1c) levels were measured from whole blood samples with the Roche Tina-quant method. First morning urine samples were collected from each participant to determine MAU by a semiquantitative assay (ImmunoDip).Results: MAU was present in 26% of Cuban Americans with T2D. A significantly higher percentage of subjects with MA had HTN (P = 0.038) and elevated A1C (P = 0.002) than those with normoalbuminuria. Logistic regression analysis showed that after controlling for covariates, subjects with poor GC were 6.76 times more likely to have MAU if they had hypertension compared with those without hypertension (P = 0.004; 95% confidence interval [CI]: 1.83, 23.05). Conclusion: The clinical significance of these findings emphasizes the early detection of MAU in this Hispanic subgroup combined with BP and good GC, which are fundamentals in preventing and treating diabetes complications and improving individuals’ renal and cardiovascular outcomes.