Inactivation of fatty acid transport protein 1 prevents fat-induced insulin resistance in skeletal muscle.

Insulin resistance in skeletal muscle plays a major role in the development of type 2 diabetes and may be causally associated with increases in intramuscular fatty acid metabolites. Fatty acid transport protein 1 (FATP1) is an acyl-CoA synthetase highly expressed in skeletal muscle and modulates fatty acid uptake and metabolism by converting fatty acids into fatty acyl-CoA. To investigate the role of FATP1 in glucose homeostasis and in the pathogenesis of insulin resistance, we examined the effect of acute lipid infusion or chronic high-fat feeding on insulin action in FATP1 KO mice. Whole-body adiposity, adipose tissue expression of adiponectin, intramuscular fatty acid metabolites, and insulin sensitivity were not altered in FATP1 KO mice fed a regular chow diet. In contrast, FATP1 deletion protected the KO mice from fat-induced insulin resistance and intramuscular accumulation of fatty acyl-CoA without alteration in whole-body adiposity. These findings demonstrate an important role of intramuscular fatty acid metabolites in causing insulin resistance and suggest that FATP1 may be a novel therapeutic target for the treatment of insulin resistance and type 2 diabetes.

Validation of a method to predict required dialysis time for cases of methanol and ethylene glycol poisoning.

BACKGROUND: Traditional dialysis management of ethylene glycol and methanol poisoning includes frequent intradialytic measurements of concentrations of the involved alcohol and its metabolite. A simple formula to predict the required dialysis time in advance by using patient age, sex, weight, height, dialyzer specifications, and initial toxin level was proposed and tested by us previously in 5 cases. To reach a 5-mmol/L-or-less toxin concentration target, required hemodialysis time, in hours, would be [-V ln (5/A)/0.06 k], where V is the Watson estimate of total-body water in liters, A is the initial toxin concentration in mmol/L, and k is 80% of the manufacturer-specified dialyzer urea clearance in milliliters per minute at the initial observed blood flow rate. METHODS: We further assessed the accuracy of this formula by reviewing all dialyzed new patients with methanol or ethylene glycol poisoning from March 2001 to March 2004 (N = 13). RESULTS: There were no clinically or statistically significant differences between mean predicted (8.7+/-3.4 [SD] hours) and required (8.4+/-3.2 hours) dialysis time. No rebound increase in toxin levels occurred. CONCLUSION: The proposed formula is a simple, yet accurate, method to predict dialysis time for patients with methanol and ethylene glycol toxicity, confirmed by validation on an independent data set. Only initial, 2 hours before termination of dialysis, and 1 to 2 hours postdialysis measurements of toxin levels are required to ensure adequate dialysis therapy.

Quality of prereferral care in patients with chronic renal insufficiency.

BACKGROUND: Appropriate care in chronic renal insufficiency (CRI) includes blood pressure and diabetes control, as well as the investigation and management of anemia, acidosis, and bone disease. There is a lack of data on the control of these parameters at the time of referral to a nephrologist. Similarly, early referral has been emphasized in the literature, yet very little published has examined current referral patterns. METHODS: A single-center retrospective/prospective review of all new outpatient referrals to nephrologists in Halifax, Canada, in 1998 and 1999 was conducted to identify patients with CRI (serum creatinine > 1.6 mg/dL [141 micromol/L] for men or >1.2 mg/dL [106 micromol/L] for women). Quality of prereferral care was based on data from the initial clinic visit. RESULTS: Of 1,050 charts reviewed, 411 patients met the study criteria. Twenty-six percent of patients had diabetes mellitus, 18% were referred with a calculated glomerular filtration rate less than 15 mL/min, and blood pressure was optimally controlled (<130 mm Hg systolic and <80 mm Hg diastolic) in only 24%. Only 44% of patients were administered an angiotensin-converting enzyme inhibitor. Patients were administered an average of 1.9 antihypertensive agents. Significant anemia (hemoglobin < 10 g/dL) was present in 21%, and appropriate investigations were performed in only 35% of these patients. Calcium levels less than 8.6 mg/dL (2.15 mmol/L) were found in 19% of patients, and only 14% of these patients were started on calcium supplement therapy. Phosphate levels greater than 5.0 mg/dL (1.6 mmol/L) were seen in 20% of patients, and 14% of these patients were on phosphate-binder therapy. Parathyroid hormone levels were more than five times normal values in 18% of patients, and 25% of patients had bicarbonate levels less than 23 mmol/L. CONCLUSIONS: A significant proportion of patients referred with CRI receive inadequate prereferral care. Continuing education programs and referral guidelines must not only emphasize the importance of early referral, but also address the related consequences of CRI to delay the progression of renal disease and avoid complications.

Relation between access blood flow and mortality in chronic hemodialysis patients.

BACKGROUND: Access blood flow (Qa) measurement is a potentially important determinant of systemic hemodynamics in hemodialysis patients. High Qa may contribute to left ventricular dilation and high output heart failure. On the other hand, low Qa might lead to underdialysis, which is associated with adverse outcomes. METHODS: In this retrospective study of incident chronic hemodialysis patients treated in three Canadian cities (Edmonton, Calgary, and Halifax), the hypothesis that extremes of Qa(low or high) would be associated with increased mortality was tested. The distribution of Qa was not Gaussian, and therefore Qa was log-transformed in analyses that treated it as a continuous variable. Qa was classified into categories defined by cutpoints of 500, 1000, 1500, and 2000 ml/min. Univariate and multivariate Cox proportional hazard models were performed to examine the relation between Qa and all-cause mortality. Patients were followed from the date of Qa measurement until death; follow-up was discontinued at loss to follow-up, kidney transplantation, or end of study. RESULTS: Of 820 participants, those with lower levels of Qa tended to be older and to have more comorbidities. During the median follow-up period of 28 mo, 206 (25.1%) participants died and 101 (12.3%) patients received a kidney transplant. When only baseline measures of Qa were considered, there was significant association between Qa and mortality [hazard ratio (HR) per unit increase in logQa 0.81, 95% confidence interval (CI) 0.67, 0.97; adjusted HR per unit increase in logQa 0.90, 95% CI 0.72, 1.11]. The adjusted risk of mortality was similar between the different categories of baseline Qa before and after adjustment for demographic characteristics, comorbidity, and access type. In analyses that included all Qa measurements per patient as a time-varying covariate, the adjusted association between Qa and death remained nonsignificant, with no evidence of increased mortality at higher Qa (HR per unit increase in logQa 0.82, 95% CI 0.67, 1.01, P = 0.066). CONCLUSION: The findings of this study do not suggest an increased risk of death at higher levels of Qa, Further studies would be needed to confirm an increased risk of death at lower Qa.

Effectiveness of a multidisciplinary kidney disease clinic in achieving treatment guideline targets.

BACKGROUND: We have demonstrated previously that at referral most chronic kidney disease (CKD) patients have suboptimal metabolic and hypertension control. Although several studies suggest that CKD clinics improve patient outcome, in fact there are minimal published data describing the actual effect of such clinics on these parameters. METHODS: We performed a historical prospective review of a cohort of 340 CKD patients referred to our multidsciplinary clinic in 1998 or 1999, with estimated creatinine clearance (CCr) <60 ml/min. Data regarding blood pressure (BP) control, metabolic/anaemia parameters, medications, access planning and dialysis starts were collected. RESULTS: The number of patients followed was 234, 144, 100 and 70 at years 1-4 of follow-up, respectively. Twenty-five percent of the patients were diabetic, and 25% were suspected to have ischaemic nephropathy; mean age was 67+/-15 years. Although phosphate control improved from referral, below a CCr of 30 ml/min, 27% of visits showed hyperphosphataemia. Thirty-one percent of patients with CCr <15 ml/min had haemoglobin <100 g/l at follow-up despite the availability of erythropoietin. BP improved from a mean of 151/80 mmHg at referral to 137/75 mmHg in subsequent visits. At follow-up visits, 62% of BPs were still >130 mmHg systolic or 85 mmHg diastolic. For proteinuric patients (>1 g/day), 75% of follow-up visits showed BP >125/75 mmHg, despite angiotensin-converting enzyme inhibitor use increasing from 35% at referral to 79% at follow-up. Twenty-four percent of patients started renal replacement therapy, initially haemodialysis (HD) in 57%, peritoneal dialysis (PD) in 35% and pre-emptive transplant in 8%. Thirty-eight percent of dialysis starts occurred within 6 months of referral, but PD was the modality in half of these. Only half of the HD patients started using an aterio-venous fistula, and of those using a central catheter 11 of 24 had been followed >6 months, but only four of them had attempted fistula creation. CONCLUSIONS: CKD clinic attendance was associated with improvements in metabolic and BP control, and was able to facilitate the use of PD even for late referrals. However, even the multidisciplinary model with nephrologists, nurse educators and dietitians was unable to achieve guideline-recommended metabolic, anaemia, BP and access targets for a significant number of patients.

Best threshold for diagnosis of stenosis or thrombosis within six months of access flow measurement in arteriovenous fistulae.

Canadian clinical practice guidelines recommend performing angiography when access blood flow (Qa) is <500 ml/min in native vessel arteriovenous fistulae (AVF), but data on the value of Qa that best predicts stenosis are sparse. Because correction of stenosis in AVF improves patency rates, this issue seems worthy of investigation. Receiver-operating characteristic curves were constructed to examine the relationship between different threshold values of Qa and stenosis in 340 patients with AVF. Stenosis was defined by the composite outcome of access failure or angiographic stenosis occurring within 6 mo of the first Qa measurement. The Qa value was then classified as true negative, true positive, false negative, or false positive for stenosis. An additional analysis was performed in which Qa was corrected for systolic BP before assigning it to one of the four diagnostic categories. The area under the curve for the composite definition of stenosis was 0.86. Graphically, Qa thresholds of <500 and <600 ml/min had similar efficacy for detecting stenosis or access failure within 6 mo, and both seemed superior to <400 ml/min. However, the frequency of the composite definition of stenosis among AVF with Qa between 500 and 600 ml/min was only 6 (25%) of 24, as compared with 58 (76%) of 76 when Qa was <500 ml/min. This suggests that most lesions that would be found using a threshold of <600 ml/min occurred in AVF with Qa <500 ml/min and that the small gain in sensitivity associated with the <600-ml/min threshold would be outweighed by the reduced specificity compared with <500 ml/min. Correcting Qa for BP did not improve diagnostic performance or change these results, which were consistent in several sensitivity analyses. Qa measurements seemed to predict stenosis or incipient access failure equally well in groups defined by diabetic status, gender, and AVF location. In conclusion, it was found that Qa <500 ml/min seems to be the most appropriate threshold for performing angiography in patients with native vessel AVF. It is recommended that clinicians arrange angiography when Qa is <500 ml/min in AVF.

Factors associated with access blood flow in native vessel arteriovenous fistulae.

BACKGROUND: Access blood flow (Qa) identifies stenosis in patients with native vessel AV fistulae (AVF), but data on factors that are associated with Qa in normally functioning accesses are sparse. Such factors could be used in conjunction with Qa to improve the diagnostic performance of screening. We examined the relationship between Qa and certain clinical characteristics in a large group of patients with AVF. METHODS: This was a retrospective study of incident and prevalent haemodialysis patients treated at a single institution, all of whom had a functioning AVF during the study period. Qa was measured bimonthly using ultrasound dilution in all subjects. Mixed models were used to explore the relationship between Qa and a group of independent variables, including systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), diabetes mellitus, patient age, sex, height, body mass index (BMI) and AVF location (forearm vs upper arm). RESULTS: A total of 4084 Qa measurements was made in 294 patients. Univariate analysis found that younger patient age, non-diabetic status, higher blood pressure (SBP, DBP, MAP, all at the time of Qa measurement), upper arm AVF location and overweight status (BMI >/=25) were significantly associated with Qa. SBP appeared to be more strongly associated with Qa than either DBP or MAP. Patient sex, height and interval between access creation and Qa measurement were not significantly associated with Qa. Tests for interaction suggested that the association between SBP and age and Qa varied significantly by access location. In a multivariate model, SBP, overweight status and diabetic status were independently associated with Qa. The strength of the association between these characteristics and Qa appeared to be clinically relevant. CONCLUSIONS: Our findings suggest that a single Qa threshold for angiography in all patients may be simplistic, and that the optimal threshold might vary by patient subgroup. The strong association between SBP and Qa suggests that adjusting Qa for SBP may improve the specificity of access screening. Further work is required to determine whether such modifications to current practice would improve the predictive power of Qa measurements for detection of stenosis in AVF.

Targeted deletion of fatty acid transport protein-4 results in early embryonic lethality.

Fatty acid transport protein-4 (FATP4) is the major FATP in the small intestine. We previously demonstrated, using in vitro antisense experiments, that FATP4 is required for fatty acid uptake into intestinal epithelial cells. To further examine the physiological role of FATP4, mice carrying a targeted deletion of FATP4 were generated. Deletion of one allele of FATP4 resulted in 48% reduction of FATP4 protein levels and a 40% reduction of fatty acid uptake by isolated enterocytes. However, loss of one FATP4 allele did not cause any detectable effects on fat absorption on either a normal or a high fat diet. Deletion of both FATP4 alleles resulted in embryonic lethality as crosses between heterozygous FATP4 parents resulted in no homozygous offspring; furthermore, no homozygous embryos were detected as early as day 9.5 of gestation. Early embryonic lethality has been observed with deletion of other genes involved in lipid absorption in the small intestine, namely microsomal triglyceride transfer protein and apolipoprotein B, and has been attributed to a requirement for fat absorption early in embryonic development across the visceral endoderm. In mice, the extraembryonic endoderm supplies nutrients to the embryo prior to development of a chorioallantoic placenta. In wild-type mice we found that FATP4 protein is highly expressed by the epithelial cells of the visceral endoderm and localized to the brush-border membrane of extraembryonic endodermal cells. This localization is consistent with a role for FATP4 in fat absorption in early embryogenesis and suggests a novel requirement for FATP4 function during development.