Lower Extremity Amputation Rates in People With Diabetes Mellitus: A Retrospective Population Based Cohort Study in Zwolle Region, The Netherlands.

OBJECTIVE: Lower extremity amputations are a major complication of diabetes mellitus (DM). In a previous Dutch study, the incident rate of major amputations was 89.2 per 100 000 person years. The primary aim of this study was to describe the lower extremity amputation rates in people with DM in the Zwolle region, where preventive and curative footcare is organised according to the guidelines of the International Working Group of the Diabetic Foot (IWGDF). The secondary aim was to evaluate outcomes and underlying characteristics of these people. METHODS: This was a retrospective regional population based cohort study. Data from all people with DM treated in primary and secondary care, living in the region Zwolle were collected. All amputations in the period 2017 to 2019 were analysed. Comparisons were made between those with and without an amputation. RESULTS: In the analysis 5 915 people with DM were included, with a mean age of 67.8 (IQR 57.9, 75.9) years. Of those people, 47% were women and the median HbA1c was 53 (IQR 47, 62) mmol/mol. Over the three year study period 68 amputations were performed in 59 people: 46 minor, 22 major. This translated into an average annual crude amputation incidence rate of non-traumatic major and minor amputations of 41.5 and 86.9 per 100 000 person years among people with diabetes. Compared with those not undergoing amputations, those who underwent an amputation were more often men, older, mainly had T2DM, were treated in secondary care, had higher diastolic blood pressure, worse diabetic footcare profile, longer DM duration and higher HbA1c. At the end of the follow up, 111 people died: 96 (1.6%) without and 15 (25.4%) with amputations (p < .001). CONCLUSIONS: This retrospective study provides detailed insight into the rate of amputations in Dutch people with diabetes in the region Zwolle. Compared with previous Dutch estimates, these data suggest a considerable decrease in the major amputation incidence rate.

An urgent call to raise the bar in oncology.

Important breakthroughs in medical treatments have improved outcomes for patients suffering from several types of cancer. However, many oncological treatments approved by regulatory agencies are of low value and do not contribute significantly to cancer mortality reduction, but lead to unrealistic patient expectations and push even affluent societies to unsustainable health care costs. Several factors that contribute to approvals of low-value oncology treatments are addressed, including issues with clinical trials, bias in reporting, regulatory agency shortcomings and drug pricing. With the COVID-19 pandemic enforcing the elimination of low-value interventions in all fields of medicine, efforts should urgently be made by all involved in cancer care to select only high-value and sustainable interventions. Transformation of medical education, improvement in clinical trial design, quality, conduct and reporting, strict adherence to scientific norms by regulatory agencies and use of value-based scales can all contribute to raising the bar for oncology drug approvals and influence drug pricing and availability.

Galectin-3 and Risk of Late Graft Failure in Kidney Transplant Recipients: A 10-year Prospective Cohort Study.

BACKGROUND: Galectin-3 may play a causal role in kidney inflammation and fibrosis, which may also be involved in the development of kidney graft failure. With novel galectin-3-targeted pharmacological therapies increasingly coming available, we aimed to investigate whether galectin-3 is associated with risk of late graft failure in kidney transplant recipients (KTR). METHODS: We studied adult KTR who participated in TransplantLines Insulin Resistance and Inflammation Biobank and Cohort Study, recruited in a university setting (2001-2003). Follow-up was performed for a median of 9.5 (interquartile range, 6.2-10.2) years. Overall and stratified (Pinteraction < 0.05) multivariable-adjusted Cox proportional-hazards regression analyses were performed to study the association of galectin-3 with risk of graft failure (restart of dialysis or retransplantation). RESULTS: Among 561 KTR (age 52 ± 12 y; 54% males), baseline median galectin-3 was 21.1 (interquartile range, 17.0-27.2) ng/mL. During follow-up, 72 KTR developed graft failure (13, 18, and 44 events over increasing tertiles of galectin-3). Independent of adjustment for donor, recipient, and transplant characteristics, galectin-3-associated with increased risk of graft failure (hazard ratios [HR] per 1 SD change, 2.12; 95% confidence interval [CI], 1.63-2.75; P < 0.001), particularly among KTR with systolic blood pressure ≥140 mmHg (HR, 2.29; 95% CI, 1.80-2.92; P < 0.001; Pinteraction = 0.01) or smoking history (HR, 2.56; 95% CI, 1.95-3.37; P < 0.001; Pinteraction = 0.03). Similarly, patients in the highest tertile of galectin-3 were consistently at increased risk of graft failure. CONCLUSIONS: Serum galectin-3 levels are elevated in KTR, and independently associated with increased risk of late graft failure. Whether galectin-3-targeted therapies may represent novel opportunities to decrease the long-standing high burden of late graft failure in stable KTR warrants further studies.

Relationship between serum B12 concentrations and mortality: experience in NHANES.

BACKGROUND: There is conflicting evidence in the literature on the association between (elevated) serum B12 concentrations and subsequent disease or mortality. We evaluated in the NHANES general population the association of serum B12 concentrations as well as vitamin B12 supplement intake with all-cause, cardiovascular, and cancer-related mortality, while taking into account demographic and lifestyle factors and significant other diseases which are known to be associated with poorer outcome. METHODS: The main outcomes of our study were all-cause mortality, cardiovascular mortality, and cancer-related mortality. Mortality status and cause of death were determined by NHANES-linked National Death Index public access files through December 31, 2015. The association of serum B12 concentrations and vitamin B12 supplement intake with mortality was assessed with Cox proportional hazard (PH) models, with adjustment for a number of relevant demographic and lifestyle factors and comorbidity. RESULTS: The final study population of 24,262 participants had a mean age of 48 (SD 19) years; 50.1% were males. The median follow-up duration was 109 months (range 1-201 months). On the census day of December 31, 2015, 3023 participants were determined as deceased (12.5%). The fully adjusted Cox PH model indicated that low serum B12 concentrations < 140 pmol/l were associated with a small increase in all-cause (hazard ratio, HR 1.39, 95% CI 1.08-1.78, p = 0.011) and cardiovascular (HR 1.64, 95% CI 1.08-2.47, p = 0.020) mortality. Similarly, high serum B12 concentrations > 700 pmol/l were associated with an increase in cardiovascular mortality only (HR 1.45, 95% CI 1.01-2.06, p = 0.042). Participants with a diagnosis of hypertension, dyslipidemia, CVD, and cancer more frequently used vitamin B12-containing supplements than those without these diagnoses. We could not demonstrate an association between vitamin B12 supplement intake and mortality, when adjusted for comorbidity. CONCLUSIONS: In the general population of NHANES, low serum B12 concentrations were associated with a moderate increase in all-cause mortality. There was a small but significant increase in cardiovascular mortality in the groups with low or high serum B12. High intake of vitamin B12 in the form of supplements was not associated with any adverse effect on mortality and therefore can be regarded as safe.

Post-transplantation plasma malondialdehyde is associated with cardiovascular mortality in renal transplant recipients: a prospective cohort study.

BACKGROUND: In renal transplant recipients (RTRs), cardiovascular mortality is the most common cause of long-term renal graft loss. Oxidative stress (OS) has been associated with cardiovascular disease and is known to be enhanced in RTRs. We aimed to prospectively investigate whether the concentration of the OS biomarker malondialdehyde (MDA) is associated with long-term risk of cardiovascular mortality in a large cohort of RTRs. METHODS: The plasma MDA concentration was measured using the thiobarbituric acid reaction assay in 604 extensively phenotyped RTRs with a functioning allograft for ≥1 year. The association between MDA and cardiovascular mortality was assessed using Cox proportional hazard regression analyses in the overall cohort and within subgroups according to significant effect modifiers. RESULTS: Median circulating MDA concentration at baseline was 5.38 [interquartile range (IQR) 4.31-6.45] µmol/L. During a follow-up period of 6.4 (IQR 5.6-6.8) years, 110 (18%) RTRs died, with 40% of deaths due to cardiovascular causes. MDA concentration was significantly associated with the risk for cardiovascular mortality {hazard ratio [HR] 1.31 [95% confidence interval (CI) 1.03-1.67] per 1-SD increment}, independent of adjustment for potential confounders, including renal function, immunosuppressive therapy, smoking status and blood pressure. The association between MDA concentration and the risk for cardiovascular mortality was stronger in RTRs with relatively lower plasma ascorbic acid concentrations [≤42.5 µmol/L; HR 1.79 (95% CI 1.30-2.48) per 1-SD increment] or relatively lower estimated glomerular filtration rates [≤45 mL/min/1.73 m2; HR 2.09 (95% CI 1.45-3.00) per 1-SD increment]. CONCLUSIONS: Circulating MDA concentration is independently associated with long-term risk for cardiovascular mortality, particularly in RTRs with relatively lower ascorbic acid concentrations or renal function. Further studies are warranted to elucidate whether OS-targeted interventions could decrease cardiovascular mortality in RTRs.

Plasma Vitamin C and Cancer Mortality in Kidney Transplant Recipients.

There is a changing trend in mortality causes in kidney transplant recipients (KTR), with a decline in deaths due to cardiovascular causes along with a relative increase in cancer mortality rates. Vitamin C, a well-known antioxidant with anti-inflammatory and immune system enhancement properties, could offer protection against cancer. We aimed to investigate the association of plasma vitamin C with long-term cancer mortality in a cohort of stable outpatient KTR without history of malignancies other than cured skin cancer. Primary and secondary endpoints were cancer and cardiovascular mortality, respectively. We included 598 KTR (mean age 51 ± 12 years old, 55% male). Mean (SD) plasma vitamin C was 44 ± 20 µmol/L. At a median follow-up of 7.0 (IQR, 6.2-7.5) years, 131 patients died, of which 24% deaths were due to cancer. In Cox proportional hazards regression analyses, vitamin C was inversely associated with cancer mortality (HR 0.50; 95%CI 0.34-0.74; P < 0.001), independent of potential confounders, including age, smoking status and immunosuppressive therapy. In secondary analyses, vitamin C was not associated with cardiovascular mortality (HR 1.16; 95%CI 0.83-1.62; P = 0.40). In conclusion, plasma vitamin C is inversely associated with cancer mortality risk in KTR. These findings underscore that relatively low circulating plasma vitamin C may be a meaningful as yet overlooked modifiable risk factor of cancer mortality in KTR.

Circulating Advanced Glycation Endproducts and Long-Term Risk of Cardiovascular Mortality in Kidney Transplant Recipients.

BACKGROUND AND OBJECTIVES: In kidney transplant recipients, elevated circulating advanced glycation endproducts (AGEs) are the result of increased formation and decreased kidney clearance. AGEs trigger several intracellular mechanisms that ultimately yield excess cardiovascular disease. We hypothesized that, in stable kidney transplant recipients, circulating AGEs are associated with long-term risk of cardiovascular mortality, and that such a relationship is mediated by inflammatory, oxidative stress, and endothelial dysfunction biomarkers. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Prospective cohort study of stable kidney transplant recipients recruited between 2001 and 2003 in a university setting. We performed multivariable-adjusted Cox regression analyses to assess the association of AGEs (i.e., Nε-[Carboxymethyl]lysine (CML) and Nε-[Carboxyethyl]lysine (CEL), measured by tandem mass spectrometry) with cardiovascular mortality. Mediation analyses were performed according to Preacher and Hayes's procedure. RESULTS: We included 555 kidney transplant recipients (age 51±12 years, 56% men). During a median follow-up of 6.9 years, 122 kidney transplant recipients died (52% deaths were due to cardiovascular causes). CML and CEL concentrations were directly associated with cardiovascular mortality (respectively, hazard ratio, 1.55; 95% confidence interval, 1.24 to 1.95; P<0.001; and hazard ratio, 1.53; 95% confidence interval 1.18 to 1.98; P=0.002), independent of age, diabetes, smoking status, body mass index, eGFR and proteinuria. Further adjustments, including cardiovascular history, did not materially change these findings. In mediation analyses, free thiol groups and soluble vascular cell adhesion molecule-1 consistently explained approximately 35% of the association of CML and CEL with cardiovascular mortality. CONCLUSIONS: In stable kidney transplant recipients, circulating levels of AGEs are independently associated with long-term risk of cardiovascular mortality. PODCAST: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2019_09_17_CJN00540119.mp3.

Beta-Blocker Use in Pregnancy and Risk of Specific Congenital Anomalies: A European Case-Malformed Control Study.

INTRODUCTION: The prevalence of chronic hypertension is increasing in pregnant women. Beta-blockers are among the most prevalent anti-hypertensive agents used in early pregnancy. OBJECTIVE: The objective of this study was to investigate whether first-trimester use of beta-blockers increases the risk of specific congenital anomalies in offspring. METHODS: A population-based case-malformed control study was conducted in 117,122 registrations of congenital anomalies from 17 European Concerted Action on Congenital Anomalies and Twins (EUROCAT) registries participating in EUROmediCAT with data for all or part of the period between 1995 and 2013. Associations previously reported in the literature (signals) were tested and an exploratory analysis was performed to identify new signals. Odds ratios of exposure to any beta-blocker or to a beta-blocker subgroup were calculated for each signal anomaly compared with two control groups (non-chromosomal, non-signal anomalies and chromosomal anomalies). The exploratory analyses were performed for each non-signal anomaly compared with all the other non-signal anomalies. RESULTS: The signals from the literature (congenital heart defects, oral clefts, neural tube defects and hypospadias) were not confirmed. Our exploratory analysis revealed that multi-cystic renal dysplasia had significantly increased odds of occurring after maternal exposure to combined alpha- and beta-blockers (adjusted odds ratio 3.8; 95% confidence interval 1.3-11.0). CONCLUSION: Beta-blocker use in the first trimester of pregnancy was not found to be associated with a higher risk of specific congenital anomalies in the offspring, but a new signal between alpha- and beta-blockers and multi-cystic renal dysplasia was found. Future large epidemiological studies are needed to confirm or refute our findings.

Intake of Marine-Derived Omega-3 Polyunsaturated Fatty Acids and Mortality in Renal Transplant Recipients.

The effect of marine-derived omega-3 polyunsaturated fatty acids (n-3 PUFA) on long-term outcome in renal transplant recipients (RTR) remains unclear. We investigated whether marine-derived n-3 PUFA intake is associated with all-cause and cardiovascular (CV) mortality in RTR. Intake of eicosapentaenoic acid plus docosahexaenoic acid (EPA-DHA) was assessed using a validated Food Frequency Questionnaire. Cox regression analyses were performed to evaluate the associations of EPA-DHA intake with all-cause and CV mortality. We included 627 RTR (age 53 ± 13 years). EPA-DHA intake was 102 (42-215) mg/day. During median follow-up of 5.4 years, 130 (21%) RTR died, with 52 (8.3%) due to CV causes. EPA-DHA intake was associated with lower risk of all-cause mortality (Hazard Ratio (HR) 0.85; 95% confidence interval (95% CI) 0.75-0.97). Age (p= 0.03) and smoking status (p = 0.01) significantly modified this association, with lower risk of all-cause and CV mortality particularly in older (HR 0.75, 95% CI 0.61-0.92; HR 0.68, 95% CI 0.48-0.95) and non-smoking RTR (HR 0.80, 95% CI 0.68-0.93; HR 0.74, 95% CI 0.56-0.98). In conclusion, marine-derived n-3 PUFA intake is inversely associated with risk of all-cause and CV mortality in RTR. The strongest associations were present in subgroups of patients, which adds further evidence to the plea for EPA-DHA supplementation, particularly in elderly and non-smoking RTR.

Causal path analyses of the association of protein intake with risk of mortality and graft failure in renal transplant recipients.

The effect of a low protein intake on survival in renal transplant recipients (RTR) is unknown. A low protein intake may increase risks of malnutrition, low muscle mass, and death. We aimed to study associations of protein intake with mortality and graft failure and to identify potential intermediate factors. Protein intake was estimated from 24-h urinary urea excretion (24-h UUE). Graft failure was defined as return to dialysis or retransplantation. We used Cox regression analyses to analyze associations with outcome and potential intermediate factors in the causal path. In 604 RTR, mean ± SD 24-h UUE was 380 ± 114 mmol/24-h. During median follow-up for 7.0 yr (interquartile range: 6.2-7.5 yr), 133 RTR died and 53 developed graft failure. In univariate analyses, 24-h UUE was associated with lower risk of mortality (HR [95% CI] = 0.80 [0.69-0.94]) and graft failure (HR [95% CI] = 0.72 [0.56-0.92]). These associations were independent of potential confounders. In causal path analyses, the association of 24-h UUE with mortality disappeared after adjustment for muscle mass. Low protein intake is associated with increased risk of mortality and graft failure in RTR. Causal path analyses reveal that the association with mortality is explained by low muscle mass. These findings suggest that protein intake restriction should not be advised to RTR.

Assessment of Cotinine Reveals a Dose-Dependent Effect of Smoking Exposure on Long-term Outcomes After Renal Transplantation.

BACKGROUND: Smoking is a risk factor for poor late outcomes in renal transplant recipients (RTR). Smoking exposure can be assessed by self-report and cotinine measurements. We investigated whether use of cotinine as a biomarker for smoking exposure can serve as an alternative for self-report and to compare associations of smoking exposure by self-report and cotinine with outcomes in RTR and assess dose dependency. METHODS: Renal transplant recipients were classified as never, former, light (≤10 cigarettes/day), and heavy smokers (>10 cigarettes/day) according to self-report and analogous categories for urine and plasma cotinine. First, we assessed agreement of self-reported smoking exposure with smoking exposure according urine and plasma cotinine. Second, we compared the associations with graft failure and mortality. RESULTS: Of 603 RTR (age 51.5 ± 12.1 years, 55% men), 36.0% RTR were never, 42.3% former, 10.6% light, and 11.1% heavy smokers according to self-report. The majority (98.6%) of never smokers had nondetectable cotinine. However, 14 and 13 RTR reporting no active smoking had respective urine or plasma cotinine consistent with active smoking. Cotinine-based measurements were dose-dependently associated with mortality and graft failure. CONCLUSIONS: Plasma and urine cotinine can serve as an alternative to self-report and were dose-dependently associated with poor late outcomes in RTR.

PROFSS: a screening tool for early identification of functional somatic symptoms.

OBJECTIVE: To develop and validate a brief screening tool for predicting functional somatic symptoms (FSS) based on clinical and non-clinical information from the general practitioner referral letter, and to assess its inter-rater reliability. METHODS: The derivation sample consisted of 357 consecutive patients referred to an internal outpatient clinic by their general practitioner. Referral letters were scored for candidate predictors for the main outcome measure, which was a final diagnosis of FSS made by the internist. Logistic regression identified the following independent predictors: type of symptoms, somatic and psychiatric comorbidity, absence of abnormal physical findings by the general practitioner, previous specialist consultation, and the use of illness terminology. Temporal validation was performed in a cohort of 94 consecutive patients in whom predictors were scored by two independent raters. RESULTS: In both the derivation and validation sample, the discriminatory power of the model was good with areas under the receiver operating characteristic curves of 0.84 (95%confidence interval: 0.80-0.88) after bootstrapping and 0.82 (95%confidence interval: 0.73-0.91), respectively. Calibration of the models was excellent in both samples and the interobserver agreement in the validation sample was very good (intraclass coefficient: 0.82 (95%confidence interval: 0.75-0.88)). Based on this model, we constructed the brief screening tool PROFSS (Predicted Risk Of Functional Somatic Symptoms). PROFSS identified patient groups with risks of FSS ranging from 17% (95%CI: 10-26%) to 92% (95%CI:86-96%). CONCLUSION: The presence of FSS can be predicted with the brief screening tool PROFSS, based on a limited set of items present in the general practitioner referral letter.

Circulating peroxiredoxin 4 and type 2 diabetes risk: the Prevention of Renal and Vascular Endstage Disease (PREVEND) study.

AIMS/HYPOTHESIS: Oxidative stress plays a key role in the development of type 2 diabetes mellitus. We previously showed that the circulating antioxidant peroxiredoxin 4 (Prx4) is associated with cardiometabolic risk factors. We aimed to evaluate the association of Prx4 with type 2 diabetes risk in the general population. METHODS: We analysed data on 7,972 individuals from the Prevention of Renal and Vascular End-stage Disease (PREVEND) study (49% men, aged 28-75 years) with no diabetes at baseline. Logistic regression models adjusted for age, sex, smoking, waist circumference, hypertension and family history of diabetes were used to estimate the ORs for type 2 diabetes. RESULTS: During a median follow up of 7.7 years, 496 individuals (288 men; 58%) developed type 2 diabetes. The median (Q1-Q3) Prx4 level was 0.84 (0.53-1.40) U/l in individuals who developed type 2 diabetes and 0.68 (0.43-1.08) U/l in individuals who did not develop type 2 diabetes. For every doubling of Prx4 levels, the adjusted OR (95% CI) for type 2 diabetes was 1.16 (1.05-1.29) in the whole population; by sex, it was 1.31 (1.14-1.50) for men and 1.03 (0.87-1.21) for women. Further adjustment for other clinical measures did not materially change the results. The addition of Prx4 to a validated diabetes risk score significantly improved the prediction of type 2 diabetes in men (p = 0.002 for reclassification improvement). CONCLUSIONS/INTERPRETATION: Our findings suggest that elevated serum Prx4 levels are associated with a higher risk of incident type 2 diabetes. For men, taking Prx4 into consideration can improve type 2 diabetes prediction over a validated diabetes risk score; in contrast, there is no improvement in risk prediction for women.

Midregional fragment of proadrenomedullin, new-onset albuminuria, and cardiovascular and all-cause mortality in patients with type 2 diabetes (ZODIAC-30).

OBJECTIVE: The midregional fragment of proadrenomedullin (MR-proADM) is a marker of endothelial dysfunction and has been associated with a variety of diseases. Our aim was to investigate whether MR-proADM is associated with new-onset albuminuria and cardiovascular (CV) and all-cause mortality in patients with type 2 diabetes treated in primary care. RESEARCH DESIGN AND METHODS: Patients with type 2 diabetes participating in the observational Zwolle Outpatient Diabetes Project Integrating Available Care (ZODIAC) study were included. Cox regression analyses were used to assess the relation of baseline MR-proADM with new-onset albuminuria and CV and all-cause mortality. Risk prediction capabilities of MR-proADM for new-onset albuminuria and CV and all-cause mortality were assessed with Harrell's C and the integrated discrimination improvement. RESULTS: In 1,243 patients (mean age 67 [±12] years), the median follow-up was 5.6 years (interquartile range 3.1-10.1); 388 (31%) patients died, with 168 (12%) CV deaths. Log2 MR-proADM was associated with CV (hazard ratio 1.96 [95% CI 1.27-3.01]) and all-cause mortality (1.78 [1.34-2.36]) after adjusting for age, sex, BMI, smoking, systolic blood pressure, cholesterol-to-HDL ratio, duration of diabetes, HbA1c, ACE inhibitor/angiotensin receptor blocker, history of CV diseases, log serum creatinine, and log albumin-to-creatinine ratio. MR-proADM slightly improved mortality risk prediction. The age- and sex-adjusted, but not multivariate-adjusted, MR-proADM levels were associated with new-onset albuminuria. CONCLUSIONS: MR-proADM was associated with CV and all-cause mortality in patients with type 2 diabetes after a median follow-up of 5.6 years. There was no independent relationship with new-onset albuminuria. In the availability of an extensive set of risk factors, there was little added effect of MR-proADM in risk prediction of CV and all-cause mortality.

Role of HDL cholesterol and estimates of HDL particle composition in future development of type 2 diabetes in the general population: the PREVEND study.

BACKGROUND AND AIMS: High-density lipoproteins (HDLs) may directly stimulate ß-cell function and glucose metabolism. We determined the relationships of fasting high-density lipoprotein cholesterol (HDL-C), plasma apolipoprotein (apo) A-I and apoA-II, and HDL-C-to-apoA-I and HDL-C-to-apoA-II ratios, as estimates of HDL particle composition, with incident type 2 diabetes mellitus. METHODS: A prospective study was carried out in the Prevention of Renal and Vascular End-Stage Disease (PREVEND) cohort after exclusion of subjects with diabetes at baseline (n = 6820; age, 28-75 years). The association of HDL-related variables with incident type 2 diabetes was determined by multivariate logistic regression analyses. RESULTS: After a median follow-up of 7.7 years, 394 incident cases of type 2 diabetes mellitus were ascertained (5.8%). After adjustment for age, sex, family history of diabetes, body mass index, hypertension, alcohol, and smoking, odd ratios (ORs) for diabetes were 0.55 (95% confidence interval [CI], 0.47-0.64; P < .001), 0.81 (0.71-0.93; P = .002), 0.02 (0.01-0.06; P < .001), and 0.03 (0.01-0.060; P < .001) per 1-SD increase in HDL-C and apoA-I and in the HDL-C-to-apoA-I and the HDL-C-to-apoA-II ratios, respectively. In contrast, apoA-II was not related to incident diabetes (OR = 1.02; 95% CI, 0.90-1.16; P=0.71). The relationships of HDL-C and the ratios of HDL-C to apoA-I and HDL-C to apoA-II remained significant after further adjustment for baseline glucose and triglycerides (OR(HDL) = 0.74 [95% CI, 0.61-0.88], OR(HDL/APO A-I) = 0.14 [0.04-0.44], and OR(HDL/APOA-II) = 0.12 [0.04-0.36]; all P ≤ .001). CONCLUSIONS: Higher HDL-C, as well as higher HDL-C-to-apoA-I and HDL-C-to-apoA-II ratios are strongly and independently related to a lower risk of future type 2 diabetes.

External validation of the KORA S4/F4 prediction models for the risk of developing type 2 diabetes in older adults: the PREVEND study.

Recently, prediction models for type 2 diabetes mellitus (T2DM) in older adults (aged ≥55 year) were developed in the KORA S4/F4 study, Augsburg, Germany. We aimed to externally validate the KORA models in a Dutch population. We used data on both older adults (n = 2,050; aged ≥55 year) and total non-diabetic population (n = 6,317; aged 28-75 year) for this validation. We assessed performance of base model (model 1: age, sex, BMI, smoking, parental diabetes and hypertension) and two clinical models: model 1 plus fasting glucose (model 2); and model 2 plus uric acid (model 3). For 7-year risk of T2DM, we calculated C-statistic, Hosmer-Lemeshow χ(2)-statistic, and integrated discrimination improvement (IDI) as measures of discrimination, calibration and reclassification, respectively. After a median follow-up of 7.7 years, 199 (9.7%) and 374 (5.9%) incident cases of T2DM were ascertained in the older and total population, respectively. In the older adults, C-statistic was 0.66 for model 1. This was improved for model 2 and model 3 (C-statistic = 0.81) with significant IDI. In the total population, these respective C-statistics were 0.77, 0.85 and 0.85. All models showed poor calibration (P < 0.001). After adjustment for the intercept and slope of each model, we observed good calibration for most models in both older and total populations. We validated the KORA clinical models for prediction of T2DM in an older Dutch population, with discrimination similar to the development cohort. However, the models need to be corrected for intercept and slope to acquire good calibration for application in a different setting.

Renoprotective effects of long-term oral nicotine in a rat model of spontaneous proteinuria.

Many proteinuric renal conditions are accompanied by renal inflammation. Nicotine is known to have anti-inflammatory properties and is used in oral form to help subjects quit smoking. A potential anti-inflammatory role of nicotine in proteinuric renal diseases has not been investigated to date. We therefore evaluated the effects of oral nicotine in a rat model of proteinuria-induced renal inflammation. We used a well-established model of adult (24 wk of age) male Munich-Wistar-Frömter rats. Animals were given three different physiological doses of nicotine in drinking water for 28 wk until 52 wk of age (long term). A group without nicotine served as a parallel control. At 52 wk of age, the control group had a 2.1 times reduction in creatinine clearance, 3.2 times increase in urinary protein excretion, an increased focal glomerulosclerosis (FGS) score, increased glomerular desmin deposition, decreased glomerular podocin, and a higher accumulation of macrophages and myofibroblasts compared with 24-wk-old animals. Oral treatment with nicotine dose dependently preserved renal function and halted proteinuria progression, which were independent of blood pressure reduction. It also reduced FGS, desmin deposition, podocin loss, and density of renal macrophages and myofibroblasts. Nicotine also reduced the level of gene expression of the renal inflammatory markers monocyte chemoattractant protein and vascular cell adhesion molecule-1. In conclusion, long-term oral nicotine preserved kidney function, reduced proteinuria, reduced renal inflammation, and protected progression of renal structural damage in a rat model of proteinuria. We further suggest evaluating nicotine as a potential additional therapeutic option for treating proteinuric kidney diseases.

Liver function tests and risk prediction of incident type 2 diabetes: evaluation in two independent cohorts.

BACKGROUND: Liver function tests might predict the risk of type 2 diabetes. An independent study evaluating utility of these markers compared with an existing prediction model is yet lacking. METHODS AND FINDINGS: We performed a case-cohort study, including random subcohort (6.5%) from 38,379 participants with 924 incident diabetes cases (the Dutch contribution to the European Prospective Investigation Into Cancer and Nutrition, EPIC-NL, the Netherlands), and another population-based cohort study including 7,952 participants with 503 incident cases (the Prevention of Renal and Vascular End-stage Disease, PREVEND, Groningen, the Netherlands). We examined predictive value of combination of the Liver function tests (gamma-glutamyltransferase, alanine aminotransferase, aspartate aminotransferase and albumin) above validated models for 7.5-year risk of diabetes (the Cooperative Health Research in the Region of Augsburg, the KORA study). Basic model includes age, sex, BMI, smoking, hypertension and parental diabetes. Clinical models additionally include glucose and uric acid (model1) and HbA1c (model2). In both studies, addition of Liver function tests to the basic model improved the prediction (C-statistic by~0.020; NRI by~9.0%; P<0.001). In the EPIC-NL case-cohort study, addition to clinical model1 resulted in statistically significant improvement in the overall population (C-statistic = +0.009; P<0.001; NRI = 8.8%; P<0.001), while addition to clinical model 2 yielded marginal improvement limited to men (C-statistic = +0.007; P = 0.06; NRI = 3.3%; P = 0.04). In the PREVEND cohort study, addition to clinical model 1 resulted in significant improvement in the overall population (C-statistic change = 0.008; P = 0.003; NRI = 3.6%; P = 0.03), with largest improvement in men (C-statistic change = 0.013; P = 0.01; NRI = 5.4%; P = 0.04). In PREVEND, improvement compared to clinical model 2 could not be tested because of lack of HbA1c data. CONCLUSIONS: Liver function tests modestly improve prediction for medium-term risk of incident diabetes above basic and extended clinical prediction models, only if no HbA1c is incorporated. If data on HbA1c are available, Liver function tests have little incremental predictive value, although a small benefit may be present in men.

Cancer patients use hospital-based care until death: a further analysis of the Dutch Bone Metastasis Study.

PURPOSE: To describe health care utilization (HCU) at the end of life in cancer patients. These data are relevant to plan palliative care services, and to develop training programs for involved health care professionals. METHODS: The Dutch Bone Metastasis Study (DBMS) was a nationwide study proving equal effectiveness of single fraction palliative radiotherapy compared with multiple fractions for painful bone metastases in 1157 patients. The 860 (74%) patients who died during follow-up were included in the current analysis. The main outcome was the frequency of hospital-based (outpatient contact or admission) and/or general practitioner (GP) contact during the last 12 weeks of life. Changes in HCU towards death were related to data on quality of life and pain intensity using a multilevel regression model. RESULTS: Hospital-based HCU was reported in 1801 (63%) returned questionnaires, whereas GP contact was stated in 1246 (43%). In 573 (20%) questionnaires, both types of HCU were reported. In multilevel regression analyses, the frequency of outpatient contacts remained constant during the weeks towards death, whereas the frequency of GP contacts increased. Lower valuation of quality of life was related to both GP- and hospital-based HCU. CONCLUSIONS: There was a high consumption of hospital-based HCU in the last 12 weeks of life of cancer patients with bone metastases. Hospital-based HCU did not decrease during the weeks towards death, despite an increase in GP contacts. Future planning of palliative care and training programs should encompass close collaboration between medical specialists and GPs to optimize end-of-life care.

Smoking is a risk factor for graft failure and mortality after renal transplantation.

BACKGROUND: Smoking in renal transplant recipients (RTR) is an acknowledged cardiovascular risk factor. It is, however, unclear whether smoking also increases the risk of graft failure (GF). METHOD: In this study, we prospectively assessed the association of current smoking versus past and never smoking with GF and mortality in 604 RTR (age 51.5 ± 12.1 years, 55% male). RESULTS: At inclusion, 133 (22%) were current smokers, 255 (42%) were past smokers and 216 (36%) never smoked. During follow-up of 5.3 (4.7-5.7) years, 41 (7%) RTR experienced GF and 95 RTR (16%) died. Current smoking RTR had higher risk for GF compared to never smoking RTR (hazard ratio, HR = 3.3, 95% CI 1.5-7.1, p = 0.002). Past smoking RTR had similar risk of GF as never smoking RTR (HR = 1.1, 95% CI 0.5-2.6, p = 0.7). Current smoking RTR and past smoking RTR were at higher risk for death than never smoking RTR (HR = 2.1, 95% CI 1.1-3.8, p = 0.016, and HR = 2.4, 95% CI 1.4-4.0, p = 0.001, respectively). CONCLUSION: Smoking after renal transplantation is associated with risk for GF and mortality. Since past smoking is a risk factor for mortality but not for GF, smoking cessation may be beneficial to RTR in delaying GF in long term.