Indoleamine-2,3-dioxygenase activity in experimental human endotoxemia

Background: Excessive tryptophan metabolism to kynurenine by the rate-limiting enzyme endothelial indoleamine 2,3-dioxygenase 1 (IDO) controls arterial vessel relaxation and causes hypotension in murine endotoxemia. However, its relevance in human endotoxemia has not been investigated so far. We thus aimed to study changes in blood pressure in parallel with tryptophan and kynurenine levels during experimental endotoxemia in humans. Findings: Six healthy male volunteers were given E. coli lipopolysaccharide (LPS; 4 ng/kg) as a 1-min intravenous infusion. They had levels of soluble E-Selectin and soluble vascular cell adhesion molecule-1 as well as IDO activity assessed as the kynurenine-to-tryptophan plasma ratio by liquid chromatography-tandem mass spectrometry at various time points during a 24 h time course. During endotoxemia, IDO activity significantly increased, reaching peak levels at 8 h after LPS infusion (44.0 ± 15.2 vs. 29.4 ± 6.8 at baseline, P<0.0001). IDO activity correlated inversely with the development of hypotension as shown by random effects linear regression models. Finally, IDO activity exhibited a kinetic profile similar to that of soluble endothelial-specific adhesion molecules. Conclusions: LPS is a triggering factor for the induction of IDO in men. Our findings strongly support the concept that the induction of IDO in the vascular endothelium contributes to hypotension in human sepsis

“The Times They Are A-Changin’” at Diabetes Care

Every five years or so, the editorial team leading Diabetes Care turns over with the appointment of new leadership. This issue of volume 46 represents the first of a new editorial team, making it the tenth group to be responsible for the scientific content of the journal. Starting in 1978 with Jay Skyler as its first editor, Diabetes Care has gone from strength to strength with new initiatives and a steady increase in its influence. This impact has been in line with the charge given at the journal’s founding by the then president of the American Diabetes Association Norbert Freinkel when he wrote, “The new journal is designed to promote better patient care by serving the expanded needs of all health professionals committed to the care of patients with diabetes.

Dialysis initiation, modality choice, access, and prescription: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference

Globally, the number of patients undergoing maintenance dialysis is increasing, yet throughout the world there is significant variability in the practice of initiating dialysis. Factors such as availability of resources, reasons for starting dialysis, timing of dialysis initiation, patient education and preparedness, dialysis modality and access, as well as varied \u201ccountry-specific\u201d factors significantly affect patient experiences and outcomes. As the burden of end-stage kidney disease (ESKD) has increased globally, there has also been a growing recognition of the importance of patient involvement in determining the goals of care and decisions regarding treatment. In January 2018, KDIGO (Kidney Disease: Improving Global Outcomes) convened a Controversies Conference focused on dialysis initiation, including modality choice, access, and prescription. Here we present a summary of the conference discussions, including identified knowledge gaps, areas of controversy, and priorities for research. A major novel theme represented during the conference was the need to move away from a \u201cone-size-fits-all\u201d approach to dialysis and provide more individualized care that incorporates patient goals and preferences while still maintaining best practices for quality and safety. Identifying and including patient-centered goals that can be validated as quality indicators in the context of diverse health care systems to achieve equity of outcomes will require alignment of goals and incentives between patients, providers, regulators, and payers that will vary across health care jurisdictions

Obesity and kidney disease: hidden consequences of the epidemic

Obesity has become a worldwide epidemic and its prevalence has been projected to grow by 40% in the next decade. This increasing prevalence has implications for the risk of diabetes, cardiovascular disease and also for chronic kidney disease (CKD). A high body mass index is one of the strongest risk factors for new-onset CKD. In individuals affected by obesity, a compensatory hyperfiltration occurs to meet the heightened metabolic demands of the increased body weight. The increase in intraglomerular pressure can damage the kidneys and raise the risk of developing CKD in the long-term. The incidence of obesity-related glomerulopathy has increased ten-fold in recent years. Obesity has also been shown to be a risk factor for nephrolithiasis, and for a number of malignancies including kidney cancer. This year, the World Kidney Day will promote education on the harmful consequences of obesity and its association with kidney disease, advocating healthy lifestyle and health policy measures that make preventive behaviors an affordable option

Supplementary Material for: The Relationship Between Ultraviolet Light Exposure and Mortality in Dialysis Patients

<b><i>Background:</i></b> Emerging data suggest that reduced exposure to ultraviolet (UV) radiation is associated with increased mortality in the general population. To date, the association between UV exposure and mortality in dialysis patients has not been examined. <b><i>Methods:</i></b> We examined the association between UV index, a proxy of UV exposure, and all-cause mortality among 47,286 US dialysis patients (entry period 2001-2006, with follow-up through 2009) from a large national dialysis organization using multivariable Cox regression. The UV index was ascertained by linking individual patients' residential zip codes to National Oceanic and Atmospheric Administration data, and was categorized as low (0-<3), moderate (3-<5), moderate-high (5-<6), high (6-<7), and very-high (≥7). In secondary analyses, we examined the UV index-mortality association within subgroups of age (<65 vs. ≥65 years old), sex, and race (white vs. non-white). <b><i>Results:</i></b> The study population's mean ± SD age was 60 ± 16 and included 46% women and 56% diabetics. Compared to patients residing in moderate-high UV index regions, those residing in high and very-high UV index regions had a lower mortality risk: adjusted HRs 0.84 (95% CI) 0.81-0.88 and 0.83 (95% CI) 0.75-0.91, respectively. A similar inverse association between UV index and mortality was observed across all subgroups, although there was more pronounced reduction in mortality among whites vs. non-whites. <b><i>Conclusion:</i></b> These data suggest that dialysis patients residing in higher UV index regions have lower all-cause mortality compared to those living in moderate-high UV regions. Further studies are needed to determine the mechanisms underlying the UV index-mortality association

Supplementary Material for: Mortality Associated with Dose Response of Erythropoiesis-Stimulating Agents in Hemodialysis versus Peritoneal Dialysis Patients

<i>Background:</i> Several studies have shown an association between erythropoietin-stimulating agent (ESA) responsiveness and mortality in chronic kidney disease (CKD) patients. In our present study, we examined the association between prescribed ESA dose and mortality in peritoneal dialysis (PD) and hemodialysis (HD) patients. We hypothesized that PD patients received lower ESA dose for the same achieved hemoglobin compared to HD patients and that ESA dose-mortality associations were different between PD and HD patients. <i>Methods:</i> We compared the prescribed doses of ESA between 139,103 HD and 10,527 PD patients treated in DaVita dialysis clinics from 7/2001 through 6/2006 using adjusted Poisson regression and examined mortality-predictability of prescribed ESA dose and ESA responsiveness index (ESA/hemoglobin) in PD and HD with follow-up through 6/2007 using Cox regression models. <i>Results:</i> Poisson adjusted ratio of ESA dose of HD to PD was 3.6 (95% CI 3.5–3.7). In PD patients, adjusted all-cause death hazard ratios (HR) for ESA doses of 3,000–5,999, 6,000–8,999 and ≧9,000 U/week (reference <3,000 U/week) were 0.97 (0.87–1.07), 0.85 (0.76–0.95) and 1.08 (0.98–1.18), respectively; whereas in HD patients across commensurate ESA dose increments of 10,000–19,999, 20,000–29,999 and ≧30,000 U/week (reference <10,000 U/week) were 1.14 (1.11–1.17), 1.54 (1.50–1.58) and 2.15 (2.10–2.21), respectively. In PD and HD patients, the adjusted death HR of the 4th to 1st quartile of ESA responsiveness index were 1.14 (1.04–1.26) and 2.37 (2.31–2.43), respectively. <i>Conclusions:</i> Between 2001 and 2006, most PD patients received substantially lower ESA dose for same achieved hemoglobin levels, and low ESA responsiveness was associated with higher mortality in both HD and PD patients

Supplementary Material for: Dialysate Potassium and Mortality in a Prospective Hemodialysis Cohort

<b><i>Background:</i></b> Studies examining the association of dialysate potassium concentration and mortality in hemodialysis patients show conflicting findings. We hypothesized that low dialysate potassium concentrations are associated with higher mortality, particularly in patients with high pre-dialysis serum potassium concentrations. <b><i>Methods:</i></b> We evaluated 624 hemodialysis patients from the prospective Malnutrition, Diet, and Racial Disparities in Kidney Disease study recruited from 16 outpatient dialysis facilities over 2011–2015 who underwent protocolized collection of dialysis treatment characteristics every 6 months. We examined the association of dialysate potassium concentration, categorized as 1, 2, and 3 mEq/L, with all-cause mortality risk in the ­overall cohort, and stratified by pre-dialysis serum potassium (< 5 vs. ≥5 mEq/L) using case-mix adjusted Cox models. <b><i>Results:</i></b> In baseline analyses, dialysate potassium concentrations of 1 mEq/L were associated with higher mortality, whereas concentrations of 3 mEq/L were associated with similar mortality in the overall cohort (reference: 2 mEq/L): adjusted hazard ratios (aHRs; 95% CI) 1.70 (1.01–2.88) and 0.95 (0.64–1.39), respectively. In analyses stratified by serum potassium, baseline dialysate potassium concentrations of 1 mEq/L were associated with higher mortality in patients with serum potassium ≥5 mEq/L but not in those with serum potassium < 5 mEq/L: aHRs (95% CI) 2.87 (1.51–5.46) and 0.74 (0.27–2.07), respectively (<i>p</i> interaction = 0.04). These findings were robust with incremental adjustment for serum potassium, potassium-binding resins, and potassium-modifying medications. <b><i>Conclusion:</i></b> Low (1 mEq/L) dialysate potassium ­concentrations were associated with higher mortality, particularly in hemodialysis patients with high pre-dialysis serum potassium. Further studies are needed to identify therapeutic strategies that mitigate inter-dialytic serum potassium accumulation and subsequent high dialysate serum potassium gradients in this population

Supplementary Material for: Impact of Non-Adherence on Renal and Cardiovascular Outcomes in US Veterans

<b><i>Background:</i></b> Adherence is paramount in treating hypertension; however, no gold standard method is available for non-adherence screening, delineating high-risk patients. An International Classification of Diseases 9th Edition non-adherence diagnostic code (V15.81) has been available for decades; but, its utility is poorly studied. We examined the association between the V15.81 code assigned prior to the initiation of anti-hypertensive drugs (AHDs) and renal and cardiovascular outcomes. <b><i>Methods:</i></b> This was a historical prospective cohort study involving 312,489 newly treated hypertensive individuals (mean age 53.8 years, 90.9% males, 20.3% black, median follow-up 8.0 years). We used crude and Cox models adjusted for baseline socio-demographic characteristics, estimated glomerular filtration rate (eGFR), body mass index, blood pressure, comorbidities, and prospective AHD adherence (measured as proportion of days covered, PDC). <b><i>Results:</i></b> In the unadjusted analysis, the V15.81 code was associated with higher risks for faster eGFR decline (hazard ratio, HR 1.22, 95% CI 1.11-1.33), incident CKD (HR 1.17, 95% CI 1.09-1.27), end-stage renal disease (ESRD) (HR 2.53, 95% CI 1.72-3.72), incident coronary artery disease (CAD) (HR 1.26, 95% CI 1.15-1.38), and stroke (HR 1.55, 95% CI 1.38-1.73). In the adjusted model, the V15.81 code remained predictive of increased risk of CKD (HR 1.33, 95% CI 1.22-1.45), ESRD (HR 1.81, 95% CI 1.18-2.78), incident CAD (HR 1.26, 95% CI 1.14-1.40), and stroke (HR 1.46, 95% CI 1.29-1.65). Additional adjustment for PDC did not alter adverse associations between V15.81 code and studied outcomes. <b><i>Conclusions:</i></b> Assignment of V15.81 code prior to AHD therapy was associated with higher risks of renal and cardiovascular outcomes in incident hypertensive US veterans. Previous history of non-adherence is a poor prognostic marker in hypertensive individuals; therefore, patients with V15.81 code may require close monitoring. The observational nature of this study limits our ability to make firm recommendations for clinical practice