Klotho Variants and Chronic Hemodialysis Mortality

Patients with end‐stage renal disease (ESRD) suffer exceptionally high mortality rates in their first year of chronic hemodialysis. Both vitamin D and fibroblast growth factor (FGF)‐23 levels correlate with survival in these patients. Klotho is a protein in the vitamin D/FGF‐23 signaling pathway that has been linked with accelerated aging and early mortality in animal models. We therefore hypothesized that genetic variation in the Klotho gene might be associated with survival in subjects with ESRD. We tested the association between 12 single nucleotide polymorphisms (SNPs) in the Klotho gene and mortality in a cohort of ESRD patients during their first year on hemodialysis (n = 1307 white and Asian). We found a significant association between the CC genotype of one tag SNP, rs577912, and increased risk for 1‐yr mortality (RR, 1.76; 95% CI, 1.19–2.59; p = 0.003). This effect was even more marked among patients who were not treated with activated vitamin D supplementation (HR, 2.51; 95% CI, 1.18–5.34; p = 0.005). In lymphoblastoid cell lines derived from HapMap subjects, the CC genotype was associated with a 16–21% lower Klotho expression compared with the AA/AC genotype. Our data suggest that a specific Klotho variant (rs577912) is linked to survival in ESRD patients initiating chronic hemodialysis and that therapy with activated vitamin D may modify this risk.     

Obstructive sleep apnea and resistant hypertension: a case-control study

BACKGROUND: Obstructive sleep apnea syndrome (OSAS) has been linked to resistant hypertension, but the magnitude of this association and its independence of confounding have not been established. METHODS: Case patients were 63 patients with resistant hypertension (BP >or= 140/90 mm Hg using at least three BP-lowering drugs, including a diuretic), and control subjects were 63 patients with controlled BP receiving drug treatment. The primary outcome was the frequency of OSAS (apnea-hypopnea index [AHI] >or= 10 episodes per hour) determined with a portable home monitor. The comparison of AHI episodes in patients truly normotensive, truly hypertensive, and in patients with white coat or masked hypertension, based on BP determined at office and by ambulatory BP monitoring (ABPM) was a secondary outcome. RESULTS: Case patients and control subjects were well matched for confounding factors. OSAS was present in 45 case patients (71%) and in 24 control subjects (38%) [p < 0.001]. In a logistic regression model, OSAS was strongly and independently associated with resistant hypertension (odds ratio, 4.8; 95% confidence interval, 2.0 to 11.7). The AHI of case patients with normal BP in ABPM (white coat hypertension) and control subjects with abnormal BP in ABPM (masked hypertension) was intermediate between the AHI of individuals with normal and abnormal BP measures in both settings (p < 0.001). CONCLUSIONS: The magnitude and independence of the risk of OSAS for resistant hypertension strengthen the concept that OSAS is a risk factor for resistant hypertension. Comorbid OSAS should be considered in patients with resistant hypertension.     

Functional modulation of Crohn's disease myofibroblasts by anti-tumor necrosis factor antibodies

BACKGROUND & AIMS: Infliximab induces immune cell apoptosis by outside-to-inside signaling through transmembrane tumor necrosis factor-alpha (mTNF). However, in inflamed gut, myofibroblasts also produce TNF-alpha, and the affects of anti-TNF antibodies on these structural cells are unknown. We investigated the action of infliximab on apoptosis, the production of matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinases (TIMP)-1, and migration of Crohn's disease (CD) myofibroblasts. METHODS: Colonic myofibroblasts were isolated from patients with active CD and controls. mTNF was evaluated by Western blotting and flow cytometry. Infliximab-treated myofibroblasts were analyzed for apoptosis by Annexin V staining and caspase-3. TIMP-1 and MMPs were measured by Western blotting, and fibroblast migration was assessed by using an in vitro wound-healing scratch assay. RESULTS: CD myofibroblasts showed higher mTNF expression than control myofibroblasts. Infliximab had no effect on CD myofibroblast apoptosis, caspase-3 activation, and production of MMP-3 and MMP-12. However, infliximab induced a significant dose-dependent increase in TIMP-1 production, which was inhibited by the p38 mitogen-activated protein kinase inhibitor SB 203580. The anti-TNF agents adalimumab, etanercept, and p55 TNF-receptor-human IgG fusion protein also increased TIMP-1 production. The migration of CD myofibroblasts was enhanced significantly by infliximab and recombinant human TIMP-1, and infliximab-induced migration was inhibited by anti-TIMP-1 neutralizing antibody. Infliximab also decreased CD myofibroblast collagen production. CONCLUSIONS: Our findings show a novel therapeutic pathway for anti-TNF therapies in enhancing TIMP-1 production and myofibroblast migration, which may reduce MMP activity and facilitate the wound healing.     

Cardiac troponin I concentrations during on-pump coronary artery surgery

Perioperative myocardial infarction remains a frequent complication after coronary artery bypass grafting, and is associated with a poor prognosis. This retrospective study compared cardiac troponin I concentrations after on-pump bypass grafting in 2 groups of patients: 100 operated on using a single-clamp technique to perform anastomoses, and 80 operated on using a double-clamp technique. Postoperative cardiac troponin I levels were not significantly different between groups. It was concluded that the double-clamp technique did not reduce the incidence of myocardial infarction after elective on-pump coronary artery bypass grafting, and use of a single clamp is safe with no adverse effect on postoperative outcome.     

The Poor Outcome of Ischemic Stroke in Very Old People: A Cohort Study of Its Determinants

OBJECTIVES: To assess how much of the excess risk of poor outcome from stroke in people aged 80 and older aging per se explains, independent of other prognostic determinants.
DESIGN: Cohort, observational.
SETTING: University hospital.
PARTICIPANTS: One thousand five hundred fifty-five patients with first-ever ischemic stroke consecutively referred to an in-hospital Clinical Pathway program were studied.
MEASUREMENTS: The relationship between age and 1-month outcome (death, disability (modified Rankin Scale 3–5), and poor outcome (modified Rankin Scale 3–6)) was assessed, with adjustment for several prognostic factors.
RESULTS: Six hundred twelve patients aged 80 and older showed worse outcome after 1 month than those who were younger, in terms of mortality (19% vs 5%, hazard ratio (HR)=3.85, 95% confidence interval (CI)=2.8–5.4) and disability (51% vs 33%, odds ratio (OR)=3.16, 95% CI=2.5–4.0), although in multivariate models, the adjusted HR for mortality decreased to 1.47 (95% CI=1.0–2.16) and the ORs for disability and poor outcome decreased to 1.76 (95% CI=1.32–2.3.) and 1.83 (95% CI=137–2.43), respectively. Stroke severity, the occurrence of at least one medical complication, and premorbid disability explained most of the risk excess in the oldest-old.
CONCLUSION: Stroke outcome is definitely worse in very old people, and most of the excess risk of death and disability is attributable to the higher occurrences of the most-severe clinical stroke syndromes and of medical complications in the acute phase. These represent potential targets for preventive and therapeutical strategies specifically for elderly people.     

Human interleukin 17-producing cells originate from a CD161+CD4+ T cell precursor

We demonstrate that CD161 is a highly up-regulated gene in human interleukin (IL) 17 T helper cell (Th17) clones and that all IL-17–producing cells are contained in the CD161⁺ fraction of CD4⁺ T cells present in the circulation or in inflamed tissues, although they are not CD1-restricted natural killer T cells. More importantly, we show that all IL-17–producing cells originate from CD161⁺ naive CD4⁺ T cells of umbilical cord blood, as well as of the postnatal thymus, in response to the combined activity of IL-1β and IL-23. These findings implicate CD161 as a novel surface marker for human Th17 cells and demonstrate the exclusive origin of these cells from a CD161⁺CD4⁺ T cell progenitor.     

The importance of transitions between dialysis and transplantation in the care of end-stage renal disease patients

Analyses describing outcomes of kidney transplantation usually exclude the survival of wait-listed patients and dialysis patients with failed kidney transplants, and thus reflect only a portion of the typical transplant process. We determined death rates during the continuum of wait-listing, transplantation, and after allograft failure among adult end-stage renal disease patients in the United States between 1995 and 2003. Before transplantation, death rates increased with longer waiting times. Death rates were lowest during the period of allograft function and highest after allograft failure. Patients were at particularly high risk during periods of transition between dialysis and transplantation (death rates during the peri-transplant period and during the re-initiation of dialysis after transplant failure were 8.2/100 patient-years (95% confidence interval (CI) 7.7, 8.8) and 17.9/100 patient-years (95% CI 15.7, 20.3), respectively compared to 6.4/100 patient-years (95% CI 6.25, 6.51) during the period of wait-listing. Diabetic patients and older patients were at increased risk at all time points. The most common known cause of death in all age subgroups was cardiovascular disease. The proportion of death owing to sepsis was greatest after allograft failure (16.8% of all deaths were due to sepsis compared to 14.0% during wait-listing, and 12.7% during the period of allograft function). Consideration of the entire transplant experience as a whole should help to focus patient care on periods of particularly high risk, and emphasizes opportunities to improve outcomes by strategies aimed at preventing death owing to cardiovascular and infectious causes.