Diagnosis and Treatment of Low Testosterone among Patients with End-Stage Renal Disease.

The prevalence of low testosterone level is particularly high among patients with end-stage renal disease (ESRD) and has been associated with mortality. In populations without ESRD, low testosterone level has also been associated with a number of morbidities including cardiovascular disease, diabetes mellitus, low muscle mass, low bone mass, low physical performance, and frailty. However, there is controversy regarding what constitutes low testosterone level in the aging population and at what level replacement therapy with testosterone is indicated. There are no randomized controlled trials investigating long-term outcomes of testosterone replacement therapy in populations with or without ESRD. Available trial results suggest equivocal improvements in sexual function. Muscle mass and bone mineral density appear to improve, but results in physical function and performance are mixed and there are no data on fracture prevention. Some recent data suggest harm when testosterone was given to men with limited mobility. Finally, there is little evidence that testosterone adds to existing erythropoietin agents in the treatment of anemia in ESRD. Due to lack of evidence supporting long-term use of testosterone, the authors recommend against the routine use of testosterone in ESRD patients with low testosterone levels. Testosterone treatment can be considered in those with low bone mass and total testosterone level <200 ng/dl, or in younger patients with sexual complaints with total testosterone level lower than the reference range. It is important to engage patients in discussion of risks and benefits before initiating testosterone therapy; testosterone therapy should be discontinued if the intended treatment effect is not observed after short-term use.

Frailty and dialysis initiation.

Frailty is a physiologic state of increased vulnerability to stressors that results from decreased physiologic reserves or dysregulation of multiple physiologic systems. The construct of frailty has been operationalized as a composite of poor physical function, exhaustion, low physical activity, and weight loss. Several studies have now examined the prevalence of frailty among chronic kidney disease (CKD) or end-stage renal disease (ESRD) patients and have found frailty to be more common among individuals with CKD than among those without. Furthermore, frailty is associated with adverse outcomes among incident dialysis patients, including higher risk of hospitalization and death. Recent evidence shows that frail patients are started on dialysis earlier (at a higher estimated glomerular filtration rate [eGFR]) on average than nonfrail patients, but it remains unclear whether these patients' frailty is a result of uremia or is independent of CKD. The survival disadvantage that has been associated with early initiation of dialysis in observational studies could be mediated in part through confounding on the basis of unmeasured frailty. However, available data do not suggest improvement in frailty upon initiation of dialysis; rather, the trajectory appears to be toward higher levels of dependence in activities of daily living (ADLs) after dialysis initiation. Overall, there are no data to suggest that frail patients derive any benefit from early initiation of dialysis either in the form of improved survival or functional status.

Will my patient fall?

CONTEXT: Effective multifactorial interventions reduce the frequent falling rate of older patients by 30% to 40%. However, clinical consensus suggests reserving these interventions for high-risk patients. Limiting fall prevention programs to high-risk patients implies that clinicians must recognize features that predict future falls. OBJECTIVE: To identify the prognostic value of risk factors for future falls among older patients. DATA SOURCES AND STUDY SELECTION: Search of MEDLINE (1966-September 2004), CINAHL (1982-September 2004), and authors' own files to identify prospective cohort studies of risk factors for falls that performed a multivariate analysis of such factors. DATA EXTRACTION: Two reviewers independently determined inclusion of articles and assessed study quality. Disagreements were resolved by consensus. Included studies were those identifying the prognostic value of risk factors for future falls among community-dwelling persons 65 years and older. Clinically identifiable risk factors were identified across 6 domains: orthostatic hypotension, visual impairment, impairment of gait or balance, medication use, limitations in basic or instrumental activities of daily living, and cognitive impairment. DATA SYNTHESIS: Eighteen studies met inclusion criteria and provided a multivariate analysis including at least 1 of the risk factor domains. The estimated pretest probability of falling at least once in any given year for individuals 65 years and older was 27% (95% confidence interval, 19%-36%). Patients who have fallen in the past year are more likely to fall again [likelihood ratio range, 2.3-2.8]. The most consistent predictors of future falls are clinically detected abnormalities of gait or balance (likelihood ratio range, 1.7-2.4). Visual impairment, medication variables, decreased activities of daily living, and impaired cognition did not consistently predict falls across studies. Orthostatic hypotension did not predict falls after controlling for other factors. CONCLUSIONS: Screening for risk of falling during the clinical examination begins with determining if the patient has fallen in the past year. For patients who have not previously fallen, screening consists of an assessment of gait and balance. Patients who have fallen or who have a gait or balance problem are at higher risk of future falls.

Frailty, dialysis initiation, and mortality in end-stage renal disease.

BACKGROUND: In light of the recent trend toward earlier dialysis initiation and its association with mortality among patients with end-stage renal disease, we hypothesized that frailty is associated with higher estimated glomerular filtration rate (eGFR) at dialysis start and may confound the relation between earlier dialysis initiation and mortality. METHODS: We examined frailty among participants of the Comprehensive Dialysis Study (CDS), a special study of the US Renal Data System, which enrolled incident patients from September 1, 2005, through June 1, 2007. Patients were followed for vital status through September 30, 2009, and for time to first hospitalization through December 31, 2008. We used multivariate logistic regression to model the association of frailty with eGFR at dialysis start and proportional hazards regression to assess the outcomes of death or hospitalization. RESULTS: Among 1576 CDS participants included, the prevalence of frailty was 73%. In multivariate analysis, higher eGFR at dialysis initiation was associated with higher odds of frailty (odds ratio [OR], 1.44 [95% CI, 1.23-1.68] per 5 mL/min/1.73 m(2); P < .001). Frailty was independently associated with mortality (hazard ratio [HR], 1.57 [95% CI, 1.25-1.97]; P < .001) and time to first hospitalization (HR, 1.26 [95% CI, 1.09-1.45]; P < .001). While higher eGFR at dialysis initiation was associated with mortality (HR, 1.12 [95% CI, 1.02-1.23] per 5 mL/min/1.73 m(2); P = .02), the association was no longer statistically significant after frailty was accounted for (HR, 1.08 [95% CI, 0.98-1.19] per 5 mL/min/1.73 m(2); P = .11). CONCLUSIONS: Frailty is extremely common among patients starting dialysis in the United States and is associated with higher eGFR at dialysis initiation. Recognition of signs and symptoms of frailty by clinicians may prompt earlier initiation of dialysis and may explain, at least in part, the well-described association between eGFR at dialysis initiation and mortality.

Initial transcribed sequence mutations specifically affect promoter escape properties.

Promoter escape efficiency of E. coli RNA polymerase is guided by both the core promoter and the initial transcribed sequence (ITS). Here, we quantitatively examined the escape properties of 43 random initial sequence variants of the phage T5 N25 promoter. The position for promoter escape on all N25-ITS variants occurred at the +15/+16 juncture, unlike the +11/+12 juncture for the wild type N25. These variants further exhibited a 25-fold difference in escape efficiency. ITS changes favoring promoter escape showed a compositional bias that is unrelated to nucleotide substrate binding affinity for the initial positions. Comparing all variants, the natural N25 promoter emerges as having evolved an ITS optimal for promoter escape, giving a high level of productive synthesis after undergoing the shortest abortive program. We supplemented GreB to transcription reactions to better understand abortive initiation and promoter escape in vivo. GreB supplementation elevated productive RNA synthesis 2-5-fold by altering the abortive RNA pattern, decreasing the abundance of the medium (6-10 nt) to long (11-15 nt) abortive RNAs without changing the levels of short (2-5 nt) and very long abortive RNAs (16-20 nt). The GreB-refractive nature of short abortive RNA production may reflect a minimum length requirement of 4-5 bp of the RNA-DNA hybrid for maintaining the stability of initial or backtracked complexes. That the very long abortive RNAs are unaffected by GreB suggests that they are unlikely to be products of polymerase backtracking. How the ITS might influence the course of early transcription is discussed within the structural context of an initial transcribing complex.