Identification and outcomes of KDIGO-defined chronic kidney disease in 1.4 million U.S. Veterans with heart failure.

AIMS: According to the Kidney Disease: Improving Global Outcomes (KDIGO) guideline, the definition of chronic kidney disease (CKD) requires the presence of abnormal kidney structure or function for >3 months with implications for health. CKD in patients with heart failure (HF) has not been defined using this definition, and less is known about the true health implications of CKD in these patients. The objective of the current study was to identify patients with HF who met KDIGO criteria for CKD and examine their outcomes. METHODS AND RESULTS: Of the 1 419 729 Veterans with HF not receiving kidney replacement therapy, 828 744 had data on ≥2 ambulatory serum creatinine >90 days apart. CKD was defined as estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m2 (n = 185 821) or urinary albumin-to-creatinine ratio (uACR) >30 mg/g (n = 32 730) present twice >3 months apart. Normal kidney function (NKF) was defined as eGFR ≥60 ml/min/1.73 m2, present for >3 months, without any uACR >30 mg/g (n = 365 963). Patients with eGFR <60 ml/min/1.73 m2 were categorized into four stages: 45-59 (n = 72 606), 30-44 (n = 74 812), 15-29 (n = 32 077), and <15 (n = 6326) ml/min/1.73 m2. Five-year all-cause mortality occurred in 40.4%, 57.8%, 65.6%, 73.3%, 69.7%, and 47.5% of patients with NKF, four eGFR stages, and uACR >30mg/g (albuminuria), respectively. Compared with NKF, hazard ratios (HR) (95% confidence intervals [CI]) for all-cause mortality associated with the four eGFR stages and albuminuria were 1.63 (1.62-1.65), 2.00 (1.98-2.02), 2.49 (2.45-2.52), 2.28 (2.21-2.35), and 1.22 (1.20-1.24), respectively. Respective age-adjusted HRs (95% CIs) were 1.13 (1.12-1.14), 1.36 (1.34-1.37), 1.87 (1.84-1.89), 2.24 (2.18-2.31) and 1.19 (1.17-1.21), and multivariable-adjusted HRs (95% CIs) were 1.11 (1.10-1.12), 1.24 (1.22-1.25), 1.46 (1.43-1.48), 1.42 (1.38-1.47), and 1.13 (1.11-1.16). Similar patterns were observed for associations with hospitalizations. CONCLUSION: Data needed to define CKD using KDIGO criteria were available in six out of ten patients, and CKD could be defined in seven out of ten patients with data. HF patients with KDIGO-defined CKD had higher risks for poor outcomes, most of which was not explained by abnormal kidney structure or function. Future studies need to examine whether CKD defined using a single eGFR is characteristically and prognostically different from CKD defined using KDIGO criteria.

Exercise for patients with chronic kidney disease: from cells to systems to function.

Chronic kidney disease (CKD) is among the leading causes of death and disability, affecting an estimated 800 million adults globally. The underlying pathophysiology of CKD is complex creating challenges to its management. Primary risk factors for the development and progression of CKD include diabetes mellitus, hypertension, age, obesity, diet, inflammation, and physical inactivity. The high prevalence of diabetes and hypertension in patients with CKD increases the risk for secondary consequences such as cardiovascular disease and peripheral neuropathy. Moreover, the increased prevalence of obesity and chronic levels of systemic inflammation in CKD have downstream effects on critical cellular functions regulating homeostasis. The combination of these factors results in the deterioration of health and functional capacity in those living with CKD. Exercise offers protective benefits for the maintenance of health and function with age, even in the presence of CKD. Despite accumulating data supporting the implementation of exercise for the promotion of health and function in patients with CKD, a thorough description of the responses and adaptations to exercise at the cellular, system, and whole body levels is currently lacking. Therefore, the purpose of this review is to provide an up-to-date comprehensive review of the effects of exercise training on vascular endothelial progenitor cells at the cellular level; cardiovascular, musculoskeletal, and neural factors at the system level; and physical function, frailty, and fatigability at the whole body level in patients with CKD.

Fatigability and the Role of Neuromuscular Impairments in Chronic Kidney Disease.

BACKGROUND: The combination of neuromuscular impairments plus psychosocial aspects of chronic kidney disease (CKD) may predispose these patients to greater risk for experiencing increased levels of fatigability. There has been extensive clinical and scientific interest in the problem of fatigue in CKD and end-stage kidney disease (ESKD) patients, whereas less attention has been directed to understanding fatigability. Accordingly, the primary purposes of this review are to (1) discuss fatigue and fatigability and their potential interactions in patients with CKD and ESKD, (2) provide evidence for increased fatigability in CKD and ESKD patients, (3) examine how commonly experienced neuromuscular impairments in CKD and ESKD patients may contribute to the severity of performance fatigability, and (4) highlight preliminary evidence on the effects of exercise as a potential clinical treatment for targeting fatigability in this population. SUMMARY: Fatigue is broadly defined as a multidimensional construct encompassing a subjective lack of physical and/or mental energy that is perceived by the individual to interfere with usual or desired activities. In contrast, fatigability is conceptualized within the context of physical activity and is quantified as the interactions between reductions in objective measures of performance (i.e., performance fatigability) and perceptual adjustments regulating activity performance (i.e., perceived fatigability). We propose herein a conceptual model to extend current understandings of fatigability by considering the interactions among fatigue, perceived fatigability, and performance fatigability. Neuromuscular impairments reported in patients with CKD and ESKD, including reductions in force capacity, skeletal muscle atrophy, mitochondrial dysfunction, abnormal skeletal muscle excitability, and neurological complications, may each contribute to the greater performance fatigability observed in these patients. KEY MESSAGES: Considering the interactions among fatigue, perceived fatigability, and performance fatigability provides a novel conceptual framework to advance the understanding of fatigability in CKD and ESKD patients. Measures of fatigability may provide valuable clinical insights into the overall health status of CKD and ESKD patients. Existing data suggest that CKD and ESKD patients are at greater risk of experiencing increased fatigability, partly due to neuromuscular impairments associated with reduced kidney function. Further investigations are warranted to determine the potential clinical role fatigability measures can play in monitoring the health of CKD and ESKD patients, and in identifying potential treatments targeting fatigability in this patient population.

Physical Activity and Exercise for Cardiorespiratory Health and Fitness in Chronic Kidney Disease.

Chronic kidney disease (CKD) is associated with an increased risk for cardiovascular disease (CVD), major adverse CVD events, and cardiovascular mortality. Low levels of physical activity and reduced cardiorespiratory fitness further compound the health consequences in this patient population. Aerobic exercise alone and the combination of aerobic and resistance exercise have beneficial effects for improving aerobic capacity while resistance exercise alone improves strength and skeletal muscle health. Given the prevalence of CVD in CKD patients and limited treatment options targeting traditional and non-traditional CVD risk factors in this population, the incoroporation of physical activity and exercise into the care of CKD seems critical for improving patient outcomes. Therefore, the purpose of this narrative review is to discuss the evidence of physical activity and exercise in CKD patients and the effects on cardiovascular outcomes and fitness.

Rate of Force Development Is Related to Maximal Force and Sit-to-Stand Performance in Men With Stages 3b and 4 Chronic Kidney Disease.

INTRODUCTION: The primary aims of the present study were to assess the relationships of early (0-50 ms) and late (100-200 ms) knee extensor rate of force development (RFD) with maximal voluntary force (MVF) and sit-to-stand (STS) performance in participants with chronic kidney disease (CKD) not requiring dialysis. METHODS: Thirteen men with CKD (eGFR = 35.17 ±.5 ml/min per 1.73 m2, age = 70.56 ±.4 years) and 12 non-CKD men (REF) (eGFR = 80.31 ± 4.8 ml/min per 1.73 m2, age = 70.22 ±.9 years) performed maximal voluntary isometric contractions to determine MVF and RFD of the knee extensors. RFD was measured at time intervals 0-50 ms (RFD0-50) and 100-200 ms (RFD100-200). STS was measured as the time to complete five repetitions. Measures of rectus femoris grayscale (RF GSL) and muscle thickness (RF MT) were obtained via ultrasonography in the CKD group only. Standardized mean differences (SMD) were used to examine differences between groups. Bivariate relationships were assessed by Pearson's product moment correlation. RESULTS: Knee extensor MVF adjusted for body weight (CKD=17.14 ±.1 N·kg0.67, REF=21.55 ±.3 N·kg0.67, SMD = 0.79) and STS time (CKD = 15.93 ±.4 s, REF = 12.23 ±.7 s, SMD = 1.03) were lower in the CKD group than the REF group. Absolute RFD100-200 was significantly directly related to adjusted MVF in CKD (r = 0.56, p = 0.049) and REF (r = 0.70, p = 0.012), respectively. STS time was significantly inversely related to absolute (r = -0.75, p = 0.008) and relative RFD0-50 (r = -0.65, p = 0.030) in CKD but not REF (r = 0.08, p = 0.797; r = 0.004, p = 0.991). Significant inverse relationships between RF GSL adjusted for adipose tissue thickness and absolute RFD100-200 (r =-0.59, p = 0.042) in CKD were observed. CONCLUSION: The results of the current study highlight the declines in strength and physical function that occur in older men with CKD stages 3b and 4 not requiring dialysis. Moreover, early RFD was associated with STS time in CKD while late RFD was associated MVF in both CKD and REF. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, identifier: NCT03160326 and NCT02277236.

The potassium regulator patiromer affects serum and stool electrolytes in patients receiving hemodialysis.

Hyperkalemia is a common and an important cause of death in maintenance hemodialysis patients. Here we investigated the effect of patiromer, a synthetic cation exchanger, to regulate potassium homeostasis. Serum and stool electrolytes were measured in 27 anuric patients with hyperkalemia receiving hemodialysis (mainly 2 mEq/L dialysate) during consecutive two weeks of no-treatment, 12 weeks of treatment with patiromer (16.8g once daily), and six weeks of no treatment. The serum potassium decreased from a mean of 5.7 mEq/L pre-treatment to 5.1 mEq/L during treatment and rebounded to 5.4 mEq/L post-treatment. During the treatment phase, serum calcium significantly increased (from 8.9 to 9.1 mg/dL) and serum magnesium significantly decreased (from 2.6 to 2.4 mg/dL) compared to pre-treatment levels. For each one mEg/L increase in serum magnesium, serum potassium increased by 1.07 mEq/L. Stool potassium significantly increased during treatment phase from pre-treatment levels (4132 to 5923 µg/g) and significantly decreased post-treatment to 4246 µg/g. For each one µg/g increase in stool potassium, serum potassium significantly declined by 0.05 mEq/L. Stool calcium was significantly higher during the treatment phase (13017 µg/g) compared to pre-treatment (7874 µg/g) and post-treatment (7635 µg/g) phases. We estimated that 16.8 g of patiromer will increase fecal potassium by 1880 µg/g and reduce serum potassium by 0.5 mEq/L. Thus, there is a complex interaction between stool and blood potassium, calcium and magnesium during patiromer treatment. Long term consequence of patiromer-induced changes in serum calcium and magnesium remains to be studied.

Preliminary Study of the Effects of Eccentric-Overload Resistance Exercise on Physical Function and Torque Capacity in Chronic Kidney Disease.

The purpose of this preliminary study was to describe changes in physical function and torque capacity in adults with chronic kidney disease (CKD) in response to a novel progressive eccentric-overload resistance exercise (ERE) regime. Participants included men (n = 4) diagnosed with CKD according to estimated glomerular filtration rate (eGFR) between 59 and 15 mL/kg/1.73 m2 and not requiring dialysis. Physical function was determined by the Short Physical Performance Battery (SPPB), five repetitions of a sit-to-stand (STS) task, and timed-up and go (TUG). Knee extensor strength was assessed using both isometric and isokinetic contractions and performance fatigability indexes were calculated during a 30-s maximal isometric test and a 30-contraction isokinetic test at 180°/second. None of the patients exhibited significant worsening in their health status after training. Participants demonstrated improvements in several measures of physical function and torque capacity following 24 sessions of ERE. Following training, performance fatigability remained relatively stable despite the increases in torque capacity, indicating the potential for greater fatigue resistance. These findings provide initial evidence for ERE as a potential treatment option to combat declines in physical function and neuromuscular impairments in people with CKD. Future research is required to determine optimal progression strategies for maximizing specific neuromuscular and functional outcomes when using ERE in this patient population.

Chronic kidney disease: considerations for monitoring skeletal muscle health and prescribing resistance exercise.

Skeletal muscle wasting has gained interest as a primary consequence of chronic kidney disease (CKD) due to the relationship between skeletal muscle mass, mortality and major adverse cardiovascular events in this population. The combination of reductions in physical function, skeletal muscle performance and skeletal muscle mass places individuals with CKD at greater risk of sarcopenia. Therefore the monitoring of skeletal muscle composition and function may provide clinical insight into disease progression. Dual-energy X-ray absorptiometry and bioelectrical impedance analysis are frequently used to estimate body composition in people with CKD within clinical research environments, however, their translation into clinical practice has been limited. Proxy measures of skeletal muscle quality can be obtained using diagnostic ultrasound, providing a cost-effective and accessible imaging modality to aid further clinical research regarding changes in muscle composition. Clinicians and practitioners should evaluate the strengths and limitations of the available technology to determine which devices are most appropriate given their respective circumstances. Progressive resistance exercise has been shown to improve skeletal muscle hypertrophy of the lower extremities, muscular strength and health-related quality of life in end-stage renal disease, with limited evidence available in CKD predialysis. Fundamental principles (i.e. specificity, overload, variation, reversibility, individuality) can be used in the development of more advanced programs focused on improving specific neuromuscular and functional outcomes. Future research is needed to determine the applicability of skeletal muscle monitoring in clinical settings and the feasibility and efficacy of more advanced resistance exercise approaches in those with CKD predialysis.

Acute Kidney Injury Recovery.

BACKGROUND: Acute kidney injury (AKI) is associated with both short- and long-term clinical consequences including progression to chronic kidney disease. Recovery of renal function has gained importance, as interventions to prevent or treat AKI are limited. Basing recovery on a return of serum creatinine values excludes mounting evidence that AKI, even when reversible, is a very serious clinical event that will result in a significant number of both renal and extra-renal complications such as late stage kidney disease, major cardiovascular events, and death. SUMMARY: Development of a definition for renal recovery is critical to organizing research in AKI treatment. Assessment of serum creatinine remains the primary measure of renal recovery despite known limitations. Patterns of renal recovery are highly associated with clinical outcomes including survival. Additional research in basic mechanisms of renal injury and repair is needed to help formulate a more comprehensive assessment of renal recovery. Novel biomarkers for assessment of AKI may also aid in the determination of renal recovery. Key Messages: (1) The concept of acute kidney disease (7-90 days post AKI) should direct clinicians as well as researchers to pay attention to a critical time period for renal recovery in which interventions may alter long-term outcomes. (2) Recent studies have evaluated AKI recovery patterns, or trajectories, and is an important step towards defining long-term prognosis. (3) Serum creatinine alone is not a reliable marker of recovery after AKI and is associated with poor clinical outcomes despite a return to baseline levels. This is a work of the U.S. Government and is not subject to copyright protection in the United States. Foreign copyrights may apply. Published by S. Karger AG, Basel.

Sequelae of AKI.

Large epidemiologic studies in a variety of patient populations reveal increased morbidity and mortality that occur months to years after an episode of acute kidney injury (AKI). Even milder forms of AKI have increased associated morbidity and mortality. Residual confounding may account for these findings, but considering the huge number of individuals afflicted with AKI, the sequelae of AKI may be a very large public health burden. AKI may simply be a marker for increased risk, but there is increasing evidence that it is part of the causal pathway to chronic kidney disease. These studies have upended the traditional view that AKI survivors who returned to baseline, or near baseline renal function, do not suffer additional long-term consequences. Recovery of renal function after AKI, short of independence from renal replacement therapy, is yet to be clearly defined but may be of significant importance in the management of AKI survivors. The association between AKI in patients who undergo cardiac surgery and clinical outcomes is of considerable importance to clinicians, surgeons, and anesthesiologists alike and is a major focus of this review.

Gut microbiome in chronic kidney disease.

NEW FINDINGS: What is the topic of this review? This review addresses the contribution of the altered gut microbiome to uraemic syndrome, with specific reference to gut microbiome-derived uraemic toxins. It also discusses the potential treatment options to normalize the disturbed microbiome in chronic kidney disease (CKD). What advances does it highlight? This review highlights the importance of the gut-kidney connection and how the altered microbial landscape in the intestine contributes to dysmetabolism and inflammation in CKD. Recent findings linking gut-derived uraemic toxins to progression of CKD, cardiovascular disease and mortality are also discussed. Finally, we briefly explain targeted therapies that have been studied to restore intestinal symbiosis in CKD. The human intestine is now recognized as an important metabolic organ powered by gut microbiota. This review addresses the alteration in the gut microbiome in patients with chronic kidney disease (CKD) and its consequence. We describe the major uraemic toxins, p-cresol sulfate, indoxyl sulfate and trimethylamine N-oxide, which are produced by the gut microbiome, and how these metabolites contribute to progression of CKD and associated cardiovascular disease. Translocation of endotoxin from the gut into the systemic circulation contributes to inflammation in CKD. Targeting the gut microbiome to restore symbiosis may prove to be a potent strategy in reducing inflammation and production of these uraemic toxins.

Association between Inflammation and Cardiac Geometry in Chronic Kidney Disease: Findings from the CRIC Study.

BACKGROUND: Left ventricular hypertrophy (LVH) and myocardial contractile dysfunction are independent predictors of mortality in patients with chronic kidney disease (CKD). The association between inflammatory biomarkers and cardiac geometry has not yet been studied in a large cohort of CKD patients with a wide range of kidney function. METHODS: Plasma levels of interleukin (IL)-1ß, IL-1 receptor antagonist (IL-1RA), IL-6, tumor necrosis factor (TNF)-α, transforming growth factor (TGF)-ß, high-sensitivity C-Reactive protein (hs-CRP), fibrinogen and serum albumin were measured in 3,939 Chronic Renal Insufficiency Cohort study participants. Echocardiography was performed according to the recommendations of the American Society of Echocardiography and interpreted at a centralized core laboratory. RESULTS: LVH, systolic dysfunction and diastolic dysfunction were present in 52.3%, 11.8% and 76.3% of the study subjects, respectively. In logistic regression analysis adjusted for age, sex, race/ethnicity, diabetic status, current smoking status, systolic blood pressure, urinary albumin- creatinine ratio and estimated glomerular filtration rate, hs-CRP (OR 1.26 [95% CI 1.16, 1.37], p<0.001), IL-1RA (1.23 [1.13, 1.34], p<0.0001), IL-6 (1.25 [1.14, 1.36], p<0.001) and TNF-α (1.14 [1.04, 1.25], p = 0.004) were associated with LVH. The odds for systolic dysfunction were greater for subjects with elevated levels of hs-CRP (1.32 [1.18, 1.48], p<0.001) and IL-6 (1.34 [1.21, 1.49], p<0.001). Only hs-CRP was associated with diastolic dysfunction (1.14 [1.04, 1.26], p = 0.005). CONCLUSION: In patients with CKD, elevated plasma levels of hs-CRP and IL-6 are associated with LVH and systolic dysfunction.

Safety and dose-finding study of activated protein C (drotrecogin alfa activated) as an anticoagulant in end-stage renal disease patients treated with hemodialysis.

BACKGROUND/AIMS: End-stage renal disease (ESRD) patients treated with hemodialysis (HD) experience a high risk of death. ESRD patients with elevated levels of pro-inflammatory cytokines are at increased risk of death from cardiovascular events and infection. HD is often facilitated by the use of an anticoagulant. We hypothesized that the use of an anticoagulant that also possessed anti-inflammatory qualities without significant immunosuppressive effects may reduce the risk of death. In this pilot study, we sought to determine the optimal dose of activated protein C (APC) to achieve adequate regional anticoagulation for HD and determine if the drug can be safely used in ESRD patients treated with HD. METHODS: Twelve stable HD patients were enrolled into this safety and dose-finding study. Varying doses of APC were administered in place of usual heparin at varying doses to determine the range of APC that can be used for extracorporeal circuit anticoagulation. Partial thromboplastin time was assessed at fixed intervals during the HD treatment. RESULTS: The average age of study patients was 49 ± 12 years. 75% of patients were African-American and 66.7% were male. The optimal dose of APC to induce adequate anticoagulation was 24-30 µg/kg/h. No patients experienced any serious adverse events. One patient had their infusion stopped early due to refractory intradialytic hypertension. CONCLUSIONS: For ESRD patients undergoing HD, an initial starting dose of 24-30 µg/kg/h achieves a target partial thromboplastin time that should be adequate for circuit anticoagulation. This dose appears safe and was well tolerated.

Pain, sleep disturbance and survival in hemodialysis patients.

BACKGROUND: Patients' perception of pain during hemodialysis (HD) and at times between HD treatment and its association with survival have not been well studied in end-stage renal disease (ESRD). We evaluated the experience of pain during HD and at times when the patient was not receiving HD, and assessed possible associations of the perception of pain and sleep disturbance with patient survival. METHODS: A total of 128 ESRD patients treated with HD completed questionnaires on psychosocial status, quality of life and sleep disorders. A modified McGill Pain questionnaire was used to assess the nature, location, frequency, intensity and duration of pain both during and at times between HD sessions. The Pittsburgh Sleep Quality Index was used to screen for sleep disturbances over a 30-day period. RESULTS: Controlling for age, diabetes mellitus, serum albumin concentration and human immunodeficiency virus infection, there was a significant association between mortality and both frequency and intensity of pain while patients were not on HD. There was no association between survival and duration of pain while off HD or any of the pain parameters while patients were on HD. There was no association between survival and the presence of a sleep disorder. CONCLUSIONS: Pain perception while off HD may be of more importance to patients than pain during HD. The mechanisms underlying the association are unknown but may involve linkage of pain with severity of medical illness or the generation of a maladaptive cytokine response. Multicenter prospective studies of pain interventions using well-validated pain perception tools are needed to establish causal relationships. Interventions directed toward treating pain on non-HD days may improve ESRD patient survival.

Spirituality, social support, and survival in hemodialysis patients.

BACKGROUND AND OBJECTIVES: No studies have evaluated the relationship among spirituality, social support, and survival in patients with ESRD. This study assessed whether spirituality was an independent predictor of survival in dialysis patients with ESRD after controlling for age, diabetes, albumin, and social support. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A total of 166 patients who had ESRD and were treated with hemodialysis completed questionnaires on psychosocial variables, quality of life, and religious and spiritual beliefs. The religious variables were categorized into three scores on a 0 to 20 scale (low to high levels): Spirituality, religious involvement, and religion as coping. Social support was assessed using the Multidimensional Scale for Perceived Social Support. Analyses were also performed including and excluding patients with HIV infection. Religious variables were categorized on the basis of means, medians, and tertiles. RESULTS: In analyses that used religious variables, only the responses on the spirituality scale split at the mean were associated with survival. The association of other religious variables with survival did not reach significance. Social support correlated with spirituality, religion as coping, and religious involvement measures. Only social support and age were associated with survival when controlling for diabetes, albumin concentration, HIV infection, and spirituality. CONCLUSIONS: These data suggest that the effects of spirituality may be mediated by social support. Larger, multicenter, prospective studies that use well-validated tools to measure religiosity and spirituality are needed to determine whether there is an independent association of spirituality variables with survival in patients with ESRD.

Urinary sediment cast scoring index for acute kidney injury: a pilot study.

BACKGROUND/AIMS: Urine microscopy is a useful diagnostic tool; however, the manner in which nephrologists prepare and examine urinary sediment is variable. We developed an acute kidney injury (AKI) cast scoring index (CSI) in order to standardize urinary microscopy. Further, we sought to assess the precision of this scoring system. METHODS: Urine from 30 patients with AKI consistent with the syndrome of acute tubular necrosis were collected. Sample preparation was uniform and standardized. A panel of 3 nephrologists blinded to the sample preparation were instructed to grade each slide using the AKI CSI. Subsequently, the AKI CSI was then tested in another 18 patients with AKI to determine if this score could predict nonrenal recovery. RESULTS: The inter-observer agreement index was 99.80%, with a coefficient of variation of 1.24%. Of the 90 paired observations, 98.8% fell within 2 standard deviations of the mean, signifying good agreement. The receiver operator characteristic area under the curve for AKI CSI to predict nonrenal recovery was 0.79. CONCLUSIONS: AKI CSI is a simple, novel, reliable scoring system to grade the degree of epithelial cell and granular casts present on urine microscopy. A standardized AKI CSI has the potential to incorporate urinary cast analysis into the advancing field of AKI diagnostics. These preliminary data endorse the notion that the AKI CSI may be useful in predicting renal outcomes.

Intramolecular cohesion of coils mediated by phenylalanine--glycine motifs in the natively unfolded domain of a nucleoporin.

The nuclear pore complex (NPC) provides the sole aqueous conduit for macromolecular exchange between the nucleus and the cytoplasm of cells. Its diffusion conduit contains a size-selective gate formed by a family of NPC proteins that feature large, natively unfolded domains with phenylalanine-glycine repeats (FG domains). These domains of nucleoporins play key roles in establishing the NPC permeability barrier, but little is known about their dynamic structure. Here we used molecular modeling and biophysical techniques to characterize the dynamic ensemble of structures of a representative FG domain from the yeast nucleoporin Nup116. The results showed that its FG motifs function as intramolecular cohesion elements that impart order to the FG domain and compact its ensemble of structures into native premolten globular configurations. At the NPC, the FG motifs of nucleoporins may exert this cohesive effect intermolecularly as well as intramolecularly to form a malleable yet cohesive quaternary structure composed of highly flexible polypeptide chains. Dynamic shifts in the equilibrium or competition between intra- and intermolecular FG motif interactions could facilitate the rapid and reversible structural transitions at the NPC conduit needed to accommodate passing karyopherin-cargo complexes of various shapes and sizes while simultaneously maintaining a size-selective gate against protein diffusion.

Withholding and withdrawing dialysis in the intensive care unit: benefits derived from consulting the renal physicians association/american society of nephrology clinical practice guideline, shared decision-making in the appropriate initiation of and withdrawal from dialysis.

Despite advances in the technology of dialysis, mortality in patients who develop acute renal failure remains high. Scoring systems have been developed to improve the ability to define prognosis in seriously ill patients with acute renal failure but predicting outcomes for individual patients is uncertain. Decisions to withhold or withdraw dialysis in seriously ill patients are difficult for patients, families, and health care providers. The clinical practice guideline, Shared Decision-Making in the Appropriate Initiation of and Withdrawal from Dialysis, provides evidence-based recommendations to aid nephrologists in discussions and the process of medical decision-making about starting and stopping dialysis. Estimating prognosis and addressing the issues of advance directives and patient and family preferences through the process of shared decision-making can clarify appropriate strategies for clinical management and interventions. Time-limited trials of dialysis may be an invaluable tool in this process. Increasing nephrologists' awareness of the guideline may facilitate decision-making around the issues of withholding and withdrawing dialysis in part by clarifying patients and situations in which it may be appropriate to withhold or withdraw dialysis.