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BACKGROUND - In patients undergoing maintenance hemodialysis (HD), hyporesponsiveness to erythropoiesis stimulating agents (ESAs) is associated with adverse clinical outcomes. Systemic inflammation is highly prevalent in HD patients and is associated with ESA hyporesponsiveness. Oxidative stress is also highly prevalent in HD patients, but no previous study has determined its association with ESA response. This study assessed the association of plasma markers of oxidative stress and inflammation with ESA resistance in patients undergoing maintenance HD.
METHODS - We analyzed data from 165 patients enrolled in the Provision of Antioxidant Therapy in Hemodialysis study, a randomized controlled trial evaluating antioxidant therapy in prevalent HD patients. Linear and mixed-effects regression were used to assess the association of baseline and time-averaged high sensitivity F2-isoprostanes, isofurans, C-reactive protein (hsCRP), and interleukin-6 (IL-6) with ESA resistance index (ERI), defined as the weekly weight-adjusted ESA dose divided by blood hemoglobin level. Unadjusted models as well as models adjusted for potential confounders were examined. Predicted changes in ERI per month over study follow-up among baseline biomarker quartiles were also assessed.
RESULTS - Patients with time-averaged isofurans in the highest quartile had higher adjusted mean ERI compared with patients in the lowest quartile (β = 14.9 ng/ml; 95% CI 7.70, 22.2; reference group <0.26 ng/ml). The highest quartiles of hsCRP and IL-6 were also associated with higher adjusted mean ERI (β = 10.8 mg/l; 95% CI 3.52, 18.1 for hsCRP; β = 10.2 pg/ml; 95% CI 2.98, 17.5 for IL-6). No significant association of F2-isoprostanes concentrations with ERI was observed. Analyses restricted to baseline exposures and ERI showed similar results. Baseline hsCRP, IL-6, and isofurans concentrations in the highest quartiles were associated with greater predicted change in ERI over study follow-up compared to the lowest quartiles (P = 0.008, P = 0.004, and P = 0.04, respectively). There was no association between baseline F2-isoprostanes quartile and change in ERI.
CONCLUSIONS - In conclusion, higher concentrations of isofurans, hsCRP and IL-6, but not F2-isoprostanes, were associated with greater resistance to ESAs in prevalent HD patients. Further research is needed to test whether interventions that successfully decrease oxidative stress and inflammation in patients undergoing maintenance HD improve ESA responsiveness.
Type 2 diabetes mellitus is a leading health issue worldwide. Among cases of diabetes mellitus nephropathy (DN), the major complication of type 2 diabetes mellitus, the nephrotic phenotype is often intractable to clinical intervention and demonstrates the rapid decline of renal function to end-stage renal disease. We recently identified the gene for glypican-5 (GPC5), a cell-surface heparan sulfate proteoglycan, as conferring susceptibility for acquired nephrotic syndrome and additionally identified an association through a genome-wide association study between a variant in GPC5 and DN of type 2 diabetes mellitus. In vivo and in vitro data showed a progressive increase of GPC5 in type 2 DN along with severity; the excess was derived from glomerular mesangial cells. In this study, diabetic kidney showed that accumulation of fibroblast growth factor (Fgf)2 strikingly induced progressive proteinuria that was avoided in Gpc5 knockdown mice. The efficacy of Gpc5 inhibition was exerted through expression of the Fgf receptors 3 and 4 provoked in the diabetic kidney attributively. Extraglomerular Fgf2 was pathogenic in DN, and the deterrence of Gpc5 effectively inhibited the glomerular accumulation of Fgf2, the subsequent increase of mesangial extracellular matrix, and the podocytes' small GTPase activity. These findings elucidate the pivotal role of GPC5, identified as a susceptible gene in the genome-wide association study, in hyperglycemia-induced glomerulopathy.
Copyright © 2015 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.
OBJECTIVE - Hyperphosphatemia is common in end-stage renal disease and associates with mortality. Phosphate binders reduce serum phosphorus levels; however, adherence is often poor. This pilot study aims to assess patients' self-motivation to adhere to phosphate binders, its association with phosphorus control, and potential differences by race.
DESIGN AND METHODS - Cross sectional design. Subjects were enrolled from one academic medical center dialysis practice from July to November 2012. Self-motivation to adhere to phosphate binders was assessed with the autonomous regulation (AR) scale (range: 1-7) and self-reported medication adherence with the Morisky Medication Adherence Scale. Linear regression models adjusting for age, sex, health literacy, and medication adherence were applied to determine associations with serum phosphorus level, including any evidence of interaction by race.
RESULTS - Among 100 participants, mean age was 51 years (±15 years), 53% were male, 72% were non-white, 89% received hemodialysis, and mean serum phosphorus level was 5.7 ± 1.6 mg/dL. More than half (57%) reported the maximum AR score (7). Higher AR scores were noted in those reporting better health overall (P = .001) and those with higher health literacy (P = .01). AR score correlated with better medication adherence (r = 0.22; P = .02), and medication adherence was negatively associated with serum phosphorus (r = -0.40; P < .001). In subgroup analysis among non-whites, higher AR scores correlated with lower serum phosphorus (high vs lower AR score: 5.55 [1.5] vs 6.96 [2.2]; P = .01). Associations between AR score (β 95% confidence interval: -0.37 [-0.73 to -0.01]; P = .04), medication adherence (β 95% confidence interval: -0.25 [-0.42 to -0.07]; P = .01), and serum phosphorus persisted in adjusted analyses.
CONCLUSIONS - Self-motivation was associated with phosphate binder adherence and phosphorus control, and this differed by race. Additional research is needed to determine if personalized, culturally sensitive strategies to understand and overcome motivational barriers may optimize mineral bone health in end-stage renal disease.
Published by Elsevier Inc.
Muscle wasting (or sarcopenia) is a common feature of the uremic phenotype and predisposes this vulnerable patient population to increased risk of comorbid complications, poor quality of life, frailty and premature death. The old age of dialysis patients is in addition a likely contributor to loss of muscle mass. As recent evidence suggests that assessment of muscle strength (i.e. function) is a better predictor of outcome and comorbidities than muscle mass, this opens new screening, assessment and therapeutic opportunities. Among established treatment strategies, the benefit of resistance exercise and endurance training are increasingly recognized among nephrologists as being effective and should be promoted in sedentary chronic kidney disease patients. Testosterone and growth hormone replacement appear as the most promising among emerging treatments strategies for muscle wasting. As treatment of muscle wasting is difficult and seldom successful in this often old, frail, sedentary and exercise-hesitant patient group, novel treatment strategies are urgently needed. In this review, we summarize recent studies on stimulation of mitochondrial biogenesis, myogenic stem (satellite) cells and manipulation of transforming growth factor family members, all of which hold promise for more effective therapies to target muscle mass loss and function in the future.
© The Author 2015. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.
OBJECTIVE - Patients with end-stage renal disease on maintenance hemodialysis are much more sedentary than healthy individuals. The purpose of this study was to assess the feasibility and safety of a 12-week intradialysis yoga intervention versus a kidney education intervention on the promotion of physical activity.
DESIGN AND METHODS - We randomized participants by dialysis shift to either 12-week intradialysis yoga or an educational intervention. Intradialysis yoga was provided by yoga teachers to participants while receiving hemodialysis. Participants receiving the 12-week educational intervention received a modification of a previously developed comprehensive educational program for patients with kidney disease (Kidney School). The primary outcome for this study was feasibility based on recruitment and adherence to the interventions and safety of intradialysis yoga. Secondary outcomes were to determine the feasibility of administering questionnaires at baseline and 12 weeks including the Kidney Disease-Related Quality of Life-36.
RESULTS - Among 56 eligible patients who approached for the study, 31 (55%) were interested and consented to participation, with 18 assigned to intradialysis yoga and 13 to the educational program. A total of 5 participants withdrew from the pilot study, all from the intradialysis yoga group. Two of these participants reported no further interest in participation. Three withdrawn participants switched dialysis times and therefore could no longer receive intradialysis yoga. As a result, 13 of 18 (72%) and 13 of 13 (100%) participants completed 12-week intradialysis yoga and educational programs, respectively. There were no adverse events related to intradialysis yoga. Intervention participants practiced yoga for a median of 21 sessions (70% participation frequency), with 60% of participants practicing at least 2 times a week. Participants in the educational program completed a median of 30 sessions (83% participation frequency). Of participants who completed the study (n = 26), baseline and 12-week questionnaires were obtained from 85%.
CONCLUSIONS - Our pilot study of 12-week intradialysis yoga and 12-week educational intervention reached recruitment goals but with less than targeted completion and adherence to intervention rates. This study provided valuable feasibility data to increase follow-up and adherence for future clinical trials to compare efficacy.
Copyright © 2015 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.
OBJECTIVES - It is unknown whether muscle wasting accounts for impaired physical function in adults on maintenance hemodialysis (MHD).
DESIGN - Observational study.
SETTING - Outpatient dialysis units and a fall clinic.
SUBJECTS - One hundred eight MHD and 122 elderly nonhemodialysis (non-HD) participants.
EXPOSURE VARIABLE - Mid-thigh muscle area was measured by magnetic resonance imaging.
MAIN OUTCOME MEASURE - Physical function was measured by distance walked in 6 minutes.
RESULTS - Compared with non-HD elderly participants, MHD participants were younger (49.2 ± 15.8 vs. 75.3 ± 7.1 years; P < .001) and had higher mid-thigh muscle area (106.2 ± 26.8 vs. 96.1 ± 21.1 cm2; P = .002). However, the distance walked in 6 minutes was lower in MHD participants (322.9 ± 110.4 vs. 409.0 ± 128.3 m; P < .001). In multiple regression analysis adjusted for demographics, comorbid conditions, and mid-thigh muscle area, MHD patients walked significantly less distance (-117 m; 95% confidence interval: -177 to -56 m; P < .001) than the non-HD elderly.
CONCLUSIONS - Even when compared with elderly non-HD participants, younger MHD participants have poorer physical function that was not explained by muscle mass or comorbid conditions. We speculate that the uremic milieu may impair muscle function independent of muscle mass. The mechanism of impaired muscle function in uremia needs to be established in future studies.
Published by Elsevier Inc.
BACKGROUND - Prognosis is a component of medical practice imbued with uncertainty. In nephrology, where mortality rates of elderly patients on dialysis are comparable to those of cancer patients, the implications of prognosis are unavoidable. Yet while most patients with end-stage renal disease (ESRD) desire to hear their prognosis, many nephrologists balk at this prospect in part owing to the uncertainty inherent in prognostic estimates.
SUMMARY - In this review, the concept of 'uncertainty' in clinical practice is considered from physician and patient perspectives. From the training perspective, providers learn that uncertainty is inescapable in medicine and develop strategies to manage its presence, including the avoidance of communicating uncertainty to their patients. This presages infrequent discussions of prognosis, which in turn influence patient preferences for treatments that have little therapeutic benefits. A general approach to conveying prognostic uncertainty to ESRD patients includes confronting our own emotional reaction to uncertainty, learning how to effectively communicate uncertainty to our patients, and using an effective interdisciplinary team approach to demonstrate an ongoing commitment to our patients despite the presence of prognostic uncertainty.
KEY MESSAGES - Uncertainty in prognosis is inevitable. Once providers learn to incorporate it into their discussions of prognosis and collaborate with their ESRD patients, such discussions can foster trust and reduce anxiety for both sides.
© 2015 S. Karger AG, Basel.
BACKGROUND - Some patients referred for kidney transplant evaluation fail to attend the visit. Our goal was to compare demographic, socioeconomic, and psychologic factors between evaluation visit attendees and absentees.
METHODS - A convenience sample of patients referred and scheduled for kidney transplant evaluation at a single center from November 2012 to December 2013 participated in a phone survey reporting socioeconomic, demographic, and clinical characteristics; health literacy; and perceived knowledge and concerns about transplantation. Absentees were matched by race with attendees. Analyses of differences between groups were performed with chi-square test, Fisher exact test, and t tests. Multivariable logistic regression was adjusted for relevant demographic characteristics.
RESULTS - One hundred four adults participated (61% men, 46% white, 52 ± 12 years). Financial concerns were the most prevalent (67.3% affording medication, 64.1% affording operation). Previous evaluation at a different transplant center (P = 0.029) and being on dialysis (P = 0.008) were significantly associated with absence. Attendance was associated with concerns about finding a living donor (P = 0.038) and higher perceived general knowledge about transplantation (P ≤ 0.001). No differences were appreciated in demographic, socioeconomic, or health literacy factors between groups.
CONCLUSION - Both attendee and absentee patients were most concerned with the financial burden of kidney transplantation. Although concerns and perceived knowledge are important correlates of behavior, other considerations such as psychologic factors and prior medical experiences may influence patients' ability to complete the kidney transplant evaluation process. Although this pilot study was conducted in a small sample and has limited generalizability, our findings can guide future research.
Renal replacement therapy was an early pioneer in both extra-corporeal organ replacement and whole organ transplantation. Today, the success of this pioneering work is directly demonstrated in the millions of patients worldwide successfully treated with dialysis and kidney transplantation. However, there remain significant shortcomings to current treatment modalities that limit clinical outcomes and quality of life. To address these problems, researchers have turned to using cell-based therapies for the development of a bioartificial kidney. These approaches aim to recapitulate the numerous functions of the healthy kidney including solute clearance, fluid homeostasis and metabolic and endocrine functions. This review will examine the state-of-the-art in kidney bioengineering by evaluating the various techniques currently being utilized to create a bioartificial kidney. These promising new technologies, however, still need to address key issues that may limit the widespread adoption of cell therapy including cell sourcing, organ scaffolding, and immune response. Additionally, while these new methods have shown success in animal models, it remains to be seen whether these techniques can be successfully adapted for clinical treatment in humans.