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Circulating cell-free mitochondrial DNA (ccf-mtDNA) may induce systemic inflammation, a common condition in chronic kidney disease (CKD), by acting as a damage-associated molecular pattern. We hypothesized that in patients with moderate to severe CKD, aerobic exercise would reduce ccf-mtDNA levels. We performed a post hoc analysis of a multicenter randomized trial (NCT01150851) measuring plasma concentrations of ccf-mtDNA at baseline and 2 and 4 mo after aerobic exercise and caloric restriction. A total of 99 participants had baseline ccf-mtDNA, and 92 participants completed the study. The median age of the participants was 57 yr, 44% were female and 55% were male, 23% had diabetes, and 92% had hypertension. After adjusting for demographics, blood pressure, body mass index, diabetes, and estimated glomerular filtration rate, median ccf-mtDNA concentrations at baseline, 2 mo, and 4 mo were 3.62, 3.08, and 2.78 pM for the usual activity group and 2.01, 2.20, and 2.67 pM for the aerobic exercise group, respectively. A 16.1% greater increase per month in ccf-mtDNA was seen in aerobic exercise versus usual activity (P = 0.024), which was more pronounced with the combination of aerobic exercise and caloric restriction (29.5% greater increase per month). After 4 mo of intervention, ccf-mtDNA increased in the aerobic exercise group by 81.6% (95% confidence interval: 8.2−204.8, P = 0.024) compared with the usual activity group and was more marked in the aerobic exercise and caloric restriction group (181.7% increase, 95% confidence interval: 41.1−462.2, P = 0.003). There was no statistically significant correlation between markers of oxidative stress and inflammation with ccf-mtDNA. Our data indicate that aerobic exercise increased ccf-mtDNA levels in patients with moderate to severe CKD. NEW & NOTEWORTHY The effects of prolonged exercise on circulating cell-free mitochondrial DNA (ccf-mtDNA) have not been explored in patients with chronic kidney disease (CKD). We showed that 4-mo aerobic exercise is associated with an increase in plasma ccf-mtDNA levels in patients with stages 3 or 4 CKD. These changes were not associated with markers of systemic inflammation. Future studies should determine the mechanisms by which healthy lifestyle interventions influence biomarkers of inflammation and oxidative stress in patients with CKD.

Rationale & Objective: Individuals with chronic kidney disease frequently suffer from chronic kidney disease-associated pruritus (CKD-aP), impacting sleep quality and quality of life (QoL) and increasing the likelihood of depression. Difelikefalin is a kappa-opioid receptor agonist recently approved in the United States for the treatment of moderate-to-severe CKD-aP in hemodialysis patients. Study 3105 was conducted to further assess the safety of difelikefalin and the effects on pruritus and QoL. Study Design: Open-label, multicenter, single-arm intervention trial. Setting & Participants: Maintenance hemodialysis patients with moderate-to-severe CKD-aP at enrollment. Intervention: Intravenous difelikefalin 0.5 μg/kg after each hemodialysis session for 12 weeks. Outcomes: The primary outcome was safety of difelikefalin. Secondary outcomes included: effectiveness of reducing itch intensity, assessed by the Worst Itching Intensity Numerical Rating Scale (WI-NRS); improving itch-related QoL, assessed with 5-D itch and Skindex-10 scales; and improvement of sleep, assessed with the Sleep Quality Numerial Rating Scale. Clinically meaningful thresholds for improvement in itch and QoL were previously established in this population. Results: Among 222 participants with baseline WI-NRS ≥5, mean [standard deviation] WI-NRS was 7.6 [1.3], mean age 58 years, 55% were male, and mean dialysis duration was 5.9 years; 197 participants (89%) completed treatment. Treatment-related treatment-emergent adverse events were reported in 16 participants (7.2%); those most commonly reported were somnolence (1.8%), hypoesthesia (1.4%), nausea (0.9%), and dizziness (0.9%). No deaths or serious treatment-emergent adverse events were considered treatment-related. Clinically meaningful reduction in itch intensity (≥3-point improvement) was reported by 74% of participants, with 70% and 63% also reporting a clinically relevant improvement in QoL as measured by 5-D itch and Skindex-10. Sleep quality improvement (≥3-point reduction on the Numerical Rating Scale) was reported in 66% of participants. Limitations: No placebo control group. Conclusions: Difelikefalin was well tolerated, and treatment was associated with clinically meaningful improvements in itch intensity and itch-related QoL measures as well as improvements in sleep quality among individuals receiving hemodialysis who had moderate-to-severe CKD-aP, providing important insights into expected real-world effectiveness. Funding: Cara Therapeutics. Trial Registration: NCT03998163.

Background and aims: Obesity is a pro-inflammatory risk factor for progression of CKD and cardiovascular disease. We hypothesized that implementation of caloric restriction and endurance exercise would improve adipocytokine profiles in patients with moderate to severe CKD. Methods and results: We enrolled patients with moderate to severe CKD through a multi-center pilot randomized trial of diet and exercise in a 4-arm design (dietary restriction of 10%-15% reduction in caloric intake, exercise three times/week, combined diet and exercise, and control) (NCT01150851). Adipocytokines (adiponectin and leptin) were measured at the beginning and end of the study period as secondary outcomes. Treatment effect was analyzed in a multivariable model adjusted for baseline outcome values, age, gender, site and diabetes. A total of 122 participants were consented, 111 were randomized (42% female, 25% diabetic, and 91% hypertensive), 104 started intervention and 92 completed the study (Figure 1). Plasma adiponectin levels increased significantly in response to diet by 23% (95% CI: 0.2%, 49.8%, p = 0.048) among participants randomized to the caloric restriction and usual activity arm but not to exercise, whereas circulating leptin did not change by either treatment. Conclusion: Our data suggest that dietary caloric restriction increases plasma adiponectin levels in stage 3-4 CKD patients, with limited effect on leptin levels. These findings suggest the potential for improving the metabolic milieu of CKD with moderate calorie restriction. (C) 2020 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved. National Institutes of Health from National Heart, Lung, and Blood InstituteUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Heart Lung & Blood Institute (NHLBI) [R01HL070938]; National Institute of Diabetes and Digestive and Kidney DiseasesUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) [K24DK62849, P30DK020593, P30DK035816]; National Institute of Environmental Health SciencesUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Environmental Health Sciences (NIEHS) [P30ES000267]; National Center for Advancing Translational SciencesUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Center for Advancing Translational Sciences (NCATS) [UL1-TR000445, UL1TR000423] This study was in part supported by National Institutes of Health grants R01HL070938 from National Heart, Lung, and Blood Institute; K24DK62849, P30DK020593, and P30DK035816 from National Institute of Diabetes and Digestive and Kidney Diseases; P30ES000267 from the National Institute of Environmental Health Sciences; and Clinical Translational Science Awards UL1-TR000445 and UL1TR000423 from the National Center for Advancing Translational Sciences. WOS:000572853200016 2-s2.0-85086927317 PubMed: 32571614

In patients with advanced-stage chronic kidney disease (CKD), progressive kidney function decline leads to increased risk for hyperkalemia (serum potassium > 5.0 or >5.5 mEq/L). Medications such as renin-angiotensin-aldosterone system inhibitors pose an additional hyperkalemia risk, especially in patients with CKD. When hyperkalemia develops, clinicians often recommend a diet that is lower in potassium content. This review discusses the barriers to adherence to a low-potassium diet and the impact of dietary restrictions on adverse clinical outcomes. Accumulating evidence indicates that a diet that incorporates potassium-rich foods has multiple health benefits, which may also be attributable to the other vitamin, mineral, and fiber content of potassium-rich foods. These benefits include blood pressure reductions and reduced risks for cardiovascular disease and stroke. High-potassium foods may also prevent CKD progression and reduce mortality risk in patients with CKD. Adjunctive treatment with the newer potassium-binding agents, patiromer and sodium zirconium cyclosilicate, may allow for optimal renin-angiotensin-aldosterone system inhibitor therapy in patients with CKD and hyperkalemia, potentially making it possible for patients with CKD and hyperkalemia to liberalize their diet. This may allow them the health benefits of a high-potassium diet without the increased risk for hyperkalemia, although further studies are needed.

Introduction Patients are often instructed to engage in multiple weekly sessions of exercise to increase physical activity. We aimed to determine whether assignment to a supervised exercise regimen increases overall weekly activity in individuals with chronic kidney disease (CKD). Methods We performed a secondary analysis of a pilot randomized 2 × 2 factorial design trial examining the effects of diet and exercise (10%−15% reduction in caloric intake, 3 supervised exercise sessions/wk, combined diet restriction/exercise, and control). Activity was measured as counts detected by accelerometer. Counts data were collected on all days for which an accelerometer was worn at baseline, month 2, and month 4 follow-up. The primary outcome was a relative change from baseline in log-transformed counts/min. Generalized estimating equations were used to compare the primary outcome in individuals in the exercise group and the nonexercise group. Results We examined 111 individuals randomized to aerobic exercise or usual activity (n = 48 in the exercise group and n = 44 controls). The mean age was 57 years, 42% were female, and 28% were black. Median overall adherence over all time was 73%. Median (25th, 75th percentile) counts/min over nonsupervised exercise days at months 2 and 4 were 237.5 (6.5, 444.4) for controls and 250.9 (7.7, 529.8) for the exercise group (P = 0.74). No difference was observed in the change in counts/min between the exercise and control groups over 3 time points (β [fold change], 0.96, 95% confidence interval [CI], 0.91, 1.02). Conclusion Engaging in a supervised exercise program does not increase overall weekly physical activity in individuals with stage 3 to 4 CKD., Graphical abstract

Introduction: There is an unmet medical need for pruritus associated with chronic kidney disease, a distressing complication characterized by generalized and persistent itch affecting 20% to 40% of patients undergoing hemodialysis. Here we report the results of a phase 2 trial evaluating the efficacy and safety of a novel peripherally restricted kappa opioid receptor agonist, difelikefalin, in adult patients undergoing hemodialysis with pruritus. Methods: In this study, 174 hemodialysis patients with moderate-to-severe pruritus were randomly assigned to receive difelikefalin (0.5, 1.0, or 1.5 μg/kg) or placebo intravenously thrice weekly after each hemodialysis session for 8 weeks in a double-blind, controlled trial. The primary endpoint was the change from baseline at week 8 in the weekly mean of the 24-hour Worst Itching Intensity Numerical Rating Scale score. The secondary efficacy endpoint was the change in itch-related quality of life measured by the Skindex-10 questionnaire. Other endpoints included safety, sleep quality, and additional measures including the 5-D itch scale. Results: A significant reduction from baseline in itch intensity scores at week 8 favored all difelikefalin doses combined versus placebo (P = 0.002). Difelikefalin also showed improvement over placebo in Skindex-10, 5-D itch, and sleep disturbance scores (P ≤ 0.005). Overall, 78% of patients receiving difelikefalin reported treatment-emergent adverse events versus 42% of patients given placebo, with diarrhea, dizziness, nausea, somnolence, and fall being the most frequent (≥5%). Conclusion: In this trial, difelikefalin effectively reduced itching intensity and improved sleep and itch-related quality of life. Keywords: chronic kidney disease, CKD-aP, CR845, hemodialysis, kappa opioid receptor agonist, uremic pruritus

Background: Patients with end-stage renal disease are sedentary, frail, and have low functional ability (FA) compared to healthy age-matched controls. The purpose of this study was to examine the effects of an intradialytic, supervised, 8-week resistance training (RT) program on strength (ST), FA, and quality of life (QOL) in a sample of patients with end-stage renal disease. Methods: Twenty hemodialysis patients were randomized to an exercise (E, n = 12) or control (C, n = 8) group. Patients randomized to E received intradialytic RT immediately before and during treatment, 3 d per week for 8 weeks. Patients randomized to C received usual care and no exercise. ST and FA were assessed at baseline and at 4 and 8 weeks with manual muscle testing and the Short Physical Performance Battery. QOL was assessed at baseline and 8 weeks with the 36-item Short Form Health Survey (SF-36). Mixed factorial ANOVAs were used to determine the effects of RT on ST, FA, and QOL. Results: Significant interactions were found for ST for the right (p = 0.006) and left (p = 0.008) gastrocnemius, right quadriceps (p = 0.003), right (p = 0.005) and left (p = 0.004) hamstrings, and right adductor (p = 0.020). ST improved for E but not C across time (p < 0.05). Significant time effects for FA were found for chair (p = 0.001) and total (p = 0.008) SPPB scores but were not different between groups (p > 0.05). Similar effects were found for the physical performance component of the SF-36 (p = 0.023). Conclusion: A supervised 8-week, intradialytic RT program improved lower body ST in patients with end-stage renal disease; however, these improvements did not impact FA or QOL.

OBJECTIVES: There are approximately 660,000 end-stage renal disease (ESRD) patients in the USA, with hemodialysis (HD) the primary form of treatment. High ultrafiltration rates (UFRs) are associated with intradialytic hypotension, a complication associated with adverse clinical outcomes including mortality. Individualized UFR profiles could reduce the incidence of intradialytic hypotension. METHODS: The patient’s fluid dynamics during HD is described by a nonlinear model comprising intravascular and interstitial pools, whose parameters are given by the patient’s estimated nominal parameter values with uncertainty ranges; the output measurement is hematocrit. We design UFR profiles that minimize the maximal UFR needed to remove a prescribed volume of fluid within a set time, with hematocrit not exceeding a specified time-varying critical profile. RESULTS: We present a novel approach to designing individualized UFR profiles, and give theoretical results guaranteeing that the system remains within a pre-defined physiologically plausible region and does not exceed a specified time-invariant critical hematocrit level for all parameters in the uncertainty ranges. We test the performance of our design using a real patient data example. The designed UFR maintains the system below a time-varying critical hematocrit profile in the example. CONCLUSION: Theoretical results and simulations show that our designed UFR profiles can remove the target amount of fluid in a given time period while keeping the hematocrit below a specified critical profile. SIGNIFICANCE: Individualization of UFR profiles is now feasible using current HD technology and may reduce the incidence of intradialytic hypotension.

Background Guiding patients with advanced chronic kidney disease (CKD) through advance care planning about future treatment obliges an assessment of prognosis. A patient-specific integrated model to predict mortality could inform shared decision-making for patients with CKD. Methods Patients with Stages 4 and 5 CKD from Massachusetts (749) and West Virginia (437) were prospectively evaluated for clinical parameters, functional status [Karnofsky Performance Score (KPS)] and their provider’s response to the Surprise Question (SQ). A predictive model for 12-month mortality was derived with the Massachusetts cohort and then validated externally on the West Virginia cohort. Logistic regression was used to create the model, and the c-statistic and Hosmer–Lemeshow statistic were used to assess model discrimination and calibration, respectively. Results In the derivation cohort, the SQ, KPS and age were most predictive of 12-month mortality with odds ratios (ORs) [95% confidence interval (CI)] of 3.29 (1.87–5.78) for a ‘No’ response to the SQ, 2.09 (95% CI 1.19–3.66) for fair KPS and 1.41 (95% CI 1.15–1.74) per 10-year increase in age. The c-statistic for the 12-month mortality model for the derivation cohort was 0.80 (95% CI 0.75–0.84) and for the validation cohort was 0.74 (95% CI 0.66–0.83). Conclusions Our integrated prognostic model for 12-month mortality in patients with advanced CKD had good discrimination and calibration. This model provides prognostic information to aid nephrologists in identifying and counseling advanced CKD patients with poor prognosis who are facing the decision to initiate dialysis or pursue medical management without dialysis.

Introduction: The safety and efficacy of extended-release calcifediol (ERC) as a treatment for secondary hyperparathyroidism (SHPT) in adults with stage 3 or 4 chronic kidney disease (CKD) and vitamin D insufficiency (VDI) has been demonstrated in prospective randomized clinical trials (RCTs). ERC (Rayaldee®) was approved by the Food and Drug Administration in 2016 on the basis of these prospective RCTs. The current retrospective study assessed the postlaunch data available with respect to ERC’s efficacy and safety in increasing serum 25-hydroxyvitamin D (25D) and reducing parathyroid hormone (PTH) in the indicated population. Materials and Methods: Medical records of 174 patients who met study criteria from 15 geographically representative United States nephrology clinics were reviewed for 1 year before and after initiation of ERC treatment. Enrolled subjects had ages ≥18 years, stage 3 or 4 CKD, and a history of SHPT and VDI. Key study variables included patient demographics, medication usage, and laboratory results, including serial 25D and PTH determinations. Results: The enrolled subjects had a mean age of 69.0 years, gender and racial distributions representative of the indicated population, and were balanced for CKD stage. Most (98%) received 30 mcg of ERC/day during the course of treatment (mean follow-up: 24 weeks). Baseline 25D and PTH levels averaged 20.3 ± 0.7 (standard error) ng/mL and 181 ± 7.4 pg/mL, respectively. ERC treatment raised 25D by 23.7 ± 1.6 ng/mL (p < 0.001) and decreased PTH by 34.1 ± 6.6 pg/mL (p < 0.001) with nominal changes of 0.1 mg/dL (p > 0.05) in serum calcium (Ca) and phosphorus (P) levels. Discussion/Conclusion: Analysis of postlaunch data confirmed ERC’s effectiveness in increasing serum 25D and reducing PTH levels without statistically significant or notable impact on serum Ca and P levels. A significant percentage of these subjects achieved 25D levels ≥30 mg/mL and PTH levels which decreased by at least 30% from baseline. Dose titration to 60 mcgs was rarely prescribed. Closer patient monitoring and appropriate dose titration may have led to a higher percentage of subjects achieving an increase in 25D levels to at least 50 ng/mL and a reduction in PTH levels of at least 30%.

INTRODUCTION: Estimated dry weight is used to guide fluid removal during outpatient hemodialysis sessions. Errors in estimated dry weight can result in intradialytic hypotension and interdialytic fluid overload. The goal of this study was to assess the accuracy of estimated dry weight by comparing it to the two-week post-transplant weight in two cohorts of hemodialysis patients. METHODS: This observational, multi-center, retrospective cohort study included maintenance hemodialysis patients who underwent kidney transplantation at two medical centers in Massachusetts. The relationship between estimated dry weight pre-transplant and weight at week 2 post-transplant in patients with good allograft function (serum creatinine ≤ 1.5 mg/dL) was analyzed. Estimated dry weight was considered accurate if it was within ±2% of the week 2 post-transplant weight. RESULTS: Fifty seven patients with good allograft function were identified: mean age 54±14 years, 32 (58%) from deceased donors, 22 (38.6%) females. 38 were Caucasian (66.7%), 11 Hispanic (19.3%), 3 black (5.3%), and 5 others (8.8%). 2-week mean post transplantation serum creatinine was 1.2±0.2 mg/dL. Mean (SD) estimated dry weight was 71.4±15.9. Before transplantation, only 14 (24.6%) patients were within ±2% of the 2-week post-transplant weight; 23 (40.3%) were above and 20 (35.1%) were below. CONCLUSIONS: Our point of view, based on the assumption that the weight of patients with good allograft function at 2 weeks post-transplant approaches their accurate dry weight, is that a majority of maintenance hemodialysis patients (75.4%) are hypervolemic or hypovolemic prior to renal transplantation. This highlights the importance of finding novel tools to achieve euvolemia in patients undertaking dialysis. Timely feedback regarding achieved weight 2 weeks post-transplant to treating nephrologists and dialysis centers may be a starting point for assessing accuracy of dry weight.

Kidney involvement in patients with coronavirus disease 2019 (COVID-19) is common, and can range from the presence of proteinuria and haematuria to acute kidney injury (AKI) requiring renal replacement therapy (RRT; also known as kidney replacement therapy). COVID-19-associated AKI (COVID-19 AKI) is associated with high mortality and serves as an independent risk factor for all-cause in-hospital death in patients with COVID-19. The pathophysiology and mechanisms of AKI in patients with COVID-19 have not been fully elucidated and seem to be multifactorial, in keeping with the pathophysiology of AKI in other patients who are critically ill. Little is known about the prevention and management of COVID-19 AKI. The emergence of regional 'surges' in COVID-19 cases can limit hospital resources, including dialysis availability and supplies; thus, careful daily assessment of available resources is needed. In this Consensus Statement, the Acute Disease Quality Initiative provides recommendations for the diagnosis, prevention and management of COVID-19 AKI based on current literature. We also make recommendations for areas of future research, which are aimed at improving understanding of the underlying processes and improving outcomes for patients with COVID-19 AKI.

Background Chronic kidney disease (CKD) is characterized by dysbiosis, elevated levels of uremic toxins, systemic inflammation, and increased markers of oxidative stress. These factors lead to an increased risk of cardiovascular disease (CVD) which is common among CKD patients. Supplementation with high amylose maize resistant starch type 2 (RS-2) can change the composition of the gut microbiota, and reduce markers of inflammation and oxidative stress in patients with end-stage renal disease. However, the impact of RS-2 supplementation has not been extensively studied in CKD patients not on dialysis. Aerobic exercise training lowers certain markers of inflammation in CKD patients. Whether combining aerobic training along with RS-2 supplementation has an additive effect on the aforementioned biomarkers in predialysis CKD patients has not been previously investigated. Methods The study is being conducted as a 16-week, double-blind, placebo controlled, parallel arm, randomized controlled trial. Sixty stage 3–4 CKD patients (ages of 30–75 years) are being randomized to one of four groups: RS-2 & usual care, RS-2 & aerobic exercise, placebo (cornstarch) & usual care and placebo & exercise. Patients attend four testing sessions: Two baseline (BL) sessions with follow up visits 8 (wk8) and 16 weeks (wk16) later. Fasting blood samples, resting brachial and central blood pressures, and arterial stiffness are collected at BL, wk8 and wk16. A stool sample is collected for analysis of microbial composition and peak oxygen uptake is assessed at BL and wk16. Blood samples will be assayed for p-cresyl sulphate and indoxyl sulphate, c-reactive protein, tumor necrosis factor α, interleukin 6, interleukin 10, monocyte chemoattractant protein 1, malondialdehyde, 8-isoprostanes F2a, endothelin-1 and nitrate/nitrite. Following BL, subjects are randomized to their group. Individuals randomized to conditions involving exercise will attend three supervised moderate intensity (55–65% peak oxygen uptake) aerobic training sessions (treadmills, bikes or elliptical machine) per week for 16 weeks. Discussion This study has the potential to yield information about the effect of RS-2 supplementation on key biomarkers believed to impact upon the development of CVD in patients with CKD. We are examining whether there is an additive effect of exercise training and RS-2 supplementation on these key variables. Trial registration Clinicaltrials.gov Trial registration#NCT03689569. 9/28/2018, retrospectively registered.

Background and Aims Extended-release calcifediol (ERC), active vitamin D analogs (VDA), and nutritional vitamin D (NVD) are the predominant vitamin D therapies (VDTs) commonly used for treatment (Tx) of secondary hyperparathyroidism (SHPT) in adults with stage 3 or 4 non-dialysis chronic kidney disease (ND-CKD) and vitamin D insufficiency (VDI). Clinical trials have demonstrated varying efficacy on serum total 25-hydroxyvitamin D (25D) and intact parathyroid hormone (iPTH) across VDTs. This study aimed to descriptively assess the real-world experience of various VDTs in increasing 25D, reducing iPTH, and modifying serum calcium (Ca). Method Medical records of the first 376 adult patients with stage 3 or 4 CKD and a history of SHPT and VDI who met study criteria from 18 geographically representative United States nephrology clinics were reviewed from 1 year before through 1 year after initiation of VDT. Key study variables included patient demographics, medication usage, and laboratory results. The study population had a mean age of 69.5 years with gender and racial distributions representative of the US ND-CKD population. Patients were stratified into cohorts based on their index therapy at index date: ERC (n=174), VDA (n=55) and NVD (n=147). Results Patients treated with NVD were predominantly CKD Stage 3 (69.4%), while CKD Stage 4 were the majority of those treated with ERC (53.4%) and VDA (61.8%). The ERC Tx’ed subjects demonstrated an increase in 25D by 23.7 ± 1.6 ng/mL (p Conclusion Clinical effectiveness and safety varied across VDTs. ERC was the only VDT which significantly reduced mean iPTH in the real world setting despite highest mean levels at baseline among the three cohorts. Additionally, subjects treated with ERC demonstrated the largest mean increase in 25D and ERC was the only VDT which raised mean 25D to the normal range (>30 ng/mL). Patients treated with ERC and NVD saw no statistically significant impact on serum Ca and P levels; however, those treated with VDAs saw a small, but statistically significant increase in serum Ca levels.

Background and Objectives Since 25 May 2010, all donors at our blood centre who tested false-positive for HIV, HBV, HCV or syphilis are eligible for re-entry after further testing. Donors who have a second false-positive screening test, either during qualification for or after re-entry, are deferred for life. This study reports on factors associated with the occurrence of such deferrals. Materials and Methods Rates of second false-positive results were compared by year of deferral, transmissible disease marker, gender, age, donor status (new or repeat) and testing platform (same or different) both at qualification for re-entry and afterwards. Chi-square tests were used to compare proportions. Cox regression was used for multivariate analyses. Results Participation rates in the re-entry programme were 42·1%: 25·6% failed to qualify for re-entry [different platform: 2·7%; same platform: 42·9% (P < 0·0001)]. After re-entry, rates of deferral for second false-positive results were 8·4% after 3 years [different platform: 1·8%; same platform: 21·4% (P < 0·0001)]. Deferral rates were higher for HIV and HCV than for HBV at qualification when tested on the same platform. The risk, when analysed by multivariate analyses, of a second deferral for a false-positive result, both at qualification and 3 years after re-entry, was lower for donors deferred on a different platform; this risk was higher for HIV, HCV and syphilis than for HBV and for new donors if tested on the same platform. Conclusion Re-entry is more often successful when donors are tested on a testing platform different from the one on which they obtained their first false-positive result.

CKD is steadily increasing along with obesity worldwide. Furthermore, obesity is a proinflammatory risk factor for progression of CKD and cardiovascular disease. We tested the hypothesis that implementation of caloric restriction and aerobic exercise is feasible and can improve the proinflammatory metabolic milieu in patients with moderate to severe CKD through a pilot, randomized, 2×2 factorial design trial. Of 122 participants consented, 111 were randomized to receive caloric restriction and aerobic exercise, caloric restriction alone, aerobic exercise alone, or usual care. Of those randomized, 42% were women, 25% were diabetic, and 91% were hypertensive; 104 started intervention, and 92 completed the 4-month study. Primary outcomes were a change from baseline in absolute fat mass, body weight, plasma F 2 -isoprostane concentrations, and peak oxygen uptake (VO 2 peak ). Compared with usual care, the combined intervention led to statistically significant decreases in body weight and body fat percentage. Caloric restriction alone also led to significant decreases in these measures, but aerobic exercise alone did not. The combined intervention and each independent intervention also led to significant decreases in F 2 -isoprostane and IL-6 concentrations. No intervention produced significant changes in VO 2 peak , kidney function, or urine albumin-to-creatinine ratio. In conclusion, 4-month dietary calorie restriction and aerobic exercise had significant, albeit clinically modest, benefits on body weight, fat mass, and markers of oxidative stress and inflammatory response in patients with moderate to severe CKD. These results suggest healthy lifestyle interventions as a nonpharmacologic strategy to improve markers of metabolic health in these patients.

Background: Fluid management remains a major challenge of hemodialysis (HD) care, with serious implications for morbidity and mortality. Intradialytic fluid management is typically guided by blood pressure, an indirect resultant of hemodynamics status. Direct measurements of hemodynamic parameters may improve cardiovascular outcomes by providing rational bases for intervention. We compare stroke volume (SV) measurements using a noninvasive, regional biompedance cardiography device (NiCaS) with Doppler echocardiography (Echo) in HD setting. Methods: Stroke volumes were simultaneously measured using the devices in 17 patients receiving maintenance HD. Measurements were made during 2 weekly HD treatments, and twice within each HD treatment during the first and last hour of each treatment, for a total of 64 SV measurements. Agreement between devices was assessed using linear regression, a Pearson's correlation coefficient, and a Bland-Altman plot all adjusted for repeated measures within patients. Results: Echo and NiCaS SV mean and 95% CIs were 58.0 (50.1, 65.8) and 56.7 (49.4, 64.0) mL, respectively. NiCaS SV correlated strongly with Echo SV during the first and last hours of treatments (r = 0.93, P

Background Chronic kidney disease (CKD) is associated with abnormal lipid profiles and altered high-density lipoprotein (HDL) particle size patterns. Lower levels of the larger, cardioprotective HDL particles found in CKD may play a role in the increased risk for cardiovascular disease in these patients. The current study was designed to assess the effects of short-term moderate-intensity aerobic exercise training on the HDL particle pattern and overall lipid profiles in stage 3 CKD patients. Methods Forty-six men and women with stage 3 CKD were randomized to either exercise (EX, n = 25) or control (CON, n = 21). Those in the EX group completed 16 weeks of supervised moderate-intensity aerobic exercise three times per week. Serum total cholesterol, HDL cholesterol (HDL-C), triglycerides (TGs), low-density lipoprotein cholesterol (LDL-C), HDL particle size, estimated glomerular filtration rate (eGFR), body composition and peak oxygen uptake (VO2peak) were assessed at baseline and week 16. Results The rate of compliance in the EX group was 97 ± 7.2%. No change was observed in eGFR over time in either group. There was an 8.2% improvement in VO2peak in the EX group (P = 0.05), while VO2peak decreased in the CON group. HDL-C, TGs, HDL particle size and body composition remained unchanged in both groups. A trend was found for lower total cholesterol (TC) (P = 0.051) and LDL-C (P = 0.07) in the CON group. Conclusion Our findings indicate that a short-term aerobic exercise training intervention in stage 3 CKD patients does not induce changes in HDL particle size or favorable lipid profile modifications.

Although multiple lines of evidence suggest a negative impact of secondary hyperparathyroidism on patients with kidney failure treated by hemodialysis, it is uncertain whether patients can detect associated symptoms. The objective was to determine whether changes in parathyroid hormone (PTH) levels are associated with changes in symptoms within this patient population.Prospective cohort.165 adults with hyperparathyroidism secondary to kidney failure diagnosed, a range of dialysis vintages, and receiving regular hemodialysis from a US single-provider organization.Change in PTH levels over 24 weeks.19 putative symptoms of secondary hyperparathyroidism measured up to 4 times using a self-administered questionnaire that assessed severity on a 5-level ordinal scale.Longitudinal associations between changes in PTH levels and symptom severity were assessed using generalized additive models.The 165 participants studied represented 81% of enrollees (N=204) who had sufficiently complete data for analysis. Mean age was 56 years and 54% were women. Increases in PTH levels over time were associated (P0.1) with worsening of bone aches and stiffness, joint aches, muscle soreness, overall pain, itchy skin, and tiredness, and the effects were more pronounced with larger changes in PTH levels.Findings may have been influenced by confounding by unmeasured comorbid conditions, concomitant medications, and multiple testing coupled with a P value threshold of 0.10.In this exploratory study, we observed that among patients with secondary hyperparathyroidism, increases in PTH levels over time were associated with worsening of 1 or more cluster of symptoms. Replication of these findings in other populations is needed before concluding about the magnitude and shape of these associations. If replicated, these findings could inform clinically useful approaches for measuring patient-reported outcomes related to secondary hyperparathyroidism.

Introduction The optimal use of erythropoiesis stimulating agents (ESAs) to treat anemia in end stage renal disease remains controversial due to reported associations with adverse events. In analyzing these associations, studies often utilize ESA resistance indices (ERIs), to characterize a patient's response to ESA. In this study, we examine whether ERI is an adequate measure of ESA resistance. Methods We used retrospective data from a nonconcurrent cohort study of incident hemodialysis patients in the United States (n = 9386). ERI is defined as average weekly erythropoietin (EPO) dose per kg body weight (wt) per average hemoglobin (Hgb), over a 3-month period (ERI = (EPO/wt)/Hgb). Linear regression was used to demonstrate the relationship between ERI and weight-adjusted EPO. The coefficient of variation was used to compare the variability of Hgb with that of weight-adjusted EPO to explain this relationship. This analysis was done for each quarter during the first year of dialysis. Findings ERI is strongly linearly related with weight-adjusted EPO dose in each of the four quarters by the equation ERI = 0.0899*(EPO/wt) (range of R(2) = 0.97-0.98) and weakly linearly related to 1/Hgb (range of R(2) = 0.06-0.16). These correlations hold independent of age, sex, hgb level, ERI level, and epo-naive stratifications. Discussion ERI is strongly linearly related to weight-adjusted (and nonweight-adjusted) EPO dose by a "universal," not patient-specific formula, and thus is a surrogate of EPO dose. Therefore, associations between ERI and clinical outcomes are associations between a confounded EPO dose and those outcomes.

Introduction: Mortality rates are high in end-stage renal disease due to cardiovascular complications. Perfusion of the myocardium declines during and after hemodialysis sessions with the potential for aerobic exercise to mitigate these during hemodialysis. Objectives: The purpose of this study was to investigate acute changes in hemodynamics in subjects with end-stage renal disease (ESRD) during exercise. Patients and Methods: Subjects (n = 10) were monitored for 1.5 hours during hemodialysis treatment during a control (CON) and an exercise (EX) session. Subjects cycled using an ergometer strapped to the reclining dialysis chair at an RPE of 11-13 for 30 minutes during the EX session beginning at 30 min into dialysis and ending at 60 minutes. Data for systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial pressure (MAP) were collected using an automated blood pressure cuff attached to the hemodialysis machine. Data for cardiac output (Q̇ ), cardiac power index (CPI), stroke volume (SV), systemic vascular resistance (SVR), and heart rate (HR) were collected using the NICaS bioelectrical impedance device. Results: During the EX session, CPI, Q̇ , SV, and HR were significantly greater (PConclusion: In conclusion, exercise during dialysis may decrease the likelihood of experiencing ischemic or hypotensive events by enhancing myocardial perfusion through increasing CPI and Q̇ .

Background and objectives In patients with end-stage renal disease (ESRD), the rate of deaths preceded by dialysis withdrawal is high. However, rates vary across studies and national renal registries. This study aimed to (i) determine how dialysis withdrawal mortality is defined in the literature and (ii) whether mortality rates preceded by dialysis withdrawal change over time. Methods MEDLINE (1946 to March 2012) and EMBASE (1980 to March 2012) databases were searched. We included epidemiological studies that reported data permitting calculation of crude (unadjusted) mortality rates preceded by dialysis withdrawal. Definitions of dialysis withdrawal were also extracted. Crude mortality rates and 95% confidence intervals were calculated using OpenEpi software. Non-English language studies were excluded. Results Twenty-three eligible studies were identified; these included 14 527 885 dialysis patients at risk from six countries. Crude mortality rates preceded by dialysis withdrawal ranged from 3 to 50.2 per 1000 person-years. Seven different definitions of dialysis withdrawal were identified, with no assessment of validity. Crude mortality rates preceded by withdrawal have increased over time across the study period 1966 (3 per 1000 person-years) to 2010 (48.6 per 1000 person-years), although these rates are difficult to interpret because of differences in classification. In the USA crude mortality rates preceded by dialysis withdrawal are higher in the older population and have increased over time in the age group 65+ years. In this age group, the crude mortality rate preceded by dialysis withdrawal was 89.4 per 1000 person-years (2008-10) compared with 26.1 per 1000 person-years in the age group 50-64 years (2008-10). Conclusion Mortality rates preceded by dialysis withdrawal over time should be interpreted with caution because of differences in classification. Types of dialysis withdrawal need more careful elucidation, and we propose a unified classification of dialysis withdrawal based on trajectories and causal criteria.

Nephrologist are often faced with the question of the appropriate initiation and withdrawal from dialysis. Many clinicians feel that patient should be offered dialysis when they have ESRD regardless of the potential risks vs. benefits. My position in this debate is that nephrologists have the obligation to order treatments that are indicated and effective for their patients and will provide more benefit that harm. They should not order dialysis in patient that are not likely to benefit from the treatment. Patients have the right to refuse treatments but not the right to demand that a clinician order an ineffective treatment. Shared decision making is the key principle in deciding on the initiation and withdrawal from dialysis. The national guideline; Shared Decision Making: The Appropriate Initiation and Withdrawal from Dialysis supports this approach.

Background and Objectives In many jurisdictions, blood donors who have an atypical pulse rate are temporarily deferred. This practice is not supported by evidence. We evaluated whether accepting donors with an atypical pulse rate increases their risk of cardiac ischaemic events. Methods We measured the cumulative incidence of hospitalizations and deaths for coronary heart disease within 1 year of follow-up among donors who, between 2002 and 2006, were temporarily deferred because of an atypical pulse ( 100 beats/min, or irregular). We compared this incidence to that observed among donors who also had an atypical pulse but who were allowed to donate, following a change in our deferral policy in 2007. The occurrence of cardiac events was determined through hospital discharge and death registries. Results Among 6076 donors who were temporarily deferred for an atypical pulse, the 1-year rate of hospitalization or death for cardiac ischaemic events was 3·5/1000, compared to 2·4 in donors who had an atypical pulse but who were allowed to donate (n = 10 671), for an adjusted odds ratio of 1·7 (95% CI, 0·9–3·0, P = 0·08). Conclusion Regardless of the clinical significance of an atypical pulse rate, our data show that accepting donors with this condition does not increase the occurrence of serious cardiac ischaemic events. We conclude that pulse rate measurement in prospective donors is not warranted.

BACKGROUND AND OBJECTIVES Blood operators routinely monitor the pH of apheresis platelets as a marker of the so-called storage lesion, which can result from manufacturing problems. It is also suspected that some donor characteristics can increase the risk of poor platelet storage. To explore this hypothesis, we analysed a large, multinational data set of quality control (QC) pH test results on apheresis platelets. MATERIALS AND METHODS For the period between September 2011 and August 2014, seven blood operators in Canada, the USA, the Netherlands, the United Kingdom, France and Australia provided pH QC test results and donor characteristics on a total of 21,671 apheresis platelets. RESULTS Some variations in pH distribution between blood operators were in part explained by differences in collection, processing and testing methods. Younger age and female gender were significantly associated with a pH value below the 10th percentile. Among donors who had two or more pH measurements (n = 3672), there was a strong correlation between pH results (r = 0·726; P < 0·0001). CONCLUSION The strong intradonor correlation of pH measurements and the association between donor characteristics and pH results suggest that donor factors play a role in the quality of platelets.

For more than 20 years, nephrologists have been reporting that they are increasingly being expected to dialyze patients whom they believe may receive little benefit from dialysis therapy. During this time, there has been substantial research about the outcomes of patients of differing ages and comorbid conditions requiring dialysis and the development of clinical practice guidelines for dialysis decision making based on research evidence, ethics, and the law. The importance of palliative medicine to the care of the patient throughout the continuum of kidney disease also has been recognized, and its application has been described. This article summarizes these advances and provides an approach for decision making and treatment for patients who are not likely to benefit from dialysis therapy.

Background and objectives: Prognostic information is rarely conveyed by nephrologists because of clinical uncertainty about accuracy. The objective of this study was to develop an integrated prognostic model of 6-mo survival for patients who receive hemodialysis (HD). Design, setting, participants, & measurements: A short-term prognostic model was developed using prospective data from a derivation cohort of 512 patients who were receiving HD at five dialysis clinics. Patient charts were reviewed for actuarial predictors (e.g., Charlson Comorbidity), and nephrologists answered the “surprise” question (SQ), “Would I be surprised if this patient died within the next 6 mo?” Survival was monitored for up to 24 mo. The prognostic model was tested with a validation cohort of 514 patients from eight clinics. Results: In a Cox multivariate analysis of the derivation cohort, five variables were independently associated with early mortality: Older age (hazard ratio [HR] for a 10-yr increase 1.36; 95% confidence interval [CI] 1.17 to 1.57), dementia (HR 2.24; 95% CI 1.11 to 4.48), peripheral vascular disease (HR 1.88; 95% CI 1.24 to 2.84), decreased albumin (HR for a 1-U increase 0.27; 95% CI 0.15 to 0.50), and SQ (HR 2.71; 95% CI 1.76 to 4.17). Area under the curve for the resulting prognostic model predictions of 6-mo mortality were 0.87 (95% CI 0.82 to 0.92) in the derivation cohort and 0.80 (95% CI 0.73 to 0.88) in the validation cohort. Conclusions: An integrated 6-mo prognostic tool was developed and validated for the HD population. The instrument may be of value for researchers and clinicians to improve end-of-life care by providing more accurate prognostic information.

This is the first description of functional immunoassay technology (FIT), which as a diagnostic tool has broad application across the whole spectrum of physiological measurements. In this paper, FIT is used to measure the renal clearance of an ultra low-dose administration of a clinically available contrast reagent for the purpose of obtaining an accurate glomerular filtration rate (GFR) measurement. Biomarker-based GFR estimates offer convenience, but are not accurate and are often misleading. FIT overcomes previous analytic barriers associated with obtaining an accurate GFR measurement. We present the performance characteristics of this diagnostic test and demonstrate the method by directly comparing GFR values obtained by FIT to those obtained by an FDA approved nuclear test in 20 adults. Two subjects were healthy volunteers and the remaining 18 subjects had diagnosed chronic kidney disease, with 12 being kidney transplant recipients. Measured GFR values were calculated by the classic UV/P method and by the blood clearance method. GFR obtained by FIT and the nuclear test correlated closely over a wide range of GFR values (10.9–102.1 ml·min−1·1.73 m−2). The study demonstrates that FIT-GFR provides an accurate and reproducible measurement. This nonradioactive, immunoassay-based approach offers many advantages, chiefly that most laboratories already have the equipment and trained personnel necessary to run an ELISA, and therefore this important diagnostic measurement can more readily be obtained. The FIT-GFR test can be used throughout the pharmaceutical development pipeline: preclinical and clinical trials.

Withholding and withdrawal of dialysis has been a reality since dialysis was invented. Only in the past 20 years has it been formally studied, and we still have a great deal to learn. The nephrology community has slowly come to accept that, for some of our patients, not having dialysis is a better option than continuing or initiating therapy. The principles of palliative care throughout the disease trajectory and hospice care at end of life are germane to this population due to its high symptom burden and mortality rate. We review what is currently known concerning patients who choose to withhold or withdraw from dialysis, and the current barriers (and solutions) to providing them with optimal palliative care.

Pruritus is a common and distressing symptom in patients with chronic kidney disease. The most recent epidemiologic data have suggested that approximately 40% of patients with end-stage renal disease experience moderate to severe pruritus and that uremic pruritus (UP) has a major clinical impact, being associated strongly with poor quality of life, impaired sleep, depression, and increased mortality. The pathogenesis of UP remains largely unclear, although several theories on etiologic or contributing factors have been proposed including increased systemic inflammation; abnormal serum parathyroid hormone, calcium, and phosphorus levels; an imbalance in opiate receptors; and a neuropathic process. UP can present somewhat variably, although it tends to affect large, discontinuous, but symmetric, areas of skin and to be most symptomatic at night. A variety of alternative systemic or dermatologic conditions should be considered, especially in patients with asymmetric pruritus or other atypical features. Treatment initially should focus on aggressive skin hydration, patient education on minimizing scratching, and optimization of the aspects of chronic kidney disease care that are most relevant to pruritus, including dialysis adequacy and serum parathyroid hormone, calcium, and phosphorus management. Data for therapy specifically for UP remain limited, although topical therapies, gabapentin, type B ultraviolet light phototherapy, acupuncture, and opioid-receptor modulators all may play a role.

This chapter examines the treatment and comprehensive management of patients with co-morbid psychiatric disorders, including eating and cognitive disorders, and CKD. Nephrologists need to coordinate care with community mental health resources. Practical and theoretical information, including pharmacologic considerations related to diminution in renal function, are necessary to assist the clinical nephrologist in the use of psychopharmacological treatments, including those for both pediatric and elderly patients with CKD.

A retrospective chart review was conducted in this pilot study of 35 patients who withdrew from dialysis and were followed by a palliative care team. Data included etiology of end-stage renal disease, comorbid illnesses, mode of dialysis and duration, survival time after withdrawal, reason for withdrawal, mental competency, symptom management, and the nature of death. Mean survival time was 10 days. The most frequent symptoms following withdrawal were confusion, agitation, pain and dyspnea. 1/3 of the sample were cognitively impaired at the time of the withdrawal decision. 17% experienced suffering during the withdrawal period, 24% had unrelieved symptoms, 19% psychological distress, while just over 1/3 of patients died alone. With the provision of palliative care, symptom prevalence in the last 24 hours dropped from 53 to 20% for pain, 68 to 33% for agitation and 46 to 26% for dyspnea. Opioids and benzodiazepines were used in the treatment of over 90% of patients. Palliative medicine has the potential to improve the care of patients who discontinue dialysis.

Background. The renal effects of cyclooxygenase-2 (COX-2) inhibitors have been incompletely elucidated, and acute renal failure (ARF) due to COX-2 inhibitors has been reported. Methods. In order to determine the causes of ARF and hyperkalaemia in five patients during COX-2 inhibitor therapy, we carefully analysed case studies of consecutive in-patients or out-patients referred to our Renal Division over a 6-month period for ARF and hyperkalaemia who had recently received COX-2 inhibitors. Results. ARF developed 2–3 weeks after COX-2 inhibitor therapy in five patients. The ARF was consistent with pre-renal azotaemia from renal hypoperfusion. Four patients were receiving the loop diuretic, furosemide. Four patients developed hyperkalaemia and decreased serum bicarbonate despite diuretic therapy, and one patient had changes in plasma renin activity and aldosterone levels consistent with reversible hyporeninaemic hypoaldosteronism. Renal failure was reversible after discontinuation of diuretics and COX-2 inhibitors. Conclusions. COX-2 inhibitors may cause reversible ARF and hyperkalaemia in patients with oedematous conditions treated with low sodium diets and loop diuretics.

Despite ongoing technological advances, patients with end-stage renal disease (ESRD) have a mortality rate of approximately 23% per year, and comorbid cardiovascular, cerebrovascular, and peripheral vascular disorders often make life on dialysis an ordeal. This patient population needs an improved approach to symptom assessment and control, as well as advance care planning and high-quality palliative care. Families need support during the lifetime and after the death of their loved ones. To address these needs, the Renal Palliative Care Initiative (RPCI) was instituted at Baystate Medical Center, a large tertiary care hospital, and at eight dialysis clinics in the Connecticut River Valley. With the cooperation of a large nephrology practice, the Western New England Renal and Transplant Associates, a core group of physicians, nurses, and social workers were trained in palliative medicine, and charged with the goals of developing and implementing innovative interventions. The RPCI's programs include symptom management protocols, advance care planning, and bereavement services for families and staff. The Initiative is increasing completion of formal advance directives by the patient population, while staff and families are particularly pleased with annual renal memorial services. The RPCI experience has much to offer the practice of nephrology, and it is relevant to ongoing efforts to extend palliative medicine beyond the traditional focus on cancer and AIDS.

Whole blood for transfusion was initially collected in glass bottles, but these are fragile, heavy to transport and prone to bacterial contamination. After the Second World War, Carl Walter experimented with plastics for collection and storage of blood, and found that di-ethylhexyl phthalate (DEHP) as plasticizer for polyvinyl chloride (PVC) had the most favourable properties [1, 2]. The breakage rate of frozen plasma in DEHP PVC is low, and the better storage properties of red cell concentrates in DEHP PVC are explained by leaching of plasticizer into the lipid bilayer of these cells, thereby improving membrane stability resulting in lower haemolysis rates [3]. However, ever since the 1970s, scientific and public concern has been raised on the toxicity of DEHP for transfused patients [4, 5]. DEHP and its metabolite mono ethylhexyl phthalate (MEHP) are associated with impairment of reproduction in animal models, resulting in testicular dysgenesis syndrome in (male) rodents, as reviewed in depth elsewhere [6], and particularly, neonates are susceptible to the risks of high exposure to DEHP. Due to the omnipresence of phthalates (not only DEHP), and some important differences in DEHP metabolism between animal models and humans [6], it is difficult to estimate the effect of DEHP toxicity in humans. A study of 234 young men showed no effect of MEHP in urine on their reproductive function [7], but others showed that DNA damage in sperm was associated with the MEHP concentration (after adjustment for other DEHP oxidative metabolites) [8]. In vitro human testis explants incubated with DEHP or MEHP showed that both significantly inhibited testosterone production [9], and a study of 881 men showed a 9% lower free androgen index between the lowest and the highest quartile of the proportion DEHP excreted as MEHP (P = 0.02) [10]. Also, an association was found between urinary MEHP concentrations and lower free T4 and lower total T3 thyroid hormones in adult men [11]. In addition to these effects on hormonal level in adult males, DEHP and its metabolites can have an effect on fetal development, with a shorter anogenital distance associated with higher metabolite concentrations in urine samples collected during pregnancy [12]. Others found no difference in T4 and testosterone levels, as well as no effect on phallic length in 13 male adolescents 14– 16 years of age that had underwent ECMO treatment in their neonatal period, as compared to ageand sexmatched controls [13]. Also, DEHP/MEHP exposure (as detected in cord blood) was significantly associated with a shorter pregnancy duration [14]. Despite these associations, they should be interpreted with care. DEHP is not the only phthalate that may cause these effects; studies that showed no association may not have been published; DEHP administered through the intestinal tract is converted to MEHP in a higher degree as by intravenously [15]; and because phthalates are everywhere in our environment, comparisons are less versus more, rather than absent versus present. DEHP-plasticized PVC has long been used as standard material for a wide range of applications, like packing foil (including food), building material, toys and plastic devices. DEHP is considered to be a ubiquitous environmental contaminant and is present in air, dust, water, soil and food. The latter is considered to be the main source of DEHP intake for the general population. The current daily intake is estimated to be between 2 and 5 lg/kg for adults and between 4 to 8 lg/kg for children [16, 17]. Various measures to reduce the use of DEHP-plasticized PVC have indeed resulted in a 2-times lower exposure to DEHP in the general population over the last two decades [18]. DEHP is applied in many medical devices, and depending on the procedure, patients can be exposed to high (peak) concentrations of DEHP, in the order of 1 mg per kg of bodyweight. One of the sources of DEHP exposure is the leaching from the blood bags into the content of the container, particularly into lipophilic solutions such as plasma [19], but also red cells. Therefore some patient groups, including pregnant or nursing women and children, are considered to be most at risk of possible harmful effects attributable to DEHP exposure by medical treatments. DEHP is broken down into various metabolites. First, it is hydrolysed to MEHP and then further oxidized to mono-(2-ethyl-5-hydroxyhexyl) phthalate (5OH-MEHP)

Background. Preliminary results from clinical trials suggest that 3-hydroxy-3-methylglutaryl co-enzyme A reductase inhibitors may help prevent acute renal allograft rejection. However, the mechanism for this putative effect of 3-hydroxy-3-methylglutaryl co-enzyme A reductase inhibitors, and whether it is independent of lipid-lowering per SE are unknown. Methods. Immediately after renal transplantation we randomly allocated (proportioned 2:1:2) patients to: 1) simvastatin (10 mg/day, n=53), 2) simvastatin placebo plus gemfibrozil (dose adjusted for renal function, n=36), and 3) simvastatin placebo (n=52). Results. Simvastatin, but not gemfibrozil, reduced total and low density lipoprotein cholesterol during the first 90 days posttransplant. There were no major adverse effects of therapy. However, there were no effects of treatment on acute rejection. Indeed, survival free of acute rejection at 90 days was 72% in the simvastatin group, 72% in the gemfibrozil group, and 77% in the placebo control group (P=0.771). A post hoc power analysis suggested that there was only a 7.5% chance that a true effect of simvastatin on acute rejection (versus placebo) was not detected, and a 2.5% chance that an effect of gemfibrozil on acute rejection (versus placebo) was not detected in this study. Conclusion. Lipid-lowering agents may not reduce the incidence of acute renal allograft rejection. However, additional studies are needed to confirm this observation. In the mean time, many if not most renal transplant recipients should be treated with HMG-CoA reductase inhibitors starting early posttransplant to prevent cardiovascular disease complications. The results of this study suggest that starting lipid-lowering therapy immediately after renal transplantation is both safe and effective in lowering total and low density lipoprotein cholesterol.

Studies performed at large metropolitan medical centers have reported an increasing incidence of idiopathic focal segmental glomerulosclerosis (FSGS) in adults. To determine whether a similar trend occurs in small urban and rural communities and to determine the role of race in these observations, we reviewed the patient records of all adults who underwent renal biopsies at our institution over the 20-year period from 1974 to 1994. The patients were grouped for analysis in 5-year intervals, 1975 to 1979, 1980 to 1984, 1985 to 1989, and 1990 to 1994, for the following diagnoses: FSGS, membranous nephropathy (MN), minimal change nephropathy (MCN), membranoproliferative glomerulonephritis (MPGN), immunoglobulin A (IgA) nephropathy, chronic glomerulonephritis, diabetic nephropathy, hypertensive nephrosclerosis, and chronic interstitial nephritis. Patients with secondary causes for these lesions were excluded. The relative frequency of FSGS increased from 13.7% during 1975 to 1979 to 25% during 1990 to 1994 (P < 0.05). The relative frequency of MN decreased from 38.3% during 1975 to 1979 to 14.5% during 1990 to 1994 (P < 0.01). There were no changes in the frequencies of MCN, MPGN, IgA nephropathy, chronic glomerulonephritis, diabetic nephropathy, hypertensive nephrosclerosis, or chronic interstitial nephritis over the 20-year period. However, there was a significant increase in the percentage of blacks with FSGS, from 0% in 1975 to 1979 to 22.6% in 1990 to 1994, and an increased percentage of Hispanics with FSGS, from 0% in 1975 to 1979 to 21.3% in 1990 to 1994 (P < 0.05). The modest increase in whites with FSGS did not reach statistical significance. The incidence of MN in blacks and whites decreased over the 20-year period. In the last 5 years, 15 patients per year had FSGS compared with 7 patients per year with MN (P < 0.05). No changes in age or sex between groups or over time accounted for these results. We conclude that FSGS is now diagnosed twice as often as MN and is the most common idiopathic glomerular disease at our hospital. Reasons for this increase include the emergence of FSGS in both Hispanics and blacks, with a modest increase of FSGS in whites. The increase in FSGS in the three most common races in our community suggests that factors other than genetic, perhaps environmental, have a role in the pathogenesis of FSGS.

Ritodrine- and terbutaline-induced hypokalemia in preterm labor: Mechanisms and consequences. The effects of ritodrine and terbutaline on potassium homeostasis, renal function, and cardiac rhythm were assessed in women treated with these drugs for preterm labor. Timed blood and urine samples were obtained for two hours before and during six hours of intravenous ritodrine (N = 5) and terbutaline (N = 5) administered in pharmacologically equivalent doses. No differences were found in any parameters affecting potassium homeostasis or renal function between these drugs. A decrease in mean plasma potassium of 0.9 mEq/liter occurred after 30 minutes of drug infusion (4.2 ± 0.1 to 3.3 ± 0.1 mEq/liter, P < 0.005) before any significant changes in plasma glucose (75.0 ± 4.7 to 93.7 ± 6.1 mg/dl, P = NS) or plasma insulin (12.4 ± 6.0 to 28.4 ±5.1 mU/ml, P = NS). The mean plasma potassium after four hours of drug infusion was 2.5 ±0.1 mEq/liter. Plasma insulin rose to a level known to induce cellular potassium uptake (39.2 ±7.7 mU/ml) after 60 minutes of drug therapy and remained at this level for four hours. Hyperlactatemia occurred at four hours (4.7 ± 0.8 mmol/liter) and the plasma lactate/pyruvate ratio increased in a 10:1 ratio. Both drugs significantly reduced glomerular filtration rate, sodium, potassium, and chloride excretion and urinary flow rate. Changes in acid-base homeostasis, plasma aldosterone, or renal potassium excretion did not contribute to ritodrine- or terbutaline-induced hypokalemia. In 83 women with preterm labor randomly assigned to ritodrine (N = 42) or terbutaline (N = 41), the maximum decrease in plasma potassium occurred after six hours of drug infusion. During Holter monitoring, 3 of 14 women treated with ritodrine or terbutaline developed symptomatic cardiac arrhythmias at the lowest plasma potassium, while no women treated with saline and morphine (N = 12) developed cardiac arrhythmias (P = 0.14). We conclude that ritodrine and terbutaline induce profound hypokalemia by stimulating cellular potassium uptake and both drugs cause significant renal sodium and fluid retention and cardiac arrhythmias. Careful monitoring of electrolytes, fluid balance, and cardiac rhythm should occur during tocolytic therapy with ritodrine or terbutaline.

Purpose of review Elderly patients comprise the fastest growing population initiating dialysis and also experience the worst outcomes, including increased mortality, loss of functional status, and impaired quality of life. Nephrologists are often challenged with how best to engage in dialysis decision-making discussions within this population. Prognostication tools can assist nephrologists in engaging in these discussions, especially in patients for whom survival benefits may be outweighed by the burdens of treatment. Recent findings This review includes the latest research in the survival of elderly patients with and without dialysis; prognostic factors associated with renal progression and survival; and integrative prognostic models to predict both short-term and long-term prognosis. The concept of kidney illness disease trajectory is defined with important outcomes including survival, health-related quality of life, and symptoms with and without dialysis. This prognostic information will then be integrated into an individualized approach to shared decision-making regarding treatment decision-making.(Figure is included in full-text article.) Summary Treatment decision-making for elderly patients with advanced kidney disease necessitates an active process between nephrologist and patient, incorporating medical information as well as patient preferences. Prognostic information and observational data can facilitate nephrologists' ability to foresee and foretell the illness trajectory both with and without dialysis, further guiding these conversations.

Objective As known abnormalities exist in the insulin-like growth factor (IGF) system in chronic kidney disease (CKD) patients, the measurement of bioactive IGF-I may provide further insight into the therapeutic potential of long-term exercise training. Design Patients ( N =21) with stages 3 and 4 CKD were recruited from a local nephrology practice in Springfield, MA and randomized into matched treatment and control groups. The treatment group participated in 48weeks of supervised, progressive exercise training and dietary counseling, while the control group received only usual care. Treadmill testing, anthropometric measurements, and blood samples for analysis of immunoreactive IGF-I, IGF-II, IGFBP-1 and -2, and bioactive IGF-I were taken at baseline, 24weeks, and 48weeks. Results There were no significant differences in any of the components of the IGF system (all p -values>0.05). Immunoreactive IGF-I levels correlated significantly with bioactive IGF-I at baseline ( r =0.50, p =0.02) and at 48weeks ( r =0.64, p =0.01). There was a significant interaction between group and time for both VO 2peak ( p =0.03) and total treadmill time (TT) ( p Conclusions Despite improvements in physical performance, a 48-week training program did not affect any of the circulating IGF system measurements. Disparities between these findings and those of other researchers reporting a biphasic response to long-term training may be explained by differences in study groups and exercise programs.

Thrombotic thrombocytopenic purpura (TTP) rarely occurs with systemic vasculitis. A 17-year-old girl presented with non-bloody diarrhea, menorrhagia, and syncope. She had severe anemia (hemoglobin = 3.8 g/dl), thrombocytopenia (platelet = 7,000/mm(3)), and acute kidney injury (serum creatinine, Cr = 2.3 mg%). Peripheral smear examination confirmed the presence of microangiopathic hemolytic anemia. Additionally, she had a positive anti-nuclear antibody (1:1600) and normal complement levels. We considered the diagnosis of TTP, possibly associated with systemic lupus erythematosus, and promptly initiated pulse methylprednisolone and daily 3-4 l of plasma exchange therapy. Following resolution of her thrombocytopenia in 48 h, we performed a kidney biopsy that revealed diffuse proliferative, focal crescentic, and necrotizing glomerulonephritis with mild IgG immunofluorescence staining. Concomitantly, autoimmune work-up was significant for positive perinuclear anti-neutrophil cytoplasmic antibodies (p-ANCA = 1:640) and decreased von Willebrand factor cleaving protease activity (5%). A final diagnosis of TTP with microscopic polyangiitis (p-ANCA-mediated) was made and treatment with daily oral cyclophosphamide and prednisone resolved her renal injury over 2 months (follow-up Cr = 1.0 mg%). Our case highlights the importance of identifying systemic disorders such as ANCA-associated vasculitis with TTP.

Background and objectives: Although uremic pruritus (UP) is a highly prevalent complication of chronic kidney disease, it remains poorly characterized. There have been no longitudinal studies of natural history, and no health-related quality of life (HR-QOL) instruments have been developed for UP. The objectives of this study were to describe the natural history of UP, to compare rating scales of itching intensity, and to assess usefulness and validity of HR-QOL instruments for UP. Design, setting, participants, & measurements: The intensity, severity, and effects of pathologic itching on HR-QOL were assessed prospectively in 103 patients with UP on chronic hemodialysis. Outcome measures were obtained at scheduled intervals over 3.5 months. Results: Itching daily or nearly daily was reported by 84% of patients and had been ongoing for >1 year in 59%. In 83%, pruritus involved large, nondermatomal areas with striking bilateral symmetry. Two thirds of the patients were using medications such as antihistamines, steroids, and various emollients without satisfactory relief of itching. Statistically significant associations were found among itching intensity, severity, and HR-QOL measures in domains such as mood, social relations, and sleep. Among patients with moderate-to-severe UP, changes in itching intensity of 20% or greater were associated with significant reductions in HR-QOL measures. Conclusions: This first longitudinal study of UP describes key features of UP and its effect on HR-QOL. The assessment instruments we have developed are easily used, are responsive to changes in UP intensity, and should facilitate clinical evaluation and research to meet the needs of afflicted patients.

Background. Haemoglobin variability may be associated with increased death. Frequent haemoglobin monitoring may allow earlier detection of trends in haemoglobin slopes, alerting staff to intercurrent events. The more frequent haemoglobin values may provide early evidence of response to erythropoietin (EPO) doses, and allow more appropriate anaemia management. Our objective is to assess whether frequent haemoglobin monitoring data (12x/month) using a computer algorithm (AMIE, Leeds, UK) will reduce haemoglobin variability compared with 1 ×/month monitoring. Methods. We performed an observational case-control study of 44 unselected patients, comprising one dialysis facility measuring Crit-Line haemoglobin, lab haemoglobin, standard deviation of residuals as surrogate of haemoglobin variability and EPO dosing. Results. Haemoglobin variability and 'percent in target haemoglobin range'significantly improved with 12×/month haemoglobin results using a computer algorithm. There was also a non-significant trend toward for lower EPO doses. Conclusion. Use of a computer algorithm to analyse 12×/month haemoglobin values provides early evidence of haemoglobin trends and allows more appropriate anaemia management, with decreased haemoglobin variability, lower EPO doses and more patients achieving target haemoglobin.

Chronic kidney disease (CKD) has increasingly become a "geriatric" disease, with a dramatic rise in incidence in the aging population. Patients aged >75 years have become the fastest growing population initiating dialysis. These patients have increased comorbid diseases and functional limitations which affect mortality and quality of life. This review describes the challenges of dialysis initiation and considerations for management of the elderly subpopulation. There is a need for an integrative approach to care, which addresses management issues, health-related quality of life, and timely discussion of goals of care and end-of-life issues. This comprehensive approach to patient care involves the integration of nephrology, geriatric, and palliative medicine practices.