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Every hemodialysis session starts with the question of how much fluid should be removed, which can currently not be answered precisely. Herein, we first revisit the "probing-dry-weight" concept, using the historical example of Tassin/France (practicing also "long, slow dialysis"): Mortality outcomes were, in the 1980s, better than registry data, but are nowadays similar to European average. In view of the negative primary end point in a recent trial on dry weight assessment, based on lung ultrasound-guided evaluation of fluid excess in the lungs, and a meta-analysis of prospective studies failing to show that bioimpedance-based interventions for correction of volume overload had a direct effect on all-cause mortality, we ask how to ever move forward. Clinical reasoning demands that as much information as possible should be gathered on the fluid status of patients undergoing dialysis. Besides body weight and blood pressure, measurements of bioimpedance and dialysate bolus-derived absolute blood volume can in principle be automatized, whereas lung ultrasound can be obtained routinely. In the era of machine learning, fluid management could consist of flexible target weight prescriptions, adjusted on a daily basis and accounting even for fluctuations in fluid-free body mass. In view of all the negative prospective results surrounding fluid management in hemodialysis, we propose this as a "never-give-up" approach.

Phenylketonuria (PKU), caused by variants in the phenylalanine hydroxylase (PAH) gene, is the most common autosomal-recessive Mendelian phenotype of amino acid metabolism. We estimated that globally 0.45 million individuals have PKU, with global prevalence 1:23,930 live births (range 1:4,500 [Italy]–1:125,000 [Japan]). Comparing genotypes and metabolic phenotypes from 16,092 affected subjects revealed differences in disease severity in 51 countries from 17 world regions, with the global phenotype distribution of 62% classic PKU, 22% mild PKU, and 16% mild hyperphenylalaninemia. A gradient in genotype and phenotype distribution exists across Europe, from classic PKU in the east to mild PKU in the southwest and mild hyperphenylalaninemia in the south. The c.1241A>G (p.Tyr414Cys)-associated genotype can be traced from Northern to Western Europe, from Sweden via Norway, to Denmark, to the Netherlands. The frequency of classic PKU increases from Europe (56%) via Middle East (71%) to Australia (80%). Of 758 PAH variants, c.1222C>T (p.Arg408Trp) (22.2%), c.1066−11G>A (IVS10−11G>A) (6.4%), and c.782G>A (p.Arg261Gln) (5.5%) were most common and responsible for two prevalent genotypes: p.[Arg408Trp];[Arg408Trp] (11.4%) and c.[1066−11G>A];[1066−11G>A] (2.6%). Most genotypes (73%) were compound heterozygous, 27% were homozygous, and 55% of 3,659 different genotypes occurred in only a single individual. PAH variants were scored using an allelic phenotype value and correlated with pre-treatment blood phenylalanine concentrations (n = 6,115) and tetrahydrobiopterin loading test results (n = 4,381), enabling prediction of both a genotype-based phenotype (88%) and tetrahydrobiopterin responsiveness (83%). This study shows that large genotype databases enable accurate phenotype prediction, allowing appropriate targeting of therapies to optimize clinical outcome. Fil: Hillert, Alicia. No especifíca; Fil: Anikster, Yair. No especifíca; Fil: Belanger Quintana, Amaya. No especifíca; Fil: Burlina, Alberto. No especifíca; Fil: Burton, Barbara K.. No especifíca; Fil: Carducci, Carla. No especifíca; Fil: Chiesa, Ana Elena. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Gobierno de la Ciudad de Buenos Aires. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Fundación de Endocrinología Infantil. Centro de Investigaciones Endocrinológicas "Dr. César Bergada"; Argentina Fil: Christodoulou, John. No especifíca; Fil: Dordevic, Maja. No especifíca; Fil: Desviat, Lourdes R.. No especifíca; Fil: Eliyahu, Aviva. No especifíca; Fil: Evers, Roeland A.F.. No especifíca; Fil: Fajkusova, Lena. No especifíca; Fil: Feillet, Francois. No especifíca; Fil: Bonfim Freitas, Pedro E.. No especifíca; Fil: Gizewska, María. No especifíca; Fil: Gundorova, Polina. No especifíca; Fil: Karall, Daniela. No especifíca; Fil: Kneller, Katya. No especifíca; Fil: Kutsev, Sergey I.. No especifíca; Fil: Leuzzi, Vincenzo. No especifíca; Fil: Levy, Harvey L.. No especifíca; Fil: Lichter Koneck, Uta. No especifíca; Fil: Muntau, Ania C.. No especifíca; Fil: Namour, Fares. No especifíca; Fil: Oltarzewsk, Mariusz. No especifíca; Fil: Paras, Andrea. No especifíca; Fil: Perez, Belén. No especifíca; Fil: Polak, Emil. No especifíca; Fil: Polyakov, Alexander V.. No especifíca; Fil: Porta, Francesco. No especifíca; Fil: Rohrbach, Marianne. No especifíca; Fil: Scholl Bürgi, Sabine. No especifíca; Fil: Spécola, Norma. No especifíca; Fil: Stojiljkovic, Maja. No especifíca; Fil: Shen, Nan. No especifíca; Fil: Santana da Silva, Luiz C.. No especifíca; Fil: Skouma, Anastasia. No especifíca; Fil: van Spronsen, Francjan. No especifíca; Fil: Stoppioni, Vera. No especifíca; Fil: Thöny, Beat. No especifíca; Fil: Trefz, Friedrich K.. No especifíca; Fil: Vockley, Jerry. No especifíca; Fil: Yu, Youngguo. No especifíca; Fil: Zschocke, Johannes. No especifíca; Fil: Hoffmann, Georg F.. No especifíca; Fil: Garbade, Sven F.. No especifíca; Fil: Blau, Nenad. No especifíca

Background: Despite a growing population of patients starting hemodialysis in China, little is known about markers of mineral bone disease (MBD) and their management. We present data on prevalence and correlates of hypocalcemia, hyperphosphatemia, and secondary hyperparathyroidism from the China Dialysis Outcomes and Practice Patterns Study (DOPPS), with evaluation of whether these laboratory markers triggered changes in management. Methods: We compared the frequency of measurement and prevalence of poor control of MBD markers in China DOPPS with other DOPPS regions. We also used generalized estimating equations to assess correlates of MBD markers, and separate models to assess predictors of vitamin D and phosphate binder prescriptions in the China DOPPS. Results: Severe hyperphosphatemia (>7 mg/dL) and secondary hyperparathyroidism (>600 pg/mL) were common (27% and 21% prevalence, respectively); both were measured infrequently (14.9% and 3.2% of patients received monthly measurements in China). Frequency of dialysis sessions was positively associated with hyperphosphatemia; presence of residual kidney function was negatively associated with both hyperphosphatemia and secondary hyperparathyroidism. Laboratory measures indicating poor control of MBD were not associated with subsequent prescription of active vitamin D or phosphate binder. Conclusions: There are substantial opportunities for improvement and standardization of MBD management in China. Development of country-specific guidelines may yield realistic targets and standardization of medication use accounting for availability and cost. Key words: Mineral bone disease; Hyperphosphatemia; Hyperparathyroidism; China; Hemodialysis; Dialysis Outcomes and Practice Patterns Study

Renin‐angiotensin‐aldosterone system inhibitors (RAASi) are recommended for chronic kidney disease (CKD) patients. In this study, we describe RAASi prescription patterns in the Chronic Kidney Disease Outcomes and Practice Patterns Study (CKDopps) in Brazil, Germany, France, and the United States (US). 5870 patients (mean age 66‐72 years; congestive heart failure [CHF] in 11%‐19%; diabetes in 43%‐54%; serum potassium ≥5 in 20%‐35%) were included. RAASi prescription was more common in Germany (80%) and France (77%) than Brazil (66%) and the United States (52%), where the prevalence of prescription decreases particularly in patients with CKD stage 5. In the multivariable regression model, RAASi prescription was least common in the United States and more common in patients who were younger, had diabetes, hypertension, or less advanced CKD. In conclusion, RAASi prescription patterns vary by country, and by demographic and clinical characteristics. RAASi appear to be underused, even among patients with strong class‐specific recommendations. Although the reasons for this variation could not be fully identified in this cross‐sectional observation, our data indicate that the risk of hyperkalemia may contribute to the underuse of this class of agents in moderate to advanced CKD.

ObjectiveTo evaluate the relationship between circulating phenylalanine and brain function as well as neuropsychiatric symptoms in adults with phenylketonuria.MethodsIn this prospective cross-sectional study, early-treated patients with phenylketonuria older than 30 years and age- and sex-matched controls were included. Extensive neurologic evaluation, neuropsychological and behavioral testing, sensory and motor evoked potentials, and MRI were performed. CSF concentrations of neurodegenerative markers were evaluated in addition in a subset of 10 patients.ResultsNineteen patients with phenylketonuria (median age 41 years) with different phenylalanine levels (median 873 μmol/L) entered the study. They showed higher prevalence of neurologic symptoms, cognitive and behavioral abnormalities, autonomic dysfunction, alterations in neurophysiologic measures, and atrophy in putamen and right thalamus compared to controls. In CSF, patients with phenylketonuria exhibited higher β-amyloid 1-42 (p= 0.003), total tau (p< 0.001), and phosphorylated tau (p= 0.032) levels compared to controls. Plasma phenylalanine levels highly correlated with the number of failed neuropsychological tests (r= 0.64,p= 0.003), neuropsychiatric symptoms (r= 0.73,p< 001), motor evoked potential latency (r= 0.48,p= 0.030), and parietal lobe atrophy.ConclusionsOur study provides strong evidence for a correlation between phenylalanine levels and clinical, neuropsychological, neurophysiologic, biochemical, and imaging alterations in adult patients with phenylketonuria.

BACKGROUND: Metabolic acidosis is a common threat for patients on hemodialysis, managed by alkaline dialysate. The main base is bicarbonate, to which small amounts of acetic, citric, or hydrochloric acid are added. The first two are metabolized to bicarbonate, mostly by the liver. Citric acid–containing dialysate might improve dialysis efficiency, anticoagulation, calcification propensity score, and intradialytic hemodynamic stability. However, a recent report from the French dialysis registry suggested this dialysate increases mortality risk. This prompted us to assess whether citric acid–containing bicarbonate-based dialysate was associated with mortality in the international Dialysis Outcomes and Practice Patterns Study (DOPPS). METHODS: Detailed patient-based information on dialysate composition was collected in DOPPS phases 5 and 6 (2012–2017). Cox regression was used to model the association between baseline bicarbonate dialysate containing citric acid versus not containing citric acid and mortality among DOPPS countries and phases where citric acid–containing dialysate was used. RESULTS: Citric acid-containing dialysate was most commonly used in Japan, Italy, and Belgium (25%, 25%, 21% and of patients who were DOPPS phase 6, respectively) and used in

BACKGROUND: Decisions about dialysis for advanced kidney disease are often strongly shaped by sociocultural and system-level factors rather than the priorities and values of individual patients. We examined international variation in the uptake of conservative approaches to the care of patients with advanced kidney disease, in particular discontinuation of dialysis. METHODS: We employed an observational cohort study design using data collected from patients maintained on long-term hemodialysis between 1996 and 2015 in facilities across 12 developed countries participating in the Dialysis Outcomes and Practice Patterns Study (DOPPS). The main outcome was discontinuation of dialysis therapy. We analyzed the association between several patient characteristics and time to dialysis discontinuation by country and phase of study entry. RESULTS: A total of 259 343 DOPPS patients contributed data to the study, of whom 48 519 (18.7%) died during the study period. Of the decedents, 5808 (12.0%) discontinued dialysis before death. Rates of discontinuation were higher within the first few months after initiation of dialysis, among older adults, among those with a greater number of comorbidities and among those living in an institution. After adjustment for age, sex, dialysis duration, diabetes and dialysis era, rates of discontinuation were highest in Canada, the United States and Australia/New Zealand (33.8, 31.4 and 21.5 per 1000/yr, respectively) and lowest in Japan and Italy (< 0.1 per 1000/yr). Crude discontinuation rates were highest in dialysis facilities that were more likely to offer comprehensive conservative renal care to older adults. INTERPRETATION: We found persistent international variation in average rates of dialysis discontinuation not explained by differences in patient case-mix. These differences may reflect physician-, facility- and society-level differences in clinical practice. There may be opportunities for international cross-collaboration to improve support for patients with end-stage renal disease who prefer a more conservative approach.

In rural regions with limited resources, the provision of clean water remains challenging. The resulting high incidence of diarrhea can lead to acute kidney injury and death, particularly in the young and the old. Membrane filtration using recycled hemodialyzers allows water purification. This study quantifies the public health effects. Between 02/2018 and 12/2018, 4 villages in rural Ghana were provided with a high-volume membrane filtration device (NuFiltration). Household surveys were collected monthly with approval from Ghana Health Services. Incidence rates of diarrhea for 5-month periods before and after implementation of the device were collected and compared to corresponding rates in 4 neighboring villages not yet equipped. Data of 1,130 villagers over 10 months from the studied communities were studied. Incidence rates showed a decline following the implementation of the device from 0.18 to 0.05 cases per person-month (ppm) compared to the control villages (0.11 to 0.08 ppm). The rate ratio of 0.27 for the study villages is revised to 0.38 when considering the non-significant rate reduction in the control villages. Provision of a repurposed hemodialyzer membrane filtration device markedly improves health outcomes as measured by diarrhea incidence within rural communities.

Background and objectives Fluid overload and intradialytic hypotension are associated with cardiovascular events and mortality in patients on hemodialysis. We investigated associations between hemodialysis facility practices related to fluid volume and intradialytic hypotension and patient outcomes. Design, setting, participants, & measurements Data were analyzed from 10,250 patients in 273 facilities across 12 countries, from phase 4 of the Dialysis Outcomes and Practice Patterns Study (DOPPS; 2009–2012). Cox regression models (shared frailty) were used to estimate associations between facility practices reported by medical directors in response to the DOPPS Medical Directors Survey and all-cause and cardiovascular mortality and hospitalization, and cardiovascular events, adjusting for country, age, sex, dialysis vintage, predialysis systolic BP, cardiovascular comorbidities, diabetes, body mass index, smoking, residual kidney function, dialysis adequacy, and vascular access type. Results Of ten facility practices tested (chosen a priori ), having a protocol that specifies how often to assess dry weight in most patients was associated with lower all-cause (hazard ratio [HR], 0.78; 99% confidence interval [99% CI], 0.64 to 0.94) and cardiovascular mortality (HR, 0.72; 99% CI, 0.55 to 0.95). Routine orthostatic BP measurement to assess dry weight was associated with lower all-cause hospitalization (HR, 0.86; 99% CI, 0.77 to 0.97) and cardiovascular events (HR, 0.85; 99% CI, 0.73 to 0.98). Routine use of lower dialysate temperature to limit or prevent intradialytic hypotension was associated with lower cardiovascular mortality (HR, 0.76; 99% CI, 0.58 to 0.98). Routine use of an online volume indicator to assess dry weight was associated with higher all-cause hospitalization (HR, 1.19; 99% CI, 1.02 to 1.38). Routine use of sodium modeling/profiling to limit or prevent intradialytic hypotension was associated with higher all-cause mortality (HR, 1.36; 99% CI, 1.14 to 1.63), cardiovascular mortality (HR, 1.34; 99% CI, 1.04 to 1.73), and cardiovascular events (HR, 1.21; 99% CI, 1.03 to 1.43). Conclusions Hemodialysis facility practices relating to the management of fluid volume and intradialytic hypotension are associated with patient outcomes.

Background Fluid overload and interdialytic weight gain (IDWG) are discrete components of the dynamic fluid balance in haemodialysis patients. We aimed to disentangle their relationship, and the prognostic importance of two clinically distinct, bioimpedance spectroscopy (BIS)-derived measures, pre-dialysis and post-dialysis fluid overload (FOpre and FOpost) versus IDWG. Methods We conducted a retrospective cohort study on 38 614 incident patients with one or more BIS measurement within 90 days of haemodialysis initiation (1 October 2010 through 28 February 2015). We used fractional polynomial regression to determine the association pattern between FOpre, FOpost and IDWG, and multivariate adjusted Cox models with FO and/or IDWG as longitudinal and time-varying predictors to determine all-cause mortality risk. Results In analyses using 1-month averages, patients in quartiles 3 and 4 (Q3 and Q4) of FO had an incrementally higher adjusted mortality risk compared with reference Q2, and patients in Q1 of IDWG had higher adjusted mortality compared with Q2. The highest adjusted mortality risk was observed for patients in Q4 of FOpre combined with Q1 of IDWG [hazard ratio (HR) = 2.66 (95% confidence interval 2.21–3.20), compared with FOpre-Q2/IDWG-Q2 (reference)]. Using longitudinal means of FO and IDWG only slightly altered all HRs. IDWG associated positively with FOpre, but negatively with FOpost, suggesting a link with post-dialysis extracellular volume depletion. Conclusions FOpre and FOpost were consistently positive risk factors for mortality. Low IDWG was associated with short-term mortality, suggesting perhaps an effect of protein-energy wasting. FOpost reflected the volume status without IDWG, which implies that this fluid marker is clinically most intuitive and may be best suited to guide volume management in haemodialysis patients.

Background: Abnormal chronic kidney disease-mineral and bone disorder (CKD-MBD) markers have been associated with adverse outcomes in hemodialysis (HD) patients. Dialysate calcium concentration (D-Ca) likely influences serum calcium and phosphorus levels. Optimal D-Ca level remains unclear. We hypothesized that higher D-Ca is associated with cardiovascular events and mortality among Japanese HD patients. Methods: Enrollment data of chronic HD patients in the prospective observational study JDOPPS, phases 1–5 (1999–2015), provided exposures and covariates. All-cause mortality, non-arrhythmic cardiovascular events (NonAR-CVE), or their composites were analyzed by D-Ca, and divided into 2.5, 2.75, and 3.0 mEq/L. To minimize confounding by indication, analyses were restricted to facilities in which at least 90% of patients received the same D-Ca prescription. Association of D-Ca level with outcomes was evaluated in Cox models stratified by phase and accounting for facility clustering. Covariates describing patient demographics, comorbidities, laboratory values, CKD-MBD therapy, and facility attributes provided adjustment. Results: Of 9,201 patients included, 25.0% had D-Ca of 2.5 mEq/L; 6.8% D-Ca 2.75; and 68.2% D-Ca 3.0. Median follow-up time was 2.03 years. D-Ca was not associated with all-cause mortality, with hazards ratios for 2.5 vs. 3.0 mEq/L of 0.90 and 95% CI (0.73–1.11), nor with other outcomes. One effect modification occurred, protective for lower D-Ca on NonAR-CVE in the absence of cardiovascular comorbidities (p = 0.032), although corresponding D-Ca effects were not significant after multiple comparisons adjustment (p = 0.261 [D-Ca 2.5] and 0.125 [D-Ca 2.75]). Conclusion: Lowering D-Ca level below 3.0 mEq/L seems not to have a meaningful effect on patient outcomes.

Background Anemia management protocols in hemodialysis (HD) units differ conspicuously regarding optimal intravenous (IV) iron dosing; consequently, patients receive markedly different cumulative exposures to IV iron and erythropoiesis-stimulating agents (ESAs). Complementary to IV iron safety studies, our goal was to gain insight into optimal IV iron dosing by estimating the effects of IV iron doses on Hgb, TSAT, ferritin, and ESA dose in common clinical practice. Methods 9,471 HD patients (11 countries, 2009-2011) in the DOPPS, a prospective cohort study, were analyzed. Associations of IV iron dose (3-month average, categorized as 0

Phenylketonuria (PKU) is an autosomal recessive inborn error of phenylalanine metabolism caused by deficiency in the enzyme phenylalanine hydroxylase that converts phenylalanine into tyrosine.In 2017 the first European PKU Guidelines were published. These guidelines contained evidence based and/or expert opinion recommendations regarding diagnosis, treatment and care for patients with PKU of all ages. This manuscript is a supplement containing the practical application of the dietary treatment.This handbook can support dietitians, nutritionists and physicians in starting, adjusting and maintaining dietary treatment.

Background and objectives Chronic kidney disease (CKD) is commonly associated with mineral and bone metabolism disorders, but these are less frequently studied in non-dialysis CKD patients than in dialysis patients. We examined and described international variation in mineral and bone disease (MBD) markers and their treatment and target levels in Stage 3–5 CKD patients. Design, setting, participants, and measurements Prospective cohort study of 7658 adult patients with eGFR Results Over two-thirds of the patients had MBD markers measured at time intervals in line with practice guidelines. P and iPTH increased and Ca decreased gradually from eGFR 60–20 mL/min/1.73m2 and more sharply for eGFR 5.5 mg/dL, phosphate binder use was 14% to 43% across the four countries. Among patients with PTH >300 pg/mL, use of active (calcitriol and related analogs) vitamin D was 12%–51%, and use of any (active or nutritional) vitamin D was 60%–87%. Conclusions Although monitoring of CKD-MBD laboratory markers by nephrologists in CKDopps countries is consistent with guidelines, target levels vary notably and prescription of medications to treat abnormalities in these laboratory markers is generally low in these cross-sectional analyses. While there are opportunities to increase treatment of hyperphosphatemia, hyperparathyroidism, and vitamin D deficiency in advanced CKD, the effect on longer-term complications of these conditions requires study.

Sex and gender differences are of fundamental importance in most diseases, including chronic kidney disease (CKD). Men and women with CKD differ with regard to the underlying pathophysiology of the disease and its complications, present different symptoms and signs, respond differently to therapy and tolerate/cope with the disease differently. Yet an approach using gender in the prevention and treatment of CKD, implementation of clinical practice guidelines and in research has been largely neglected. The present review highlights some sex- and gender-specific evidence in the field of CKD, starting with a critical appraisal of the lack of inclusion of women in randomized clinical trials in nephrology, and thereafter revisits sex/gender differences in kidney pathophysiology, kidney disease progression, outcomes and management of haemodialysis care. In each case we critically consider whether apparent discrepancies are likely to be explained by biological or psycho-socioeconomic factors. In some cases (a few), these findings have resulted in the discovery of disease pathways and/or therapeutic opportunities for improvement. In most cases, they have been reported as merely anecdotal findings. The aim of the present review is to expose some of the stimulating hypotheses arising from these observations as a preamble for stricter approaches using gender for the prevention and treatment of CKD and its complications.

BackgroundChronic kidney disease (CKD) is less prevalent among men than women, but more men than women initiate kidney replacement therapy. Differences in CKD awareness may contribute to this gender gap, which may further vary by race/ethnicity. We aimed to investigate trends in CKD awareness and the association between individual characteristics and CKD awareness among US men versus women.Methods and findingsWe conducted a serial, cross-sectional analysis of 10 cycles (1999–2018) from the National Health and Nutrition Examination Survey (NHANES). Adult participants with CKD stages G3-G5 (estimated glomerular filtration rate [eGFR] 2) were included, unless they were on dialysis or medical information was missing. Serum creatinine was measured during NHANES medical exams. CKD stage was classified by eGFR, based on the CKD-EPI formula. CKD awareness was assessed with the question: “Have you ever been told by a health care professional you had weak or failing kidneys”, asked in standardized NHANES questionnaires on each survey. Using logistic regression models, we evaluated the association between sex and CKD awareness, adjusting for potential confounders including age, race/ethnicity and comorbidities. We stratified CKD awareness by 5 pre-defined calendar-year periods and conducted all analyses for the complete study population as well as the Caucasian and African American subpopulations. We found that among 101871 US persons participating in NHANES, 4411 (2232 women) had CKD in stages G3-G5. These participants were, on average, 73±10 years old, 25.3% reported diabetes, 78.0% reported hypertension or had elevated blood pressure during medical examinations and 39.8% were obese (percentages were survey-weighted). CKD awareness was more prevalent among those with higher CKD stage, younger age, diabetes, hypertension and higher body mass index. CKD awareness was generally low (ConclusionsCKD awareness is lower among US women than men. The narrowing gap between the sexes in more recent years and the results on CKD awareness by serum creatinine indicate that health care professionals have previously been relying on serum creatinine to inform patients about their condition, but in more recent years have been using eGFR, which accounts for women’s lower serum creatinine levels due to their lower muscle mass. Additional efforts should be made to increase CKD awareness among both sexes.

To the Editor: The prognostic importance of residual kidney function (RKF) for maintenance hemodialysis (HD) patients has previously been recognized.1, 2, 3, 4, 5, 6 In previous studies, monitoring of RKF typically required urine collection preceding the HD session and a predialysis blood sample from the end of collection to compute the renal clearance of urea/creatinine (ie, urinary urea/creatinine divided by serum concentration2, 4, 5) and more specifically, renal Kt/Vurea.3 Urine volume, the prerequisite for RKF, can also be estimated by patient self-report.7 In the present analysis of the DOPPS, we evaluated predictors and outcomes of self-reported urine volume; specifically, whether a positive response to the question: “Did the patient have urine output > 200 mL/d or 1 cup/day at the time of enrollment?” was associated with mortality during follow-up periods of 2 to 3 years.

Biogenic amines synthesis in phenylketonuria (PKU) patients with high phenylalanine (Phe) concentration is thought to be impaired due to inhibition of tyrosine and tryptophan hydroxylases and competition with amino acids at the blood-brain barrier. Dopamine and serotonin deficits might explain brain damage and progressive neuropsychiatric impairment in adult PKU patients. Ten early treated adult PKU patients (mean age 38.2 years) and 15 age-matched controls entered the study. Plasma and cerebrospinal fluid (CSF) Phe, 5-hydroxyindoleacetic acid (5-HIAA), 5-hydroxytryptophan (5-HTP), 3,4-dihydroxy-l-phenylalanine (l-DOPA) and homovanillic acid (HVA) were analyzed. Voxel-based morphometry statistical nonparametric mapping was used to test the age-corrected correlation between gray matter atrophy and CSF biogenic amines levels. 5-HIAA and 5-HTP were significantly reduced in PKU patients compared to controls. Significant negative correlations were found between CSF 5-HIAA, HVA, and 5-HTP and Phe levels. A decrease in 5-HIAA and 5-HTP concentrations correlated with precuneus and frontal atrophy, respectively. Lower HVA levels correlated with occipital atrophy. Biogenic amines deficits correlate with specific brain atrophy patterns in adult PKU patients, in line with serotonin and dopamine projections. These findings may support a more rigorous Phe control in adult PKU to prevent neurotransmitter depletion and accelerated brain damage due to aging.

Background The putative benefits of cinacalcet therapy for management of secondary hyperparathyroidism (SHPT) are thought to be most manifested when patients are taking it consistently and as prescribed. Real-world descriptions of cinacalcet prescription discontinuation and reinitiation in European hemodialysis patients are lacking. To address this knowledge gap, we used Dialysis Outcomes and Practice Patterns Study (DOPPS) data, based on dialysis facility medical records, from seven European countries to estimate rates and predictors of cinacalcet prescription discontinuation and reinitiation in hemodialysis patients and to describe the trajectories of CKD-MBD laboratory values after discontinuation. Methods Cox regression analyses were used to predict (1) cinacalcet discontinuation among 613 patients with ≥3 consecutive months without cinacalcet prescription immediately prior to a new cinacalcet prescription and (2) cinacalcet reinitiation among 415 patients with a newly discontinued cinacalcet prescription immediately after ≥3 consecutive months of prescribed use. Results Cinacalcet was discontinued in 21 and 35% of new users after 6 and 12 months, respectively. Cinacalcet was reinitiated in 38 and 49% of newly-discontinued users after 6 and 12 months, respectively. Predictors of discontinuation included lower parathyroid hormone (PTH) in the previous month (

BACKGROUND: Despite a higher prevalence of chronic kidney disease among women, more men than women start renal replacement therapy (RRT). We hypothesized that gender differences in health care access exist and therefore aimed at determining whether characteristics and outcomes of haemodialysis patients over time differ by sex. METHODS: We studied all 28 323 adults who began haemodialysis during 1965-2014 in the Austrian Dialysis Registry, analysing trends in patient characteristics by sex and decade with mortality (via Cox regression), which was compared with the mortality of the Austrian general population. RESULTS: More men than women started haemodialysis (60.1% men versus 39.9% women overall), with minor differences among decades and age groups. The male:female mortality rate ratio in the general population ranged from 1.2 to 2.4 for age groups >18 years and in haemodialysis patients ranged from 0.80 to 1.3 (closer to 1 than in the general population, but consistently >1 in Decades 3-5). In recent decades, diabetes and hypertension replaced glomerulonephritis as the primary cause of end-stage renal disease in both men and women. Interaction analyses showed the mortality risk associated with haemodialysis access (only recorded in Decade 5) was significantly lower for men than for women. CONCLUSIONS: The male:female mortality rate ratio and the proportion of women starting haemodialysis were remarkably stable, which does not support the hypothesis of gender differences in health care/haemodialysis access or could imply that such differences might have persisted over decades. Future research should expand to other countries and other forms of RRT.

For years, erythropoiesis-stimulating agent (ESA) use among patients on dialysis was much higher in the United States than in Europe or Japan. Sweeping changes to dialysis reimbursement and regulatory policies for ESA in the United States in 2011 were expected to reduce ESA use and hemoglobin levels. We used the Dialysis Outcomes and Practice Patterns Study (DOPPS) data from 7129 patients in 223 in–center hemodialysis facilities (average per month) to estimate and compare time trends in ESA dose and hemoglobin levels among patients on hemodialysis in the United States, Germany, Italy, Spain, the United Kingdom, and Japan. From 2010 to 2013, substantial declines in ESA use and hemoglobin levels occurred in the United States but not in other DOPPS countries. Between August of 2010 and April of 2013, mean weekly ESA dose in the United States decreased 40.4% for black patients and 38.0% for nonblack patients; mean hemoglobin decreased from 11.5 g/dl in black patients and 11.4 g/dl in nonblack patients to 10.6 g/dl in both groups. In 2010 and 2013, adjusted weekly ESA doses per kilogram were 41% and 11% lower, respectively, in patients in Europe and 60% and 18% lower, respectively, in patients in Japan than in nonblack patients in the United States. Adjusted hemoglobin levels in 2010 and 2013 were 0.07 g/dl lower and 0.56 g/dl higher, respectively, in patients in Europe and 0.93 and 0.01 g/dl lower, respectively, in patients in Japan than in nonblack patients in the United States. In conclusion, ESA dosing reductions in the United States likely reflect efforts in response to changes in reimbursement policy and regulatory guidance.

Background and objectives Anemia management changed substantially among dialysis patients in the United States around the time of implementation of the new Centers for Medicare & Medicaid Services bundled payment system and erythropoiesis-stimulating agent (ESA) label change in 2011. Among these, average ferritin levels increased dramatically and have remained high since; this study sought to gain understanding of this sustained rise in ferritin levels. Design, setting, participants, & measurements Trends in mean ferritin, hemoglobin, IV iron dose, and ESA dose from 2009 to 2013 were examined in 9735 patients from 91 United States Dialysis Outcomes and Practice Patterns Study facilities. Linear mixed models were used to assess the extent to which intravenous (IV) iron and ESA dose accounted for patients’ changes in ferritin over time. Results Mean ESA dose and hemoglobin levels declined throughout the study. Mean IV iron dose increased from 210 mg/mo in 2009–2010 to a peak of 280 mg/mo in 2011, then declined back to 200 mg/mo and remained stable from 2012 to 2013. Mean ferritin increased from 601 ng/ml in the third quarter of 2009 to 887 ng/ml in the first quarter of 2012; models suggest that higher IV iron dosing was a primary determinant during 2011, but lower ESA doses contributed to the sustained high ferritin levels thereafter. In a subset of 17 facilities that decreased IV iron dose in 2011, mean ferritin rose by 120 ng/ml to 764 ng/ml, which appeared to be primarily due to ESA reduction. Together, changes in IV iron and ESA doses accounted for 46% of the increase in ferritin over the study period. Conclusions In contrast to expectations, the rise in average IV iron dose did not persist beyond 2011. The sustained rise in ferritin levels in United States dialysis patients after policy changes in 2011, to average levels well in excess of 800 ng/ml, appeared to be partly due to reductions in ESA dosing and not solely IV iron dosing practices. The effect of these changes in ferritin on health outcomes requires further investigation.

To avoid potentially severe outcomes, phenylketonuria (PKU) must be detected as soon as possible after birth and managed with life-long treatment. A questionnaire-based survey was performed to document diagnosis and management practices for PKU in a region of Southern and Eastern Europe. Prevalence and management data were obtained from 37/59 (63 %) centres within 19/22 (86 %) contacted countries (N = 8600 patients). The main results’ analysis was based on completed questionnaires obtained from 31 centres (53 %) within 15 countries (68 %). A median of 10 % of patients per centre had been diagnosed after the newborn period. Metabolic dieticians and specialised adult PKU clinics were lacking in 36 and 84 % of centres, respectively. In 26 % of centres, treatment initiation was delayed until >15 days of life. Blood phenylalanine (Phe) thresholds to start treatment and upper Phe targets were inconsistent across centres. Ten percent of centres reported monitoring Phe every 2 weeks for pregnant women with PKU, which is insufficient to minimise risk of neonatal sequalae. Sapropterin dihydrochloride treatment was available in 48 % of centres, with 24-h responsiveness tests most common (36 %). Only one centre among the five countries lacking newborn screening provided a completed questionnaire. Conclusion: Targeted efforts by health care professionals and governments are needed to optimise diagnostic and management approaches for PKU in Southern and Eastern Europe.“What is Known”• PKU must be detected early and optimally managed throughout life to avoid poor outcomes, yet newborn screening is not universal and diagnostic and management practices for PKU are known to vary widely between different centres and countries. • Targeted efforts by health care professionals and governments are needed to optimise diagnostic and management approaches. “What is New”• PKU management practices are documented in 19 South and Eastern European countries indicating a heterogeneous situation across the region. • Key areas for improvement identified in surveyed centres include a need for comprehensive screening in all countries, increased number of metabolic dietitians and specialised adult PKU clinics, delayed time to treatment initiation, appropriate Phe thresholds, Phe targets and monitoring frequencies, and universal access to currently available treatment options. Electronic supplementary material The online version of this article (doi:10.1007/s00431-015-2622-5) contains supplementary material, which is available to authorized users.

Background Since the bundled end-stage renal disease prospective payment system began in 2011 in the United States, some hemodialysis practices have changed substantially, raising the question of whether vascular access practice also has changed. We describe monthly US vascular access use from August 2010 to August 2013 with international comparisons, and other aspects of US vascular access practice. Study Design Prospective observational cohort study of vascular access. Setting & Participants Maintenance hemodialysis patients in the Dialysis Outcomes and Practice Patterns Study (DOPPS) Practice Monitor (DPM) in the United States (N=3,442; US patients) and 19 other nations (N=8,478). Predictors Country, patient demographics, time period. Outcomes Vascular access use, pre–end-stage renal disease access timing of first nephrologist care and arteriovenous access placement, patient self-reported vascular access preferences (United States only), treatment practices as stated by medical directors. Results In the United States from August 2010 to August 2013, arteriovenous fistula (AVF) use increased from 63% to 68%, while catheter use declined from 19% to 15%. Although AVF use did not differ greatly across age groups, arteriovenous graft use was 2-fold higher among black (26%) versus nonblack US patients (13%) in 2013. Across 20 countries in 2013, AVF use ranged from 49% to 92%, whereas catheter use ranged from 1% to 45%. Patient-reported vascular access preferences differed by sex and race, with 16% to 20% of patients feeling uninformed regarding benefits/risks of different vascular access types. Among new (incident) US hemodialysis patients, AVF use remains low, with ∼70% initiating hemodialysis therapy with a catheter (60% starting with catheter when having ≥4 months of predialysis nephrology care). In the United States, longer typical times to first AVF cannulation were reported. Limitations Noncompletion of surveys may affect the generalizability of findings to the wider hemodialysis population. Conclusions AVF use has increased, with catheter use decreasing among prevalent US hemodialysis patients since the introduction of the prospective payment system. However, AVF use at dialysis therapy initiation remains low, suggesting that reforms affecting predialysis care may be necessary to incentivize improvements in fistula rates at dialysis therapy initiation as achieved for prevalent hemodialysis patients.

International audience; Neonatal loading studies with tetrahydrobiopterin (BH4) are used to detect hyperphenylalaninemia due to BH4 deficiency by evaluating decreases in blood phenylalanine (Phe) concentrations post BH4 load. BH4 responsiveness in phenylalanine hydroxylase (PAH)-deficient patients introduced a new diagnostic aspect for this test. In older children, a broad spectrum of different levels of responsiveness has been described. The primary objective of this study was to develop a pharmacodynamic model to improve the description of individual sensitivity to BH4 in the neonatal period. Secondary objectives were to evaluate BH4 responsiveness in a large number of PAH-deficient patients from a neonatal screening program and in patients with various confirmed BH4 deficiencies from the BIODEF database. Descriptive statistics in patients with PAH deficiency with 0-24-h data available showed that 129 of 340 patients (37.9%) had a >30% decrease in Phe levels post load. Patients with dihydropteridine reductase deficiency (n = 53) could not be differentiated from BH4-responsive patients with PAH deficiency. The pharmacologic turnover model, "stimulation of loss" of Phe following BH4 load, fitted the data best. Using the model, 193 of 194 (99.5%) patients with a proven BH4 synthesis deficiency or recycling defect were classified as BH4 sensitive. Among patients with PAH deficiency, 216 of 375 (57.6%) patients showed sensitivity to BH4, albeit with a pronounced variability; PAH-deficient patients with blood Phe 1200 μmol/L. External validation showed good correlation between the present approach, using 0-24-h blood Phe data, and the published 48-h prognostic test. Pharmacodynamic modeling of Phe levels following a BH4 loading test is sufficiently powerful to detect a wide range of responsiveness, interpretable as a measure of sensitivity to BH4. However, the clinical relevance of small responses needs to be evaluated by further studies of their relationship to long-term response to BH4 treatment.

The nature of phenylalanine hydroxylase (PAH) variants determines residual enzyme activity, which modifies the clinical phenotype in phenylketonuria (PKU). We exploited the statistical power of a large genotype database to determine the relationship between genotype and phenotype in PKU.A total of 9336 PKU patients with 2589 different genotypes, carrying 588 variants, were investigated using an allelic phenotype value (APV) algorithm.We identified 251 0-variants encoding inactive PAH, and assigned APVs (0 = classic PKU; 5 = mild PKU; 10 = mild hyperphenylalaninaemia) to 88 variants in PAH-functional hemizygous patients. The genotypic phenotype values (GPVs) were set equal to the higher-APV allele, which was assumed to be dominant over the lower-APV allele and to determine the metabolic phenotype. GPVs for 8872 patients resulted in cut-off ranges of 0.0-2.7 for classic PKU, 2.8-6.6 for mild PKU and 6.7-10.0 for mild hyperphenylalaninaemia. Genotype-based phenotype prediction was 99.2% for classic PKU, 46.2% for mild PKU and 89.5% for mild hyperphenylalaninaemia. The relationships between known pretreatment blood phenylalanine levels and GPVs (n = 4217), as well as tetrahydrobiopterin responsiveness and GPVs (n = 3488), were significant (both P 0.001).APV and GPV are powerful tools to investigate genotype-phenotype associations, and can be used for genetic counselling of PKU families.

The benefits of renin angiotensin-aldosterone system inhibitors (RAASi) are well-established in the general population, particularly among those with diabetes, congestive heart failure (CHF), or coronary artery disease (CAD). However, conflicting evidence from trials and concerns about hyperkalemia limit RAASi use in hemodialysis patients, relative to other antihypertensive agents, including beta blockers and calcium channel blockers. Therefore, we investigated prescription patterns and associations with mortality for RAASi and other antihypertensive agents using data from the international Dialysis Outcomes and Practice Patterns Study (DOPPS). Cox regression was used to estimate the effect of the prescription of RAASi and other antihypertensive agents at study entry on mortality in 11,421 incident (120 days or less) hemodialysis and 37,124 prevalent (over 120 days) hemodialysis patients from DOPPS phases 2-5 (2002-2015). Over 95% of RAASi were angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. RAASi prevalence was 39% and varied minimally by CHF and CAD. The adjusted hazard ratio for RAASi (vs. no RAASi) was 0.89 (95% confidence interval 0.80-0.99) among incident and 0.94 (0.90-0.99) among prevalent hemodialysis patients, with no convincing evidence of interaction with diabetes, CAD or CHF. Inverse associations with mortality were also observed for beta blockers and calcium channel blockers, and were stronger for angiotensin receptor blockers than angiotensin-converting enzyme inhibitors, but this latter finding requires further study. Thus, our observations suggest a relatively small survival benefit of RAASi and other antihypertensive agents in hemodialysis patients, though randomized prospective studies are needed to potentially change prescribing criteria.

Background With its convective component, hemodiafiltration (HDF) provides better middle molecule clearance compared with hemodialysis (HD) and is postulated to improve survival. A previous analysis of Dialysis Outcomes and Practice Patterns Study (DOPPS) data in 1998-2001 found lower mortality rates for high replacement fluid volume HDF versus HD. Randomized controlled trials have not shown uniform survival advantage for HDF; in secondary (non-randomized) analyses, better outcomes were observed in patients receiving the highest convection volumes. Methods In a 'real-world' setting, we analyzed patients on dialysis >90 days from seven European countries in DOPPS Phases 4 and 5 (2009-15). Adjusted Cox regression was used to study HDF (versus HD) and mortality, overall and by replacement fluid volume. Results Among 8567 eligible patients, 2012 (23%) were on HDF, ranging from 42% in Sweden to 12% in Germany. Median follow-up was 1.5 years during which 1988 patients died. The adjusted mortality hazard ratio (95% confidence interval) was 1.14 (1.00-1.29) for any HDF versus HD and 1.08 (0.92-1.28) for HDF >20 L replacement fluid volume versus HD. Similar results were found for cardiovascular and infection-related mortality. In an additional analysis aiming to avoid treatment-by-indication bias, we did not observe lower mortality rates in facilities using more HDF (versus HD). Conclusions Our results do not support the notion that HDF provides superior patient survival. Further trials designed to test the effect of high-volume HDF (versus lower volume HDF versus HD) on clinical outcomes are needed to adequately inform clinical practices.

Background The Kidney Disease: Improving Global Outcomes guidelines have cautioned against administering intravenous (IV) iron to hemodialysis patients with high serum ferritin levels due to safety concerns, but prior research has shown that the association between high ferritin and mortality could be attributed to confounding by malnutrition and inflammation. Our goal was to better understand the ferritin–mortality association and relative influence of IV iron and inflammation in the USA, where ferritin levels have recently increased dramatically, and in Europe and Japan, where ferritin levels are lower and anemia management practices differ. Methods Data from 18 261 patients in Phases 4 and 5 (2009–15) of the international Dialysis Outcomes and Practice Patterns Study, a prospective cohort study, were analyzed. Using Cox regression, we modeled the association between baseline ferritin and 1-year mortality with restricted cubic splines and assessed the impact of potential confounders. Results Median ferritin levels were 718 ng/mL in the USA, 405 in Europe and 83 in Japan. High ferritin levels were associated with elevated mortality (relative to region-specific medians) in all three regions. The strength of this association was attenuated more by adjustment for malnutrition and inflammation than by IV iron and erythropoiesis-stimulating agent dose in each region. Conclusion The utility of high ferritin as a biomarker for clinical risk due to excess iron stores may be limited, although caution regarding IV iron dosing to higher upper ferritin targets remains warranted. Research to resolve biomarker criteria for iron dosing, and whether optimal anemia management strategies differ internationally, is still needed.

Missed hemodialysis (HD) treatments not due to hospitalization have been associated with poor clinical outcomes and related in part to treatment nonadherence. Using data from the Dialysis Outcomes and Practice Patterns Study (DOPPS) phase 5 (2012-2015), we report findings from an international investigation of missed treatments among patients prescribed thrice-weekly HD.Prospective observational study.8,501 patients participating in DOPPS, on HD therapy for more than 120 days, from 20 countries. Longitudinal and cross-sectional analyses were performed based on the 4,493 patients from countries in which 4-month missed treatment risk was5%.The main predictor of patient outcomes was 1 or more missed treatments in the 4 months before DOPPS phase 5 enrollment; predictors of missed treatments included country, patient characteristics, and clinical factors.Mortality, hospitalization, laboratory measures, patient-reported outcomes, and 4-month missed treatment risk.Outcomes were assessed using Cox proportional hazards, logistic, and linear regression, adjusting for case-mix and country.The 4-month missed treatment risk varied more than 50-fold across all 20 DOPPS countries, ranging from 1% in Italy and Japan to 24% in the United States. Missed treatments were more likely with younger age, less time on dialysis therapy, shorter HD treatment time, lower Kt/V, longer travel time to HD centers, and more symptoms of depression. Missed treatments were positively associated with all-cause mortality (HR, 1.68; 95% CI, 1.37-2.05), cardiovascular mortality, sudden death/cardiac arrest, hospitalization, serum phosphorus level 5.5mg/dL, parathyroid hormone level 300pg/mL, hemoglobin level 10g/dL, higher kidney disease burden, and worse general and mental health.Possible residual confounding; temporal ambiguity in the cross-sectional analyses.In the countries with a 4-month missed treatment risk5%, HD patients were more likely to die, be hospitalized, and have poorer patient-reported outcomes and laboratory measures when 1 or more missed treatments occurred in a 4-month period. The large variation in missed treatments across 20 nations suggests that their occurrence is potentially modifiable, especially in the United States and other countries in which missed treatment risk is high.

Contains fulltext : 182674.pdf (Publisher’s version ) (Open Access) Phenylketonuria (PKU) is an autosomal recessive inborn error of phenylalanine metabolism caused by deficiency in the enzyme phenylalanine hydroxylase that converts phenylalanine into tyrosine. If left untreated, PKU results in increased phenylalanine concentrations in blood and brain, which cause severe intellectual disability, epilepsy and behavioural problems. PKU management differs widely across Europe and therefore these guidelines have been developed aiming to optimize and standardize PKU care. Professionals from 10 different European countries developed the guidelines according to the AGREE (Appraisal of Guidelines for Research and Evaluation) method. Literature search, critical appraisal and evidence grading were conducted according to the SIGN (Scottish Intercollegiate Guidelines Network) method. The Delphi-method was used when there was no or little evidence available. External consultants reviewed the guidelines. Using these methods 70 statements were formulated based on the highest quality evidence available. The level of evidence of most recommendations is C or D. Although study designs and patient numbers are sub-optimal, many statements are convincing, important and relevant. In addition, knowledge gaps are identified which require further research in order to direct better care for the future.

The purpose of this study was to analyse the changes produced by surgically assisted rapid palatal expansion (SARPE) longitudinally on 14 patients aged between 18 and 41 years. A pre-fabricated Hyrax appliance was cemented prior to the surgical intervention, which consisted of a maxillary buccal corticotomy with pterygoid separation. Models and postero-anterior (PA) headfilms were taken before expansion (T1), at the end of expansion (T2), at the end of retention (T3) and at least 1 year post-surgery (T4). Overall expansion and relapse were measured directly on the casts. Transverse distances increased more at the first molars (8.7 mm) and premolars (8.1 and 8.3 mm) than in the canine (5.2 mm) and second molar (5.5 mm) region. Minimal relapse occurred during the retention phase. The arch width decreased more during the post-retention period, with more pronounced reduction at the teeth used as anchorage during the expansion procedure (-2.0 mm for the first premolars and -2.6 mm for the first molars). The mean total dental relapse was 28 per cent. PA radiographic analysis for angular changes showed 9.6 degrees of lateral tipping per side during expansion. One-third of this movement relapsed during the retention period (-3.3 degrees) and this trend (-6.0 degrees) continued during the post-retention phase to reach practically the original value at T1. Skeletal changes monitored on the PA headfilms were minimal with great individual variation. The mean expansion measured in the proximity of the osteotomy site was only 1.3 mm. From this amount, 0.4 mm was lost during the retention and post-retention periods. Based on these findings, it appears that maxillary skeletal expansion by SARPE is mainly a lateral rotation of the two maxillary halves with only minimal horizontal translation.

When randomized controlled trials are unavailable, clinicians have to rely on observational studies. However, analyses using observational data to evaluate specific treatments and their associations with outcomes often are biased through confounding by clinical indication for the treatment of interest. Given the rich observational data and limited clinical trial data available in the dialysis population, successfully accounting for this bias can lead to substantial knowledge generation. In recent decades, much has been learned about statistical methods for observational data, including the fact that even extensive adjustments may not always overcome this bias, particularly when unmeasured confounders exist. In this article, examples based on the international DOPPS (Dialysis Outcomes and Practice Patterns Study) are used to demonstrate the value of practice-based instrumental variable analyses. This methodology leverages the marked differences in practice patterns among dialysis facilities and uses the reasonable assumption that patients are assigned to a dialysis facility without consideration of its specific treatment pattern in order to minimize bias in analyses relying on observational data. Examples using the dialysis facility as an instrument that are reviewed in depth in this article include studies of dialysate sodium concentration, systolic blood pressure targets, and treatment time, demonstrate the value of this methodology to produce advanced knowledge. However, practice-based analyses have potential limitations. Specifically, observation of sufficiently large differences in practice patterns is required and these analyses should consider that the treatment of interest may be associated with other facility treatment practices. These examples from the DOPPS hopefully will stimulate advances in methodologies and critical clinical work toward improving patient care by identifying beneficial treatment practices applicable to dialysis, chronic kidney disease, and beyond.

European journal of anaesthesiology 32(2), 106-116 (2015). doi:10.1097/EJA.0000000000000183, Published by Lippincott Williams & Wilkins, Philadelphia, Pa.

background Diffusive sodium removal has been recommended to control hypertension in hemodialysis patients. Recent evidence on hospitalizations and mortality, however, challenged the benefit of lower dialysate sodium prescriptions and ignited a debate in the dialysis community. We therefore studied the relationship between dialysate sodium and blood pressure over the longer term. methods We used multiply adjusted linear mixed models to estimate the association between dialysate sodium and predialysis systolic blood pressure (SBP) as well as change in SBP (delta SBP; postdialysis minus predialysis) in 23,962 patients from the international Dialysis Outcomes and Practice Patterns Study. results We found that 43% of hemodialysis facilities had variable (individualized) dialysate sodium prescriptions (125–155 mEq/L), whereas 57% had uniform dialysate sodium prescriptions (135–145 mEq/L) for ≥90% patients. Between-group comparisons of these 2 facility types suggested that dialysate sodium, when variably prescribed, might have been used to modify predialysis SBP (Pinteraction = 0.01) and perhaps delta SBP levels (Pinteraction = 0.08). Within facilities not prone to indication bias, because dialysate sodium was not variable, higher uniform dialysate sodium (per 2 mEq/L) was associated with slightly higher SBP (+0.9 mm Hg, 95% confidenc e interval (CI) = 0.1–1.6 among all patients; +1.7 mm Hg, 95% CI = 0.1–3.2 among patients not treated with blood pressure medication) and no increase in delta SBP. conclusions Patients assigned to hemodialysis facilities with uniformly higher dialysate sodium do not have markedly higher predialysis SBP, providing rather limited support for lowering dialysate sodium to control hypertension, particularly in view of hospitalization and mortality risks associated with lower dialysate sodium.

Background Most hemodialysis patients worldwide are treated with bicarbonate dialysis using sodium bicarbonate as the base. Few studies have assessed outcomes of patients treated with different dialysate bicarbonate levels, and the optimal concentration remains uncertain. Study Design The Dialysis Outcomes and Practice Patterns Study (DOPPS) is an international prospective cohort study. Setting & Participants This study included 17,031 patients receiving thrice-weekly in-center hemodialysis from 11 DOPPS countries (2002-2011). Predictor Dialysate bicarbonate concentration. Outcomes All-cause and cause-specific mortality and first hospitalization, using Cox regression to estimate the effects of dialysate bicarbonate concentration, adjusting for potential confounders. Measurements Demographics, comorbid conditions, laboratory values, and prescriptions were abstracted from medical records. Results Mean dialysate bicarbonate concentration was 35.5 ± 2.7 (SD) mEq/L, ranging from 32.2 ± 2.3 mEq/L in Germany to 37.0 ± 2.6 mEq/L in the United States. Prescription of high dialysate bicarbonate concentration (≥38 mEq/L) was most common in the United States (45% of patients). Approximately 50% of DOPPS facilities used a single dialysate bicarbonate concentration. 3,913 patients (23%) died during follow-up. Dialysate bicarbonate concentration was associated positively with mortality (adjusted HR, 1.08 per 4 mEq/L higher [95% CI, 1.01-1.15]; HR for dialysate bicarbonate ≥38 vs 33-37 mEq/L, 1.07 [95% CI, 0.97-1.19]). Results were consistent across levels of pre–dialysis session serum bicarbonate and between facilities that used a single dialysate bicarbonate concentration and those that prescribed different concentrations to individual patients. The association of dialysis bicarbonate concentration with mortality was stronger in patients with longer dialysis vintage. Limitations Due to the observational nature of the present study, we cannot rule out that the reported associations may be biased by unmeasured confounders. Conclusions High dialysate bicarbonate concentrations, especially prolonged exposure, may contribute to adverse outcomes, likely through the development of postdialysis metabolic alkalosis. Additional studies are warranted to identify the optimal dialysate bicarbonate concentration.

OBJECTIVE We determined prevalence, risk factors, phenotype, and pathophysiological mechanism of new-onset diabetes after transplantation (NODAT) to generate strategies for optimal pharmacological management of hyperglycemia in NODAT patients. RESEARCH DESIGN AND METHODS Retrospective cohort study comparing demographics, laboratory data, and oral glucose tolerance test (OGTT)-derived metabolic parameters from kidney transplant recipients versus subjects not receiving transplants. RESULTS Among 1,064 stable kidney transplant recipients (≥6 months posttransplantation), 113 (11%) had a history of NODAT and 132 (12%) had pretransplant diabetes. In the remaining patients, randomly assigned OGTTs showed a high prevalence of abnormal glucose metabolism (11% diabetes; 32% impaired fasting glucose, impaired glucose tolerance, or both), predominantly in older patients who received tacrolimus as the primary immunosuppressant. Compared with 1,357 nontransplant subjects, stable kidney transplant recipients had lower basal glucose, higher glycated hemoglobin, lower insulin secretion, and greater insulin sensitivity in each of the three subgroups, defined by OGTT 2-h glucose ( CONCLUSIONS Glucose metabolism differs substantially between kidney transplant recipients and nontransplant controls. Because impaired insulin secretion appears to be the predominant pathophysiological feature after renal transplantation, early therapeutic interventions that preserve, maintain, or improve β-cell function are potentially beneficial in this population.

Long-haul flights (LHF) are known to be connected with an increased risk of deep vein thrombosis. There is still some lack of clarity about the impact of hypoxia and lower levels of air pressure and humidity on passengers during flight. This cross-over study researched interstitial fluid shifts traced by measurements of tissue thickness (TT) under controlled simulated conditions of a LHF.There were 18 male volunteers (28.4 +/- 8.1 yr) who were subjected to both procedure 1 (altitude: 2500 m/humidity: 15%)and procedure 2 (altitude: 0 m/humidity: 50%), each lasting 8 h. Measurements forTT at tibia (TT-t) and forehead sites (TT-f) were made using a miniature A-mode ultrasonic device. Fluid intake, bodyweight, heart rate, oxygen saturation, and systolic and diastolic blood pressure were recorded over time. Blood samples were collected before (t0) and after 8 h (t8) to analyze plasma viscosity (PV).We found an increased TT-t over time at an altitude of 0 m (t0: 4.8 +/- 1.2; t8: 5.2 +/- 1.3) and 2500 m (t0: 4.7 +/- 1.2; t8: 5.3 +/- 1.2), respectively, without differences between study groups. TT-f increased significantly over time at 2500 m (t0: 4.6 +/- 0.8; t8: 4.9 +/- 0.8) with significantly higher TT compared to 0 m at t8 (4.5 +/- 0.7). No further significant differences were found.This study suggests that the controlled variable "sitting position" seems to have the strongest influence on leg edema formation during LHF. PV appears not to be affected as long as passengers receive adequate fluid intake. Further studies should be conducted to investigate different methods of preventing venous congestion. These pre-emptive efforts could be tested easily using a miniature handheld ultrasound device.

Oral nutritional supplementation (ONS) was provided to ESRD patients with hypoalbuminemia as part of Fresenius Medical Care Health Plan's (FMCHP) disease management. This study evaluated the association between FMCHP's ONS program and clinical outcomes.Analyses included FMCHP patients with ONS indication (n=470) defined as 2-month mean albumin3.8 g/dl until reaching a 3-month mean ≥3.8 g/dl from February 1, 2006 to December 31, 2008. Patients did not receive ONS if deemed inappropriate or refused. Patients on ONS were compared with patients who were not, despite meeting ONS indication. Patients with ONS indication regardless of use were compared with Medicare patients with similar serum albumin levels from the 2007 Centers for Medicare and Medicaid Services Clinical Performance Measures Project (CPM). Cox models calculated adjusted hospitalization and mortality risks at 1 year.Among patients with indication for ONS, 276 received supplements and 194 did not. ONS use was associated with 0.058 g/dl higher serum albumin overall (P=0.02); this difference decreased by 0.001 g/dl each month (P=0.05) such that the difference was 0.052 g/dl (P=0.04) in month 6 and the difference was no longer significant in month 12 . In analyses based on ONS use, ONS patients had lower hospitalization at 1 year (68.4%; P0.01) versus patients without ONS (88.7%), but there was no significant reduction in mortality risk (P=0.29). In analyses based on ONS indication, patients with indication had lower mortality at 1 year (16.2%) compared with CPM patients (23.4%; P0.01).These findings suggest that ONS use was associated with significantly lower hospitalization rates but had no significant effect on mortality in a disease management setting.

Background Sudden death is a leading cause of death in patients on maintenance hemodialysis therapy. During hemodialysis sessions, the gradient between serum and dialysate levels results in rapid electrolyte shifts, which may contribute to arrhythmias and sudden death. Controversies exist about the optimal electrolyte concentration in the dialysate; specifically, it is unclear whether patient outcomes differ among those treated with a dialysate potassium concentration of 3 mEq/L compared to 2 mEq/L. Study Design Prospective cohort study. Setting & Participants 55,183 patients from 20 countries in the Dialysis Outcomes and Practice Patterns Study (DOPPS) phases 1 to 5 (1996-2015). Predictor Dialysate potassium concentration at study entry. Outcomes Cox regression was used to estimate the association between dialysate potassium concentration and both all-cause mortality and an arrhythmia composite outcome (arrhythmia-related hospitalization or sudden death), adjusting for potential confounders. Results During a median follow-up of 16.5 months, 24% of patients died and 7% had an arrhythmia composite outcome. No meaningful difference in clinical outcomes was observed for patients treated with a dialysate potassium concentration of 3 versus 2 mEq/L (adjusted HRs were 0.96 [95% CI, 0.91-1.01] for mortality and 0.98 [95% CI, 0.88-1.08] for arrhythmia composite). Results were similar across predialysis serum potassium levels. As in prior studies, higher serum potassium level was associated with adverse outcomes. However, dialysate potassium concentration had only minimal impact on serum potassium level measured predialysis (+0.09 [95% CI, 0.05-0.14] mEq/L serum potassium per 1 mEq/L greater dialysate potassium concentration). Limitations Data were not available for delivered (vs prescribed) dialysate potassium concentration and postdialysis serum potassium level; possible unmeasured confounding. Conclusions In combination, these results suggest that approaches other than altering dialysate potassium concentration (eg, education on dietary potassium sources and prescription of potassium-binding medications) may merit further attention to reduce risks associated with high serum potassium levels.

BackgroundHigh interdialytic weight gain (IDWG) is associated with adverse outcomes in hemodialysis (HD) patients. We identified temporal and regional trends in IDWG, predictors of IDWG, and associations of IDWG with clinical outcomes.Study DesignAnalysis 1: sequential cross-sections to identify facility- and patient-level predictors of IDWG and their temporal trends. Analysis 2: prospective cohort study to assess associations between IDWG and mortality and hospitalization risk.Setting & Participants21,919 participants on HD therapy for 1 year or longer in the Dialysis Outcomes and Practice Patterns Study (DOPPS) phases 2 to 5 (2002-2014).PredictorsAnalysis 1: study phase, patient demographics and comorbid conditions, HD facility practices. Analysis 2: relative IDWG, expressed as percentage of post-HD weight (

Phenylketonuria (PKU, phenylalanine hydroxylase deficiency), an inborn error of metabolism, can be detected through newborn screening for hyperphenylalaninemia (HPA). Most individuals with HPA harbor mutations in the gene encoding phenylalanine hydroxylase (PAH), and a small proportion (2%) exhibit tetrahydrobiopterin (BH4) deficiency with additional neurotransmitter (dopamine and serotonin) deficiency. Here we report six individuals from four unrelated families with HPA who exhibited progressive neurodevelopmental delay, dystonia, and a unique profile of neurotransmitter deficiencies without mutations in PAH or BH4 metabolism disorder-related genes. In these six affected individuals, whole-exome sequencing (WES) identified biallelic mutations in DNAJC12, which encodes a heat shock co-chaperone family member that interacts with phenylalanine, tyrosine, and tryptophan hydroxylases catalyzing the BH4-activated conversion of phenylalanine into tyrosine, tyrosine into L-dopa (the precursor of dopamine), and tryptophan into 5-hydroxytryptophan (the precursor of serotonin), respectively. DNAJC12 was undetectable in fibroblasts from the individuals with null mutations. PAH enzyme activity was reduced in the presence of DNAJC12 mutations. Early treatment with BH4 and/or neurotransmitter precursors had dramatic beneficial effects and resulted in the prevention of neurodevelopmental delay in the one individual treated before symptom onset. Thus, DNAJC12 deficiency is a preventable and treatable cause of intellectual disability that should be considered in the early differential diagnosis when screening results are positive for HPA. Sequencing of DNAJC12 may resolve any uncertainty and should be considered in all children with unresolved HPA.

The Dialysis Outcomes and Practice Patterns Study (DOPPS) is a leading source of up-to-date, representative, and comprehensive data on hemodialysis practice and patient outcomes worldwide. Since its inception, the study’s primary aim has been to identify practices that extend survival and improve