Werner Kleophas

Greater First-Year Survival on Hemodialysis in Facilities in Which Patients Are Provided Earlier and More Frequent Pre-nephrology Visits

BACKGROUND AND OBJECTIVES The aim of this study was to evaluate the relation between pre-nephrology visit (PNV) and 1-yr patient survival after hemodialysis (HD) induction. DESIGN, SETTING PARTICIPANTS, & MEASUREMENTS Data were analyzed from 8500 incident HD patients (on HD <or=30 d) in the Dialysis Outcomes and Practice Patterns Study (DOPPS) phases I and II. A visit to a nephrologist at least 1 mo before starting HD was regarded as PNV. Cox regression was used to estimate the adjusted hazard ratio (AHR) for mortality in the first year of HD in both patient- and facility-level analyses. All models were adjusted for age, sex, race, socioeconomic factors, cause of ESRD, 14 comorbid conditions, hemoglobin, serum albumin, and serum creatinine; accounted for facility clustering effects; and were stratified by country. RESULTS In patient-level analysis, PNV was associated with significantly lower risk for death (AHR 0.57; P < 0.0001). Facility-level analysis also showed a significant lower risk for death in facilities with greater prevalence of PNV in both continuous models (AHR 0.92 per 10% greater facility mean %PNV; P < 0.0004) and in categorical models (AHR 0.71 for facilities with >90% of patients receiving PNV [first quartile] compared with facilities with <71% of patients receiving PNV [fourth quartile]; P = 0.001). CONCLUSIONS These results provide not only patient-level but also facility practice evidence that PNV is related to improved patient survival during the first year after initiation of HD, indicating the possible mortality benefits with more increased attention to PNV.

Uric Acid Levels and All-Cause and Cardiovascular Mortality in the Hemodialysis Population

BACKGROUND AND OBJECTIVES Hyperuricemia is associated with hypertension, coronary artery disease, and chronic kidney disease. However, there are no specific data on the relationship of uric acid to cardiovascular disease in the chronic hemodialysis setting. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Data from 5827 patients on chronic hemodialysis from six countries affiliated with the Dialysis Outcomes and Practice Patterns Study (DOPPS) were analyzed. All laboratory data were based upon the initial cross-section of patients in DOPPS I and II. Cox regression was used to calculate the hazard ratio (HR) of all-cause and cardiovascular (CV) mortality with adjustments for case-mix including 14 classes of comorbidity. RESULTS There were no clinically significant differences in baseline characteristics between those who had measured uric acid (n = 4637) and those who did not (n = 1190). Uric acid level was associated with lower all-cause mortality (HR: 0.95, 95% confidence interval [CI]: 0.90 to 1.00 per 1 mg/dl higher uric acid level) and CV mortality (HR: 0.92, 95% CI: 0.86 to 0.99). When analyzed as a dichotomous variable, the adjusted HR at uric acid ≤8.2 mg/dl compared with >8.2 mg/dl was 1.24 (95% CI: 1.03 to 1.49) for all-cause mortality and 1.54 (95% CI: 1.15 to 2.07) for CV mortality. CONCLUSIONS Higher uric acid levels were associated with lower risk of all-cause and CV mortality in the hemodialysis population. These results are in contrast to the association of hyperuricemia with higher cardiovascular risk in the general population and should be the subject of further research.

International study of health care organization and financing: development of renal replacement therapy in Germany

The German health system represents the case of a global budget with negotiated fees and competing medical insurance companies. Physicians in private practice and non-profit dialysis provider associations provide most dialysis therapy. End-stage renal disease (ESRD) modalities are well integrated into the overall health care system. Dialysis therapy, independent of the mode of treatment, is reimbursed at a weekly flat rate. Mandatory health insurance covers health expenses, including those related to ESRD, for more than 90% of the population. Both employees and employers contribute to the premium for this insurance. Private medical insurance covers the remainder of the population. Access to treatment, including dialysis therapy, is uniformly available.

Implementation and first results of a German chronic kidney disease registry.

Advanced chronic kidney disease (CKD) is gaining increasing medical and economical importance, but little information exists about treatment variation and the impact of routine clinical treatments on survival, quality of life, and cost. We demonstrate the first results of a national electronic registry of nephrology clinic data that will serve as a resource for the prospective observation of CKD patients in Germany. A large network of German nephrologist practices is currently joining the project. Routinely obtained clinical data for non-dialysis dependent CKD patients are documented in health records electronically, and elements from these data are extracted using QuaNT (Qualitätssicherung Nephrologie und Transplantation) to create a centralized database. Here, we report cross-sectional data from 59 participating nephrology clinics and 6,187 patients with CKD Stage 3 - 5 in 2011. Mean age ± standard deviation (SD) was 72 ± 12 years. The distribution of CKD 3, 4, and 5 (non-dialysis) was 60%, 33%, and 8%, respectively. The major renal diseases were hypertension/vascular nephropathy (47%) and diabetic nephropathy (26%). Reninangiotensin-system inhibitor prescription was 78%. Vitamin D prescription was 50%, phosphate binders 6%, iron (oral or i.v.) 19%, and erythropoietin-stimulating agents 14%. This electronic registry follows clinical nephrology care and outcomes for CKD patients in Germany, and increased participation is anticipated. As a component of the initiative, variation in patient care will be studied to identify best treatment practices in analyses integrated into the international CKD Outcomes and Practice Patterns Study (CKDopps).

Vasculoprotective Effects of Dietary Cocoa Flavanols in Patients on Hemodialysis: A Double–Blind, Randomized, Placebo–Controlled Trial

BACKGROUND AND OBJECTIVES Hemodialysis (HD) per se entails vascular dysfunction in patients with ESRD. Endothelial dysfunction is a key step in atherosclerosis and is characterized by impaired flow-mediated dilation (FMD). Interventional studies have shown that cocoa flavanol (CF)-rich supplements improve vascular function. Aim of this study was to investigate the effect of flavanol-rich bioactive food ingredients on acute and chronic HD-induced vascular dysfunction in ESRD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS We conducted a randomized, double-blind, placebo-controlled trial from 2012 to 2013. Fifty-seven participants were enrolled, ingested CF-rich beverages (900 mg CF per study day), and were compared with those ingesting CF-free placebo. This included (1) a baseline cross-over acute study to determine safety and efficacy of CF and (2) a subsequent chronic parallel group study with a 30-day follow-up period to study effects of CF on HD-mediated vascular dysfunction entailing (3) an acute substudy during HD in flavanol-naive patients and (4) an acute on chronic study during HD. Primary and secondary outcome measures included changes in FMD and hemodynamics. RESULTS CF ingestion was well tolerated. Acute ingestion improved FMD by 53% (3.2±0.6% to 4.8±0.9% versus placebo, 3.2±0.7% to 3.3±0.8%; P<0.001), with no effects on BP or heart rate. A 30-day ingestion of CF led to an increase in baseline FMD by 18% (3.4±0.9% to 3.9±0.8% versus placebo, 3.5±0.7% to 3.5±0.7%; P<0.001), with reduced diastolic BP (73±12 to 69±11 mmHg versus placebo, 70±11 to 73±13 mmHg; P=0.03) and increased heart rate (70±12 to 74±13 bpm versus placebo, 75±15 to 74±13 bpm; P=0.01). No effects were observed for placebo. Acute ingestion of CF during HD alleviated HD-induced vascular dysfunction (3.4±0.9% to 2.7±0.6% versus placebo, 3.5±0.7% to 2.0±0.6%; P<0.001). This effect was sustained throughout the study (acute on chronic, 3.9±0.9% to 3.0±0.7% versus placebo, 3.5±0.7% to 2.2±0.6; P=0.01). CONCLUSIONS Dietary CF ingestion mitigates acute HD-induced and chronic endothelial dysfunction in patients with ESRD and thus, improves vascular function in this high-risk population. Larger clinical trials are warranted to test whether this translates into an improved cardiovascular prognosis in patients with ESRD.

Macrophage migration inhibitory factor is associated with vascular dysfunction in patients with end-stage renal disease.

BACKGROUND Patients with end-stage renal disease (ESRD) show a high prevalence of cardiovascular disease with arterial stiffness, atherosclerosis and endothelial dysfunction, leading to increased morbidity and mortality. The cytokine macrophage migration inhibitory factor (MIF) exhibits proinflammatory and proatherogenic functions and has recently emerged as a major regulator of atherogenesis. Studies examining the relationship between circulating MIF levels and vascular dysfunction in this high-risk population do not exist. METHODS In patients with ESRD (n = 39) and healthy controls (n = 16) we assessed endothelial function by flow-mediated dilation of the brachial artery and arterial stiffness (augmentation pressure, augmentation index and pulse pressure) using applanation tonometry. High-sensitive Troponin and subendocardial viability ratio were determined to assess myocardial injury. RESULTS Patients with ESRD had impaired endothelial function and higher plasma MIF levels. MIF levels negatively correlated with endothelial function (r = -0.345, P = 0.031) and positively with arterial stiffness indices in patients with ESRD (pulse pressure r = -0.374, P = 0.019 and augmentation pressure r = -0.423, P = 0.025). In multivariate regression models besides age, gender, weight, and heart rate, MIF was an independent predictor for arterial stiffness. Impact on myocardial end-organ damage was reflected by correlation with high-sensitive Troponin I (r = 0.43, P = 0.009). CONCLUSION Our findings show that high MIF plasma levels are associated with diminished endothelial function and arterial stiffness and are correlated with myocardial injury. Further studies are necessary to investigate whether modulation of MIF might have an impact on atherosclerotic disease in this high-risk population.

Barriers to adopting a fistula-first policy in Europe: an international survey among national experts

Purpose The purpose of this study is to explore how vascular access care was reimbursed, promoted, and organised at the national level in European and neighbouring countries. Methods An electronic survey among national experts to collect country-level data. Results Forty-seven experts (response rate, 76%) from 37 countries participated. Experts from 23 countries reported that 50% or less of patients received routine pre-operative imaging of vessels. Nephrologists placed catheters and created fistulas in 26 and 8 countries, respectively. Twenty-one countries had a fee per created access; the reported fee for catheter placement was never higher than for fistula creation. As the number of haemodialysis patients in a centre increased, more countries had a dedicated coordinator or multidisciplinary team responsible for vascular access maintenance at the centre-level; in 11 countries, responsibility was always with individual nephrologists, independent of a centres size. In 23 countries, dialysis centres shared vascular access care resources, with facilitation from a service provider in 4. In most countries, national campaigns (n = 35) or educational programmes (n = 29) had addressed vascular access-related topics; 19 countries had some form of training for creating fistulas. Forty experts considered the current evidence base robust enough to justify a fistula-first policy, but only 13 believed that more than 80% of nephrologists in their country would attempt a fistula in a 75-year-old woman with comorbidities. Conclusions Suboptimal access to surgical resources, lack of dedicated training of clinicians, limited routine use of pre-operative diagnostic imaging and patient characteristics primarily emerged as potential barriers to adopting a fistula-first policy in Europe.

Changes in dialysis treatment modalities during institution of flat rate reimbursement and quality assurance programs

Dialysis procedure rates in Germany were changed in 2002 from per-session to weekly flat rate payments, and quality assurance was introduced in 2009 with defined treatment targets for spKt/V, dialysis frequency, treatment time, and hemoglobin. In order to understand trends in treatment parameters before and after the introduction of these changes, we analyzed data from 407 to 618 prevalent patients each year (hemodialysis over 90 days) in 14-21 centers in cross-sections of the Dialysis Outcomes and Practice Patterns Study (phases 1-4, 1998-2011). Descriptive statistics were used to report differences over time in the four quality assurance parameters along with erythropoietin-stimulating agent (ESA) and intravenous iron doses. Time trends were analyzed using linear mixed models adjusted for patient demographics and comorbidities. The proportion of patients with short treatment times (less than 4 h) and low spKt/V (below 1.2) improved throughout the study and was lowest after implementation of quality assurance. Hemoglobin levels have increased since 1998 and remained consistent since 2005, with only 8-10% of patients below 10 g/dl. About 90% of patients were prescribed ESAs, with the dose declining since peaking in 2006. Intravenous iron use was highest in 2011. Hence, trends to improve quality metrics for hemodialysis have been established in Germany even after introduction of flat rate reimbursement. Thus, analysis of facility practice patterns is needed to maintain quality of care in a cost-containment environment.

Filtration of Macrophage Migration Inhibitory Factor (MIF) in Patients with End Stage Renal Disease Undergoing Hemodialysis.

Background End stage renal disease (ESRD) patients are characterized by increased morbidity and mortality due to highest prevalence of cardiovascular disease. Macrophage migration inhibitory factor (MIF) is an inflammatory cytokine that controls cellular signaling in human physiology, pathophysiology, and diseases. Increased MIF plasma levels promote vascular inflammation and development of atherosclerosis. We have shown that MIF is associated with vascular dysfunction in ESRD patients. Whether hemodialysis (HD) affects circulating MIF plasma levels is unknown. We here aimed to investigate whether HD influences the circulating MIF pool in ESRD patients. Methods and Results An observational single-center study was conducted. MIF plasma levels in ESRD patients were assessed before, during, and after a HD session (n = 29). Healthy age-matched volunteers served as controls to compare correlations of MIF plasma levels with inflammatory plasma components (n = 20). MIF removed from the circulating blood pool could be detected in the dialysate and allowed for calculation of totally removed MIF (MIF content in dialysate 219±4 μg/HD-session). MIF plasma levels were markedly decreased 2 hour after initiation of HD (MIF plasma level pre-HD 84.8±6 ng/ml to intra-HD 61.2±5 ng/ml p<0.001) and were replenished already 20 min after termination of HD to basal levels (intra-HD 61.2±5 ng/ml to post-HD 79.8±5 ng/ml, p<0.001). Conclusion MIF is a dialyzable plasma component that is effectively filtrated during HD from the patient blood pool in large amounts. After removal of remarkable amounts of MIF during a single HD session, MIF plasma pool is early reconstituted after termination of HD from unknown sources.

Mortality risk in patients on hemodiafiltration versus hemodialysis: a 'real-world' comparison from the DOPPS.

Abstract 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.