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Purpose Secondary hyperparathyroidism (SHPT) of renal origin is a progressive complication in chronic kidney disease (CKD) and is associated with serious osseous and non-osseous complications, CKD progression, and economic burden for healthcare systems worldwide. We aimed at assessing characteristics, healthcare resource utilization, and costs of incident SHPT patients in CKD stage 3 (CKD3) and 4 (CKD4), using administrative claims data. Methods German claims data were used to identify CKD3 and CKD4 patients, who were stratified by the occurrence of incident SHPT. Patients with SHPT were matched 1:1 to non-SHPT patients with the same CKD stage using propensity scores. Matched groups were compared during a 2-year follow-up period. Results Overall, 1156 CKD3 and 517 CKD4 incident SHPT patients and their respective matches were identified. Mean number of all-cause hospitalizations were significantly higher among SHPT patients (2.7 vs. 2.0 in CKD3, 2.8 vs. 1.5 in CKD4) during follow-up. Similarly, the mean number of outpatient encounters was significantly higher among the SHPT cohorts (95.0 vs. 64.3 in CKD3, 101.4 vs. 49.8 in CKD4). SHPT patients progressed to CKD5 more often (6.1% vs. 1.2% from CKD3, 26.7% vs. 2.9% from CKD4, both P P Conclusions Patients with CKD3&4 and incident SHPT of renal origin presented with significantly higher healthcare resource utilization and costs, as well as increased disease progression compared to non-SHPT patients.

Incidence of kidney replacement therapy (KRT) varies widely across countries. Its relations to individual characteristics, nephrology practices for slowing chronic kidney disease (CKD) progression, and KRT access remain unclear.We investigated intercountry differences in kidney failure (KF) rate, defined by a sustained estimated glomerular filtration rate (eGFR) 15 ml/min per 1.73 mAmong 7381 patients with CKD stage 3 to 4 at enrollment, 1297 progressed to KF and 947 initiated KRT over a 3-year follow-up period. Compared to the United States, demographic-adjusted and eGFR-adjusted hazard ratios (HRs) (HRs, 95% confidence intervals [CI]) for a sustained low eGFR were 0.77 (95% CI, 0.57-1.02) in Brazil, 0.90 (95% CI, 0.75-1.08) in France, and 1.03 (95% CI, 0.86-1.03) in Germany. Further adjustment for comorbidities, albuminuria, systolic BP, and RAASi prescription did not substantially change these HRs. In contrast, compared with the United States, the fully-adjusted HR for KRT remained significantly lower in Brazil (0.55, 95% CI 0.39-0.79), higher in Germany (95% CI, 1.36, 1.09-1.69), and similar in France (95% CI, 1.07, 0.81-1.39).Individual risk factors for CKD progression in nephrology patients appeared to explain most intercountry variations in KF but not KRT incidence. This suggests a prominent role for differences in practices related to KRT initiation or access, but not those for slowing disease progression. This study also shows that using KRT as a KF surrogate may bias estimates of associations with CKD progression risk factors.

BACKGROUND AND AIMS Hemodialysis (HD) patients (pts) with atrial fibrillation (AF) are at high risk for cardiovascular events, severe bleeding and rapid vascular/valvular calcification. Thus, antivitamin-K based oral anticoagulation (VK-OAC) for HD patients is debated, since prospective trials are missing and US register studies are often limited to 3–6 months OAC use. We studied AF risk-factors, long-term antithrombotic therapies and clinical outcomes in a large German HD cohort. METHOD We analysed pseudonymized benchmarking data in a German out-patient dialysis center network (Verband Deutsche Nierenzentren, DN) based on quarterly electronically transmitted data. Diagnoses coded by ‘International Classification of Diseases (ICD)’ and ‘Anatomical Therapeutical Chemical (ATC)’ drug codes of adult HD patients 2013–2018. RESULTS In 2013, 2753 (18%) of 15 682 HD-pts had AF as coded diagnosis. Baseline CHA2DS2-VASc (4.0/1.5 mean/SD) and HAS-BLED (3.2/0.9) risk-scores indicated high risk for embolism and bleeding. Charlson Comorbidity Index (CCI) was high (6.4/2.8) and median observation was 2.1 years (range 0.01–6 years). Beside HD-related heparin, four main OAC approaches were applied: no active therapy, VK-OAC+/-aspirin/clopidogrel (VK-OAC+/-Asp/Clop), heparin-based therapy (heparin+/-Asp/Clop) or 1–2 antithrombocyte drugs (Asp/Clop). A total of 959 pts (35%) changed therapy, but 1794 pts (65%) had no change in OAC regime during the 6 year study period and were used for final therapy-related outcome analysis (Table 1). Both AF risk-scores overestimated de-novo events. Total 6-year event rate was low (7.5%; Survival (Kaplan–Meier) was analysed for matched controls by propensity-score based on mortality risk factors in multivariate Cox regression: age (HR 1.05), sex (female HR 0.78), CCI (HR 1.07) and albumin (HR 0.93). Six-year mortality rates were high (63%) and matched analysis showed significant lower survival (P CONCLUSION Our large study showed that baseline CHA2DS2-VASc and HAS-BLED scores had no predictive value for clinical events in HD pts with AF. Cerebral ischemic event rates over 6 years were low ( Since median survival on Asp/Clop is similar to VK-OAC therapy and even 1 year better than on no active or heparin-based therapy, we conclude that antithrombotic therapy in HD patients with AF can effectively be done with Asp/Clop and VK-OAC should be avoided. For future prospective trials, we recommend to apply Asp/Clop as first-line control therapy evaluating new direct-acting oral anticoagulants (DOAK) and/or interventional approaches (i.e. left atrial appendage closure) in HD patients with AF.

BACKGROUND AND AIMS Chronic kidney disease (CKD) is likely to significantly affect the lives of patients and their carers, including increasing the economic burden. The relationship between CKD progression and these life impacts remains poorly characterized. The patient, carer and economic burden (PaCE) CKD study aims to enhance understanding of patient and carer experiences of CKD, including financial impact. METHOD In-depth, semi-structured, qualitative interviews were conducted with 20 patients with CKD and 19 informal carers in Australia, France, Germany, Italy, the UK and the USA. Participants were asked about their experiences with CKD and the associated economic burden. A quantitative online survey is ongoing, with 150–200 patients and 75–100 carers anticipated to participate per country. A Work Productivity and Activity Impairment (WPAI) questionnaire for patients and caregivers is being used to understand and estimate the financial burden of CKD on patients and caregivers. Patients are also being asked about their disease background, including the stage of CKD and treatment history. RESULTS In total, 20 patients and 19 carers participated in the qualitative interviews, with at least 3 patients and 3 carers included from each country. Eleven patients were male. Most patients were 75 years old or younger (18/20; overall range 30–81 years, overall mean 61.7 years). Patients reported their CKD stages: 3/20 stage 5; 2/20 stage 4–5; 2/20 stage 4; 2/20 stage 3–4; 8/20 stage 3; 1/20 stage 2; and 2/20 unknown. A third of patients underwent dialysis (7/20), including at least one patient from each country. Nine patients were working full- or part-time. Carers were 30–90 years old (mean 55.1 years), predominantly women (13/19) and were primarily relatives of the patient (8/19 partner, 5/19 daughter/son, 2/19 daughter-/son-in-law). More than half of the carers were employed (13/19 employed, 5/19 unemployed/retired, 1/19 unknown). Carer support varied between 4 and 35 h/week. Support included activities of daily living, visits to the hospital and emotional/psychological support; support was noted as more critical for patients with later-stage CKD. The degree of financial burden experienced by patients and carers varied between countries, potentially reflecting differences in local healthcare systems; however, the impact of reduced work hours on finances was consistent across all countries. Both patients and carers reported a loss of work hours, and in some cases, participants reported that they had to stop working. Patients who were employed reported lower productivity, and carers reported taking days off work without pay. Expenses related to the cost of managing CKD, including dietary needs, medical aids and hospital transport, further increased the economic burden. The extent of these impacts varied depending on the severity of CKD. Results from the quantitative survey will be presented at the congress. CONCLUSION Responses from qualitative interviews suggest that CKD increases the financial burden for both patients and carers, particularly as the disease progresses. When combined with data from the quantitative survey, these findings will provide important insights into the economic burden of CKD for patients and carers.

International audience; Objective: Conflicting findings and knowledge gaps exist regarding links between anemia, physical activity, health-related quality of life (HRQOL), chronic kidney disease (CKD) progression, and mortality in moderate-to-advanced CKD. Using the CKD Outcomes and Practice Patterns Study, we report associations of hemoglobin (Hgb) with HRQOL and physical activity, and associations of Hgb and physical activity with CKD progression and mortality in stage 3-5 nondialysis (ND)-CKD patients. Design and Methods: Prospectively collected data were analyzed from 2,121 ND-CKD stage 3-5 patients, aged ≥18 years, at 43 nephrologist-run US and Brazil CKD Outcomes and Practice Patterns Study–participating clinics. Cross-sectional associations were assessed of Hgb levels with HRQOL and physical activity levels (from validated Kidney Disease Quality of Life Instrument and Rapid Assessment of Physical Activity surveys). CKD progression (first of ≥40% estimated glomerular filtration rate [eGFR] decline, eGFR12 g/dL. Odds of being highly physically active were substantially greater at Hgb>10.5 g/dL. Lower Hgb was strongly associated with greater CKD progression and mortality, even after extensive adjustment. Physical inactivity was strongly associated with greater mortality and weakly associated with CKD progression. Possible residual confounding is a limitation. Conclusion: This multicenter international study provides real-world observational evidence for greater HRQOL, physical activity, lower CKD progression, and greater survival in ND-CKD patients with Hgb levels >12 g/dL, exceeding current treatment guideline recommendations. These findings help inform future studies aimed at understanding the impact of new anemia therapies and physical activity regimens on improving particular dimensions of ND-CKD patient well-being and clinical outcomes.

Background Chronic kidney disease (CKD) progression among German patients in a representative setting has not been described previously. The Verband Deutsche Nierenzentren and Chronic Kidney Disease Outcomes and Practice Patterns Study established a longitudinal observational cohort among German CKD patients to research variations in patient care and outcomes in real-world nephrology practices. Methods A cohort of CKD Stages 3 (25%) and 4 (75%) patients was established from German nephrologist-run CKD clinics in 2013–16. Linear models were used to determine the estimated glomerular filtration rate (eGFR) slope during follow-up and Cox models were used to assess outcomes of end-stage kidney disease (ESKD) and death. Results A total of 1834 patients (median age 75 years, 58% male, 42% diabetics, median baseline eGFR 25 mL/min/1.73 m2) were followed for a median of 29 months. More than 50% had slow or no decline and 17% declined ≥5 mL/min/1.73 m2/year. After 4.5 years, the incidence of ESKD was 8% and of deaths without ESKD 16% among patients with eGFR ≥30 mL/min/1.73 m2 and 37% and 19% for eGFR Conclusions Routine nephrology care of patients in Germany comprises mostly elderly patients, many with slow CKD progression. Identification of risk factors for CKD progression and mortality may help guide resources by closer follow-up of high-risk patients.

More men than women start kidney replacement therapy (KRT) although the prevalence of chronic kidney disease (CKD) is higher in women than men. We therefore aimed at analyzing sex-specific differences in clinical outcomes among 8237 individuals with CKD in stages 3 to 5 from Brazil, France, Germany, and the United States participating in the Chronic Kidney Disease Outcomes and Practice Patterns Study (CKDopps).Fine and Gray models, evaluating the effect of sex on time to events, were adjusted for age, Black race (model A); plus diabetes, cardiovascular disease, albuminuria (model B); plus estimated glomerular filtration rate (eGFR) slope during the first 12 months after enrollment and first eGFR after enrollment (model C).There were more men than women at baseline (58% vs. 42%), men were younger than women, and men had higher eGFR (28.9 ± 11.5 vs. 27.0 ± 10.8 ml/min per 1.73 mMen had a higher probability of commencing dialysis before death, unexplained by CKD progression alone. Although the causal mechanisms are uncertain, this finding helps interpret the preponderance of men in the dialysis population.

Background Approximately 30%-45% of patients with nondialysis CKD have iron deficiency. Iron therapy in CKD has focused primarily on supporting erythropoiesis. In patients with or without anemia, there has not been a comprehensive approach to estimating the association between serum biomarkers of iron stores, and mortality and cardiovascular event risks. Methods The study included 5145 patients from Brazil, France, the United States, and Germany enrolled in the Chronic Kidney Disease Outcomes and Practice Patterns Study, with first available transferrin saturation (TSAT) and ferritin levels as exposure variables. We used Cox models to estimate hazard ratios (HRs) for all-cause mortality and major adverse cardiovascular events (MACE), with progressive adjustment for potentially confounding variables. We also used linear spline models to further evaluate functional forms of the exposure-outcome associations. Results Compared with patients with a TSAT of 26%-35%, those with a TSAT ≤15% had the highest adjusted risks for all-cause mortality and MACE. Spline analysis found the lowest risk at TSAT 40% for all-cause mortality and MACE. Risk of all-cause mortality, but not MACE, was also elevated at TSAT ≥46%. Effect estimates were similar after adjustment for hemoglobin. For ferritin, no directional associations were apparent, except for elevated all-cause mortality at ferritin ≥300 ng/ml. Conclusions Iron deficiency, as captured by TSAT, is associated with higher risk of all-cause mortality and MACE in patients with nondialysis CKD, with or without anemia. Interventional studies evaluating the effect on clinical outcomes of iron supplementation and therapies for alternative targets are needed to better inform strategies for administering exogenous iron.

Contains fulltext : 215593.pdf (Publisher’s version ) (Closed access) Although blood pressure control is a major goal in chronic kidney disease, no worldwide overview of either its achievement or antihypertensive prescriptions is currently available. To evaluate this we compared crude prevalence of uncontrolled blood pressure among 17 cohort studies, including 34 602 individuals with estimated glomerular filtration rate under 60 ml/min/1.73 m(2) and treated hypertension across four continents, and estimated observed to expected prevalence ratios, adjusted for potential confounders. Crude prevalence of blood pressure of 140/90 mm Hg or more varied from 28% to 61% and of blood pressure of 130/80 or more from 54% to 84%. Adjusted prevalence ratios indicated poorer hypertension control than expected in cohorts from European countries, India, and Uruguay, and better control in patients from North American and high-income Asian countries. Four antihypertensive drug classes or more were prescribed to more than 30% of participants in North American and some European cohorts, but this practice was less common elsewhere. Renin angiotensin-aldosterone system inhibitors were the most common antihypertensive drugs, prescribed for 54% to 91% of cohort participants. Differences for other drug classes were much stronger, ranging from 11% to 79% for diuretics, 22% to 70% for beta-blockers, and 27% to 75% for calcium-channel blockers. The confounders studied explain only a part of the international variation in blood pressure control among individuals with chronic kidney disease. Thus, considerable heterogeneity in prescription patterns worldwide calls for further investigation into the impact of different approaches on patient outcomes.

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.

Background and Aims Blood pressure (BP) control and renin-angiotensin-aldosterone system (RAAS) blockade are key measures to slow CKD progression, and the achievement of targets for these measures vary greatly across countries. We sought to evaluate to what extend this might explain international variations in kidney failure incidence. Method We used data from the CKD Outcomes and Practice Patterns Study (CKDopps), a cohort study of adult patients recruited from national samples of nephrology clinics. Patients with CKD G3 or G4, from Brazil (n=498), France (n=2702), Germany (n=2314), and the US (n=905) were included. Those neither with hypertension nor with albuminuria were excluded (n=103). We assessed systolic BP and RAAS inhibitor prescription at baseline, and their association with time to kidney failure, defined as an estimated glomerular filtration rate (eGFR) < 15 ml/min/1.73m² or kidney replacement therapy initiation. Death was treated as a competing event. Cox proportional-hazards model was used to estimate cause-specific hazard ratios (cs-HR) and 95% confidence intervals (CI) for kidney failure according to country, before and after adjusting for systolic BP and RAAS inhibitor prescription, as well as demographics, and known risk factors for CKD progression. Results Median age (years) ranged from 67 in Brazil to 75 in Germany; and mean baseline eGFR (ml/min/1.73m²), from 27 in Germany to 33 in France. Prevalence of diabetes ranged from 20% in France to 36% in Brazil, and that of stage A3 albuminuria (>300 mg/g), from 31% in Brazil to 44% in the US. Mean systolic BP (mm Hg) ranged from 132 in Brazil to 143 in France, and the percentage of patients prescribed RAAS inhibitor, from 58% in the US to 81% in Germany. After median follow-up of 4.0 (2.6-5.0) years, 1897 participants progressed to kidney failure and 522 died before meeting this outcome. Two-year crude cumulative incidence of kidney failure was the lowest in France (14%), where patients were recruited at an earlier CKD stage, and similar across Germany (25%), the US (26%), and Brazil (27%); that for all-cause death, the lowest in Brazil (2.5%), followed by France (3.4%), the US (4.4%), and Germany (4.6%). Sequential adjustment for demographics and progression risk factors, in particular baseline eGFR and albuminuria, significantly reduced the gap between France and the other countries (Figure). Despite the associations of systolic BP (cs-HR 1.14, 95%CI 0.95-1.38 for 120-129; 1.18, 95%CI 0.95-1.46 for 130-139; and 1.46, 95%CI 1.23-1.74 for ≥140 versus Conclusion In CKD patients under nephrology care, BP control and RAAS inhibitor prescription were associated with lower risk of kidney failure and substantially varied across countries. Despite this variation in practice, BP control and RAAS inhibitor prescription appear to explain little of the differences in risk of kidney failure by country.

Background and Aims Hyperkalemia (HK) (serum K>5.0 mEq/L) is a chronic condition in patients with chronic kidney disease (CKD) associated with high morbidity and mortality, and it is a frequent reasons for renin angiotensin aldosterone inhibition (RAASi) discontinuation. Patiromer is a non-absorbed, sodium-free, K+ binder that has been shown to reduce serum K+ in patients with HK, and thereby enable RAASi therapy, which is supported by randomized trial evidence. The description of patiromer utilization in patients with moderate to advanced CKD in the real-world setting in Europe is lacking. The objective of this analysis was to describe predictors of patiromer initiation and time to discontinuation among CKD patients using contemporary (April 2018-October 2020) data from German participants in CKD Outcomes and Practice Patterns Study (CKDopps). Method We identified 136 patiromer users (116 with matching K measurement) during the observation period. Patients with eGFR Results Patiromer was prescribed to ≥2 patients in 11 clinics, one patient in 19 clinics, and zero patients in 57 clinics. Patients prescribed patiromer had lower eGFR (23.2 [15.8, 28.6] vs 36.9 [27.7, 46.3]ml/min) and higher serum K levels (5.6 [5.4, 6.1] vs 4.6 [4.3, 5.0]ml/min). There were no major differences according to patiromer use in other demographic, clinical, and biochemical characteristics. Despite the differences in serum K, use of RAAS inhibitors was similar in patiromer users (83%) versus non-users (80%). Thirty three percent of patiromer users were prescribed polystyrene sulfonate (SPS) before patiromer initiation. In a multiple logistic regression models (including serum K, CKD stage, gender, age, prescription of RAASi, diabetes, coronary artery disease, heart failure), patiromer use was strongly associated more advanced CKD stage (independently of high serum K), with odds ratios of initiation >3 for CKD stage 4 or 5 versus CKD stage 3. Among new users, 90% of patients had active prescription at 30 days and about one-half had active prescription at one year (Figure). Conclusion The main predictors of Patiromer initiation were advanced CKD stage and hyperkalemia. Treatment decisions did not appear to be based on other patient or clinical characteristics. Patiromer was often prescribed to patients already receiving alternative HK treatment (SPS), suggesting use for chronic hyperkalemia rather than response to acute event. Further analysis with a larger population and measurements of K+ before and after patiromer initiation may improve the understanding of its pharmacoutilization in moderate to advanced CKD.

Background and Aims Hemodialysis (HD) patients with atrial fibrillation (AF) are at high risk for cardio-vascular events, severe bleeding and rapid vascular/valvular calcification. Thus, higher than low standard dialysate Mg (d-Mg) may improve outcome by less arrhythmic or calcification impact, but clinical data are missing. Our study evaluated applied d-Mg, risk-factors and antithrombotic therapies on long-term outcome in a large representative German HD-cohort. Method We used pseudonymized benchmarking data (2013-2018) of 16226 adult chronic HD patients (informed consent) from DNeV dialysis network. Diagnoses were coded by “International Classification of Diseases (ICD)” and drugs via “Anatomical Therapeutical Chemical (ATC)” codes. Risk scores (Carlson Comorbidity Index=CCI, CHA2DS2-VASc and HAS-BLED) were tested for de-novo outcome prediction. Results At baseline, 2752 (17%) HD-patients had coded AF. CHA2DS2-VASc (4.0/SD1.5) and HAS-BLED (3.2/0.9) estimated high risk for embolism/bleeding. Standard dialysate-Mg (sd-Mg; 0.5 mmol/L) was used by 1317 (48%), d-Mg 0.75 had 331 (12%), d-Mg >1.0 had 134 (5%) and 970 (35%) patients changed from 0.5 to 0.75 during the study period (change group). Median study time was 2.1 yrs (Range=R: 0.01–6 yrs.). Overall 6-yr mortality was high (63%; Kaplan Meier median survival of 2.9 yrs. Unchanged d-Mg levels were significantly (p1.0 (3.4 yrs; p=0.02). The change group had the same survival (3.1 yrs) as the 0.75 group (p1.0 (hazard ratio=HR 0.74), d-Mg 0.75 (HR 0.79), serum albumin (HR 0.93), age (HR 1.04) and CCI (HR 1.06) as independently related to mortality (p=0.002). Sd-Mg had higher (p1.0 group (3.7%). Apart from dialysis-related heparin-supply four main approaches regarding anti-coagulation were identified: No therapy, VK-OAC, Heparin or only Aspirin/Clopidogrel (Asp/Clop): VK-OAC and Asp/Clop had same median survival (2.8 yrs) both better (p Conclusion Use of higher d-Mg in HD-patients with AF significantly improved survival and cerebral outcome, is a feasible cost-effective approach and has more relative impact than well established survival risk-factors such as age, comorbidity (=CCI) and serum albumin. Our data warrant prospective trials comparing higher d-Mg levels with anti-thrombotic drugs and/or left atrial appendage occlusion for better evidence. So far, therapy of HD patients with AF should base on implementation of higher d-Mg, prefer Asp/Clop as best anti-thrombotic drugs and clearly avoid more harmful VK-OAC.

Previously lacking in the literature, we describe longitudinal patterns of anemia prescriptions for non-dialysis-dependent chronic kidney disease (NDD-CKD) patients under nephrologist care. We analyzed data from 2818 Stage 3-5 NDD-CKD patients from Brazil, Germany, and the US, naïve to anemia medications (oral iron, intravenous [IV] iron, or erythropoiesis stimulating agent [ESA]) at enrollment in the CKDopps. We report the cumulative incidence function (CIF) of medication initiation stratified by baseline characteristics. Even in patients with hemoglobin (Hb)

Background and Aims Previously lacking in the literature, this analysis aims to comprehensively describe longitudinal patterns of anaemia management, including prescriptions of ESA and iron replacement, for non-dialysis dependent chronic kidney disease (NDD-CKD) stage 3 to 5 patients under nephrologist care. Method We analysed data from a prospective cohort of 2455 NDD-CKD patients from Brazil, Germany and the US, who were not using anaemia medications (oral iron, intravenous [IV] iron, or erythropoiesis stimulating agent [ESA]) at enrolment in the Chronic Kidney Disease Outcomes and Practice Patterns Study (CKDOPPS). We excluded 26% (N=862) of patients who were using any anaemia treatment from the source population at CKDOPPS study entry; we further excluded patients with (a) missing data for demographics and/or clinical history, or (b) no laboratory and medication data during follow-up. We reported the cumulative incidence (CI) of anaemia treatment initiation, stratified by biochemical parameters and patient characteristics. For patients that started therapy, we report the frequency of medication type at the moment of initiation, as well as switches and discontinuation over 12 months. Results The CI of any anaemia treatment initiation at 12 months was 18% for the whole sample, and 54% for patients with haemoglobin (Hb) Conclusion Anaemia treatment is initiated in a limited number of NDD-CKD patients with clinical signs that would indicate to do so, and many patients discontinue treatment, for reasons yet to be clarified. Although haemoglobin was the main factor associated with prescriptions, only about half of patients with Hb

Background and Aims ESRD (end stage renal disease) patients on hemodialysis (HD) with persistent atrial fibrillation (AF) are at high risk for cardio-vascular events, severe bleeding and rapid vascular/valvular calcification. In such patients standard vitamin-K based oral anticoagulation (VK-OAC) is debated, since prospective OAC studies are missing and smaller short-term register data showed conflicting results. Our study evaluated risk-factors, use of anticoagulants and clinical long-term outcome in a large representative German HD-cohort. Method After informed consent, we analysed pseudonymized benchmarking data (2013-2018) of 16226 adult chronic HD patients treated in a German outpatient dialysis network (Verband Deutsche Nierenzentren, DN) based on quarterly electronically transmitted data. Diagnoses were coded by “International Classification of Diseases (ICD)” and drugs via “Anatomical Therapeutical Chemical (ATC)” codes. Results At baseline in 2013, 2812 (17%) HD-patients had AF as coded diagnosis. AF-prevalence increased significantly (p75 yrs: 34%) without gender differences. Baseline CHA2DS2-Vasc (4.0/1.5) and HAS-Bled (3.2/0.9) risk scores indicated high risk for embolism and bleeding. Median observation time was 2.1 yrs (Range: 0–6 yrs.). Apart from dialysis-related heparin-supply four main approaches were applied: No active therapy, standard VK-OAC+/- aspirin/clopidogrel (VK-OAC+/-Asp/Clop), heparin-based therapy (Heparin+/-Asp/Clop) or only anti-thrombocyte drugs (Asp/Clop). Baseline risk scores were not related to any adverse events. Outcome data are shown in the Table: event rates were low (8.8%) and comparable for all anticoagulant therapies, especially for cerebral adverse events (3.8%, range 3.3-4.5%). Patients on any anti-thrombotic therapy had similar outcome rates as patients without anticoagulant therapy. The latter had fewer overall bleeding events (3.8% vs. 5.0%; NS). Finally, overall actual 6-yr mortality rates were high (55.8%; median survival 4.4 yrs) and significantly (p Conclusion De-novo cerebral event-rates were rather low (

The randomized, controlled STOP-IgAN trial in patients with IgA nephropathy (IgAN) and substantial proteinuria showed no benefit of immunosuppression added on top of supportive care on renal function over three years. As a follow-up we evaluated renal outcomes in patients over a follow-up of up to ten years in terms of serum creatinine, proteinuria, end-stage kidney disease (ESKD), and death. The adapted primary endpoint was the time to first occurrence of a composite of death, ESKD, or a decline of over 40% in the estimated glomerular filtration rate (eGFR) compared to baseline at randomization into STOP-IgAN. Data were analyzed by Cox-regression models. Follow-up data were available for 149 participants, representing 92% of the patients originally randomized. Median follow-up was 7.4 years (inter quartile range 5.7 to 8.3 years). The primary endpoint was reached in 36 of 72 patients randomized to supportive care and 35 of 77 patients randomized to additional immunosuppression (hazard ratio 1.20; 95% confidence interval 0.75 to 1.92). ESKD occurred in 17 of the patients with supportive care and in 20 of the patients with additional immunosuppression. Additionally, the rates of eGFR loss over 40% and annual eGFR loss did not differ between groups. Two patients died with supportive care and three with additional immunosuppression. Thus, within the limitations of a retrospective study, over a follow-up of up to ten years, and using an adapted primary endpoint, we failed to detect differences in key clinical outcomes in IgAN patients randomized to receive added immunosuppression on top of supportive care versus supportive care alone.

Introduction We present a new approach to evaluate the importance of ambulatory nephrology care in patients with chronic kidney disease (CKD). Methods An anonymized health claims database of German insurance companies was searched in a retrospective analysis for patients with CKD using the codes of the International Classification of Diseases, 10th German modification. A total of 105,219 patients with CKD were identified. Patients were assigned to the group “timely referral,” when nephrology care was present in the starting year 2009, or initiated during the following 3 years in CKD1–4. Using frequency matching for age and gender, 21,024 of the late referral group were matched with the equal number of patients in the timely referral group. Hospital admission rates, total treatment costs, and kidney function (change in CKD stages, start of dialysis, mortality) were documented each year during the 4-year follow-up. Results Hospital admission rates (110%–186%) and total treatment costs (119%–160%) were significantly higher (P < 0.03) in late referral compared with timely referral. In the timely referral group, significantly more patients did not change their CKD stage (65%–72.9% vs. 52%–64.6%, P < 0.05) compared with late referral. Starting in CKD3 more patients tended to start dialysis in 1 year in timely referral (1.9 ± 0.6 vs. 1.0 ± 0.4, P = 0.1). In contrast, death rates were significantly higher in the late referral group (18.8 ± 1.8% vs. 6.7 ± 0.4%, P = 0.0001). Discussion Timely referral to outpatient nephrology care is associated with slowed disease progression, less hospital admissions, reduced total treatment costs, and improved survival in patients with CKD.

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.

Background International variation in anemia assessment and management practices in chronic kidney disease (CKD) is poorly understood. Methods We performed a cross-sectional analysis of anemia laboratory monitoring, prevalence and management in the prospective Chronic Kidney Disease Outcomes and Practice Patterns Study (CKDopps). A total of 6766 participants with CKD Stages 3a–5ND from nephrology clinics in Brazil, France, Germany and the USA were included. Results Among patients with anemia (hemoglobin Conclusions Hemoglobin and iron stores are measured less frequently than per guidelines. Among all regions, there was a substantial proportion of anemic patients with iron deficiency who were not treated with iron, highlighting an area for practice improvement in CKD care.

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.

Aims: To assess the treatment efficacy and tolerability of lanthanum car - bonate (LC) in patients with end-stage re- nal disease (ESRD) and hyperphosphatemia under daily-practice conditions. Patients and methods: 698 patients on dialysis in 116 outpatient dialysis centers in Germany were enrolled in this post-marketing surveillance study (mean treatment duration 6 months). LC treatment was compared to pretreatment (no or other phosphate binders) regarding laboratory parameters, adverse events and tablet burden. Results: Compared to base- line, LC significantly reduced mean serum phosphate (SP), serum calcium, and cal- cium × phosphate product (p < 0.0001). In monotherapy with LC, mean tablet burden was decreased to 3.0 tablets per day thus reducing the mean pre-study phosphate- binder tablet burden by nearly 50%. Ad- verse drug reactions associated with LC were reported in only 2.0% of the patients (n = 14). Overall, LC was considered safe and well tolerated. Conclusions: Under daily-practice conditions, LC at an average dose of 2,509 ± 936 mg/d was well tolerated and effective in adjusting and maintaining control of SP in patients previously being unsatisfactorily controlled on other phos- phate binders. The daily tablet burden with a phosphate binder can be reduced to 3 tab- lets of LC, particularly in patients on mono- therapy. The lack of a comparison group should be considered in terms of careful interpretation of the study results.

A 44-year-old man developed acute renal failure, associated with reddish brown urine, after severe physical exertion. Since childhood his physical capacity was known to be limited. Muscular indurations, cramps and pains had occurred after muscular work. Serum creatinine level on the day before hospitalization was 10.0 mg/dl, creatine-kinase activity 3,790 U/l, lactate dehydrogenase activity 670 U/l, myoglobin level 701 ng/ml. Cause of the rhabdomyolysis was thought to be McArdle's disease (glycogen storage disease type V: abnormal skeletal muscle glycogen utilization). 31P-magnetic resonance spectroscopy, which gives characteristic spectra with anaerobic muscle work, provided the diagnosis, which was confirmed by measurement of myophosphorylase activity in a muscle biopsy (zero activity). After two dialysis sessions and alkalinization of the urine diuresis again occurred and the retention indicators fell to normal in the course of the subsequent 18 months. Creatinine kinase activity remained elevated.

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.

Background Minimizing clinical complications in patients with advanced chronic kidney disease (CKD) and improving the transition to dialysis therapy and transplantation represents a challenge, requiring reliable evidence regarding the effects of CKD care on outcomes. Study design The CKD Outcomes and Practice Patterns Study (CKDopps) is a new international prospective cohort study designed to describe and evaluate variation in nephrologist-led CKD practices. Setting & participants CKDopps is underway in Brazil, France, Germany, Japan, and the United States. Diverse national samples of nephrology clinics are being recruited based on random selection stratified by geographic region and clinic characteristics. CKDopps aims to enroll 12,200 non-dialysis-dependent patients with CKD (75% and 25% with estimated glomerular filtration rates Predictors Demographic, comorbid condition, laboratory, and treatment-related variables are collected at 6-month intervals; patient-reported data are collected annually and more frequently near the transition to end-stage kidney disease; nephrologist practice surveys are collected annually. Outcomes Outcomes include mortality, end-stage kidney disease, other clinical events (eg, acute kidney injury, hospitalizations, infections, cardiovascular events, and transplant wait-listing), and patient-reported outcomes. Results For the targeted sample size of 12,200 patients and 160 clinics, CKDopps has 80% power to detect HRs of 1.31 for mortality and 1.19 for mortality or transition to end-stage kidney disease. Limitations CKDopps does not capture care provided in settings outside nephrology clinics (eg, primary care) or patients with CKD not receiving medical care. Conclusions CKDopps is designed to characterize nephrology clinic practice variation and identify practices associated with better outcomes, with particular focus on advanced CKD, transition to end-stage kidney disease, and the patient experience. Because data will be collected during routine clinical care in real-world practice, analyses may yield practical readily implementable findings. CKDopps aims to establish a multinational infrastructure for research, collaboration, and ancillary investigation. Additional countries are encouraged to join.

Background: The carboxy-terminal cross-linking telopeptide of type I collagen (β-CrossLaps, β-CTX) is released into the circulation during degradation of type I collagen and serves as a marker of bone resorption. β-CTX is known to undergo a diurnal rhythm in normal individuals and to accumulate in chronic renal failure. β-CTX has a potential role in noninvasive diagnosis of renal bone disease. Methods: Serum β-CTX was compared to parathyroid hormone (PTH) and other biochemical bone markers in 90 unselected hemodialysis patients. Results: Mean β-CTX was elevated above the normal range (1.72 ± 0.93 µg/l); there were large individual variations. Serum β-CTX was significantly correlated with various PTH assays (r >0.56) and with tartrate-resistant acid phosphatase 5b (TRACP 5b, r = 0.629), bone-specific alkaline phosphatase (r = 0.404) and osteocalcin (r = 0.534, all correlations p < 0.001). The correlation between β-CTX and PTH was significantly higher than the correlation between TRACP 5b and PTH. Several factors which could confound interpretation of serum β-CTX were assessed in further studies: (i) There was no recognizable influence of the time of blood sampling (morning dialysis shift versus afternoon dialysis shift) on serum β-CTX. (ii) Serum β-CTX was not significantly related to residual diuresis of patients. Conclusions: We found a high association between β-CTX and other established markers of bone and calcium metabolism demonstrating the potential utility of β-CTX as marker of bone resorption in renal bone disease. However, further studies employing bone histology are still warranted to exactly define the influence of glomerular retention on serum β-CTX in end-stage renal disease.

In this study, the effects of PTH on binding of [3H]-1,25-dihydroxyvitamin D3 11,25(OH) 2 D3] and on vitamin D receptor (VDR) mRNA concentration were assessed in intestinal mucosa of subtotally nephrectomized rats (Nx) and in intestinal mucosa of sham-operated rats with normal kidney function (Intact). Intestinal 1,25(OH) 2 D3 binding capacity of Intact remained unchanged (i) after parathyroidectomy (PTx), (ii) after administration of PTH for up to 6 days, and (iii) after PTx and subsequent administration of PTH (n=4 experiments). In contrast, PTx of subtotally nephrectomized animals (Nx-PTx) decreased 1,25(OH) 2 D3 binding capacity from 757 ± 95 fmol/mg protein in Nx to 417±42 in Nx-PTx (P

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 (Qualitatssicherung 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).

We have developed an immunochemiluminometric assay (ICMA) with two monoclonal antibodies for the N-terminal sequence of human parathyroid hormone (hPTH). One monoclonal antibody (A1-70) was physically adsorbed onto polystyrene beads, the other (B1-70) was labelled with acridinium ester and synthetic hPTH (1-38) was used as standard. This assay has cross-reactions with synthetic hPTH (1-34) and hPTH (1-84) but no cross-reactions with hPTH (4-16), (28-48), (39-84), (44-68), (53-84) and hPTH-rP (1-86). The assay detection limit is 0.4 pmol/l. The normal range is 1.3-12 pmol/l based on 72 normal volunteers. About 91% of study patients (n = 58) with surgically proven primary hyperparathyroidism (1 degree HPT) had PTH values above normal and one of them showed a low normal intact PTH value but elevated PTH values with use of this assay. After immunoabsorption of plasma samples from patients with secondary hyperparathyroidism (2 degrees HPT) on hemodialysis with polystyrene beads containing antibodies against hPTH (39-84), some patients still showed significant amounts of PTH in this new ICMA but not intact PTH. The data reveal that significant amounts of amino-terminal immunoreactive PTH fragments rarely exist in 1 degree HPT but are present in some patients with 2 degrees HPT. The major advantage of this assay is to measure both amino-terminal PTH fragments and intact PTH with no interference from carboxy-terminal PTH fragments because two anti-N-terminal hormone sequence monoclonal antibodies are used.

The low concentration of the biologically active metabolite of vitamin D, namely 1 alpha,25-dihydroxyvitamin D3 (1,25(OH)2D3), is critical to the pathogenesis of secondary hyperparathyroidism in chronic renal failure. The actions of 1,25(OH)2D3 are mediated through binding to a cellular receptor protein, the vitamin D receptor (VDR). In order to further investigate expression and regulation of VDR in uremia, we measured specific [3H]-1,25(OH)2D3 binding capacity and VDR mRNA concentration in intestinal mucosa and in parathyroid glands of subtotally nephrectomized rats (Nx) and compared Nx to sham-operated rats with normal kidney function (Intact). Intestinal [3H]-1,25(OH)2D3 binding capacity in short-term Nx (6-10 days after nephrectomy) was 663 +/- 114 fmol/mg protein; it was 517 +/- 34 in Intact (p = 0.06, n = 6 experiments). Intestinal VDR mRNA concentration was comparable between Nx and Intact. Specific 1,25(OH)2D3 binding capacity in parathyroid glands was higher in Nx (195 +/- 9 fmol/mg protein) than in Intact (116 +/- 14 fmol/mg protein, n = 5, p0.05). The affinity of the VDR for 1,25(OH)2D3 (KD) did not change in Nx. The 1,25(OH)2D3 binding capacity in intestinal mucosa of more long-term uremic animals (14-16 weeks after subtotal Nx) was 519 +/- 32 fmol/mg protein versus 349 +/- 31 in Intact (n = 3, p0.01). Parathyroid VDR was 171 +/- 9 fmol/mg protein in long-term Nx and 125 +/- 3 in Intact (p0.01). These results were confirmed when 1,25(OH)2D3 binding capacity in uremic rats with hereditary polycystic kidney disease was compared to control rats with normal kidney function (757 +/- 54 fmol/mg protein versus 495 +/- 59 in intestinal mucosa, p0.05; 273 +/- 48 versus 104 +/- 27 in parathyroid glands, p0.05). In parallel to changes in intestinal 1,25(OH)2D3 binding capacity, 1,25(OH)2D3-mediated stimulation of intestinal 25(OH)D3-24-hydroxylase activity was significantly higher in long-term subtotally Nx (1.43 +/- 0.06 pmol 24,25-dihydroxyvitamin D3/mg protein) than in sham-operated normal rats (1.04 +/- 0.10, p0.05). Administration of 1,25(OH)2D3 to sham-operated normal rats resulted in an increase of 1,25(OH)2D3 binding capacity by 20-40% in intestinal mucosa and by 40-50% in parathyroid glands. In contrast, 1,25(OH)2D3 caused down-regulation of mean 1,25(OH)2D3 binding capacity in short-term Nx by 38% in intestinal mucosa (p0.01) and by 43% in parathyroid glands (p0.01). In long-term Nx, mean 1,25(OH)2D3 binding capacity was reduced by 20% in intestinal mucosa (p0.05) and by 22% in parathyroid glands (p0.01). After prolonged exposure to 1,25(OH)2D3 for 6 weeks, intestinal 1,25(OH)2D3 binding capacity was markedly down-regulated in uremic rats (43% versus vehicle-treated animals p0.05). Taken together, our results provide evidence for abnormal expression and regulation of VDR in experimental uremia. This may be relevant for responsiveness to 1,25(OH)2D3 in renal insufficiency.

Markers of bone formation determined in serum include alkaline phosphatase, bone-specific alkaline phosphatase, osteocalcin [bone gamma-carboxyglutamic acid peptide (BGP) and procollagen type I carboxyterminal propeptide. Recently, advances have been made in the immunoassay of bone-specific alkaline phosphatase. This is a marker for osteoblastic activity; it is very stable and is not primarily dependent on kidney function because it is degraded in the liver. BGP is not specific for bone formation because it increases in serum during bed rest (which involves increased bone resorption), and it is not stable. Furthermore, the elimination of BGP is dependent on glomerular filtration rate. Procollagen type I carboxyterminal propeptide is not as sensitive as bone-specific alkaline phosphatase because it increases less in women after the menopause. Urinary pyridinoline and deoxypyridinoline determined by high-performance liquid chromatography are regarded as the best methods for measuring bone resorption. These might be replaced by type I collagen crosslinked N-telopeptide or CrossLaps in the future in laboratories not equipped with a high-performance liquid chromatography system. Serum markers of bone resorption are currently under investigation. An immunoassay for the tartrate-resistant acid phosphatase in serum should be a very promising tool for the quantification of bone resorption.

Intermittent versus continuous administration of 1,25-dihydroxyvitamin D3 in experimental renal hyperparathyroidism. Conflicting results have been reported regarding the efficacy of intermittent versus continuous administration of 1,25(OH)2D3 in renal secondary hyperparathyroidism. To address this issue we examined sham-operated control rats and hyperparathyroid rats with subtotal (5/6) nephrectomy (Nx). The Nx animals (20 to 22 animals per group) were subjected to three treatment protocols: (i) solvent treatment (Nx-solvent); (ii) two i.p. injections of 35 pmol 1,25(OH)2D3 on days 0 and 4 (Nx-bolus); and (iii) continuous infusion of 70 pmol 1,25(OH)2D3 over six days via osmotic minipump (Nx-infusion). All measurements were performed six days after start of treatment. As compared to sham-operated controls, the pre-pro-PTH/β-actin mRNA ratio was 2.04-fold higher in Nx-solvent. Both modes of administration of 1,25(OH)2D3 resulted in inhibition of PTH mRNA concentrations relative to Nx-solvent. The pre-pro-PTH/β-actin mRNA ratio was, however, significantly lower (P < 0.05) in Nx-bolus than in Nx-infusion (Nx-bolus 1.26 higher than sham-operated controls; Nx-infusion 1.65 higher than sham-operated controls). Aminoterminal PTH (N-PTH) serum concentrations were higher in Nx-solvent (52 ± 4 pg/ml) than in sham-operated controls (32 ± 3 pg/ml, P < 0.01). N-PTH concentrations in Nx-bolus (38 ± 4 pg/ml) were significantly lower than in Nx-solvent (P < 0.01) and in Nx-infusion (46 ± 4 pg/ml, P < 0.05). Parathyroid gland weight (μg/g body wt) was higher in Nx-solvent (1.30 ± 0.08 pg/ml) than in sham-operated controls (0.79 ± 0.04 pg/ml, P < 0.02). Again, parathyroid weight was lower in Nx-bolus (0.99 ± 0.014 pg/ml, P < 0.05 vs. Nx-solvent) than in Nx-infusion (1.16 ± 0.06 pg/ml). Differential effects of bolus versus infusion treatment were not explained by changes in serum calcium or phosphate. Analysis of the 1,25(OH)2D3 concentration time-profile showed higher peak concentrations in bolus-treated animals (170 to 200 pg/ml after 8 hr) than in infusion-treated animals (125 to 130 pg/ml after 48 hr). The time-averaged mean increase in 1,25(OH)2D3 serum concentrations was, however, higher in infusion-treated animals (42.3 pg/ml/24 hr) than in bolus-treated animals (26.0 pg/ml/24 hr). We conclude that the stimulation of parathyroid gland function in experimental uremia is more effectively suppressed when the same total dose of 1,25(OH)2D3 is given by intermittent bolus administration than by continuous infusion. Our results are compatible with the notion that the 1,25(OH)2D3 concentration time-profile, that is, the 1,25(OH)2D3 peak concentration, is an important determinant of the response of parathyroid glands to 1,25(OH)2D3.

It has been well established that human mononuclear phagocytes have the capacity to produce 1,25-dihydroxy-vitamin D3 [1,25(OH)3D3] and express the vitamin D receptor (VDR). However, 1 alpha-hydroxylase activity and VDR receptor expression during differentiation of monocytes (MO) into mature macrophages (MAC) have not been previously examined. The in vitro maturation of blood MO can serve as a model for the in vivo transformation of immature blood MO into MAC. Here, when cultured in the presence of serum, MO undergo characteristic changes in morphology, antigenic phenotype, and functional activity consistent with their differentiation into MAC. We serially measured 1,25(OH)2D3 and 24,25- dihydroxyvitamin D3 [24,25(OH)2D3] synthesis, specific [3H]-1,25(OH)2D3 binding, and VDR mRNA levels during in vitro maturation of MO into MAC and correlated these functions with maturation-associated changes in the phenotype (MAX.1 and CD71) and secretory repertoire (interleukin-1 beta [IL-1 beta], neopterin) of the cells. MO showed only little conversion of 25-(OH)D3 into 1,25(OH)2D3 (1.4 +/- 0.4 pmol/10(6) cells/6 h, n = 5) that increased gradually during maturation into MAC at day 8 of culture (5.3 +/- 4.3 pmol/10(6) cells/6 h, n = 5). Interferon-gamma (IFN-gamma) increased baseline 1,25(OH)2D3-synthesis approximately twofold during all phases of differentiation. The time course of increased 1,25(OH)2D3-synthesis correlated with enhanced secretion of neopterin and expression of MAX.1 and CD71. The addition of exogenous 1,25(OH)2D3 did not influence constitutive 1,25(OH)2D3 synthesis, but IFN-gamma-stimulated production was suppressed to baseline levels. Exogenous 1,25(OH)2D3 also stimulated 24,25(OH)2D3 synthesis in freshly isolated MO (from 1.0 +/- 0.8 pmol/6 h to 5.6 +/- 0.9 pmol), whereas matured MAC showed no 24,25(OH)2D3 synthesis. Furthermore, we examined the expression of the VDR during the differentiation process. VDR mRNA and protein were constitutively expressed in MO, whereas VDR was downregulated in mature MAC on both the mRNA and protein levels. Homologous upregulation of VDR protein by 1,25(OH)2D3 occurred in MO and, to a lesser degree, in MAC. In contrast, VDR mRNA concentrations were not influenced by 1,25(OH)2D3. Taken together, our results show that MO into MAC differentiation in vitro is associated with (1) an enhanced capacity to synthesize 1,25(OH)2D3, (2) a loss of 24,25(OH)2D3-synthesizing activity, and (3) a decrease in the expression of VDR mRNA and protein. Because 1,25(OH)2D3 was shown to induce differentiation of MO into MAC, our data sugest an autoregulatory mechanism of MO/MAC generation by 1,25(OH)2D3.