Angel L.M. de Francisco

Serum iPTH, calcium and phosphate, and the risk of mortality in a European haemodialysis population

Background. A number of US observational studies reported an increased mortality risk with higher intact parathyroid hormone (iPTH), calcium and/or phosphate. The existence of such a link in a European haemodialysis population was explored as part of the Analysing Data, Recognising Excellence and Optimising Outcomes (ARO) Chronic Kidney Disease (CKD) Research Initiative. Methods. The association between the markers of mineral and bone disease and clinical outcomes was examined in 7970 patients treated in European Fresenius Medical Care facilities over a median of 21 months. Baseline and time-dependent (TD) Cox regression were performed using Kidney Disease Outcomes Quality Initiative (KDOQI) target ranges as reference categories, adjusting for demographics, medical history, dialysis parameters, inflammation, medications and laboratory parameters. Fractional polynomial (FP) models were also used. Results. Hazard ratio (HR) estimates from baseline analysis for iPTH were U-shaped [>600 pg/mL, HR = 2.10, 95% confidence interval (CI) 1.62–2.73; <75 pg/mL, HR = 1.46, 95% CI 1.17–1.83]. TD analysis confirmed the results for iPTH. Baseline analysis showed that calcium >2.75 mmol/L increased risk of death (HR = 1.70, 95% CI 1.19–2.42). TD analysis showed that both low (HR = 1.19, 95% CI 1.04–1.37) and high calcium (HR = 1.74, 95% CI 1.30–2.34) increased risk of death. Baseline analysis for phosphate showed a U-shaped pattern (<1.13 mmol/L, HR = 1.18, 95% CI 1.01–1.37; >1.78 mmol/L, HR = 1.32, 95% CI 1.13–1.55). TD analysis confirmed the results for phosphate <1.13 mmol/L. HR estimates were higher in patients with diabetes versus those without diabetes for baseline analysis only (P-value = 0.014). FP analysis confirmed the results of baseline and TD analyses. Conclusion. Patients with iPTH, calcium and phosphate levels within the KDOQI target ranges have the lowest risk of mortality compared with those outside the target ranges.

Evaluation of calcium acetate/magnesium carbonate as a phosphate binder compared with sevelamer hydrochloride in haemodialysis patients: a controlled randomized study (CALMAG study) assessing efficacy and tolerability

Background. Phosphate binders are required to control serum phosphorus in dialysis patients. A phosphate binder combining calcium and magnesium offers an interesting therapeutic option. Methods. This controlled randomized, investigator-masked, multicentre trial investigated the effect of calcium acetate/magnesium carbonate (CaMg) on serum phosphorus levels compared with sevelamer hydrochloride (HCl). The study aim was to show non-inferiority of CaMg in lowering serum phosphorus levels into Kidney Disease Outcome Quality Initiative (K/DOQI) target level range after 24 weeks. Three hundred and twenty-six patients from five European countries were included. After a phosphate binder washout period, 255 patients were randomized in a 1:1 fashion. Two hundred and four patients completed the study per protocol (CaMg, N = 105; dropouts N = 18; sevelamer-HCl, N = 99; dropouts N = 34). Patient baseline characteristics were similar in both groups. Results. Serum phosphorus levels had decreased significantly with both drugs at week 25, and the study hypothesis of CaMg not being inferior to sevelamer-HCl was confirmed. The area under the curve for serum phosphorus (P = 0.0042) and the number of visits above K/DOQI (≤1.78 mmol/L, P = 0.0198) and Kidney disease: Improving global outcomes (KDIGO) targets (≤1.45 mmol/L, P = 0.0067) were significantly lower with CaMg. Ionized serum calcium did not differ between groups; total serum calcium increased in the CaMg group (treatment difference 0.0477 mmol/L; P = 0.0032) but was not associated with a higher risk of hypercalcaemia. An asymptomatic increase in serum magnesium occurred in CaMg-treated patients (treatment difference 0.2597 mmol/L, P < 0.0001). There was no difference in the number of patients with adverse events. Conclusion. CaMg was non-inferior to the comparator at controlling serum phosphorus levels at Week 25. There was no change in ionized calcium; there was minimal increase in total serum calcium and a small increase in serum magnesium. It had a good tolerability profile and thus may represent an effective treatment of hyperphosphataemia.

Creatinine Reduction Ratio on Post-Transplant Day Two as Criterion in Defining Delayed Graft Function

Delayed graft function (DGF) is a common complication after renal transplant, affecting its outcome. A common definition of DGF is the need for dialysis within the first week of transplantation, but this criterion has its drawbacks. We tried to validate an earlier and better defined parameter of DGF based on the creatinine reduction ratio on post‐transplant day 2 (CRR2). We analyzed the clinical charts of 291 cadaver kidney recipients to compare the outcome of patients with immediate graft function (IGF), dialyzed patients (D‐DGF) and nondialyzed CRR2‐defined DGF patients (ND‐DGF) and to identify risk factors for D‐DGF and ND‐DGF.

Maintenance treatment of renal anaemia in haemodialysis patients with methoxy polyethylene glycol-epoetin beta versus darbepoetin alfa administered monthly: a randomized comparative trial

Background. Several studies with erythropoiesis-stimulating agents claim that maintenance therapy of renal anaemia may be possible at extended dosing intervals; however, few studies were randomized, results varied, and comparisons between agents were absent. We report results of a multi-national, randomized, prospective trial comparing haemoglobin maintenance with methoxy polyethylene glycol-epoetin beta and darbepoetin alfa administered once monthly. Methods. Haemodialysis patients (n = 490) on stable once-weekly intravenous darbepoetin alfa were randomized to methoxy polyethylene glycol-epoetin beta once monthly or darbepoetin alfa every 2 weeks for 26 weeks, with dose adjustment for individual haemoglobin target (11–13 g/dL; maximum decrease from baseline 1 g/dL). Subsequently, patients entered a second 26-week period of once-monthly methoxy polyethylene glycol-epoetin beta and darbepoetin alfa. The primary endpoint was the proportion of patients who maintained average haemoglobin ≥10.5 g/dL, with a decrease from baseline ≤1 g/dL, in Weeks 50–53; the secondary endpoint was dose change over time. The trial is registered at www.ClinicalTrials.gov, number NCT00394953. Results. Baseline characteristics were similar between groups. One hundred and fifty-seven of 245 patients treated with methoxy polyethylene glycol-epoetin beta and 99 of 245 patients with darbepoetin alfa met the response definition (64.1% and 40.4%; P < 0.0001). Doses increased by 6.8% with methoxy polyethylene glycol-epoetin beta and 58.8% with darbepoetin alfa during once-monthly treatment. Death rates were equal between treatments (5.7%). Most common adverse events included hypertension, procedural hypotension, nasopharyngitis and muscle spasms, with no differences between groups. Conclusions. Methoxy polyethylene glycol-epoetin beta maintained target haemoglobin more successfully than darbepoetin alfa at once-monthly dosing intervals despite dose increases with darbepoetin alfa.

A comparison of calcium acetate/magnesium carbonate and sevelamer-hydrochloride effects on fibroblast growth factor-23 and bone markers: post hoc evaluation from a controlled, randomized study

Background Different phosphate binders exert differing effects on bone mineral metabolism and levels of regulating hormones. The objective of this post hoc evaluation of the CALcium acetate MAGnesium carbonate (CALMAG) study was to compare the effects of calcium acetate/magnesium carbonate (CaMg) and a calcium-free phosphate binder, sevelamer-hydrochloride (HCl), on serum levels of fibroblast growth factor-23 (FGF-23) and markers of bone turnover. Methods This secondary analysis of the controlled, randomized CALMAG study, comparing the effect of CaMg and sevelamer-HCl on serum phosphorus (P), aimed to investigate the parameters described above. The analysis included 204 patients who completed the initial study per protocol (CaMg, n = 105; sevelamer-HCl, n = 99). Results The study showed that serum levels of FGF-23 were significantly reduced with CaMg and sevelamer-HCl, with no difference between groups at Week 25 [analysis of covariance (ANCOVA); log-intact FGF-23 (iFGF-23), P = 0.1573]. FGF-23 levels strongly correlated with serum P levels at all time points in both groups. The bone turnover parameters alkaline phosphatase (AP), bone AP (BAP), procollagen type 1 amino-terminal propeptide 1 (P1NP), osteoprotegerin (OPG), beta-crosslaps (β-CTX) and tartrate-resistant acid phosphatase 5b (TRAP 5b) increased significantly in the sevelamer-HCl group; they remained almost unchanged in the CaMg group, after the initial phase of P lowering (ANCOVA, P < 0.0001 for all except OPG, P = 0.1718). Conclusions CaMg and sevelamer-HCl comparably lower serum levels of iFGF-23. Changes in bone parameters were dependent on characteristics of the phosphate binder; in contrast with sevelamer-HCl, CaMg had no influence on bone turnover markers.

Inflammation and its impact on anaemia in chronic kidney disease: from haemoglobin variability to hyporesponsiveness

The availability of erythropoiesis-stimulating agents (ESAs) has revolutionized the treatment of anaemia in patients with chronic kidney disease. However, maintaining patients at haemoglobin (Hb) levels that are both safe and provide maximal benefit is a continuing challenge in the field. Based on emerging data on the potential risks of Hb treatment targets >13 g/dL, treatment targets have recently been lowered. In the latest revision (March 2008) of the European product labelling for the ESA class of drugs, the target treatment range was lowered to 10–12 g/dL. Fluctuation of Hb levels or ‘Hb variability’ during treatment with ESAs is a well-documented phenomenon. Hb levels that are either too high or too low may have an adverse effect on patient outcomes; thus, it is important to understand the causes of Hb variability in order to achieve optimal treatment. Several factors are believed to contribute to variation in the Hb level, including patient comorbidities and intercurrent events. Inflammation is also an important factor associated with Hb variability, and the consequences of persistent inflammatory activity are far-reaching in affected patients. This review addresses the complex role of inflammation in chronic kidney disease, as evidenced by the apparent state of deranged inflammatory markers. The mechanisms by which inflammatory cytokines may affect the response to ESAs, the development of anaemia and poor treatment outcomes are also examined. In addition, various options for intervention to enhance the response to ESAs in haemodialysis patients with inflammation are considered.

High cardiovascular event rates occur within the first weeks of starting hemodialysis

Early mortality is high in hemodialysis (HD) patients, but little is known about early cardiovascular event (CVE) rates after HD initiation. To study this we analyzed data in the AROii cohort of incident HD patients from over 300 European Fresenius Medical Care dialysis centers. Weekly rates of a composite of CVEs during the first year and monthly rates of the composite and its constituents (coronary artery, cerebrovascular, peripheral arterial, congestive heart failure, and sudden cardiac death) during the first 2 years after HD initiation were assessed. Of 6308 patients that started dialysis within 7 days, 1449 patients experienced 2405 CVEs over the next 2 years. The first-year CVE rate (30.2/100 person-years; 95% CI, 28.7–31.7) greatly exceeded the second-year rate (19.4/100; 95% CI, 18.1–20.8). Composite CVEs were highest during the first week with increased risk compared with the second year, persisting until the fifth month. Except for sudden cardiac death, temporal patterns of rates for all CVE categories were very similar, with highest rates during the first month and a high-risk period extending to 4 months. Higher or lower cumulative weekly dialysis dose, lower blood flow, and lower net ultrafiltration during dialysis were associated with CVE during the high-risk period, but not during the post high-risk period. Thus, the incidence of CVE in the first weeks after HD initiation is much higher than during subsequent periods which raises concerns that HD initiation may trigger CVEs.

Hipertensión arterial y política de salud en España

José R. Banegas a,b, , Albert Jovell , Benjamı́n Abarca , Manuel Aguilar Diosdado , Luis Aguilera , Pedro Aranda , Vicente Bertoméu , Pedro Capilla , Pedro Conthe , Fernando De Álvaro , Antonio Fernández-Pro , Xavier Formiguera , Jesús Frı́as , Lucı́a Guerrero , José L. Llisterri , José M. Lobos , Juan F. Macı́as , Ángel L. Martı́n De Francisco , Jesús Millán , Juan C. Morales , Vicente Palomo , Alex Roca-Cusachs , Javier Román , Carlos Sanchis , Antonio Sarriá , Julián Segura , Álex De La Sierra , Luis Verde , Julio Zarco n y Luis M. Ruilope a,u a Asociación de la Sociedad Española de Hipertensión y Liga Española para la Lucha contra la Hipertensión Arterial b Universidad Autónoma de Madrid, CIBERESP (CIBER de Epidemiologı́a y Salud Pública), Madrid c Foro Español de Pacientes d Sociedad Española de Medicina General e Sociedad Española de Diabetes f Sociedad Española de Medicina de Familia y Comunitaria g Sociedad Española de Cardiologı́a h Consejo General de Colegios Oficiales de Farmacéuticos i Sociedad Española de Medicina Interna j Sociedad Española de Nefrologı́a en el Comité Español Interdisciplinario para la Prevención Cardiovascular k Sociedad Española para el Estudio de la Obesidad l Departamento de Farmacologı́a y Terapéutica, Universidad Autónoma de Madrid, Madrid m Asociación de Enfermerı́a de Hipertensión y Riesgo Cardiovascular (EHRICA) n Sociedad Española de Médicos de Atención Primaria o Comité Español Interdisciplinar de Prevención Cardiovascular (CEIP) p Sociedad Española de Geriatrı́a y Gerontologı́a q Sociedad Española de Nefrologı́a r Sociedad Española de Arteriosclerosis s Sociedad Española de Farmacéuticos de Atención Primaria t Ibermutuamur-Corporación Mutua-Proyectos Sanitarios u Agencia de Evaluación de Tecnologı́as Sanitarias. Instituto de Salud Carlos III, Madrid v Asociación para la Prevención del Riesgo Cardiovascular (PRECAR) x Sociedad Española de Directivos de Atención Primaria, España

Effects of weight loss after biliopancreatic diversion on metabolism and cardiovascular profile.

Background: Obesity is associated with increased prevalence of cardiovascular risk factors. Biliopancreatic diversion (BPD) for morbid obesity has been reported to produce anemia and malnutrition in short-term follow-up. The aim of our study was to analyze the effect of weight reduction on cardiovascular profile, renal function and nutritional status. Methods: 35 morbidly obese patients underwent BPD. We analyzed the presence of cardiovascular risk factors, renal status, proteinuria and nutritional status before and 1 year after BPD. Results: Excess weight loss was 67% at 1 year after BPD. All cardiovascular risk factors (hypertension, diabetes, hyperlipidemia) improved during follow-up. We could not find any relevant signs of malnutrition in the patients. Microalbuminuria decreased and proteinuria disappeared after weight loss. We observed less urinary calcium and citrate excretion, with an increase in oxaluria, but these changes did not increase the incidence of renal stones. Conclusions: BPD was followed by improved cardiovascular profile and a lower pro-inflammatory state. BPD did not produce significant malnutrition, anemia or renal stone disease.

Vitamin D Therapy Modulates Cytokine Secretion in Patients with Renal Failure

In studies in vitro calcitriol (1,25-dihydroxyvitamin D3) inhibits lymphocyte proliferation and modulates several monocyte functions, including the secretion of prostaglandins and monokines. However its effects on monokine production in vivo are not known. Therefore we studied the secretion of interleukin (IL)-1, IL-6 and tumor necrosis factor (TNF) by peripheral blood mononuclear cells (PBMC) from 7 patients on periodic hemodialysis, before and after oral treatment with calcitriol (0.5 microgram daily) for 1 month. Calcitriol therapy resulted in significant increases in the phorbol myristate acetate (PMA)-induced secretion of IL-1 and IL-6 (p = 0.04 and 0.03, respectively). This was a transient effect, observable by day 7 of therapy, but no longer evident by day 30. However, calcitriol induced a progressive reduction of TNF secretion (down to 53% of control values by day 30, p = 0.02). There were no correlations between the individual changes in calcium/PTH and cytokine release. These results show that doses of calcitriol within the therapeutic range induce marked changes in cytokine secretion by PBMC from uremic patients.