Myostatin and Insulin-Like Growth Factor 1 Are Biomarkers of Muscle Strength, Muscle Mass, and Mortality in Patients on Hemodialysis.

OBJECTIVE: Muscle strength is frequently altered in hemodialysis patients. In the present work, five potential muscle biomarkers have been studied in their ability to assess muscular strength, muscular mass and to predict mortality of hemodialysis patients: activin-A, procollagen III N-terminal peptide, follistatin, myostatin and insulin-like growth factor-1 (IGF-1). DESIGN AND METHODS: Three independent cohorts of prevalent hemodialysis patients (2 from Liège, Belgium and 1 from Marseille, France) were considered in this observational prospective study. The biomarkers were first measured in the Liege1 cohort. Two of them, myostatin and IGF-1, were then assessed in the whole population of patients (Liege1, Liege2 and Marseille). Muscle strength was assessed with handgrip strength (HGS) and muscle mass with bioimpedance analysis. One-year mortality predictive value of biomarkers was also studied in the Liège1 and Marseille cohorts. RESULTS: In the Liège1 cohort (n=67), HGS was only associated with concentrations of myostatin and IGF-1. These associations were confirmed in the whole population of 204 patients (r=0.37, P<0.001 and r=0.46, P<0.001, respectively) and remained significant (P<0.05) in multivariable models. The association between muscle mass and concentrations of myostatin and IGF-1were also significant. The ability of myostatin, IGF-1 and serum creatinine to detect a low HGS compared by Receiver Operating Characteristic curves analysis were not significantly different. Both myostatin and IGF-1 had a significant and comparable area under the curve to predict one-year mortality: 0.73 (95% CI: 0.64 to 0.83) and 0.72 (95% CI: 0.61 to 0.82), respectively. CONCLUSION: Our results suggest that myostatin and IGF-1 are two biomarkers of interest to assess muscle status of dialysis patients. Both biomarkers are associated with HGS, muscular mass, and one-year mortality.

Clinical and biological determinants of sclerostin plasma concentration in hemodialysis patients.

BACKGROUND: Sclerostin is a potent inhibitor of bone formation, but the meaning of its serum levels remains undetermined. We evaluated the association between sclerostin levels and clinical or biological data in hemodialyzed patients (HD), notably parathormone (PTH), biomarkers of bone turnover, vascular calcifications and mortality after 2 years. METHODS: 164 HD patients were included in this observational study. The calcification score was assessed with the Kauppila method. Patients were followed for 2 years. RESULTS: Median sclerostin levels were significantly (p < 0.0001) higher in HD versus healthy subjects (n = 94) (1,375 vs. 565 pg/ml, respectively). In univariate analysis a significant association (p < 0.05) was found between sclerostin and age, height, dialysis vintage, albumin, troponin, homocysteine, PTH, C-terminal telopeptide of collagen type I, bone-specific alkaline phosphatase and osteoprotegerin, but not with the calcification score. In a multivariate model, the association remained with age, height, dialysis vintage, troponin, homocysteine, phosphate, PTH, but also with vascular calcifications. Association was positive for all variables, except PTH and vascular calcifications. The baseline sclerostin concentration was not different in survivors and non-survivors. CONCLUSIONS: We confirm a higher concentration of sclerostin in HD patients, a positive association with age and a negative association with PTH. A positive association with phosphate, homocysteine and troponin calls for additional research. The clinical interest of sclerostin to assess vascular calcifications in HD is limited and no association was found between sclerostin and mortality.

Dephosphorylated-uncarboxylated Matrix Gla protein concentration is predictive of vitamin K status and is correlated with vascular calcification in a cohort of hemodialysis patients.

BACKGROUND: Matrix Gla protein (MGP) is known to act as a potent local inhibitor of vascular calcifications. However, in order to be active, MGP must be phosphorylated and carboxylated, with this last process being dependent on vitamin K. The present study focused on the inactive form of MGP (dephosphorylated and uncarboxylated: dp-ucMGP) in a population of hemodialyzed (HD) patients. Results found in subjects being treated or not with vitamin K antagonist (VKA) were compared and the relationship between dp-ucMGP levels and the vascular calcification score were assessed. METHODS: One hundred sixty prevalent HD patients were enrolled into this observational cohort study, including 23 who were receiving VKA treatment. The calcification score was determined (using the Kauppila method) and dp-ucMGP levels were measured using the automated iSYS method. RESULTS: dp-ucMGP levels were much higher in patients being treated with VKA and little overlap was found with those not being treated (5604 [3758; 7836] vs. 1939 [1419; 2841] pmol/L, p < 0.0001). In multivariate analysis, treatment with VKA was the most important variable explaining variation in dp-ucMGP levels even when adjusting for all other significant variables. In the 137 untreated patients, dp-ucMGP levels were significantly (p < 0.05) associated both in the uni- and multivariate analysis with age, body mass index, plasma levels of albumin, C-reactive protein, and FGF-23, and the vascular calcification score. CONCLUSION: We confirmed that the concentration of dp-ucMGP was higher in HD patients being treated with VKA. We observed a significant correlation between dp-ucMGP concentration and the calcification score. Our data support the theoretical role of MGP in the development of vascular calcifications. We confirmed the potential role of the inactive form of MGP in assessing the vitamin K status of the HD patients. TRIAL REGISTRATION: B707201215885.

Cholecalciferol in haemodialysis patients: a randomized, double-blind, proof-of-concept and safety study.

BACKGROUND: The role of cholecalciferol supplementation in end-stage renal disease (ESRD) patients has been questioned. The objective of this randomized double-blinded study is to assess whether cholecalciferol therapy can increase serum 25-hydroxyvitamin D [25(OH)D] levels in haemodialysed patients and the safety implications of this therapy on certain biological parameters and vascular calcifications score. METHODS: Forty-three haemodialysis patients were randomized to receive placebo or cholecalciferol (25,000 IU) therapy every 2 weeks. The biological parameters, serum calcium, phosphorus, 25(OH)D and parathormone (PTH) levels, were monitored monthly for 12 consecutive months. Vascular calcifications were assessed by lateral X-ray radiography. RESULTS: At baseline, the mean serum 25(OH)D levels were low and similar in both groups. Thirty patients (16 treated and 14 placebo) completed the study: 11 patients died (5 placebo and 6 treated), 1 patient dropped out and 1 patient was transplanted (both from the placebo group). After 1 year, the percentage of 25(OH)D deficient patients was significantly lower in the treated group. None of the patients developed hypercalcaemia. The PTH levels tended to increase over the study period under placebo and to decrease in the cholecalciferol group. The median changes in PTH levels from baseline to 1 year were statistically different between the two groups [+80 (-58 to 153) and -115 (-192 to 81) under placebo and cholecalciferol treatment, respectively, P=0.02].The calcification scores increased equivalently in both groups (+2.3 per year). CONCLUSIONS: Cholecalciferol is effective and safe, and does not negatively affect calcium, phosphorus, PTH levels and vascular calcifications. Additional studies are needed to compare the impacts of nutritional and active vitamin D agents on vascular calcification and mortality.

Monitoring 25-OH and 1,25-OH vitamin D levels in hemodialysis patients after starting therapy: Does it make sense?

BACKGROUND AND AIMS: In hemodialysis patients, monitoring 25-hydroxyvitamin D (25(OH)D) levels is recommended. It is however unclear if monitoring 1,25-dihydroxyvitamin D (1,25(OH)2D) levels is interesting. MATERIALS AND METHODS: We repeatedly measured 1,25(OH)2D (DiaSorin Liaison analyser) and 25(OH)D (LCMS/MS) concentrations in patients newly treated by active or native vitamin D to study the impact of such treatments on serum concentrations. RESULTS: Ten patients were included in the native and 12 in the active vitamin D group. In the native group, a significant increase was observed between the baseline and the last 25(OH)D concentrations available (21.65[17.39;25.26] versus 33.49[28.60;40.30] ng/mL, p = 0.0059). The baseline and last available 1,25(OH)2D concentrations were not different (12.15[4.25;15.40] versus 11.35[9.72;21.85] pg/mL, p = 0.5566). In the active group, no difference was observed between the baseline and the last 25(OH)D concentrations (51.70[42.97;63.95] versus 50.89[42.02;64.49] ng/mL, p = 0.5186). The same observation was made for 1,25 (OH)2D concentrations (25.65[17.05;41.85] versus 28.70[23.36;43.73] pg/mL, p = 0.6221). Using a linear mixed model, a significant change over time was only observed in 25(OH)D serum levels for patients treated by with native vitamin D. CONCLUSION: Measuring 1,25(OH)2D levels in patients newly treated by active vitamin D does not seem useful in monitoring active vitamin D therapy.

The percentage of non-oxidized PTH concentration remains stable over a period of 1 year in hemodialyzed patients.

INTRODUCTION: Non-oxidized (n-ox) PTH could better reflect PTH activity. We have evaluated the evolution of n-ox PTH and intact PTH (iPTH) in hemodialyzed (HD) patients over a period of 1 year. MATERIAL AND METHODS: We measured iPTH and n-ox PTH in 66 stable HD patients and we measured iPTH and n-ox PTH at baseline and after 1, 3, 6 and 12 months. We considered that no significant changes in iPTH and n-ox PTH occurred if two consecutives measurements of iPTH and n-ox PTH for the same patient remained in the baseline value ±43%. We also considered that changes over time were concordant if both values of the same patients increased or decreased together (in the same direction) by more than 43%. RESULTS: The median [p25; p75] was 229.4 [1.5,4; 352.5] pg/mL for iPTH and 24.4 [15,1; 38.7] pg/mL for n-ox PTH. N-ox PTH fraction represented 11.3 [9.0; 13.7]% of the total iPTH and the ratio n-oxPTH/iPTH ranged from 5.1 to 35.7%. After 1 year, 84% of the patients presented a perfect concordance of the evolution of the 2 moieties and no severe discordance was noticed. CONCLUSIONS: The percentage of n-ox PTH is stable over time in stable HD patients.

Variations of parathyroid hormone and bone biomarkers are concordant only after a long term follow-up in hemodialyzed patients.

End-stage renal disease is associated with mineral and bone disorders. Guidelines recommending therapies should be based on serial assessments of biomarkers, and thus on variations (Δ), rather than scattered values. We analyzed the correlations between ΔPTH and Δbone biomarkers such as bone-specific alkaline phosphatase (b-ALP), Beta-CrossLaps (CTX), osteocalcin, intact serum procollagen type-1 N-propeptide (P1NP), and tartrate-resistant acid phosphatase 5B (TRAP-5B) at different time-points. In this prospective observational analysis, variations of biomarkers were followed after 6-week (n = 129), 6-month (n = 108) and one-year (n = 93) period. Associations between variations were studied by univariate linear regression. Patients followed for one-year period were classified (increaser or decliner) according to variations reaching the critical difference. Over the 6-week period, only ΔCTX was correlated with ΔPTH (r = 0.38, p < 0.0001). Over the one-year period, correlations between ΔPTH and Δbone biomarkers became significant (r from 0.23 to 0.47, p < 0.01), except with ΔTRAP-5b. Correlations between Δbone biomarkers were all significant after one-year period (r from 0.31 to 0.68, p < 0.01), except between Δb-ALP and ΔTRAP-5b. In the head-to-head classifications (decliners/increasers), the percentage of concordant patients was significantly higher over the one-year than the 6-week period. A concordance between ΔPTH and Δbone biomarkers is observed in dialysis patients, but only after a long follow-up.

Survey on treatment of hypertension and implementation of World Health Organization/International Society of Hypertension risk stratification in primary care in Belgium.

OBJECTIVE: To gain insight into the prevalence, treatment and control of hypertension and into the implementation of the 1999 World Health Organization/International Society of Hypertension guidelines for the management of hypertension in general practice in Belgium. DESIGN: A prospective cross-sectional survey. SETTING: Primary care. METHODS: Participating physicians enrolled the first 15 men, at least 55 years old, who visited the surgery, measured their blood pressure with a validated automatic device and recorded data on age, medical history, drug utilization, cardiovascular risk factors and target organ damage. Patients were considered to have hypertension when systolic blood pressure was >or= 140 mmHg, diastolic blood pressure was >or= 90 mmHg or when they were under antihypertensive therapy. RESULTS: Among 3761 evaluable patients, 74% were considered to be hypertensive, 80% of whom were treated with antihypertensive drugs. Blood pressure was under control in 38% of the treated patients and in 31% of all hypertensives. Among the 1316 hypertensive patients in whom risk stratification was possible, 47, 56 and 86% of the patients in, respectively, the medium, high and very high risk groups were treated with antihypertensive drugs. Among the treated patients, 46, 37 and 31%, respectively, had reached goal pressure. Within each risk category, patients were treated more frequently when baseline blood pressure was higher. Logistic regression analysis revealed that hypertension grade and level of risk contributed independently to the odds of being treated. CONCLUSIONS: The results indicate that a large number of older hypertensive men are treated with antihypertensive drugs in primary care, but that the goal blood pressure is not reached in a substantial number of patients due to undertreatment. Furthermore, whereas patients at higher risk are treated more frequently than patients at lower risk, blood pressure itself remains an important factor for the initiation of antihypertensive drug therapy within each risk category.

[Acute kidney injury: from concept to practice]. / L'insuffisance rénale aiguë : du concept à la pratique.

Definition and classification of acute renal failure evolved in recent years. The acronym "Acute Kidney Injury" replaces "Acute Renal Failure". The RIFLE classification spreads the AKI in three degrees of severity, and two degrees of disease duration. The group Acute Kidney Injury Network refines this classification into three stages, to improve the sensitivity in detecting moderate forms. The epidemiology of AKI remains imprecise. In the ICU, more than 30% of patients suffered from AKI, often in a context of multiple organs failure. In addition to serum creatinine and urine output, new biomarkers can be assessed. Their early detection should enable a clearer distinction between "acute tubular necrosis" and other causes of AKI, but also to distinguish patients at risk for pejorative evolution of renal function. The management of AKI based on an optimal resuscitation. The administration of loop diuretics or low dose dopamine showed no benefit. Hydration in prevention of the contrast-induced nephropathy is confirmed. The role of acetylcysteine must be determined. The ideal time to initiate a renal replacement therapy and the choice of the technique remain unresolved. The same goes for the dose of dialysis administered. A systematic application of an algorithm, such as proposed by Bagshow would make comparisons easier and the realisation of multicenter studies will help to clarify these points.

Mature erythrocyte parameters as new markers of functional iron deficiency in haemodialysis: sensitivity and specificity.

BACKGROUND: The percentage of hypochromic red blood cells (RBCs) (%HYPO) has been demonstrated as the best predictor of response to iron loading in haemodialysis patients treated with recombinant human erythropoietin (rHuEPO). However, we have previously shown that this parameter is positively influenced by erythropoietic activity since reticulocytes are considered hypochromic by cell counters. New cell counters are able to determine cell volume and haemoglobin (Hb) concentration separately on reticulocytes and mature erythrocytes. The aim of this study was to assess the sensitivity and specificity of mature erythrocyte parameters in detecting functional iron deficiency (FID). METHODS: A total of 32 stable chronic haemodialysis patients in the maintenance phase of rHuEPO therapy were included. Classical parameters of iron monitoring and mature erythrocyte parameters were measured after a 4-week iron-free period. Patients were classified as responders (R) or non-responders (NR) to an iron load of 100 mg iron sucrose at each dialysis session for 4 weeks, according to whether their Hb increased by >1 g/dl at the end of iron loading. RESULTS: Twelve patients were identified as responders. Receiver operating characteristic (ROC) curve analysis demonstrated %HYPO and its corresponding parameter on mature erythrocyte, %HYPOm, as the best predictors of FID. The other parameters were ordered as follows: tranferrin saturation (TSAT), ferritin (FRT), mature RBC Hb content (CHm), mean corpuscular Hb concentration (MCHC), percentage of mature erythrocytes with a low CHm (%lowCHm), mean content in Hb (MCH) and reticulocyte Hb content CHr. Comparing the parameters at different cut-offs, the best sensitivity, specificity and efficiency were demonstrated for %HYPOm> 6%. CONCLUSION: The best efficiency to predict FID was found for %HYPOm> 6%. The predictive value of %HYPO was quite similar. The clinical impact of %HYPOm in iron monitoring should also be tested in the induction phase of rHuEPO treatment because of its independence from erythropoietic activity.