Lilian Cuppari

Early Control of PTH and FGF23 in Normophosphatemic CKD Patients: A New Target in CKD-MBD Therapy?

BACKGROUND AND OBJECTIVES Levels of parathyroid hormone (PTH) and the phosphaturic hormone FGF23, a fibroblast growth factor (FGF) family member, increase early in chronic kidney disease (CKD) before the occurrence of hyperphosphatemia. This short-term 6-wk dose titration study evaluated the effect of two phosphate binders on PTH and FGF23 levels in patients with CKD stages 3 to 4. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS Patients were randomized to receive over a 6-wk period either calcium acetate (n = 19) or sevelamer hydrochloride (n = 21). RESULTS At baseline, patients presented with elevated fractional excretion of phosphate, serum PTH, and FGF23. During treatment with both phosphate binders there was a progressive decline in serum PTH and urinary phosphate, but no change in serum calcium or serum phosphate. Significant changes were observed for FGF23 only in sevelamer-treated patients. CONCLUSIONS This study confirms the positive effects of early prescription of phosphate binders on PTH control. Prospective and long-term studies are necessary to confirm the effects of sevelamer on serum FGF23 and the benefits of this decrease on outcomes.

Etiology of the Protein-Energy Wasting Syndrome in Chronic Kidney Disease: A Consensus Statement From the International Society of Renal Nutrition and Metabolism (ISRNM)

Protein-energy wasting (PEW), a term proposed by the International Society of Renal Nutrition and Metabolism (ISRNM), refers to the multiple nutritional and catabolic alterations that occur in chronic kidney disease (CKD) and associate with morbidity and mortality. To increase awareness, identify research needs, and provide the basis for future work to understand therapies and consequences of PEW, ISRNM provides this consensus statement of current knowledge on the etiology of PEW syndrome in CKD. Although insufficient food intake (true undernutrition) due to poor appetite and dietary restrictions contribute, other highly prevalent factors are required for the full syndrome to develop. These include uremia-induced alterations such as increased energy expenditure, persistent inflammation, acidosis, and multiple endocrine disorders that render a state of hypermetabolism leading to excess catabolism of muscle and fat. In addition, comorbid conditions associated with CKD, poor physical activity, frailty, and the dialysis procedure per se further contribute to PEW.

Phosphate Binder Impact on Bone Remodeling and Coronary Calcification – Results from the BRiC Study

Backgroundand Aims: Calcium-containing phosphate binders have been shown to increase the progression of vascular calcification in hemodialysis patients. This is a prospective study that compares the effects of calcium acetate and sevelamer on coronary calcification (CAC) and bone histology. Methods: 101 hemodialysis patients were randomized for each phosphate binder and submitted to multislice coronary tomographies and bone biopsies at entry and 12 months. Results: The 71 patients who concluded the study had similar baseline characteristics. On follow-up, the sevelamer group had higher levels of intact parathyroid hormone (498 ± 352 vs. 326 ± 236 pg/ml, p = 0.017), bone alkaline phosphatase (38 ± 24 vs. 28 ± 15 U/l, p = 0.03) and deoxypyridinoline (135 ± 107 vs. 89 ± 71 nmol/l, p = 0.03) and lower LDL cholesterol (74 ± 21 vs. 91 ± 28 mg/dl, p = 0.015). Phosphorus (5.8 ± 1.0 vs. 6 ± 1.0 mg/dl, p = 0.47) and calcium (1.27 ± 0.07 vs. 1.23 ± 0.08 mmol/l, p = 0.68) levels did not differ between groups. CAC progression (35 vs. 24%, p = 0.94) and bone histological diagnosis at baseline and 12 months were similar in both groups. Patients of the sevelamer group with a high turnover at baseline had an increase in bone resorption (eroded surface, ES/BS = 9.0 ± 5.9 vs. 13.1 ± 9.5%, p = 0.05), whereas patients of both groups with low turnover at baseline had an improvement in bone formation rate (BFR/BS = 0.015 ± 0.016 vs. 0.062 ± 0.078, p = 0.003 for calcium and 0.017 ± 0.016 vs. 0.071 ± 0.084 μm3/μm2/day, p = 0.010 for sevelamer). Conclusions: There was no difference in CAC progression or changes in bone remodeling between the calcium and the sevelamer groups.

Waist Circumference and Visceral Fat in CKD: A Cross-sectional Study

BACKGROUND In the general population, waist circumference was noted to be a reliable predictor of visceral fat. In addition, increased waist circumference was strongly associated with risk factors for cardiovascular disease. In patients with chronic kidney disease (CKD), the association of waist circumference with visceral fat was never tested. STUDY DESIGN Cross-sectional study. SETTING & PARTICIPANTS 122 patients with CKD not yet on dialysis therapy (75 men; diabetes mellitus, 30%; age, 55.3 +/- 11.3 years; body mass index, 27.1 +/- 5.2 kg/m(2); estimated glomerular filtration rate, 35.4 +/- 15.2 mL/min/1.73 m(2)) were studied. PREDICTOR Waist circumference. OUTCOMES & MEASUREMENTS Anthropometry, abdominal visceral fat measured by means of computed tomography, and cardiovascular disease risk factors. RESULTS Waist circumference strongly correlated with visceral fat (r = 0.75 for men, r = 0.81 for women; P < 0.01). kappa Statistic was 0.56, indicating relatively good agreement between methods. Body mass index showed a lower correlation coefficient (r = 0.68 for men, r = 0.76 for women; P < 0.01) and poor agreement (0.36) with visceral fat in comparison to waist circumference. In men, waist circumference and visceral fat similarly correlated with high-density lipoprotein cholesterol level, triacylglycerol level, and Homeostasis Model Assessment Index (P < 0.05). In women, waist circumference correlated with age, C-reactive protein level, and Homeostasis Model Assessment Index, whereas visceral fat also correlated with low-density lipoprotein cholesterol and triacylglycerol levels (P < 0.05). LIMITATIONS Findings are restricted to patients with CKD not yet on dialysis therapy from a single center. CONCLUSIONS Waist circumference was strongly associated with visceral fat in patients with CKD. Associations between waist circumference and cardiovascular disease risk factors were similar to those observed for visceral fat, particularly in men. These findings suggest that waist circumference may be a simple and inexpensive tool to be used in epidemiological studies.

Association of Changes in Bone Remodeling and Coronary Calcification in Hemodialysis Patients: A Prospective Study

BACKGROUND Vascular calcification is common and constitutes a prognostic marker of mortality in the hemodialysis population. Derangements of mineral metabolism may influence its development. The aim of this study is to prospectively evaluate the association between bone remodeling disorders and progression of coronary artery calcification (CAC) in hemodialysis patients. STUDY DESIGN Cohort study nested within a randomized controlled trial. SETTING & PARTICIPANTS 64 stable hemodialysis patients. PREDICTOR Bone-related laboratory parameters and bone histomorphometric characteristics at baseline and after 1 year of follow-up. OUTCOMES Progression of CAC assessed by means of coronary multislice tomography at baseline and after 1 year of follow-up. Baseline calcification score of 30 Agatston units or greater was defined as calcification. Change in calcification score of 15% or greater was defined as progression. RESULTS Of 64 patients, 38 (60%) of the patients had CAC and 26 (40%) did not [corrected]. Participants without CAC at baseline were younger (P < 0.001), mainly men (P = 0.03) and nonwhite (P = 0.003), and had lower serum osteoprotegerin levels (P = 0.003) and higher trabecular bone volume (P = 0.001). Age (P = 0.003; beta coefficient = 1.107; 95% confidence interval [CI], 1.036 to 1.183) and trabecular bone volume (P = 0.006; beta coefficient = 0.828; 95% CI, 0.723 to 0.948) were predictors for CAC development. Of 38 participants who had calcification at baseline, 26 (68%) had CAC progression in 1 year. Progressors had lower bone-specific alkaline phosphatase (P = 0.03) and deoxypyridinoline levels (P = 0.02) on follow-up, and low turnover was mainly diagnosed at the 12-month bone biopsy (P = 0.04). Low-turnover bone status at the 12-month bone biopsy was the only independent predictor for CAC progression (P = 0.04; beta coefficient = 4.5; 95% CI, 1.04 to 19.39). According to bone histological examination, nonprogressors with initially high turnover (n = 5) subsequently had decreased bone formation rate (P = 0.03), and those initially with low turnover (n = 7) subsequently had increased bone formation rate (P = 0.003) and osteoid volume (P = 0.001). LIMITATIONS Relatively small population, absence of patients with severe hyperparathyroidism, short observational period. CONCLUSIONS Lower trabecular bone volume was associated with CAC development, whereas improvement in bone turnover was associated with lower CAC progression in patients with high- and low-turnover bone disorders. Because CAC is implicated in cardiovascular mortality, bone derangements may constitute a modifiable mortality risk factor in hemodialysis patients.

Vitamin D status in a sunny country: Where has the sun gone?

BACKGROUND & AIMS Hypovitaminosis D [serum 25 vitamin D<30 ng/ml] is related to the development of metabolic bone disease and greater risk of chronic illnesses. However, it is frequently under-diagnosed, mainly in countries where UV radiation is abundant. We prospectively determined the prevalence and the predictors of serum 25 vitamin D (s25(OH)D) in a healthy Brazilian population after the winter and after the summer. METHODS 603 (118M and 485F) healthy Brazilian volunteers aged 18-90 years from a universitary hospital were selected after the winter of 2006. From the initial sample, 209 volunteers (31M and 178F) accepted to participate in a second health check after the subsequent summer. RESULTS After the winter, median s25(OH)D was 21.4 ng/mL and 77.4% of the population presented hypovitaminosis D. s25(OH)D was significantly related to age, BMI, PTH and race. In multivariate linear regression analysis, s25(OH)D was significantly and independently dependent on age, glycemia and skin color. Significant increase in s25(OH)D was verified after summer [10.6 (3.7-19.3 ng/ml); p<0.001] and this improvement was dependent on age. We also observed a significant decrease in hyperparathyroidism prevalence (20.8% vs. 4.9%; P<0.0001). CONCLUSION In São Paulo, at the end of winter, we observed a high prevalence of hypovitaminosis D and secondary hyperparathyroidism in healthy adults. s25(OH)D was dependent on age and skin color. After summer, we observed a decrease in the prevalence of hypovitaminosis D. This unexpected finding emphasizes the need for a strong recommendation to monitor s25(OH)D, even in a sunny country such as Brazil.

Physical activity and energy expenditure in haemodialysis patients: an international survey

BACKGROUND The assessment of physical activity and energy expenditure is relevant to the care of maintenance haemodialysis (MHD) patients. In the current study, we aimed to evaluate measurements of physical activity and energy expenditure in MHD patients from different centres and countries and explored the predictors of physical activity in these patients. METHODS In this cross-sectional multicentre study, 134 MHD patients from four countries (France, Switzerland, Sweden and Brazil) were included. The physical activity was evaluated for 5.0 ± 1.4 days (mean ± SD) by a multisensory device (SenseWear Armband) and comprised the assessment of number of steps per day, activity-related energy expenditure (activity-related EE) and physical activity level (PAL). RESULTS The number of steps per day, activity-related EE and PAL from the MHD patients were compatible with a sedentary lifestyle. In addition, all parameters were significantly lower in dialysis days when compared to non-dialysis days (P < 0.001). The multivariate regression analysis revealed that diabetes and higher body mass index (BMI) predicted a lower PAL and older age and diabetes predicted a reduced number of steps. CONCLUSIONS The physical activity parameters of MHD patients were compatible with a sedentary lifestyle. This inactivity was worsened by aging, diabetes and higher BMI. Our results indicate that MHD patients should be encouraged by the health care team to increase their physical activity.

Increased Resting Energy Expenditure in Hemodialysis Patients with Severe Hyperparathyroidism

Several metabolic derangements, including enhanced protein catabolism, have been suggested to be associated with increased circulating parathyroid hormone (PTH) in patients with secondary hyperparathyroidism (HPT). Such conditions, therefore, might lead to an increase in energy expenditure. The present study examined by indirect calorimetry the resting energy expenditure (REE) of 15 hemodialysis patients who have severe HPT (PTH = 1457 +/- 676 pg/ml) and were pair-matched for age and gender to 15 hemodialysis patients with mild to moderate HPT (PTH = 247 +/- 196 pg/ml). Both groups were also pair-matched for age and gender to a group of 15 healthy adult subjects (control). In six patients from the severe HPT group submitted to total parathyroidectomy, REE was determined 6 mo after the surgery. The groups were not different regarding lean body mass (LBM) measured by bioelectric impedance, serum C-reactive protein, and bicarbonate. Thyroid-stimulating hormone was within the normal range in all groups. Nonadjusted REE was significantly higher in the severe HPT group (1674 +/- 337 kcal/d) compared with patients with mild to moderate HPT (1388 +/- 229 kcal/d; P < 0.05). Both groups did not differ from the control group (1468 +/- 323 kcal/d). When adjustment of REE for LBM was performed using the multiple regression analysis, patients with mild to moderate HPT and control subjects had significantly lower REE (-231 and -262 kcal, respectively) than that of the severe HPT group. Considering all patients together, nonadjusted REE correlated directly with LBM (r = 0.61; P < 0.01). PTH correlated strongly with LBM in the severe HPT group (r = -0.82; P < 0.01). In the multiple linear regression analysis, only LBM and PTH were independent determinants of REE (n = 30; R(2) = 0.47). REE decreased significantly in the six patients who were evaluated 6 mo after parathyroidectomy (from 1617 +/- 339 to 1226 +/- 253; P = 0.02). These results demonstrate that hemodialysis patients with severe HPT have increased REE that might be reduced after parathyroidectomy.

Fibroblast Growth Factor 23 in Hemodialysis Patients: Effects of Phosphate Binder, Calcitriol and Calcium Concentration in the Dialysate

Background: Fibroblast growth factor 23 (FGF23) concentrations increase early in chronic kidney disease (CKD), and the influence of current CKD-mineral and bone disorder (MBD) therapies on serum FGF23 levels is still under investigation. Methods: In this post-hoc analysis of a randomized clinical trial, phosphate binders and calcitriol were washed out of 72 hemodialysis patients who were then submitted to bone biopsy, coronary tomography and biochemical measures, including FGF23. They were randomized to receive sevelamer or calcium acetate for 1 year and the prescription of calcitriol and the calcium concentration in the dialysate were adjusted according to serum calcium, phosphate and PTH and bone biopsy diagnosis. Results: At baseline, bone biopsy showed that 58.3% had low-turnover bone disease, whereas 38.9% had high-turnover bone disease, with no significant differences between them with regard to FGF23. Median baseline FGF23 serum levels were elevated and correlated positively with serum phosphate. After 1 year, serum FGF23 decreased significantly. Repeated measures ANOVA analysis showed that the use of a 3.5-mEq/l calcium concentration in the dialysate, as well as the administration of calcitriol and a calcium-based phosphate binder were associated with higher final serum FGF23 levels.Conclusions: Taken together, our results confirm that the current CKD-MBD therapies have an effect on serum levels of FGF23. Since FGF23 is emerging as a potential treatment target, our findings should be taken into account in the decision on how to manage CKD-MBD therapy.

Sarcopenia in chronic kidney disease on conservative therapy: prevalence and association with mortality

BACKGROUND In chronic kidney disease (CKD), multiple metabolic and nutritional abnormalities contribute to the impairment of skeletal muscle mass and function thus predisposing patients to the condition of sarcopenia. Herein, we investigated the prevalence and mortality predictive power of sarcopenia, defined by three different methods, in non-dialysis-dependent (NDD) CKD patients. METHODS We evaluated 287 NDD-CKD patients in stages 3-5 [59.9 ± 10.5 years; 62% men; 49% diabetics; glomerular filtration rate (GFR) 25.0 ± 15.8 mL/min/1.73 m(2)]. Sarcopenia was defined as reduced muscle function assessed by handgrip strength (HGS <30th percentile of a population-based reference adjusted for sex and age) plus diminished muscle mass assessed by three different methods: (i) midarm muscle circumference (MAMC) <90% of reference value (A), (ii) muscle wasting by subjective global assessment (B) and (iii) reduced skeletal muscle mass index (<10.76 kg/m² men; <6.76 kg/m² women) estimated by bioelectrical impedance analysis (BIA) (C). Patients were followed for up to 40 months for all-cause mortality, and there was no loss of follow-up. RESULTS The prevalence of sarcopenia was 9.8% (A), 9.4% (B) and 5.9% (C). The kappa agreement between the methods were 0.69 (A versus B), 0.49 (A versus C) and 0.46 (B versus C). During follow-up, 51 patients (18%) died, and the frequency of sarcopenia was significantly higher among non-survivors. In crude Cox analysis, sarcopenia diagnosed by the three methods was associated with a higher hazard for mortality; however, only sarcopenia diagnosed by method C remained as a predictor of mortality after multivariate adjustment. CONCLUSIONS The prevalence of sarcopenia in CKD patients on conservative therapy varies according to the method applied. Sarcopenia defined as reduced handgrip strength and low skeletal muscle mass index estimated by BIA was an independent predictor of mortality in these patients.