João M. Frazão

The OPTIMA Study: Assessing a New Cinacalcet (Sensipar/Mimpara) Treatment Algorithm for Secondary Hyperparathyroidism

BACKGROUND AND OBJECTIVES Cinacalcet, a novel calcimimetic, targets the calcium-sensing receptor to lower parathyroid hormone (PTH), calcium, and phosphorus levels in dialysis patients with secondary hyperparathyroidism (SHPT). This study compared the efficacy of a cinacalcet-based regimen with unrestricted conventional care (vitamin D and phosphate binders) for achieving the stringent National Kidney Foundation Kidney Disease Outcomes Quality Initiative (KDOQI) targets for dialysis patients. STUDY DESIGN In this multicenter, open-label study, hemodialysis patients with poorly controlled SHPT were randomized to receive conventional care (n = 184) or a cinacalcet-based regimen (n = 368). Doses of cinacalcet, vitamin D sterols, and phosphate binders were adjusted during a 16-wk dose-optimization phase with the use of algorithms that allowed cinacalcet to be used with adjusted doses of vitamin D. The primary end point was the proportion of patients with mean intact PTH < or =300 pg/ml during a 7-wk efficacy assessment phase. RESULTS A higher proportion of patients receiving the cinacalcet-based regimen versus conventional care achieved the targets for PTH (71% versus 22%, respectively; P < 0.001), Ca x P (77% versus 58%, respectively; P < 0.001), calcium (76% versus 33%, respectively; P < 0.001), phosphorus (63% versus 50%, respectively; P = 0.002), and PTH and Ca x P (59% versus 16%, respectively, P < 0.001), and allowed a 22% reduction in vitamin D dosage in patients receiving vitamin D at baseline. Achievement of targets was greatest in patients with less severe disease (intact PTH range, 300 to 500 pg/ml) and the cinacalcet dose required was lower in these patients (median = 30 mg/d). CONCLUSIONS Compared with conventional therapy, a cinacalcet-based treatment algorithm increased achievement of KDOQI treatment targets in dialysis patients in whom conventional therapy was no longer effective in controlling this disease.

Effects of Sevelamer Hydrochloride and Calcium Carbonate on Renal Osteodystrophy in Hemodialysis Patients

Disturbances in mineral metabolism play a central role in the development of renal bone disease. In a 54-wk, randomized, open-label study, 119 hemodialysis patients were enrolled to compare the effects of sevelamer hydrochloride and calcium carbonate on bone. Biopsy-proven adynamic bone disease was the most frequent bone abnormality at baseline (59%). Serum phosphorus, calcium, and intact parathyroid hormone were well controlled in both groups, although calcium was consistently lower and intact parathyroid hormone higher among patients who were randomly assigned to sevelamer. Compared with baseline values, there were no changes in mineralization lag time or measures of bone turnover (e.g., activation frequency) after 1 yr in either group. Osteoid thickness significantly increased in both groups, but there was no significant difference between them. Bone formation rate per bone surface, however, significantly increased from baseline only in the sevelamer group (P = 0.019). In addition, of those with abnormal microarchitecture at baseline (i.e., trabecular separation), seven of 10 in the sevelamer group normalized after 1 yr compared with zero of three in the calcium group. In summary, sevelamer resulted in no statistically significant changes in bone turnover or mineralization compared with calcium carbonate, but bone formation increased and trabecular architecture improved with sevelamer. Further studies are required to assess whether these changes affect clinical outcomes, such as rates of fracture.

Low Bone Volume—A Risk Factor for Coronary Calcifications in Hemodialysis Patients

BACKGROUND AND OBJECTIVES There is increasing evidence that altered bone metabolism is associated with cardiovascular calcifications in patients with stage 5 chronic kidney disease on hemodialysis (HD). This study was conducted to evaluate the association between bone volume, turnover, and coronary calcifications in HD patients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS In a cross-sectional study, bone biopsies and multislice computed tomography were performed in 38 HD patients. Bone volume/total volume, activation frequency, and bone formation rate/bone surface were determined by histomorphometry and coronary calcifications were quantified by Agatston scores. RESULTS Prevalence of low bone turnover was 50% and of low bone volume was 16%. Among the studied traditional cardiovascular risk factors, only age was found to be associated with coronary calcifications. Lower bone volume was a significant risk factor for coronary calcifications during early years of HD, whereas this effect was not observed in patients with dialysis duration >6 yr. Histomorphometric parameters of bone turnover were not associated with coronary calcifications. CONCLUSIONS Low bone volume is associated with increased coronary calcifications in patients on HD.

Adynamic bone disease: clinical and therapeutic implications.

Purpose of reviewAdynamic bone disease has recently been associated with increased risk of vascular calcification. This review focuses on the emerging data in adynamic bone disease, its clinical consequences and therapeutic implications. Recent findingsThere is a lack of good biochemical markers of parathyroid status, bone formation and reabsorption to allow a secure diagnosis of bone disease. Recent data have suggested a possible link between bone activity and vascular calcification. Cardiovascular calcification is an independent predictor of mortality. Adynamic bone is associated with a very low capacity of bone to incorporate calcium in the bone compartment and inability to handle an extra calcium load. A positive association between vascular calcifications and low bone turnover has been suggested. Calcium-containing phosphate binders, active vitamin D therapy and high calcium dialysate may enhance vascular calcifications in the presence of adynamic bone disease. SummaryThere is recent evidence suggesting a negative impact of calcium load in the progression of vascular calcification in dialysis patients with chronic kidney disease stage 5 with adynamic bone disease. The current therapeutic approach to these patients should focus on reduction of calcium and vitamin D load to restore parathyroid activity.

Non-Calcium-Containing Phosphate Binders: Comparing Efficacy, Safety, and Other Clinical Effects

Phosphate-binder therapy for hyperphosphataemia is key to the treatment of patients with chronic kidney disease (CKD)-mineral and bone disorder (MBD). Calcium-free phosphate binders are increasingly favoured since calcium-based agents potentially cause harmful calcium overload and vascular calcification that confound the benefits of reducing serum phosphorus. Several calcium-free phosphate binders are available, including the non-absorbed agent sevelamer and the absorbed agents, e.g. lanthanum and magnesium salts. Randomised controlled studies consistently show that sevelamer and lanthanum carbonate offer equivalent lowering of serum phosphorus and often effectively achieve phosphorus targets versus calcium salts, with sevelamer having a positive effect on bone disease, vascular calcification, and patient-level outcomes in dialysis patients in several trials. There is also evidence that lanthanum carbonate can improve bone health, but data are limited to its effects to vascular calcification or patient-level outcomes. Magnesium salts have also been shown to reduce serum phosphorus levels, but clear evidence is lacking on bone, vascular, or clinical outcomes. It also remains to be established whether long-term systemic accumulation of lanthanum and magnesium, in tissues including bone, has clinically relevant toxic effects. This review summarises the evidence of efficacy and safety for newer calcium-free phosphate binders in CKD-MBD management.

Femoral bone mineral density reflects histologically determined cortical bone volume in hemodialysis patients

SummaryWe evaluated the associations between dual energy X-ray absorptiometry (DXA) and histologically determined cancellous and cortical bone volume by controlling for vascular calcifications and demographic variables in hemodialysis (HD) patients. Femoral bone mineral density (f-BMD) was associated with cortical porosity.IntroductionAssessment of bone mass in chronic kidney disease patients is of clinical importance because of the association between low bone volume, fractures, and vascular calcifications. DXA is used for noninvasive assessment of bone mass whereby vertebral results reflect mainly cancellous bone and femoral results reflect mainly cortical bone. Bone histology allows direct measurements of cancellous and cortical bone volume. The present study evaluates the association between DXA and histologically determined cancellous and cortical bone volumes in HD patients.MethodsIn 38 HD patients, DXA was performed for assessment of bone mass, anterior iliac crest bone biopsies for bone volume, and multislice computed tomography for vascular calcifications.ResultsWhile lumbar bone mineral density (l-BMD) by DXA was not associated with histologically measured cancellous bone volume, coronary Agatson score showed a borderline statistically significant association (P = 0.055). When controlled for age and dialysis duration, f-BMD by DXA was associated with cortical porosity determined by histology (P = 0.005).ConclusionsThe usefulness of l-BMD for predicting bone volume is limited most probably because of interference by soft tissue calcifications. In contrast, f-BMD shows significant association with cortical porosity.

Nutrition and dietary intake and their association with mortality and hospitalisation in adults with chronic kidney disease treated with haemodialysis: protocol for DIET-HD, a prospective multinational cohort study

Introduction Adults with end-stage kidney disease (ESKD) treated with haemodialysis experience mortality of between 15% and 20% each year. Effective interventions that improve health outcomes for long-term dialysis patients remain unproven. Novel and testable determinants of health in dialysis are needed. Nutrition and dietary patterns are potential factors influencing health in other health settings that warrant exploration in multinational studies in men and women treated with dialysis. We report the protocol of the “DIETary intake, death and hospitalisation in adults with end-stage kidney disease treated with HaemoDialysis (DIET-HD) study,” a multinational prospective cohort study. DIET-HD will describe associations of nutrition and dietary patterns with major health outcomes for adults treated with dialysis in several countries. Methods and analysis DIET-HD will recruit approximately 10 000 adults who have ESKD treated by clinics administered by a single dialysis provider in Argentina, France, Germany, Hungary, Italy, Poland, Portugal, Romania, Spain, Sweden and Turkey. Recruitment will take place between March 2014 and June 2015. The study has currently recruited 8000 participants who have completed baseline data. Nutritional intake and dietary patterns will be measured using the Global Allergy and Asthma European Network (GA2LEN) food frequency questionnaire. The primary dietary exposures will be n-3 and n-6 polyunsaturated fatty acid consumption. The primary outcome will be cardiovascular mortality and secondary outcomes will be all-cause mortality, infection-related mortality and hospitalisation. Ethics and dissemination The study is approved by the relevant Ethics Committees in participating countries. All participants will provide written informed consent and be free to withdraw their data at any time. The findings of the study will be disseminated through peer-reviewed journals, conference presentations and to participants via regular newsletters. We expect that the DIET-HD study will inform large pragmatic trials of nutrition or dietary interventions in the setting of advanced kidney disease.

Treatment of hyperphosphatemia with sevelamer hydrochloride in dialysis patients: effects on vascular calcification, bone and a close look into the survival data

In chronic kidney disease patients, bone and mineral abnormalities have a major impact on morbidity and mortality. Hyperphosphatemia has been associated with increased mortality and with the development of cardiovascular calcification, an independent predictor of mortality. Vascular calcifications have been associated with low bone turnover, low bone volume and lower activation frequency. In dialysis patients, the treatment of hyperphospathemia with calcium based compounds, when compared with sevelamer, is associated with more frequent episodes of hypercalcemia, suppression of intact parathyroid hormone and with progression of coronary calcifications. In the presence of adynamic bone disease, calcium load has a significantly higher impact on aortic calcifications and stiffening. A randomized, prospective, open label study, evaluated patients with bone biopsies at the beginning and after 1 year treatment period with sevelamer hydrochloride or calcium carbonate. Sevelamer treatment resulted in no statistically significant changes in bone turnover or mineralization compared with calcium carbonate, but bone formation rate increased and trabecular architecture improved only with sevelamer. In incident dialysis patients, treatment with sevelamer has been associated with better survival, while in prevalent patients a clear benefit could only be demonstrated in older patients and in patients treated for more than 2 years.In conclusion, the treatment of hyperphosphatemia with sevelamer hydrochloride, a non-calcium and non-metal containing phosphate binder, is associated with a beneficial effect on vascular calcification progression, bone disease and most likely with a survival benefit in some hemodialysis patients populations.

Higher Mineralized Bone Volume is Associated with a Lower Plain X-Ray Vascular Calcification Score in Hemodialysis Patients

Background and objectives In dialysis patients, there is an increasing evidence that altered bone metabolism is associated with cardiovascular calcifications. The main objective of this study was to analyse, in hemodialysis patients, the relationships between bone turnover, mineralization and volume, evaluated in bone biopsies, with a plain X-ray vascular calcification score. Design, setting, participants and measurements In a cross-sectional study, bone biopsies and evaluation of vascular calcifications were performed in fifty hemodialysis patients. Cancellous bone volume, mineralized bone volume, osteoid volume, activation frequency, bone formation rate/bone surface, osteoid thickness and mineralization lag time were determined by histomorphometry. Vascular calcifications were assessed by the simple vascular calcification score (SVCS) in plain X-Ray of pelvis and hands and, for comparison, by the Agatston score in Multi-Slice Computed Tomography (MSCT). Results SVCS≥3 was present in 20 patients (40%). Low and high bone turnover were present in 54% and 38% of patients, respectively. Low bone volume was present in 20% of patients. In multivariable analysis, higher age (p = 0.015) and longer hemodialysis duration (p = 0.017) were associated with SVCS≥3. Contrary to cancellous bone volume, the addition to this model of mineralized bone volume (OR = 0.863; 95%CI: 0.766, 0.971; p = 0.015), improved the performance of the model. For each increase of 1% in mineralized bone volume there was a 13.7% decrease in the odds of having SVCS≥3 (p = 0.015). An Agatston score>400 was observed in 80% of the patients with a SVCS≥3 versus 4% of patients with a SVCS<3, (p<0.001). Conclusion Higher mineralized bone volume was associated with a lower plain X-ray vascular calcification. This study corroborates the hypothesis of the existence of a link between bone and vessel and reinforces the clinical utility of this simple and inexpensive vascular calcification score in dialysis patients.

Evolution of bone disease after kidney transplantation: A prospective histomorphometric analysis of trabecular and cortical bone

Post‐transplant bone disease results from multiple factors, including previous bone and mineral metabolism disturbances and effects from transplant‐related medications. Bone biopsy remains the gold‐standard diagnostic tool.