Pablo Ureña Torres

The ADVANCE study: a randomized study to evaluate the effects of cinacalcet plus low-dose vitamin D on vascular calcification in patients on hemodialysis

BACKGROUND This prospective, randomized, controlled trial compared the progression of vascular and cardiac valve calcification in 360 prevalent adult hemodialysis patients with secondary hyperparathyroidism treated with either cinacalcet plus low-dose vitamin D sterols or flexible doses of vitamin D sterols alone. METHODS Eligible subjects were on hemodialysis for ≥ 3 months with parathyroid hormone (PTH) > 300 pg/mL or PTH 150-300 pg/mL with calcium-phosphorus product > 50 mg(2)/dL(2) while receiving vitamin D. All subjects received calcium-based phosphate binders. Coronary artery calcification (CAC) and aorta and cardiac valve calcium scores were determined both by Agatston and volume scoring using multi-detector computed tomography. Subjects with Agatston CAC scores ≥ 30 were randomized to cinacalcet (30- 180 mg/day) plus low-dose calcitriol or vitamin D analog (≤ 2 μg paricalcitol equivalent/dialysis), or flexible vitamin D therapy. The primary end point was percentage change in Agatston CAC score from baseline to Week 52. RESULTS Median (P10, P90) Agatston CAC scores increased 24% (-22%, 119%) in the cinacalcet group and 31% (-9%, 179%) in the flexible vitamin D group (P = 0.073). Corresponding changes in volume CAC scores were 22% (-12%, 105%) and 30% (-6%, 133%; P = 0.009). Increases in calcification scores were consistently less in the aorta, aortic valve and mitral valve among subjects treated with cinacalcet plus low-dose vitamin D sterols, and the differences between groups were significant at the aortic valve. CONCLUSIONS In hemodialysis patients with moderate to severe secondary hyperparathyroidism, cinacalcet plus low-dose vitamin D sterols may attenuate vascular and cardiac valve calcification.

Dramatic beneficial effect of interleukin-1 inhibitor treatment in patients with familial Mediterranean fever complicated with amyloidosis and renal failure

BACKGROUND Familial Mediterranean fever (FMF) is an autosomal recessive autoinflammatory disorder, for which systemic AA amyloidosis is the major complication revealed most of the time by renal abnormalities. Current treatment is daily colchicine that prevents both recurrent inflammatory attacks and amyloidosis deposition in most patients. However, some patients still develop amyloidosis and renal failure. Functional studies suggest that interleukin (IL)-1 is implicated in the inflammatory reaction in FMF and therefore, IL-1 inhibitors could be a new approach to treat FMF. The aim of this series study was to evaluate anakinra in patients with FMF complicated with amyloidosis and renal failure. METHODS We studied a series of adult patients with FMF complicated with amyloidosis and treated with anakinra in one reference centre were reviewed. A search for published patients with FMF associated amyloidosis treated with anakinra was performed by screening PubMed. RESULTS We report four cases of patients with FMF-associated amyloidosis treated with anakinra and discuss the clinical pertinence of its use in these particular clinical settings. CONCLUSIONS Anakinra has a strong effect on both inflammatory attacks and general status in patients with FMF-associated amyloidosis. It may contribute to changing the prognosis of these patients. Long-term studies are needed to appreciate the effect of anakinra or other IL-1 inhibitors on the natural history of amyloidosis in these patients.

New insights into the FGF23-Klotho axis.

Abnormal mineral metabolism is a hallmark in patients with advanced chronic kidney disease (CKD). Hyperphosphatemia, and the homeostatic mechanisms controlling phosphate metabolism, have received particular attention over the past decade. The phosphate-regulating hormone fibroblast growth factor-23 (FGF23) was discovered through studies of rare hypophosphatemic disorders, whereas Klotho, which subsequently turned out to be a co-receptor for FGF23, was identified in a mouse model showing hyperphosphatemia and multiple aging-like traits. The FGF23-Klotho endocrine axis is a pivotal regulator of mineral metabolism. In CKD, early onset of Klotho deficiency contributes to renal FGF23 resistance and a maladaptive increase in circulating FGF23. FGF23 is an early biomarker of renal injury and increased FGF23 predicts adverse clinical outcomes, in particular cardiovascular disease. A paradigm of FGF23 excess and Klotho deficiency is proposed, in which FGF23 preferentially stimulates left ventricular hypertrophy, and loss of Klotho augments fibrosis, endothelial dysfunction, and vascular calcification. The clinical benefit of FGF23 and Klotho measurements remain uncertain, nevertheless, the FGF23-Klotho axis is a solid candidate for a novel diagnostic and therapeutic target in CKD.

Study design and subject baseline characteristics in the ADVANCE Study: effects of cinacalcet on vascular calcification in haemodialysis patients

BACKGROUND The ADVANCE (A Randomized Study to Evaluate the Effects of Cinacalcet plus Low-Dose Vitamin D on Vascular Calcification in Subjects with Chronic Kidney Disease Receiving Haemodialysis) Study objective is to assess the effect of cinacalcet plus low-dose active vitamin D versus flexible dosing of active vitamin D on progression of coronary artery calcification (CAC) in haemodialysis patients. We report the ADVANCE Study design and baseline subject characteristics. METHODS ADVANCE is a multinational, multicentre, randomized, open-label study. Adult haemodialysis patients with moderate to severe secondary hyperparathyroidism (intact parathyroid hormone [iPTH] >300 pg/mL or bio-intact PTH >160 pg/mL) and baseline CAC score >or=30 were stratified by CAC score (>or=30-399, >or=400-999, >or=1000) and randomized in a 1:1 ratio to cinacalcet (30-180 mg/day) plus low-dose active vitamin D (cinacalcet group) or flexible dosing of active vitamin D alone (control). The study had three phases: screening, 20-week dose titration and 32-week follow-up. CAC scores obtained by cardiac computed tomography were determined at screening and weeks 28 and 52. The primary end point was percentage change in CAC score from baseline to Week 52. RESULTS Subjects (n = 360) were randomized to cinacalcet or control. Mean age was 61.5 years, 43% were women, and median dialysis vintage was 36.7 months (range, 2.7-351.5 months). The baseline geometric mean CAC score by the Agatston method was 548.7 (95% confidence interval, 480.5-626.6). Baseline CAC score was independently associated with age, sex, dialysis vintage, diabetes and iPTH. Subjects also had extensive aortic and valvular calcification at baseline. CONCLUSIONS Subjects enrolled in ADVANCE have extensive CAC at baseline. The ADVANCE Study should help determine whether cinacalcet attenuates progression of vascular calcification.

When, How, and Why a Bone Biopsy Should Be Performed in Patients With Chronic Kidney Disease

In chronic kidney disease the excessive production of parathyroid hormone increases the bone resorption rate and leads to histologic bone signs of secondary hyperparathyroidism. However, in other situations, the initial increase in parathyroid hormone and bone remodeling may be slowed down excessively by a multitude of factors including age, ethnic origin, sex, and treatments such as vitamin D, calcium salts, calcimimetics, steroids, and so forth, leading to low bone turnover or adynamic bone disease. Both high and low bone turnover diseases actually are observed equally in chronic kidney disease patients treated by dialysis, and all types of renal osteodystrophy are associated with an increased risk of skeletal fractures, reduced quality of life, and poor clinical outcomes. Unfortunately, the diagnosis of these bone abnormalities cannot be obtained correctly by current clinical, biochemical, and imaging methods. Therefore, bone biopsy has been, and still remains, the gold standard analysis for assessing the exact type of renal osteodystrophy. It is also the unique way to assess the mechanisms of action, safety, and efficacy of new bone-targeting therapies.

Effectiveness of cinacalcet in patients with recurrent/persistent secondary hyperparathyroidism following parathyroidectomy: results of the ECHO study

BACKGROUND Progressive secondary hyperparathyroidism (sHPT) is characterized by parathyroid gland hyperplasia which may ultimately require parathyroidectomy (PTX). Although PTX is generally a successful treatment for those patients subjected to surgery, a significant proportion develops recurrent sHPT following PTX. ECHO was a pan-European observational study which evaluated the achievement of KDOQI(TM) treatment targets with cinacalcet use in patients on dialysis. Previously published results showed that cinacalcet plus flexible vitamin D therapy lowered serum PTH, phosphorus and calcium in the clinical practice with similar efficacy as seen in phase III trials. METHODS This subgroup analysis of ECHO describes the real-world cinacalcet treatment effect in patients with recurrent or persistent sHPT after PTX (n = 153) compared to sHPT patients without prior history of PTX (n = 1696). RESULTS Both groups of patients had substantially elevated serum PTH with comparable sHPT severity at baseline. After 12 months of cinacalcet treatment, 20.3% (26/128) of patients with prior PTX and 18.2% (253/1388) of patients without prior PTX achieved serum PTH and Ca × P values within the recommended KDOQI(TM) target ranges. CONCLUSIONS Our data support the successful use of cinacalcet in patients with recurrent/persistent sHPT after PTX.

Iron-based phosphate binders: do they offer advantages over currently available phosphate binders?

Increased cardiovascular morbidity and mortality has been associated with the hyperphosphatemia seen in patients with end-stage chronic kidney disease (CKD). Oral phosphate binders are prescribed in these patients to prevent intestinal absorption of dietary phosphate and reduce serum phosphate. In prospective observational cohorts they have shown to decrease all-cause and cardiovascular mortality risk. Different problems have been associated with currently available phosphate binders as positive calcium balance and impaired outcomes with calcium-based phosphate binders or increased costs with non-calcium-based phosphate binders. Iron-based phosphate binders represent a new class of phosphate binders. Several iron-based phosphate binders have undergone testing in clinical trials. Ferric citrate (JTT-751) and sucroferric oxyhydroxide (PA21) are the two iron-based binders that have passed to the clinical field after being found safe and effective in decreasing serum phosphate. Iron from ferric citrate is partially absorbed compared to sucroferric oxyhydroxide. Ferric citrate usage could result in an important reduction in erythropoiesis-stimulating agent (ESA) and IV iron usage, resulting in significant cost savings. Sucroferric oxyhydroxide was effective in lowering serum phosphorus in dialysis patients with similar efficacy to sevelamer carbonate, but with lower pill burden, and better adherence. Ferric citrate may be more suited for the treatment of chronic hyperphosphatemia in CKD patients requiring iron supplements but its use may have been hampered by potential aluminum overload, as citrate facilitates its absorption; sucroferric oxyhydroxide may be more suited for hyperphosphatemic CKD patients not requiring iron supplementation, with low pill burden.

Blueprint for a European calciphylaxis registry initiative: the European Calciphylaxis Network (EuCalNet).

Calcific uraemic arteriolopathy (CUA) is a rare disease and continues to be a clinical challenge. The typical course of CUA is characterized by painful skin discolouration and induration evolving to necrotic ulcerations. Medial calcification of cutaneous arterioles and extensive extracellular matrix remodelling are the hallmarks of CUA. The epidemiology and risk factors associated with this disease are still not fully understood. Moreover, CUA treatment strategies vary significantly among centres and expert recommendations are heterogeneous. Registries may provide important insights and information to increase our knowledge about epidemiology and clinical aspects of CUA and may help to optimize its therapeutic management. In 2006, we established an internet-based registry in Germany (www.calciphylaxie.de) to allow online notification of patients with established or suspected CUA. The registry includes a comprehensive database with questions covering >70 parameters and items regarding patient-related and laboratory data, clinical background and presentation as well as therapeutic strategies. The next phase will be to allow international patient registration via www.calciphylaxis.net as part of the multinational EuCalNet (European Calciphylaxis Network) initiative, which is supported by the ERA-EDTA scientific working group ‘CKD-MBD’. Based on the valuable experience with the previous German CUA registry, EuCalNet will be a useful tool to collect data on the rare disease CUA and may become a basis for prospective controlled trials in the near future.

Bone and mineral disorders in chronic kidney disease: implications for cardiovascular health and ageing in the general population

The patient with chronic kidney disease (CKD) represents an extreme model for arteriosclerosis, vascular calcification, and bone disorders, all of which are also associated with ageing in the general population. These pathological features are also relevant to other common chronic health disorders such as diabetes, and chronic inflammatory and cardiovascular diseases. Although management and interventions for these major risk factors are now incorporated into most public health guidelines (eg, smoking cessation and control of bodyweight and blood pressure, as well as glucose and cholesterol concentrations), some residual cardiovascular risk is not reduced by implementation of these interventions. CKD should be regarded as an atypical disease in which both traditional and novel cardiovascular risk factors have effects on outcomes. But CKD can also be viewed conceptually as an accelerator of traditional cardiovascular risk factors. Findings from research into mineral bone disorder associated with CKD (CKD-MBD) could help the medical community to better understand the vascular actions of certain molecules, such as phosphates, fibroblast growth factor 23, parathyroid hormone, sclerostin, or vitamin D and their relevance to the management of different pathologies in the general population. Importantly, these components, which are recognised in nephrology, could help to explain residual risk of cardiovascular events in the general population. Thus, achieving a better understanding of CKD-MBDs could provide substantial insight into future treatments for arteriosclerosis and osteoporosis, which are strongly associated with ageing and morbidity in the general population.

Evaluation of fracture risk in chronic kidney disease

Chronic kidney disease (CKD) is associated with mineral and bone disorders (MBD) that are now considered as a syndrome. Bone fragility and a four to tenfold increased rate of skeletal fractures are often reported in CKD patients. The evaluation of the risk of these fractures in CKD patients should explore the same risk factors identified for the general population including low body weight, menopause, personal and familial history of osteoporosis, chronic inflammatory diseases, and corticosteroid therapy. The aim of this article is to provide a critical review of the tools used for the evaluation of bone loss and the risk of fracture in CKD patients, ranging from the measurement of bone mineral density (BMD), fracture risk assessment (Frax™), quantitative computed tomography (QCT), high-resolution peripheral quantitative computed tomography (HRpQTC), to circulating biomarkers of bone metabolism including vitamin D, parathyroid hormone (PTH), bone-specific alkaline phosphatase, osteocalcin, and some collagen type 1-related molecules indicators of bone remodeling.