Phosphate and bone fracture risk in chronic kidney disease patients

Author(s):  
Maria Fusaro ◽  
Rachel Holden ◽  
Charmaine Lok ◽  
Giorgio Iervasi ◽  
Mario Plebani ◽  
...  

Abstract In chronic kidney disease (CKD), phosphate homoeostasis plays a central role in the development of mineral and bone disorder (MBD) together with decreased serum calcium and elevated serum parathyroid hormone, fibroblast growth factor 23 and sclerostin levels. Today there are only a few data exploring the direct role of abnormal phosphate homoeostasis and hyperphosphataemia in the development of CKD-MBD. On the other hand, several studies have looked at the link between hyperphosphataemia and cardiovascular morbidity and mortality in CKD, but there is a lack of evidence to indicate that lowering phosphate levels improves cardiovascular outcomes in this population. Furthermore, the impact of liberalizing phosphate targets on CKD-MBD progression and bone fracture is currently not known. In this review we discuss the central role of phosphate in the pathogenesis of CKD-MBD and how it may be associated with fracture risk, both in hyper- and hypophosphataemia.

Author(s):  
Sharjeel Usmani ◽  
Najeeb Ahmed ◽  
Gopinath Gnanasegaran ◽  
Fahad Marafi ◽  
Tim van den Wyngaert

BMJ Open ◽  
2019 ◽  
Vol 9 (2) ◽  
pp. e024382 ◽  
Author(s):  
Nicole Lioufas ◽  
Nigel D Toussaint ◽  
Eugenia Pedagogos ◽  
Grahame Elder ◽  
Sunil V Badve ◽  
...  

IntroductionPatients with chronic kidney disease (CKD) are at heightened cardiovascular risk, which has been associated with abnormalities of bone and mineral metabolism. A deeper understanding of these abnormalities should facilitate improved treatment strategies and patient-level outcomes, but at present there are few large, randomised controlled clinical trials to guide management. Positive associations between serum phosphate and fibroblast growth factor 23 (FGF-23) and cardiovascular morbidity and mortality in both the general and CKD populations have resulted in clinical guidelines suggesting that serum phosphate be targeted towards the normal range, although few randomised and placebo-controlled studies have addressed clinical outcomes using interventions to improve phosphate control. Early preventive measures to reduce the development and progression of vascular calcification, left ventricular hypertrophy and arterial stiffness are crucial in patients with CKD.Methods and analysisWe outline the rationale and protocol for an international, multicentre, randomised parallel-group trial assessing the impact of the non-calcium-based phosphate binder, lanthanum carbonate, compared with placebo on surrogate markers of cardiovascular disease in a predialysis CKD population—the IMpact of Phosphate Reduction On Vascular End-points (IMPROVE)-CKD study. The primary objective of the IMPROVE-CKD study is to determine if the use of lanthanum carbonate reduces the burden of cardiovascular disease in patients with CKD stages 3b and 4 when compared with placebo. The primary end-point of the study is change in arterial compliance measured by pulse wave velocity over a 96-week period. Secondary outcomes include change in aortic calcification and biochemical parameters of serum phosphate, parathyroid hormone and FGF-23 levels.Ethics and disseminationEthical approval for the IMPROVE-CKD trial was obtained by each local Institutional Ethics Committee for all 17 participating sites in Australia, New Zealand and Malaysia prior to study commencement. Results of this clinical trial will be published in peer-reviewed journals and presented at conferences.Trial registration numberACTRN12610000650099.


Author(s):  
Stuart M. Sprague ◽  
Menaka Sarav

The kidneys play a critical role in maintaining normal serum calcium and phosphorus concentrations, under the regulation of three main hormones: parathyroid hormone, calcitriol, and fibroblast growth factor 23. With the progression of chronic kidney disease (CKD), most patients develop CKD–mineral and bone disorder (CKD-MBD), which is a systemic disorder involving derangement in mineral metabolism, renal osteodystrophy, and extraskeletal calcification. Disturbances in mineral metabolism develop early in CKD and include phosphate retention, hypocalcaemia, vitamin D deficiency, and hyperparathyroidism. Renal osteodystrophy involves pathologic changes of bone morphology related to progressive CKD and is quantifiable by histomorphometry, based on bone biopsy. CKD-MBD is associated with significant morbidity, including bone loss, fractures, cardiovascular disease, immune suppression, as well as increased mortality. As the disorder begins early in the course of CKD, a proactive approach with intervention is important. Therapeutic strategies could then be employed to prevent and correct these disturbances, aiming to improve cardiovascular outcomes and survival. Current practice guidelines for CKD-MBD are based on insufficient data and high-quality studies are required before specific treatment can be advocated strongly.


Author(s):  
Jonathan P. Law ◽  
Anna M. Price ◽  
Luke Pickup ◽  
Ashwin Radhakrishnan ◽  
Chris Weston ◽  
...  

Abstract Chronic kidney disease is highly prevalent, affecting 10% to 15% of the adult population worldwide and is associated with increased cardiovascular morbidity and mortality. As chronic kidney disease worsens, a unique cardiovascular phenotype develops characterized by heart muscle disease, increased arterial stiffness, atherosclerosis, and hypertension. Cardiovascular risk is multifaceted, but most cardiovascular deaths in patients with advanced chronic kidney disease are caused by heart failure and sudden cardiac death. While the exact drivers of these deaths are unknown, they are believed to be caused by uremic cardiomyopathy: a specific pattern of myocardial hypertrophy, fibrosis, with both diastolic and systolic dysfunction. Although the pathogenesis of uremic cardiomyopathy is likely to be multifactorial, accumulating evidence suggests increased production of fibroblast growth factor‐23 and αKlotho deficiency as potential major drivers of cardiac remodeling in patients with uremic cardiomyopathy. In this article we review the increasing understanding of the physiology and clinical aspects of uremic cardiomyopathy and the rapidly increasing knowledge of the biology of both fibroblast growth factor‐23 and αKlotho. Finally, we discuss how dissection of these pathological processes is aiding the development of therapeutic options, including small molecules and antibodies, directly aimed at improving the cardiovascular outcomes of patients with chronic kidney disease and end‐stage renal disease.


2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
M Burnier ◽  
L R Ruilope ◽  
G B Bader ◽  
S D Durg ◽  
P B Brunel

Abstract Background Blood pressure (BP) control is critical in delaying the progression of chronic kidney disease (CKD), which otherwise results in an increased risk of cardiovascular morbidity and mortality. Angiotensin II receptor blockers (ARBs) or angiotensin-converting enzyme inhibitors, are recommended by several guidelines as first-line treatment for patients with hypertension and CKD. Purpose We reviewed and analysed the effect of ARB treatment on BP and renal outcomes (estimated glomerular filtration rate (eGFR), serum creatinine (SCr), creatinine clearance (CrCl) or proteinuria) in patients with hypertension and CKD with or without diabetes, including large clinical trials such as RENAAL and IDNT. Methods MEDLINE, EMBASE, and BIOSIS databases were searched for literature from the earliest available date to July 2017. Randomised (parallel-group) controlled trials of ≥8 weeks assessed the impact of ARBs on systolic/diastolic BP (SBP/DBP), eGFR, SCr, CrCl or proteinuria were included in the analysis. Meta-analysis (post- versus pre-treatment) and meta-regression were conducted in R-statistical software (v3.4.1) using meta- and metafor-packages. Mean difference (MD, generic inverse variance) with 95% confidence intervals (CIs) was used to pool data for an outcome in a single forest plot. The risk of bias (quality) of included studies was assessed by the six items of the Cochrane instrument. Results Of the 165 articles assessed for eligibility, 24 studies were included in the analysis (19 evaluated ARBs as monotherapy, 4 evaluated ARBs in combination with other antihypertensives and 1 evaluated ARBs both as mono- and combination therapy). Treatment with ARBs as monotherapy for ≥8 weeks to <1 year significantly reduced mean office SBP (MD, −12.60 mmHg; 95% CI, −18.53 to −6.67)/DBP (−6.52 mmHg; −11.27 to −1.77) (p<0.01). BP reduction was also significant (p<0.01) with ARB monotherapy for ≥1 year SBP (−14.84 mmHg; −17.82 to −11.85)/DBP (−10.27 mmHg; −12.26 to −8.27). ARBs also significantly reduced SBP/DBP when combined with other antihypertensive treatments for ≥8 weeks to <1 year as well as for ≥1 year (Figure). Moreover, ARBs induced significant reductions (p<0.01) in proteinuria (≥8 weeks to <1 year [MD, −0.6 g/L; 95% CI, −0.93 to −0.26; ≥1 year [−0.9 g/L; −1.22 to −0.59]), but no significant changes in eGFR, CrCl or SCr levels. The beneficial effect of ARBs was maintained overtime with no significant additional impact on SBP change (estimate: 0.025; 95% CI, –0.14 to 0.19) or eGFR (estimate: 0.068; 95% CI, −0.14 to 0.28; p=0.53). The overall risk of bias was judged to be low. Effect of ARBs on blood pressure changes Conclusion Treatment with ARBs effectively and sustainably lowered BP and proteinuria with no significant change in eGFR in patients with hypertension and CKD with or without diabetes.


2018 ◽  
Vol 2018 ◽  
pp. 1-6 ◽  
Author(s):  
Kenichi Akiyama ◽  
Takaaki Kimura ◽  
Kazuhiro Shiizaki

Calciprotein particles (CPPs) are a new biological marker of chronic kidney disease-mineral and bone disorder (CKD-MBD). CPPs consist of phosphate, calcium, and some proteins, with phosphate being the major contributor to the level and biological activity of CPPs. Recent studies have shown the physiological and pathological significance of CPPs, including contributions to bone and mineral metabolism, and to tissue and organ impairments such as cardiovascular damage and inflammatory responses. These actions are well known as important aspects of CKD-MBD. Fibroblast growth factor 23 (FGF23), which is secreted from the bone as the phosphaturic hormone, is markedly elevated in CKD-MBD. Many clinical studies have shown significant relationships between the level of FGF23 and outcomes such as mortality, prevalence of cardiovascular disease, bone fracture, and levels of inflammatory markers. Basic and clinical studies have suggested that CPPs contribute to synthesis and secretion of FGF23. Surgical treatments such as renal transplantation and parathyroidectomy for patients with CKD-MBD suppress excess levels of phosphate, calcium, parathyroid hormone (PTH), and FGF23, which are related to the CPP level. Therefore, suppression of CPPs might also contribute to improved clinical outcomes after these treatments.


2014 ◽  
Vol 2014 ◽  
pp. 1-9 ◽  
Author(s):  
Rika Jimbo ◽  
Tatsuo Shimosawa

Patients with chronic kidney disease (CKD) are at increased risk of mortality, mainly from cardiovascular disease. Moreover, abnormal mineral and bone metabolism, the so-called CKD-mineral and bone disorder (MBD), occurs from early stages of CKD. This CKD-MBD presents a strong cardiovascular risk for CKD patients. Discovery of fibroblast growth factor 23 (FGF23) has altered our understanding of CKD-MBD and has revealed more complex cross-talk and endocrine feedback loops between the kidney, parathyroid gland, intestines, and bone. During the past decade, reports of clinical studies have described the association between FGF23 and cardiovascular risks, left ventricular hypertrophy, and vascular calcification. Recent translational reports have described the existence of FGF23-Klotho axis in the vasculature and the causative effect of FGF23 on cardiovascular disease. These findings suggest FGF23 as a promising target for novel therapeutic approaches to improve clinical outcomes of CKD patients.


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