Development of a quantitative systems pharmacology model of chronic kidney disease - metabolic bone disorder

2020 ◽  
Author(s):  
Adam E Gaweda ◽  
Devin E McBride ◽  
Eleanor D. Lederer ◽  
Michael E. Brier
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Kidney Diseases ◽  
Mineral Metabolism ◽  
Individual Variability ◽  
Systems Pharmacology ◽  
Quantitative Systems Pharmacology ◽  
Therapeutic Goals ◽  
Metabolic Bone Disorder ◽  
Bone Disorder

Chronic kidney disease mineral bone disorder (CKD-MBD) is a virtually universal complication of kidney diseases, starting early in the course of disease and resulting in devastating clinical consequences ranging from bone fragility to accelerated atherosclerosis and early cardiovascular death. Guidelines for therapeutic goals for CKD-MBD have been published, and achievement of these guidelines is associated with improved survival. However, the incomplete understanding of CKD-MBD and the individual variability in the manifestations of CKD-MBD has made it difficult to achieve these guidelines. We hypothesized that the progression of MBD through all stages of CKD, including End Stage Kidney Disease could be represented by a Quantitative Systems Pharmacology/Systems Biology (QSP) model. To address this hypothesis, we constructed a QSP model of CKD-MBD, building on an open-source model of calcium and phosphorus metabolism. Specifically, we estimated and validated the model using data from 5496 CKD patients enrolled in the Chronic Renal Insufficiency Cohort (CRIC) Study. Our model accurately predicted changes in markers of mineral metabolism related to progressing CKD. We demonstrated that the incorporation of FGF23 and the soft tissue compartment is essential for accurate modeling of the changes in calcium, phosphorus, iPTH and calcitriol in CKD-MBD.

Chronic kidney disease-mineral and bone disorder

2018 ◽  
Author(s):  
Stuart M. Sprague ◽  
Menaka Sarav
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Renal Osteodystrophy ◽  
Mineral Metabolism ◽  
Bone Biopsy ◽  
Fibroblast Growth Factor 23 ◽  
Critical Role ◽  
Specific Treatment ◽  
Mineral And Bone Disorder ◽  
Bone Disorder

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.

scholarly journals Biological and Clinical Effects of Calciprotein Particles on Chronic Kidney Disease-Mineral and Bone Disorder

2018 ◽  
Vol 2018 ◽  
pp. 1-6 ◽  
Author(s):  
Kenichi Akiyama ◽  
Takaaki Kimura ◽  
Kazuhiro Shiizaki
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Clinical Studies ◽  
Inflammatory Responses ◽  
Mineral Metabolism ◽  
Fibroblast Growth Factor 23 ◽  
Clinical Effects ◽  
Mineral And Bone Disorder ◽  
Calciprotein Particles ◽  
Bone Disorder

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.

scholarly journals Recent advances in understanding and managing secondary hyperparathyroidism in chronic kidney disease

F1000Research ◽  
2020 ◽  
Vol 9 ◽  
pp. 1077 ◽  
Author(s):  
María E. Rodríguez-Ortiz ◽  
Mariano Rodríguez
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Secondary Hyperparathyroidism ◽  
Mineral Metabolism ◽  
Mineral And Bone Disorder ◽  
Parathyroid Function ◽  
Vitamin D Levels ◽  
Bone Disorder ◽  
New Evidence ◽  
Shed Light

Secondary hyperparathyroidism is a complex pathology that develops as chronic kidney disease progresses. The retention of phosphorus and the reductions in calcium and vitamin D levels stimulate the synthesis and secretion of parathyroid hormone as well as the proliferation rate of parathyroid cells. Parathyroid growth is initially diffuse but it becomes nodular as the disease progresses, making the gland less susceptible to be inhibited. Although the mechanisms underlying the pathophysiology of secondary hyperparathyroidism are well known, new evidence has shed light on unknown aspects of the deregulation of parathyroid function. Secondary hyperparathyroidism is an important feature of chronic kidney disease–mineral and bone disorder and plays an important role in the development of bone disease and vascular calcification. Thus, part of the management of chronic kidney disease relies on maintaining acceptable levels of mineral metabolism parameters in an attempt to slow down or prevent the development of secondary hyperparathyroidism. Here, we will also review the latest evidence regarding several aspects of the clinical and surgical management of secondary hyperparathyroidism.

CHRONIC KIDNEY DISEASE AND MINERAL BONE DISORDER AS RECOMMEND BY KDIGO 2017

2017 ◽  
pp. 19-31
Author(s):  
Thanh Minh Nguyen ◽  
Tam Vo
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Transplantation ◽  
Clinical Practice ◽  
Kidney Disease ◽  
Clinical Practice Guideline ◽  
Practice Guideline ◽  
Kidney Diseases ◽  
Target Range ◽  
Mineral And Bone Disorder ◽  
Bone Disorder

KDIGO 2017 Clinical Practice Guideline Update for the Diagnosis, Evaluation, Prevention, and Treatment of Chronic Kidney Disease-Mineral and Bone Disorder (CKD- MBD) is used to assist practitioners on caring for patients with chronic kidney diseases. New evidence has changed significantly clinical guidelines of dialysis and kidney transplantation. This evaluation material highlights core aspects of KDIGO 2017 Clinical Practice Guideline Update for CKD-MBD, including the reasons why the old version was modified. The topics of the material consists of updated guidelines related to the diagnosis of bone abnormalities in patients with Mineral and Bone Disorder (MBD), treating CKD-MBD by lowering serum phosphate levels to the target range and maintaining stable calcium levels, the treatment of abnormalities of parathyroid hormone in patients suffering from CKD-MBD, managing bone disorders by osteoporosis drugs, the treatment and evaluation after kidney transplantation. Key words: Chronic kidney disease; mineral and bone disorder.

scholarly journals Chronic Kidney Disease –Mineral Bone Disorder (CKD- MBD) – Further Insight at the Indian patients.

JMS SKIMS ◽  
2019 ◽  
Vol 22 (3) ◽  
Author(s):  
Muzaffar Maqsood Wani ◽  
Imtiyaz Ahmad Wani
Keyword(s):  
Chronic Kidney Disease ◽  
Vitamin D ◽  
Kidney Disease ◽  
Mineral Metabolism ◽  
Left Ventricular ◽  
Normal Serum ◽  
Vitamin D Metabolism ◽  
Mineral Bone Disorder ◽  
Bone Disorder ◽  
Normal Serum Calcium

The kidneys play an important role in maintaining normal serum calcium (Ca) and phosphorous (P) concentrations. Chronic kidney disease (CKD) is associated with significant disturbances in bone and mineral metabolism, leading to altered serum concentrations of Ca, P, vitamin D and parathyroid hormone (PTH)1,2,3. These changes are initially detected when the glomerular filtration rate (GFR) falls to ≤60 mL/min and are nearly uniform as GFR drops to <30ml/min2,3. This leads to a number of bone abnormalities previously called “renal osteodystrophy”, renamed as CKD-Mineral Bone Disorder (CKD-MBD) by National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NKF KDOQI) consensus group4 . CKD-MBD is a systemic disorder manifested by either one or a combination of a) abnormalities of Ca, P, PTH or vitamin D metabolism, b) abnormalities in bone turnover, mineralization, volume, linear growth or strength c) vascular or soft tissue calcification. This has over time been expanded to include left ventricular hypertrophy, hypertension, immune dysfunction and inflammation5,6. 

Updated mechanisms of calcification of cardiovascular system and its correction in chronic kidney disease

2020 ◽  
Vol 24 (5) ◽  
pp. 18-28
Author(s):  
F. U. Dzgoeva ◽  
O. V. Remizov ◽  
V. G. Goloeva ◽  
Z. R. Ikoeva
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Vascular Calcification ◽  
Mineral Metabolism ◽  
Fibroblast Growth Factor 23 ◽  
Aortic Pulse Wave Velocity ◽  
Left Ventricular ◽  
Elastic Fibers ◽  
Protein Energy Wasting ◽  
Therapeutic Goals

In chronic kidney disease (CKD), progressive decline in kidney function leads to disorders of mineral metabolism, which are usually called secondary hyperparathyroidism. An increase in the serum concentration of the parathyroid hormone is associ­ated with a decrease in the level of calcium and calcitriol and/or an increase in the level of fibroblast growth factor-23 and inorganic phosphate in serum. CKD-related disorders of mineral and bone metabolism are associated with other metabolic disorders, such as acidosis, protein-energy wasting, inflammation, and accumulation of uremic toxins. This contributes to vascular calcification, which is a consequence of an imbalance between numerous inhibitors and promoters of soft tissue min­eralization. Vascular calcification is a degenerative process characterized by the accumulation of calcium and phosphate salts in the artery wall. This is observed in almost all vascular areas and can develop in the media, intima, or both vascular layers of the arteries. Calcification of the intima usually occurs due to atherosclerosis and may be responsible for coronary ischemic events. Conversely, media calcification is non-exclusive and predominantly develops along elastic fibers. As a result, media calcification increases vascular stiffness, aortic pulse wave velocity, systolic and pulse blood pressure, contributing to the de­velopment of left ventricular hypertrophy and heart failure. This review examines the current understanding of the mechanisms that lead to the development of vascular calcification in CKD. The participation of factors such as inflammation, age glycation end products, indoxyl sulfate, and others in calcification processes is discussed. Promising therapeutic goals associated with a new understanding of the mechanisms of cardiovascular calcification in CKD are identified.

Current Approaches in the Treatment of Chronic Kidney Disease Mineral and Bone Disorder

2008 ◽  
Vol 21 (3) ◽  
pp. 196-213 ◽  
Author(s):  
Priscilla P. How ◽  
Darius L. Mason ◽  
Alan H. Lau
Keyword(s):  
Chronic Kidney Disease ◽  
Vitamin D ◽  
Kidney Disease ◽  
Vascular Calcification ◽  
Mineral Metabolism ◽  
High Morbidity ◽  
Mineral And Bone Disorder ◽  
Vitamin D Analogs ◽  
Bone Disorder ◽  
Stage Renal Disease

Patients with chronic kidney disease (CKD) develop mineral and bone disorder (MBD), a common and important complication, as a result of impaired phosphorus excretion and reduced vitamin D activation. Altered mineral metabolism is now recognized as an independent cardiovascular risk factor in end-stage renal disease patients and contributes to the risk for accelerating vascular calcification. CKD patients are at high risk for cardiovascular disease and vascular calcification which account for the high morbidity and mortality in this patient population. Pharmacotherapeutic interventions are necessary to manage and treat the condition. Multiple classes of agents including phosphorus binders, vitamin D analogs, and calcimimetics are now available to treat CKD-MBD. Recent data have shown that treatment with sevelamer and vitamin D analogs are associated with a reduction in calcification and cardiovascular mortality and improved survival. This article provides an overview of the strategies and considerations for the management of CKD-MBD, as well as their implications on clinical outcomes.

scholarly journals Analysis of the Prevalence and Severity of Dysregulated Bone Mineral Homeostasis in Nondialyzed Chronic Kidney Disease Patients

2021 ◽  
Author(s):  
Digishaben D. Patel ◽  
Uday Vachhani ◽  
Ajay Rajput ◽  
Pratik Raghavani ◽  
Deepak N. Parchwani ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Mineral Metabolism ◽  
Total Calcium ◽  
Female Ratio ◽  
Mineral Homeostasis ◽  
Serum Total Calcium ◽  
Mineral Bone Disorder ◽  
Bone Disorder ◽  
Calcium Phosphorus

Abstract Background Progressive loss of kidney function in chronic kidney disease (CKD) leads to altered mineral homeostasis, reflected by the imbalance in calcium and phosphorus, and has been associated with progression of renal failure. Aims The aim of this study was to investigate CKD-mineral bone disorder (CKD-MBD)-associated candidate variables and its relationship with parathyroid hormone (PTH), as well as to quantify the prevalence of CKD-associated mineral disturbances in nondialyzed CKD patients. Study Design, Materials, and Methods This cross-sectional analytical study included 124 CKD patients and 157 control participants. Blood samples were analyzed for serum total calcium, phosphorus, PTH, electrolytes, and other hematological/hemodynamic parameters by standard methods. Suitable descriptive statistics was used for different variables. Results The 124 patients had a mean age of 50.2 ± 7.8 years with male to female ratio of 1.58; majority of patients had stage 3 CKD (40.32%), and the most common comorbid conditions were diabetes mellitus ( n = 78 [62.9%]) and hypertension ( n = 63 [50.8%]). A high prevalence of mineral metabolite abnormalities was observed in a patient cohort; overall prevalence of hyperparathyroidism was found in 57.25% patients, hypocalcemia in 61.29%, and hyperphosphatemia in 82.25% patients. Prevalence of abnormal homeostasis (with regard to total calcium, phosphate, and PTH) increased progressively with the severity of disease (analysis of variance; p < 0.05). Significant differences in the mean values of total calcium, phosphorus, alkaline phosphatase, and PTH were seen compared with healthy participants ( p < 0.0001). Furthermore, there was a significant positive correlation between serum PTH with serum phosphorous ( R 2: 0.33; p < 0.0001), serum creatinine ( R 2: 0.084; p < 0.0259), serum potassium ( R 2: 0.068; p < 0.0467), and a significant negative correlation with serum total calcium ( R 2: 0.37; p < 0.0001). Conclusions CKD patients are at risk of or may already have developed secondary hyperparathyroidism apparent from PTH-linked derangements in mineral metabolism in predialysis CKD patients. These abnormalities start in early stages of CKD and worsen with disease progression. This accentuates the significance of early recognition of mineral bone disorder, understanding its pathophysiological consequences and scheduling necessary interventions/management strategies to protect the CKD patients from a plethora of complications.

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