Treatment of chronic kidney disease-mineral and bone disorder (CKD-MBD)

Disturbances in mineral and bone metabolism play a critical role in the pathogenesis of cardiovascular complications in patients with chronic kidney disease (CKD). The term "renal osteodystrophy" has recently been replaced with "CKD-mineral and bone disorder (CKD-MBD)", which includes vascular calcification as well as bone abnormalities. Following this paradigm shift, the Japanese Society for Dialysis Therapy released guidelines for the management of secondary hyperparathyroidism in chronic dialysis patients, which prioritized improvement in survival, but not in bone abnormalities. According to these guidelines, parathyroid intervention, such as parathyroidectomy and percutaneous ethanol injection therapy, should be indicated if mineral disorders cannot be managed by pharmacological means. Recently, several novel therapeutic tools, including sevelamer hydrochloride, calcitriol analogs, and cinacalcet hydrochloride have been introduced in the clinical setting in Japan. Harmonizing these therapeutic modalities, we should expect more effective management of CKD-MBD, leading to the improvement of morbidity and mortality in this patient population.     

Troubles minéraux et osseux dans la maladie rénale chronique : physiopathologie,conséquences et prise en charge

Chronic Kidney Disease (CKD) is associated with a strong impact on phosphocalcic homeostasis, due to the chronic reduction in glomerular filtration rate (GFR) (phosphate excretion decrease), the inhibition of calcitriol synthesis and dietary restrictions. CKD-Mineral and Bone Disorders (CKD-MBD) must be monitored in CKD patients with biological work-up associated with bone markers and bone density dual X-ray absorptiometry. Adapted diet (phosphate restriction, normalization of calcium intake) and medications (vitamin D, phosphate binders, calcimimetics) help to correct CKD-MBD. Serum parathormone must be kept between 2 to 9 times the usual values, to limit renal osteodystrophy and avoid tertiary hyperparathyroidism. CKD patients are also at risk of artery calcifications, which can significantly increase the morbidity and mortality of the affection. Bisphosphonates may be used after correction of biological abnormalities, in patients with estimated GFR above 30 ml/min/1,73 m². Even if transplantation aims to normalize kidney function, kidney transplant recipients remain at risk of CKD-MBD. Biology and bone density dual X-ray absorptiometry must be regularly assessed, especially in the few months following the transplantation. More studies are needed to know if treatments of CKD-MBD are well tolerated in severe CKD and if they are associated with a decrease of bone fracture and vascular calcifications.     

Pediatric Patients with Chronic Kidney Disease-Mineral Bone Disorder

Chronic kidney disease-mineral bone disorder (CKD-MBD) is a systemic disorder of mineral and bone metabolism that has deleterious consequences on skeletal and cardiovascular health. Nowhere is the morbidity of this disorder more telling than in children. During childhood and adolescence, CKD-MBD may result in poor growth and skeletal deformities, while the mineral dysregulation can manifest in cardiovascular disease in early adulthood, a development that places the patients at high risk for severe morbidity and early mortality. Unfortunately, management of CKD-MBD has been less than satisfactory in children despite recent advances and is limited by the lack of evidence-based treatment guidelines. More positive are ongoing research efforts, such as the Chronic Kidney Disease in Children and the Cardiovascular Comorbidity in Children with CKD (4C) studies that are currently providing important insights which should help better elucidate the pathogenesis and progression of mineral dysregulation and its clinical impact in children. Data from these studies and others will undoubtedly also help formulate clinical trials and the generation of evidence-based therapeutic options designed to provide more effective management of CKD-MBD in the pediatric population.     

Clinical Features and Manifestations of CKD-MBD

Chronic kidney disease-mineral and bone disorder (CKD-MBD) is a complex interplay of risk factors, diseases and outcomes. In the last two decades, there has been a steady drift towards definitions depending ever more closely on laboratory abnormalities, which only represent at best possible risk factors for downstream pathology. In the early years of nephrology, especially when the therapeutic agents we had available to combat CKD?CMBD were modest, bone and muscle problems were often advanced, and symptomatic, with bone and muscle pain, fractures and myopathy. This ??old style?? hyperparathyroidism paradigm has become substantially less common now, and we can forget how symptomatic, and how draining of life-quality, CKD-MBD can be. In this chapter, we explore in the main the most feared complication of all, that of a fracture, which not only are dramatically more common in CKD patients, but also have a much heightened mortality over similar fractures but not in a CKD setting.     

K/DOQI clinical practice guidelines for management of renal osteodystrophy in predialysis patients

Blood levels of PTH (parathyroid hormone) begin to rise when GFR falls below 60 mL/min/1.73 m2, and evidence of bone disease due to hyperparathyroidism may be present at Stage 3 of chronic kidney disease (CKD). IntactPTH(i-PTH) is a useful test in detecting high turnover bone disorder and low turnover bone disorder. The Work Group taken target range of serum i-PTH in predialysis patients by their opinion. Dietary phosphorus should be restricted when the serum levels of i-PTH are elevated above target range of CKD stage. If phosphorus and i-PTH levels can not be controlled within the target range, despite dietary phosphorus restriction, phosphate binders should be prescribed. Only calcium based phosphate binders are available in predialysis patients in Japan. To avoid soft tissue calcification, total elemental calcium intake should not exceed 2,000 mg/day. If vitamin D deficiency are present, vitamin D2 should be supplied. But we can't measure serum 25(OH) D and prescribe vitamin D2 in Japan. Low dose of active vitamin D sterols are effective on renal osteodystrophy in predialysis patient. Active vitamin D sterols should be prescribed from low doses and serum calcium levels and renal function should be checked frequently. It is necessary to evaluate this K/DOQI (Kidney disease outcomes quality initiative) guideline and to establish guideline in Japan.     

Diffuse soft tissue and vascular calcification in systemic lupus erythematosus with chronic kidney disease

The systemic disorder of mineral and bone metabolism which is related to chronic kidney disease (CKD) is called mineral and bone disorder (MBD). Calcifications related to CKD-MBD may occur in ophthalmic tissue, arterial walls, subcutaneous and periarticular soft tissues and organs. The vascular calcifications are the most important causes of mortality and morbidity in CKD. Here, we present a case of systemic lupus erythematosus with early and disseminated calcifications of vascular and periarticular soft tissues related to CKD-MBD.     

Biochemical Abnormalities in Chronic Kidney Disease–Mineral Bone Disease

Chronic kidney disease?Cmineral and bone disorders (CKD-MBD) is a term introduced by the Kidney Disease: Improving Global Outcomes (KDIGO) work group on mineral and bone disorder as a syndrome of interrelated biochemical, bone, and vascular abnormalities encountered in CKD. Biochemical abnormalities in CKD represent primary indicators for the diagnosis and management of CKD-MBD. This review discusses each abnormality separately, with references to both the Kidney Dialysis Outcomes Quality Initiative (KDOQI) Clinical Practice Guidelines for Bone Metabolism and Disease in Chronic Kidney Disease and KDIGO Guidelines for Mineral and Bone Disorder. Selected references to the association between biochemical abnormalities and adverse clinical outcomes in CKD population are provided.     

Diagnosis of renal osteodystrophy

Chronic Kidney Disease (CKD) is commonly associated with alterations in bone and mineral metabolism (renal osteodystrophy). To date, bone biopsy remains the gold standard for the diagnosis and classification of the various types of renal osteodystrophy, namely: osteitis fibrosa, mixed uremic osteodystrophy, osteomalacia, aplastic and adynamic bone disease. However, due to its invasive nature and the fact that it is quite expensive, there has been a clamor for a search for other tests. Traditionally, the level of parathyroid hormone (PTH) has been considered a surrogate of bone turnover. At this time, the search continues for a specific and sensitive biochemical marker for monitoring bone turnover in CKD., e.g., alkaline phosphatase, osteocalcin, collagen degradation products, etc. In this chapter, we also present the common radiographic findings that are commonly seen in patients with renal osteodystrophy. Other radiographic techniques such as, dual energy x-ray absorptiometry (DEXA) and deferoxamine challenge test (DFO) are also briefly discussed.     

Specific Bone and Mineral Disorders in Patients with Chronic Kidney Disease

Bone lesions, collectively known as renal osteodystrophy (ROD), are a common complication of chronic kidney disease (CKD). Besides osteitis fibrosa and mixed lesions, other bone and mineral disorders such as adynamic bone disease, osteomalacia, osteoporosis, dialysis-related amyloidosis, and calcific uremic arteriolopathy are increasingly recognized in patients with CKD. Although bone lesions usually begin early in the course of CKD and are progressive, symptoms and signs such as bone pain and fractures may not occur until the patient is already on maintenance dialysis. More importantly, these disorders are associated with increased risk of cardiovascular disease and mortality in patients with CKD. The term ROD does not reflect the full spectrum of bone pathology or clinical manifestations of bone and mineral disorders in patients with CKD. Accordingly, the National Kidney Foundation and, more recently the Kidney Disease: Improving Global Outcomes, now consider ROD to represent only one measure of the skeletal component of the broader syndrome of chronic kidney disease-mineral and bone disorders in which abnormalities in bone and mineral metabolism or extraskeletal calcification are observed. In this review, we will discuss, in detail, the epidemiology, pathogenesis, histopathology, clinical manifestation, diagnosis, and treatment of these disorders.     

慢性肾脏病矿物质和骨代谢紊乱血清生化学指标变化的临床分析

目的综合分析骨代谢的状态,指导临床上慢性肾脏病矿物质及骨代谢紊乱(CKD-MBD)的诊断、分型及治疗。方法对2008年11月至2009年2月在中国医科大学附属第一医院肾内科住院的56例CKD4期、5期及长期血液透析(5年以上)三组不同分期的慢性肾功不全患者清晨空腹抽血化验血清钙、磷、iPTH、bAP、TRACP,并行骨密度检查。结果三组不同分期慢性肾功不全患者CKD-MBD的发生率分别为36.4%、73.0%、87.5%(χ2=6.861,P0.05),其中高转运性骨病占65.79%,低转运性骨病占34.21%。高转运性骨病患者血清bAP和TRACP活性明显升高,而低转运性骨病患者血清bAP和TRACP活性降低。结论CKD-MBD是慢性肾功不全患者常见的并发症,以高转运性骨病为主,但低转运性骨病不容忽视。bAP和TRACP是反映成骨细胞和破骨细胞活性的敏感指标,临床上可作为鉴别高、低转运性骨病的可靠依据,结合血清钙、磷、iPTH、骨密度的改变,可以综合分析骨代谢状态,指导CKD-MBD的诊断、分型、药物的选择和综合治疗。     

Treatment of renal osteodystrophy

Chronic kidney disease (CKD) is accompanied by disturbances in calcium, phosphate, vitamin D, and parathyroid hormone (PTH) homeostasis known to play an important role in the pathophysiology of renal osteodystrophy. Increased cardiovascular morbidity and mortality rate among CKD patients, correlates with these disturbances in bone and mineral metabolism and underscores the nephrologist’s concern about the effectiveness of the present therapeutic approach. Treatment directed to normalize the calcium/phosphate, vitamin D and PTH abnormalities may adversely affect endothelial, vascular and bone cells activity. This article discusses the therapeutic approaches focuses for renal osteodystrophy.     

Mineral metabolism and bone abnormalities in children with chronic renal failure

Abnormalities in mineral metabolism and changes in skeletal histology may contribute to growth impairment in children with chronic renal failure. Hyperphosphatemia, hypocalcemia, metabolic acidosis, alterations in vitamin D and IGF synthesis and parathyroid gland dysfunction play significant roles in the development of secondary hyperparathyroidism and subsequently, bone disease in renal failure. The recent KDIGO conference has made recommendations to consider this as a systemic disorder (chronic kidney disease-mineral bone disorder) and to standardize bone histomorphometry to include bone turnover, mineralization and volume (TMV). The use of DXA to assess bone mass is controversial in children with chronic renal failure. Questions arise regarding the accuracy of bone measurements and difficulty in data interpretation especially in children with renal failure who are not only growth retarded but often have pubertal delay and osteosclerosis. The validity and feasibility of new modalities of skeletal imaging which can detect changes in both trabecular and cortical bone are currently being investigated in children. The management of mineral abnormalities and bone disease in chronic renal failure is multifactorial. To manage hyperphosphatemia, dietary phosphate restriction accompanied by intake of calcium-free and metal-free phosphate binding agents are widely utilized. Vitamin D analogs remain the primary therapy for secondary hyperparathyroidism, although the use of the less hypercalcemic agents is preferred due to concerns of calciphylaxis and vascular calcification. Future clinical studies are needed to evaluate the long-term effects of calcimimetic agents and bisphosphonate therapy in children with chronic renal failure.     

Cancellous Bone Volume Is an Indicator for Trabecular Bone Connectivity in Dialysis Patients

Background and objectives: A new assessment system for bone histology, termed the turnover-mineralization-volume system, is advocated for patients with chronic kidney disease-related mineral and bone disorder. The system measures cancellous bone volume (BV/TV) as a third major evaluation axis; however, the physiologic significance of BV/TV remains unclear.Design, setting, participants, & measurements: Conventional bone histomorphometry was performed in 75 iliac bone samples obtained from dialysis patients. In 47 of the 75 samples, the remaining samples were subjected to direct microfocus x-ray computed tomographic observation. Quantitative morphologic examinations, including micro-bone mineral densitometry, and marrow space star volume, Euler number, and node-strut analyses, were performed in the virtual three-dimensional space reconstructed from the microfocus x-ray computed tomographic images.Results: The levels of BV/TV were comparable in each of the conventional bone histomorphometric criteria. No significant correlations were found between BV/TV and other parameters. Two- and three-dimensional BV/TVs were significantly correlated with cancellous bone mass but not with cortical bone thickness or cortical bone mass. Two- and three-dimensional BV/TVs were significantly correlated with trabecular bone connectivity as determined by marrow space star volume, Euler number, and node-strut analyses.Conclusions: In dialysis patients, BV/TV is not dependent on bone turnover or bone mineralization. BV/TV is unlikely to indicate the balance between bone formation and bone resorption. Instead, it reflects trabecular bone connectivity, and improved trabecular bone connectivity is physiologically beneficial in terms of bone quality. The turnover-mineralization-volume system offers an advantage over the conventional system for the assessment of bone quality.Chronic kidney disease (CKD) is associated with various forms of metabolic bone disorders (1), which are accompanied by mineral and parathyroid metabolic abnormalities. These abnormalities are considered to be symptoms of a systemic syndrome called CKD-related mineral and bone disorder (CKD-MBD) (2).The current gold standard for assessing bone status in CKD-MBD is bone histology (3). Bone histology is conventionally classified into five categories on the basis of tetracycline labeling-dependent bone histomorphometric findings. In this conventional classification, the histologic findings are classified according to two major assessment criteria: bone turnover and bone mineralization (4). However, the Kidney Disease: Improving Global Outcomes recently advocated the addition of cancellous bone volume (BV/TV) as a third major evaluation criterion for bone histology in CKD-MBD patients. The concept of this system, called turnover-mineralization-volume (TMV) classification (2,5), has become widely recognized.The Kidney Disease: Improving Global Outcomes considers BV/TV to be the result of a balance between bone formation and bone resorption. However, the target for bone histomorphometric analysis is currently confined to cancellous bone area in most cases. Therefore, BV/TV actually indicates the balance between cancellous bone formation and cancellous bone resorption, which may not be identical to the balance between bone formation and bone resorption. The significance of knowing the balance between cancellous bone formation and cancellous bone resorption remains unknown.Thus, the justification of the use of BV/TV in the TMV system has not yet been demonstrated. First, it has not been confirmed whether BV/TV is independent of bone turnover and bone mineralization. If significant associations were found between these factors, the significance of BV/TV as an evaluation criterion would be limited.Moreover, the reason why BV/TV should be included in this classification has not been fully explained. It must be clarified whether BV/TV can theoretically enhance the balance between bone formation and bone resorption. It is unknown whether BV/TV reflects cortical bone mass, which is the major determinant of bone strength. Other factors that affect bone strength are referred to as bone quality (6), which includes the chemical and structural properties. In terms of chemical properties, bone turnover and bone mineralization can be assessed by conventional bone histomorphometry. However, it is unknown whether BV/TV is associated with the structural properties of bone quality. The validation of the TMV system in terms of these aspects has not yet been performed.On the basis of this background, we performed three-dimensional quantitative morphologic analyses of biopsied iliac bone samples obtained from CKD stage 5D (CKD5D) patients. We performed microfocus computed tomography (MCT) and novel three-dimensional image analysis (7–9). The aims of this study were (1) to confirm whether BV/TV, a new assessment criterion applied to the TMV system, is independent of bone turnover and bone mineralization, and (2) to determine whether and/or how BV/TV could be used to predict bone strength.     

Treatment of bone disease in chronic kidney disease and in renal transplant recipients under K/DOQI clinical practice guidelines

The National Kidney Foundation's Kidney Disease Outcomes Quality Initiative (K/DOQI) provides evidence based clinical practice guidelines developed for all phases of kidney disease and related complications, from diagnosis to monitoring and management. Bone disease sets in during the early stages of Chronic Kidney Disease (CKD). Bone disease is observed in almost patients with chronic renal failure and after renal transplantation. Hyperparathyroid (high turnover) bone disease in patients with chronic renal failure is found most frequently followed by mixed osteodystrophy, low-turn over bone disease, and osteomalasia. Ninety to one hundred percent of kidney transplant patients have histological evidence of osteodystrophy and osteopenia (reduction of bone mass) following renal transplantation. Furthermore, osteoporosis is also appeared in many renal transplant recipients. After renal transplantation, renal osteodystrophy generally improves but bone mineral density (BMD) often worsens. When renal bone disease is assessed using a combination of biochemical markers, histology and bone densitometry, early intervention and carefully effective therapies might be reduced the morbidity associated with these common problems.     

Parathyroid hormone variability parameters for identifying high turnover osteodystrophy disease in hemodialysis patients: an observational retrospective cohort study

Abnormalities in bone morphology that develop secondary to chronic kidney disease are defined as renal osteodystrophy and are identified by bone biopsy. As systematic and sequential bone biopsy is not practicable on a large number of patients, various chemical bone markers are commonly used to detect the bone remodeling status in chronic kidney disease and to grade bone disease in the clinical setting. Recent literature has considered the effect of absolute levels of parathyroid hormone (PTH) on clinical outcomes and not the measurement of their change over time, the PTH variability. In a retrospective observational study, we examined PTH variability parameters in a group of hemodialysis patients as independent risk factors for high vs. low turnover osteopathy, and investigated their usefulness with respect to commonly used markers of renal osteodystrophy. The study was conducted on 90 chronic hemodialysis patients undergoing regular treatment at the same dialysis centre (Catanzaro, Italy) with standard bicarbonate dialysis. Patients were classified into either high or medium-low turnover osteopathy for the diagnosis based on renal osteodystrophy using the following criteria: PTH ≥ 400 pg/mL associated with bone ALP ≥ 20 ng/mL. We used a regression-based measurement of PTH variability, which was characterized by different parameters: PTH-Res-SD, PTH-Slope, PTH-Intercept, PTH-Abs-Var, and PTH-Res-SD. In our analysis, these parameters of PTH variability were demonstrated to be good independent predictive factors for high turnover osteodystrophy, and they had a greater sensitivity than the use of a single and/or mean PTH measurements in renal osteodystrophy classification.     

Target range of PTH in ESRD patients

The normal bone turnover is important for ESRD patients in not only skeletal problem but also patients QOL and survival. The abnormal bone turnover often induces the renal osteodystrophy and ectopic calcification. The major regulative factor on bone turnover is PTH. We propose here the target zone of PTH in ESRD patients with skeletal resistance for PTH. We recommended the intact-PTH 100 - 150 pg/mL for normal Ca/Pi/bone metabolism. This range of intact-PTH is equivalent to C-PTH 4.0 - 6.2 ng/mL, HS-PTH 10.0 - 16.0 ng/mL, and whole-PTH 80 - 110 pg/mL. The maintenance of normacalcemia and normophosphatemia are important for the arrival into the target zone of PTH using active vitamin D.     

Mineral-bone disorder with chronic kidney disease

Mineral-bone disorder in chronic kidney disease is a clinical syndrome provoked by the combination of three factors: abnormal laboratory results, bone morphology disorder and extra-bone calcification. Its onset in adult age is linked with a decrease in glomerular filtration (GF < 1 ml/s). Fully developed forms occur in the course of regular dialysis treatment. The use of the traditional denomination "renal osteodystrophy" is currently restricted to the bone morphology finding. As there are two threshold types of bone turnover (low and high) and two degrees of mineralisation (low and normal), there is a total of four basic variants of mineral-bone disorder. The high turnover variants--secondary hyperparathyreosis and a combined disorder--are still the most frequent and are diagnosed in 70 to 80% of cases. Low turnover disorders include osteomalatia (OM) and adynamic bone disease (ABD). While OM is becoming increasingly rare, the occurrence of ABD is on the rise. The main reason for this may be the steady growth in the age of dialised patients and a number of risk factors, as well as treatment with inadequately high doses of vitamin D. Progressive chronic kidney disease may be linked with D-hormone deficit, negative calcium balance and with positive phosphate balance. Phosphates become a key factor in the development and progression of secondary hyperparathyreosis and extra-bone calcification in the case of D-hormone substitution. Therefore, maintaining a good phosphate balance by restricting their intake or by reducing their intestinal resorption through the use of phosphate binders is the most efficient therapeutic procedure. In patients with chronic kidney failure, adequate dialysis treatment is necessary. Hyperphosphatemia and extra-bone calcification are new independent risk factors of cardiovascular morbidity and mortality.     

Pathogenesis and treatment of renal osteodystrophy

Renal osteodystrophy is the term used to describe the many different patterns of the skeletal abnormalities that occur in patients with chronic kidney disease. The main two conditions are osteitis fibrosa, characterized by high bone turnover, increased osteoclastic and osteoblastic activity, and high levels of circulating parathyroid hormone (PTH) and adynamic bone disease characterized by low bone turnover and low levels of circulating PTH. Retention of phosphorus, decreased levels of calcitriol in blood, decreased levels of serum ionized calcium, reduced numbers of vitamin D receptors and calcium sensors in the parathyroid gland, and skeletal resistance to the calcemic action of PTH play a major role in the development of renal osteodystrophy. This review will describe the current approach for the treatment of renal osteodystrophy.     

Bone morphogenetic proteins in vascular calcification

Vascular calcification is a common problem among the elderly and those with chronic kidney disease (CKD) and diabetes. The process of tunica media vascular calcification in CKD appears to involve a phenotypic change in the vascular smooth muscle cell (VSMC) resulting in cell-mediated mineralization of the extracellular matrix. The bone morphogenetic proteins (BMPs) are important regulators in orthotopic bone formation, and their localization at sites of vascular calcification raises the question of their role. In this review, we will discuss the actions of the BMPs in vascular calcification. Although the role of BMP-2 in vascular calcification is not proven, it has been the most studied member of the BMP family in this disease process. The role of BMP-2 may be through inducing osteoblastic differentiation of VSMCs through induction of MSX-2, or by inducing apoptosis of VSMCs, a process thought critical in the initiation of vascular calcification. Additionally, BMP-2 may be related to loss of regulation of the matrix Gla protein. A second BMP, BMP-7, less studied than BMP-2 may have opposing actions in vascular calcification. In postnatal life, BMP-7 is expressed primarily in the kidney, and expression is diminished by renal injury. BMP-7 is an important regulator of skeletal remodeling and the VSMC phenotype. BMP-7 restores skeletal anabolic balance in animal models of CKD with disordered skeletal modeling, also reducing serum phosphate in the process. BMP-7 also reverses vascular calcification in CKD, and reduction in vascular calcification is due, in part, to reduced serum phosphate, an important inducer of VSMC-mediated vascular mineralization and in part to direct actions on the VSMC.