Chronic Kidney Disease-Mineral Bone Disorder: Definitions and Rationale for a Systemic Disorder

Over the past decade there has been an increasing awareness of the complexity of bone and mineral complications observed in chronic kidney disease (CKD) and recognition that the consequences of these abnormalities affect not only the skeleton, but also the cardiovascular system. These scientific advances led to the naming of a systemic disorder, ??Chronic Kidney Disease-Mineral Bone Disorder?? (CKD-MBD) defined as abnormalities in mineral-related biochemistries, bone modeling/remodeling and strength, and extraskeletal calcification. CKD-MBD begins early in the course of progressive CKD, at estimated glomerular filtration rates of 60?ml/min or earlier, with progression such that all dialysis patients have one or more components. The older term, renal osteodystrophy is one component of CKD-MBD and should be used exclusively to define the histopathologic abnormalities of CKD-related bone remodeling. This diagnostic criteria has been further refined using a new classification system ??turnover, mineralization, and volume??, that defines bone turnover, mineralization, and volume to allow for a more complete evaluation of renal osteodystrophy. The recognition of this inter-relationship between biochemical changes, bone, and extraskeletal calcification as the systemic disorder CKD-MBD allows for enhanced communication, increased awareness/diagnosis, and improved treatment approaches with the ultimate goal of improving morbidity and mortality in patients with CKD.     

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.     

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.     

Definition and classification of renal osteodystrophy

One of the major complications that arise as a result of chronic kidney disease is that of ‘renal osteodystrophy.’ It is believed to be a multifactorial disorder of altered bone modeling. Bone biopsy occupies a central role in the differentiation of the various kinds of renal osteodystrophy based on histological findings. However, due to its limitations of being a rather invasive and costly procedure, it is performed rather infrequently. Therefore, scientists started to focus on alternative measures of classifying the various types, e.g., the parathyroid hormone (PTH). PTH has been used as an indicator of bone turnover, thereby dividing the diseases into those of high turnover and low turnover. To further our understanding of this particular disease entity, a unified definition and classification was formulated and adopted by well-renowned experts from both local and international scenes, and this is presented in some detail in this chapter. It is hoped, that such unification will enhance communication, facilitate clinical decision making, and promote the evolution of evidence-based clinical practice guidelines worldwide. (2)     

Musculoskeletal manifestations of chronic renal failure

Musculoskeletal problems remain among the main limitations of the quality of life of renal failure patients, in particular of those treated with long-term maintenance dialysis. Renal osteodystrophy continues to receive great attention. The mechanisms of uremic skeletal resistance to parathormone (PTH) are further investigated. The assay used for the dosage of "intact PTH" has been found to detect 7-84 fragments with an inhibitory effect on the action of the whole hormone. A decrease in the density of PTH receptor on osteoblasts is another recently evidenced factor. Investigations of the recently described RANK-RANKL system have demonstrated an increase in serum osteprotegerin levels, which, together with the two above-mentioned abnormalities, may explain bone resistance to PTH. These are important advances in the understanding of renal osteodystrophy as skeletal resistance to PTH appears to play an important part in the pathophysiology of secondary hyperparathyroidism and of adynamic bone disease. Because of this skeletal resistance, it has been recommended for several years that serum PTH level be monitored and kept twofold to threefold above the upper value of the normal level to maintain normal bone turnover in dialysis patients. Relative hypoparathyroidism has recently been found to be associated with increased spontaneous fracture rate and mortality, so this recommendation appears to hold adequate, despite the demonstration that serum PTH levels in this range are a poor predictor of bone turnover and that chronic parathyroid gland hyperplasia is likely to favor parathyroid gland autonomization. Recent publications have insisted on the role that hyperphosphatemia plays not only in the development of secondary hyperparathyroidism, but also of vascular, especially coronary, calcification and as a predictor of mortality. This "silent killer" of uremic patients is one of the main targets for therapeutic intervention. Extensive use of calcium-containing phosphate binders has been recently criticized as calcium overload appears to favor vascular calcification. Sevelaner (RenaGel) is a calcium- and aluminum-free phosphate binder that is an important advance in the management of renal osteodystrophy, especially in patients with extraskeletal calcification and hypercalcemia. The use of vitamin D derivatives has also raised concern because they enhance calcium and phosphorus absorption and reduce bone turnover. New metabolites with fewer hypercalcemic effects have been developed. Calcium-sensing receptor agonists are stimulating interest and are likely to take an important place in the future management of renal osteodystrophy. Uremic myopathy has received recent attention. Impaired muscle capillary oxygen transfer has been identified as a pathophysiologic factor, and progressive resistance training has been shown to improve the condition. Finally, a new entity, nephrogenic fibrosing dermopathy, has been described, which must be distinguished from calciphylaxis and scleromyxedema.     

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.     

Treatment of metabolic bone disease in patients with chronic renal disease: A perspective for rheumatologists

As glomerular filtration rate (GFR) declines from age-related bone loss or disease that specifically induces a decline in GFR, there are a number of metabolic bone conditions that may accompany the decline in GFR. These metabolic bone conditions span a spectrum from mild-to-severe secondary hyperparathyroidism in early stages of chronic kidney disease (CKD) to the development of additional heterogeneous forms of bone diseases each with distinctly quantitative bone histomorphometric characteristics. Osteoporosis can also develop in patients with CKD and end-stage renal disease (ESRD) for many reasons beyond age-related bone loss and postmenopausal (PMO) bone loss. Diagnosing osteoporosis in patients with severe CKD or ESRD is not as easy to do as it is in patients with PMO. The diagnosis of osteoporosis in patients with CKD/ESRD must be done by first excluding other forms of renal osteodystrophy, through biochemical profiling or by double tetracycline-labeled bone biopsy and the finding of low trabecular bone volume. In such patients oral bisphosphonates seem to be safe and effective down to GFR levels of 15 mL/min. In patients with stage 5 CKD, who are fracturing because of osteoporosis or who are on chronic glucocorticoids, reducing the oral bisphosphonate dosage to half of its usual prescribed dosing for PMO seems reasonable from known bisphosphonate pharmacokinetics. However, we need better scientific data to fully understand bisphosphonate usage in this population. This paper deals with the evidence available to understand management of patients with CKD and opinions on what might be a reasonable clinical approach where evidence is currently lacking.     

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.     

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.     

Pathophysiology of renal osteodystrophy

Renal osteodystrophy is a common complication of chronic Kidney disease, and abnormalities of bone metabolism are a reflection of broad-based disturbances in the control mechanisms for mineral metabolism. Secondary hyperparathyroidism is a major contributor to the high turnover form of renal osteodystrophy. Detailed investigations over the past several decades have uncovered many of the mechanisms involved in the initiation and maintenance of secondary hyperparathyroidism and it is these mechanisms that provide the basis for therapeutic intervention to control this complication of chronic kidney disease. An additional form of renal osteodystropy is characterized by abnormally low bone turnover, which also is multi-factorial in origin. Again, an understanding of the mechanisms involved in abnormal bone and mineral homeostasis provide the basis for therapy. It is only with a through understanding of the mechanisms involved in the initiation and maintenance of these complications that rational approaches to treatment may be instituted.     

腺嘌呤诱导肾性骨病大鼠模型的生物力学分析

目的:观察腺嘌呤诱导的慢性肾脏病(CKD)肾性骨病大鼠模型的腰椎及股骨的生物力学特点。方法:20只雄性SD大鼠分为正常对照组和CKD组。第6周末处死大鼠,行血清生化标志物检测,取股骨和第五腰椎做骨密度(BMD)及骨生物力学分析。结果:在第6周末,CKD组大鼠血清尿素氮、血清肌酐、血清无机磷、血清甲状旁腺激素较正常对照组均明显升高,血清钙明显降低。与正常对照组比较,CKD组的股骨和第五腰椎椎体BMD均明显降低。骨生物力学,股骨三点弯曲实验结果提示,CKD组大鼠的股骨结构力学指标和材料力学指标均明显降低;腰椎压缩实验结果提示,CKD组大鼠腰椎的结构力学指标和材料力学指标均明显降低。结论:腺嘌呤诱导的大鼠CKD模型能较好地模拟CKD时出现的高转运肾性骨病的生物力学特征,表现为皮质骨和松质骨材料力学和结构力学性能的下降,有望成为CKD肾性骨病模型的研究载体。     

Adynamic bone and chronic renal failure: an overview

Renal osteodystrophy may present with a wide spectrum of bone lesions, ranging from high bone turnover to low bone turnover. Decreased serum calcium and 1,25-dihydroxy vitamin D synthesis and retention of phosphate are involved in the pathogenesis of high bone turnover. However, several factors may influence the evolution of this disorder. The use of different therapeutic approaches (such as calcium supplements, phosphate binders, vitamin D metabolites, etc.), the type of treatment (either hemodialysis or continuous ambulatory peritoneal dialysis), and also the changes in the type of patients to whom we are offering dialysis (more diabetics and older patients are currently included in dialysis programs) may have introduced changes modifying the form of presentation of the bone metabolic disorders. As a result, recent studies reported a greater prevalence of adynamic forms of renal osteodystrophy. Patients with adynamic bone (with or without aluminum) would have more difficulties in handling and buffering calcium loads; consequently, they would have a higher risk of extraosseous calcifications.     

Bone mass measurement and its evaluation: their usefulness and problem

In this paper, bone mass measurement and its evaluation have been reviewed. The bone lesions in renal osteodystrophy are classified into high- and low turnover, and the decreased rate of bone mineral density (BMD) might be different in osteitis fibrosa and adynamic bone disease. Secondary hyperparathyroid patients showed lower BMD values in mainly composed of the cortical bone than those in mainly composed of the trabecular bone.     

Different patterns of renal osteodystrophy in Iberoamerica

The various forms of renal osteodystrophy are predominant hyperparathyroid bone disease, mixed uremic osteodystrophy, low turnover osteomalacia, and adynamic bone disease. The present study analyses a total number of 1,209 bone biopsies from 5 different countries (Brazil, Uruguay, Argentina, Portugal, and Spain). Low turnover osteomalacia and mixed uremic osteodystrophy were more common in Brazil, Uruguay, and Argentina than in Portugal and Spain whereas predominant hyperparathyroid bone disease was seen more often in Portugal and Spain. In all centers, independent of the aluminum staining technique used, the extent of aluminum deposited in bone was greater in patients presenting with low bone turnover, whether from low turnover osteomalacia or adynamic bone disease, than in the predominant hyperparathyroid bone disease. In summary, even though recent reports have indicated that, over the last decade, the incidence of aluminum-induced toxicity was reduced, aluminum still seems to be implicated in a great percentage of symptomatic low bone remodelling lesions in Iberoamerica.     

Pathogenesis of adynamic bone disease

Both relative hypoparathyroidism and low turnover bone play crucial roles in the pathogenesis of adynamic bone disease (ABD), which is the most common form renal osteodystrophy (ROD). In addition to individual factors, including diabetes, elder age, and/or uremic toxins, dialysis therapy and treatment for ROD, administration of calcium-containing phosphorus binder or active vitamin D (VD) metabolite, are associated with the pathological processes. Recently it has been suggested a potential association ABD and VD receptor polymorphism, or malnutrition state.     

Renal osteodystrophy in children: A systemic disease associated with cardiovascular manifestations

The increasing prevalence of chronic kidney disease (CKD) in the United States demands a closer evaluation of and attention to associated morbidities, and, particularly, the rising mortality related to cardiovascular disease in all age groups. Patients with CKD demonstrate an increased risk of coronary artery disease due to calcium deposition and subsequent arterial stiffening, in addition to left ventricular dysfunction with associated heart failure and arrhythmias. While clearly impacted by the traditional risk factors for development of cardiovascular disease (CVD), patients with CKD are also affected by non-traditional risk factors, including calcium overloading related to aggressive management of secondary hyperparathyroidism.Recent data have shown that a substantial number of patients with CKD are deficient in vitamin D on a nutritional basis, in addition to the known decrease in the kidney-produced active metabolite during progressive CKD. Historically, vitamin D has been described as an endocrine hormone that regulates blood calcium and parathyroid hormone levels. It has become increasingly clear, through the recognition of a vitamin D receptor in most tissues, that vitamin D possesses functions well beyond calcium homeostasis, such that a deficiency may contribute to the development of CVD. In this brief review, the role of vitamin D activation through its vitamin D receptor will serve as an introduction to the magnitude of the nutritional deficits in children, adults, and those with CKD. As therapeutic entities in the management of renal osteodystrophy, vitamin D analogues play an important role in cardiovascular health that continues to evolve. Preliminary studies indicate that vitamin D therapy for control of secondary hyperparathyroidism may confer cardioprotection and reduce mortality. Attention to care of osteodystrophy in CKD must take into account heart health as well.     

Renal osteodystrophy and biochemical markers of bone turnover

Renal osteodystrophy which associates with high rates of morbidity in patients with chronic renal failure is not an uniform metabolic bone disease. Although bone histomorphometry is the most reliable diagnostic method, several biochemical markers have been proposed for evaluation of bone turnover in hemodialysis patients. This review assesses the value and the limitations of several serum markers of bone metabolism in patients with chronic renal failure.     

Biochemical and histological spectrum of renal osteodystrophy in Argentina

Between 1994-2001 we have performed 57 bone biopsies for diagnostic purposes in symptomatic CRF patients. We analyzed here 52 samples where the material was optimal for study, and divided them into 2 periods according to when the biopsy was performed: 1994-1996 and 1997-2001, to verify changes in the spectrum of renal osteodystrophy. Mean serum values were: serum calcium 9.9 +/- 1.8 mg/dl, phosphate 5.8 +/- 3.2 mg/dl, alkaline phosphatase 693.9 +/- 968.9 Ul/L, iPTH 562.0 +/- 598.5 pg/ml, serum aluminum 65.7 +/- 79.3 ug/L and bone aluminum 22.8 +/- 22.4 ug/g. Hyperparathyroidism was the most common histological diagnosis as severe in 13 patients (25%), or as mild in 14 (27%). Ten patients had osteomalacia (19%), adynamic bone disease was diagnosed in 5 (9.6%) and mixed renal osteodystrophy in 10 (19.2%). Low bone turnover patients showed higher bone and serum aluminum than high bone turnover patients. We observed a relative increment in high turnover bone disease in the later period (1997-2001) without changes in low turnover bone disease. These data showed a high prevalence of hyperparathyroidism and aluminum-related low turnover bone disease, with no significant changes between the two time-periods analyzed here.