Bone health and vascular calcification relationships in chronic kidney disease

Abnormal bone in chronic kidney disease (CKD) may adversely affect vascular calcification via disordered calcium and phosphate metabolism. In this context, bone health should be viewed as a prerequisite for the successful prevention/treatment of vascular calcification (VC) along with controlled parathyroid hormone (PTH) secretion, the use of calcium-based phosphate binders and vitamin D therapy. In CKD patients, VC occurs more frequently and progresses more rapidly than in the general population, and is associated with increased cardiovascular disease (CVD) morbidity and mortality. A number of therapies aimed at reducing PTH concentration are associated with an increase of calcaemia and Ca × P product, e.g. calcium-containing phosphate binders or active vitamin D. The introduction of calcium-free phosphate binders has reduced calcium load, attenuating VC and improving trabecular bone content. In addition, a major breakthrough has been achieved through the use of calcimimetics, as first agents which lower PTH without increasing the concentrations of serum calcium and phosphate. Nowadays, it is becoming evident that even early stage CKD is recognised as an independent CVD risk factor. Moreover, the excess of CVD among dialysis patients cannot be explained entirely on the basis of abnormal mineral and bone metabolism. Hence, much controversy has surrounded the cost-effectiveness of treatment with the new phosphate-binding drugs as well as new vitamin D analogs and calcimimetics. Thus, it seems prudent and reasonable that maintaining bone health and mineral homeostasis should rely on some modifications of standard phosphate binding and calcitriol therapy. Hypophosphataemia and hypercalcaemia in adynamic bone disease (ABD) might be treated by reducing the number of calcium carbonate/acetate tablets in order to increase serum phosphate and decrease serum calcium, which, in turn, might positively stimulate PTH secretion. The same rationale is assumed for the use of a low calcium dialysate. On the other hand, secondary hyperparathyroidism with hyperphosphataemia and hypocalcaemia should be treated with a substantial number of calcium carbonate/acetate tablets in combination with calcitriol and low calcium dialysate in order to decrease serum phosphate and maintain the Ca × P product within K/DOQI guidelines (<4.4 mmol l⁻¹). Finally, it becomes apparent that prevention, with judicious use of calcium-based binders, vitamin D and a low calcium dialysate without adverse effects on Ca × P or oversuppression of PTH, provides the best management of VC and mineral and bone disorder in CKD patients.     

Hyperphosphatemia: pharmacologic intervention yesterday, today and tomorrow

Control of serum phosphorus continues to be of utmost importance in renal replacement therapy, due to the high prevalence of hyperphosphatemia in the dialysis population. Hyperphosphatemia has traditionally been associated with secondary hyperparathyroidism, soft tissue calcification, and renal osteodystrophy. Recent evidence implicates poor phosphorus control as an important factor in the development of cardiovascular calcification, cardiac disease, and death in patients with chronic renal failure. Dietary restriction of phosphorus, while an important factor in the control of serum phosphorus, has practical problems that limit its success in most patients. Aluminum was used in the past to inhibit phosphorus absorption, but its accumulation has serious, toxic effects on bone. Calcium-based binders have largely replaced aluminum; however, these binders are limited by the excessive amounts of calcium absorbed, which can frequently lead to positive calcium balance, suppression of bone turnover, and hypercalcemia. Calcium overloading is also associated with soft tissue and cardiovascular calcification. More recent strategies for managing hyperphosphatemia and renal bone disease include the use of nonabsorbed phosphate binders that are aluminum- and calcium-free and the development of vitamin D analogs that control parathyroid hormone activity with less calcemic effects. Future goals include defining optimal target levels of phosphorus, calcium, and parathyroid hormone and developing clinical approaches that will promote parathyroid glands, bone, and cardiac health.     

Phosphate binders for control of phosphate retention in chronic renal failure

In patients with chronic renal insufficiency, phosphate retention is a major factor in the development of secondary hyperparathyroidism, renal osteodystrophy, and soft tissue calcification, and may contribute to progression of renal failure. Prevention of phosphate retention with dietary and pharmacological means, along with the administration of calcitriol, may prevent or reverse secondary hyperparathyroidism. With more-advanced renal failure, phosphate binders become necessary to maintain phosphate balance and to prevent hyperphosphatemia. Because of toxicity, aluminum-containing phosphate binders are no longer used. Currently, calcium-containing phosphate binders, such as calcium carbonate and calcium acetate, are the most widely prescribed. Although calcium salts eliminate the problems associated with aluminum toxicity, they often result in transient hypercalcemia, requiring discontinuation of calcitriol and the use of low-calcium dialysate. Several new non- aluminum- and non-calcium-containing phosphate binders are currently at various stages of development, and may provide an alternative to the currently used binders. It is unlikely, however, that the newer compounds will completely replace calcium salts, since mild hypercalcemia may be necessary in chronic renal failure patients to suppress parathyroid hormone production. Other areas of investigation must include the development of drugs to inhibit soft tissue and renal calcifications, and to enhance urinary phosphate excretion. Received: 21 October 1998 / Revised: 7 April 1999 / Accepted: 7 April 1999     

An introduction to phosphate binders for the treatment of hyperphosphatemia in patients with chronic kidney disease

Chronic kidney disease has the potential to induce sequelae that can have severe and mortal outcomes. In particular, impaired glomerular filtration can cause a hyperphosphatemic state, which, if left unchecked, can lead to secondary hyperparathyroidism, vascular calcification, and renal osteodystrophy. Therapeutic management of hyperphosphatemia must maintain both phosphorus and calcium serum concentrations within the recommended guidelines. The balance of both minerals is regulated by parathyroid hormone; thus, an imbalance of one affects the other. In end-stage renal disease, patients often present with hypocalcemic levels due to the kidneys' inability to generate active vitamin D to promote calcium absorption in the intestine. Absorption of calcium can be increased by the administration of active vitamin D analogues. Minimizing phosphorus intake through a strict dietary regimen, combined with the use of phosphate binders to absorb excess ingested phosphate, can help to maintain serum phosphate levels near the recommended concentration of 5.5 mg/dL. Phosphate-binding compounds have evolved from the original aluminum-based binders pioneered in the 1970s to calcium-based binders such as calcium acetate, and more recently, to the following additions to the nephrologist's armamentarium: sevelamer--a polyhydrochloride polymer, and lanthanum carbonate. One of the top 2 common clinical treatments for hyperphosphatemia, calcium acetate, has an established history of efficacy since the 1980s, and has been shown to be cost effective and well tolerated, as well.     

Secondary hyperparathyroidism in diabetic and nondiabetic patients on long-term continuous ambulatory peritoneal dialysis (CAPD)

Serum values of calcium, phosphate, alkaline phosphatases and parathyroid hormone (PTH) are reported for 24 diabetic and 26 nondiabetic patients treated with continuous ambulatory peritoneal dialysis (CAPD) for a total of 779 months, without the use of vitamin D or calcium supplements. Radiographic data are reported for 25 patients followed on CAPD for at least 12 months. Serum calcium was well maintained and control of hyperphosphataemia acceptable, but phosphate-binding therapy had to be continued in the majority of patients. Diabetic patients had lower serum phosphate levels and higher serum calcium than nondiabetic patients during the first year of CAPD. In nondiabetic patients the institution of CAPD was followed by a fall in PTH, possibly largely reflecting transperitoneal PTH elimination. No patient achieved normalization of serum PTH on CAPD. Although no symptomatic bone disease was observed, radiographic evidence of progressive hyperparathyroid bone disease developed in 3 of the 25 examined patients, all nondiabetic. In summary, long-term CAPD with a dialysate calcium concentration of 1.75 mmol/l seems to be compatible with normocalcaemia and a steady-state situation with regard to secondary hyperparathyroidism in the majority of patients. Despite transperitoneal elimination, serum PTH remains elevated, and definite progression of hyperparathyroidism is observed in some patients, however, probably making a case for vitamin D therapy and/or intraperitoneal or peroral calcium supplementation in these patients.     

Role of parathyroid hormone and therapy with active vitamin D sterols in renal osteodystrophy

Renal osteodystrophy (ROD) represents a spectrum of bone lesions ranging from a high-turnover to a low-turnover state. The expression of the histologic bone lesions is modulated by parathyroid hormone (PTH), vitamin D, calcium, phosphorus, and aluminum that act as major regulators of osteoblastic activity and bone formation rate. The availability of immunometric PTH assays has allowed reasonable prediction of the subtypes of bone lesions in patients with chronic kidney disease (CKD). PTH levels as measured by these assays, however, may not reflect the true bone turnover state during treatment with intermittent active vitamin D. Early diagnosis and appropriate treatment of renal bone disease are essential in preventing the debilitating consequences of ROD on the growing skeleton. Calcitriol and calcium-containing phosphate binders have been the mainstay of treatment for secondary hyperparathyroidism. Complications such as hypercalcemia, vascular calcifications, and the development of adynamic bone may arise from aggressive treatment. New vitamin D analogs and calcium-free phosphate binders are promising in terms of limiting these complications. The management of ROD should be tailored to maintain normal rates of bone formation and turnover with age-appropriate serum calcium and phosphorus levels and with serum PTH levels that correspond to normal rates of skeletal remodeling. These treatment goals would maintain bone health, maximize growth potential, and prevent the development of soft tissue and vascular calcifications.     

Acute effect of dialysate calcium concentration and intravenous vitamin D3 on the secretion of parathyroid hormone in hemodialysis patients.

We studied the suppression of intact parathyroid hormone (PTH) in ten patients on chronic hemodialysis using different calcium concentrations of dialysate. Secondly, giving i.v. vitamin D3 at commencement of dialysis we investigated whether 1 alpha (OH)D3 or 1,25(OH)2D3 acutely modifies the responsiveness of the parathyroid gland to the suppressive effect of increased serum calcium. Dialysis with high-calcium dialysate (1.75 mmol/l) reverted the plasma PTH to normal limits. Lower-calcium dialysate (1.5 mmol/l) induced only a partial suppression of hyperparathyroidism. We found no differences in the suppression of hyperparathyroidism whether 1 alpha (OH)D3 or 1,25(OH)2D3 was given at the beginning of the dialysis or not. We conclude that the suppressibility of hyperparathyroidism in dialysis patients can be evaluated by different calcium concentrations of dialysate, and that i.v. vitamin D3 does not acutely modify the responsiveness of the parathyroid gland to the effect of calcium.     

Cardiovascular calcification in patients with end-stage renal disease: a century-old phenomenon

The mortality risk from cardiovascular disease is increased in patients with end-stage renal disease (ESRD). This is due to both traditional and dialysis-specific factors. Recently, a number of the dialysis-specific risk factors have been implicated in the pathogenesis of cardiovascular calcification. These include: hyperphosphatemia, high calcium-phosphate (Ca x P) product, elevated parathyroid hormone levels, duration of dialysis, and treatment with calcium-containing phosphate binders and vitamin D analogs. The recent availability of electron beam computed tomography (EBCT) has triggered increased awareness of the occurrence of cardiovascular calcification in ESRD patients. Given the development of transient hypercalcemia with calcium-containing binders, a link between calcium load from use of calcium-containing phosphate binders and development coronary calcification has been proposed. However, a causal relationship between use of these agents and cardiovascular calcification has not been established. Moreover, this phenomenon had been recognized over a century ago, long before these phosphate binders became available. Although its pathogenesis is likely to be multifactorial, available data strongly implicate elevated serum phosphorus as the primary culprit. Furthermore, the risk of calcification may be aggravated by vitamin D therapy, particularly in patients with severe secondary hyperparathyroidism. Therefore, achieving vigorous control of serum phosphorus, Ca x P product and parathyroid hormone level might decrease cardiovascular calcification and improve survival of patients on maintenance hemodialysis. Since calcium acetate is the most cost-effective phosphate binder available, we recommend that it should remain the first line treatment of hyperphosphatemia in patients with ESRD.     

Calcimimetics in CKD—results from recent clinical studies

Secondary hyperparathyroidism (sHPT) is a frequent complication in patients with chronic kidney disease (CKD) and a known contributor to the development of vascular calcification and renal osteodystrophy (CKD-BMD). Secondary hyperparathyroidism is also related to increased cardiovascular mortality in CKD patients. With the discovery that molecules can modulate the calcium-sensing receptor (CaR) of the parathyroid gland, new treatment options are now available to control sHPT. Calcimimetics activate the CaR and-by increasing its sensitivity to calcium-can effectively decrease parathyroid hormone (PTH) secretion. Calcimimetic treatment with cinacalcet has resulted in an effective lowering of PTH levels in both animal and clinical studies. Most clinical studies have been performed in dialysis patients, and only a few studies have been carried out in patients with CKD stage 3 & 4 and renal transplant patients. In haemodialysis patients with sHPT, cinacalcet treatment could increase the number of patients achieving National Kidney Foundation Kidney Disease Outcomes Quality Initiative targets (PTH, calcium, phosphate) compared to standard therapy. In stage 3 and 4 CKD patients, cinacalcet has been reported to reduce PTH levels, however, at the expense of increasing phosphate serum levels. Several small studies have reported that calcimimetics reduced PTH levels and hypercalcaemia after renal transplantation. In addition, two studies on paediatric dialysis patients with sHPT reported effective PTH lowering. This review summarizes recent clinical studies with cinacalcet treatment in CKD patients.     

Effect of 24,25-dihydroxycholecalciferol on intestinal absorption of calcium and phosphate and on parathyroid hormone secretion in chronic renal failure.

Twelve patients with chronic renal failure (CRF) requiring dialysis, 7 of whom were hypercalcaemic, were treated with 24,25-dihydroxycholecalciferol [24,25(OH)2D3; 10 micrograms daily for 3 months] or placebo and the treatment then crossed over for a further 3 months. Treatment with 24,25(OH)2D3 was associated with small but significant increments in the fractional rates of absorption of calcium (p less than 0.01) and phosphate (p less than 0.05) measured by a combined radioisotope test, but even during treatment, the absorption of both calcium and phosphate remained subnormal. A significant fall in immunoreactive parathyroid hormone (i-PTH) levels occurred during treatment (p less than 0.05) in the absence of significant changes in plasma ionised calcium and plasma phosphate levels. In 7 patients, treatment with 24,25(OH)2D3 converted parathyroid glands which were non-suppressible by calcium infusion before treatment to suppressible ones (greater than 50% suppression of i-PTH levels) at similar levels of ionised calcium. 24,25(OH)2D3 may have a role in the treatment of renal osteodystrophy, especially in patients with hypercalcaemic hyperparathyroidism.     

Use of vitamin D analogs in chronic renal failure

Renal osteodystrophy is the term used to describe the spectrum of bone diseases associated with chronic renal failure. Deficiency of 1,25-dihydroxycholecalciferol (calcitriol) plays a major role in the development of renal osteodystrophy, in particular the evolution of secondary hyperparathyroidism. In recent decades, our understanding of the complex interactions between calcium, phosphorus, vitamin D, and parathyroid hormone (PTH) has increased, resulting in a rational approach to therapy in which vitamin D analogs have become an essential component. The initial vitamin D analogs that have been in widespread clinical use include calcitriol (1,25-[OH](2)D(3)) and alfacalcidol (1alpha-[OH]D(3)). These agents have been extensively studied to optimize their effects on secondary hyperparathyroidism. The occurrence of significant hypercalcemia and hyperphosphatemia limiting their use has led to the development of alternative vitamin D analogs that effectively reduce PTH secretion without causing these complications. Recently, 3 such analogs, 22-oxa-1,25-(OH)(2)D(3) (OCT), 1alpha-(OH)D(2) (doxercalciferol), and 19-nor-1,25-(OH)(2)D(2) (paricalcitol), have been released for clinical use. Only paricalcitol has been studied in comparative human clinical trials with calcitriol in dialysis patients. Preliminary findings suggest a clinical advantage over calcitriol, however, analysis of the larger comparative studies are forthcoming.     

Understanding and managing hyperphosphatemia in patients with chronic renal disease

Controlling serum phosphorus levels continues to be a challenge in patients with chronic renal disease. Hyperphosphatemia is implicated in the development and worsening of secondary hyperparathyroidism and renal osteodystrophy (ROD) through its effects on serum calcium and calcitriol levels, parathyroid hormone (PTH) overproduction, and parathyroid cell hyperplasia. In the past serum phosphorus control with aluminum-containing phosphate binders was associated with insidious but serious development of aluminum toxicity. More recent approaches using non aluminum-containing calcium salts as phosphate binders are limited because of the excessive calcium load resulting from concomitant enhanced intestinal calcium absorption. Moreover serum phosphorus does not only result from dietary phosphate intake but also from enhanced bone breakdown due to secondary hyperparathyroidism. Strategies for managing ROD including early control of serum phosphorus and PTH, prevention of parathyroid hyperplasia; establishment of optimal PTH levels for bone health, and the availability of new therapeutic tools for controlling phosphorus may help prevent complications and improve patient outcomes.     

Control of hyperphosphatemia among patients with ESRD

Derangements of mineral metabolism occur during the early stages of chronic kidney disease (CKD). Hyperphosphatemia develops in the majority of patients with ESRD and has long been associated with progression of secondary hyperparathyroidism and renal osteodystrophy. More recent observational data have associated hyperphosphatemia with increased cardiovascular mortality among dialysis patients. Adequate control of serum phosphorus remains a cornerstone in the clinical management of patients with CKD not only to attenuate the progression of secondary hyperparathyroidism but also possibly to reduce the risk for vascular calcification and cardiovascular mortality. These measures include dietary phosphorus restriction, dialysis, and oral phosphate binders. Dietary restriction is limited in advanced stages of CKD. Phosphate binders are necessary to limit dietary absorption of phosphorus. Aluminum hydroxide is an efficient binder; however, its use has been nearly eliminated because of concerns of toxicity. Calcium salts are inexpensive and have been used effectively worldwide as an alternative to aluminum. Concerns of calcium overload have led to the investigation of alternatives. Currently, only two Food and Drug Administration-approved noncalcium, nonaluminum binders are available. Sevelamer hydrochloride is an exchange resin and was not as effective as calcium acetate in meeting new guideline recommendations in one double-blind clinical trial. Lanthanum carbonate is a rare earth element and has been studied less extensively. Concerns of long-term administration and toxicity exist. Furthermore, these agents are significantly more expensive than calcium salts, which may contribute to patient noncompliance.     

慢性肾脏病患者心血管钙化的影响因素分析

慢性肾脏病(chronic kidney disease,CKD)患者因高龄、高血压、高血脂、糖尿病、吸烟、男性等传统心血管钙化危险因素,加上CKD特有因素:矿物质代谢紊乱、含钙磷结合剂及活性维生素D的不合理使用、微炎症状态、氧化应激等常引起严重的心血管钙化,病情进一步发展会加速心血管事件的发生,影响CKD患者的预后。使用磷结合剂、活性维生素D及其类似物、西那卡塞等药物控制高钙、高磷、高PTH对预防心血管钙化至关重要。药物治疗无效或在治疗过程中出现不能控制的矿物质代谢异常,则要考虑手术切除甲状旁腺。甲状旁腺切除术(parathyroidectomy,PTX)作为难治性继发性甲状旁腺功能亢进患者的有效治疗之一,可迅速降低甲状旁腺素(parathyroid hormone,PTH)和血清钙磷水平,减少活性维生素D等药物的使用,缓解骨痛、瘙痒、肌无力等症状,但PTX后是否可以减轻心血管钙化?术后长期的低PTH状态与心血管钙化的关系如何?目前还没有明确的结论,本文就CKD患者心血管钙化的影响因素,尤其是PTX对CKD患者心血管钙化的影响作一综述。     

Detection and quantification of cardiovascular calcifications with electron beam tomography to estimate risk in hemodialysis patients

Cardiovascular disease is the leading cause of death in dialysis patients, accounting for nearly half of all deaths among end-stage renal disease (ESRD) patients. Even young dialysis patients are at risk. Cardiovascular disease in chronic renal failure patients has been associated with elevated serum phosphorus levels and elevated calcium-phosphorus (Ca x P) product, and mismanagement of calcium and phosphorus metabolism has been implicated as a major factor in the development of soft tissue calcification and cardiovascular disease. ESRD patients frequently face hyperphosphatemia as well as excess calcium load, which elevate the Ca x P product, thereby contributing to the development of calcific complications. Electron beam computed tomography (EBCT) can be used to detect different calcification stages in a variety of tissues, and is a sensitive tool for detecting calcified coronary artery plaques as well as cardiac and valvular calcifications. Hemodialysis patients have high calcium scores on EBCT imaging, and these are associated with elevations in Ca x P product. In a recent study, patients with calcification were found to have had twice the daily calcium intake from calcium-based phosphate binders than patients without calcification. Strategies to reduce cardiac risk in hemodialysis patients include use of a dialysate low in calcium, use of vitamin D analogs that are less calcemic, and use of calcium-free phosphate binders. EBCT can be a useful adjunct to these therapies, since it permits sensitive and quantitative initial assessment, as well as ongoing monitoring of disease progression.     

The clinical management of hyperphosphatemia

As renal function declines in patients with end-stage renal disease (ESRD), excess dietary phosphorus accumulates in the bloodstream. Routine dialysis removes up to 70% of absorbed phosphorus; therefore, hyperphosphatemia is found in the majority of patients with ESRD. The consequences of this imbalance include secondary hyperparathyroidism and osteodystrophy. Recent studies have also documented that hyperphosphatemia can lead to soft-tissue and vascular calcification; the latter is strongly associated with cardiovascular disease and, thus, increased mortality and morbidity. The reduction of phosphorus levels is, therefore, an important therapeutic target in this patient group. Management of hyperphosphatemia using conventional phosphate binders is not always successful. However, emerging therapies aim to reduce the incidence of hyperparathyroidism, bone disease, and calcification in this patient population. In this article, the consequences of hyperphosphatemia are reviewed, and recent developments in the treatment of the condition are discussed.     

腹膜透析患者继发性甲状旁腺功能亢进的诊治

继发性甲状旁腺功能亢进(SHPT)是慢性肾脏病的常见并发症,与钙磷代谢紊乱共同参与透析患者的骨骼代谢、心血管及软组织钙化,严重降低了透析患者的生活质量,增加其死亡率。其中影响维持性腹膜透析患者钙、磷、甲状旁腺激素(PTH)代谢的因素诸多,包括饮食、残余肾功能、腹膜的转运特性、透析液的钙离子浓度、磷结合剂的应用。早期诊断及合理治疗是延缓此类并发症的重要手段。临床工作中针对腹膜透析患者合并SHPT的治疗主要包括药物疗法及甲状旁腺切除术。目前国内应用的药物主要包括活性维生素D、钙剂、拟钙剂,新型钙敏感受体激动剂AMG-416已经显示出较好的临床疗效。甲状旁腺切除术主要应用于难治性SHPT患者,主要包括甲状旁腺次全切除术和甲状旁腺全切加自体移植术。     

Phosphate binders in CKD: chalking out the differences

Plasma phosphate levels are important in the evolution of hyperparathyroidism and ectopic calcification in chronic kidney disease (CKD). Although dietary management may be adequate to control plasma phosphate in its early stages, most patients develop hyperphosphataemia by CKD stages 3?4 and require the addition of a phosphate binder. Calcium-containing phosphate binders are the most used and cheapest binders but have fallen out of favour because of the potential for positive calcium balance and calcium toxicity. This problem may be attenuated by newer phosphate binders such as sevelamer hydrochloride and lanthanum carbonate. In this review, the role of phosphate as a uraemic toxin and the advantages and disadvantages of the currently available phosphate binders are discussed.     

Renal osteodystrophy in developing countries

There are distinct differences between developing and developed countries regarding the pathogenesis and management of renal osteodystrophy. Such differences are due to ethnic factors, dialysis quality, types of membranes, dialysate water, lack of technical facilities to perform bone biopsies, beta2-microglobulin, aluminium and strontium toxicity, and iron overload as well as economic factors hampering the use of effective yet more expensive phosphate binders and active vitamin D. The prevalence of renal osteodystrophy in developing countries is higher than in developed countries. It ranges from 24.4% to 63%. Aluminium related bone disease is a common cause. High strontium levels and iron overload in developing countries play a major role in the development of renal bone disease among dialysis patients.