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Background: The management of chronic kidney disease-mineral and bone disorder requires the assessment of bone turnover, which most often is based on parathyroid hormone (PTH) concentration, the utility of which remains controversial., Study Design: Cross-sectional retrospective diagnostic test study., Setting & Participants: 492 dialysis patients from Brazil, Portugal, Turkey, and Venezuela with prior bone biopsy and stored (-20 °C) serum., Index Tests: Samples were analyzed for PTH (intact [iPTH] and whole PTH), bone-specific alkaline phosphatase (bALP), and amino-terminal propeptide of type 1 procollagen (P1NP)., Reference Test: Bone histomorphometric assessment of turnover (bone formation rate/bone surface [BFR/BS]) and receiver operating characteristic curves for discriminating diagnostic ability., Results: The biomarkers iPTH and bALP or combinations thereof allowed discrimination of low from nonlow and high from nonhigh BFR/BS, with an area under the receiver operating characteristic curve > 0.70 but < 0.80. Using iPTH level, the best cutoff to discriminate low from nonlow BFR/BS was <103.8 pg/mL, and to discriminate high from nonhigh BFR/BS was >323.0 pg/mL. The best cutoff for bALP to discriminate low from nonlow BFR/BS was <33.1 U/L, and for high from nonhigh BFR/BS, 42.1U/L. Using the KDIGO practice guideline PTH values of greater than 2 but less than 9 times the upper limit of normal, sensitivity and specificity of iPTH level to discriminate low from nonlow turnover bone disease were 65.7% and 65.3%, and to discriminate high from nonhigh were 37.0% and 85.8%, respectively., Limitations: Cross-sectional design without consideration of therapy. Potential limited generalizability with samples from 4 countries., Conclusions: The serum biomarkers iPTH, whole PTH, and bALP were able to discriminate low from nonlow BFR/BS, whereas iPTH and bALP were able to discriminate high from nonhigh BFR/BS. Prospective studies are required to determine whether evaluating trends in biomarker concentrations could guide therapeutic decisions., (Copyright © 2016 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Development of CKD-mineral and bone disorder (MBD) increases morbidity and mortality in men and women with CKD. The corresponding link among bone disease, fracture, and extraskeletal calcifications has been the subject of much focus. In the general population, the incidence of cardiovascular disease is higher in men than women, and this gender differences in degree of calcification and morbidity is maintained in kidney disease. Gender differences in phosphorus and fibroblast growth factor-23 (FGF-23) have been described. Increases in both have been linked with increasing likelihood of death in the CKD population as a whole; however, this link is not as well described when looking at women alone. The clinical significance of these differences, and the potential associated outcomes, are poorly understood. Traditional understanding of bone disease in women without kidney disease may not be fully applicable in women with CKD. Use of bone densitometry is limited in this population, and the traditional preventative interventions may not be fully transferrable to women with CKD., (Copyright © 2013 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Kidney transplantation, the most effective treatment for the metabolic abnormalities of chronic kidney disease (CKD), only partially corrects CKD-mineral and bone disorders. Posttransplantation bone disease, one of the major complications of kidney transplantation, is characterized by accelerated loss of bone mineral density and increased risk of fractures and osteonecrosis. The pathogenesis of posttransplantation bone disease is multifactorial and includes the persistent manifestations of pretransplantation CKD-mineral and bone disorder, peritransplantation changes in the fibroblast growth factor 23-parathyroid hormone-vitamin D axis, metabolic perturbations such as persistent hypophosphatemia and hypercalcemia, and the effects of immunosuppressive therapies. Posttransplantation fractures occur more commonly at peripheral than central sites. Although there is significant loss of bone density after transplantation, the evidence linking posttransplantation bone loss and subsequent fracture risk is circumstantial. Presently, there are no prospective clinical trials that define the optimal therapy for posttransplantation bone disease. Combined pharmacologic therapy that targets multiple components of the disordered pathways has been used. Although bisphosphonate or calcitriol therapy can preserve bone mineral density after transplantation, there is no evidence that these agents decrease fracture risk. Moreover, bisphosphonates pose potential risks for adynamic bone disease., (Copyright © 2013 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

This commentary provides a US perspective on the 2009 KDIGO (Kidney Disease: Improving Global Outcomes) Clinical Practice Guideline for the Diagnosis, Evaluation, Prevention, and Treatment of Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD). KDIGO is an independent international organization with the primary mission of the promotion, coordination, collaboration, and integration of initiatives to develop and implement clinical practice guidelines for the care of patients with kidney disease. The National Kidney Foundation's Kidney Disease Outcomes Quality Initiative (KDOQI), recognizing that international guidelines need to be adapted for each country, convened a group of experts to comment on the application and implementation of the KDIGO guideline for patients with CKD in the United States. This commentary puts the KDIGO guideline into the context of the supporting evidence and the setting of care delivered in the United States and summarizes important differences between prior KDOQI guidelines and the newer KDIGO guideline. It also considers the potential impact of a new bundled payment system for dialysis clinics. The KDIGO guideline addresses the evaluation and treatment of abnormalities of CKD-MBD in adults and children with CKD stages 3-5 on long-term dialysis therapy or with a kidney transplant. Tests considered are those that relate to laboratory, bone, and cardiovascular abnormality detection and monitoring. Treatments considered are interventions to treat hyperphosphatemia, hyperparathyroidism, and bone disease in patients with CKD stages 3-5D and 1-5T. Limitations of the evidence are discussed. The lack of definitive clinical outcome trials explains why most recommendations are not of level 1 but of level 2 strength, which means weak or discretionary recommendations. Suggestions for future research highlight priority areas., (Copyright 2010 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Chronic kidney disease and end-stage kidney disease are associated with significant disturbances in bone and mineral metabolism. With advances in the management of chronic kidney disease and improved outcomes of kidney transplantation, posttransplantation bone disease is a serious cause of morbidity in long-term survivors. The management of post-kidney transplantation bone disease is difficult because of its complex pathophysiology. Furthermore, studies of therapeutic options that may show improvement in bone mineral density have not necessarily been shown to decrease fracture risk. Evaluating and managing post-kidney transplantation bone disease remains an integral part of posttransplant medical care.

Chronic kidney disease (CKD) is accompanied by disturbances in calcium, phosphate, vitamin D, and parathyroid hormone (PTH) homeostasis that play an important role in the pathophysiology of renal bone disease. The increased cardiovascular morbidity and mortality observed among patients with CKD has recently been recognized to be associated with these disturbances in mineral metabolism. Thus, disturbances in mineral metabolism observed in renal failure results in a multisystem disorder, making the development of a standardized definition of these disorders a top priority. Therefore, the Board of Directors of Kidney Disease: Improving Global Outcomes proposed to define the broader category of mineral disorders associated with CKD as CKD-mineral and bone disorder (CKD-MBD). This newly proposed definition will include the disorders of mineral metabolism, bone histology (renal osteodystrophy), and the extraskeletal manifestations such as vascular calcification. This new definition and stratification of disease should result in improvement not only in the clinical management of patients but also will facilitate the interpretation and translation of clinical research. Renal osteodystrophy is now considered as 1 component of this disorder and will be defined as a morphologic alteration only, based on unification of the histomorphometric definitions that will include parameters of turnover, mineralization, and volume. An internationally accepted classification system will enable the consensus for bone biopsy evaluation as well as for the role of biomarkers. This article will focus on the newly proposed definitions of bone disease as part of CKD-MBD, based on the complex pathophysiologic process underlying bone disease in CKD stages 2 to 5.

Background: The safety and efficacy of paricalcitol injection have been well established for the prevention and treatment of secondary hyperparathyroidism (SHPT) in patients with chronic kidney disease (CKD) stage 5. The capsule form of paricalcitol was developed to provide a convenient dosage form for patients with stages 3 and 4 CKD., Methods: Three randomized, placebo-controlled, phase-3 trials were conducted in patients with stages 3 and 4 CKD with SHPT. Enrollment criteria included an estimated glomerular filtration rate between 15 and 60 mL/min/1.73 m2 (0.25 and 1.00 mL/s/1.73 m2), an average of 2 consecutive intact parathyroid hormone (iPTH) levels greater than 150 pg/mL (ng/L), 2 consecutive serum calcium levels between 8.0 and 10.0 mg/dL (2.00 and 2.50 mmol/L), and 2 consecutive serum phosphorus levels of 5.2 mg/dL or less (< or = 1.68 mmol/L). Two studies used a thrice-weekly dosing regimen and 1 study used a once-daily dosing regimen for 24 weeks. Dosing was based on serum iPTH, calcium, and phosphorus levels. The primary efficacy end point is 2 consecutive decreases in iPTH levels greater than 30% from baseline., Results: Two hundred twenty patients participated (n = 107, paricalcitol; n = 113, placebo). At least 2 consecutive decreases in iPTH levels of 30% or greater from baseline occurred in 91% of paricalcitol versus 13% of placebo patients (P < 0.001). Incidences of hypercalcemia, hyperphosphatemia, and elevated calcium-phosphorus product levels were not significantly different between groups. Similarly, no significant differences in urinary calcium and phosphorus excretion or deterioration in kidney function were detected in patients administered paricalcitol compared with placebo., Conclusion: Paricalcitol capsule was well tolerated and effectively decreased iPTH levels with minimal or no impact on calcium levels, phosphorus balance, and kidney function in patients with stages 3 and 4 CKD.

Advances in immunosuppressive therapy have allowed for enhanced allograft survival in kidney transplantation. With this increasing success of transplantation, however, has come a greater appreciation of subsequent complications, such as bone and mineral disease. In patients with chronic kidney disease who are awaiting transplantation, disorders in mineral metabolism and renal osteodystrophy are an essentially universal finding, and several different pathophysiologic mechanisms are believed to contribute to the development of these disorders.

Background: Calcitriol lowers parathyroid hormone (PTH) levels in patients with chronic kidney disease (CKD) stages 3 and 4, but its use is limited by a low therapeutic index and concerns regarding hypercalcemia and acceleration of kidney disease. We evaluated doxercalciferol (1alpha-hydroxyvitamin D2) as an alternative therapy in a randomized, double-blinded, placebo-controlled, multicenter trial., Methods: Fifty-five adults with stage 3 or 4 CKD and an intact PTH (iPTH) level greater than 85 pg/mL (ng/L) completed 8 baseline weeks, followed by 24 weeks of oral therapy with doxercalciferol or placebo. Pretreatment demographics and biochemical features did not differ between groups. Dosages were increased gradually if iPTH level was not decreased by 30% or greater and serum calcium and phosphorus levels were stable. Regular monitoring included plasma iPTH, serum calcium and phosphorus, urinary calcium, bone-specific serum markers, and serum lalpha,25-dihydroxyvitamin D levels. Glomerular filtration rate (GFR) was measured before and after treatment., Results: Mean plasma iPTH level decreased by 46% from baseline after 24 weeks of doxercalciferol treatment (P <0.001), but was unchanged with placebo. After 6 weeks, iPTH level reductions with doxercalciferol treatment exceeded those with placebo at all subsequent intervals (P <0.001). No clinically significant differences in mean serum calcium or phosphorus or urinary calcium levels or incidence of hypercalcemia, hyperphosphatemia, or hypercalciuria were noted between groups. Serum C- and N-telopeptide and bone-specific alkaline phosphatase levels decreased with doxercalciferol treatment relative to both baseline and placebo (P <0.01). Adverse-event rates and changes in GFR did not differ between groups., Conclusion: Doxercalciferol is safe and effective in controlling secondary hyperparathyroidism of patients with CKD stages 3 and 4.

Kidney transplantation is the optimal form of renal replacement therapy for many with end-stage kidney disease. However, kidney transplantation comes with a unique set of medical complications, important among them is bone disease. Posttransplant bone disorders are manifestations of pathologic processes occurring posttransplant that are superimposed on preexisting disorders of bone and mineral metabolism secondary to kidney failure and/or diabetes mellitus. As a consequence of early rapid bone loss, which is seen commonly within the first 3 to 6 months of transplant, the fracture risk posttransplant increases and has been reported as high as 5% to 44%. Posttransplant fractures occur more commonly at peripheral than central sites. Patients with a history of diabetes mellitus are at particular risk for fracture. Parathyroid hormone (PTH) and osteocalcin levels generally decrease after transplantation. Alkaline phosphatase and urinary collagen cross-links are unpredictable. Bone histology varies. No single biomarker unequivocally distinguishes between the various bone disorders found on biopsy examination. Immunosuppression is a major cause of posttransplant bone disorders. Glucocorticoids lead to decreased bone formation whereas the calcineurin inhibitors appear to cause increased bone turnover. Evaluating and managing posttransplant bone disease is an integral part of posttransplant medical care.

Bone disease develops relatively early in the development of chronic renal failure. Much of what is known about the evaluation and management of renal osteodystrophy in chronic renal failure is based on knowledge obtained in the dialysis population. The classic bone lesion found in the dialysis population is osteitis fibrosa, the high turnover lesion of secondary hyperparathyroidism. Clearly, hypocalcemia, hyperphosphatemia, and calcitriol deficiency play major roles in the development and maintenance of the high turnover disease. Interestingly, in both the dialysis and nondialysis patients, the incidence of adynamic bone disease, a low turnover lesion, is increasing. It is postulated that the aggressive use of calcium-containing phosphate binders and the use of calcitriol and other vitamin D analogs to treat secondary hyperparathyroidism may contribute to this shift in bone lesions. Treatment in the nondialysis kidney disease patient remains aggressive correction of hypocalcemia and hyperphosphatemia. The use of calcitriol and other agents to maintain serum calcium and to suppress elevated parathyroid hormone remains well supported. However, the increase in extraskeletal calcifications and incidence of adynamic bone disease in these patients raises concern about current management techniques., (Copyright 2002, Elsevier Science (USA). All rights reserved.)

Renal failure is associated with many complex bone and mineral complications. The spectrum of diseases is wide, encompassing defects in bone turnover, remodeling, and mineralization. Disease is currently defined in terms of whether a high or low turnover lesion is present. Measurement of serum parathyroid hormone levels (PTH) remains an important aspect in the management of renal bone disease, however, is limited by its lack of sensitivity in many clinical settings. Multiple biochemical markers are also available both commercially and experimentally to assist in assessing the degree of bone formation or resorption. However, when definitive diagnosis is important, when the clinical setting is confusing or complex, or when parathyroidectomy is being considered, the use of percutaneous bone biopsy is an essential tool in the understanding of underlying bone pathology and in directing therapy intervention., (Copyright 2002, Elsevier Science.)

Paricalcitol was introduced recently as an effective alternative to calcitriol for the suppression of parathyroid hormone (PTH) in patients with end-stage renal disease. An international, multicenter, double-blinded, randomized, comparative study of intravenous paricalcitol and calcitriol was performed. Results from 38 patients at dialysis units affiliated with the Northwestern University Medical School (Chicago and Evanston, IL) are reported here while a report of the full clinical trial is being completed. Results were evaluated in terms of obtaining the following end points: decrease of at least 50% in baseline PTH concentration and the occurrence of hypercalcemia and hyperphosphatemia. Paricalcitol therapy was started at a dose of 0.04 microgram/kg and increased by 0.04 microgram/kg increments every 4 weeks to a maximum allowable dose of 0.24 microgram/kg or until there was at least a 50% decrease in serum PTH concentration. Calcitriol therapy was started at a dose of 0.01 microgram/kg and increased by 0.01 microgram/kg increments every 4 weeks to a maximum allowable dose of 0.06 microgram/kg or until there was at least a 50% decrease in serum PTH concentration. Mean baseline serum PTH, calcium, and phosphorus concentrations were similar. Reductions in PTH occurred more rapidly in subjects administered paricalcitol compared with calcitriol, with no difference in serum calcium levels throughout the study between groups. The percentage of subjects experiencing severe hyperphosphatemia (serum phosphorus >8.0 mg/dL) was greater in those administered calcitriol compared with paricalcitol. In conclusion, our data suggest that paricalcitol reduces PTH levels more rapidly, with fewer episodes of hyperphosphatemia, than intravenous calcitriol.

Paricalcitol (19-nor-1,25-dihydroxyvitamin D(2)), a new vitamin D analogue, recently became available for the treatment of hyperparathyroidism in patients with end-stage renal disease. It is safe and effective in suppressing parathyroid hormone, with apparently less propensity for hypercalcemia than calcitriol (1, 25-dihydroxyvitamin D(3)). However, the mechanism of action on bone has not been fully elucidated. This study compares the effects of paricalcitol and calcitriol on the bone mineral. Neonatal (5- to 7-day-old) mouse calvariae were incubated in the absence or presence of either paricalcitol or calcitriol for 48 hours, and calcium flux, osteocalcin and acid and alkaline phosphatase activity, and interleukin-6 (IL-6) release were determined. Increasing concentrations of both calcitriol and paricalcitol increased calcium efflux. At lower concentrations, paricalcitol had no effect on acid phosphatase activity; however, at 10(-8) mol/L, paricalcitol caused a significant increase similar to that of calcitriol at 10(-9) mol/L. Increasing concentrations of paricalcitol had no effect on alkaline phosphatase activity, whereas calcitriol (10(-8) mol/L) caused significant inhibition. At low concentrations, paricalcitol had no effect on osteocalcin release; however, at 10(-8) mol/L, both compounds significantly increased osteocalcin production. Neither compound had an effect on IL-6 release. These data show that: (1) at low concentrations, both compounds induce a similar calcium efflux from cultured bone; (2) at low concentrations, paricalcitol has no effect on osteocalcin or acid and alkaline phosphatase activity; (3) at greater concentrations, paricalcitol and calcitriol have similar effects on acid phosphatase and osteocalcin activity; (4) calcitriol, but not paricalcitol, inhibits alkaline phosphatase release; and (5) the bone-resorbing effect of both compounds is independent of IL-6 release. Thus, although both compounds have similar effects on calcium efflux from bone, at therapeutic concentrations, paricalcitol does not seem to inhibit osteoblast activity. This may explain, in part, the lower calcemic effect of paricalcitol.

Advances over the last several years have led to a better understanding of the etiology of hyperparathyroidism in renal disease and to more effective means of medical prevention and therapy. Thus, in most dialysis populations, many of the serious complications, such as bone fractures, refractory hypercalcemia, and hyperphosphatemia with vascular and other extraskeletal calcifications, have diminished. Furthermore, more aggressive medical management has decreased the requirement for parathyroidectomy. Unfortunately, not all patients respond to medical management and few still develop refractory hyperparathyroidism with associated morbidity. Of the many complications of refractory hyperparathyroidism in dialysis patients, the development of life-threatening hypocalcemia has not been described. We describe a patient with severe secondary hyperparathyroidism who presented with the acute development of hypocalcemia. To our knowledge, this represents the fourth case, the first reported in a patient with end-stage renal disease, of parathyroid autoinfarction presenting as acute hypocalcemia.

To determine what factors contribute to and change bone mineral density (BMD) in dialysis patients, serial lumbar spine dual x-ray absorptiometry studies were analyzed by stepwise regression analysis in 67 black dialysis patients. The patients were 50.5 +/- 2.0 years of age (mean +/- SE) and 49% were men; the patients had received dialytic therapy for 3.7 +/- 0.5 years. The mean initial BMD z-score was 0.147 +/- 0.182. By cross-sectional analysis, the BMD increased in the male and premenopausal female patients but decreased in the postmenopausal female patients by 2.5% g/cm2/decade of life, less than that observed in black patients with normal renal function. Univariate analysis and stepwise regression analysis demonstrated radiographic evidence of osteopenia (beta-coefficient = -0.180 +/- 0.050; P = 0.001) and prior parathyroidectomy (beta-coefficient = 0.133 +/- 0.070; P = 0.054) as the only variables significantly correlated to the BMD. The effects of biochemical variables and different treatments on the delta BMD, calculated as the difference between each patient's first and second BMDs divided by the interval in years, were evaluated by stepwise regression analysis in 41 patients. The mean interval between the two BMDs was 18.4 +/- 1.02 months (range, 5 to 34 months) and the delta BMD was 0.025 +/- 0.018 g/cm2/yr, increasing in 65% of the patients. By univariate and stepwise regression analysis, the mean monthly serum total alkaline phosphatase concentration was the only variable that correlated with the delta BMD (beta-coefficient = 0.0001; P = 0.030).(ABSTRACT TRUNCATED AT 250 WORDS)

To assess the safety and efficacy of low-dose intravenous (IV) calcitriol therapy for the treatment of secondary hyperparathyroidism, 21 hemodialysis patients with amino-terminal parathyroid hormone (N-PTH) levels greater than 4 times normal were treated for 12 to 24 months in a prospective trial. The initial dose was 0.50 microgram, which was titrated every 3 months thereafter, as dictated by predialysis calcium, phosphorus, and N-PTH concentration. Dialysate calcium concentration was 1.5 mmol/L. Low-dose IV calcitriol decreased the N-PTH concentration to 48 +/- 6% and 29 +/- 5% of baseline following 12 and 24 months of therapy, respectively. The maximum dose of calcitriol was 0.92 +/- 0.11 microgram (0.50 to 2.25 micrograms). After 12 months of therapy, serum calcium increased from 2.22 +/- 0.04 to 2.41 +/- 0.03 mmol/L (8.9 +/- 0.2 to 9.7 +/- 0.1 mg/dL) without change thereafter. Baseline serum phosphorus was 1.44 +/- 0.09 mmol/L (4.5 +/- 0.3 mg/dL), and was unaltered by calcitriol therapy. Control of serum phosphorus was achieved with calcium-containing phosphate binders, except in three patients who were subsequently withdrawn from the study after 12 months because of persistent hyperphosphatemia due to noncompliance. We conclude that long-term, low-dose IV calcitriol is a safe and effective therapy for most hemodialysis patients with secondary hyperparathyroidism. In contrast to conventional dosing regimens, low-dose IV therapy does not necessitate the use of aluminum-containing phosphate binders and/or a low-calcium dialysate bath.

Beta 2-microglobulin (beta 2M) amyloidosis is common in patients on long-term hemodialysis, but the clinical conditions associated with disease activity are poorly understood. This study was designed to determine if the serum amyloid P (AP) component concentration is predictive of beta 2M amyloid disease activity. Serum AP component concentrations were determined by rocket immunoelectrophoresis and beta 2M concentrations by a commercially available kit. Radiographic evidence of beta 2M amyloidosis was determined from bone films of the hips, shoulders, and hands. Serum AP component concentrations were not different in dialysis and control patients. However, AP component concentrations in long-term (greater than or equal to 5 years) dialysis patients were significantly lower than in short-term (less than 5 years) dialysis patients (43.0 +/- 16.9 micrograms/mL [n = 28] v 56.0 +/- 18.3 micrograms/mL [n = 31], P less than 0.05). The patients on hemodialysis for 5 or more years who had radiographic evidence of severe beta 2 M amyloidosis were significantly older (57.9 +/- 9.5 v 38.3 +/- 11.3 years, P less than 0.001) and their serum AP concentrations were significantly lower (34.3 +/- 15.0 v 50.1 +/- 15.6 micrograms/mL, P less than 0.05) than long-term dialysis patients without radiographic evidence of disease. Stepwise regression analysis showed that the patient's age and serum AP component concentration were predictors of radiographic evidence of beta 2 M amyloidosis. Thus, serum AP component concentrations are decreased in long-term dialysis patients, suggesting accelerated deposition into amyloid deposits.(ABSTRACT TRUNCATED AT 250 WORDS)

These data taken together might indicate that increased tissue burdens of aluminum begin early in chronic renal disease as a consequence of oral aluminum administration. The initiation of dialysis leads to additional aluminum exposure via dialysate. Elevated endogenous parathyroid hormone levels could further enhance the absorption of orally ingested aluminum and alter tissue distribution of aluminum resulting in high brain aluminum concentration.