Vitamin D and the kidney.

In the course of chronic kidney disease, alterations in vitamin D metabolism contribute to increases in the levels of parathyroid hormone and the development of skeletal disorders, and in addition, may contribute to hypertension, systemic inflammation and cardiovascular risk. In the course of chronic kidney disease, the production of 1,25-dihydroxyvitamin D from the kidney shows a progressive decline due to several factors, which include a reduction in the ability to convert 25-hydroxyvitamin-D to the active hormone, 1,25-dihydroxyvitamin D. The resulting 1,25-dihydroxyvitamin D, as well as 25-hydroxyvitamin D deficiency, correlates strongly with accelerated disease progression and mortality. An understanding of the pathophysiology involved leads to therapeutic strategies to correct these abnormalities, with the ultimate view to improve outcomes for patients with CKD.

Long-term management of CKD-mineral and bone disorder.

Chronic kidney disease-mineral and bone disorder (CKD-MBD) is the term used to describe the abnormalities of bone and mineral metabolism that occur in the setting of kidney disease. The spectrum of these abnormalities is wide, ranging from severe high-turnover bone disease on one end to marked low bone turnover bone disease on the other. Similarly, some patients have severe vascular calcifications while others do not, and the values for biochemistry determinations, including calcium, phosphorus, and parathyroid hormone, also may vary widely among patients. This variability may be influenced by such things as the chronicity of the particular kidney disease, effects of therapies such as corticosteroids on modifying the course of kidney disease, and comorbid conditions, such as diabetes, heart disease, age, and osteoporosis. The heterogeneity of CKD-MBD makes strict protocol-driven therapeutic approaches difficult; accordingly, considerable individualized therapy is required. Using a case history, we explore several of the variables and difficulties involved in patient management.

Vitamin D in chronic kidney disease.

In chronic kidney disease (CKD), abnormalities in vitamin D metabolism contribute to the development of mineral and skeletal disorders, elevations in parathyroid hormone (PTH), hypertension, systemic inflammation, renal and cardiovascular damage. CKD induces a progressive loss of the capacity of the kidney not only to convert 25-hydroxyvitamin D [25(OH)D] to circulating calcitriol, the vitamin D hormone, but also to maintain serum 25(OH)D levels for non-renal calcitriol synthesis. The resulting calcitriol and 25(OH)D deficiency associates directly with accelerated disease progression and death. This chapter presents our understanding of the pathophysiology behind 25(OH)D and calcitriol deficiency in CKD, of the adequacy of current recommendations for vitamin D supplementation and PTH suppression, and of potential markers of renal and cardiovascular lesions unrelated to PTH suppression, a knowledge required for the design of trials to obtain evidence-based recommendations for vitamin D and calcitriol replacement that improve outcomes at all stages of CKD.

Prevention and control of phosphate retention/hyperphosphatemia in CKD-MBD: what is normal, when to start, and how to treat?

Phosphate retention and, later, hyperphosphatemia are key contributors to chronic kidney disease (CKD)-mineral and bone disorder (MBD). Phosphate homeostatic mechanisms maintain normal phosphorus levels until late-stage CKD, because of early increases in parathyroid hormone (PTH) and fibroblast growth factor-23 (FGF-23). Increased serum phosphorus, and these other mineral abnormalities, individually and collectively contribute to bone disease, vascular calcification, and cardiovascular disease. Earlier phosphate control may, therefore, help reduce the early clinical consequences of CKD-MBD, and help control hyperphosphatemia and secondary hyperparathyroidism in late-stage CKD. Indeed, it is now widely accepted that achieving normal phosphorus levels is associated with distinct clinical benefits. This therapeutic goal is achievable in CKD stages 3 to 5 but more difficult in dialysis patients. Currently, phosphate control is only initiated when hyperphosphatemia occurs, but a potentially beneficial and simple approach may be to intervene earlier, for example, when tubular phosphate reabsorption is substantially diminished. Early CKD-MBD management includes dietary phosphate restriction, phosphate binder therapy, and vitamin D supplementation. Directly treating phosphorus may be the most beneficial approach because this can reduce serum phosphorus, PTH, and FGF-23. This involves dietary measures, but these are not always sufficient, and it can be more effective to also consider phosphate binder use. Vitamin D sterols can improve vitamin D deficiency and PTH levels but may worsen phosphate retention and increase FGF-23 levels, and thus, may also require concomitant phosphate binder therapy. This article discusses when and how to optimize phosphate control to provide the best clinical outcomes in CKD-MBD patients.

Clinical consequences and management of hypomagnesemia.

Magnesium deficiency and hypomagnesemia remain quite prevalent, particularly in patients in intensive care units, and may have important clinical consequences. Magnesium should be measured directly in clinical circumstances in which a risk for magnesium deficiency exists and appropriately corrected when found. This commentary reviews the current knowledge of magnesium homeostasis and the risk factors and clinical consequences of magnesium deficiency and outlines approaches to therapy.

Parathyroid hormone assay: problems and opportunities.

The assay of parathyroid hormone continues to remain problematic as a result of the presence in the circulation of a variety of parathyroid hormone (PTH) peptides derived from secretion and from peripheral metabolism. The detection of these PTH fragments to varying degrees leads to widely differing results in the various assays used, particularly in the setting of chronic kidney disease, where PTH fragments accumulate as glomerular filtration rate (GFR) falls. The differing results not only lead to problems in comparing values from various laboratories but also limit efforts to develop useful clinical practice guidelines. At the same time, research into the precise identification of the PTH fragments which contribute to the assay problems has uncovered a relatively new area of parathyroid research that has pointed to potential biologic activity of PTH peptides previously thought to be biologically inactive and which may act on a novel PTH receptor. These issues have brought new focus to the difficulties in standardization of PTH assays and have provoked efforts to provide standards to help in the characterization of PTH assays and to facilitate the development of clinical practice guidelines.

Changes in serum 25-hydroxyvitamin D and plasma intact PTH levels following treatment with ergocalciferol in patients with CKD.

BACKGROUND: Vitamin D insufficiency and deficiency are very common in patients with chronic kidney disease (CKD). The effect of ergocalciferol administration on serum 25-hydroxyvitamin D and plasma intact parathyroid hormone (PTH) levels in these patients is not known. STUDY DESIGN: Retrospective study. SETTING & PARTICIPANTS: Patients with CKD stage 3 or 4 who had a serum 25-hydroxyvitamin D level less than 30 ng/mL (<75 nmol/L) and increased plasma intact PTH level were treated with 50,000 IU of ergocalciferol once weekly for 12 weeks and once monthly thereafter for a total of 6 months. Patients were excluded if they had a history of active vitamin D sterol use. OUTCOME & MEASUREMENTS: 25-Hydroxyvitamin D and intact PTH were measured at baseline and follow-up. RESULTS: 66 patients met inclusion criteria. Average age was 70.4 +/- 1.3 (SE) years (range, 40 to 88 years), and 97% were men. There were 44 patients (66%) with CKD stage 3 and 22 patients (33%) with CKD stage 4. After a median follow-up of 6 months, there was a significant increase in 25-hydroxyvitamin D levels from 16.6 +/- 0.7 to 27.2 +/- 1.8 ng/mL (41 +/- 2 to 68 +/- 4 nmol/L; P < 0.05) and a significant decrease in plasma intact PTH levels from 231 +/- 26 to 192 +/- 25 pg/mL (ng/L; P < 0.05). A multivariate logistic regression model showed that an increase in 25-hydroxyvitamin D level greater than 5 ng/mL (>12 nmol/L) is associated with a significant likelihood of a greater than 30% decrease in plasma intact PTH level (odds ratio, 4.5; 95% confidence interval, 1.5 to 15.1; P < 0.05). Although posttreatment 25-hydroxyvitamin D levels were not different between patients with CKD stages 3 and 4, only patients with CKD stage 3 had a significant decrease in plasma intact PTH levels. LIMITATIONS: This is a retrospective study with mostly male patients. CONCLUSIONS: Results show that ergocalciferol administration has a favorable effect on PTH levels if therapy results in an increase in 25-hydroxyvitamin D levels; this effect is more evident in patients with CKD stage 3.

Metabolic bone disease in chronic kidney disease.

Metabolic bone disease is a common complication of chronic kidney disease (CKD) and is part of a broad spectrum of disorders of mineral metabolism that occur in this clinical setting and result in both skeletal and extraskeletal consequences. Detailed research in that past 4 decades has uncovered many of the mechanisms that are involved in the initiation and maintenance of the disturbances of bone and mineral metabolism and has been translated successfully from "bench to bedside" so that efficient therapeutic strategies now are available to control the complications of disturbed mineral metabolism. Recent emphasis is on the need to begin therapy early in the course of CKD. Central to the assessment of disturbances in bone and mineral metabolism is the ability to make an accurate assessment of the bone disease by noninvasive means. This remains somewhat problematic, and although measurements of parathyroid hormone are essential, recently recognized difficulties with these assays make it difficult to provide precise clinical practice guidelines for the various stages of CKD at the present time. Further research and progress in this area continue to evaluate the appropriate interventions to integrate therapies for both the skeletal and extraskeletal consequences with a view toward improving patient outcomes.

Difficulties in achieving the K/DOQI practice guidelines for bone and mineral metabolism.

Hyperparathyroidism and alterations in bone and mineral metabolism are known to occur early in the course of chronic kidney disease (CKD). The etiology of these abnormalities is multifactorial. Phosphate retention and alterations in vitamin D metabolism play important roles. The recent practice guidelines from the National Kidney Foundation (NKF) have emphasized the need to approach these problems early in the course of CKD by measuring the levels of parathyroid hormone when glomerular filtration rates (GFRs) fall to less than 60 ml/min. If hyperparathyroidism is detected, then treatment must be undertaken to try to prevent its progression. Strict guidelines have been proposed for the management of these alterations in bone and mineral metabolism when kidney disease progresses to CKD stage V. Although the initial recommendations were often opinion based, evidence is accumulating to support these views. However, with our current therapeutic armamentarium, there is considerable difficulty in achieving these practice guidelines for calcium, phosphorus, calcium-phosphorus product, and parathyroid hormone on a sustained basis. New therapeutic agents are becoming available that will help with phosphorus control and control of hyperparathyroidism, and minimize the calcium load. Additional beneficial effects of vitamin D analogs are being uncovered and are being intensively investigated. It is hoped that with attention to these practice guidelines, control of the abnormalities of mineral metabolism will be improved and will lead to improved patient outcomes.

Challenges in the therapy of secondary hyperparathyroidism.

Derangements in mineral metabolism are known to occur early in the course of chronic kidney disease (CKD). Recent clinical practice guidelines are designed to focus on the problem early in the course of kidney disease, when it is recommended to evaluate the levels of parathyroid hormone (PTH) and to try to intervene early if the levels are elevated. To begin early intervention for hyperparathyroidism in chronic kidney disease will require involvement of primary care physicians and other subspecialty groups to identify the patients at risk and begin to intervene with measures to control hyperparathyroidism and its consequences on mineral metabolism. It has recently been demonstrated that chronic kidney disease is a significant risk factor for vitamin D deficiency and since abnormalities in vitamin D metabolism are important in the generation of hyperparathyroidism, this is an issue that needs direct attention. Studies are needed to assess the effects of correcting this vitamin D deficiency in early CKD. As kidney disease progresses, efforts to control hyperparathyroidism will likely need to be intensified and several therapeutic options are available, such as phosphate binders, repletion of vitamin D, the use of active vitamin D sterols, or the use of vitamin D analogs. In addition, it is important to define the appropriate PTH values that need to be achieved to minimize complications on bone. Such studies are in progress at the present time to validate the current more specific PTH assays. Strict guidelines have been proposed for the management of bone and mineral metabolism in patients with CKD stage V on dialysis, and although these challenging recommendations were initially opinion-based, there is mounting evidence which provides confirmation of these targets as relevant. Treatment options for patients on dialysis involve the full spectrum of agents which include phosphate binders, active vitamin D sterols (often given parenterally), the use of calcimimetic agents, surgical parathyroidectomy, and evaluation of appropriate levels of dialysate calcium. Similar to early stages of CKD, studies are in progress to refine the PTH targets with the newer PTH assays. With increased focus on the complications of bone and mineral metabolism as part of the continuum of chronic kidney disease, and with a variety of new therapies available, it is anticipated that improved patient outcomes should be achievable in this patient group.

Thrombotic thrombocytopenic purpura in a patient treated with imatinib mesylate: true association or mere coincidence?

Thrombotic thrombocytopenic purpura (TTP), characterized by thrombocytopenia and microangiopathic hemolytic anemia, is a relatively rare disorder. The majority of cases have no defined causes. TTP has been reported in association with many drugs, but not with imatinib mesylate. We report a 22-year-old African-American woman who developed idiopathic hypereosinophilic syndrome. She was treated with imatinib mesylate and subsequently developed microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure. TTP was diagnosed. A kidney biopsy was performed and was diagnostic of thrombotic microangiopathy. The patient was treated with plasma exchange and hemodialysis. Her eosinophilia resolved, but she remained dialysis dependent. To our knowledge, this is the first case report of the possible association between imatinib mesylate and TTP.

Vitamin D analogs: actions and role in the treatment of secondary hyperparathyroidism.

Although calcitriol has been shown to have an important role in the pathogenesis of hyperparathyroidism, its use as a therapeutic agent often has been limited by calcemic and phosphatemic toxicity. Vitamin D analogs and the synthetic prohormones, with the potential to have lesser effects on calcium and phosphorus, have been introduced and shown to be effective therapeutic agents. Paricalcitol is used widely in the United States and may be associated with improved clinical outcomes. Further studies on the effects of these vitamin D sterols on the skeleton and further studies of potential differential effects on calcification processes will be forthcoming, and as the mechanisms of their lesser toxicity become understood, perhaps this will pave the way for a future generation of vitamin D analogs with even greater specificity for the suppression of hyperparathyroidism with lesser toxicity.

Vitamin D insufficiency and deficiency in chronic kidney disease. A single center observational study.

BACKGROUND: Kidney disease has been identified as a risk factor for vitamin D deficiency in hospitalized patients, and low levels of 25-hydroxyvitamin D have been suggested to be a risk factor for hyperparathyroidism in patients with chronic kidney disease (CKD). However, little is known about the magnitude of vitamin D deficiency in patients with CKD living in the United States. METHODS: In this regard, we examined the levels of 25(OH)D in 43 patients with CKD and serum creatinine between 1 and 5 mg/dl (calculated glomerular filtration rate 111-11 ml/min per 1.73 m2) as well as in 103 patients undergoing hemodialysis. RESULTS: In the predialysis patients, we found that 37 of the 43 patients (86%) had suboptimal levels of vitamin D (<30 ng/ml). Regression analysis indicated that there was a negative correlation between 25(OH)D and intact parathyroid hormone (PTH). Alkaline phosphatase showed a similar but less sensitive relationship. Serum albumin levels correlated with 25(OH)D levels. In contrast to findings reported in normal individuals, the levels of calcitriol correlated with those of 25(OH)D in the patients with CKD. In the group undergoing maintenance hemodialyis, we found that 97% of the patients had vitamin D levels in the suboptimal range, and there was no correlation of 25(OH)D levels with either PTH or serum albumin values. These data indicate that vitamin D insufficiency and deficiency are highly prevalent in patients with CKD and may play a role in the development of hyperparathyroidism. The functional significance of low levels of 25(OH)D in patients with stage 5 CKD remains to be determined.

Achieving K/DOQI laboratory target values for bone and mineral metabolism: an uphill battle.

BACKGROUND: The National Kidney Foundation has recently published the Kidney Disease Outcomes Quality Initiative (K/DOQI) Clinical Practice Guidelines for Bone Metabolism and Disease in Chronic Kidney Disease (CKD). According to these guidelines, in patients with stage 5 CKD, the adjusted calcium level should be 8.4- 9.5 mg/dl, the serum phosphate should be 3.5-5.5 mg/dl, the calcium phosphorous product should be <55 mg(2)/dl(2) and the intact parathyroid hormone (PTH) level should be 150-300 pg/ml. METHODS: In order to evaluate our ability to meet these targets, we reviewed laboratory parameters of bone and mineral metabolism of 140 patients over a 6-month period in an inner city hemodialysis unit. Serum calcium and phosphate levels were determined using standard assays and PTH levels were determined using the Nichols Intact PTH assay. RESULTS: We found that the levels of serum calcium and serum phosphorus fell within the range recommended by the K/DOQI guidelines 49 and 36% of the time respectively. 57% of the determinations for calcium x phosphorus product were <55 mg(2)/dl(2). PTH levels were within the recommended values in 20% of the determinations. Only 7% of the determinations met all four criteria simultaneously in spite of meeting other K/DOQI targets such as hematocrit and dialysis adequacy. CONCLUSION: These data indicate that current practice for the management of bone and mineral metabolism in hemodialysis falls far short of meeting the K/DOQI guidelines.

Biologic effects of parathyroid hormone metabolites: implications for renal bone disease.

PTH fragments consisting of the C-terminal portion of the molecule may have biologic effects and may modify the actions of PTH. Evidence for the presence of a C-terminal PTH receptor further supports a biologic role for such fragments. Because C-PTH fragments accumulate in patients with renal insufficiency, it is possible that they may contribute to renal bone disease. The precise role of circulating C-PTH fragments in the pathogenesis, diagnosis, and management of renal osteodystrophy, however, remains to be determined. Future studies of the biologic effects and regulation of these fragments may lead to better understanding of skeletal biology and may also improve our approach to the diagnosis and treatment of renal bone disease.

Regulation of PTH1 receptor expression by uremic ultrafiltrate in UMR 106-01 osteoblast-like cells.

BACKGROUND: Homologous down-regulation/desensitization of the parathyroid hormone receptor (PTH1R)/adenylate cyclase system has been demonstrated in uremia, and may contribute to parathyroid hormone (PTH) resistance; however, additional studies have shown that parathyroidectomy fails to normalize the down-regulation of the PTH1R. The present studies were designed to test directly, in vitro, the hypothesis that factors circulating in the uremic environment, other than PTH, decrease the response of osteoblastic cells to PTH. METHODS: Studies were conducted in confluent cultures of UMR 106-01 osteoblast-like cells. Uremic ultrafiltrate (UUF) was obtained from patients on hemodialysis. Cells were exposed to media containing 50% uremic ultrafiltrate for periods of up to 72 hours. Control cultures were exposed to a buffered salt solution containing a comparable ionic composition to that of the UUF. PTH-stimulated cyclic adenosine monophosphate (cAMP) generation was determined by radioimmunoassay (RIA), PTH binding and PTH1R mRNA levels were determined by radioligand binding and Northern analysis, respectively. RESULTS: PTH-stimulated cAMP generation from cultures treated with uremic ultrafiltrate for 48 hours was 1385.8 +/- 183.2 pmol/culture/5 minutes, whereas control cultures generated 2389.5 +/- 271 pmol cAMP/culture/5 minutes (P < 0.05). PTH binding was decreased by 30% in cultures incubated with UUF as compared to controls. The decrease in binding induced by UUF was accompanied by a decrease in PTH1R mRNA levels. CONCLUSION: These findings demonstrate that factors present in UUF decrease PTH-stimulated cAMP generation by a mechanism that involves a decrease in the levels of PTH1R mRNA levels. Thus, the skeletal resistance to PTH in the setting of chronic kidney disease, may be explained, at least in part, by circulating factors other than PTH.

Parathyroid hormone: new assays, new receptors.

Accurate measurements of parathyroid hormone (PTH) in plasma are necessary for the assessment, monitoring, and therapy of disorders of bone and mineral metabolism including renal osteodystrophy. Assays for PTH have evolved to provide 2-site immunometric assays that are highly specific for the intact 84 amino-acid peptide, PTH (1-84). With the advent of such assays, it has been shown that the prior generation of assays, thought to measure intact PTH, in fact, also detected a PTH peptide that was truncated at the N-terminus and that appeared to be similar to PTH (7-84). There has been renewed interest in such circulating PTH fragments in view of the demonstration that PTH (7-84) (and other PTH peptides) might have biologic effects. These effects include an action to oppose the calcemic effect of PTH in vivo and to inhibit bone resorption and osteoclast generation in vitro. These effects appear to be mediated by actions of a receptor for PTH peptides with specificity for the C-terminal region of PTH and distinct from the PTH receptor known to be responsible for all of the classic actions of PTH. Although the C-PTH receptor has not yet been cloned, the observations have opened a new field of research in parathyroid physiology. Clinical applications of the assay of such PTH fragments in relation to the amount of circulating PTH (1-84) concentrations are being sought actively as the new PTH assay methodology is applied to the clinical arena and as the biology of the C-PTH receptor and C-terminal PTH fragments are investigated.

Metabolic acidosis up-regulates PTH/PTHrP receptors in UMR 106-01 osteoblast-like cells.

BACKGROUND: Metabolic acidosis results in skeletal demineralization by multiple mechanisms. One of these involves the inorganic phase of bone by which hydrogen ion is buffered by bone carbonate. In addition, the cellular components of bone participate by the induction and repression of several skeletal genes. Previous studies have suggested that the action of parathyroid hormone (PTH), a major regulator of bone turnover, might be altered by acidosis. The present studies were designed to test directly, in vitro, whether acidosis altered the effects of PTH in UMR 106-01 osteoblast-like cells. METHODS: Studies were conducted in confluent cultures of UMR 106-01 cells in modified Eagle's medium (MEM) with 5% fetal bovine serum (FBS) at pH values varying from 7.4 to 7.1 by addition of HCl. After time periods of 4 to 48 hours, cells were tested for cyclic AMP generation in response to PTH. PTH binding and PTH/PTHrP receptor mRNA levels were determined by radioligand binding assay and Northern analysis respectively. RESULTS: After 48 hours, decreases in pH from 7.4 to 7.1 resulted in a progressive increase in PTH-stimulated cyclic-AMP generation from 1978 +/- 294 to 4968 +/- 929 pmol/culture/5 min (P < 0.05). Basal cyclic AMP concentrations were unchanged. PTH binding increased 1.5- to twofold. Competitive inhibition binding revealed an increase in receptor number supported by up-regulation of PTH/PTHrP receptor mRNA up to twofold from control levels. CONCLUSIONS: These findings demonstrate that metabolic acidosis stimulates the response to PTH in UMR 106-01 osteoblast-like cells by a mechanism that involves an increase in the levels of PTH/PTHrP receptor mRNA. Thus, the skeletal response to acidosis that includes an increase in bone resorption may result, at least in part, from an increase in PTH/PTHrP receptors leading to an enhanced effect of PTH on bone.

Mechanisms of the regulation of EGF receptor gene expression by calcitriol and parathyroid hormone in UMR 106-01 cells.

BACKGROUND: We have previously demonstrated that parathyroid hormone (PTH) and calcitriol increase the expression of epidermal growth factor receptors (EGFR) in UMR 106-01 osteoblast-like cells. The effect of PTH is mediated by cAMP and it involves an increase in the level of EGFR mRNA. The present studies were designed to investigate the mechanisms involved in the regulation of EGFR expression by PTH and calcitriol. METHODS: To examine the mechanism of the effect of calcitriol on EGFR expression, confluent cultures of UMR 106-01 cells were exposed to calcitriol and levels of EGFR mRNA were determined by reverse transcription-polymerase chain reaction (RT-PCR). In order to study the effect of calcitriol on EGFR gene transcription, a candidate vitamin D-responsive element (VDRE) was identified in the EGFR gene promoter and complimentary 30-mer oligonucleotides spanning this region were tested for binding to recombinant VDR using EMSA. Transcriptional activity in response to calcitriol and PTH was tested in UMR 106-01 cells stably transfected with a luciferase reporter construct containing the full length EGFR gene promoter. The effect of calcitriol on EGFR mRNA stability was examined in transcriptionally arrested cells. RESULTS: Treatment with calcitriol resulted in a time and dose dependent increase in EGFR mRNA levels in confluent cultures of UMR 106-01 osteoblast-like cells. Using EMSA, we demonstrated that the putative human EGFR VDRE binds to recombinant VDR in a retinoid X receptor (RXR)-dependent manner; however, calcitriol failed to increase transcriptional activity from a luciferase reporter construct containing the full-length EGFR gene promoter in stably transfected UMR 106-01 cells. Therefore, EGFR mRNA degradation was examined in transcriptionally arrested cells and calcitriol was found to prolong the half life of EGFR mRNA. Treatment of the cultures with PTH resulted in a ninefold increase in luciferase activity after four hours of exposure, a finding that was reproduced by treatment with forskolin. CONCLUSIONS: These studies demonstrate that the calciotropic hormones PTH and calcitriol increase EGF receptor expression by different mechanisms. The former increases EGFR gene transcription whereas the latter increases EGFR mRNA stability.

Treatment of a murine model of high-turnover renal osteodystrophy by exogenous BMP-7.

BACKGROUND: The secondary hyperparathyroidism of chronic kidney disease (CKD) produces a high turnover osteodystrophy that is associated with peritrabecular fibrosis. The nature of the cells involved in the development of peritrabecular fibrosis may represent osteoprogenitors expressing a fibroblastic phenotype that are retarded from progressing through osteoblast differentiation. METHODS: To test the hypothesis that osteoblast differentiation is retarded in secondary hyperparathyroidism due to CKD producing bone marrow fibrosis, we administered bone morphogenetic protein 7 (BMP-7), a physiologic regulator of osteoblast regulation, to C57BL6 mice that had CKD produced by electrocautery of one kidney followed by contralateral nephrectomy two weeks later. Following the second surgical procedure, a subgroup of mice received daily intraperitoneal injections of BMP-7 (10 microg/kg). Three to six weeks later, the animals were sacrificed, blood was obtained for measurements of blood urea nitrogen (BUN) and parathyroid hormone (PTH) levels, and the femora and tibiae were processed for histomorphometric analysis. RESULTS: The animals had significant renal insufficiency with BUN values of 77.79 +/- 22.68 mg/dL, and the level of renal impairment between the CKD untreated mice and the CKD mice treated with BMP-7 was the same in the two groups. PTH levels averaged 81.13 +/- 51.36 and 75.4 +/- 43.61 pg/mL in the CKD and BMP-7 treated groups, respectively. The animals with CKD developed significant peritrabecular fibrosis. In addition, there was an increase in osteoblast surface and osteoid accumulation as well as increased activation frequency and increased osteoclast surface consistent with high turnover renal osteodystrophy. Treatment with BMP-7 eliminated peritrabecular fibrosis, increased osteoblast number, osteoblast surface, mineralizing surface and single labeled surface. There was also a significant decrease in the eroded surface induced by treatment with BMP-7. CONCLUSIONS: These findings indicate that BMP-7 treatment in the setting of high turnover renal osteodystrophy prevents the development of peritrabecular fibrosis, affects the osteoblast phenotype and mineralizing surfaces, and decreases bone resorption. This is compatible with a role of osteoblast differentiation in the pathophysiology of osteitis fibrosa.