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PubMed2001

Intravenous versus oral vitamin d therapy in dialysis patients: what is the question?

The debate regarding the administration of vitamin D (parenteral versus pulse oral) in dialysis patients has centered on the efficacy of parathyroid hormone (PTH) suppression while ignoring other questions related to complications and compliance. Past studies looking at efficacy showed no differences during short-term treatment, although the small number of patients studied reduces the significance of these findings. Long-term studies with larger populations have shown that parenteral calcitriol is more effective than pulse oral calcitriol in suppressing PTH. When considering the questions of complications and compliance the current literature demonstrates that parenteral vitamin D therapy is associated with fewer episodes of hypercalcemia and hyperphosphatemia and that patients receiving pulse oral calcitriol require more phosphate binders. Because of the documented high noncompliance rate with oral medications in the dialysis population, parenterally administered vitamin D is expected to more completely suppress PTH long term and result in fewer parathyroidectomies. Based on these considerations it is suggested that parenteral vitamin D analogs are superior to pulse oral calcitriol for the long-term control of hyperparathyroidism in dialysis patients.

Administration, Oral↗

PubMed2001

Vitamin D analogues for the management of secondary hyperparathyroidism.

Secondary hyperparathyroidism complicating chronic kidney disease requires therapy to minimize the effects of parathyroid hormone (PTH) on bone and other tissues. Low levels of calcitriol in blood play a major role in the initiation and maintenance of hyperparathyroidism. Accordingly, administration of calcitriol has been demonstrated to be an effective form of therapy. While this therapy is effective in controlling hyperparathyroidism, side effects of calcitriol, including increased intestinal absorption of calcium and phosphate, often complicate therapy by giving rise to hypercalcemia and hyperphosphatemia, which may be important risk factors for extraskeletal calcifications. Over the last several years, interest has turned toward vitamin D analogs, which may be able to affect parathyroid function with lesser effects on calcium and phosphorus in serum, and thereby, minimizing the undesirable toxicities of vitamin D therapy. Two vitamin D analogs are available in this country for the control of hyperparathyroidism in the setting of advanced kidney disease, and include 19-nor-1,25-dihydroxyvitamin D(2) (paricalcitol), and more recently, 1-alpha-hydroxyvitamin D(2) (doxercalciferol). 19-nor-1,25-dihydroxyvitamin D(2) is widely used and was evaluated extensively in animals, revealing that this vitamin D sterol had a selective effect on increasing PTH suppression, with lesser effects on calcium and phosphorus metabolism. These studies lead to clinical trials which showed the efficacy of this therapy in that PTH could be lowered satisfactorily in patients with calcium and phosphorus values within the normal range. The selectivity of 19-nor-1,25-dihydroxyvitamin D(2) seen in animals has also been found in humans, such that therapy with this sterol can achieve control of hyperparathyroidism with a wider therapeutic window than the predecessor, calcitriol. 1-alpha-hydroxyvitamin D(2) has recently been introduced, but in contrast to paracalcitol, there is little reason to believe that there is any selectivity in its actions in terms of suppressing PTH, compared with its ability to raise serum calcium or phosphorus in serum. However, this vitamin D sterol can effectively decrease PTH levels in patients with advanced renal failure. Comparative studies of paricalcitol and doxercalciferol have not been undertaken at the present time. Further studies on the mechanism of actions might explain the differences between these sterols and their effects on the intestinal absorption of calcium and phosphate. At the present, the use of vitamin D analogs can achieve control of hyperparathyroidism with a wider therapeutic window than the native sterol, calcitriol.

Animals↗

PubMed2001

Paricalcitol in dialysis patients with calcitriol-resistant secondary hyperparathyroidism.

Paricalcitol was evaluated for the treatment of secondary hyperparathyroidism (SHPT) in a long-term, prospective, open-label study of 37 patients with end-stage renal failure resistant to intravenous calcitriol. All patients had an intact parathyroid hormone (iPTH) level of 600 pg/mL or greater before being converted from calcitriol to paricalcitol therapy. Paricalcitol therapy was initiated at a 1:4 calcitriol to paricalcitol dose conversion ratio for the initial 14 patients and a 1:3 dose ratio for the next 23 patients. Subsequent dosing was based on iPTH, calcium, and phosphorus determinations. All patients underwent hemodialysis three times weekly and received structured nutritional counseling. Mean iPTH level (baseline, 901 +/- 58 pg/mL) decreased rapidly during the initial 2 months and was 165 +/- 24 pg/mL at 16 months. Alkaline phosphatase levels decreased from 280 +/- 27 IU at baseline to 65 +/- 12 IU at 16 months. Mean calcium and phosphorus levels did not change significantly over the 16 months of paricalcitol therapy. The baseline mean calcium level of 9.4 +/- 0.2 mg/dL increased to 9.7 +/- 0.2 mg/dL (P = 0.86), and phosphorus level decreased from 6.1 +/- 0.2 to 5.8 +/- 0.2 mg/dL (P = 0.77). The greater paricalcitol doses afforded by the initial dose conversion ratio of 1:4 produced unacceptably rapid iPTH suppression and subsequent hypercalcemia. Mean doses of paricalcitol decreased six- to sevenfold throughout the course of therapy while maintaining acceptable iPTH suppression. Eight patients developed hypercalcemia, which successfully managed by dietary counseling, phosphate-binder adjustment, and paricalcitol dose reduction. Six patients developed hyperphosphatemia; 3 patients responded adequately to dietary manipulation and phosphate binders, but 3 patients had repeated episodes. Three patients did not respond adequately to paricalcitol therapy and required parathyroidectomy. In summary, paricalcitol was successful at controlling SHPT in patients resistant to calcitriol therapy with minimal impact on calcium and phosphorus homeostasis. The 1:3 initial dose conversion provided the smoothest iPTH control with only a single episode of hypercalcemia in patients treated with this initial dose. Doses of paricalcitol decreased over time.

Calcitriol↗

PubMed2002

Analysis of renal bone disease treatment in dialysis patients.

End-Stage Renal Disease Network 11 initiated a renal osteodystrophy quality improvement activity in 1999. One component was the collection and assessment of dialysis facility renal osteodystrophy protocols, whereas another component was the analysis of bone disease-related medication use. Two hundred eighty-eight facilities were invited to submit protocols. A model bone disease and mineral metabolism protocol was developed as the standard for comparison. From the model protocol, an instrument was created to evaluate eight key areas (baseline screening of key laboratory data, dietary intervention, phosphate-binder use, vitamin D use, monitoring of key laboratory indicators, management of hypercalcemia, oversuppression of parathyroid hormone [PTH], and guidelines for both hemodialysis and peritoneal dialysis patients). A bone disease-related prescription survey was completed for 749 randomly selected patients. Survey information included vitamin D and phosphate-binder use and related laboratory values (calcium, phosphorus, intact PTH [iPTH], and calcium x phosphorus product). Although 45% of facilities had six or more points on the evaluation tool, protocols were still incomplete compared with the model. Mean facility-specific scores among the five states in the Network ranged from 1.0 to 5.9 (possible scores, 0 to 8). Most patients were prescribed a phosphate binder; however, 31.8% had average phosphorus levels greater than 6.0 mg/dL during the 3-month period. Only 58% of patients with average iPTH concentrations greater than 260 pg/mL were prescribed vitamin D. Of patients treated with vitamin D, 39% had iPTH concentrations less than 130 pg/mL. There is opportunity to improve renal osteodystrophy protocols in Network 11 and reinforce potential hazards of sustained hyperphosphatemia and hyperparathyroidism.

Algorithms↗

PubMed2002

Pseudohyperphosphatemia in a hyperphosphatemic hemodialysis patient.

Hyperphosphatemia is a predictable consequence of end-stage renal disease. Pseudohyperphosphatemia is a spurious elevation of serum phosphate in samples containing a substance that interferes with the laboratory assay for phosphate. The most common cause is a paraprotein in disorders such as Waldenström's macroglobulinemia and multiple myeloma. We report here a case of pseudohyperphosphatemia in a hyperphosphatemic patient with end-stage renal disease on long-term hemodialysis caused by a saline solution containing phosphorus used to dilute the patient's serum sample in the clinical chemistry laboratory. Investigations showed that the phosphorus most likely was introduced at the time of saline manufacture. Pseudohyperphosphatemia resulting from the manufacture and distribution of saline-containing phosphorus could be a cause of abnormally high serum phosphate measurements in hyperphosphatemic dialysis patients whose serum samples must be diluted in the laboratory. Such spuriously elevated results can lead to inappropriate changes in medications and subject patients to additional hemodialysis treatments.

Artifacts↗

PubMed2003

New strategies for the treatment of secondary hyperparathyroidism.

Classic pathogeneses of secondary hyperparathyroidism (2HPT), hyperphosphatemia, vitamin D deficiency, and hypocalcemia, have been treated by the administration of phosphorus binders and vitamin D derivatives. However, these therapies have not brought about a successful result. The main reason could be attributed to hypercalcemia resulting from the administration of calcium salts as a phosphorus binder and the calcemic action of vitamin D. To prevent hypercalcemia, non-calcium-containing phosphorus binders and vitamin D analogues, which suppress parathyroid hormone (PTH) secretion with minimum calcemic action, have been developed. Furthermore, calcimimetics that stimulate the calcium-sensing receptor of parathyroid cells and suppress PTH secretion are now under clinical trial. Direct injection therapy of vitamin D analogues or calcimimetics into the parathyroid gland also has been reported. These new strategies are expected to effectively and safely suppress 2HPT, which has been resistant to conventional medical treatments.

Animals↗

PubMed2003

Renal osteodystrophy: role of calcimimetics.

In patients with secondary hyperparathyroidism (HPT), increased parathyroid hormone (PTH) secretion is triggered by low plasma calcitriol levels, hypocalcemia, and hyperphosphatemia. Vitamin D analogues have been used successfully to reduce PTH levels, but increases in serum calcium, phosphorus, and calcium x phosphorus ion product levels may occur. Second-generation calcimimetics have been shown to suppress PTH levels and also reduce calcium x phosphorus ion product. Potential indications are patients with secondary HPT, particularly those who respond to calcitriol therapy with an increase in calcium x phosphorus ion product. Coadministration of active vitamin D compounds may be necessary to overcome intestinal malabsorption of calcium and maintain normocalcemia in patients on long-term treatment with calcimimetics.

Calcium↗

PubMed2007

Calcium in chronic kidney disease: recommended intake and serum targets.

Abnormal mineral metabolism has the potential to significantly increase mortality in patients with chronic kidney disease, especially by the time renal replacement therapy is required. While excess phosphorus and hyperphosphatemia have long been identified as risks for increased morbidity and mortality, the roles of calcium load and serum calcium levels have been less clear. Calcium-based recommendations in the K/DOQI Clinical Practice Guidelines for Bone Metabolism and Disease in Chronic Kidney Disease were labeled as expert opinion. The rationale behind the opinion-based recommendations is reviewed along with additional supportive information that has become available since the bone and mineral guidelines were published.

Adolescent↗

PubMed2004

Restless legs syndrome in patients on dialysis.

The past decade has seen an explosion of interest in both idiopathic and secondary restless legs syndrome (RLS). Secondary RLS occurs in patients with uremia, pregnancy, and iron deficiency. Patients experience an irresistible urge to move the legs that is worse during inactivity and at night. RLS affects 6.6% to 62% of patients on long-term dialysis therapy and is associated with a greater mortality risk. The wide range of reported prevalence is explained in part by variations in methods of diagnosis. The International Restless Legs Syndrome Study Group defined diagnostic criteria that have improved the quality of RLS research. Advanced neurological imaging techniques suggest the pathophysiological state of idiopathic RLS involves dysfunction of subcortical areas of the brain. Dopaminergic pathways and neuronal iron handling have been implicated. Limited studies of patients with uremic RLS suggested similar mechanisms, but anemia, hyperphosphatemia, and psychological factors also may have a role. The few clinical trials in uremic RLS suggest that treatment should involve the reduction of potential exacerbating agents (tricyclic antidepressants, selective serotonin uptake inhibitors, lithium, and dopamine antagonists), correction of anemia (with erythropoietin and iron), and use of levodopa or dopamine agonists. Other agents shown to be of benefit in idiopathic RLS can be tried, but may be limited by side effects in patients with uremia (benzodiazepines, opioids, gabapentin, carbamazepine, and clonidine). Symptoms of uremic RLS will disappear within a few weeks of successful renal transplantation. The progress made to date in unraveling the pathophysiological state of uremic RLS should stimulate additional research toward targeted therapy.

Dopamine Agents↗

PubMed2004

Doxercalciferol safely suppresses PTH levels in patients with secondary hyperparathyroidism associated with chronic kidney disease stages 3 and 4.

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.

Aged↗

PubMed2006

Paricalcitol capsule for the treatment of secondary hyperparathyroidism in stages 3 and 4 CKD.

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.

Adult↗

PubMed2006

Fulminant pulmonary calciphylaxis and metastatic calcification causing acute respiratory failure in a uremic patient.

Calciphylaxis is a rare and life-threatening disorder characterized by small-vessel mural calcification with intimal proliferation, fibrosis, and thrombosis, resulting in tissue ischemic necrosis. Although it has been viewed as a systemic disease involving mainly the dermis, subcutaneous fat, or muscle, calciphylaxis of other organs rarely is reported. We describe the case of a 25-year-old uremic woman who rapidly developed massive pulmonary calcification that led to acute respiratory failure after the initiation of hemodialysis therapy. Chest radiography and high-resolution computed tomography showed typical pulmonary calcification. Pulmonary calciphylaxis and metastatic calcification were confirmed further by lung tissue biopsy. No skin or muscle calciphylaxis was discovered. Despite multiple factors precipitating pulmonary calciphylaxis in this patient, we speculate that hemodialysis was the main culprit in accelerating the development of fulminant pulmonary calciphylaxis and metastatic calcification. Alteration in the local environment from an acid to an alkaline condition and a relatively high dialysate calcium level in the presence of systemic hyperphosphatemia are believed to have facilitated the deposition of calcification. This case highlights the importance of "visceral calciphylaxis" and early identification of its causes.

Acute Disease↗

PubMed2006

Parathyromatosis and the challenge of treatment.

Parathyromatosis, consisting of hyperfunctioning parathyroid tissues scattered throughout the neck, is a rare cause of recurrent hyperparathyroidism after parathyroidectomy. Medical management of patients with parathyromatosis usually is ineffective. Repeated surgery often is necessary, but generally is unsuccessful. We describe a case of parathyromatosis as a cause for recurrent hyperparathyroidism. A 32-year-old woman with a history of end-stage renal disease on hemodialysis therapy for 13 years developed secondary hyperparathyroidism requiring subtotal parathyroidectomy. Three years later, hyperparathyroidism relapsed. A technetium Tc 99m-sestamibi scan showed remnant parathyroid tissue on the left inferior thyroid lobe. Percutaneous ethanol infusion therapy failed to suppress parathormone excess, and neck exploration was performed. Histological examination of pathological lesions confirmed the diagnosis of parathyromatosis. Despite extended resection of multiple parathyroid nodules, symptoms worsened, leading progressively to severe morbidity. Imaging studies at this point showed widespread hyperfunctioning parathyroid tissue within the neck. The patient refused a third operation; thus, we resorted to coadministration of paricalcitol, a less hypercalcemic vitamin D analogue, and ibandronate, a new-generation bisphosphonate. Parathormone secretion was suppressed partially with this regimen, even at the expense of hypercalcemia and hyperphosphatemia. Sustained normalization of hormone levels and normocalcemia were accomplished only after substitution of ibandronate for the calcimimetic agent cinacalcet. The question of whether calcimimetics may maximize the chance of complete cure of parathyromatosis, especially when surgical treatment fails or is not feasible, remains to be answered by future studies.

Adult↗

PubMed2006

Results of a randomized crossover study comparing once-daily and thrice-daily sevelamer dosing.

BACKGROUND: Patients with renal failure require complex regimens of renal replacement therapies and medications, including ingestion of phosphate-binding agents 3 times daily. Previous studies suggested that sevelamer may provide extended phosphate binding and be effective with once-daily dosing, thus simplifying the phosphate-binder regimen. METHODS: Twenty-four patients were enrolled in this study, 21 of whom were randomly assigned to sevelamer administration at their previously prescribed dose, either once daily with the largest meal or thrice daily with meals, with crossover to the other regimen after 4 weeks. Eighteen patients completed both treatment periods. The primary efficacy measure for which the study was powered is comparison of the effect of once-daily versus standard thrice-daily sevelamer dosing on serum phosphorus level control, determined by using equivalence testing. Secondary efficacy measures are the effects of the 2 regimens on serum calcium level corrected for albumin level; calcium x phosphorus product; albumin; intact parathyroid hormone; total, low-density lipoprotein, high-density lipoprotein, and non-high-density lipoprotein cholesterol; and triglyceride levels. RESULTS: Once-daily sevelamer was as effective as thrice-daily dosing of sevelamer in controlling serum phosphorus, calcium, calcium x phosphorus product, serum albumin, and serum lipid levels. Bioequivalence was not shown for intact parathyroid hormone, likely because of high variability. Mean serum phosphorus levels were 4.6 +/- 0.3 mg/dL (1.49 +/- 0.10 mmol/L) during thrice-daily dosing and 5.0 +/- 0.3 mg/dL (1.61 +/- 0.10 mmol/L) during once-daily dosing. The average prescribed dose of sevelamer during both treatment regimens was 6.7 +/- 2.4 g. Routine laboratory measures were similar in the 2 groups. Both regimens were well-tolerated. CONCLUSION: Despite concerted patient-directed educational efforts, phosphorus level control in patients with renal failure is suboptimal and contributes to increased mortality risk. Once-daily sevelamer could simplify these regimens and encourage medication compliance, perhaps improving hyperphosphatemia management.

Aged↗

PubMed2004

Cardiovascular risk in stage 4 and 5 nephropathy.

Severity of heart disease of almost all types, as well as mortality risk associated with heart disease, increases in step with severity of kidney disease, although not necessarily in a linear fashion. Heart failure is more common and just as lethal as ischemic heart disease in patients with severe chronic kidney disease (CKD). The incidence of nonfatal heart disease in dialysis and transplant populations has now been described in detail. Although standard risk factors for heart disease that are more common among patients with CKD than in the general population do not adequately explain the greatly increased risk of heart disease in patients with severe CKD, neither do as yet identified "nontraditional" risk factors. However, in addition to the factors not common in the general population, such as anemia, hyperphosphatemia, and markers of systemic inflammation, patients with CKD in the modern era may also exhibit excessive thrombotic tendencies. Screening for heart disease in this population relies mainly on dobutamine stress echocardiography or nuclear scintigraphy. The role of electron beam CT (EBCT) scanning is currently controversial. The indications for coronary angiography are the same for patients with CKD as for the general population, but patients with CKD are at greatly increased risk for contrast-associated nephropathy, the least controversial preventive therapy, which consists of isotonic saline and N-acetylcysteine. Finally, patients with CKD do not currently receive adequate medical therapy for prevention and treatment of heart disease.

Cardiovascular Diseases↗

PubMed2006

Impact of convective flow on phosphorus removal in maintenance hemodialysis patients.

OBJECTIVE: Hyperphosphatemia leads to increased risk of death in maintenance hemodialysis patients (MHD). This study investigated phosphorus (P) removal, P reduction rate (PRR), and P rebound, comparing on-line, high-volume hemodiafiltration in postdilution (HDF) and high-flux hemodialysis (HD) in a setting of an equal amount of produced dialysate solution in both modalities. METHODS: A total of 22 MHD patients, treated with regular 3 x 4 hours HDF weekly, were randomly dialyzed with one 4-hour session of HDF and of HD. In both modalities, an equal amount of produced dialysate solution of 800 mL/minute was used. The only variable was the fact that in HDF, 100 mL/min of this produced dialysate solution was used as replacement fluid. The other parameters were kept identical: blood flow rate, 350 mL/min; high-flux polysulfone F80 dialyzer; and 4800 E monitor, (Fresenius, Bad Homburg, Germany). The P removal was measured in total spent dialysate and ultrafiltrate volumes. Statistical analyses were done with the paired t-test. RESULTS: The mean total P removed with HDF was 1159 +/- 296 mg, and 972 +/- 312 mg with HD (P < .001), ie, 19% higher in HDF; PRR was significantly higher in HDF (63.3%) versus HD (58.6%) (P = .014). The mean serum P did not differ: 5.3 mg/dL in HDF and 5.2 mg/dL in HD. There was a linear correlation between serum P and P removal. With a serum P level up to 5 to 5.5 mg/dL, HDF achieved a higher P removal compared with HD. The difference gradually decreased as the serum P value increased. Above 7 mg/dL, no difference in total P removal was observed. There was a high but equal rebound percentage at 60 minutes in HDF (42%) and HD (39%) (P = .42). With HDF, no predialysis metabolic acidosis was noted. CONCLUSIONS: Treatment with on-line HDF in postdilution resulted in a higher P removal and higher PRR compared with HD. The long-term implementation of this modality may result in a more optimal serum P control, without an increase in the number of or lengthening of the dialysis sessions.

Aluminum Hydroxide↗

PubMed2006

Disordered mineral metabolism and vascular calcification in nondialyzed chronic kidney disease patients.

It is well established that abnormalities in mineral metabolism are apparent early in the course of chronic kidney disease (CKD) and result in clinically relevant consequences such as renal osteodystrophy. Furthermore, there is emerging evidence linking some of these abnormalities (hyperphosphatemia) to the high cardiovascular morbidity and mortality experienced by nondialyzed patients with CKD. Most studies have evaluated vascular calcification in patients with stage 5 CKD. Reports published over the last 2 years show that the process begins rather early in CKD and is particularly severe among elderly and type 2 diabetic patients. Furthermore, "calcium begets calcium", such that the calcification burden in early CKD is an important predictor of subsequent progression, including the rapid increase seen in stage 5 CKD. There is an increasing body of evidence that supports the thesis that elevated serum levels of phosphorus and calcium and deficiency of inhibitors of calcification (for example, fetuin-A) are important in the progression of vascular calcification in patients with end-stage renal disease. However, the concentrations of calcium and phosphorus shown to induce mineralization in cell culture studies are not observed in most patients until late in stage 4 or stage 5 CKD. Cross-sectional and longitudinal studies have also been unable to show a correlation between serum levels of markers of disordered mineral metabolism and severity of vascular calcification. Future studies should evaluate the pathogenetic role of phosphorus retention, which occurs early in the course of CKD, in the induction and/or progression of vascular calcification. Finally, there is a need to identify alternative pathogenetic mechanisms that may be important causes of the high calcification burden observed early in CKD.

Bone Density↗

PubMed2004

Vitamin D receptor and analogs.

In chronic kidney disease (CKD), high circulating levels of parathyroid hormone (PTH) cause osteitis fibrosa, bone loss, and cardiovascular complications that increase morbidity and mortality. Impaired production of 1,25-dihydroxyvitamin D (calcitriol), the hormonal form of vitamin D, is a major contributor to the generation and maintenance of parathyroid hyperplasia and increased synthesis and secretion of PTH. Calcitriol inhibits PTH gene transcription and ameliorates parathyroid hyperplasia by suppressing the expression of and growth signals from the autocrine transforming growth factor alpha (TGFalpha)/epidermal growth factor receptor (EGFR)-growth loop, a main determinant of parathyroid cell proliferation. Calcitriol reduction of parathyroid hyperplasia and serum PTH levels demands a functional vitamin D receptor (VDR). Although VDR is normal in CKD, parathyroid VDR content is reduced markedly. Furthermore, VDR function, as a transcriptional regulator of vitamin D responsive genes, is impaired by several factors including hypocalcemia, hyperphosphatemia, accumulation of uremic toxins, and reduction in cellular levels of the VDR partner, retinoid X receptor. Therapy with calcitriol analogs can overcome the antagonism on calcitriol-VDR actions induced by CKD. Although not all analog formulations are equally effective, they offer a wider therapeutic window in counteracting vitamin D resistance and survival advantage over exclusive calcitriol therapy.

Calcitriol↗