Posted by James
The modern strategies to prevent secondary HPT in CRF patients give great relevance to vitamin D replacement therapy, which requires to take into account the stage of CRF, the underlying renal disorder, the levels of circulating PTH, the condition of the bone, the vitamin D stores, the parameters of bone turnover and the values of calcium and phosphate in serum. The administration of 1,25(OH)2D or its analogues is unavoidable in dialysis patients when secondary HPT is often already established. Its association with 25(OH)D or ergocalciferol or cholecalciferol may be beneficial for the bones, if a deficit of vitamin D stores is present (serum levels of 25(OH)D below 2030 ng/mL). Therapeutic use of 25(OH)D or ergocalciferol is indicated in earlier stages of CRF to support renal ^-hydroxylase activity. At these stages, low doses of 1,25(OH)2D may also be employed to prevent HPT since they are not harmful for renal function. The dose of vitamin D metabolites should be titrated on serum concentrations of calcium and phosphate, to avoid an excessively high calcium-phosphate product, and on serum PTH concentrations, to avoid excessive PTH suppression and an adynamic condition of the bone. The aim of vitamin D replacement therapy is to prevent HPT since the early stages of CRF, because parathyroid hyperplasia and osteodystrophy cannot be completely reverted once developed. The attention of nephrologists has largely focused on dialysis patients and, unfortunately, few studies have analyzed the outcome of vitamin D therapy in non-uremic patients. Because of the lack of clinical studies in this population no guidelines are available on when to start vitamin D replacement therapy in CRF patients. Therefore, it is likely that HPT and osteodystrophy are undertreated in a significant proportion of CRF patients. We have tried to summarize the criteria proposed in the current literature: one common criteria is that vitamin D therapy should be considered when serum 25(OH)D concentration is below 30 ng/mL. Instead, we do not know when 1,25(OH)2D can be safely prescribed to non-uremic patients and whether there are additional benefits by its association with 25(OH)D or ergocalciferol.
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Posted by James
Vitamin D analogues
Several new vitamin D analogues have been developed and investigated with the rationale to treat secondary HPT decreasing the risk of hypercalemia and hyperphosphatemia in CRF patients. Vitamin D analogues have variable affinity for the components of the vitamin D system, including the vitamin D-binding protein and the nuclear VDR. Some of the effects are genomic and mediated through changes in the structural configuration of the vitamin D-VDR complex or in the affinity of the vitamin D-VDR complex for the key response elements in various target genes. There are currently three vitamin D analogues approved for use in CRF patients with secondary HPT in the US, 1,25-dihydroxy-22-oxavitamin D3 (22-oxacalcitriol, OCT), 1,25-dihydroxy-19-norvitamin D2 (19-norD2), 1a-hydrox- yvitamin D2 (1aOHD2). 19-norD2 is approved for the treatment of secondary HPT in Italy.
OCT is a vitamin D3 derivate, which differs from 1,25(OH)2D3 for the substitution of carbon 22 with an oxygen. Oral and i.v. preparations are available. Experience in rats showed that it is less potent than 1,25(OH)2D to suppress parathyroid glands and much less active on plasma calcium. OCT is commonly administered to hemodialysis (HD) patients three times a week (Table III). In the first trial, episodes of hypercalcemia occurred in 33% of patients and serum alkaline phosphatase decreased significantly after OCT therapy, suggesting the correction of high-turnover bone disease. The reduction in PTH and the increment of calcium and phosphate were dose-dependent. The initial OCT oral dose was 5 jg three times a week when plasma iPTH concentration was 300-500 pg/mL and 10 jg three times a week when iPTH was above 500 pg/mL. OCT was also successfully used in CRF patients with creati- nine clearance above 15 mL/min at the oral dose of 1-5 jg/day with no deleterious effects on renal function. The different activity of OCT and 1,25(OH)2D has been attributed to the different pharmacokinetics of the two compounds. OCT affinity for VDR and vitamin D-binding protein is lower than that of 1,25(OH)2D and, thus, it is rapidly cleared from the blood. OCT treatment is also associated with the inhibition of renal 1 a-hydroxylase and a consequent reduction in serum levels of 1,25(OH)2D. The short half-life and the 1,25(OH)2D deficiency explain the scarce effect of OCT on intestine and bone and, ultimately, on calcium concentrations. On the other hand, OCT has a prolonged activity on parathyroid glands, where it is retained in the nuclei.
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Posted by James
1,25(OH)2D remains a milestone for the treatment of secondary HPT in CRF patients. It may be prescribed to patients with secondary HPT at every stage of CRF, although theoretically it should be used in the presence of normal serum levels of 25(OH)D. Exogenous administration of 1,25(OH)2D becomes inevitable in patients with creatinine clearance below 15 mL/min (Table III), provided that the serum values of calcium, phosphate and PTH indicate its use. In CRF patients with creatinine clearance above 15 mL/min, 1,25(OH)2D treatment may begun at the oral dose of 0.25 jg/day, according to the K/DOQI guidelines. Clinical trials aimed to study the outcome of 1,25(OH)2D treatment showed that CRF patients, who had received 1,25(OH)2D (0.25-0.5 jg/day per os) for one year, had lower circulating PTH and normal bone histology at the end of follow-up. A significantly higher bone turnover and lower bone mineral density were observed in patients who had not received 1,25(OH)2D. Therefore, although protective against HPT, 1,25(OH)2D treatment is likely to expose patients with early CRF to the risk of adynamic bone disease and may also accelerate renal function decline, probably due to vascular deposition of calcium-phosphate salts. However, the dosage of 0.125-0.25 jg/day was well tolerated in patients with mild-moderate CRF and appeared safe for bone and kidney.
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Posted by James
Vitamin D deficit is frequent in CRF and its correction prevents or cures secondary HPT and achieves the specific beneficial effects of 25(OH)D on muscles and bones. Vitamin D supplements are recommended in patients with creatinine clearance above 15 mL/min and with serum concentrations of 25(OH)D below 30 ng/mL (75 nmol/L), because their kidney is stimulated to produce 1,25(OH)2D by the increase of ^-hydroxylase substrate, 25(OH)D. Ergocalciferol is the most convenient product to replace vitamin D stores, due to its availability, cost and efficacy. K/DOQI guidelines recommend to administer 50000 IU/month per six months orally in patients with serum 25(OH)D concentrations of 16-30 ng/mL (40-75 nmol/L), or six-month courses with more frequent doses in the presence of lower 25(OH)D levels. During this treatment, plasma calcium concentration should not exceed 2.51 mmol/L (10.5 mg/dL) and serum phosphate 1.49 mmol/L (4.6 mg/dL). To prevent vitamin D deficiency in CRF patients, Schomig and Ritz proposed oral supplementation with 1000 IU day of cholecalciferol, or 10000 IU/week. Alternatively, 25(OH)D may be administered orally at the dose of 10-40 jg/day, according to the serum levels of this metabolite and calcium, as usually employed in osteoporosis.
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Posted by James
Treatment of secondary hyperparathyroidism: role of vitamin D and its analogues
Prevention and treatment of secondary HPT commonly requires control of both phosphate and 1,25(OH)2D levels in serum. Phosphate levels are usually controlled by reducing dietary phosphate intake, by dialysis, and by using phosphate- binders. 1,25(OH)2D effectively suppresses PTH production and improves bone histology in some patients. Vitamin D and its analogues act after binding to VDR in parathyroid cell cytosol. The vitamin D-VDR complex controls the rate of PTH gene transcription by interacting with VDRE, located 100-120 bases upstream from the PTH gene. Furthermore, vitamin D upregulates CaSR expression on cell membrane, thus leading to a greater inhibition on PTH secretion. Through CaSR the increase in circulating calcium ions can inhibit tonic PTH secretion by stimulation of mitogen-activated protein ki- nase pathways. VDRE regions are present in the two pro- motors of the CaSR gene. Calcium ions inhibit PTH secretion not only through CaSR, but also by interacting with cytoso- lic proteins affecting the stability of PTH mRNA. Hypocalcemia favors the activity of cytosolic proteins protecting PTH mRNA from the degrading effect of ribonucleases. On the other hand, hypercalcemia favors the activity of proteins degrading PTH mRNA. Furthermore, a trascriptional activity of calcium has been hypothesized. Postranscriptional and transcriptional effects of calcium ions are indirectly influenced by the calcium-repleting activity of vitamin D.
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Posted by James
Secondary HPT causes both skeletal and extra-skeletal complications. Bone-associated consequences include with osteitis fibrosa and renal osteodystrophy, while non-skeletal consequences include cardiovascular calcification, soft-tissue calcification, endocrine disturbances, compromised immune system, neurobehavioral changes, and altered erythropoiesis.
Renal osteodystrophy
Renal osteodystrophy refers to a bone disorder that occurs in patients with CRF, characterized by abnormal bone turnover. PTH directly stimulates calcium mobilization from the bone by acting on the osteoclasts and indirectly by stimulating bone resorption and formation through the increase of vitamin D synthesis in the kidney. It is well known that vitamin D stimulates osteoblast activity and increases both osteoclast amount and function. In CRF patients vitamin D deficit leads to a loss in normal osteoblast activity and a reduction in bone mineralization. Furthermore, high serum PTH levels stimulate osteoclasts to mobilize more calcium from bone tissue, with bone mass reduction.
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Posted by James
In the 5/6 nephrectomized rats, 1,25(OH2)D3 suppresses uremia-induced parathyroid cell proliferation both in vitro, and in vivo.
Naveh-Many showed that PTH mRNA was much higher in parathyroid glands from vitamin D-deficient normocalcemic rats than controls, and that in vitamin D-deficient hypocalcemic rats the upregulation of PTH mRNA was even more pronounced. Moreover, many studies have been conducted to assess whether supplementation with vitamin D sterols can prevent or ameliorate secondary HPT in CRF.
In the early-uremia rat model (7 days of renal failure), 1,25(OH2)D and the less hypercalcemic vitamin D analog 1,25-dihydroxy- 19-norvitamin D2 (19-norD2) controlled both serum PTH levels and parathyroid hyperplasia similarly to what is described with phosphate restriction. The suppression of uremic rat parathyroid cell growth by vitamin D treatment can be partially accounted for by the increased expression of p21. Furthermore, studies in patients with secondary HPT suggest an important role for increased p21 expression in parathyroid growth arrest.
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