Secondary hyperparathyroidism (2HPT) is a common and serious complication of chronic kidney disease (CKD). Calcitriol (1,25-dihydroxyvitamin D, the hormonal form of vitamin D) deficiency, phosphate retention, and hypocalcemia, all resulting from the progressive decrease in kidney function, are the main contributors to enhanced parathyroid cell growth and elevations in serum parathyroid hormone (PTH). Calcitriol replacement therapy has proven effective in treating 2HPT, but is often limited by hypercalcemia and hyperphosphatemia, which spurred the development and implementation of analogs with...
Secondary hyperparathyroidism (2HPT) is a common and serious complication of chronic kidney disease (CKD). Calcitriol (1,25-dihydroxyvitamin D, the hormonal form of vitamin D) deficiency, phosphate retention, and hypocalcemia, all resulting from the progressive decrease in kidney function, are the main contributors to enhanced parathyroid cell growth and elevations in serum parathyroid hormone (PTH). Calcitriol replacement therapy has proven effective in treating 2HPT, but is often limited by hypercalcemia and hyperphosphatemia, which spurred the development and implementation of analogs with wider therapeutic windows. Subsequent observational studies in hemodialysis patients revealed that the analogs conferred a greater survival benefit than calcitriol, and that mortality was highest in patient not receiving any vitamin D therapy. The survival benefits of calcitriol and its less calcemic analogs can be only partially accounted for by their efficacy in suppressing 2HPT; they appear to involve active vitamin D protection from renal and cardiovascular damage. This chapter presents the evidence, gained from animal models of kidney disease and from clinical trials, for the efficacy of the analogs available to treat 2HPT in protecting parathyroid, renal, and cardiovascular function, as well as the current limited understanding of the mechanisms for their selective properties, with the goal of providing solid bases to expedite the design of the pre-clinical studies and prospective trials required to improve outcomes from vitamin D (analog) interventions in early and advanced CKD.
In patients with CKD, the development of 2HPT can be attributed to phosphate retention, progressive reduction in the synthesis of calcitriol and the resulting hypocalcemia. This common and serious disorder is characterized by parathyroid hyperplasia and elevations in serum levels of PTH. High serum PTH causes disturbances in mineral and bone metabolism, which are responsible for the decreased quality of life, extra-skeletal calcifications, and markedly increased cardiovascular mortality (reviewed in ref. 1 and summarized in Fig. 25.1). The low serum calcitriol levels increase PTH indirectly via a reduction in intestinal calcium absorption and also directly through the loss of a direct transcriptional repression of the PTH gene. Phosphate retention aggravates both 2HPT and calcitriol deficiency in CKD. Hyperphosphatemia can stimulate parathyroid hyperplasia and PTH secretion directly, and also indirectly by either reducing ionized calcium or by inducing serum levels of the phosphatonin, fibroblast growth factor 23 (FGF23). FGF23 further reduces serum calcitriol through dual mechanisms, inhibition of the already defective renal calcitriol synthesis and enhancement of serum calcitriol degradation through the induction of 24-hydroxylase, the enzyme responsible for calcitriol inactivation.
The efficacy of calcitriol to induce intestinal calcium absorption and to suppress parathyroid cell growth and PTH gene transcription led to its successful use for the treatment of 2HPT for more than two decades in the United States. However, in advanced kidney disease, the severity of parathyroid hyperplasia markedly reduces the efficacy of calcitriol therapy in suppressing parathyroid cell growth and serum PTH through a reduction in parathyroid levels of the vitamin D receptor (VDR) and the calcium sensing receptor. The calcitriol dose escalation required to effectively suppress serum PTH is limited by the development of hypercalcemia and hyperphosphatemia, secondary to increases in intestinal absorption and bone mobilization of calcium and phosphate. The hypercalcemic toxicity of calcitriol is further aggravated by the concomitant use of large doses of calcium-containing phosphate-binders. Hypercalcemia predisposes to extra-osseous calcifications per se, and also through PTH over-suppression causing adynamic bone disease. To minimize the toxicities of calcitriol therapy, structural modifications in the calcitriol molecule led to the development of pro-hormone and calcitriol analogs that retain the capacity to suppress parathyroid function, both PTH synthesis and parathyroid cell growth, with lesser effects on kidney and bone. Section 2 of this chapter presents the relative potencies of a pro-hormone and three calcitriol analogs in the control of 2HPT and in mitigating the abnormalities in mineral and bone disease. Section 3 summarizes the current understanding and the unknowns on the biological and physiological bases for the selective actions of vitamin D analogs for 2HPT.
The improvements in biochemical markers of mineral and bone disease achieved with analog therapy were strongly supported by several retrospective studies in dialysis patients demonstrating that analog usage was associated with a reduced mortality. However, the results from a large historical cohort demonstrated not only that calcitriol dosage also conferred a survival advantage compared with non-users of any active vitamin D therapy, but more intriguingly, that the favorable outcome in these patients could only partly be attributed to improvements in the control of 2HPT. The identification of important renal and cardiovascular protective actions of active vitamin D therapy as the main contributors to the favorable outcomes have suggested the potential benefits of either intervening earlier in the course of kidney disease, or of extending vitamin D therapy regardless of serum PTH, calcium, and phosphate levels in advanced kidney disease. However, recent meta-analysis on the survival advantage of active vitamin D therapy has both questioned and confirmed the results from these trials, raising valid concerns as to whether the available level of evidence is sufficient to change current clinical practice. The last section of this chapter analyses the available evidence on the safety and efficacy of the renal and cardioprotective actions of vitamin D therapy obtained exclusively from in vivo studies in experimental models of kidney disease and clinical trials, which can help expedite the implementation of safe vitamin D interventions that maximize favorable outcomes in attenuating the progression of renal and cardiovascular damage in the course of kidney disease.
Chapter. 10922 words. Illustrated.
Subjects: Rheumatology ; Nephrology
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