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Keywords:

  • vitamin D agonist;
  • chronic kidney disease;
  • bone disease;
  • fibroblast growth factor-23

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. BONE METABOLIC DISTURBANCES IN EARLY CKD
  5. MULTI-ORGAN BIOLOGICAL FUNCTION
  6. THERAPY WITH VITAMIN D
  7. REFERENCES

Chronic kidney disease (CKD) has been recognized as a significant public health problem, with ∼20 million Americans, or ∼11% of the adult population, currently living with CKD. A significant source of morbidity associated with CKD is the development of disturbances of mineral metabolism, which occurs in virtually all patients during the progression of their disease, and is associated with bone loss and fractures, cardiovascular disease, immune suppression, and increased mortality. As kidney disease develops, there is decreased functional renal mass and a tendency to retain phosphorus. The reduction in functional renal mass and the retained phosphorus act to reduce renal 1α-hydroxylase activity and thus the renal production of calcitriol. Further compensation to maintain normal serum calcium and phosphorus homeostasis includes increased production and release of PTH and potentially other phosphaturic factors, such as fibroblast growth factor-23 (FGF23). This increase in FGF23 contributes to maintain normal serum phosphate independent of PTH but may worsen calcitriol deficiency by also inhibiting renal 1α-hydroxylase activity. The decrease in calcitriol also results in promoting further hyperparathyroidism and parathyroid gland hyperplasia, because calcitriol normally inhibits the production of prepro-PTH and parathyroid cell proliferation.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. BONE METABOLIC DISTURBANCES IN EARLY CKD
  5. MULTI-ORGAN BIOLOGICAL FUNCTION
  6. THERAPY WITH VITAMIN D
  7. REFERENCES

Deficiency in vitamin D is not limited to the active hormone, calcitriol; calcidiol (25-hydroxycholecalciferol) is also deficient in most patients with chronic kidney disease (CKD), independent of their underlying renal function. Decreases in calcitriol occur relatively early in the progression of kidney disease and may predate the increase in PTH. These changes in calcitriol and PTH contribute to the maintenance of relatively normal serum and calcium concentrations until the glomerular filtration rate (GFR) decreases to <20–25%; however, the result is the potential development of bone and vascular disease. In addition to the direct disturbances in bone and mineral metabolism associated with calcitriol deficiency, there are increasing epidemiological data suggesting that vitamin D deficiency may play a role in overall morbidity and mortality associated with CKD.

CKD is a worldwide epidemic and escalating problem. Approximately 20 million adults in the United States are in various stages of CKD,[1] with >400,000 individuals with end-stage kidney disease and >300,000 individuals requiring maintenance hemodialysis.[2] It has been projected that by 2030, >2 million individuals will need dialysis or transplantation for kidney failure as a result of an aging population and the increasing prevalence of type 2 diabetes.[3] The Kidney Disease Outcomes Quality Initiative (K/DOQI) of the National Kidney Foundation (NKF) has defined CKD as structural or functional abnormalities of the kidney, with or without a decreased GFR that lasts for at least 3 mo. Furthermore, the NKF has recommended that CKD be staged based on the estimated GFR (Table 1). Guidelines are being established on how to evaluate and treat patients with CKD based on the stage of the disease. Of particular concern are disturbances of mineral metabolism that are an almost universal problem in CKD.

Table Table 1.. Stages of CKD
  1. eGFR, estimated glomerular filtration rate (ml/min per 1.73 m2).

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It is well established that CKD is accompanied by decreased production of 1,25-dihydroxyvitamin D. In most patients, 1,25-dihydroxyvitamin D levels decline to the lower limit of the normal in advance stage 2 CKD and progress to low and very low levels in patients with stage 3 and 4 CKD.[4, 5] The major determinant of low 1,25-dihydroxyvitamin D levels is the reduction in renal mass with decreased 1α-hydroxylase available for converting 25-dihydroxyvitamin D by the proximal tubular cells. Recently, fibroblast growth factor-23 (FGF23), which is markedly increased in the very early stages of CKD, has been shown to also be implicated in causing low 1,25-dihydroxyvitamin D levels.[6] Additionally, hyperphosphatemia, metabolic acidosis and other yet unidentified uremic toxins may also suppress 1α-hydroxylase activity and 1,25-dihydroxyvitamin D synthesis, but their impact is maximal in advanced CKD, such as stages 4 and 5.[7, 8]

Independent of CKD progression, a low substrate level of 25-dihydroxyvitamin D per se is associated with low 1,25-dihydroxyvitamin D levels.[9] Low 1,25-dihydroxyvitamin D levels are involved in several adverse effects on patients with CKD, including disturbed bone mineral and PTH homeostasis, extraskeletal calcifications, and impaired multiorgan biological function.

BONE METABOLIC DISTURBANCES IN EARLY CKD

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. BONE METABOLIC DISTURBANCES IN EARLY CKD
  5. MULTI-ORGAN BIOLOGICAL FUNCTION
  6. THERAPY WITH VITAMIN D
  7. REFERENCES

Data on bone histology of patients with CKD stages 2–5 show a significant percentage of patients with predominant low turnover bone disease. Early in CKD, there are several different metabolic disturbances that may cause patients to progress between adynamic (low turnover) bone through mild mixed bone disease and osteomalacia, to the higher turnover hyperparathyroid bone disease. In addition, many may exhibit a combination of lesions. The correlation between the stage of CKD (degree of GFR) impairment and the bone turnover rate has shown that low turnover bone was observed mostly in patients with higher GFR and lower PTH concentrations, whereas hyperparathyroid bone becomes evident as the GFR drops and higher PTH levels develop.[10] These data were confirmed by an animal model of CKD and metabolic syndrome, in which adynamic bone develops in early renal insufficiency despite mild secondary hyperparathyroidism,[11] suggesting that, in the incipient stages of CKD, there is a deficiency in bone anabolic agents such as 1,25-dihydroxyvitamin D, vitamin D receptor (VDR) expression, and PTH. Indeed, PTH levels in early CKD stages may not be significantly increased to stimulate bone turnover, because the phosphate homeostasis is mostly supported by increased FGF23. Besides increasing the phosphate excretion, the elevated FGF23 levels may also have a deleterious effect on osteoblastic function, inducing apoptosis and a defect in mineralization.[12] The interaction between 1,25-dihydroxyvitamin D and its receptor, the VDR, was also found to be crucial for the normal coupling of bone remodeling.[13] VDR activation was recently shown in a model of knockout mice to be required to promote bone formation and to maintain normal bone forming activity, as well as to prevent osteoblastic apoptosis.[14, 15] Thus, insufficient 1,25-dihydroxyvitamin D and high FGF23 levels may result in suppressed bone metabolism with reduced bone formation in early stages of CKD, where a mild elevation of PTH is not sufficient to override these suppressive effects on bone turnover.

In addition to vitamin D, PTH, and FGF23, the newly described antiaging factor klotho could also be involved in the skeletal abnormalities occurring in early CKD. Studies performed in the klotho knockout mouse concluded that a defect in klotho gene expression caused the independent impairment of both osteoblast and osteoclast differentiation, leading to low-turnover osteopenia. Klotho is mostly produced by the distal renal tubule cells, suggesting that a reduction in its synthesis or expression in CKD could adversely affect bone metabolism.[16] It was also suggested that klotho synthesis is partly regulated by 1,25-dihydroxyvitamin D, because its synthesis is significantly increased by 1,25-dihydroxyvitamin D administration.[17] Optimizing vitamin D levels by administration of small physiologic doses of VDR activators in mild CKD was shown to normalize bone metabolism, not only in forms of predominant hyperparathyroid bone disease, but also in forms of low parathyroid, low turnover bone disease.[18]

With further impairment of kidney function, FGF23 can no longer maintain normal phosphate homeostasis, and increasing concentrations of PTH are required to normalize serum phosphate. In addition, low 1,25-dihydroxyvitamin D levels increase the skeletal resistance to PTH and further stimulate parathyroid cell proliferation and activity.[13, 18] The ensuing severe and sometimes refractory hyperparathyroidism and the consequent metabolic disturbances require the administration of pharmacological doses of active vitamin D compounds and calcium-based phosphate binders. These treatments have led to several adverse effects including elevation in serum calcium and phosphate concentration and an increased likelihood of low turnover bone disease and extraskeletal mineralization. Studies in both human and animals have implicated the elevation of serum phosphate and calcium–phosphate product and low PTH levels with increased mortality and cardiovascular diseases (CVD).[19-22]

MULTI-ORGAN BIOLOGICAL FUNCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. BONE METABOLIC DISTURBANCES IN EARLY CKD
  5. MULTI-ORGAN BIOLOGICAL FUNCTION
  6. THERAPY WITH VITAMIN D
  7. REFERENCES

In the last several years, the pleotropic actions of vitamin D have been recognized. Disorders of vitamin D metabolism have been linked to varied pathological conditions such as hypertension, congestive heart failure and hypertrophic cardiomyopathy, immune diseases, and cancer. Essentially all tissues possess the VDR, and activation of the VDR has a multitude of beneficial biologic effects, including stimulation of insulin production, modulation of the immune system, regulation of blood pressure through modulation of renin production in the kidney, and control of myocardial structure and function.[13] Thus, these data suggest that activation of the VDR in patients with CKD at all stages may provide a net benefit, regardless of the serum phosphate, calcium, or PTH concentration.

THERAPY WITH VITAMIN D

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. BONE METABOLIC DISTURBANCES IN EARLY CKD
  5. MULTI-ORGAN BIOLOGICAL FUNCTION
  6. THERAPY WITH VITAMIN D
  7. REFERENCES

There are limited data concerning treatment of patients with CKD with vitamin D. The current K/DOQI guidelines recommend screening for hyperparathyroidism in patients with stages 3 and 4 CKD at least annually.[23] In patients with elevated PTH concentrations, measurement of calcidiol levels is recommended.[23] For patients noted to have calcidiol insufficiency, K/DOQI recommends therapy with ergocalciferol, with the dose being dependent on the severity of calcidiol deficiency.[23] However, these recommendations were developed without available data to suggest exactly how much ergocalciferol should be administered and whether such therapy impacts vitamin D and serum PTH concentrations. A preliminary study in patients with stages 3 and 4 CKD treated a small number of patients according to the K/DOQI recommendations.[24] They found an increase in both 25- and 1,25-vitamin D levels to the low normal range, with a 20% decrease in PTH concentrations in patients with stage 3 CKD but no change in those with stage 4 disease. Although PTH decreased in the stage 3 patients, they remained significantly elevated. Studies with calcitriol in patients with stages 3 and 4 CKD showed a significant decrease in PTH; however, hypercalcemia and hypercalciuria limited the effectiveness. The prohormones, alfacalcidiol and doxercalciferol, have also been successfully used to decrease PTH in stages 3 and 4 CKD; however, there was still some degree of hypercalcemia and hypercalciuria.[25] Of note, the study that used alfacalcidiol also noted an improvement in BMD associated with the decrease in PTH.[26] The VDR-specific agonist, paricalcitol, has also been shown to significantly decrease PTH in CKD, and in contrast to other compounds that result in activation of the VDR, it does not seem to increase urinary calcium and has minimal if any effect on serum calcium and phosphorus concentrations.[27]

In summary, disorders of vitamin D occur very early in CKD and are present before the detection of the mineral disorders typically associated with kidney failure, hyperphosphatemia, hypocalcemia, and hyperparathyroidism (Fig. 1). Although there is a high prevalence of 25-hydroxycholecalciferol deficiency, the defect in 1,25-dihdroxycholecalciferol seems to be independent of calcidiol and is more likely the result of increased FGF23, decreased renal mass, and a relative decrease in PTH. Repletion of 25-hydroxycholecalciferol has some effect in decreasing PTH in stage 3 CKD; however, the present data suggest that compounds that stimulate the VDR have to also be administered. Presently, there are no data on the effect of disorders in vitamin D metabolism on the extraskeletal actions of vitamin D. Clearly, further research on the manifestation of vitamin D deficiency and CKD are needed.

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Figure FIG. 1.. Changes in mineral metabolism observed with the development of CKD. Graphical depiction of the changes in 1,25-vitamin D, 25-vitamin D, PTH, and phosphorus associated with a decreasing GFR. 25-vitamin D is deficient across the range of CKD but is not necessarily altered by decreases in GFR, whereas 1,25-vitamin D decreases early and progressively declines with the development of CKD. PTH begins to increase at a GFR of ∼60–70 ml/min and markedly increases at a GFR of <30 ml/min. Phosphorus remains relatively normal until the GFR reaches 20–25 ml/min and progressively increases. Compiled from data in References (28–30).

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REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. BONE METABOLIC DISTURBANCES IN EARLY CKD
  5. MULTI-ORGAN BIOLOGICAL FUNCTION
  6. THERAPY WITH VITAMIN D
  7. REFERENCES
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