We have made significant advances in understanding of the pathogenesis and treatment of secondary hyperparathyroidism in chronic kidney disease (CKD). These include: (1) the discovery of the calcium-sensing receptor CaSR and the development of calcimimetics to target this receptor to suppress PTH secretion and production; (2) the recognition that metabolic derangements in calcium and phosphate have a significant impact on morbidity and mortality, possibly through effects on vascular calcification; (3) the discovery of the FGF23-bone kidney axis, where FGF23 produced by osteoblasts/osteocytes suppresses 1,25(OH) 2 D production as an early adaptive response to the loss of kidney function; (4) the finding that elevated serum FGF23 concentration is an important predictor of mortality and progression of kidney disease; (5) the development of less hypercalcemic and hyperphosphatemic vitamin D analogues with the potential of reduced toxicity; (6) the recognition of the possible importance of nutritional vitamin D deficiency on innate immune function; and (7) the availability of non-calcium containing phosphate binders. The National Kidney Foundation Kidney Disease Outcomes Quality Initiative (KDOQI TM ) and more recently KDIQGO have also provided guidelines for earlier interventions and management of mineral metabolism disorders in CKD. These new pharmacological agents and treatment paradigms offers the potential to more effectively and safely manage disordered mineral metabolism in patients with CKD.
Bone, secondary Hyperparathyroidism, parathyroid glands, calcimimetics, vitamin D, renal osteodystrophy, FGF23, PTH, phosphate binders, hyperphosphatemia
We have made significant advances in understanding of the pathogenesis and treatment of secondary hyperparathyroidism in chronic kidney disease (CKD). These include: (1) the discovery of the calcium-sensing receptor CaSR and the development of calcimimetics to target this receptor to suppress PTH secretion and production; (2) the recognition that metabolic derangements in calcium and phosphate have a significant impact on morbidity and mortality, possibly through effects on vascular calcification; (3) the discovery of the FGF23-bone kidney axis, where FGF23 produced by osteoblasts/osteocytes suppresses 1,25(OH) 2 D production as an early adaptive response to the loss of kidney function, (4) the finding that elevated serum FGF23 concentration is an important predictor of mortality and progression of kidney disease; (5) the development of less hypercalcemic and hyperphosphatemic vitamin D analogs with the potential of reduced toxicity; (6) the recognition of the possible importance of nutritional vitamin D deficiency on innate immune function; and (7) the availability of non-calcium containing phosphate binders. The National Kidney Foundation Kidney Disease Outcomes Quality Initiative (KDOQI TM ) and more recently KDIQGO have also provided guidelines for earlier interventions and management of mineral metabolism disorders in CKD. These new pharmacological agents and treatment paradigms offers the potential to more effectively and safely manage disordered mineral metabolism in patients with CKD.
Parathyroid Gland Disease versus Mineral Metabolism Disorders in CKD
Secondary hyperparathyroidism is an adaptive response to the loss of kidney function. Progressive parathyroid gland disease (i.e., hypertrophy and hyperplasia) and pathological consequences of elevated serum PTH levels have dominated the clinical focus of disordered mineral metabolism in CKD. PTH actions are mediated through PTH receptor (PTH1R) in the kidney, whose activation inhibits renal Pi reabsorption, decreases renal tubular calcium excretion and increases 1,25(OH) 2 D 3 production. Activation of PTH1R in osteoblasts in bone stimulates bone formation and osteoclastic bone resorption. Chronic elevation of PTH in SHPT leads to increased bone remodeling which plays crucial role in mineral homeostasis by providing access to the stores in bones Ca and Pi. Thus, PTH is a calcemic hormone that maintains serum calcium levels by stimulating 1,25(OH) 2 D production, renal calcium conservation and bone calcium efflux. The phosphaturic actions of PTH permit excretion of phosphate that accompanies the gastrointestinal absorption and bone efflux of calcium.
It is clinically important to prevent and treat secondary hyperparathyroidism, since increments in PTH (typically levels that exceed the 400–600 pg/ml range) are associated with increased mortality in CKD. In addition, elevated PTH is associated with progressive parathyroid disease leading to tertiary hyperparathyroidism that may require parathryoidectomy and high cortical bone remodeling leading to an increase in the risk of bone fractures.
In spite of the importance of PTH, the recognition that hyperphosphatemia, vascular calcifications and different treatment strategies may have a greater impact upon survival of patients with CKD has lead to a broadening of our conceptualization of hyperparathyroidism and “renal osteodystrophy” to include other metabolic abnormalities, termed, Chronic Kidney Disease—Mineral and Bone Disorder (CKD-MBD). CKD-MBD describes a clinical syndrome that includes multiple metabolic/endocrine abnormalities, parathyroid gland dysfunction, bone disease, and unique CKD associated cardiovascular risk factors as well as other adverse clinical outcomes, such as fractures, vascular and soft tissue calcifications.
Because of the integration and interdependence of the calcium, phosphate, vitamin D and PTH axis, it is difficult to elucidate the primary or proximate causes of secondary hyperparathyroidism in CKD. Hyperphosphatemia, 1,25(OH) 2 D 3 and hypocalemia, acting through distinct molecular mechanisms, act in concert to cause secondary hyperparathyroidism in CKD. However, elevations of FGF23 and secondary suppression of 1,25(OH) 2 D production may the initial abnormality in CKD that leads to increments in PTH, which may further stimulate FGF23 levels. Nevertheless, suppression of PTH, while minimizing hyperphosphatemia, providing adequate vitamin D replacement, and maintaining bone health, remains the major goal of therapy. Different strategies to achieve this are based on different molecular targets for the available therapies that include, phosphate binders, vitamin D analogues and calcimimetics.
Molecular Targets for Suppressing Parathyroid Gland Function in CKD
Role of Hyperphosphatemia
A decline in GFR and reduced renal phosphate excretion is associated with increased PTH secretion by the parathyroid glands in CKD. In patients on maintenance hemodialysis, increased levels of serum phosphate strongly predict the degree of serum PTH elevation. The importance of phosphate is also supported by the observation that phosphate restriction can attenuate the development of secondary hyperparathyroidism in CKD. The stimuli linking hyperphosphatemia and increments in PTH are likely to be both direct and indirect. The molecular mechanism mediating the direct effects of phosphate on the parathyroid gland, however, are poorly understood. Increments in media phosphate concentrations increases PTH synthesis in parathyroid cell cultures, regulates PTH message stability, and dietary restriction of phosphorus retards the development of hyperparathyroidism. Phosphorus also modulates parathyroid growth and hypertrophy through activation of MAPK (mitogen activated protein kinases), TGF-alpha, and cyclin dependent kinases. To date, no specific receptors, transporters or other molecular targets have been identified that mediate direct effects of phosphate on the parathyroid gland function.
Indirect effects of hyperphosphatemia on parathyroid gland function have greater experimental support, and are potentially mediated via FGF23, 1,25(OH) 2 D 3 , and calcium, acting on their respective receptors in the parathyroid gland. Phosphate loading can also decrease 1,25(OH) 2 D 3 production by the kidney, which in turn can decrease dietary absorption of calcium, thereby regulating parathyroid gland function indirectly through both the calcium sensing receptor and the vitamin D receptor.
Vitamin D Receptor and the Role of 1, 25(OH) 2 D 3 Deficiency
Decrements in both 25(OH)D and 1,25(OH) 2 D occur early in the course of CKD-MBD. Low levels of vitamin D are associated with increased mortality in CKD and treatment in vitamin D analogs are believed to have a survival benefit. (1,25(OH) 2 ) acts on the vitamin D receptor (VDR) in the parathyroid gland to suppress PTH transcription, but not PTH secretion, whereas calcitriol acts on the small intestines to increase active transport of both calcium and phosphate. Reductions in serum 1,25(OH) 2 D levels play a central role in the pathogenesis of secondary hyperparathyroidism. Cross sectional studies of patients with CKD show that serum 1, 25(OH) 2 D 3 levels decline as a function of the severity of renal impairment. Increments in PTH are inversely correlated with serum 1, 25 (OH) 2 D 3 levels below GFRs of 60 ml/min/m 2 . Low levels of 1,25(OH) 2 D stimulate PTH though both loss of direct effects of 1,25(OH) 2 D 3 on vitamin D receptors (VDR) in the parathyroid glands and due to reductions in gastrointestinal absorption of calcium, which leads inhibition of the calcium sensing receptor (CaSR) in the parathyroid gland.
Nutritional deficiency of vitamin D as measured by low circulating 25(OH)D 3 levels, is also common in patients with CKD, likely due to poor nutritional status, inadequate exposure to sunlight and chronic illness. The negative correlation between serum PTH concentrations and 25(OH) vitamin D, the precursor to 1,25(OH) 2 D 3 , is well established in the general population, and may also contribute to secondary hyperparathyroidism in stage 3 and 4 CKD.
Role of the Calcium Sensing Receptor (CaSR) and Hypocalcemia
Calcium acting through CaSR is the major regulator of PTH transcription, secretion, and parathyroid gland hyperplasia. From a biological standpoint, calcium and CaSR are more important that phosphate and 1,25(OH) 2 D 3 acting through the vitamin D receptor (VDR) in regulating parathyroid gland function. This conclusion is supported by mouse genetic approaches that have evaluated the phenotype in CaR, VDR, and 1 α-hydroxylase deficient mice has overlapping functions with CaR. For example, secondary hyperparathyroidism and bone abnormalities in VDR-deficient mice can be corrected by normalizing serum calcium concentrations, whereas increased 1,25(OH) 2 D 3 levels is not sufficient to normalize PTH secretion and parathyroid gland growth in the absence of CaR. These mouse genetic studies are potentially important in setting the theoretical basis for selecting therapeutic strategies that target CaR as the dominant target in the parathyroid gland function, compared to VDR and phosphate.
Role of the FGF23-FGF Receptor/Klotho Signaling Network
FGF23, is a novel phosphaturic hormone produced by bone is important in regulating phosphate homeostasis. Elevations in circulating FGF23 levels are one of the earliest abnormalities in CKD-MBD and are strongly associated with increased all-cause mortality. Elevations of FGF23 inversely correlate with GFR. Patients with end-stage renal disease (ESRD) have markedly elevated levels of FGF23 that parallels with degree of hyperphosphatemia and SHPT. FGF23 interacts with FGF receptors (FGFR) in the presence of the members of Klotho family of proteins. The mechanism of increased FGF23 in CKD is poorly understood. The increase in serum FGF23 is not explained by reduced FGF23 clearance; and the proximate stimulus in early CKD that leads to increments in FGF23 are not clear. Nevertheless, FGF23 production is likely increased to counteract Pi retention due to reduced nephron mass by promoting urinary Pi excretion. Elevations in FGF23 precede increments in PTH in CKD and animal studies show that blockade of FGF23 by neutralizing antibodies lead to normalization of 1,25(OH) 2 D 3 and PTH levels in models of CKD. The effects of FGF23 on parathyroid gland function, however, are controversial. While some studies suggest that FGF23 promotes parathyroid gland hyperplasia, other studies indicate that FGF23 directly suppresses PTH secretion via activation of FGF receptor/klotho complexes located in the parathyroid gland, thereby explaining the apparent paradox between elevated FGF23 in patients with CKD and hyperparathyroidism. Additional studies will be needed to understand the direct effects of FGF23 in the pathogenesis secondary hyperparathyroidism.
Clinical Manifestations of Disordered Mineral Metabolism in CKD
The major abnormalities in CKD-MBD that require treatment are parathyroid gland dysfunction (i.e., increase PTH secretion and parathyroid gland hyperplasia), metabolic bone disease, and vascular calcifications/non-traditional cardiovascular risk.
Parathyroid Gland Abnormalities
Parathyroid disease in CKD is a progressive disorder characterized by increased PTH secretion as well as by an increase in the number of the PTH-secreting chief cells (hyperplasia). Disease progress correlates with hypocalcemia, hyperphosphatemia and duration of renal failure. Unless adequately treated, secondary hyperparathyroidism inexorably progresses, with the frequency of parathyroidectomy proportional to the number of years of renal replacement therapy. The difficulty in treating hyperparathyroidism is due in part to massive hyperplasia and adenomatous transformation of the parathyroid gland that occur as a result of the chronic stimulation of PTH production in CKD. As the hyperplastic parathyroid glands enlarge, increments in basal, calcium-independent PTH secretion contributes to the elevated circulating PTH levels, although the glands retain responsiveness to calcium-mediated PTH suppression, i.e., normal set point. With further progress there is adenomatous transformation along with reductions in CaR and VDR, resulting in a right-ward shift in the set point typically associated with marked elevations of PTH and spontaneous hypercalcemia.
Bone disease in CKD is classically defined by bone histological analysis that assesses bone formation and resorption (rate of turnover or remodeling) and the presence or absence of a superimposed mineralization defect (osteomalacia). The major classifications include osteitis fibrosa (high turnover due to PTH stimulation of osteoblasts that are coupled to osteoclastic mediated bone resorption), osteomalacia (defective mineralization), and adynamic bone disease (low turnover due to low PTH and/or excessive treatment with vitamin D). Symptomatic musculoskeletal disease, particularly tendon rupture, bone pain, muscle pain and weakness, and periarticular pain have decreased because of the success in suppressing PTH and the use of purer water to generate dialysate. Nevertheless, hip fractures occur 4-times more often in stage 5 CKD patients compared to the general population. Attempts to link the type of histological bone disease or a specific level of PTH to increased fracture risk have been inconclusive. The utility of bone mineral density measurements to measure fracture risk have not been validated in CKD. Bone biopsy after tetracycline labeling remains the standard for diagnosing bone disease in CKD. The use of bone biopsies, however, is diminishing because of cost and its invasiveness. Recent analysis of a cross section of patients with CKD found racial differences in the type of bone disease in CKD. In this regard, whites exhibit low turnover whereas blacks have a greater prevalence of high turnover bone disease. A greater reliance is being placed on assessment of PTH and serum markers of bone turnover, which provide imprecise measures of bone disease.
The pathogenesis of the different forms of renal osteodystrophy is complex and not completely understood. PTH is the predominant factor controlling bone remodeling in CKD. In addition, the presence of C-terminal PTH fragments, which constitute 80% of circulating PTH, could potentially compete with PTH for type I PTH/PTHrP receptor or activate a novel C-PTH receptor with biological effects opposite to those of human PTH(1–84). Whether the assessment of the PTH-(1–84)/C-PTH fragment ratio adds to the prediction of the underlying bone disease remains to be determined. Active vitamin analogues also target osteoblasts and chondrocytes in vitro, but it has been difficult to separate the direct effects of vitamin D on bone and growth plate from that of PTH and calcium. Mouse genetic approaches to delete the VDR and 1α-hydroxylase suggest an independent role of Vitamin D in the growth plate and action in concert with calcium and PTH to activate osteoblasts and osteoclasts.
The type of bone disease can influence serum calcium and phosphate levels. High bone turnover states contribute to elevated serum calcium and phosphate levels through increased release from bone, whereas low turnover states can also make patients more susceptible to developing hypercalcemia after dietary loads or vitamin D therapy, due to the diminished buffering capacity for calcium resulting from the diminished bone remodeling. Adynamic bone disease may increase the risk of vascular and soft tissue calcifications, possibly due to limited calcium buffering capacity or to a calcium surfeit state. An inverse relationship between vascular calcification and bone density is also found in stage 5 CKD. Other examples of the impact of bone turnover on serum calcium and phosphate in ESRD are hungry bone syndrome following parathyroidectomy, hyercalcemina observed with immobilization, and hypocalcemia following treatment with anti-resorptive therapies.
Vascular Calcifications, Disordered Mineral Metabolism and Cardiovascular Disease/Morbidity and Mortality
Disordered bone and mineral metabolism in CKD contributes to calcification of soft tissues, particularly vessels, heart valves and skin. Vascular calcifications are very prevalent in CKD and cardiovascular disease accounts for approximately half of all deaths in dialysis patients. Several types of vascular calcification have been described in patients in CKD, including intimal/atherosclerotic/fibrotic calcification, medial calcification, heart valve calcification, and calciphylaxis/calcific uremic arteriolopathy. First, intimal calcification occurs as focal calcification associated with lipid-laden foam cells seen in atherosclerotic plaques. Atherosclerotic/fibrotic calcification can have components of endochondral bone formation in the vessel wall. These calcifications may increase plaque fragility and risk for plaque rupture, or alternatively might stabilize the plaque, or merely represent an epiphenomena of atherosclerotic disease. Second, medial calcification is diffuse calcification that is not associated with atherosclerotic plaques and occurs in the media of vessels. Medial calcification, also called “Monckeberg’s sclerosis,” is seen with aging, diabetes, and with progressive renal failure. Valvular calcification represents the third major type of vascular calcification. This is a dystrophic calcification that is also associated with atherosclerotic disease. There is a strong association between cardiac valve calcifications and vascular calcifications.
Calciphylaxis/calcific uremic arteriolopathy is the fourth type of calcification that results from amorphous calcium phosphate deposition in the vessel lumen leading to occlusion and tissue necrosis. The pathogenesis of calciphylaxis is not clear, but is associated with obesity, older age, female gender, diabetes mellitus, warfarin use, recent trauma, and calcium ingestion. Recently, studies in mice lacking fetuin, a calcium phosphate binding protein, have provided potential insights into the pathogenesis of this disorder. Fetuin binds to calcium phosphate to facilitate the clearing of this complex from the circulation. The absence of fetuin results in soft tissue calcification in mouse models. Low fetuin levels, which can be caused by inflammation, have been identified in dialysis patients with vascular calcifications and increased cardiovascular mortality. Treatment of calciphylaxis with phosphate binders and parathyroidectomy typically are ineffective. Case reports suggest that sodium thiosulfate treatment can improve calciphylaxis-calcific uremic arteriolopathy.
Coronary artery and vascular calcifications increase as a function of the number of years on renal replacement therapy and successful renal transplantation can lead to significant reductions in coronary artery calcifications by six months. There is debate regarding whether the intimal calcification, which has predictive power in diagnosing coronary artery disease in non-uremic population, has the same significance in end stage renal disease. Traditional “non-uremic” factors, such as hypertension, diabetes, and hyperlipidemia, may account for the increase in risk of cardiovascular disease. Interestingly, a multicenter, randomized, double-blind, prospective study of atorvastatin in type 2 diabetes mellitus CKD 5 showed that a 42% reduction in low-density lipoprotein cholesterol was not associated with a reduction in composite of death from cardiac causes, nonfatal myocardial infarction, and stroke. Treatments to reduce cardiovascular mortality in non-dialysis patients may not be as effective in stage V CDK patients. Unique factors associated with renal failure may have a greater importance. Epidemiological data implicate hyperphosphatemia and elevated Ca X P product as being risk factors for increased mortality.
Medial calcification of blood vessels had been thought to be of little clinical significance for many years, but its effect to increase blood vessel stiffness and reduce vascular compliance resulting in a widened pulse pressure, increased afterload, and left ventricular hypertrophy are potential mechanisms whereby vascular calcification could contribute to cardiovascular morbidity. In addition, retrospective analysis indicates that the presence of intimal and medial calcification are both associated with increased all-cause mortality and cardiovascular mortality in patients with ESRD.
While hyperphosphatemia is believed to be the major the major cause of vascular calcification, it has not been proven that strategies to prevent hyperphosphatemia or efforts to maintain neutral phosphate homeostasis will prevent vascular calcifications in CKD.
Treatment Goals: K/DOQI™ Guidelines for Mineral Metabolism in CKD
Clinical practice guidelines for bone metabolism and disease in stage 3, 4, and 5 CKD have been developed by the National Kidney Foundation Kidney Disease Outcomes Quality Initiative (KDOQI TM ) ( Table 91.1 ). The K/DOQI recommendations are influenced by the compelling evidence that elevated serum phosphorus and calcium x phosphorus product contribute to increased mortality and the belief that excessive calcium loading may increase the risk of cardiovascular calcification. The K/DOQI guidelines recommend attaining serum calcium, phosphorus, Ca X P product and PTH levels in a range that permits control of metabolic bone disease while limiting the potential toxicity of increased Ca X P product. The respective upper limit for serum phosphate in stage 5 CKD is 5.5 mg/dl, the corrected serum calcium is 9.5 mg/dL (corrected serum calcium=0.8 x (4 – g/dL of serum albumin), and the Ca X P product <55 and intact PTH 300 pg/ml).