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Long-term Management of CKD–Mineral and Bone Disorder
In Practice Long-term Management of CKD–Mineral and Bone Disorder Kevin J. Martin, MB, BCh, and Esther A. González, MD Chronic kidney disease–mineral and bone disorder (CKD-MBD) is the term used to describe the abnormalities of bone and mineral metabolism that occur in the setting of kidney disease. The spectrum of these abnormalities is wide, ranging from severe high-turnover bone disease on one end to marked low bone turnover bone disease on the other. Similarly, some patients have severe vascular calcifications while others do not, and the values for biochemistry determinations, including calcium, phosphorus, and parathyroid hormone, also may vary widely among patients. This variability may be influenced by such things as the chronicity of the particular kidney disease, effects of therapies such as corticosteroids on modifying the course of kidney disease, and comorbid conditions, such as diabetes, heart disease, age, and osteoporosis. The heterogeneity of CKD-MBD makes strict protocol-driven therapeutic approaches difficult; accordingly, considerable individualized therapy is required. Using a case history, we explore several of the variables and difficulties involved in patient management. Am J Kidney Dis. 60(2):308-315. © 2012 by the National Kidney Foundation, Inc. INDEX WORDS: Chronic kidney disease–mineral and bone disorder (CKD-MBD); hyperparathyroidism; renal osteodystrophy.
CASE PRESENTATION A 56-year-old white woman with a history of lupus nephritis class 4, which had been treated with prednisone and intravenous cyclophosphamide with an apparent good response, returned to the nephrology clinic after a 6-year absence. During that time, she had remained asymptomatic, discontinued all medications, and did not seek medical care. Evaluation showed the following values: serum creatinine, 4.1 mg/dL (362.44 mol/L; estimated glomerular filtration rate [eGFR], 12 mL/min/1.73 m2 [0.20 mL/s/1.73 m2]), which previously was 1.2 mg/dL (106.1 mol/L); calcium, 8.9 mg/dL (2.22 mmol/L); phosphorus, 4.8 mg/dL (1.55 mmol/L); 25hydroxyvitamin D, 14 ng/mL (34.94 nmol/L); intact parathyroid hormone (iPTH), 432 pg/mL (432 ng/L); and hemoglobin, 9.4 g/dL (94 g/L). Ultrasound showed kidney size to be 9.1 and 8.7 cm. Urinary protein-creatinine ratio was 2.4 g/g. Urine sediment was unremarkable. Anti–double-stranded DNA was negative and C3 and C4 levels were normal. Blood pressure was 152/82 mm Hg, and there was mild peripheral edema. Therapy was initiated with furosemide; lisinopril; ergocalciferol, 50,000 units every 2 weeks; darbepoetin; and calcium carbonate, 500 mg, with meals. After 3 months of treatment, 25-hydroxyvitamin D level increased to 26 ng/mL (64.90 nmol/L), and iPTH level decreased to 296 pg/mL (296 ng/L). During the next 6 months, serum creatinine level slowly increased, and hemodialysis therapy was initiated when serum creatinine level reached 8.7 mg/dL (769.1 mol/L; eGFR, 5 mL/min/1.73 m2 [0.08 mL/s/1.73 m2]) through an arteriovenous fistula. While receiving hemodialysis, the patient remained clinically well during the next 2 years and was placed on the transplant
From the Division of Nephrology, Saint Louis University, St Louis, MO. Received July 7, 2011. Accepted in revised form January 4, 2012. Originally published online April 23, 2012. Address correspondence to Kevin J. Martin, MB, BCh, Division of Nephrology, Saint Louis University Medical Center, Division of Nephrology (9-FDT), 3635 Vista Ave, St Louis, MO 63110. E-mail: [email protected] © 2012 by the National Kidney Foundation, Inc. 0272-6386/$36.00 doi:10.1053/j.ajkd.2012.01.027 308
list. Cardiac stress echocardiography was negative for ischemia, but left ventricular hypertrophy and modest calcification of the mitral valve were noted. Calcium carbonate therapy was stopped and sevelamer was begun as a phosphate binder to treat phosphorus values ranging from 5.4-6.2 mg/mL (1.74-2.0 mmol/L). iPTH levels progressively increased, peaking at 562 pg/mL (562 ng/L); treatment with paricalcitol, 2 g per dialysis treatment, was begun. PTH level remained at 364-486 pg/mL (364-486 ng/L) for the next year. After approximately 3 years on dialysis therapy, the patient began to notice vague pains in her hip and knee joints and legs and back. Pain was aggravated by exercise, and overall, she felt that her health was declining. These symptoms gradually became worse during the ensuing months. Review of laboratory values for the past year showed calcium values in the low-normal range, phosphorus values of 5.1-6.2 mg/dL (1.6-2.0 mmol/L), and iPTH values of 372-463 pg/mL (372-463 ng/L). Alkaline phosphatase level was 192 U/L, having increased from 139 U/L 1 year earlier. Dual-energy x-ray absorptiometry showed a T score of ⫺2.3 at the hip. Bone biopsy showed severe osteitis fibrosa. Paricalcitol therapy was intensified, and iPTH values stabilized near 200 pg/mL (200 ng/L) during the next 6 months, with a marked decrease in skeletal symptoms occurring after 3 months of intensified paricalcitol therapy.
INTRODUCTION Our view of the consequences of abnormal bone and mineral metabolism in the setting of chronic kidney disease (CKD) has evolved from focusing entirely on the skeleton to a broader perspective in which not only are bone abnormalities observed and require therapy, but these abnormalities also seem to be related to cardiovascular disease (specifically vascular calcification) and are implicated in increased mortality risk. Accordingly, the term renal osteodystrophy can be considered to represent the skeletal abnormalities, whereas the broader term CKD–mineral and bone disorder (CKD-MBD) spans the full spectrum of the consequences of abnormal bone and mineral metabolism in people with CKD.1 Secondary hyperparaAm J Kidney Dis. 2012;60(2):308-315
Long-term Management of CKD-MBD
thyroidism is a major part of the MBD spectrum and has been one focus of research to understand the factors that generate and maintain hyperparathyroidism.2 To date, it is well established that phosphate retention and abnormalities in vitamin D metabolism result from CKD and, either directly or by inducing changes in serum calcium levels, stimulate the growth and activity of the parathyroid glands. The resultant high levels of PTH in blood can affect the bone, causing osteitis fibrosa (high-turnover bone disease), manifest with demineralization of bone, predisposition to fractures, and not infrequently, bone pain. In addition, the consequences of high PTH levels may extend to nonskeletal tissue, contributing to abnormalities in multiple systems throughout the body, most notably cardiovascular disease, with manifestations including left ventricular hypertrophy, vascular calcification, and hypertension. Abnormalities in vitamin D metabolism occur early in the course of CKD, with 1,25-dihydroxyvitamin D levels having been shown to decrease progressively, thereby promoting increases in PTH levels. One reason for the decrease in 1,25-dihydroxyvitamin D levels is phosphate retention, which may directly suppress the activity of 1-hydroxylase or may act indirectly by increasing levels of fibroblast growth factor 23 (FGF-23), which in turn will decrease 1␣hydroxylase activity and increase 24-hydroxylase activity.3,4 Compensatory efforts to maintain the concentration of 1,25-dihydroxyvitamin D are compromised because 25-hydroxyvitamin D levels have been shown to be reduced in many people with CKD, possibly contributing to the inability of the damaged kidney to augment 1,25-dihydroxyvitamin D production when needed, even in the presence of hyperparathyroidism.5 The accumulation of N-terminally truncated PTH fragments also may decrease 1␣-hydroxylase activity.6 Ultimately, when kidney disease is advanced, 1,25-dihydroxyvitamin D production may be limited most by the marked decrease in renal parenchymal mass.
PRINCIPLES OF THERAPY As the pathophysiology of secondary hyperparathyroidism has been elucidated over the past, our understanding of this pathophysiology has provided a rational framework for therapy in which the abnormalities noted to contribute to hyperparathyroidism are directly targeted with therapeutic efforts. As listed in Box 1, the principles of therapy for hyperparathyroidism are to control phosphorus levels and prevent phosphate retention, correct hypocalcemia if it is present because this is the major driver of PTH secretion, supply vitamin D sterols to counteract the Am J Kidney Dis. 2012;60(2):308-315
Box 1. Principles of Therapy of Hyperparathyroidism in ESRD Consider calcium balance ● ● ●
Control hyperphosphatemia/phosphate retention Correct hypocalcemia (if present) Consider vitamin D sterols
Consider use of calcimimetic therapy or parathyroidectomy in select patients Abbreviation: ESRD, end-stage renal disease.
abnormalities in vitamin D metabolism, and, finally, consider the use of a calcimimetic agent or parathyroidectomy to directly control PTH secretion at the level of the parathyroid gland. These measures are undertaken in the context of minimizing the calcium burden to the patient to prevent excessive calcium loading, which may aggravate the progression of vascular calcification. Just as there is a wide spectrum of clinical and biochemical abnormalities in patients with CKD, there is also a wide spectrum of therapeutic approaches to the patient with CDK-MBD, as illustrated in Fig 1. Thus, some clinicians favor a vitamin D–based approach with calcimimetic as add-on therapy, whereas others favor the use of a low-dose vitamin D sterol as background for calcimimetic-based therapy. The details of individual patients likely determine the appropriate approach, as well as issues of treatment adherence, cost, and comorbid conditions. There presently are no definitive long-term data to compare these approaches. These principles have been derived mostly from observations in patients with end-stage renal disease (ESRD), but to some degree may be applied to the earlier stages of CKD when the abnormalities in bone and mineral homeostasis begin. Calcimimetic therapy is not approved for use in patients with CKD not on dialysis therapy and therefore is not recommended for such patients at this time. In the patient under discussion, the opportunity to begin therapy early in the course of CKD was not possible because of loss of follow-up. However, in general, therapy should be undertaken at this time if possible. Because clinically measurable hyperphosphatemia does not occur until GFR is ⬍20 mL/min/ 1.73 m2 (⬍0.33 mL/s/1.73 m2), the use of phosphate binders is not part of routine clinical practice. However, phosphate binders perhaps should be considered in light of extensive experimental observations in animals, in which dietary phosphorus restriction in proportion to the decrease in GFR was shown to be effective in preventing the development of secondary hyperparathyroidism.7,8 It is possible that in the future, measurements of FGF-23 might be useful in early CKD because these values may increase even before elevations in PTH levels are seen.9 However, current practice guidelines 309
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Vitamin D Sterol
Calcimimec
Non-calcium based binders
Calcium based binders
Figure 1. The spectrum of therapies for chronic kidney disease–mineral and bone disorder (CKD-MBD). This reflects the strategies of principally using vitamin D sterols together with non– calcium-based phosphate binders and possibly a low-dose calcimimetic compared with an alternate strategy of using calcimimetic therapy together with calcium-based phosphate binders and low-dose vitamin D sterols.
recommend measurement of PTH in patients with GFR ⬍60 mL/min/1.73 m2 (⬍1.0 mL/s/1.73 m2) and, if values are elevated, suggest assessing the level of vitamin D nutrition with measurement of 25-hydroxyvitamin D. When the patient returned to the nephrology clinic, 25-hydroxyvitamin D levels were low and hyperparathyroidism was established. Administration of ergocalciferol, as currently is recommended, resulted in only a modest increment of 25-hydroxyvitamin D levels, although iPTH levels decreased somewhat. This result is similar to previous findings in a larger group of patients.10,11 Use of oral active vitamin sterols might have been considered in this patient, but eGFR was low and decreasing progressively and they were not prescribed. In applying these principles of therapy to patients with advanced CKD, including patients with ESRD being treated with dialysis, clinical practice guidelines for therapeutic biochemical targets, initially introduced by the National Kidney Foundation’s KDOQI (Kidney Disease Outcomes Quality Initiative) guidelines and later modified and updated by the KDIGO (Kidney Disease: Improving Global Outcomes) guidelines, can serve as a useful resource. The later iteration of the CKD-MBD guidelines, published in 2009, was far more transparent regarding the data limitations inherent in this field.12,13 Both the KDOQI and KDIGO clinical guidelines for therapy are summarized in Table 1. Initial recommendations by KDOQI were to target iPTH levels in dialysis patients of 150-300 pg/mL (150-300 ng/L) because the prevailing opinion at the time was that this range was associated with relatively normal bone turnover. Levels of serum calcium were recommended to be in the normal 310
range, with the opinion of the guideline development team that calcium levels preferably should be in the lower half of this range. It also was recommended that phosphate values be controlled to 3.5-5.5 mg/dL (1.1-1.8 mmol/L), although the upper level of this range exceeded the typical laboratory normal range. The more recent KDIGO clinical practice guideline sought to limit recommendations to those with convincing data to support them. Accordingly, these guidelines broaden the range for iPTH to 2-9 times the upper limit of normal and continue to suggest that serum calcium levels be maintained within the normal range, but advocated trying to move phosphorus values toward the normal range, if achievable. Of note, these are all level 2, or weak, clinical guidelines and cautiously worded as suggestions rather than recommendations. The most notable change between the KDOQI and KDIGO guidelines is the difference in iPTH target level. In the patient under consideration, these laboratory values were mostly within the recommended ranges, except to note that values for iPTH exceeded the KDOQI recommendations, but were within the KDIGO target. One major limitation with regard to PTH target levels is the actual measurement of PTH, reflecting a lack of PTH standards for assays, as well as the fact that many of the commercially available iPTH assays show varying degrees of cross-reactivity to Nterminally truncated PTH peptides that circulate and may accumulate in patients with advanced kidney disease, particularly patients treated with dialysis.14,15 The variable cross-reactivity of PTH assays to these fragments that can accumulate in CKD renders the recommendation as a multiple of the upper limit of normal as conceptually problematic (in the opinion of the authors) because of the amplification of the contriTable 1. Mineral Metabolism Treatment Goals: KDOQI and KDIGO Targets in CKD Stage 5 Parameter
KDOQI Goal
KDIGO Goal
iPTH (pg/mL)
150-300
2-9 ⫻ upper limit of normal
Ca (mg/dL)
8.4-10.2a
8.4-10.2 Toward normal
P (mg/dL) Ca ⫻ P (mg2/dL2)
3.5-5.5 ⬍55
Not specified
Note: Conversion factors for units: calcium in mg/dL to mmol/L, ⫻0.2495; phosphorus in mg/dL to mmol/L, ⫻0.3229. No conversion necessary for iPTH in pg/mL and ng/L. Abbreviations: Ca, calcium; Ca ⫻ P, calcium-phosphorus product; CKD, chronic kidney disease; iPTH, intact parathyroid hormone; KDIGO, Kidney Disease: Improving Global Outcomes; KDOQI, Kidney Disease Outcomes Quality Initiative; P, phosphorus. a Lower half of range preferable. Am J Kidney Dis. 2012;60(2):308-315
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bution of these PTH peptides to measured values caused by the accumulation of these peptides in the absence of kidney function. Thus, an assay that measures PTH fragments will result in markedly higher values as GFR decreases compared with results of an assay that does not recognize these fragments. Thus, the range recommended by KDIGO includes the widest range possible considering all the PTH assays that are available. However, such a range would include values indicative of moderate to severe hyperparathyroidism for many of the assays that are in use at the present time. KDIGO guidelines also suggest evaluation of changes in PTH levels over time as an additive consideration that may be clinically useful. The issue is complicated further because iPTH values are not a precise index of the underlying bone histology. These issues are reflected in the uncertainty of an appropriate range for PTH measurements in patients with ESRD. In the patient discussed in the clinical vignette, it was unclear whether the bone pain might represent hyperparathyroidism or could reflect microfractures as a result of osteoporosis from prior corticosteroid therapy and/or postmenopausal status or be due to another cause altogether. Although the PTH values might be considered within the KDIGO target, the increased alkaline phosphatase level was suggestive of high-turnover bone. For this reason, a bone biopsy was performed, showed severe hyperparathyroid bone disease, and indicated that intensified therapy for hyperparathyroidism was required. Such therapy was successful in decreasing PTH values to the lower part of recommended ranges and achieved marked improvement in symptoms. Bone biopsy is not done often in clinical practice, but is useful in a case such as this, for which the diagnosis may be unclear and bone biopsy can be very useful in guiding the approach to therapy. It is important to emphasize that the recommended values for PTH initially were focused on the effects of PTH on bone; however, it now is recognized that measurements of PTH alone are not a precise predictor of the state of bone turnover, particularly in patients receiving dialysis. More recent studies have looked to find the relationship between PTH values and patient outcome, with large retrospective epidemiologic studies conducted in the United States, Europe, and South America all showing that the lowest mortality, most of which is cardiovascular in nature, is seen with iPTH values within the range recommended by the initial KDOQI group, that is, iPTH values of 150300 pg/mL (150-300 ng/L).16-18 Such epidemiologic observations indicate only an association of PTH level with outcome and should not be conAm J Kidney Dis. 2012;60(2):308-315
strued as indicating cause and effect. It is important to note that such studies should be considered with the realization that there is considerable potential for residual confounding and limitations of the artificial constraints induced by the statistical modeling in these types of studies. Certain patient groups may require slightly higher PTH values, so that any recommendations with regard to the target range for PTH should be considered “soft” and other factors should be considered according to clinical circumstances. Recommendations of appropriate PTH values in the earlier stages of CKD are entirely opinion based at this time.
CONTROL OF HYPERPHOSPHATEMIA Physiologically, it is intuitive that it should be important to control hyperphosphatemia, reflecting potential consequences for bone and mineral metabolism and for the cardiovascular system, as shown in Fig 2. Thus, hyperphosphatemia can decrease calcitriol production, cause resistance to the actions of calcitriol and PTH, and lead directly to increased PTH secretion and stimulate parathyroid growth. In addition, hyperphosphatemia is associated with an increased risk of metastatic calcification, including calcification in the vasculature,19-21 and has been shown to be associated, as an independent risk factor, with increased mortality risk.16-18,22 For these reasons, it is reasonable to try to control hyperphosphatemia in patients on dialysis therapy. Phosphorus control is accomplished best by addressing both intake and clearance. Accordingly, a multifaceted approach could encompass dietary phosphorus restriction, use of phosphate binders to complex phosphate in the intestine to prevent its absorption, adequate hemodialysis or peritoneal dialysis to facilitate phosphorus removal, and efforts to control secondary hyperparathyroidism to try to minimize phosphate efflux from bone as a contributor to hyperphosphatemia. The quantitative contribution of each of these approaches is not well understood at the present time, and there are insufficient data to show that these efforts will have a favorable influence on mortality. Phosphate binders are an essential part of the therapy and have evolved over many years, from the use of aluminum compounds to the use of calcium-containing phosphate binders, such as calcium carbonate or calcium acetate, to magnesium carbonate, sevelamer hydrochloride, and later, to sevelamer carbonate and lanthanum carbonate, and in the future, to other phosphate binders that are currently in development, as listed in Table 2. The aluminum-based phosphate binders largely have been abandoned in the United States because of the risk of aluminum toxicity, but 311
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↑ Pi ↓ Ca++ PTH Resistance
↓ Calcitriol Calcitriol Resistance
↑ PTH Secretion ↑ Parathyroid Cell Growth Increased Risk of Metastatic Calcification
↑ Mortality
↑ FGF-23
are still used throughout the world. If aluminumbased phosphate binders are used, it is reasonable to have continued surveillance of serum aluminum levels. Calcium-containing phosphate binders are widely used, but in certain settings may be associated with the development and maintenance of hypercalcemia. Several, but not all, trials comparing calcium- versus non–calcium-containing binders suggest that increased calcium absorption may contribute to progression of vascular calcification, as suggested with the Treat-to-Goal and other studies.23,24 This issue remains somewhat controversial.25,26 Thus, the CARE 2 (Calcium Acetate Renagel Evaluation-2) Study compared prevalent hemodialysis patients randomly assigned to calcium acetate or sevelamer hydrochloride treatment, with both groups receiving atorvastatin to lower cholesterol levels. Although there was a high dropout rate, no difference in progression of vascular calcification was observed.26 Similarly, the BRiC (Phosphate Binder Impact on Bone Remodeling and Coronary Calcification) study did not show a difference in rate of progression of vascular calcification in
Figure 2. The consequences of hyperphosphatemia. Elevations in serum phosphate levels can affect end-organ response to parathyroid hormone (PTH) and calcitriol, can directly stimulate PTH secretion and parathyroid growth, and are associated with increased fibroblast growth factor 23 (FGF23) levels and increased risk of vascular calcification and death. Abbreviations: Ca, calcium; Pi, inorganic phosphorus.
patients treated with calcium acetate compared with sevelamer acetate.27 Nonetheless, caution regarding the use of high calcium intake is advised, especially in the presence of vascular calcification. Accordingly, if calcium-containing phosphate binders are used, according to the KDOQI recommendations, the amount should be limited to no more than 1.5 g of elemental calcium per day. No specific limit was suggested by KDIGO, but this would appear to be a reasonable limit unless it is desirable to promote a positive calcium balance. In the patient under discussion, because of mitral valve calcification noted on pretransplant cardiac evaluation, calcium carbonate was reduced and sevelamer was prescribed. Lanthanum carbonate also might have been considered to limit the calcium load. In theory, it seems intuitive that adding to the substrate that precipitates in the vasculature (calcium and phosphorus) would be undesirable because the more vascular calcification that is present, the worse the survival probability for the patient.28 To further explore this theory, several studies have compared survival in individuals prescribed calcium-containing
Table 2. Phosphate Binders Type
CaCO3 CaAc Ca citrate Sevelamer HCl Sevelamer carbonate Mg/CaCO3 MgCO3/CaAc La2(CO3)3 Al(OH)3
Cation Content
200 mg Ca in 500 mg CaCO3 169 mg Ca in 667 mg CaAc 200 mg Ca in 950 mg Ca citrate None None 114 mg Mg in 400 MgCO3; 80 mg Ca in 200 mg CaCO3 60 mg Mg in 235 MgCO3; 110 mg Ca in 435 mg CaAc 250, 500, 1,000 mg La/tablet 100-200 mg Al/tablet
Advantages
Disadvantages
Inexpensive; widely available Inexpensive; widely available — No Ca; 2 LDL No Ca; 2 LDL 2 Ca load
1 Ca 1 Ca; pill burden 1 Ca; 1Al absorption GI side effects; cost; pill burden GI side effects; cost; pill burden Mg accumulation; not widely available
2 Ca load
Mg accumulation; not widely available
Potent Potent
Chewable; GI side effects Al toxicity
Abbreviations: Al, aluminum; Al(OH)3, aluminum hydroxide; Ca, calcium; CaAc, calcium acetate; CaCO3, calcium carbonate; GI, gastrointestinal; HCl, hydrochloride; La2(CO3)3, lanthanum carbonate; LDL, low-density lipoprotein cholesterol; Mg, magnesium; MgCO3, magnesium carbonate. 312
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or non–calcium-containing phosphate binders. The Dialysis Clinical Outcomes Revisited (DCOR) Study, conducted in 2,103 prevalent dialysis patients, randomly assigned participants to either sevelamer or calcium-based phosphate binders, with primary study end points of all-cause mortality and cardiovascular death. Overall, the study was negative and was complicated by a nearly 50% dropout rate, although a nonprespecified subgroup analysis showed a benefit of uncertain methodologic validity in patients 65 years and older,29 the KDIGO CKD-MBD work group states that this subgroup analysis “could be, at best, considered hypothesis generating and should be interpreted with extreme caution.”13(pS55) These results are contrasted with those in the RIND (Reversible Ischemic Neurological Deficit) Study, which examined this issue in 127 incident dialysis patients. In RIND, although the numbers of patients were considerably smaller, use of the non–calcium-containing phosphate binder was associated with decreased progression of vascular calcification over time.23 Follow-up of these patients (albeit uncontrolled) over the subsequent several years showed an apparent survival benefit for patients treated with sevelamer,30 raising the issue that the DCOR results potentially may not fully reflect the benefits of the non–calcium-containing binder because of the use of prevalent patients, and calling to attention that perhaps this question should be examined earlier in the course of CKD.
VITAMIN D STEROLS Several active vitamin D sterols are available for use in patients to control hyperparathyroidism; in the United States, these agents include calcitriol, paricalcitol, and doxercalciferol. Use of vitamin D sterols is an important part of the therapy for hyperparathyroidism, not only because of the efficacy in controlling PTH secretion, but also because of observations that use of vitamin D sterols appears to be associated with a survival advantage, first noticed in patients on hemodialysis therapy and later in patients with CKD.31-35 The vitamin D analogue paricalcitol was introduced and developed to try to obtain more selective action on the parathyroid gland while minimizing the effects of active vitamin D sterols to cause hypercalcemia or hyperphosphatemia (the main manifestations of vitamin D toxicity) and was supported in detailed preclinical studies. The vitamin D2 prohormone doxercalciferol, because it also was based on the D2 structure, also appeared to have the potential for decreased hypercalcemia and is widely used. Direct head-to-head randomized studies in patients are limited at the present time. In one observational study, we noted that withdrawal of paricalcitol therapy does not significantly change serum phosphate values, sugAm J Kidney Dis. 2012;60(2):308-315
gesting that the effects of paricalcitol on increasing phosphate absorption are rather small.36 In contrast, in a crossover study in which paricalcitol was compared with doxercalciferol, there were more episodes of hyperphosphatemia with doxercalciferol than with paricalcitol, suggesting that there are potential differences between these vitamin D sterols that may become relevant to their use. In patients with CKD not on dialysis therapy, the oral forms of these active vitamin D sterols may be used, but there are no definitive studies of the relative efficacy or toxicity. A substantial body of evidence in experimental animals confirms that there are important differences between the various vitamin D sterols, particularly dramatic in terms of vascular calcification, as shown in the work of Mizobuchi et al,37 in which calcitriol and doxercalciferol appear to be associated with severe vascular calcification, whereas paricalcitol was not. Comparable data in patients are not available at the present time. Because 25-hydroxyvitamin D levels are low in many patients with advanced kidney disease, an important clinical question is whether this needs to be supplemented, especially in patients who are receiving active vitamin D sterols. In this regard, one should consider the observations of Wolf et al,38 who found that mortality in the first 90 days of dialysis therapy appears to stratify by 25-hydroxyvitamin D levels, and if these patients were given an active vitamin D sterol, this stratification was abolished. These observations suggest that administration of an active vitamin D sterol may be sufficient to achieve the apparent mortality benefit shown with this therapy. One also should consider results of studies in 1␣-hydroxylase knockout animals, in which calcitriol administration has been shown to have beneficial effects on cardiac hypertrophy that conceivably may be relevant to this issue and suggesting that the circulating hormonal form of active vitamin D may have important effects on the cardiovascular system.39 However, cholecalciferol supplementation may decrease the amount of active vitamin D sterol required and also may decrease the amount of erythropoietic-stimulating agent required.40 If hyperparathyroidism cannot be controlled with adequate control of hyperphosphatemia, correction of hypocalcemia, and the use of vitamin D sterols, an additional approach in patients with ESRD is to directly target PTH secretion from the parathyroid gland by the use of a calcimimetic agent or to consider parathyroidectomy in selected patients. The calcimimetic cinacalcet was introduced for this purpose and by targeting the calcium receptor, can decrease PTH levels effectively, significantly decrease serum calcium levels, and achieve a slight decrease in serum 313
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phosphate values if taken in conjunction with the other therapeutic measures.41,42 Recent data for 360 patients in the ADVANCE (Action in Diabetes and Cardiovascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation) trial suggest that this approach is associated with a trend toward decreasing the progression of vascular and valvular calcification and was significant for aortic valvular calcification.43 Because this agent is administered orally, one has to ensure patient adherence to the regimen, which may be somewhat problematic, as shown by the studies of Gincherman et al.44 If medical therapy cannot achieve sustained control of hyperparathyroidism, consideration should be given to parathyroidectomy. This usually is reserved for patients with severe hyperparathyroidism for whom medical therapy cannot be tolerated. A recent consideration for the therapeutic approach to this important clinical problem relates to FGF-23 levels. Thus, vitamin D therapy might be expected to directly increase FGF-23 levels. However, because FGF-23 comes from bone, reductions in bone cell activity might be expected to decrease FGF-23 levels. This issue may become important because epidemiologic studies indicate that high FGF-23 levels appear to be associated with increased mortality for patients on hemodialysis therapy.45,46 This observation also appears to extend to patients with earlier stages of CKD.47 Although the exact mechanism for this mortality association is not known, recent studies show important direct effects of FGF-23 on the heart, particularly in causing left ventricular hypertrophy.48 At the very least, FGF-23 appears to be an important biomarker for adverse outcomes, and it may be causative for inducing left ventricular hypertrophy. It may become useful in the future to consider what happens to FGF-23 during our therapeutic efforts and perhaps develop approaches to modify its production or action. Calcimimetic therapy would be expected to decrease FGF-23 by decreasing PTH levels, whereas vitamin D sterols would be expected to increase FGF-23 production by a direct effect on gene transcription. However, in one clinical trial that compared cinacalcet plus fixed-dose active vitamin D sterol therapy versus active vitamin D sterol therapy alone to control hyperparathyroidism, there appeared to be a greater decrease in FGF-23 levels in the cinacalcet arm.49 Further studies are required of the consequences of changes in FGF-23 levels with the current approach to treatment of abnormalities in CKDMBD. Much of our approach to the treatment of mineral and bone disorders in CKD has been in patients who are treated with dialysis, and despite decades of clinical experience, there remains a paucity of high-quality 314
data and many therapeutic challenges to achieving effective and sustained control of MBD. Given the limited overall success with addressing disease in patients with kidney failure, at which time much of the milieu promoting MBD has been present for years or even decades, it becomes important to try to address these problems earlier in the course of CKD.2,50 Possibly, if addressed early, improved and more constant control of MBD during kidney failure might be facilitated. Further ongoing research and future developments of new therapeutic agents may facilitate our efforts on this important clinical problem.
ACKNOWLEDGEMENTS Support: None. Financial Disclosure: Dr Martin has served as a consultant for Abbott, Cytochroma, Genzyme, and KAI Pharmaceuticals and as a speaker for Abbott and Genzyme. Dr González declares that she has no relevant financial interests.
REFERENCES 1. Moe SM, Drueke T, Lameire N, Eknoyan G. Chronic kidney disease-mineral-bone disorder: a new paradigm. Adv Chronic Kidney Dis. 2007;14(1):3-12. 2. Martin KJ, Gonzalez EA. Metabolic bone disease in chronic kidney disease. J Am Soc Nephrol. 2007;18(3):875-885. 3. Perwad F, Zhang MY, Tenenhouse HS, Portale AA. Fibroblast growth factor 23 impairs phosphorus and vitamin D metabolism in vivo and suppresses 25-hydroxyvitamin D-1alpha-hydroxylase expression in vitro. Am J Physiol. 2007;293(5):F1577-F1583. 4. Shimada T, Hasegawa H, Yamazaki Y, et al. FGF-23 is a potent regulator of vitamin D metabolism and phosphate homeostasis. J Bone Miner Res. 2004;19(3):429-435. 5. Nykjaer A, Dragun D, Walther D, et al. An endocytic pathway essential for renal uptake and activation of the steroid 25-(OH) vitamin D3. Cell. 1999;96(4):507-515. 6. Usatii M, Rousseau L, Demers C, et al. Parathyroid hormone fragments inhibit active hormone and hypocalcemia-induced 1,25(OH)2D synthesis. Kidney Int. 2007;72(11):1330-1335. 7. Slatopolsky E, Caglar S, Gradowska L, Canterbury J, Reiss E, Bricker NS. On the prevention of secondary hyperparathyroidism in experimental chronic renal disease using “proportional reduction” of dietary phosphorus intake. Kidney Int. 1972; 2(3):147-151. 8. Slatopolsky E, Caglar S, Pennell JP, et al. On the pathogenesis of hyperparathyroidism in chronic experimental renal insufficiency in the dog. J Clin Invest. 1971;50(3):492-499. 9. Isakova T, Wahl P, Vargas GS, et al. Fibroblast growth factor 23 is elevated before parathyroid hormone and phosphate in chronic kidney disease. Kidney Int. 2011;79(12):1370-1378. 10. Al-Aly Z, Qazi RA, Gonzalez EA, Zeringue A, Martin KJ. Changes in serum 25-hydroxyvitamin D and plasma intact PTH levels following treatment with ergocalciferol in patients with CKD. Am J Kidney Dis. 2007;50(1):59-68. 11. Zisman AL, Hristova M, Ho LT, Sprague SM. Impact of ergocalciferol treatment of vitamin D deficiency on serum parathyroid hormone concentrations in chronic kidney disease. Am J Nephrol. 2007;27(1):36-43. 12. National Kidney Foundation. K/DOQI Clinical Practice Guidelines for Bone Metabolism and Disease in Chronic Kidney Disease. Am J Kidney Dis. 2003;42(4)(suppl 3):S1-S201. 13. Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Work Group. KDIGO clinical practice guideline for Am J Kidney Dis. 2012;60(2):308-315
Long-term Management of CKD-MBD the diagnosis, evaluation, prevention, and treatment of chronic kidney disease-mineral and bone disorder (CKD-MBD). Kidney Int. 2009;76(Suppl 113):S1-S130. 14. Martin KJ, Gonzalez EA. Parathyroid hormone assay: problems and opportunities. Pediatr Nephrol. 2007;22(10):1651-1654. 15. Souberbielle JC, Boutten A, Carlier MC, et al. Inter-method variability in PTH measurement: implication for the care of CKD patients. Kidney Int. 2006;70(2):345-350. 16. Floege J, Kim J, Ireland E, et al. Serum iPTH, calcium and phosphate, and the risk of mortality in a European haemodialysis population. Nephrol Dial Transplant. 2011;26(6):1948-1955. 17. Kalantar-Zadeh K, Kuwae N, Regidor DL, et al. Survival predictability of time-varying indicators of bone disease in maintenance hemodialysis patients. Kidney Int. 2006;70(4):771-780. 18. Naves-Diaz M, Passlick-Deetjen J, Guinsburg A, et al. Calcium, phosphorus, PTH and death rates in a large sample of dialysis patients from Latin America. The CORES Study. Nephrol Dial Transplant. 2011;26(6):1938-1947. 19. Kendrick J, Chonchol M. The role of phosphorus in the development and progression of vascular calcification. Am J Kidney Dis. 2011;58(5):826-834. 20. Roman-Garcia P, Carrillo-Lopez N, Fernandez-Martin JL, Naves-Diaz M, Ruiz-Torres MP, Cannata-Andia JB. High phosphorus diet induces vascular calcification, a related decrease in bone mass and changes in the aortic gene expression. Bone. 2010;46(1): 121-128. 21. Srivaths PR, Goldstein SL, Silverstein DM, Krishnamurthy R, Brewer ED. Elevated FGF 23 and phosphorus are associated with coronary calcification in hemodialysis patients. Pediatr Nephrol. 2011;26(6):945-951. 22. Block GA, Hulbert-Shearon TE, Levin NW, Port FK. Association of serum phosphorus and calcium x phosphate product with mortality risk in chronic hemodialysis patients: a national study. Am J Kidney Dis. 1998;31(4):607-617. 23. Block GA, Spiegel DM, Ehrlich J, et al. Effects of sevelamer and calcium on coronary artery calcification in patients new to hemodialysis. Kidney Int. 2005;68(4):1815-1824. 24. Chertow GM, Burke SK, Raggi P. Sevelamer attenuates the progression of coronary and aortic calcification in hemodialysis patients. Kidney Int. 2002;62(1):245-252. 25. Navaneethan SD, Palmer SC, Craig JC, Elder GJ, Strippoli GF. Benefits and harms of phosphate binders in CKD: a systematic review of randomized controlled trials. Am J Kidney Dis. 2009; 54(4):619-637. 26. Qunibi W, Moustafa M, Muenz LR, et al. A 1-year randomized trial of calcium acetate versus sevelamer on progression of coronary artery calcification in hemodialysis patients with comparable lipid control: the Calcium Acetate Renagel Evaluation-2 (CARE-2) Study. Am J Kidney Dis. 2008;51(6):952-965. 27. Barreto DV, Barreto Fde C, de Carvalho AB, et al. Phosphate binder impact on bone remodeling and coronary calcification—results from the BRiC Study. Nephron Clin Pract. 2008; 110(4):c273-c283. 28. Blacher J, Guerin AP, Pannier B, Marchais SJ, London GM. Arterial calcifications, arterial stiffness, and cardiovascular risk in end-stage renal disease. Hypertension. 2001;38(4):938-942. 29. Suki WN, Zabaneh R, Cangiano JL, et al. Effects of sevelamer and calcium-based phosphate binders on mortality in hemodialysis patients. Kidney Int. 2007;72(9):1130-1137. 30. Block GA, Raggi P, Bellasi A, Kooienga L, Spiegel DM. Mortality effect of coronary calcification and phosphate binder choice in incident hemodialysis patients. Kidney Int. 2007;71(5): 438-441.
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31. Kovesdy CP, Ahmadzadeh S, Anderson JE, Kalantar-Zadeh K. Association of activated vitamin D treatment and mortality in chronic kidney disease. Arch Intern Med. 2008;168(4):397-403. 32. Shoben AB, Rudser KD, de Boer IH, Young B, Kestenbaum B. Association of oral calcitriol with improved survival in nondialyzed CKD. J Am Soc Nephrol. 2008;19(8):1613-1619. 33. Teng M, Wolf M, Lowrie E, Ofsthun N, Lazarus JM, Thadhani R. Survival of patients undergoing hemodialysis with paricalcitol or calcitriol therapy. N Engl J Med. 2003;349(5):446456. 34. Teng M, Wolf M, Ofsthun MN, et al. Activated injectable vitamin D and hemodialysis survival: a historical cohort study. J Am Soc Nephrol. 2005;16(4):1115-1125. 35. Tentori F, Albert JM, Young EW, et al. The survival advantage for haemodialysis patients taking vitamin D is questioned: findings from the Dialysis Outcomes and Practice Patterns Study. Nephrol Dial Transplant. 2009;24(3):963-972. 36. Martin KJ. When is vitamin D contraindicated in dialysis patients? Semin Dial. 2009;22(3):247-249. 37. Mizobuchi M, Finch JL, Martin DR, Slatopolsky E. Differential effects of vitamin D receptor activators on vascular calcification in uremic rats. Kidney Int. 2007;72(6):709-715. 38. Wolf M, Shah A, Gutierrez O, et al. Vitamin D levels and early mortality among incident hemodialysis patients. Kidney Int. 2007;72(8):1004-1013. 39. Zhou C, Lu F, Cao K, Xu D, Goltzman D, Miao D. Calcium-independent and 1,25(OH)2D3-dependent regulation of the renin-angiotensin system in 1alpha-hydroxylase knockout mice. Kidney Int. 2008;74(2):170-179. 40. Matias PJ, Jorge C, Ferreira C, et al. Cholecalciferol supplementation in hemodialysis patients: effects on mineral metabolism, inflammation, and cardiac dimension parameters. Clin J Am Soc Nephrol. 2010;5(5):905-911. 41. Block GA, Martin KJ, de Francisco AL, et al. Cinacalcet for secondary hyperparathyroidism in patients receiving hemodialysis. N Engl J Med. 2004;350(15):1516-1525. 42. Moe SM, Chertow GM, Coburn JW, et al. Achieving NKF-K/DOQI bone metabolism and disease treatment goals with cinacalcet HCl. Kidney Int. 2005;67(2):760-771. 43. Raggi P, Chertow GM, Torres PU, et al. The ADVANCE study: a randomized study to evaluate the effects of cinacalcet plus low-dose vitamin D on vascular calcification in patients on hemodialysis. Nephrol Dial Transplant. 2011;26(4):1327-1339. 44. Gincherman Y, Moloney K, McKee C, Coyne DW. Assessment of adherence to cinacalcet by prescription refill rates in hemodialysis patients. Hemodial Int. 2010;14(1):68-72. 45. Gutierrez OM, Mannstadt M, Isakova T, et al. Fibroblast growth factor 23 and mortality among patients undergoing hemodialysis. N Engl J Med. 2008;359(6):584-592. 46. Jean G, Terrat JC, Vanel T, et al. High levels of serum fibroblast growth factor (FGF)-23 are associated with increased mortality in long haemodialysis patients. Nephrol Dial Transplant. 2009;24(9):2792-2796. 47. Isakova T, Xie H, Yang W, et al. Fibroblast growth factor 23 and risks of mortality and end-stage renal disease in patients with chronic kidney disease. Jama. 2011;305(23):2432-2439. 48. Faul C, Amaral AP, Oskouei B, et al. FGF23 induces left ventricular hypertrophy. J Clin Invest. 2011;121(11):4393-4408. 49. Wetmore JB, Liu S, Krebill R, Menard R, Quarles LD. Effects of cinacalcet and concurrent low-dose vitamin D on FGF-23 levels in ESRD. Clin J Am Soc Nephrol. 2010;5(1):110116. 50. Martin KJ, Gonzalez EA. Prevention and control of phosphate retention/hyperphosphatemia in CKD-MBD: what is normal, when to start, and how to treat? Clin J Am Soc Nephrol. 2011;6(2):440-446.
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CASE PRESENTATION A 56-year-old white woman with a history of lupus nephritis class 4, which had been treated with prednisone and intravenous cyclophosphamide with an apparent good response, returned to the nephrology clinic after a 6-year absence. During that time, she had remained asymptomatic, discontinued all medications, and did not seek medical care. Evaluation showed the following values: serum creatinine, 4.1 mg/dL (362.44 mol/L; estimated glomerular filtration rate [eGFR], 12 mL/min/1.73 m2 [0.20 mL/s/1.73 m2]), which previously was 1.2 mg/dL (106.1 mol/L); calcium, 8.9 mg/dL (2.22 mmol/L); phosphorus, 4.8 mg/dL (1.55 mmol/L); 25hydroxyvitamin D, 14 ng/mL (34.94 nmol/L); intact parathyroid hormone (iPTH), 432 pg/mL (432 ng/L); and hemoglobin, 9.4 g/dL (94 g/L). Ultrasound showed kidney size to be 9.1 and 8.7 cm. Urinary protein-creatinine ratio was 2.4 g/g. Urine sediment was unremarkable. Anti–double-stranded DNA was negative and C3 and C4 levels were normal. Blood pressure was 152/82 mm Hg, and there was mild peripheral edema. Therapy was initiated with furosemide; lisinopril; ergocalciferol, 50,000 units every 2 weeks; darbepoetin; and calcium carbonate, 500 mg, with meals. After 3 months of treatment, 25-hydroxyvitamin D level increased to 26 ng/mL (64.90 nmol/L), and iPTH level decreased to 296 pg/mL (296 ng/L). During the next 6 months, serum creatinine level slowly increased, and hemodialysis therapy was initiated when serum creatinine level reached 8.7 mg/dL (769.1 mol/L; eGFR, 5 mL/min/1.73 m2 [0.08 mL/s/1.73 m2]) through an arteriovenous fistula. While receiving hemodialysis, the patient remained clinically well during the next 2 years and was placed on the transplant
From the Division of Nephrology, Saint Louis University, St Louis, MO. Received July 7, 2011. Accepted in revised form January 4, 2012. Originally published online April 23, 2012. Address correspondence to Kevin J. Martin, MB, BCh, Division of Nephrology, Saint Louis University Medical Center, Division of Nephrology (9-FDT), 3635 Vista Ave, St Louis, MO 63110. E-mail: [email protected] © 2012 by the National Kidney Foundation, Inc. 0272-6386/$36.00 doi:10.1053/j.ajkd.2012.01.027 308
list. Cardiac stress echocardiography was negative for ischemia, but left ventricular hypertrophy and modest calcification of the mitral valve were noted. Calcium carbonate therapy was stopped and sevelamer was begun as a phosphate binder to treat phosphorus values ranging from 5.4-6.2 mg/mL (1.74-2.0 mmol/L). iPTH levels progressively increased, peaking at 562 pg/mL (562 ng/L); treatment with paricalcitol, 2 g per dialysis treatment, was begun. PTH level remained at 364-486 pg/mL (364-486 ng/L) for the next year. After approximately 3 years on dialysis therapy, the patient began to notice vague pains in her hip and knee joints and legs and back. Pain was aggravated by exercise, and overall, she felt that her health was declining. These symptoms gradually became worse during the ensuing months. Review of laboratory values for the past year showed calcium values in the low-normal range, phosphorus values of 5.1-6.2 mg/dL (1.6-2.0 mmol/L), and iPTH values of 372-463 pg/mL (372-463 ng/L). Alkaline phosphatase level was 192 U/L, having increased from 139 U/L 1 year earlier. Dual-energy x-ray absorptiometry showed a T score of ⫺2.3 at the hip. Bone biopsy showed severe osteitis fibrosa. Paricalcitol therapy was intensified, and iPTH values stabilized near 200 pg/mL (200 ng/L) during the next 6 months, with a marked decrease in skeletal symptoms occurring after 3 months of intensified paricalcitol therapy.
INTRODUCTION Our view of the consequences of abnormal bone and mineral metabolism in the setting of chronic kidney disease (CKD) has evolved from focusing entirely on the skeleton to a broader perspective in which not only are bone abnormalities observed and require therapy, but these abnormalities also seem to be related to cardiovascular disease (specifically vascular calcification) and are implicated in increased mortality risk. Accordingly, the term renal osteodystrophy can be considered to represent the skeletal abnormalities, whereas the broader term CKD–mineral and bone disorder (CKD-MBD) spans the full spectrum of the consequences of abnormal bone and mineral metabolism in people with CKD.1 Secondary hyperparaAm J Kidney Dis. 2012;60(2):308-315
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thyroidism is a major part of the MBD spectrum and has been one focus of research to understand the factors that generate and maintain hyperparathyroidism.2 To date, it is well established that phosphate retention and abnormalities in vitamin D metabolism result from CKD and, either directly or by inducing changes in serum calcium levels, stimulate the growth and activity of the parathyroid glands. The resultant high levels of PTH in blood can affect the bone, causing osteitis fibrosa (high-turnover bone disease), manifest with demineralization of bone, predisposition to fractures, and not infrequently, bone pain. In addition, the consequences of high PTH levels may extend to nonskeletal tissue, contributing to abnormalities in multiple systems throughout the body, most notably cardiovascular disease, with manifestations including left ventricular hypertrophy, vascular calcification, and hypertension. Abnormalities in vitamin D metabolism occur early in the course of CKD, with 1,25-dihydroxyvitamin D levels having been shown to decrease progressively, thereby promoting increases in PTH levels. One reason for the decrease in 1,25-dihydroxyvitamin D levels is phosphate retention, which may directly suppress the activity of 1-hydroxylase or may act indirectly by increasing levels of fibroblast growth factor 23 (FGF-23), which in turn will decrease 1␣hydroxylase activity and increase 24-hydroxylase activity.3,4 Compensatory efforts to maintain the concentration of 1,25-dihydroxyvitamin D are compromised because 25-hydroxyvitamin D levels have been shown to be reduced in many people with CKD, possibly contributing to the inability of the damaged kidney to augment 1,25-dihydroxyvitamin D production when needed, even in the presence of hyperparathyroidism.5 The accumulation of N-terminally truncated PTH fragments also may decrease 1␣-hydroxylase activity.6 Ultimately, when kidney disease is advanced, 1,25-dihydroxyvitamin D production may be limited most by the marked decrease in renal parenchymal mass.
PRINCIPLES OF THERAPY As the pathophysiology of secondary hyperparathyroidism has been elucidated over the past, our understanding of this pathophysiology has provided a rational framework for therapy in which the abnormalities noted to contribute to hyperparathyroidism are directly targeted with therapeutic efforts. As listed in Box 1, the principles of therapy for hyperparathyroidism are to control phosphorus levels and prevent phosphate retention, correct hypocalcemia if it is present because this is the major driver of PTH secretion, supply vitamin D sterols to counteract the Am J Kidney Dis. 2012;60(2):308-315
Box 1. Principles of Therapy of Hyperparathyroidism in ESRD Consider calcium balance ● ● ●
Control hyperphosphatemia/phosphate retention Correct hypocalcemia (if present) Consider vitamin D sterols
Consider use of calcimimetic therapy or parathyroidectomy in select patients Abbreviation: ESRD, end-stage renal disease.
abnormalities in vitamin D metabolism, and, finally, consider the use of a calcimimetic agent or parathyroidectomy to directly control PTH secretion at the level of the parathyroid gland. These measures are undertaken in the context of minimizing the calcium burden to the patient to prevent excessive calcium loading, which may aggravate the progression of vascular calcification. Just as there is a wide spectrum of clinical and biochemical abnormalities in patients with CKD, there is also a wide spectrum of therapeutic approaches to the patient with CDK-MBD, as illustrated in Fig 1. Thus, some clinicians favor a vitamin D–based approach with calcimimetic as add-on therapy, whereas others favor the use of a low-dose vitamin D sterol as background for calcimimetic-based therapy. The details of individual patients likely determine the appropriate approach, as well as issues of treatment adherence, cost, and comorbid conditions. There presently are no definitive long-term data to compare these approaches. These principles have been derived mostly from observations in patients with end-stage renal disease (ESRD), but to some degree may be applied to the earlier stages of CKD when the abnormalities in bone and mineral homeostasis begin. Calcimimetic therapy is not approved for use in patients with CKD not on dialysis therapy and therefore is not recommended for such patients at this time. In the patient under discussion, the opportunity to begin therapy early in the course of CKD was not possible because of loss of follow-up. However, in general, therapy should be undertaken at this time if possible. Because clinically measurable hyperphosphatemia does not occur until GFR is ⬍20 mL/min/ 1.73 m2 (⬍0.33 mL/s/1.73 m2), the use of phosphate binders is not part of routine clinical practice. However, phosphate binders perhaps should be considered in light of extensive experimental observations in animals, in which dietary phosphorus restriction in proportion to the decrease in GFR was shown to be effective in preventing the development of secondary hyperparathyroidism.7,8 It is possible that in the future, measurements of FGF-23 might be useful in early CKD because these values may increase even before elevations in PTH levels are seen.9 However, current practice guidelines 309
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Vitamin D Sterol
Calcimimec
Non-calcium based binders
Calcium based binders
Figure 1. The spectrum of therapies for chronic kidney disease–mineral and bone disorder (CKD-MBD). This reflects the strategies of principally using vitamin D sterols together with non– calcium-based phosphate binders and possibly a low-dose calcimimetic compared with an alternate strategy of using calcimimetic therapy together with calcium-based phosphate binders and low-dose vitamin D sterols.
recommend measurement of PTH in patients with GFR ⬍60 mL/min/1.73 m2 (⬍1.0 mL/s/1.73 m2) and, if values are elevated, suggest assessing the level of vitamin D nutrition with measurement of 25-hydroxyvitamin D. When the patient returned to the nephrology clinic, 25-hydroxyvitamin D levels were low and hyperparathyroidism was established. Administration of ergocalciferol, as currently is recommended, resulted in only a modest increment of 25-hydroxyvitamin D levels, although iPTH levels decreased somewhat. This result is similar to previous findings in a larger group of patients.10,11 Use of oral active vitamin sterols might have been considered in this patient, but eGFR was low and decreasing progressively and they were not prescribed. In applying these principles of therapy to patients with advanced CKD, including patients with ESRD being treated with dialysis, clinical practice guidelines for therapeutic biochemical targets, initially introduced by the National Kidney Foundation’s KDOQI (Kidney Disease Outcomes Quality Initiative) guidelines and later modified and updated by the KDIGO (Kidney Disease: Improving Global Outcomes) guidelines, can serve as a useful resource. The later iteration of the CKD-MBD guidelines, published in 2009, was far more transparent regarding the data limitations inherent in this field.12,13 Both the KDOQI and KDIGO clinical guidelines for therapy are summarized in Table 1. Initial recommendations by KDOQI were to target iPTH levels in dialysis patients of 150-300 pg/mL (150-300 ng/L) because the prevailing opinion at the time was that this range was associated with relatively normal bone turnover. Levels of serum calcium were recommended to be in the normal 310
range, with the opinion of the guideline development team that calcium levels preferably should be in the lower half of this range. It also was recommended that phosphate values be controlled to 3.5-5.5 mg/dL (1.1-1.8 mmol/L), although the upper level of this range exceeded the typical laboratory normal range. The more recent KDIGO clinical practice guideline sought to limit recommendations to those with convincing data to support them. Accordingly, these guidelines broaden the range for iPTH to 2-9 times the upper limit of normal and continue to suggest that serum calcium levels be maintained within the normal range, but advocated trying to move phosphorus values toward the normal range, if achievable. Of note, these are all level 2, or weak, clinical guidelines and cautiously worded as suggestions rather than recommendations. The most notable change between the KDOQI and KDIGO guidelines is the difference in iPTH target level. In the patient under consideration, these laboratory values were mostly within the recommended ranges, except to note that values for iPTH exceeded the KDOQI recommendations, but were within the KDIGO target. One major limitation with regard to PTH target levels is the actual measurement of PTH, reflecting a lack of PTH standards for assays, as well as the fact that many of the commercially available iPTH assays show varying degrees of cross-reactivity to Nterminally truncated PTH peptides that circulate and may accumulate in patients with advanced kidney disease, particularly patients treated with dialysis.14,15 The variable cross-reactivity of PTH assays to these fragments that can accumulate in CKD renders the recommendation as a multiple of the upper limit of normal as conceptually problematic (in the opinion of the authors) because of the amplification of the contriTable 1. Mineral Metabolism Treatment Goals: KDOQI and KDIGO Targets in CKD Stage 5 Parameter
KDOQI Goal
KDIGO Goal
iPTH (pg/mL)
150-300
2-9 ⫻ upper limit of normal
Ca (mg/dL)
8.4-10.2a
8.4-10.2 Toward normal
P (mg/dL) Ca ⫻ P (mg2/dL2)
3.5-5.5 ⬍55
Not specified
Note: Conversion factors for units: calcium in mg/dL to mmol/L, ⫻0.2495; phosphorus in mg/dL to mmol/L, ⫻0.3229. No conversion necessary for iPTH in pg/mL and ng/L. Abbreviations: Ca, calcium; Ca ⫻ P, calcium-phosphorus product; CKD, chronic kidney disease; iPTH, intact parathyroid hormone; KDIGO, Kidney Disease: Improving Global Outcomes; KDOQI, Kidney Disease Outcomes Quality Initiative; P, phosphorus. a Lower half of range preferable. Am J Kidney Dis. 2012;60(2):308-315
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bution of these PTH peptides to measured values caused by the accumulation of these peptides in the absence of kidney function. Thus, an assay that measures PTH fragments will result in markedly higher values as GFR decreases compared with results of an assay that does not recognize these fragments. Thus, the range recommended by KDIGO includes the widest range possible considering all the PTH assays that are available. However, such a range would include values indicative of moderate to severe hyperparathyroidism for many of the assays that are in use at the present time. KDIGO guidelines also suggest evaluation of changes in PTH levels over time as an additive consideration that may be clinically useful. The issue is complicated further because iPTH values are not a precise index of the underlying bone histology. These issues are reflected in the uncertainty of an appropriate range for PTH measurements in patients with ESRD. In the patient discussed in the clinical vignette, it was unclear whether the bone pain might represent hyperparathyroidism or could reflect microfractures as a result of osteoporosis from prior corticosteroid therapy and/or postmenopausal status or be due to another cause altogether. Although the PTH values might be considered within the KDIGO target, the increased alkaline phosphatase level was suggestive of high-turnover bone. For this reason, a bone biopsy was performed, showed severe hyperparathyroid bone disease, and indicated that intensified therapy for hyperparathyroidism was required. Such therapy was successful in decreasing PTH values to the lower part of recommended ranges and achieved marked improvement in symptoms. Bone biopsy is not done often in clinical practice, but is useful in a case such as this, for which the diagnosis may be unclear and bone biopsy can be very useful in guiding the approach to therapy. It is important to emphasize that the recommended values for PTH initially were focused on the effects of PTH on bone; however, it now is recognized that measurements of PTH alone are not a precise predictor of the state of bone turnover, particularly in patients receiving dialysis. More recent studies have looked to find the relationship between PTH values and patient outcome, with large retrospective epidemiologic studies conducted in the United States, Europe, and South America all showing that the lowest mortality, most of which is cardiovascular in nature, is seen with iPTH values within the range recommended by the initial KDOQI group, that is, iPTH values of 150300 pg/mL (150-300 ng/L).16-18 Such epidemiologic observations indicate only an association of PTH level with outcome and should not be conAm J Kidney Dis. 2012;60(2):308-315
strued as indicating cause and effect. It is important to note that such studies should be considered with the realization that there is considerable potential for residual confounding and limitations of the artificial constraints induced by the statistical modeling in these types of studies. Certain patient groups may require slightly higher PTH values, so that any recommendations with regard to the target range for PTH should be considered “soft” and other factors should be considered according to clinical circumstances. Recommendations of appropriate PTH values in the earlier stages of CKD are entirely opinion based at this time.
CONTROL OF HYPERPHOSPHATEMIA Physiologically, it is intuitive that it should be important to control hyperphosphatemia, reflecting potential consequences for bone and mineral metabolism and for the cardiovascular system, as shown in Fig 2. Thus, hyperphosphatemia can decrease calcitriol production, cause resistance to the actions of calcitriol and PTH, and lead directly to increased PTH secretion and stimulate parathyroid growth. In addition, hyperphosphatemia is associated with an increased risk of metastatic calcification, including calcification in the vasculature,19-21 and has been shown to be associated, as an independent risk factor, with increased mortality risk.16-18,22 For these reasons, it is reasonable to try to control hyperphosphatemia in patients on dialysis therapy. Phosphorus control is accomplished best by addressing both intake and clearance. Accordingly, a multifaceted approach could encompass dietary phosphorus restriction, use of phosphate binders to complex phosphate in the intestine to prevent its absorption, adequate hemodialysis or peritoneal dialysis to facilitate phosphorus removal, and efforts to control secondary hyperparathyroidism to try to minimize phosphate efflux from bone as a contributor to hyperphosphatemia. The quantitative contribution of each of these approaches is not well understood at the present time, and there are insufficient data to show that these efforts will have a favorable influence on mortality. Phosphate binders are an essential part of the therapy and have evolved over many years, from the use of aluminum compounds to the use of calcium-containing phosphate binders, such as calcium carbonate or calcium acetate, to magnesium carbonate, sevelamer hydrochloride, and later, to sevelamer carbonate and lanthanum carbonate, and in the future, to other phosphate binders that are currently in development, as listed in Table 2. The aluminum-based phosphate binders largely have been abandoned in the United States because of the risk of aluminum toxicity, but 311
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↑ Pi ↓ Ca++ PTH Resistance
↓ Calcitriol Calcitriol Resistance
↑ PTH Secretion ↑ Parathyroid Cell Growth Increased Risk of Metastatic Calcification
↑ Mortality
↑ FGF-23
are still used throughout the world. If aluminumbased phosphate binders are used, it is reasonable to have continued surveillance of serum aluminum levels. Calcium-containing phosphate binders are widely used, but in certain settings may be associated with the development and maintenance of hypercalcemia. Several, but not all, trials comparing calcium- versus non–calcium-containing binders suggest that increased calcium absorption may contribute to progression of vascular calcification, as suggested with the Treat-to-Goal and other studies.23,24 This issue remains somewhat controversial.25,26 Thus, the CARE 2 (Calcium Acetate Renagel Evaluation-2) Study compared prevalent hemodialysis patients randomly assigned to calcium acetate or sevelamer hydrochloride treatment, with both groups receiving atorvastatin to lower cholesterol levels. Although there was a high dropout rate, no difference in progression of vascular calcification was observed.26 Similarly, the BRiC (Phosphate Binder Impact on Bone Remodeling and Coronary Calcification) study did not show a difference in rate of progression of vascular calcification in
Figure 2. The consequences of hyperphosphatemia. Elevations in serum phosphate levels can affect end-organ response to parathyroid hormone (PTH) and calcitriol, can directly stimulate PTH secretion and parathyroid growth, and are associated with increased fibroblast growth factor 23 (FGF23) levels and increased risk of vascular calcification and death. Abbreviations: Ca, calcium; Pi, inorganic phosphorus.
patients treated with calcium acetate compared with sevelamer acetate.27 Nonetheless, caution regarding the use of high calcium intake is advised, especially in the presence of vascular calcification. Accordingly, if calcium-containing phosphate binders are used, according to the KDOQI recommendations, the amount should be limited to no more than 1.5 g of elemental calcium per day. No specific limit was suggested by KDIGO, but this would appear to be a reasonable limit unless it is desirable to promote a positive calcium balance. In the patient under discussion, because of mitral valve calcification noted on pretransplant cardiac evaluation, calcium carbonate was reduced and sevelamer was prescribed. Lanthanum carbonate also might have been considered to limit the calcium load. In theory, it seems intuitive that adding to the substrate that precipitates in the vasculature (calcium and phosphorus) would be undesirable because the more vascular calcification that is present, the worse the survival probability for the patient.28 To further explore this theory, several studies have compared survival in individuals prescribed calcium-containing
Table 2. Phosphate Binders Type
CaCO3 CaAc Ca citrate Sevelamer HCl Sevelamer carbonate Mg/CaCO3 MgCO3/CaAc La2(CO3)3 Al(OH)3
Cation Content
200 mg Ca in 500 mg CaCO3 169 mg Ca in 667 mg CaAc 200 mg Ca in 950 mg Ca citrate None None 114 mg Mg in 400 MgCO3; 80 mg Ca in 200 mg CaCO3 60 mg Mg in 235 MgCO3; 110 mg Ca in 435 mg CaAc 250, 500, 1,000 mg La/tablet 100-200 mg Al/tablet
Advantages
Disadvantages
Inexpensive; widely available Inexpensive; widely available — No Ca; 2 LDL No Ca; 2 LDL 2 Ca load
1 Ca 1 Ca; pill burden 1 Ca; 1Al absorption GI side effects; cost; pill burden GI side effects; cost; pill burden Mg accumulation; not widely available
2 Ca load
Mg accumulation; not widely available
Potent Potent
Chewable; GI side effects Al toxicity
Abbreviations: Al, aluminum; Al(OH)3, aluminum hydroxide; Ca, calcium; CaAc, calcium acetate; CaCO3, calcium carbonate; GI, gastrointestinal; HCl, hydrochloride; La2(CO3)3, lanthanum carbonate; LDL, low-density lipoprotein cholesterol; Mg, magnesium; MgCO3, magnesium carbonate. 312
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Long-term Management of CKD-MBD
or non–calcium-containing phosphate binders. The Dialysis Clinical Outcomes Revisited (DCOR) Study, conducted in 2,103 prevalent dialysis patients, randomly assigned participants to either sevelamer or calcium-based phosphate binders, with primary study end points of all-cause mortality and cardiovascular death. Overall, the study was negative and was complicated by a nearly 50% dropout rate, although a nonprespecified subgroup analysis showed a benefit of uncertain methodologic validity in patients 65 years and older,29 the KDIGO CKD-MBD work group states that this subgroup analysis “could be, at best, considered hypothesis generating and should be interpreted with extreme caution.”13(pS55) These results are contrasted with those in the RIND (Reversible Ischemic Neurological Deficit) Study, which examined this issue in 127 incident dialysis patients. In RIND, although the numbers of patients were considerably smaller, use of the non–calcium-containing phosphate binder was associated with decreased progression of vascular calcification over time.23 Follow-up of these patients (albeit uncontrolled) over the subsequent several years showed an apparent survival benefit for patients treated with sevelamer,30 raising the issue that the DCOR results potentially may not fully reflect the benefits of the non–calcium-containing binder because of the use of prevalent patients, and calling to attention that perhaps this question should be examined earlier in the course of CKD.
VITAMIN D STEROLS Several active vitamin D sterols are available for use in patients to control hyperparathyroidism; in the United States, these agents include calcitriol, paricalcitol, and doxercalciferol. Use of vitamin D sterols is an important part of the therapy for hyperparathyroidism, not only because of the efficacy in controlling PTH secretion, but also because of observations that use of vitamin D sterols appears to be associated with a survival advantage, first noticed in patients on hemodialysis therapy and later in patients with CKD.31-35 The vitamin D analogue paricalcitol was introduced and developed to try to obtain more selective action on the parathyroid gland while minimizing the effects of active vitamin D sterols to cause hypercalcemia or hyperphosphatemia (the main manifestations of vitamin D toxicity) and was supported in detailed preclinical studies. The vitamin D2 prohormone doxercalciferol, because it also was based on the D2 structure, also appeared to have the potential for decreased hypercalcemia and is widely used. Direct head-to-head randomized studies in patients are limited at the present time. In one observational study, we noted that withdrawal of paricalcitol therapy does not significantly change serum phosphate values, sugAm J Kidney Dis. 2012;60(2):308-315
gesting that the effects of paricalcitol on increasing phosphate absorption are rather small.36 In contrast, in a crossover study in which paricalcitol was compared with doxercalciferol, there were more episodes of hyperphosphatemia with doxercalciferol than with paricalcitol, suggesting that there are potential differences between these vitamin D sterols that may become relevant to their use. In patients with CKD not on dialysis therapy, the oral forms of these active vitamin D sterols may be used, but there are no definitive studies of the relative efficacy or toxicity. A substantial body of evidence in experimental animals confirms that there are important differences between the various vitamin D sterols, particularly dramatic in terms of vascular calcification, as shown in the work of Mizobuchi et al,37 in which calcitriol and doxercalciferol appear to be associated with severe vascular calcification, whereas paricalcitol was not. Comparable data in patients are not available at the present time. Because 25-hydroxyvitamin D levels are low in many patients with advanced kidney disease, an important clinical question is whether this needs to be supplemented, especially in patients who are receiving active vitamin D sterols. In this regard, one should consider the observations of Wolf et al,38 who found that mortality in the first 90 days of dialysis therapy appears to stratify by 25-hydroxyvitamin D levels, and if these patients were given an active vitamin D sterol, this stratification was abolished. These observations suggest that administration of an active vitamin D sterol may be sufficient to achieve the apparent mortality benefit shown with this therapy. One also should consider results of studies in 1␣-hydroxylase knockout animals, in which calcitriol administration has been shown to have beneficial effects on cardiac hypertrophy that conceivably may be relevant to this issue and suggesting that the circulating hormonal form of active vitamin D may have important effects on the cardiovascular system.39 However, cholecalciferol supplementation may decrease the amount of active vitamin D sterol required and also may decrease the amount of erythropoietic-stimulating agent required.40 If hyperparathyroidism cannot be controlled with adequate control of hyperphosphatemia, correction of hypocalcemia, and the use of vitamin D sterols, an additional approach in patients with ESRD is to directly target PTH secretion from the parathyroid gland by the use of a calcimimetic agent or to consider parathyroidectomy in selected patients. The calcimimetic cinacalcet was introduced for this purpose and by targeting the calcium receptor, can decrease PTH levels effectively, significantly decrease serum calcium levels, and achieve a slight decrease in serum 313
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phosphate values if taken in conjunction with the other therapeutic measures.41,42 Recent data for 360 patients in the ADVANCE (Action in Diabetes and Cardiovascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation) trial suggest that this approach is associated with a trend toward decreasing the progression of vascular and valvular calcification and was significant for aortic valvular calcification.43 Because this agent is administered orally, one has to ensure patient adherence to the regimen, which may be somewhat problematic, as shown by the studies of Gincherman et al.44 If medical therapy cannot achieve sustained control of hyperparathyroidism, consideration should be given to parathyroidectomy. This usually is reserved for patients with severe hyperparathyroidism for whom medical therapy cannot be tolerated. A recent consideration for the therapeutic approach to this important clinical problem relates to FGF-23 levels. Thus, vitamin D therapy might be expected to directly increase FGF-23 levels. However, because FGF-23 comes from bone, reductions in bone cell activity might be expected to decrease FGF-23 levels. This issue may become important because epidemiologic studies indicate that high FGF-23 levels appear to be associated with increased mortality for patients on hemodialysis therapy.45,46 This observation also appears to extend to patients with earlier stages of CKD.47 Although the exact mechanism for this mortality association is not known, recent studies show important direct effects of FGF-23 on the heart, particularly in causing left ventricular hypertrophy.48 At the very least, FGF-23 appears to be an important biomarker for adverse outcomes, and it may be causative for inducing left ventricular hypertrophy. It may become useful in the future to consider what happens to FGF-23 during our therapeutic efforts and perhaps develop approaches to modify its production or action. Calcimimetic therapy would be expected to decrease FGF-23 by decreasing PTH levels, whereas vitamin D sterols would be expected to increase FGF-23 production by a direct effect on gene transcription. However, in one clinical trial that compared cinacalcet plus fixed-dose active vitamin D sterol therapy versus active vitamin D sterol therapy alone to control hyperparathyroidism, there appeared to be a greater decrease in FGF-23 levels in the cinacalcet arm.49 Further studies are required of the consequences of changes in FGF-23 levels with the current approach to treatment of abnormalities in CKDMBD. Much of our approach to the treatment of mineral and bone disorders in CKD has been in patients who are treated with dialysis, and despite decades of clinical experience, there remains a paucity of high-quality 314
data and many therapeutic challenges to achieving effective and sustained control of MBD. Given the limited overall success with addressing disease in patients with kidney failure, at which time much of the milieu promoting MBD has been present for years or even decades, it becomes important to try to address these problems earlier in the course of CKD.2,50 Possibly, if addressed early, improved and more constant control of MBD during kidney failure might be facilitated. Further ongoing research and future developments of new therapeutic agents may facilitate our efforts on this important clinical problem.
ACKNOWLEDGEMENTS Support: None. Financial Disclosure: Dr Martin has served as a consultant for Abbott, Cytochroma, Genzyme, and KAI Pharmaceuticals and as a speaker for Abbott and Genzyme. Dr González declares that she has no relevant financial interests.
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31. Kovesdy CP, Ahmadzadeh S, Anderson JE, Kalantar-Zadeh K. Association of activated vitamin D treatment and mortality in chronic kidney disease. Arch Intern Med. 2008;168(4):397-403. 32. Shoben AB, Rudser KD, de Boer IH, Young B, Kestenbaum B. Association of oral calcitriol with improved survival in nondialyzed CKD. J Am Soc Nephrol. 2008;19(8):1613-1619. 33. Teng M, Wolf M, Lowrie E, Ofsthun N, Lazarus JM, Thadhani R. Survival of patients undergoing hemodialysis with paricalcitol or calcitriol therapy. N Engl J Med. 2003;349(5):446456. 34. Teng M, Wolf M, Ofsthun MN, et al. Activated injectable vitamin D and hemodialysis survival: a historical cohort study. J Am Soc Nephrol. 2005;16(4):1115-1125. 35. Tentori F, Albert JM, Young EW, et al. The survival advantage for haemodialysis patients taking vitamin D is questioned: findings from the Dialysis Outcomes and Practice Patterns Study. Nephrol Dial Transplant. 2009;24(3):963-972. 36. Martin KJ. When is vitamin D contraindicated in dialysis patients? Semin Dial. 2009;22(3):247-249. 37. Mizobuchi M, Finch JL, Martin DR, Slatopolsky E. Differential effects of vitamin D receptor activators on vascular calcification in uremic rats. Kidney Int. 2007;72(6):709-715. 38. Wolf M, Shah A, Gutierrez O, et al. Vitamin D levels and early mortality among incident hemodialysis patients. Kidney Int. 2007;72(8):1004-1013. 39. Zhou C, Lu F, Cao K, Xu D, Goltzman D, Miao D. Calcium-independent and 1,25(OH)2D3-dependent regulation of the renin-angiotensin system in 1alpha-hydroxylase knockout mice. Kidney Int. 2008;74(2):170-179. 40. Matias PJ, Jorge C, Ferreira C, et al. Cholecalciferol supplementation in hemodialysis patients: effects on mineral metabolism, inflammation, and cardiac dimension parameters. Clin J Am Soc Nephrol. 2010;5(5):905-911. 41. Block GA, Martin KJ, de Francisco AL, et al. Cinacalcet for secondary hyperparathyroidism in patients receiving hemodialysis. N Engl J Med. 2004;350(15):1516-1525. 42. Moe SM, Chertow GM, Coburn JW, et al. Achieving NKF-K/DOQI bone metabolism and disease treatment goals with cinacalcet HCl. Kidney Int. 2005;67(2):760-771. 43. Raggi P, Chertow GM, Torres PU, et al. The ADVANCE study: a randomized study to evaluate the effects of cinacalcet plus low-dose vitamin D on vascular calcification in patients on hemodialysis. Nephrol Dial Transplant. 2011;26(4):1327-1339. 44. Gincherman Y, Moloney K, McKee C, Coyne DW. Assessment of adherence to cinacalcet by prescription refill rates in hemodialysis patients. Hemodial Int. 2010;14(1):68-72. 45. Gutierrez OM, Mannstadt M, Isakova T, et al. Fibroblast growth factor 23 and mortality among patients undergoing hemodialysis. N Engl J Med. 2008;359(6):584-592. 46. Jean G, Terrat JC, Vanel T, et al. High levels of serum fibroblast growth factor (FGF)-23 are associated with increased mortality in long haemodialysis patients. Nephrol Dial Transplant. 2009;24(9):2792-2796. 47. Isakova T, Xie H, Yang W, et al. Fibroblast growth factor 23 and risks of mortality and end-stage renal disease in patients with chronic kidney disease. Jama. 2011;305(23):2432-2439. 48. Faul C, Amaral AP, Oskouei B, et al. FGF23 induces left ventricular hypertrophy. J Clin Invest. 2011;121(11):4393-4408. 49. Wetmore JB, Liu S, Krebill R, Menard R, Quarles LD. Effects of cinacalcet and concurrent low-dose vitamin D on FGF-23 levels in ESRD. Clin J Am Soc Nephrol. 2010;5(1):110116. 50. Martin KJ, Gonzalez EA. Prevention and control of phosphate retention/hyperphosphatemia in CKD-MBD: what is normal, when to start, and how to treat? Clin J Am Soc Nephrol. 2011;6(2):440-446.
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