Pathogenic, clinical, and therapeutic aspects of secondary hyperparathyroidism in chronic renal failure

Pathogenic, Clinical, and Therapeutic Aspects of Secondary Hyperparathyroidism in Chronic Renal Failure Francisco Llach, MD, and Michael Yudd, MD INDEX WORDS: Uremic hyperparathyroidism; clinical therapy; hyperphosphatemia.

R

ENAL OSTEODYSTROPHY occurs early in the course of chronic renal failure (CRF).1 It includes metabolic and clinical abnormalities. Among the most important is the development of secondary hyperparathyroidism (2°HPT) and its bone pathology, osteitis fibrosa cystica.2 Significant advances has been made in understanding the pathogenesis of 2°HPT. It is believed that low levels of calcitriol and hyperphosphatemia are both important factors in the generation of 2°HPT.3 Thus, early in renal failure, the main factor generating 2°HPT is a decrease in calcitriol synthesis by the diseased kidney (Fig 1).4 Low serum phosphorus (P) levels are commonly noted in early CRF.5,6 Furthermore, patients with glomerular filtration rates of 60 to 80 mL/m receiving an oral P load showed low serum P rather than hyperphosphatemia and a more rapid excretion of P compared with control subjects.7 Nonetheless, despite the absence of P retention in early renal failure, these patients already show high PTH levels. As renal function deterioration progresses, hyperphosphatemia develops, usually at a glomerular filtration rate of 20 mL/m.3 Thus, it appears that early in CRF, low calcitriol levels may be the main factor causing the high parathyroid hormone (PTH) levels and later, near end-stage renal disease, hyperphosphatemia becomes an important factor in worsening 2°HPT.3 ROLE OF CALCITRIOL

In vitro studies have shown a direct inhibitory effect of calcitriol on the parathyroid gland through the suppression of PTH messenger RNA (mRNA).8 This reduction in PTH mRNA expression occurs primarily at the transcriptional level.9 A decrease in the levels of calcitriol increases the synthesis of PTH. Elevated PTH mRNA levels have been shown in experimental CRF.10 The biological action of calcitriol appeared to be mediated through a hormone cytoplasmatic receptor complex responsible for its genomic effect. The human vitamin D receptor (VDR) is a 427– amino acid peptide with a DNA binding domain

(from residues 25 to 112) and a ligand-binding domain (approximately from residues 200 to 400). It belongs to the large family of nuclear receptors that includes the steroid, thyroid, and retinoid acid receptors.11 The DNA binding domain of the VDR is characteristic of the nuclear receptor superficially and contains two zinc fingers that mediate the binding of the VDR to specific regulatory promoter regions of the DNA 5-flanking sequence of vitamin D responsive genes.12 This is called the vitamin D responsive element (VDRE), and the binding of the vitamin D-VDR complex to these sequences alters DNA transcription of specific precursor mRNA molecules.12,13 The VDR is found widely spread in different tissues, including intestine and parathyroid gland, as well as osteoblast-like cells. Both uremic animals and patients with CRF have a reduced density and binding of VDR.14,15 It has also been noted that an increase in calcitriol levels will upregulate VDR, whereas a decrease in calcitriol levels will downregulate VDR.16 A reduced VDR function renders the parathyroid glands less responsive to the inhibitory action of calcitriol. The replacement of calcitriol in patients with CRF restores the intestinal receptor concentration by increasing VDR mRNA levels and the half-life of VDR.17 Also, calcitriol treatment in the uremic rat increases the VDR content of the parathyroid glands.16 Recent data have also shown that a high dietary calcium (Ca) intake, per se, upregulates VDR, whereas low dietary Ca and hypocalcemia downregulate VDR.18 Furthermore, in vitamin D–deficient rats, the prevention of 2°HPT with a high dietary Ca intake avoided the decrease in the VDR of the parathyroid glands, suggesting that the upregulaFrom the Nephrology Division, Newark Beth Israel Medical Center, Newark; and the Department of Veteran Affairs Medical Center, East Orange, NJ. Address reprint requests to Francisco Llach, MD, Newark Beth Israel Medical Center, Division of Nephrology, 201 Lyons Ave, Newark, NJ 07112. E-mail: [email protected]

r 1998 by the National Kidney Foundation, Inc. 6386/98/3204-0201$3.00/0

American Journal of Kidney Diseases, Vol 32, No 4, Suppl 2 (October), 1998: pp S3-S12

S3

S4

Fig 1. Calcitriol and PTH values in 150 patients with various levels of chronic renal insufficiency. Note that calcitriol values decreased significantly ahead of the increment of PTH levels. Modified from Martinez I, Saracho R, Montenegro J, Llach F: A deficit of calcitriol may not be the initial factor in the pathogenesis of secondary hyperparathyroidism. Nephrol Dial Transplant 11:22-28, 1996, with permission of Oxford University Press.

tion of VDR expression by calcitriol may be mediated by increasing serum Ca concentrations.19 Thus, VDR concentrations are increased by calcitriol and by Ca in various tissues, mainly kidney and parathyroid glands, whereas the effect of calcitriol in intestine is less clear. A point with important therapeutic implications is that the stimulatory effect of calcitriol on VDR appears to be more marked when adequate amounts of Ca are present.18 Thus, the synergistic effect of Ca and calcitriol PTH inhibition and increasing VDR have important therapeutic implications. In dialysis patients with 2°HPT, the appropriate use of calcitriol, together with the maintenance of adequate serum Ca concentrations, are essential for a successful therapy. Data from Fukagawa et al20 have shown that normal Ca, P, and calcitriol levels do not preclude that development of 2°HPT. It has also recently been shown that biochemical and histological evidence of 2°HPT developed in rats with mild CRF with normal VDR concentrations.21 This observation would suggest the presence of resistance to physiological levels of calcitriol in mild CRF, providing an additional explanation of the high PTH level noted in early CRF. Also, in dialysis patients, physiological levels of serum calcitriol may not be enough to suppress 2°HPT,

LLACH AND YUDD

and higher peak levels derived by the intermittent administration of intravenous (IV) calcitriol may be needed to treat 2°HPT.22 The transient supraphysiological levels of calcitriol may lead to a better binding of calcitriol to VDR and suppress PTH; this, in turn, would explain the resistance of the parathyroid cells to physiological levels of calcitriol in uremia. In support of this hypothesis, Hsu et al,23 using intestine as a source of VDR, have recently shown that uremic ultrafiltrate reduced the receptor interaction with DNA. It appears that CRF interferes with the metabolism and action of calcitriol, not only at the synthesis and clearance level, but also affecting VDR synthesis, calcitriol binding, the uptake of calcitriol-VDR complex by the nucleus, and the binding of calcitriol VDR to the VDRE.23 It is known that calcitriol has important biological action in many target cells of the body. Thus, VDRs are found in intestine, kidney, bone, parathyroid gland, white blood cells, epidermis, and so on. Calcitriol, once it binds to its VDR, will induce an effect that will vary depending on the end-target organ. Thus, in the gut, calcitriol increases gut absorption of Ca and P through the activation of the VDR at the intestinal mucosa. In bone, calcitriol increases both bone formation and resorption, and in the parathyroids, it inhibits PTH synthesis. Ideally, in the therapy of patients with CRF and 2°HPT, a vitamin D analogue that inhibits PTH but does not have a significant effect in bone or gut will be highly desirable. Thus, PTH inhibition can be achieved with no significant hypercalcemia and hyperphosphatemia. The new vitamin D analogue, 19-nor-1␣, 25-dihydroxy vitamin D2 (paricalcitol) may be such a compound. EFFECT OF HIGH PHOSPHORUS

Recently, a direct effect of P on the parathyroid glands has been shown.24,25 Previously, it was shown that the administration of a low-P diet to patients with advanced CRF decreased serum PTH levels, whereas ionized Ca and calcitriol levels did not increase.24 In addition, P restriction in dogs with advanced CRF improved 2°HPT independent of changes in serum Ca and calcitriol levels.25 These results suggested an effect of a low-P diet in the control of PTH secretion. Recently, it has been shown that P per se has a direct stimulatory effect on PTH secretion and

SECONDARY HYPERPARATHYROIDISM IN CRF

parathyroid cell proliferation both in vitro and in vivo.26,27 A posttranscriptional decrease in PTH mRNA levels was noted in rats fed a low-P diet.26 Also, in the experimental rat with renal failure, a high-P diet increased and a low-P diet decreased parathyroid cell proliferation.27 Furthermore, P restriction decreased PTH mRNA expression in rats with mild CRF.28 Conversely, a high-P diet increased PTH mRNA expression per cell and parathyroid cell hyperplasia in normal rats independent of Ca, calcitriol, or VDR changes.29 Various investigators, in vitro either in parathyroid glands or in parathyroid gland slices, have shown that P has a direct stimulatory effect on PTH secretion (Fig 2).30-32 This effect is most likely posttranscriptional. Contrary to the effect of hypocalcemia, hypophosphatemia correlates with a decreased binding of parathyroid cytosolic protein to the PTH mRNA 38 untranslated region that determines a decrease in mRNA stability.26 The effect of hyperphosphatemia on the parathyroid glands is of clinical importance. First, through the noted effects on the worsening 2°HPT, and second, by inducing a state of resistance to calcitriol on the parathyroid glands and

Fig 2. Time course for PTH secretion by normal intact rat parathyroid glands, incubated with low (0.2 mmol/L; n ⴝ 8) or high (2.8 mmol/L; n ⴝ 8) phosphorus in the media (P F 0.05). The effects of phosphorus were not evident for 3 hours. Modified from Slatopolsky E, Finch J, Denda M, Ritter C, Zhong A, Dusso A, Macdonald P, Brown AJ: Phosphate restriction prevents parathyroid cell growth in uremic rats. High phosphate directly stimulates PTH secretion in vitro. J Clin Invest 97:2534-2540, 1996 by copyright permission of The American Society for Clinical Investigation.31

S5

thus, a lack of response to calcitriol therapy.33 The available data experimentally and clinically suggest that the control of hyperphosphatemia is an essential first step in the management of 2°HPT. Secondary hyperparathyroidism is characterized by diffused parathyroid hyperplasia. However, recent studies have shown nodular parathyroid hyperplasia in dialysis patients with 2°HPT.34 Also, nodular hyperplasia may be associated with a decrease in VDRs compared with diffused hyperplasia.35 Whether glands with nodular hyperplasia are less responsive to calcitriol therapy remains to be elucidated. Heterogenous genetic abnormalities have been suggested to contribute to the development of nodular hyperplasia. Thus, Falchetti et al36 have reported that the genetic mutation could be responsible for the severe 2°HPT of some dialysis patients. Thus, autonomous monoclonal parathyroid cell proliferation may develop in some uremic patients through the inactivation of a tumor-suppressor gene on this chromosome.36 Several comprehensive reviews on the molecular genetics of primary and 2°HPT have been recently published.37 Recently, Brown et al38 have cloned and characterized a calcium sensor receptor (CaR) from various organs, parathyroid cells, kidney, and others. This protein, located in the cellular membrane, has been independently cloned and characterized by another group,39 and it interacts not only with Ca, but also with other divalent and trivalent ions, as well as polycations. This novel finding has clarified our knowledge of the mechanism through which Ca exerts its action on cells and tissues. In the parathyroid glands, a decrement in serum Ca is sensed through this Gprotein–coupled CaR and causes the release of preformed PTH.40 Conversely, an increase in extracellular Ca level activates the CaR, which then mobilizes Ca from intracellular sources and inhibits PTH secretion.41 The CaR not only mediates the inhibitory effect of Ca on PTH secretion, but likely affects the expression of the PTH gene and parathyroid cell proliferation.42,43 The identification of inherited diseases that arise from mutation in the CaR has proved by genetic means the central role of CaR in Ca homeostasis.44 Thus, familiar hypocalcuric hypercalcemia, severe neonatal HPT, and dominant autosomal HPT are linked to an abnormality in

S6

the CaR.44-46 Mutation of the receptor genes had not been detected in sporadic parathyroid adenoma or in 2°HPT.46 However, allosteric CaR agonist (calcimimetics) have recently been shown to suppress parathyroid proliferation in experimental CRF.47 Because the 2°HPT of CRF is associated with an abnormality to sense extracellular Ca concentration,48 it was postulated that an abnormal CaR may have an early role in 2°HPT.49 Patients with primary adenomas, as well as uremic patients with 2°HPT, have shown a reduced expression of the CaR; both at the mRNA and the protein level.50,51 Moreover, CaR mRNA and protein were often noted to be depressed in nodular compared with adjacent nonnodular hyperplastic glands.51 However, these findings have not always been consistent in other experimental models.52 The development of CaR agonists may be an important advance in the future management of 2°HPT. Preliminary data in both primary and 2°HPT have shown that PTH levels can be decreased significantly, although transiently, after the administration of a calcimimetic agent.53,54 Specific Clinical Aspects The clinical manifestations of 2°HPT have changed significantly over the last three decades. Earlier, the presence of bone pain, myopathy, muscular weakness, pruritus, extraskeletal calcifications, spontaneous tendon fracture, calciphylaxis, and skeletal deformities were observed. Today, the majority of dialysis patients are asymptomatic. Early control of 2°HPT and preventive measures are essential. In general, when symptoms appear, it is because of a long-term protracted course with persistent hyperphosphatemia and/or lack of appropriate calcitriol therapy. By the time the patient is symptomatic, significantly high PTH levels, as well as other biochemical abnormalities, are present. Two protracted remaining clinical problems are hyperphosphatemia and calciphylaxis. • Hyperphosphatemia is a common and serious problem in our dialysis population. As shown recently by Block et al,55 hyperphosphatemia occurs in up to 50% of our overall dialysis population. Block et al55 grouped patients by serum P quintiles (Fig 3). Patients with serum P levels greater than 6.5 mg/dL had a significant increase in mortality risk. A serum P level greater than 7.9 mg/dL had an even higher mortality risk

LLACH AND YUDD

Fig 3. Relative mortality risk by serum phosphorus quintiles (n ⴝ 6,407). Modified with permission from Block et al.55

(P ⬍ 0.0001). The mortality risk of these patients was not affected by the presence of hypercalcemia. As shown in Fig 4, a serum Ca level greater than 10 mg/dL was not associated with an increased mortality. Thus, it appears that the clinical significant of hypercalcemia may be different from hyperphosphatemia. The causes of hyperphosphatemia are multiple. As shown in Fig 5, the major factors in the causation of hyperphosphatemia are as follows: (1) A high intake of P, which is the most common cause, dietary P restriction is mandatory in the control of serum P levels. (2) The use of P

Fig 4. Relative nortality risk by serum calcium quintiles (n ⴝ 2,669). Modified with permission from Block et al.55

SECONDARY HYPERPARATHYROIDISM IN CRF

Fig 5. Schematic representation of the multifactorial nature of hyperphosphatemia.

binders is a necessary second step. Ca carbonate and Ca acetate are the commonly used P binders. Unfortunately, neither are excellent binders, which necessitates the use of a large dosage of these agents to achieve adequate control of serum P levels. Most important, these binders contain Ca, and, as a result, large amounts of elemental Ca are routinely administered to dialysis patients. The clinical significance of the Ca overload is uncertain, but it may be an important factor in inducing soft tissue calcification and calciphylaxis. (3) Appropriate dialysis removal of P is mandatory. Although the removal of P during a 4-hour dialysis treatment is finite, it is significant. Recently, the effect of intensive dialysis on serum P concentration has been evaluated.56 Thus, the efficacy and long-term effects of nocturnal hemodialysis (NHD) 6 nights weekly versus conventional hemodialysis (CHD) in controlling serum P levels in patients with end-stage renal disease was compared. After 6 months, patients treated with NHD had a mean serum P level of 4.0 mg/dL, whereas patients treated with CHD had a mean P level of 6.5 mg/dL. Most important, in patients treated with NHD, the dietary intake of P increased by 50% and none of the patients had taken any P binders. Thus, it is not surprising that recent data have shown that persistent and protracted hyperphosphatemia may be a reflection of inadequate dialysis.57 (4) Finally, a minority of patients with severe 2°HPT have a marked increase in a osteoclastic bone resorption, which facilitates the release of Ca and P from bone and may contribute to the hyperphosphatemia.

S7

The clinical consequences of persistent hyperphosphatemia are serious. First, as previously mentioned, hyperphosphatemia may lead to soft tissue calcification. Previous studies have shown that the magnitude of the Ca ⫻ P product correlated with the incidence of calcifications.58 Also, hyperphosphatemia, as previously discussed, is a major factor in the worsening of 2°HPT through a direct effect of P in the parathyroid glands, stimulating PTH synthesis and worsening parathyroid hyperplasia. Recent data in dialysis patients with severe 2°HPT have shown that the higher the serum P concentration, the higher the PTH level.59 thus, the sigmoidal relationship of PTH-Ca is shifted toward the right with hyperphosphatemia. The control of the hyperphosphatemia decreases PTH levels and shifts back toward the left the PTH-Ca curve. The lower the serum P, the lower the PTH level. Additionally, hyperphosphatemia induces a state of calcitriol resistance. Thus, once the serum P level is greater than 7 to 7.5 mg/dL, calcitriol, either orally or IV, does not inhibit PTH synthesis.60 Calcitriol orally or IV in the presence of hyperphosphatemia does not decrease PTH levels.61 Calcitriol resistance eventually leads to surgical parathyroidectomy (PTX).62 It follows that the control of hyperphosphatemia is necessary for successful calcitriol therapy. Finally, it appears that hyperphosphatemia and not hypercalcemia is the major factor in the therapeutic failure of dialysis patients to control 2°HPT. We recently evaluated 42 patients with significant hyperparathyroid bone disease treated with calcitriol for 3 years.62 The initial mean PTH values were 1,570 pg/mL. After 3 years of IV calcitriol, the mean PTH level was reduced to 195 pg/mL. However, hyperphosphatemia was present in 12 patients (30%). Five patients had isolated episodes of hyperphosphatemia that resulted in a delta PTH increment of 820 pg/mL; these five patients were controlled with further dietary instruction and better compliance. However, the other seven patients had protracted hyperphosphatemia, PTH levels remained high, calcitriol had to be discontinued multiple times, and eventually PTX had to be performed in five patients. Conversely, eight patients had 16 episodes of hypercalcemia (mean serum Ca level, 11.7 mg/dL), which was controlled with a transient decrease of the calcitriol dose and adjust-

S8

ment of the P binder and/or switching to Mg CO3. All patients were asymptomatic and eventually the 2°HPT was controlled. • A second important problem in dialysis patients that may be related to an abnormality of divalent ion metabolism is a development of uremic calciphylaxis. This is a relatively rare disorder encountered mostly in uremic patients. This syndrome was first described by Seyle63 in 1962 in an experimental animal model. He postulated that two steps were required to produce ectopic systemic calcification. First, a systemic sensitization induced by various agents, such as PTH, vitamin D, or a diet high in Ca and P. Second, after a time interval (the critical period), exposure to the appropriate challenging agents by subcutaneous ingestion resulted in microscopically visible deposits of Ca systemically and at the site of injection within 2 to 3 days. A few years later, a syndrome characterized by peripheral ischemic tissue necrosis and cutaneous ulceration was reported in uremic patients and, because of the resemblance to the animal model of Seyle,63 it was also named calciphylaxis.64 It is worth mentioning that the syndrome of calciphylaxis described in uremic patients remotely resembles Seyle’s experimental model. The latter was characterized by metastatic systemic calcification developing after significant manipulation of the animal model, and local vascular calcification was not present; whereas uremic calciphylaxis is a local superficial lesion with microvascular calcification noted at the lesions.65 This syndrome, characterized by cutaneous eruption, usually occurs in patients undergoing maintenance dialysis or after renal transplantation. The skin lesions often present as areas of painful mottling that resemble livedo reticularis, with superficial violatious nodules involving the tips of the toes or fingers or occurring about the ankles, thighs, or buttocks. As the lesions progress, they become hemorrhagic, with ischemic dry necrosis. The bilateral symmetry, superficial nature of this lesion, and the persistence of palpable pulses distal to the necrosis were characteristic findings. As the lesions progressed, cutaneous necrosis ensued, as well as the development of skin digital pain and, in many cases, gangrene of the digits. At that time, biopsy of the skin nodules showed Ca deposits within a small arterial side of the vessel wall that were associ-

LLACH AND YUDD

ated with lobular fat necrosis, calcification, and an infiltrate of neutrophils, lymphocytes, and macrophages. In the early report, the lesions were located distally in the extremities and there was significant 2°HPT.64 The link between calciphylaxis and HPT was further supported by the early observation that PTX dramatically improved the syndrome.66 The pathogenesis of calciphylaxis remains unclear. It is important, however, to review certain pathogenic factors. First and most important is the presence of a uremic millieu, together with a high Ca ⫻ P product noted in the early report.64 Second, the Ca content of the skin was high.67 It was found to be higher when a dialysis Ca concentration of 4.0 mEq/L was used.51 In addition, a decrease in dialysis Ca dramatically reversed the calciphylaxis.68 Furthermore, high intake of Ca carbonate resulting in hypercalcemia triggered this syndrome and it was reversed with the cessation of Ca carbonate ingestion.69 The majority of the dialysis patients are treated with Ca-containing P binders and, thus, they ingest large doses of elemental Ca. It is our impression that the large oral Ca intake of dialysis patients may be an important factor in the pathogenesis of this syndrome. A third important pathogenic factor was the presence of high PTH levels. Earlier, Gipstein et al64 described a series of patients with calciphylaxis, most with peripheral digital ulcers in which PTX resulted in a dramatic healing of the ulcer. Also, it is worth emphasizing that a marked period of hyperphosphatemia was present in each patient at some time before the appearance of this syndrome. Later, hyperphosphatemia was also associated with this syndrome. In the presence of low PTH levels, severe P restriction was shown to reverse calciphylaxis.70 In the last decades, a substantial number of cases of calciphylaxis and low PTH levels had been described. With the advent of calcitriol therapy and better control of divalent ion metabolism, other factors have surfaced. Thus, massive obesity, especially in white women, may be an important predisposing factor.71 The prognosis of patients with calciphylaxis is poor, most dying of sepsis and ischemic events, and because we do not have a clear understanding of this syndrome, therapy is extremely difficult. The first most important step is the normal-

SECONDARY HYPERPARATHYROIDISM IN CRF

ization of Ca ⫻ P product, together with the control of 2°HPT. The second step is aggressive wound care with debridement of the necrotic tissue and systemic antibiotic therapy, because sepsis is the major cause of mortality. PTX should be performed only in patients with high PTH levels. The available data strongly suggest that PTX should not be performed in patients with low PTH levels. Thus, in a review of 47 patients with calciphylaxis, 31 patients underwent PTX and 50% died within the medium period of 9 weeks after PTX.72 Special emphasis should be placed on using a dialysate Ca concentration no greater than 2.5 mEq/L. The use of Ca-containing P binders should be avoided, because the ingestion of large amounts of Ca has been associated with this syndrome. Alternative P binders, such as magnesium carbonate or, in the future, RenaGel (Geltex Pharmaceuticals, Waltham, MA), should be considered. Therapeutic Considerations The cornerstone in the treatment of 2°HPT is calcitriol. Both oral and IV calcitriol are effective. As previously mentioned, both hyperphosphatemia and hypercalcemia are the most important hazards with the use of calcitriol. Oral calcitriol may have a incidence as high as 70% to 75%, whereas IV calcitriol may have a lower incidence. However, there are a substantial number of patients with hypercalcemia and hyperphosphatemia who cannot be treated with calcitriol. These patients may benefit from a vitamin D analogue devoid of hypercalcemic and hyperphosphatemia effects. Some dialysis patients with severe 2°HPT may not respond to calcitriol. There are several factors responsible for such therapeutic failures. First, familarity with either oral or IV calcitriol is essential. A common cause of high P or Ca levels is underdosing. The initial dose of calcitriol should be commensurate with the severity of the HPT. The higher the PTH, the higher the initial dose. In this setting, the underdosing of calcitriol may not inhibit PTH synthesis and may facilitate gut absorption of Ca and P. Second, in our experience, the highest incidence of hyperphosphatemia occurs not within the first few weeks, as it has been suggested,62 but later, once PTH levels approach normal. As PTH and aklaline phosphatase approach normal levels, bone remin-

S9

Fig 6. A patient with 2°HPT treated with IV calcitriol for 42 weeks. (Left) Serum Ca2ⴙ and phosphorus levels during this period. (Right) Serum PTH levels. Note that although the patient developed severe hyperphosphatemia (dietary noncompliance) and despite appropriate IV calcitriol treatment and serum Ca2ⴙ levels in the upper limit of normal, PTH progressively increased after the fifth week. Modified with permission from Rodriguez et al.60

eralization decreases and the ability of bone to buffer Ca and P is reduced. Then, dietary Ca and P, inappropriate use of binders, or excessive doses of Ca may lead to hyperphosphatemia or hypercalcemia. Third, the most common cause of failure of calcitriol, is hyperphosphatemia. In this setting, calcitriol, even in large doses, will not inhibit PTH (Fig 6). Fourth, the severity of HPT may be a factor in a minority of cases in inducing a calcitriol-resistant state. It has been suggested that patients with resistance to calcitriol present a tendency toward larger glands than those who respond.60 Thus, hypothetically, the larger the gland, the more severe the HPT and the more likely the presence of resistance to calcitriol. Before a state of calcitriol resistance is established, hyperphosphatemia should be corrected and a trial of high-dose IV calcitriol should be attempted. In summary, 2°HPT and osteitis fibrosa cystica still remain the predominant problems in our dialysis patients. Significant advances have been made in the understanding of 2°HPT. Therapeutically, certain points should be emphasized: first, hyperphosphatemia is an important factor in the worsening of 2°HPT. It should be controlled before calcitriol therapy. Second, the currently available Ca-containing P binders are unsatisfactory. Development of new P binders are necessary. Third, appropriate dosing of vitamin D is essential to achieve a successful inhibition of PTH. Dosing should be commensurate with the severity of the HPT. Fourth, the incidence of hypercalcemia and hyperphosphatemia is significant during calcitriol therapy. Thus, the search for a vitamin D analogue devoid of these side

S10

LLACH AND YUDD

effects has been intense. This issue of AJKD deals with such an analogue. REFERENCES 1. Llach F: Secondary hyperparathyroidism in renal failure: The trade-off hypothesis revisited. Am J Kidney Dis 25:663-679, 1995 2. Malluche H, Faugere MC: Renal bone disease 1990: An unmet challenge for the nephrologist. Kidney Int 38:193211, 1990 3. Slatopolsky E, Delmez JA: Pathogenesis of secondary hyperparathyroidism. Am J Kidney Dis 23:229-236, 1994 4. Llach F, Massry SG: On the mechanism of the prevention of secondary hyperparathyroidism in moderate renal insufficiency. J Clin Endocrinol Metab 61:601-606, 1985 5. Llach F, Massry SG, Singer FR, Kurokawa K, Kaye JH, Coburn JW: Skeletal resistance of endogenous parathyroid hormone in patients with early renal failure. A possible cause for secondary hyperparathyroidism. J Clin Endocrinol Metab 41:339-345, 1975 6. Portale AP, Booth BE, Halloran BP, Morris RC Jr: Effect of dietary phosphorus on circulating concentrations of 1,25 dihydroxyvitamin D and immunoreactive parathyroid hormone in children with moderate renal insufficiency. J Clin Invest 73:1580-1589, 1984 7. Wilson L, Felsenfeld AJ, Drezner MK, Llach F: Altered divalent ion metabolism in early renal failure: Role of 1,25-(OH)2D. Kidney Int 27:565-573, 1985 8. Silver J, Rusell J, Sherwood LM: Regulation by vitamin D metabolites of messenger ribonucleic acid for preproparathyroid hormone in isolated bovine parathyroid cells. Proc Natl Acad Sci USA 82:4270-4273, 1985 9. Russell J, Lettieri D, Sherwood LM: Suppression by 1,25(OH)2D3 of transcription of the pre-parathyroid hormone gene. Endocrinology 119:2864-2866, 1986 10. Shvil Y, Naveh-Many T, Barach P, Silver J: Regulation of parathyroid cell gene expression in experimental uremia. J Am Soc Nephrol 1:99-104, 1990 11. Demay MB, Kiernan MS, Deluca HF: Sequences in the human parathyroid hormone gene that binds the 1,25dihydroxyvitamin D3 receptor and mediates transcriptional repression in response to 1,25-dihydroxyvitamin D3. Proc Natl Acad Sci USA 89:8097-8101, 1992 12. Demay MD, Gerardi JM, Deluca HF, Kronenberg HM: DNA sequences in the rat osteocalcin gene that bind the 1,25-dihydroxyvitamin D3 receptor and confer responsiveness to 1,25-dihydroxyvitamin D3. Proc Natl Acad Sci USA 89:8097-8101, 1992 13. Naveh-Many T, Marx R, Keshet E, Pike JW, Silver J: Regulation of 1,25-dihydroxyvitamin D3 receptor gene expression by 1,25-dihydroxyvitamin D3 in the parathyroid in vivo. J Clin Invest 86:1968-1975, 1990 14. Merke J, Hugel U, Zlotkowski A, Szabo A, Bommer J, Mall G, Ritze E: Diminished parathyroid 1,25-(OH)2D3 receptors in experimental uremia. Kidney Int 32:350-353, 1987 15. Brown AJ, Duso A, Lopez-Hilker S, Lewis-Finch J, Grooms P, Slatopolsky E: 1,25(OH)2D receptors are decreased in parathyroid glands from chronically uremic dogs. Kidney Int 35:19-23, 1989

16. Denda M, Finch J, Brown AJ, Nishi Y, Kubodera N, Slatopolsky E: 1,25-dihydroxyvitamin D3 and 22-oxacalcitriol prevent the decrease in vitamin D receptor content in the parathyroid glands of uremic rats. Kidney Int 50:34-39, 1996 17. Patel SR, Ke Hq, Hsu CH: Regulation of calcitriol receptor and its mRNA in normal and renal failure rats. Kidney Int 45:1020-1027, 1994 18. Russell J, Bar A, Sherwood LM, Hurwitz S: Interaction between calcium and 1,25-dihydroxyvitamin D3 in the regulation of preproparathyroid hormone and vitamin D receptor messenger ribonucleic acid in avian parathyroids. Endocrinology 132:2639-2644, 1993 19. Brown AJ, Zhong M, Finch J, Ritter C, Slatopolsky E: The roles of calcium and 1,25-dihydroxyvitamin D3 in the regulation of vitamin D receptor expression by rat parathyroid glands. Endocrinology 136:1419-1425, 1995 20. Fukagawa M, Kaname S, Igarashi T, Ogata E, Kurokawa K: Regulation of parathyroid hormone synthesis in chronic renal failure in rats. Kidney Int 39:874-881, 1991 21. Sawaya BP, Koszewski NJ, Qi Q, Langub C, MonierFaugere MC, Malluche HH: Secondary hyperparathyroidism and vitamin D receptor binding to vitamin D response elements in rats with incipient renal failure. J Am Soc Nephrol 9:1324, 1997 22. Slatopolsky E, Weerts C, Thielan J, Horst R, Harter H, Martin KJ: Marked suppression of secondary hyperparathyroidism by intravenous administration of 1,25-dihydroxycholecalciferol in uremic patients. J Clin Invest 74:21362143, 1984 23. Hsu CH, Patel SR, Young EW: Mechanism of decreased calcitriol degradation in renal failure. Am J Physiol 262:F192-F198, 1992 24. Lucas PA, Brown RC, Woodhead JS, Coles G: 1,25dihydroxycholecalciferol and parathyroid hormone in advanced renal failure: Effect of simultaneous protein and phorphorus restriction. Clin Nephrol 25:7-12, 1986 25. Lopez-Hilker S, Dusso AS, Rapp NS, Martin KJ, Slatopolsky E: Phosphorus restriction reverses hyperparathyroidism in uremia independent of changes in calcium and calcitriol. Am J Physiol 259:F432-F437, 1990 26. Kilav R, Silver J, Naveh-Many T: Parathyroid hormone gene expression in hypophosphatemic rats. J Clin Invest 96:327-333, 1995 27. Naveh-Many T, Rahamimov R, Livini N, Silver J: Parathyroid cell proliferation in normal and chronic renal failure rats: The effects of calcium, phosphate and vitamin D. J Clin Invest 96:1786-1793, 1995 28. Yi H, Fukagawa M, Yamato H, Kumagai M, Watanabe T, Kurokawa K: Prevention of enhanced parathyroid hormone secretion, synthesis and hyperplasia by mild dietary phosphorus restriction in early chronic renal failure in rats: Possible direct role of phosphorus. Nephron 70:242248, 1995 29. Hernandez A, Concepcion MT, Rodriguez M, Salido E, Torres A: High phosphorus diet increases preproPTH mRNA independent of calcium and calcitriol in normal rats. Kidney Int 50:1872-1878, 1996 30. Almaden Y, Canalejo A, Hernandez A, Ballesteros E, Garcia-Nararro S, Torres A, Rodriguez M: Direct effect of phosphorus on parathyroid hormone secretion from whole

SECONDARY HYPERPARATHYROIDISM IN CRF

rat parathyroid glands in vitro. J Bone Miner Res 11:970976, 1996 31. Slatopolsky E, Finch J, Denda M, Ritter C, Zhong A, Dusso A, Macdonald P, Brown AJ: Phosphate restriction prevents parathyroid cell growth in uremic rats. High phosphate directly stimulates PTH secretion in vitro. J Clin Invest 97:2534-2540, 1996 32. Nielsen PK, Feldt-Rasmusen U, Olgaard K: A direct effect of phosphate on PTH release from bovine parathyroid tissue slices but not from dispersed parathyroid cells. Nephrol Dial Transplant 11:1762-1768, 1996 33. Parfitt AM: The hyperparathyroidism of chronic renal failure: A disorder of growth. Kidney Int 52:3-9, 1997 34. Lloyd HM, Parfitt AM, Jacobi JM, Willgoss DA, Craswell PW, Petrie JJB, Boyle PD: The parathyroid glands in chronic renal failure: A study of their growth and other properties made on the basis of findings in patients with hypercalcemia. J Lab Clin Med 114:358-367, 1989 35. Fukuda N, Tanaka H, Tominaga Y, Fukagawa M, Kurokawa K, Seino Y: Decreased 1,25 dihydroxyvitamin D3 receptor density is associated with a more severe form of parathyroid hyperplasia in chronic uremic patients. J Clin Invest 92:1436-1443, 1993 36. Falchetti A, Bale AE, Amorosi A, Bordi C, Cicchi P, Bandini S, Marx SJ, Bandi ML: Progression of uremic hyperparathyroidism involves allelic loss on chromosome 11. J Clin Endocrinol Metab 76:139-144, 1993 37. Arnold A, Brown MF, Urena P, Gaz RD, Sarfati E, Drueke TB: Monoclonality of parathyroid tumors in chronic renal failure and in primary parathyroid hyperplasia. J Clin Invest 95:2047-2053, 1995 38. Brown EM, Gamba G, Riccardi D, Lombardi M, Butters R, Kifor O, Sun A, Hediger MA, Lytton J, Hebert SC: Cloning and characterization of an extracellular Ca2⫹sensing receptor from bovine parathyroid. Nature 368:575580, 1993 39. Rask L, Lundgren S, Hjlam G, Hellman P, Ek B, Juhlin C, Klareskog I, Rastad J, Akerstrom G: Molecular cloning of a calcium receptor of the parathyroid, placental cytotrophoblasts and proximal kidney tubule cells. J Bone Miner Res 8:S147-S151, 1993 (suppl1) 40. Brown EM, Pollak M, Hebert SC: Sensing of extracellular Ca2⫹ by parathyroid and kidney cells: Cloning and characterization of an extracellular Ca2⫹-sensing receptor. Am J Kidney Dis 25:506-513, 1995 41. Silver J, Moallem E, Kilav R, Epstein E, Sela A, Naveh-Many T: New insights into the regulation of parathyroid hormone synthesis and secretion in chronic renal failure. Nephrol Dial Transplant 11:2-5, 1996 42. Brown EM, Pollack M, Hebert SC: The extracellular calcium-sensing receptor: Its role in health and disease. Annu Rev Med 49:15-29, 1998 43. Brown EM, Katz C, Butters R, Kifor O: Polyarginine, polylysine and protamine mimic the effects of high extracellular calcium concentrations on dispersed bovine parathyroid cells. J Bone Miner Res 6:1217-1225, 1991 44. Pollack MR, Brown EM, Chou YW, Hebert SC, Seidman CE, Seidman JG: Mutations in the human Ca2⫹sensing receptor gene cause familial hypocalciuric hypercalcemia, neonatal severe hyperparathyroidism, and autosomal

S11

dominant hypocalcemia. J Am Soc Nephrol 5:871, 1994 (abstr) 45. Hosokawa Y, Pollack MR, Brown EM, Arnold A: Mutational analysis of the extracellular Ca (2⫹)-sensing receptor gene in hyman parathyroid tumors. J Clin Endocrinol Metab 80:3107-3110, 1995 46. Degenhardt S, Toell A, Weidemann W, Dotzenrath C, Spindler K, Grabensee B: Point mutations of the human parathyroid calcium receptor gene are not responsible for nonsuppressible renal hyperparathyroidism. Kidney Int 53: 556-561, 1998 47. Wada M, Furuya Y, Sakiyama J, Kobayashi N, Miyata S, Ishii H, Nagano N: The calcimimetic compound NPS R-568 suppresses parathyroid cell proliferation in rats with renal insufficiency—Control of parathyroid cell growth via a calcium receptor. J Clin Invest 100:2977-2983, 1997 48. Felsenfeld AJ, Llach F: Parathyroid gland function in chronic renal failure. Kidney Int 43:771-789, 1993 49. Martinez I, Saracho R, Montenegro J, Llach F: A deficit of calcitriol may not be the initial factor in the pathogenesis of secondary hyperparathyroidism. Nephrol Dial Transplant 11:22-28, 1996 50. Kifor O, Moore FD, Wang P, White M: Reduced immunostaining for the extracellular Ca2⫹-sensing receptor in primary and uremic secondary hyperparathyroidism. J Clin Endocrinol Metab 81:1598-1606, 1996 51. Gogusev J, Duchambon P, Hory B, Giovannini M, Sarfatie T, Drueke TB: Depressed expression of calcium receptor in parathyroid gland tissue of patients with primary or secondary uremic hyperparathyroidism. Kidney Int 51: 328-336, 1997 52. Fox J, Brown EM, Hebert SC, Rogers KV: Parathyroid gland calcium receptor gene expression is unaffected by chronic renal failure or low dietary calcium in rats. J Am Soc Nephrol 5:879, 1994 (abstr) 53. Silverberg SJ, Bone HG, Harriott TB, Locker FG, Thys-Tawb S, Dziem G, Kaatz S, Sanguinetti EL, Bilezikiam JP: Short-term inhibition of parathyroid hormone secretion by a calcium receptor agonist in patients with primary hyperparathyroidism. N Engl J Med 337:15061510, 1997 54. Antonsen JE, Sherrard DJ, Andress DL: A calcimimetic agent acutely suppresses parathyroid hormone levels in patients with chronic renal failure. Kidney Int 53:223227, 1998 55. Block GA, Hulbert-Shearon E, Levin NW, Port FK: Associations of serum phosphorus and calcium ⫻ phosphate product with mortality risk in chronic hemodialysis patients: A national study. Am J Kidney Dis 31:607-617, 1998 56. Nucsi I, Hercz G, Uldall R, Ouwendyk M, Francoeur R, Pierratos A: Control of serum phosphate without any phosphate binders in patients treated with nocturnal hemodialysis. Kidney Int 53:1399-1404, 1998 57. Lowrie EG, Lew NL: Death risk in hemodialysis patients: The predictive value of commonly measured variables and an evaluation of death rate differences between facilities. Am J Kidney Dis 15:458-482, 1990 58. Parfitt AM: Soft tissue calcification in uremia. Arch Intern Med 124:544-552, 1969 59. Llach F, Hervas T, Yudd M, Goldblat MV: Hyperphosphatemia worsened parathyroid function in dialysis patients

S12

with severe hyperparathyroidism receiving intravenous calcitriol. J Am Soc Nephrol 7:1784, 1996 (abstr) 60. Rodriguez M, Felsenfeld AJ, Dunlay R, Williams C, Pederson JA, Llach F: The effect of long-term intravenous calcitriol administration on parathyroid function in hemodialysis patients. J Am Soc Nephrol 2:1014-1020, 1991 61. Quarles LD, Yohay DA, Carroll BA, Spritzer CE, Minda SA, Bartholomay D, Lobaugh BA: A prospective trial of pulse oral versus intravenous calcitriol treatment of hyperparathyroidism in ESRD. Kidney Int 45:1710-1721, 1994 62. Yudd M, Goldblat MV, Llach F: Hyperphosphatemia and not hypercalcemia is the major factor in the therapeutic failure of dialysis patients with hyperparathyroid bone disease. To be presented at the 31st Annual American Society of Nephrology, Philadelphia, PA, October 24-28, 1998 63. Seyle H: Calciphylaxis. Chicago, IL, University of Chicago Press, 1962 64. Gipstein RM, Coburn JW, Adams DA, Massry SG: Calciphylaxis in man. Arch Intern Med 136:1273-1280, 1976 65. Richens G, Piepkora MW, Kruege GC: Calcifying panniculitis associated with renal failure. J Am Acad Dermatol 6:537-539, 1982 66. Biedermann K, Brunner U, Helfenstein U, Berg G: Uremic small artery disease with medical calcification and

LLACH AND YUDD

intimal hypertrophy (so called calciphylaxis): A complication of chronic renal failure and benefits from parathyroidectomy. J Am Acad Dermatol 33:954-962, 1995 67. Massry SG, Coburn JW, Hartenbower DL, Shinaberger JH, DePalma JR, Chapman E, Kleeman CR: Mineral content of human skin in uremia. Effect of secondary hyperparathyroidism and hemodialysis. Proc Eur Dial Transplant Assoc 7:146-148, 1970 68. Massry SG, Coburn JW, Hartenbower DL, Shinaberger JH, DePalma JR, Chapman E, Kleeman CR: The effect of calcemic disorders and uremia or the mineral content of the skin. Israel J Med Sci 7:514-517, 1971 69. Campistol JM, Almirall J, Martin E, Torras A, Revert L: Calcium-carbonate–induced calciphylaxis. Nephrol 51: 549-550, 1989 70. McAuley K, Devereux F, Walker R: Calciphylaxis in two noncompliant patients with end-stage renal failure. Nephrol Dial Transplant 12:1061-1063, 1997 71. Bleyer AJ, Choi M, Igwemezie B, De La Torre S, White WL: A case control study of proximal calciphylaxis. Am J Kidney Dis 32:376-383, 1998 72. Budisavijevic MN, Cheek D, Ploth DW: Calciphylaxis in chronic renal failure. J Am Soc Neph 7:978-982, 1996