Considerations for the Treatment of Secondary Hyperparathyroidism in Renal Failure

Transcription

1 DISEASEOF THE MONTH Considerations for the Treatment of Secondary Hyperparathyroidism in Renal Failure ARNOLD J. FELSENFELD Department of Medicine, West Los Angeles Veterans Affairs Medical Center, and the University of California- Los Angeles, Los Angeles, ( ahifornia. Secondary hyperparathyroidism develops in virtually all dialysis patients and continues to be a cause of morbidity in the dialysis population. Secondary hyperparathyroidism (2#{176} HPT) is often observed early in renal failure and progresses as renal failure worsens. The magnitude of 2#{176} HPT varies considerably among azotemic patients and in the dialysis population. Although much is known about the factors in renal failure that result in 2#{176} HPT, many questions remain regarding the development and treatment of 2#{176} HPT. The goal of this review is to frame a perspective to address the following questions: (1) What are the factors beading to the development of 2#{176} HPT renal failure? (2) Should 2#{176} HPT in the predialysis patient be treated? (3) What level of parathyroid hormone (PTH) should be considered as desirable in the dialysis patient? (4) What dialysate calcium should be used? (5) How important is the control of serum phosphorus? (6) What are the indications for calcitriol treatment and which dialysis patients respond? and (7) When should a patient be considered for parathyroidectomy? What Are the Factors Leading to the Development of 2#{176} HPT in Renal Failure? The development of 2#{176} HPT in renal failure is a result of a complex interplay of factors that include a deficiency of cabcitriol, retention of phosphorus, and skeletal resistance to the calcemic action of PTH, all of which lead to a tendency to develop hypocalcemia. However, it may be difficult to isolate specific factors in early renal failure because the increase in PTH serves to prevent hypocalcemia, hyperphosphatemia, and a decrease in calcitriol. These concepts are shown in Figure 1, which is from a study ( 1 ) in which non-azoternic and azotemic rats were evaluated on a normal diet. To prevent changes in PTH, a group of normal rats and a group of rats with moderate renal failure were parathyroidectomized (PTX) and given a normal replacement dose of PTH via a subcutaneously implanted miniosmotic pump. Thus, in these two PTX groups, the PTH level was fixed at normal. The control groups were normal rats and rats with moderate renal failure, both with Correspondence to Dr. Arnold J. Felsenfeld. Nephrology Section L. West Los Angeles VA Medical Center. I 1301 Wilshire Boulevard. Los Angeles. CA l / $03.0()/() Journal of the American Society of Nephrology Copyright to 1997 by the American Society of Nephrology in intact parathyroid glands. By definition, the normal PTH replacement dose in the non-azotemic, PTX rat should and did maintain a normal serum phosphorus, calcium, and calcitriol level (Figure 1 ). However, as shown in the PTX group with moderate renal failure, the inability to increase PTH above normal levels resulted in an increase in serum phosphorus and a decrease in serum calcium and calcitriol levels. Conversely, the compensatory increase in PTH from 40 ± S to 75 ± 12 pg/mb in the parathyroid-intact rats with moderate renal failure resulted in a normal serum phosphorus, calcium, and calcitriob level. These results clearly show that in early to moderate renal failure, the compensatory increase in PTH is critical for the maintenance of a normal serum calcium, calcitriob, and phosphorus bevel. In patients with early to moderate renal failure, a decrease in serum calcium and calcitriol and an increase in serum phosphorus levels is generally not observed because of a compensatory increase in PTH (2,3). Thus, it is difficult to accept the statement from a recent study, in which elevated PTH and normal calcitriol levels were present in early renal failure, that a deficit in calcitriol may not be the initial factor in the pathogenesis of 2#{176} HPT (3). Based on the results presented in Figure 1, a more plausible explanation is that the serum cabcitriol was normal because of the increase in PTH. As is observed in #{176} HPT, a high PTH should produce a high calcitriol level. Finally, it should be appreciated that hypocalcemia, hyperphosphatemia, and a calcitriol deficiency may only become apparent in more advanced renal failure when the compensatory effect of an increase in PTH is no longer sufficient to maintain homeostasis. Should 2#{176} HPT in the Predialysis Patient Be Treated? Although 2#{176} HPT is present in early to moderate renal failure, the increase in PTH is generally modest. The available experimental evidence suggests that in moderate renal failure, it is easier to prevent the eventual development of severe 2#{176} HPT and marked parathyroid gland hyperplasia than it is to treat severe 2#{176} HPT and to induce a regression of marked parathyroid gland hyperplasia (4). Furthermore, it has been suggested that the higher the PTH level is at the start of dialysis, the more likely a patient will develop overt 2#{176} HPT during hemodialysis (5). Thus, interventions to retard the progression of 2#{176} HPT in moderate renal failure may prevent overt 2#{176} HPT in the dialysis patient.

2 994 Journal of the American Society of Nephrology N Nx N Nx N Nx I Intact PIGs a=p<o.05 vs intact PIGs PTX-PTHR x=p<o.05 vs N Figure 1. Serum phosphorus, calcium, and calcitriol levels are shown for rats with normal renal function (N) and renal failure (Nx); rats either had intact parathyroid glands (open bars) or were parathyroidectomized and received a normal replacement dose of PTH infused via a subcutaneously implanted miniosmotic pump (solid bars). All rats were fed a normal-phosphorus diet (0.6% phosphorus). Values are presented as mean ± SEM. (From reference 1). The most frequently studied intervention in moderate renal failure, calcitriol treatment, will be the focus of this section. However, it should be noted that in both experimental and clinical studies, phosphorus restriction has been shown to retard the development of 2#{176} HPT; although these studies will not be discussed, a comprehensive review can be found elsewhere (6). It should also be noted that besides its effect on calcitriob metabolism and the skeletal response to PTH, a high phosphorus concentration has recently been shown to directly stimulate PTH secretion (7). The early studies of calcitriol or 1-a hydroxyvitamin D treatment in patients with moderate renal failure were, in general, performed with doses of at least 1 j.g/day (8). Although a reduction in PTH bevels was generally observed, both hypercalcemia and hypercalcemia-associated decreases in renab function were common (8). More recent studies have shown that lower doses of cabcitriol (0.25 to 0.5 tg daily) and equivalent doses of alfacalcidol effectively reduced PTH levels and improved renal osteodystrophy (9-1 1). Although the stated goal of these studies was to use a dose of at beast 0.5 jig/day, most patients could not tolerate this dose because of hypercalcemia and hypercalciuria, and the studies were completed at bower doses. In these studies (9-1 1), the decrease in renal function during the study was not different between the placebo and treated groups. Thus, if hypercalcemia and hypercalciuria are avoided, calcitriob treatment should not accelerate the decline in renal function. Moreover, it should be noted that calcitriol doses in excess of 0.5 pg daily may decrease tubular secretion of creatinine, resulting in an increase of serum crcatinine that does not reflect decreased renal function (8). Thus, the benefits of calcitriol treatment in patients with moderate renal failure and increased PTH levels include (1) a reduction or stabilization of PTH levels; (2) an improvement in renal osteodystrophy; and (3) possible control of parathyroid gland hyperplasia. However, it must be emphasized that unless calcitriol treatment is adequately monitored, the development of hypercalcemia and hypercalciuria may accelerate the deterioration in renal function; also, concern has been raised that calcitriol treatment may increase the incidence of adynamic bone (10). In a recent study ( 12), an even lower dose of calcitriol (0.125 jtg/day) was used in patients with moderate renal failure and moderate 2#{176} HPT. After 1 2 months of calcitriol treatment, serum calcium and phosphorus levels and urinary calcium excretion were not different from baseline (pretreatment) nor different from those in the placebo group; PTH levels in the treatment group were unchanged from baseline and were lower than those in the placebo group. These data suggest that in early to moderate renal failure, the parathyroid gland may be quite sensitive to the effects of calcitriol. These results would be in keeping with earlier experimental studies in which calcitriol was more effective at preventing parathyroid cell proliferation than inducing regression of existing parathyroid gland hyperplasia (4). If these clinical data can be confirmed, it would suggest that bow-dose calcitriol may be a safe and effective treatment for retarding the progression of 2#{176} HPT without the attendant risks of hypercalcemia, hyperphosphaternia, and hypercalciuria. What Level of PTH Should Be Considered as Desirable in the Dialysis Patient? Resistance to the action of PTH is present in renal failure. Thus, it should not be surprising that when bone histology is evaluated, dialysis patients with mild to moderate elevations of PTH often fail to show increased bone remodeling. This find-

3 Secondary Hyperparathyroidism 995 ing becomes an important issue when calcitriol treatment for 2#{176} that the increase in serum calcium and the decrease in PTH HPT and renal osteodystrophy is considered. Two recent stud- return to prediabysis values within several hours ( 1 8), longer ies evaluated the level of intact PTH needed for normal bone remodeling in the dialysis patient (13,14). In both studies, an intact PTH level of approximately two to four times normal was required to maintain a normal osteoblast surface and bone formation rate; this appears to be true for both hemodialysis and continuous ambulatory peritoneal dialysis (CAPD) patients. Bone marrow fibrosis was not observed until PTH levels exceeded 200 to 250 pg/mb, and severe hyperparathyroid bone disease was not observed until PTH levels were greater than approximately 500 pg/ml. Finally, it should also be noted that in the predialysis patient (creatinine clearance rate < 10 ml! mm), resistance to PTH was greater than in the dialysis patient because PTH levels of 300 to 500 pg/mi were required to maintain a normal osteoblast surface ( I 4). These data serve to confirm that PTH resistance is present in dialysis patients and indicate that in general, calcitriol treatment for 2#{176} HPT in the dialysis patient should not be initiated until intact PTH levels are greater than 400 pg/mb. What Dialysate Calcium Concentration Should Be Used? The selection of a dialysate calcium concentration is an important consideration in the treatment of 2#{176} HPT. As recently reviewed by Hsu, the selection of a diabysate calcium also needs to be viewed in the context of calcium balance and extraosseous calcifications (15). The problem in dialysis patients is that excess calcium cannot be excreted via the kidney and when the capacity of the bone to accept calcium is cxceeded, it is likely that calcium deposition occurs elsewhere. As summarized by Hsu, a body of literature has accumulated that has shown the presence of increases in soft tissue, vascular, and cardiac calcifications in dialysis patients and that these calcifications may produce functional cardiac and pulmonary impairment (15). In addition to the myocardium, cardiac cabcifications have been shown to include the coronary arteries and the mitral and aortic valves (15). Whether in the long-term hemodialysis patient, low bone turnover states with a decreased bone-buffering capacity ( I 6), or other factors such as age or high PTH levels result in more extensive extraosseous calcifications deserves study. Because of the limitation of space, the selection of a calcium concentration for CAPD will not be discussed; the reader is referred elsewhere for a comprehensive review ( 17). The most commonly used dialysate calcium concentrations for hemodialysis are 2.5, 3, and 3.5 meqfl. In addition to the dialysate calcium concentration, other factors such as convective bosses (ultrafiltration) and the concentration gradient (difference between serum and dialysate) also contribute to calcium balance. In general, both the 3 and 3.5 meq/l dialysate calcium concentrations have been shown to result in a positive calcium balance, to induce an increase in serum calcium, and to suppress PTH during the hemodialysis session. Although shortterm studies with a 3.5 meq/l calcium dialysate have shown studies have shown that this dialysate concentration results in an increase in serum calcium and suppression of PTH ( I 9). Although earlier reports have suggested that the use of a 2.5 meq/l calcium dialysate was neutral with respect to calcium balance, serum calcium, and PTH, a more recent study has reported that during a hemodialysis session with a 2.5 meq/l calcium diabysate, the serum calcium does not change only because PTH stimulation during dialysis maintains the serum calcium (20). Moreover, long-term studies have shown that continual use of a 2.5 meq/l calcium dialysate induces an increase in the prediabysis PTH level (20,21). It is important to appreciate that the selection of a dialysate calcium must be individualized for the needs of the patient. If the predialysis PTH level is <200 pg/mb, the serum calcium bevel is normal or increased, and the patient is ingesting calcium-based phosphate binders, it would be reasonable to use a 2.5 meqfl or perhaps a 3 meqll dialysate calcium concentration. Such a patient (PTH <200 pg/mb) would be expected to have decreased or normal bone turnover. Thus, the use of a 3.5 meqfl calcium dialysate would be expected to further lower PTH, induce hypercalcemia, and likely increase the risk of extraosseous calcifications. It should also be emphasized that if a 2.5 meq/l calcium dialysate is used, the nephrobogist managing the patient must be vigilant to note increases in PTH levels and change the diabysate calcium concentration accordingly. When hemodiabysis patients are treated with calcitriob or other analogs, a 2.5 meqll dialysate calcium concentration is generally used to minimize increases in serum calcium levels. Despite the lower dialysate calcium concentration, increases in serum calcium are generally observed during calcitriob treatment. With higher serum calcium levels, it is probable that PTH is stimulated during each dialysis with a 2.5 meq/l calcium dialysate (20); whether PTH is stimulated during dialysis and diminishes the effectiveness of calcitriob treatment deserves to be studied. How Important Is Control of the Serum Phosphorus Level? The control of the serum phosphorus level to retard the progression of 2#{176} HPT and for the successful treatment of 2#{176} HPT deserves special emphasis. Studies have shown that dietary phosphorus loading in azotemic animals results in dramatic increases in PTH levels by inducing hypocalcemia, decreasing the serum calcitriol level, and further reducing an already decreased calcemic response to PTH ( I,22,23). The detrimental effects of phosphorus excess are shown in Figure 2. In this experimental study (22), rats with normal renal function and mild, moderate, and advanced renal failure were placed on a normal- or high-phosphorus diet. The high-phosphorus diet resulted in a higher serum PTH and phosphorus level and a lower serum calcium and calcitriob level than did the normal-phosphorus diet at all stages of renal failure. Thus, it should be appreciated that phosphorus loading affects all the

4 996 Journal of the American Society of Nephrology SERUM PHOSPHORUS SERUM Serum Phosphorus (mgldi) Serum PTH (pg/mi) PTH Serum Creatinine 1.o mg/di EiO.75 mg/di IZIO.50 mg/di RO.25 mg/di Serum Creatinine Li.o mg/di El 0.75 mg/di DO.50 mg/di I 0.25 mg/di HPD NPD HPD NPD SERUM CALCIUM SERUM CALCITRIOL Serum Calcium (mg/di) Serum Calcitriol (pg/mi) Serum Creatinln. ES1O.25 mg/di E10.50 mg/dl EZIO.75 mg/dl #{149}1.0mg/dI Serum Creatinine 0.25 mg/di mg/di J 0.75 mg/di #{149}1.0mg/di HPD NPD HPD NPD Figure 2. The serum phosphorus. PTH, calcium, and calcitriob levels are shown in normal rats and rats with different stages of experimental renal failure. The respective serum creatinine values were 0.25 mg/dl (normal). 0.5 mg/dl (mild renal failure), 0.75 mg/dl (moderate renal failure), and I mg/dl (advanced renal failure). It should be noted that the sequence of serum creatinine is reversed in the bottom two groups (serum calcium and calcitriol). These groups of rats with different degrees of renal function were placed on either a normal-phosphorus diet (NPD, 0.6% P) or a high-phosphorus diet (HPD, 1.2% P) Dietary calcium was 0.6% for both diets. In both dietary groups, the serum PTH increased as renal function decreased, but the PTH level was greater in the HPD group at every stage of renal function. In addition, the high-phosphorus diet but not the normal-phosphorus diet, resulted in a progressive increase in serum phosphorus level and a progressive decrease in serum calcium and calcitriol levels as renal function decreased. * < 0.05 versus previous group. Values are presented as mean ± SEM. (Adapted from reference 22). counter-regulatory systems for restoring calcium homeostasis. In addition, recent studies have shown that a high phosphorus concentration may directly stimulate PTH secretion (7,23). Thus, at any level of renal failure, it is reasonable to expect that persistent excesses in dietary phosphorus will exacerbate 2#{176} HPT. In the clinical setting, the use of calcitriol or similar analogs for the treatment of 2#{176} HPT has been shown to increase the serum phosphorus because of enhanced gut absorption of phosphorus (24). Because hyperphosphatemia decreases the effectiveness of calcitriol treatment (25,26), the serum phosphorus bevel should be maintained at least below 6 mg/dl and preferably in the S mg/dl range to maximize the effect of calcitriol treatment. What Are the Indications for Calcitriol Treatment and Which Dialysis Patients Respond? Many studies have evaluated the effectiveness of calcitriol or its analogs for the treatment of 2#{176} HPT in the dialysis patient. Calcitriol has been administered as continuous (daily) or intermittent (pulse) therapy with the latter generally being administered either orally or intravenously after each hemodialysis (thrice weekly). In some studies, the PTH response to calcitriol treatment has been good, but in other studies the PTH response to treatment has been suboptimal. In this section, an attempt will be made to (1) analyze factors that affect the response to calcitriol, (2) review the data on the relative merits

5 Secondary Hyperparathyroidism 997 of continuous versus intermittent calcitriol treatment and intermittent oral versus intermittent intravenous calcitriol treatment, (3) evaluate, among the different studies, possible reasons for differences in the PTH response to calcitriol, and (4) discuss an approach for the use of calcitriol for the treatment of 2#{176} HPT in the dialysis patient. Certain intrinsic and extrinsic factors (Table I ) may help to explain some of the variation in results among the different studies in which calcitriol was used. Among the intrinsic factors, the magnitude of parathyroid gland hyperplasia is of HPT, the more likely a markedly enlarged parathyroid gland with nodular hyperplasia will be present; it should be noted that nodular hyperplasia is characterized by resistance to calcitnob treatment. Furthermore, it should be emphasized that nodular hyperplasia is not unique to the parathyroid gland but is also observed as a result of long-standing stimulation in other endocrine glands, such as the thyroid and adrenal (27). When hyperplasia is a result of prolonged, intense stimulation in endocrine organs, it has been shown that endocrine cells with a greater proliferative capacity are preferentially selected (27); perhaps because of the greater proliferative capacity of these Table 1. Intrinsic and extrinsic factors that affect the parathyroid hormone (PTH) response to calcitriol treatment Intrinsic factorsa in renal failure parathyroid gland hyperplasia nodular hyperplasia-greater parathyroid gland mass ( - )b diffuse hyperplasia vitamin D receptor uremia-decreased binding (-) nodular hyperplasia-decreased receptor density ( -) decreased expression of the calcium receptor ( -) increased parathyroid cell proliferation (-) probably greater in nodular hyperplasia (-) increased set point for PTH release (-) higher PTH level ( -) hypocalcemia ( +) hypercalcemia (-) Extrinsic factors hyperphosphatemia (-) calcitriob-induced increase in serum calcium ( +) use of a low-calcium diabysate ( -?) a There are several factors that are interrelated; for example, the presence of nodular hyperplasia is associated with a greater parathyroid gland weight, a higher PTH level, an increased set point, and hypercalcemia. L The presence of ( - ) indicates that the factor decreases the probability of a PTH response to calcitriol treatment. The presence of (+) indicates that the factor increases the probability of a PTH response to calcitriol; however, in the case of a calcitriol-induced increase in serum calcium level (extrinsic factor), the PTH response may be a result of the increase in serum calcium level and not a specific effect of calcitriol. selected cells, it has been shown that hyperplasia is not a fully reversible process (27,28). Although a recent study has suggested that cells with a greater proliferative capacity are often monoclonal (29), it should also be noted that monocbonality is not necessary for the development of nodular hyperplasia (27). Finally, the greater proliferative capacity of parathyroid cells from areas of nodular hyperplasia is also the likely reason that after parathyroidectomy, the recurrence of hyperparathyroidism is greater when remnant tissue with nodular hyperplasia is left behind in the neck or autotranspbanted to the arm (30). A primary importance. In general, the greater the magnitude of 2#{176} schematic diagram summarizing the cellular and clinical characteristics of nodular hyperplasia of the parathyroid gland is shown in Figure 3. The clinical message is that the more severe the hyperparathyroidism, the more likely it is that marked parathyroid gland enlargement and nodular hyperplasia will be present and the less likely the patient will be to respond to calcitriol. Calcitriol decreases PTH levels by reducing transcription of PTH mrna. Both uremia, perhaps by factors inherent to uremia (3 1 ), and parathyroid gland hyperplasia, especially nodular hyperplasia (32), contribute to the progression of 2#{176} HPT by reducing vitamin D receptor binding and density, respectively. Thus, along with the greater cell proliferative capacity in patients with severe 2#{176} HPT and nodular hyperplasia, the decreased vitamin D receptor expression also contributes to a reduced responsiveness to calcitriol treatment. Furthermore, it is also possible that as suggested in a recent study (33), decreased expression of the calcium receptor in the parathyroid gland in uremia may contribute to less efficient control of PTH secretion and consequently to resistance to calcitriol treatment. Potential reasons why the proliferation of parathyroid cells is controlled in healthy subjects and stimulated in subjects with renal failure are shown in Figure 4. In healthy subjects, the PTH response to hypocalcemia effectively restores the serum calcium level to normal and likely stimulates calcitriol production and decreases the serum phosphorus level; these batter two are likely anti-proliferative, and it is also possible that the relatively short duration of any hypocalcemic episode may not be sufficient to stimulate parathyroid cell proliferation. Conversely, in renal failure, the hypocalcemia is more prolonged and the low serum calcitriol level, together with a tendency toward hyperphosphatemia, may act in concert to stimulate parathyroid cell proliferation. Moreover, an abnormality in the set point control for PTH secretion may be a continual stimulus for parathyroid cell proliferation in renal failure (34). Finally, decreases in the vitamin D and calcium receptors in the parathyroid gland may also be important for stimulation of PTH secretion and parathyroid cell proliferation in renal failure (3 1-33). At this time, it would seem appropriate to propose a hypothesis that may serve to (I) explain how parathyroid cell proliferation might evolve during the development of parathyroid gland hyperplasia in renal failure and (2) provide a rationale why the parathyroid gland may be more sensitive to calcitriol in moderate than advanced renal failure. As shown in Figure 5, the hypothesis suggests that the normal parathyroid gland is

6 998 Journal of the American Society of Nephrology I Parathyroid Gland I I Calcium I Set Point Size I Basal/Maximal I, PTH ratio Figure 3. Graphic representation of nodular hyperplasia of the parathyroid gland. In the inset box superimposed on the graphic representation of the parathyroid gland are cellular features that characterize the nodular hyperplasia ofthe parathyroid gland in uremia. In the box on the right are clinical features that characterize the dialysis patient with nodular hyperplasia of the parathyroid gland. composed of a small number of morphobogicably similar cells that have a greater inherent proliferative capacity. Such a concept has been shown in studies of thyroid hyperplasia and suggested in studies of hyperplasia in other endocrine glands (27,34). As renal failure develops, the parathyroid gland is released from the hierarchical control, which prevents parathyroid cell proliferation in healthy subjects (Figure 4). This release of control favors the growth of parathyroid cells with a high proliferative capacity. In moderate renal failure (Figure 5), these cells may still be sensitive to the anti-proliferative effects ofcalcitriol (4) because they comprise a relatively small number of the total cells and, perhaps more importantly, these cells may not yet have evolved to an unresponsive state. However, during the constant stimulus of renal failure, a sebection process that favors the further evolution of these parathyroid cells with a high proliferative capacity may develop and lead to a predominance of parathyroid cells with both an enhanced proliferative capacity and reduced responsiveness. It is the continual stimulation of these parathyroid cells with enhanced proliferative capacity that results in nodular hyperplasia. The explanation provided for the evolution of nodular hyperplasia also suggests that hyperplastic nodules could be either monocbonal or polycbonal. For example, if a hyperplastic nodule were derived from one cell with an enhanced proliferative capacity, the nodule would be monoclonal. However, if a nodule were derived from two or three cells with enhanced proliferative capacity that were originally in close proximity, the nodule would then be pobyclonab (27). Thus, based on the proposed sequence of events, it perhaps should not be surprising that low-dose calcitriob is effective in controlling 2#{176} HPT in moderate renal failure and that high-dose calcitriol may not be effective in treating severe 2#{176} HPT in advanced renal failure. Another factor that may predict the PTH response to calcitriol is the serum calcium bevel. It is likely that for the same PTH level, patients with a higher serum calcium bevel are less likely to respond to calcitriol (35). The reason for this statement is illustrated in Figure 6. When hemodialysis patients with prediabysis PTH values greater than 500 pg/mb were separated into two groups based on serum calcium level (<9 mg/db and >9 mg/dl), prediabysis (basal) PTH levels were not different (846 ± 108 versus I 153 ± 140 pg/mb) (Figure 6A). However, the maximal PTH level induced by hypocalcemia was greater in the normocalcemic than the hypocalcemic group; the respective maximal PTH values were 2739 ± 412 versus 1219 ± 204 pg/mb, P < 0.01 (Figure 6A). The reason for these results is that in the hypocalcemic group, hypocalcemia served to stimulate PTH secretion, resulting in similar prediabysis (basal) PTH values even though the maximal secretory capacity of the parathyroid gland (maximal PTH) was less. This concept is illustrated in Figure #{212}B, in which the basal PTH as a percent of the maximal PTH was greater in the hypocalcemic group, 73 ± 6 versus 47 ± 5%, P < The clinical message is that for the same predialysis (basal) PTH level, it is more likely for the hypocalcemic than the hypercalcemic dialysis patient to respond to calcitriol treatment. Although it is the subject of continued debate, it is likely that in dialysis patients with hypercalcemia and severe 2#{176} HPT, the hypercalcemia is a result of an increased set point for PTH release. The increased set point reflects a decreased sensitivity to calcium inhibition and is associated with an increased parathyroid gland mass. The concept that parathyroid cells from uremic patients are less sensitive to the suppressive effects of calcium has been shown in in vitro studies (36). The situation in the clinical setting is more complex because as shown recently, the set point can also be modified by sustained changes in the serum calcium induced by the dialysate calcium or calcitriol (37). The clinical message is that in the dialysis patient in whom the serum calcium bevel has not been modified by calcitriol or the dialysate calcium, hypercalcemia associated with a markedly elevated PTH is, in general, indicative of refractoriness to calcitriob treatment. As shown in Table 1, important extrinsic factors include (1) hyperphosphatemia; (2) the increase in serum calcium bevel during calcitriol treatment; and possibly (3) the diabysate cal-

7 Secondary Hyperparathyroidism 999 NORMAL RENAL FUNCTION MODERATE RENAL FAILURE rj Parathyroid Proilferation Ccii Hypocalcemla Parathyroid Ccii tt Proiiferation *PTH 4+PTH SP-normai VDR-normai CaR#{149}normai?SP error?vdr+?car+ ADVANCED RENAL FAILURE Hypocaic.mia PTH = Parathyrold Hormone CTR= CalcItriol P=Phosphorus SP=Set Point VDR=Vltamln D Receptor CaR=Calclum Receptor Parathyroid Ccii Proliferation P (increased) sp error VDR * CaR* Figure 4. Potential factors that may control or prevent parathyroid cell proliferation in the healthy individual and may contribute to the stimulation of parathyroid cell proliferation in patients with moderate and advanced renal failure. In healthy individuals. any episode of hypocalcemia should be transient because of the efficiency of the homeostatic system. Moreover, PTH-induced increases in serum calcitriol level and decreases in serum phosphorus level should have an anti-proliferative effect on the parathyroid cell. In moderate and advanced renal failure, the calcium homeostatic system becomes progressively less efficient. Decreases in calcitriol production and increases in serum phosphorus bevel stimulate PTH secretion and probably stimulate proliferation of parathyroid cells. A set-point error. in which a reduced efficiency of PTH to maintain a normal serum calcium level results in the stimulation of parathyroid cell proliferation, is also present in renal failure. Finally, decreases in the vitamin D and calcium receptors result in less efficient control of PTH secretion and may also contribute to parathyroid cell proliferation. cium concentration. Studies have shown that a serum phosphofl s level greater than 7 mg/dl adversely affects the PTH response to calcitriol (25,26). Whether the adverse effect of an increasing serum phosphorus is a continuum or threshold remains to be determined, but studies suggest that serum phosphorus values greater than even 6 mg/dl decrease the probability of response to calcitriol treatment. Moreover, calcitriob may antagonize its own suppressive effect on PTH secretion because it increases gut absorption of phosphate (24). In the study by Quarles ci al. (26), despite no change in dietary phosphate, it was necessary during calcitriol treatment to increase phosphate binding capacity by approximately twofold to prevent an increase in serum phosphorus level. Another important consideration is whether PTH reduction during calcitriob treatment is the result of a direct effect of calcitriob or an associated increase in serum calcium bevel. It should be emphasized that an increase in serum calcium level independently decreases PTH bevels; thus, it is often difficult to separate whether a reduction in PTH is specifically a result of calcitriob or an associated increase in serum calcium level. This analysis is potentially further complicated by the fact that the relationship between the increase in serum calcium level and the decrease in PTH is not linear. The final extrinsic factor represents a theoretical consideration that has not been evaluated. It is generally suggested that with calcitriol treatment, patients be placed on a 2.5 meq/l

8 1000 Journal of the American Society of Nephrology Relative Weight of, Parathyroid Gland 1 k 5 40% 99% I % 85% (:I:::: Normal Renal Moderate Renal Function Failure Parathyroid Cell Proliferative Capacity LiLow Hlgh 60%?Nodu/ar Hyperplasfa Advanced Renal Failure Figure 5. A hypothesis for the development of the 2#{176} HPT in renal failure is presented. It is suggested that in the normal parathyroid gland, a small number of morphologicably similar cells have a much greater proliferative capacity. Excessive proliferation in the healthy individual is prevented by a hierarchical structure that likely includes the anti-proliferative effects of calcitriol. As renal failure develops, it is likely that these parathyroid cells with a greater proliferative capacity grow more rapidly and become an increasingly greater percentage of the total parathyroid cells in the hyperplastic parathyroid gland. In moderate renal failure, when parathyroid gland hyperplasia may not yet be severe, parathyroid cells may still be sensitive to the anti-proliferative effects of calcitriol. In advanced renal failure with marked parathyroid gland hyperplasia, the parathyroid cells with enhanced proliferative capacity predominate, and rapid proliferation results in nodular hyperplasia that is resistant to control with calcitriol. The relative weight of the parathyroid gland provided in the diagram is based on actual reported weights of normal parathyroid glands and parathyroid glands with nodular hyperplasia from dialysis patients. The relative weight of parathyroid glands in moderate renal failure is an estimate based on PTH levels. The percentage of parathyroid cells with low and high proliferative capacity in moderate and advanced renal failure are not known. and the numbers shown are given only to illustrate the concept. calcium diabysate to reduce the risk of hypercalcemia. However, PTH is stimulated in normocalcernic hemodialysis patients during hemodialysis with a 2.5 meq/l calcium dialysate (20). Thus, during calcitriob-induced hypercalcemia or increases to a high normal serum calcium level, each dialysis with a 2.5 meq/l calcium dialysate would be expected to stimulate PTH. Whether such a sequence develops and whether PTH stimulation thrice weekly could potentially act to antagonize the suppressive effect of calcitriob deserves to be evabuated. Other important considerations for the treatment of 2#{176} HPT are whether pulse calcitriol therapy is superior to continuous (daily) calcitriob treatment and whether pulse intravenous cabcitriol is superior to pulse oral calcitriob. Because parathyroid gland hyperplasia is present in dialysis patients treated with calcitriol, it may be necessary to use a threshold dose of calcitriol to achieve a response; this dose would appear to be approximately 0.75 pg daily or its weekly equivalent (38). At this dose of calcitriol, Herrmann et al. did not observe any difference in PTH response between continuous and pulse calcitriol treatment (39). It should also be noted that in the experimental study most often cited to show the superiority of pulse therapy (40), hypercalcemia was present in both the pulse and continuous calcitriol groups of rats and thus could have accounted for the small but significant difference in PTH between the control and treated groups. Furthermore, although the PTH level was minimally less in the pulse than in the continuous calcitriol group, the serum calcium level tended to be greater in the pulse group (mean versus mg/dl). Thus, it would seem that this experimental study fails to establish with certainty the superiority of pulse therapy. It has been suggested that pulse as opposed to continuous calcitriol treatment might result in less hypercalcemia because of less gut absorption of calcium and phosphorus. The rationale for such a belief is that with pulse therapy, there are days in which rapidly dividing intestinal cells are not exposed to cabcitriol; thus intestinal calcium and phosphorus absorption might be less than with daily treatment. However, studies of continuous versus pulse calcitriol have not reported any difference in the incidence of hypercalcemia and hyperphosphatemia (39,4 1 ). Although a review of the available data fails to provide compelling proof that pulse is better than continuous calcitriol treatment, it should be noted that in the cited study used for comparison (39), pretreatment PTH levels were only moderately increased. In addition, a major advantage of pulse therapy is that patient compliance can be easily monitored because the calcitriob is administered at the time of hemodialysis. Several years ago, it was suggested that pulse intravenous calcitriol treatment would be superior to pulse oral calcitriol treatment because the peak serum calcitriol level is much greater with intravenous calcitriol; however, the total area

9 Secondary Hyperparathyroidisni l()ol A PTH (pg/mi) (Thousands) 3 2 #{149} Maximal PTH (P<O.O1) B PTH (%) I I Basal 4 PTH. Maximal t 4 4 would suggest that the PTH response to pulse oral and intravenous calcitriol treatment is not different. Pr.dialysls Calcium It is important to be able to predict which patients will +<9mg/dl respond to calcitriol treatment. The author has had the oppor- #{149}>9mg/di calcitriol: (1) high PTH level (negative), and (2) hyperphosphatemia (negative). It should be reemphasized that the predi- (P<O.02) alysis PTH bevel is likely to be reflective of parathyroid gland Serum Calcium (mg/di) PTH t. V Basal\ Ratloof NPTH 4. Basal/Maxima (P<O.O1) PTH Serum Calcium (mg/dl) Figure 6. Twenty-one hemodialysis patients with prediabysis PTH levels greater than 500 pg/mi were separated into two groups based on their predialysis serum calcium (<9 mg/dl, n = 8 and >9 mg/dl, a = 13). PTH-calcium curves were performed in all patients to determine the maximal and minimal PTH levels; hypocalcemia was induced with a low-calcium dialysate (I meqll) and hypercalcemia with a high-calcium dialysate (4 meqfl). (A) Even though the predialysis (basal) PTH level was not different between the two groups, the maximal PTH induced by hypocalcemia and the minimal PTH induced by hypercalcemia were both significantly less in the hypocalcemic group. (B) The maximal PTH was changed to 100%, and the basal and minimal PTH are shown as a percentage of the maximal PTH. The ratio of basal to maximal PTH indicates the relative degree of PTH stimulation in the basal (predialysis) state. The significantly higher basal to maximal ratio in the hypocalcemic group suggests that hypocalcemia stimulated PTH in the basal state and resulted in similar basal (predialysis) PTH levels in the two groups, even though the maximal PTH level was less (see Figure 6A) in the hypocalcemic group. Values are presented as mean ± SEM. (Adapted from reference 35). under the curve for the same oral and intravenous calcitriol dose is similar (42). Moreover, most studies that have directly compared pulse oral and pulse intravenous calcitriob treatment have reported that PTH responses were similar (26,42,43). Furthermore, studies that have compared pulse oral and intra- venous calcitriol have reported no difference in the incidence of hypercalcemia and hyperphosphatemia, both of which were commonly observed (26,42,43). Thus, the available studies tunity to analyze the unpublished results of 50 hemodialysis patients treated with calcitriol. The following pretreatment criteria were important predictive factors of a PTH response to mass; thus with a greater parathyroid gland mass, the greater is the likelihood of nodular hyperplasia and a decrease in the vitamin D receptor. In addition to the pretreatment factors, the magnitude of increase in serum calcium level during calcitriol treatment was a positive predictive factor; the latter is mdcpendent of calcitriob and likely a result of the suppressive effect of calcium on PTH. It is of interest to note that some patients with relatively bow PTH levels (300 to 500 pg/mi) responded to Pr.dialysis calcitriol treatment despite hyperphosphatemia. Conversely, 4. <9 mg/di patients with prediabysis PTH bevels greater than 800 pg/mb. >9 my/di responded to calcitriol treatment only when serum phosphorus level was controlled. In both instances, the increase in the % serum calcium bevel enhanced the response to calcitriob. a. With these concepts in mind, it is instructive to review two Minimal PTH series with different responses to calcitriob treatment (26,44) and to determine whether it is possible to decide on factors that might account for the differences. In the study by Cannella et al., which is representative of a good response to calcitriol, an intravenous calcitriol dose of 2. 1 pg/70 kg thrice weekly was used, and eight of nine patients responded (44). The predialysis PTH level was 966 ± 160 pg/mb, which is higher than in most series. However, the pretreatment serum calcium level was only 9.20 ± 0.05 mg!dl and the serum phosphorus level, initially 5.20 ± 0.19 mg/dl, was well-controlled throughout the study. Serum ionized calcium bevel increased from 4.76 to 5.36 mg/db during treatment. Thus, although the PTH level was actually higher than in most series, the relatively bow serum calcium level may have contributed to the higher PTH (Figure 6). The fact that the serum phosphorus level was well-controbled and the serum calcium level increased markedly during treatment also contributed to the good response. The study by Quarles et al. is representative of a suboptimal response to calcitriob (26): the calcitriol doses were similar, if not greater, than those in the study by Cannella ci al. The predialysis PTH exceeded 900 pg/mi, which is relatively high but similar to the value in the study by Cannebba ci al. (44); the predialysis serum calcium level was 9.2 mg/dl and increased to approximately 10 mg/dl during treatment. The predialysis serum phosphorus level was in the 7 mg/dl range and was maintained in this range during treatment; however, this required a doubling of the binding capacity of oral phosphate binders, and episodes of hyperphosphatemia defined as greater than 7 mg/db were frequent. A mubtivariate analysis showed that increases in serum calcium level were associated with a positive response, and

10 1002 Journal of the American Society of Nephrology hyperphosphatemia with refractoriness to calcitriol treatment. Thus, the failure to adequately control serum phosphorus level was likely to have been a major factor in the poorer response to calcitriol treatment. Because of the limitation of space, detailed specific recommendations for the use of calcitriol are beyond the scope of this review. For a pragmatic and detailed approach to the use of calcitriob for the treatment of 2#{176} HPT, the reader is referred to a recent comprehensive review (38). The author agrees with the recommendation of Coburn ci al. that calcitriob treatment should not be initiated until the predialysis PTH exceeds 400 pg/mb. However, the author is less enthusiastic about exceeding a calcitriob dose of 2 j.tg thrice weekly for severe, refractory 2#{176} ciated-whether calcitriol treatment can induce involution of a HPT. The primary concern is that to prevent the hyperphosphatemia associated with such calcitriol doses, it may be nec- treatment does not control the 2#{176} HPT when markedly hyperplastic parathyroid gland. Thus, if calcitriol hyperphos- essary to restrict dietary protein to an extent detrimental to the patient. Thus in the patient who is refractory to calcitriob treatment, has a marked elevation in PTH (> 1200 pg/mb), and especially if hypercalcemia is present, the focus becomes whether one actually believes that calcitriob treatment is capable of inducing involution of a markedly enlarged parathyroid gland with presumed nodular hyperplasia. This concept is discussed in more detail later, but the author believes it may be better to proceed to parathyroidectomy because even a decrease in PTH bevels may not be accompanied by a significant reduction in parathyroid gland mass. At the present time, several analogs of calcitriob are being evaluated. Such analogs would be beneficial if they have the same genomic effect on PTH mrna as calcitriol and increase the margin of safety and efficacy by having less hyperphosphatemic and hypercalcemic effects; in this manner, it may be possible to have a greater suppressive effect on PTH transcription because a higher dose could be safely used. A different approach is the use of the compound R-568, which mimics the effect of calcium on the calcium receptor and results in decreased PTH secretion; R-568 is currently in the early stages of clinical trials. An interesting hybrid approach to the treatment of refractory 2#{176} HPT is discussed because it serves to remind us of the pathophysiobogy of parathyroid gland hyperplasia (45). It is well-known that at the time of parathyroidectomy for severe 2#{176} HPT, there is marked asymmetry among parathyroid glands with respect to weight and pathology with markedly enlarged parathyroid glands being characterized by nodular hyperplasia (46). In the study by Kitaoka ci al., hemodialysis patients refractory to calcitriol treatment had ethanol injected into the largest parathyroid gland, which had been identified by Doppicr ultrasound (45). Sometimes a second injection was required, either into the same gland or the second largest parathyroid gland; subsequently the hyperparathyroidism was easily controlled with calcitriob treatment. Such an approach requires a skilled technician for ethanol injections and the ability to identify the parathyroid glands. In a healthy dialysis patient, it may be more advantageous to proceed directly to parathyroidectomy by a skilled surgeon. Nevertheless, this study reminds us that parathyroid gland hyperplasia is asymmetrical and illustrates that refractory hyperparathyroidism may be the result of a single, markedly hyperplastic parathyroid gland. When Should a Patient Be Considered for Parathyroidectomy? The indications for parathyroidectomy are controversial, and for an extensive review of this topic the reader is referred to two recent articles (30,47). The author believes the question of whether a parathyroidectomy should be performed is really two-dimensional. It depends on whether calcitriol therapy can successfully control the 2#{176} HPT and-perhaps less well-appre- phatemia is prevented, this is an indication for parathyroidectomy. A PTH response to calcitriob should be seen within the first 4 to 8 weeks of treatment (47). If hyperphosphatemia develops during calcitriob treatment, a diligent effort should be made to control the serum phosphorus level before proceeding to parathyroidectomy, but this should not include significant protein restriction. To date, no clear evidence that calcitriol treatment decreases parathyroid gland mass in patients with severe 2#{176} HPT has been provided. In a recent experimental study (28), a very high-phosphorus diet induced marked parathyroid gland enbargement; this was a result of a combination of cell hyperplasia and hypertrophy. Discontinuation of the high-phosphorus diet resulted in a resolution of the hypertrophy but not the hyperplasia (28). Such a result is consistent with reports of endocrine hyperplasia in other glands (27). It should be noted that in most clinical studies in which patients with severe 2#{176} HPT were shown by imaging techniques to have marked parathyroid gland enlargement, calcitriol treatment did not result in a significant ieduction of parathyroid gland size (26,48); moreover, it should be remembered that in such parathyroid glands, modest reductions in size with calcitriol treatment could be the result of resolution of parathyroid cell hypertrophy and not the hyperplasia. It should also be noted that in a study which sometimes has been quoted to indicate a significant reduction in parathyroid gland size during calcitriob-induced reductions in PTH bevels (44), the scintigraphy test performed indicates parathyroid function rather than physical size of the parathyroid gland. Thus, the prevailing evidence to date would suggest that in markedly enlarged, hyperplastic parathyroid glands, significant involution probably does not occur, despite some reduction in PTH levels. This consideration would appear to favor proceeding to parathyroidectomy in such patients as an early treatment choice. In summary, a personal perspective of factors leading to the development and progression of 2#{176} HPT has been presented. Indications for treatment and potential treatments for 2#{176} HPT in the patient with moderate renal failure and in the dialysis population were discussed. Current evidence would appear to suggest that it may be easier to control the progression of moderate 2#{176} HPT with low-dose calcitriol than to treat severe 2#{176} HPT with high-dose calcitriol; in the latter condition, it may

11 Secondary Hyperparathyroidism l0()3 not be possible to induce involution of the parathyroid gland, and the presence of nodular hyperplasia may preclude an effective response to calcitriob. Acknowledgments The author wishes to thank Drs. Mariano Rodriguez and Barton Levine for their many helpful suggestions and comments during the preparation of this manuscript. References I. Tallon 5, Berdud I, Hernandez A, Concepcion MT, Almaden Y, Torres A, Martin-Mabo A, Felsenfeld AJ, Aljama P, Rodriguez M: The relative effects of PTH and dietary phosphorus on calcitriol production in normal and azotemic rats. Kidney mt 49: , Reichel H, Deibert B, Schmidt-Gayk H, Ritz E: Calcium metabobism in early chronic renal failure: Implications for the pathogenesis of hyperparathyroidism. Nephrol Dial Transplant 6: , Martinez I, Saracho R, Montenegro I, Llach F: A deficit of calcitriol synthesis may not be the initial factor in the pathogenesis of secondary hyperparathyroidism. 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12 l()04 Journal of the American Society of Nephrology 33. Gogusev J, Duchambon P. Hory B, Giovannini M, Goureau Y, Sarfati E, Drueke TB: Depressed expression of calcium receptor in parathyroid gland tissue of patients with hyperparathyroidism. Kidney tnt 51: , Parfitt AM: Parathyroid growth: Normal and abnormal. In: The Paratbivroids: Basic and Clinical Concepts, edited by Bilezikian JP, Marcus R. Levine MA, New York, Raven Press, 1994, pp Felsenfeld Al, Jara A, Pahl M, Bover I, Rodriguez M: Differences in the dynamics of PTH secretion in hemodialysis patients with marked secondary hyperparathyroidism. J Am Soc Nephrol 6: , Brown EM: Four-parameter model of the sigmoidal relationship between parathyroid hormone release and extracellular calcium concentration in normal and abnormal parathyroid tissue. J Chin Endocrinol Metab 56: , Rodriguez M, Caravaca F, Fernandez E, Borrego MJ, Lorenzo V. Cubero I, Martin-Malo A, Betriu A, Rodriguez AP. Febsenfeld Al: Evidence for both abnormal set point of calcium and adaptation to serum calcium in hemodialysis patients with hyperparathyroidism. J Bone Miiier Res 12: , Coburn JW, Frazao J: Calcitriol in the management of renal osteodystrophy. Semiii Dial 9: , Herrmann P. Ritz E, Schmidt-Gayk H, Schafer I, Geyer J, Nonnast-Daniel B, Koch K-M, Weber U, H#{246}rl W, Haas-W#{246}rle A, KUhn K, Bierther B, Schneider P: Comparison of intermittent and continuous oral administration of calcitriol in dialysis patients: A randomized prospective trial. Nephron 67: 48-53, Reichel H, Szabo A, Uhl I, Pesian 5, Schmutz A, Schmidt-Gayk H, Ritz E: Intermittent versus continuous administration of I,25- dihydroxyvitamin D3 in experimental renal hyperparathyroidism. Kidney tnt 44: , Caravaca F, Cubero Ii, Jimenez F, Lopez JM, Aparicio A, Cid MC, Pizarro IL, Liso I, Santos I: Effect of the mode of calcitriol administration of PTH-ionized calcium relationship in uraemic patients with secondary hyperparathyroidism. Nephrol Dial Transplant I 0: , Levine BS, Song M: Pharmacokinetics and efficacy of pulse oral versus intravenous calcitriol in hemodialysis patients. J Am Soc Nephrol 7: , Fischer ER, Harris DCH: Comparison of intermittent oral and intravenous calcitriol in hemodialysis patients with secondary hyperparathyroidism. Chin Nephrob 40: , Cannella G, Bonucci E, Rolla D, Ballanti P. Moriero E, Dc Grandi R, Augeri C, Claudiani F, Di Maio G: Evidence of healing of secondary hyperparathyroidism in chronically hemodialyzed uremic patients treated with long-term intravenous calcitriol.kidnei tnt 46: , Kitaoka M, Fukagawa M, Ogata E, Kurokawa K: Reduction of functioning parathyroid cell mass by ethanol injection in chronic dialysis patients. Kidney tnt 46: , Krause MW, Hedinger CE: Pathologic study of parathyroid glands in tertiary hyperparathyroidism. Hum Pathob 16: , Ritz E: Early parathyroidectomy should be considered as the first choice. Nephrol Dial Transplant 9: , Fukagawa M, Kitaoka M, Yi H, Fukuda N, Matsumoto 1, Ogata E, Kurokawa K: Serial evaluation of parathyroid size by ultrasonography is another useful marker for the long-term prognosis of calcitriol pulse therapy in chronic dialysis patients. Nephron 68: , 1994