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From the Clinical Research Centers |
Division of Endocrinology and Metabolism, University of Pittsburgh School of Medicine (M.A.S., M.J.H., M.B.T., A.G.-O., A.F.S.), and the Graduate School of Public Health, University of Pittsburgh (S.R.W.), Pittsburgh, Pennsylvania 15213
Address all correspondence and requests for reprints to: Andrew F. Stewart, M.D., Department of Endocrinology, University of Pittsburgh School of Medicine, BST E-1140, 3550 Terrace Street, Pittsburgh, Pennsylvania 15213. E-mail: stewart{at}msx.dept-med.pitt.edu
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Abstract |
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Normal subjects were infused with saline (placebo), PTHrP, or calcium. Subjects receiving PTHrP, as expected, displayed mild hypercalcemia (10.2 mg/dL), suppression of endogenous PTH-(1–84), and phosphaturia. Subjects receiving the hypercalcemic calcium clamp displayed indistinguishable degrees of hypercalcemia and PTH suppression. Despite their matched degrees of hypercalcemia and PTH suppression, the two groups differed importantly with regard to fractional calcium excretion (FECa). The hypercalcemic calcium clamp group was markedly hypercalciuric (FECa averaged 6.5%), whereas FECa in the PTHrP-infused subjects was approximately 50% lower (between 2.5–3.7%), and no different from that in the normal controls, which ranged from 1.5–3.0%.
These studies demonstrate that PTHrP is able to stimulate renal calcium reabsorption in healthy volunteers. These studies suggest that PTHrP-induced renal calcium reabsorption, in concert with the well established acceleration of osteoclastic bone resorption, contributes in a significant way to the hypercalcemia observed in patients with HHM.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Despite the clarification of these pathogenic mechanisms, there are four mechanistic differences between the two syndromes. First, in patients with HHM, circulating PTH is reduced, and circulating PTHrP is elevated, whereas in HPT, the reverse is true (3, 4, 5, 6, 7, 8). The reasons for this are clear. Second, in patients with HHM, circulating concentrations of 1,25-hydroxyvitamin D [1,25-(OH)2D], the active form of vitamin D, are reduced, whereas they are elevated in patients with HPT (3, 4, 5, 6, 7, 8). The reasons for this are unclear, particularly as we and others have reported that a brief (6- to 12-h) infusion of PTHrP into normal subjects leads to increases in circulating 1,25-(OH)2D (10, 11, 12). Third, although osteoclastic bone resorption is increased in both HPT and HHM, osteoblastic bone formation is increased in the former, but reduced in the latter (5, 7, 13, 14, 15, 16). That is, bone formation and resorption are coupled in HPT, but uncoupled in HHM. The cellular biological basis for this observation remains elusive. Finally, although it is clear that PTH stimulates renal calcium reabsorption in the distal nephron (17, 18) and that this is important pathogenetically in inducing hypercalcemia in HPT, controversy surrounds the role of role of PTHrP in stimulating renal calcium reabsorption in humans with HHM. Some groups have reported that PTHrP-induced renal calcium reabsorption is unimportant pathophysiologically in HHM (3, 4, 19), whereas others have suggested that the reverse is true (7, 20, 21, 22, 23). In part, this discord relates to the precarious clinical status of study subjects with HHM and in part to methodological considerations.
The current study was undertaken to clearly delineate the role of PTHrP in regulating renal calcium reabsorption in normal healthy human volunteers. This required the development of continuous, steady state PTHrP infusions as well as a hypercalcemic calcium clamp technique in which serum calcium, and therefore filtered loads of calcium, were matched in subjects receiving iv PTHrP or iv calcium so that renal tubular handling of calcium could be studied independently of serum calcium, glomerular filtration rate (GFR), or filtered load of calcium. The results indicate that PTHrP is indeed a potent stimulator of renal calcium reabsorption in the normal human kidney, and that renal calcium reabsorption probably contributes in a significant way to the hypercalcemia in patients with HHM.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Study subjects included 25 healthy male and female volunteers between the ages of 24 and 35 yr. Five subjects participated in more than 1 of the 3 arms of the study, but in each such case, there was a 3-month washout period between studies. Twenty subjects were randomized in a double blinded fashion to receive either placebo (saline) infusion (n = 10, 5 men and 5 women) or PTHrP infusion (n = 10, 5 men and 5 women). Five subjects (4 men and 1 women) were then added to form the hypercalcemic calcium clamp group, once the mean serum calcium values in the PTHrP group had been determined. Each of the subjects was completely healthy, had no underlying illness, and was taking no medications, neither prescribed nor over the counter. Renal function was normal in each subject before participation in the study (mean ± SD serum creatinine, 0.86 ± 0.17 mg/dL), as was serum calcium (mean ± SD, 9.06 ± 0.37 mg/dL). All subjects provided written informed consent, and these studies were approved in advance by the University of Pittsburgh institutional review board for human studies. The studies were performed at the General Clinical Research Center, University of Pittsburgh School of Medicine (Pittsburgh, PA).
PTHrP-(1–36) and placebo
Human PTHrP-(1–36) was prepared and packaged as described previously in detail (9, 10, 11). Briefly, the peptide was synthesized and aliquoted into sterile vials and tested for peptide composition, content, purity, sterility, and pyrogenicity. Each vial contained 60 µg PTHrP-(1–36), as determined using amino acid analysis. The peptide was prepared and used in accord with FDA IND 49175. PTHrP-(1–36) was stored at -80 C in lyophilized vials until the day of the study, at which time they were reconstituted with 1 mL bacteriostatic saline and added to 100 mL normal saline containing 0.7 mL of the study subject’s blood to prevent adherence of PTHrP to the iv bag or iv tubing (10). Two 50-mL aliquots of this 60 µg/100 mL stock were placed into two 60-mL syringes and either infused immediately over 8 h or stored at 4 C for no longer than 8 h. This procedure was repeated every 16 h during the study for each subject, to ensure that fresh peptide was administered throughout the study. PTHrP or placebo was infused using an AS50 Autosyringe Programmable Infusion Pump (Baxter, Andover, MA), with fresh infusate being added every 8 h during the infusion, as we have previously demonstrated that PTHrP-(1–36) is stable under these conditions (10). The infusion rate was 8 pmol/kg·h in a volume of 3–5 mL/h vehicle, a rate derived from a prior study (10) that demonstrated that this dose induced mild, but statistically significant, hypercalcemia in normal volunteers.
Study design
Twenty subjects were initially assigned, in a single-blinded fashion, to receive either PTHrP or placebo. Once the serum calcium achieved by the PTHrP-(1–36) infusion on day 2 of the study was determined from these studies, a third group was enrolled to receive a hypercalcemic calcium clamp. Each subject was placed on a 400 mg calcium, 800 mg phosphorus, 2 g sodium, 20% protein, 50% carbohydrate, 30% fat, and 40 Cal/kg diet throughout the study. Smoking and caffeine were not allowed. Meals were provided at the times indicated in the figures. Each subject fasted from midnight of the night before admission to the study, and the fasting was continued until 1600 h on day 1 of the study. Each study lasted 48 h, and the subject was hospitalized for 48 h at the General Clinical Research Center for the duration of the study. The PTHrP-(1–36) infusion was begun on day 1 at 0800 h and continued for 46 h as shown in the figures. Subjects assigned to the placebo group followed the same regimen, except that they received saline only, at a rate of 3–5 mL/h, identical to that of the PTHrP group.
Blood and urine samples were collected as described in the figures for the determination of serum total and ionized calcium, phosphorus, creatinine, and PTH-(1–84) and urinary calcium, phosphorus, and creatinine. Blood pressure, pulse, and temperature were monitored every 8 h, and questioning regarding adverse effects was conducted several times each day.
Hypercalcemic calcium clamp
The five subjects in the hypercalcemic calcium clamp group were
treated identically to those in the placebo group for the first day,
except that they remained fasting from 2200 h on day 1 through
1600 h on day 2. Also, there was no attempt to blind the study
subjects or the investigators in this group, because the goal was to
match their serum calcium to those in the PTHrP group. Beginning at
0800 h on the second day, these subjects received an 8-h calcium
infusion, with serum ionized calcium values being determined and the
rate of the infusion being adjusted at 15-min intervals, so that the
serum ionized calcium approximated the value of 5.3 mg/dL achieved in
the PTHrP-infused group, as shown in Fig. 1
. Calcium was administered as calcium
chloride, and the infusion rate was titrated to individual subjects
such that subjects received approximately 4–6 mg/kg·h for the first
5–10 min, 3–4 mg/kg·h for the next 5–10 min, 2 mg/kg·h for the
next 15–30 min, 1 mg/kg·h for the next 60–120 min, and then 0.5
mg/kg·h for the remainder of the 8-h infusion. The total amount of
calcium infused during the 8-h infusion was (mean ±
SE) 410.6 ± 29.6 mg/subject, or 0.73 ± 0.016
mg/kg·h. The rates of saline infused during the placebo, PTHrP, and
calcium infusions were 4.2, 4.1, and 3.98 mL/h, respectively. Each
subject tolerated the procedure very well, and none had any adverse
effect. Blood and urine were collected as described for the first two
groups in the preceding paragraph and in the figures.
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Blood and urinary calcium, phosphorus, and creatinine were measured using standard autoanalyzer methods at the University of Pittsburgh Medical Center clinical chemistry laboratory. PTH was measured using the Allegro Intact PTH-(1–84) two-site immunochemiluminometric assay (Nichols Institute, Inc., San Juan Capistrano, CA). Ionized calcium was measured using an ion-specific electrode (model ABL 625, Radiometer, Copenhagen, Denmark). Fractional calcium excretion (FECa) was calculated as (UCa/UCr) x (SCr/SCa), where SCa is the serum ionized calcium in milligrams per dL.
Statistical analysis
For each of the parameters shown in the figures, a repeated measures ANOVA was conducted to determine whether there was an effect of treatment and time. An interaction between treatment and time (differential response to treatment over time) was included in each model. If differences were detected, pairwise comparisons were made. The pairwise comparisons also used a repeated ANOVA with Bonferroni’s correction.
This process was repeated for FECa, focusing on the two time points during the calcium clamp. The other parameters had only one measurement during the calcium clamp. A one-way ANOVA was used to determine whether the groups were different at this time point. If differences were detected, post-hoc pairwise comparisons were made using Duncan’s multiple range test. P < 0.05 was considered significant.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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. As shown in the figure, serum
total and ionized calcium remained normal in the 10 subjects in the
placebo (saline) group for the 48 h of the study. In contrast, the
10 subjects infused with PTHrP-(1–36) at 8 pmol/kg·h developed mild
sustained hypercalcemia, which appeared to reach a steady state at
24 h, remaining constant at 10.2 mg/dL (total) or 5.2 mg/dL
(ionized) for the second 24 h of the study. The five subjects
in the calcium clamp group demonstrated normal serum calcium
values for the first day of the study, but rapidly (within minutes)
achieved sustained serum calcium values that were
indistinguishable from those in the PTHrP group for the duration of the
calcium clamp. They promptly returned to normal at the conclusion of
the calcium infusion. These studies demonstrate that it is technically
possible to clamp serum calcium in normal volunteers for 8 h at a
preselected hypercalcemic level, and that this can be done safely and
reliably.
Figure 2 shows the effects of the three
study conditions on circulating PTH concentrations. As shown in the
figure, endogenous PTH-(1–84) concentrations remained stable and
normal in the placebo group for the duration of the study. In contrast,
as expected, induction of hypercalcemia, whether by calcium infusion or
by PTHrP infusion, promptly suppressed endogenous PTH. The suppression
of PTH by the latter two measures was chronologically rapid and
quantitatively large.
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also reveals the effects of the three interventions on FECa.
The placebo-treated controls revealed a steady FECa, ranging from
1.5–3.0%, averaging approximately 2%, with peaks occurring after
meals. The PTHrP-infused subjects demonstrated a progressive increase
in FECa during the first day of the study, coincident with their
progressive increase in serum calcium (Fig. 1), and on the second day
this ranged from 2.5–3.7%. The differences between the PTHrP group
and the control group did not reach statistical significance. In contrast to the normal to mildly elevated FECa in the PTHrP group, the subjects in the calcium clamp group, despite having identically matched serum total and ionized serum calcium concentrations to their counterparts in the PTHrP group and therefore identical filtered loads of serum calcium, displayed dramatically higher fractional excretion of calcium than both the PTHrP group and the placebo group. The calcium clamp group FECa was approximately 6.5%, some 3-fold higher than that in the placebo controls, and 2-fold higher than that in the PTHrP-infused subjects with identical serum calcium values. These differences were highly significant in statistical terms. Importantly, serum creatinine was normal and comparable at the outset of the study in each group (mean ± SD, 0.82 ± 0.17, 0.84 ± 0.16, and 0.94 ± 0.18 in the placebo, PTHrP, and calcium clamp groups, respectively) and remained normal throughout the study in each group (mean ± SD at the conclusion of the study, 0.87 ± 0.06, 0.91 ± 0.06, and 0.92 ± 0.04 mg/dL in the placebo, PTHrP, and calcium clamp groups, respectively).
The serum phosphorus and tubular maximum for phosphorus (TmP)/GFR in
the three groups are shown in Fig. 3. As
can be seen in the figure and as anticipated, TmP/GFR and serum
phosphorus remained normal in the placebo-infused subjects, except for
minor variations coincident with meals. Subjects infused with PTHrP
displayed slightly lower serum phosphorus concentrations and very
significantly lower TmP/GFR values. Subjects in the hypercalcemic clamp
group demonstrated a rise in both their phosphorus concentrations and
their TmP/GFR values during the period of hypercalcemia and suppression
of PTH.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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In contrast, Ralston and colleagues (7, 20, 21, 22, 23) reported that renal tubular calcium reabsorption contributes significantly to the hypercalcemia observed in subjects with HHM. These studies have employed as a measure of renal tubular calcium reabsorption the tubular calcium reabsorption index (TRCaI), an index intended to correct renal calcium reabsorption for changes in GFR and for serum calcium. This index is hampered by its dependence on normative data on calcium clearance derived from the 1960s in a different laboratory (24) in subjects with hypo- or hyperparathyroidism, but who were otherwise healthy, had normal renal function, and were in steady state. Such studies have consistently demonstrated an increase or normal values for TRCaI in subjects with HHM (7, 20, 21, 22, 23). However, normal TRCaI values are also observed in subjects who would be predicted to have reductions in TRCaI. These include patients with hypercalcemia due to vitamin D intoxication, immobilization, sarcoidosis, and skeletal metastases, in all of whom PTH and PTHrP are suppressed or undetectable (7, 20, 23). Indeed, in the most recent series of subjects with MAHC reported by the Rizzoli group (7), although TRCaI was increased in subjects with MAHC, there were no differences in TRCaI values in subgroups of subjects with elevated PTHrP compared with that in subjects in whom it was reduced or absent. These findings could be interpreted to indicate that PTHrP does not affect TRCaI.
The essence of this problem is that one cannot reliably measure FECa or TRCaI in subjects in whom the GFR cannot be reliably measured, in whom volume status cannot be accurately assessed, and who are not in steady state. Unfortunately, patients with MAHC are typically dehydrated and in the process of becoming more volume contracted, have been treated with diuretics to promote calciuresis, and/or have been treated with saline for rehydration and calciuresis. Saline infusion, diuretics, or continuing dehydration influence renal tubular calcium handling and glomerular filtration of calcium in important ways, so that these confounders render meaningful interpretation of FECa or TRCaI difficult or impossible. Moreover, patients with advanced cancer, which typifies MAHC, have reduced muscle mass and therefore reduced creatine production and circulating creatinine concentrations, which may potentially interfere with clearance measures and with TRCaI and FECa calculations. Finally, the critical nature of the illness and urgent requirements for treatment in subjects with MAHC are such that multiple steady state urine samples cannot ethically be obtained, and TRCaI and FECa measures are therefore obtained from a single, nonsteady state urine collection obtained under the suboptimal conditions described above. Thus, perhaps it is not surprising that data obtained from human MAHC studies have been conflicting and inadequate.
Two studies have examined renal calcium handling in normal human volunteers during the infusion of PTHrP-(1–34) or PTHrP-(1–36) (10, 12), but these have been of insufficiently long duration to achieve steady state and were not accompanied by a control hypercalcemic group against whom the filtered load of calcium could be matched.
Animal studies have uniformly demonstrated that PTHrP peptides stimulate renal tubular calcium reabsorption in vivo and in vitro. This is true whether the PTHrP is infused by minipump, secreted by human tumors (passaged in immunodeficient mice or rats), from rat tumors passaged in rats, or added to the perfusate of isolated perfused rodent kidney preparations (25, 26, 27, 28, 29). Perhaps the most elegant of these is a study reported by the Rizzoli group in which they demonstrated that hypocalciuria occurred in rats bearing the Walker 256 mammary carcinosarcoma (a model of PTHrP-mediated hypercalcemia) before these rats developed hypercalcemia (25). Thus, all researchers would agree that in rodent kidneys, PTHrP is anticalciuric. The question arises as to whether the rodent kidney responds to PTHrP in the same fashion as does the human kidney. This is particularly vexing, because in at least one critical way, highly relevant to HHM, rodent kidneys do not mimic the human situation: rodents with HHM display elevated 1,25-(OH)2D concentrations in the setting of HHM (30, 31, 32, 33, 34). Thus, any definitive answer to the question regarding renal tubular calcium handling in humans will need to be based on studies performed in humans.
To circumvent these issues, we developed two novel investigative tools for studying PTHrP-regulated renal calcium handling in normal human volunteers: 1) continuous, multiday, steady state PTHrP infusions; and 2) 8-h hypercalcemic calcium clamp techniques. Although similar clamp techniques have been used for decades by researchers in diabetes, they have not been applied to research in bone and mineral metabolism. Prior PTHrP infusion studies have been limited to 6–12 h (10, 11, 12), and prior attempts to infuse calcium iv have been brief (minutes to 2 h) (35, 36, 37), too short a time to collect multiple steady state urine samples for fractional calcium excretion measurements. The studies reported herein clearly achieve steady state for sustained periods of time (6–8 h for the hypercalcemic calcium clamp studies and considerably >24 h for the PTHrP infusion studies). Moreover, the combination of PTHrP and calcium infusions in a single study permits the clear comparison of fractional calcium excretion in a single group of subjects in whom renal function has been clearly defined. Significantly, such techniques have not yet been applied to the study of PTH renal actions in humans.
The studies reported herein make it unequivocally clear that PTHrP-(1–36) does indeed stimulate renal calcium reabsorption in the normal human kidney. Normal human volunteers infused with either PTHrP or calcium, such that their serum total and ionized calcium values were identical and displayed markedly different fractional calcium excretion (subjects infused with PTHrP displayed fractional calcium values that were some 50% of those observed in the hypercalcemic calcium clamp group). These differences were not due to differences in GFR, serum calcium, filtered load of calcium, hydration status, or saline infusion rates or to interfering medications, lack of steady state, or differences in circulating PTH concentrations and therefore can only be ascribed to differences in renal tubular handling of calcium. We presume, but have not proven, that the site of regulation by PTHrP of renal calcium reabsorption is the distal tubule, as is the case for PTH (17, 18). These studies make it clear that in addition to accelerated osteoclastic bone resorption, enhanced renal calcium reabsorption induced by PTHrP is likely to be important pathogenetically in the hypercalcemia of HHM.
The remainder of the observations reported herein [induction of hypercalcemia by PTHrP infusion, reductions in endogenous PTH-(1–84) with calcium or PTH infusion, reductions in serum phosphorus and TmP/GFR by PTHrP infusion] are not novel; they merely serve in the current study to document that the expected effects of PTHrP or endogenous PTH were present. Increases in nephrogenous cAMP excretion and 1,25-(OH)2D concentrations also have been reported previously in response to PTHrP-(1–36) infusion and injection (10, 11, 12).
Importantly, as reported by ourselves and others previously (10, 11, 12), no adverse effects of PTHrP administration were observed over the 48 h of the study.
This study has important limitations that should not be overlooked. First, although PTHrP-(1–36) has been shown to be one authentic secretory form of PTHrP (9, 10, 38), it is not likely to be the sole circulating form of PTHrP in subjects with HHM. A larger amino-terminal form(s), a midregion form(s), and a carboxyl-terminal form(s) also circulate in subjects with HHM (8, 39), and it is therefore possible that these additional circulating forms may have effects on renal calcium handling that are distinct from those of PTHrP-(1–36). These alternate circulating forms have not been fully characterized in structural and functional terms, however, and therefore cannot reasonably be employed for studies in humans. We are aware of no information that might suggest that these other PTHrP peptides might lead to different effects on renal calcium handling than those reported herein. Second, although these studies suggest that renal calcium reabsorption does contribute to the hypercalcemia in HHM, it is difficult to assign a quantitative contribution for the role of renal calcium reabsorption compared with that of osteoclastic bone resorption in the pathophysiology of HHM. Our bias would be that the fundamental or primary etiology of hypercalcemia in patients with HHM is bone resorption. This bias is based on the marked advances in the treatment of HHM with the availability of potent antiresorptive agents such as the bisphosphonates. However, as suggested by Ralston and co-workers, it is likely that the renal component may be the predominant etiological mechanism in selected patients with lower than average rates of bone resorption and adequate hydration/GFR (7, 20, 21, 22, 23). Finally, this study suffers from a lack of direct comparison of the potency of the anticalciuric effects of PTHrP-(1–36) to those of PTH-(1–34) or PTH-(1–84). With the development of the methods described herein, this question can now be addressed in subsequent studies.
In summary, these studies demonstrate that PTHrP-(1–36) is a potent stimulator of renal tubular calcium reabsorption and suggest that the hypercalcemia observed in patients with HHM results not only from the skeletal resorptive effects of PTHrP, but also from the anticalciuric effects of PTHrP. This reduces the unanswered questions surrounding the pathogenesis of HHM from three to two: why are bone formation and resorption uncoupled in HHM and coupled in HPT? and why is circulating 1,25-(OH)2D reduced in HHM but elevated in HPT? The techniques described herein may be useful in addressing these questions as well and in studying the relative potencies of PTH and PTHrP in stimulating renal calcium reabsorption.
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Acknowledgments |
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Footnotes |
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Received September 14, 2000.
Revised November 16, 2000.
Accepted December 14, 2000.
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References |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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-hydroxylase activity in rodents. Am J
Physiol. 258:E297–E303.
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| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
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, Subjects receiving PTHrP;
, those receiving calcium; 
and - - -, those receiving placebo.
, Meals. *, Statistical difference from placebo by both ANOVA of
repeated measures and one-way ANOVA at the 29 h point during the
calcium clamp. To convert total calcium and ionized calcium from
milligrams per dL to millimoles per L, divide by 4. The calcium clamp
group did not receive the meals at 24 and 28 h, but remained
fasting instead.
