The renal response to exogenous parathyroid hormone in treated pseudohypoparathyroidism

Bone, 14, 727-735, (1993) Printed in the USA. All rights reserved.

87X+3282/93 $6.00 + .OO Copyright 0 1993 Pergamon Press Ltd.

The Renal Response to Exogenous Parathyroid Hormone in Treated Pseudohypoparathyroidism M. D. STONE,’ H. G. WORTH4

I). J. HOSKING,*

C. GARCIA-HIMMELSTINE,3

D. A. WHITE,3 D. ROSENBLUM3

and

’ Metabolic Unit, University Hospital, Nottingham, NG7 2VH, UK ’ City Hospital, Nottingham, NG5 IPB, UK 3 Department of Biochemistry, Medical School, Nottingham, UK 4 King’s Mill Hospital, Mansfield, Nottinghamshire, UK Address for corresoondence and reorints: Cardiff, CF2 lS2, UK.

M. D. Stone. Detxutment of Geriatric Medicine, Cardiff Royal Infirmary (West Wing), Newport Road, .

Abstract Resistance to the renal actions of parathyroid hormone (PTH) in pseudohypoparathyroidism (PSI-I) may be improved after treatment with vitamin D or its metabolites, but reports conflict. WC have examined the renal response to infusion of 35 pg of 1-38 PTH in patients with PSI-Itype I (n = 8) and PsH type L3(n = 1) during treatment and related this to prevailing endlogenous serum PTH and calcium levels. Nine patients with postsurgicai or idiopathic hypoparathy roidism (HP) served as controls. The urinary CAMP increase (AcAMP) was lower (p < 0.001) in the PsH type I(175 f 6.4 nmoi/i glomerular fdtrate) than in the HP group (3251 f 515 nmoYl giomeruiar filtrate). AcAMP in the PsH type I subjects was dependent on endogenous PTH concentrations (r = -0.76; p = 0.046) and serum calcium (r = 0.74; p = 0.037). Phosphaturic responses (expressed as % decrease in TmPO,/ giomerular fdtration rate) were lower (p = 0.013) in the PsH type I (28.8 f 3.75) compared with those of the HP patients (43 f 3.48). The phosphaturic responses in the PSI-Itype I patients were strongly dependent on endogenous PTH (r = 0.94; p < 0.001) and1serum calcium levels (r = 0.94; p < 0.001) so that the responses of subjects with normal or low PTH levels were no different @ = 0.16) from the HP group. Renal handling of cakium and sodium in response to exogenous PTH was identical in patients with PsH (types I and II) and HP. Renal tubular reabsorption during a calcium infusion was normal in all patients with PsH. These results emph.asise the importance of the modulatory effects due to associated biochemical abnormalities in PsH on the responses to exogenous PTH. They also confirm that renal handling of calciuim and sodium is probably normal in treated PsH. Key Words: Pseudohypoparathyroidism-Parathyroid mone-Renal response.

hor-

Introduction Pseudohypoparathyroidism (PsH) is the classical example of a condition due to target organ hormone resistance (Albright et al. 1942). The mechanisms which underlie this resistance are com-

plex and involve both inherited and acquired defects in target cell response (Hosking & Kerr 1988; Breslau 1989). Although there is a primary resistance to parathyroid hormone (PTH), effects consequent upon the associated biochemical abnormalities may also be important. Thus, correction of hypocalcaemia and secondary hyperparathyroidism following treatment with vitamin D or calcium may restore the phosphaturic effect of PTH in PsH (Suh et al. 1970; Stogman & Fisher 1975), although reports conflict (Breslau et al. 1980; Yamamoto et al. 1988). Hitherto, there has been surprisingly little work examining renal calcium handling in PsH. One study has shown impaired calcium reabsorption in response to bovine PTH infusions (Moses et al. 1976), whilst another using l-34 human PTH demonstrated normal responsiveness (Yamamoto et al. 1988). Both of these studies only examined patients with type 1 PsH. Only one study has specifically examined sodium excretion in PsH, and the results were extremely variable, with both high and low values reported in comparison to controls (Moses et al. 1976). No one has shown a significant rise in glomerular filtration rate (GFR) in PsH after PTH infusion, which has been described in normal subjects (Broadus 1981). In an attempt to resolve some of these uncertainties, we have studied the renal response to human l-38 PTH in type I and type II PsH, comparing this with the response seen in hormonedeficient hypoparathyroidism. Patients and Methods Patients

Nine patients with PsH were compared with nine patients with idiopathic (n = 1) or postsurgical (n = 8) hypoparathyroidism (HP). In each case of PsH the diagnosis was based on a combination of the clinical features, pretreatment biochemistry (including immunoreactive PTH), and, in some cases, on the CAMP response to highly purified bovine PTH (National Institute of Biological Standards and Control, London). A bone biopsy was performed to exclude osteomalacia in the patient with PsH type II (Rao et al. 1985). The clinical and biochemical findings at presentation and at the time of testing are summarised in Table I. The patients were classified on clinical criteria (Breslau 1989): In type I PsH both the CAMP and phosphaturic responses to exogenous PTH are reported to be abnormal; cases are subclas-

M. D. Stone et al.: Renal response to PTH in treated pseudohypoparathyroidism

728

Table I. Clinical details of patients with pseudohypoparathyroidism At testing

At presentation Case 1 2” 3 4b 5 6 7 8 9 Mean SE Normal range

Age/sex

PSH type

Ca (mmol/l)

P (mmolll)

37 M 44F I, 59 M 31F 23 F 33F 21M 14M 81F

la la ,, lb lb lb lb lb lb 11

1.15 1.88 ,, 1.55 1.90 1.27 1.29 1.33 1.45 1.77

2.55 1.14 n 1.70 1.67 2.5 2.22 3.33 2.62 1.20

70 70 ,, 80 84 47 63 55 62 75

1.51 0.51

2.10 0.26

2.2-2.6

0.8-1.4

38.1 7.0

Great (t.rmol/l)

iPTH (XULN)

TmPO&FR Ca (mmoY1) (mmoU1)

Great (*moW

2.36 2.37 2.58 2.28 2.17 2.17 2.32 2.13 2.05 2.21

1.41 1.35 1.15 1.20 1.69 1.04 1.49 2.00 1.06

67.3 0.42

2.21 0.05

1.40 0.10

79.3 6.8

60-120

2.2-2.6

0.8-1.4

60-120

ND ND I, ND 1.48 2.50 2.33 2.17 4.13 ND

105 105 145 86 80 50 63 90 62 73

iPTH (ngll) 10 10 < 10 29 30 73 24 142 103 13

Treatmentday Calcitriol 1.0 pg CalcitriolO.5 *g Calcitriol 1.0 pg Calciferol 1.25 mg Calcitriol 1.0 pg Alfacalcidol 1.0 wg Alfacalcidol 1.0 p,g Alfacalcidol 1.0 bg Alfacalcidol 1.5 t.r.g Calcitriol 0.5 p,g

48 16.7 lo-55

ULN = upper limit of normal range, iPTH = immunoreactive PTH, ND = not done. “Tested on two separate occasions. “Only tested with 200 units of bovine PTH also treated with bendrofluazide 5 mg, atenolol 100 mg daily.

sified on the basis of the presence (type Ia) or absence (type Ib) of Albright’s hereditary osteodystrophy (AHO) or multiple hormone resistance. In type II PsH the CAMP response to exogenous PTH is retained, but the phosphaturia is deficient. There were eight patients with type I and one patient with type II PsH. The patients with HP were selected because they were euthyroid and normocalcaemic when tested and had undetectable levels of intact PTH (< 10 ngll) and normal renal function. Clinical details of the hypoparathyroid patients at the time of testing with PTH are summarised in Table II. There was no significant difference between the ages of the two groups (p = 0.08) or the serum calcium at the time of testing @ = 0.63). Informed consent was obtained from all patients in the study, which was approved by the Ethical Committee of the University Hospital, Nottingham. Methods

All patients except one were tested with the synthetic 1-38 amino terminal fragment of human PTH (hPTH), obtained from Bis-

sendorf Peptides, Hannover, Germany. It was administered by slow intravenous injection over l-2 min in a dose of 35 p,g (equivalent to 400 units of WHO standard for bovine PTH) diluted in 20 ml 0.9% sodium chloride. The remaining patient (in the PsH group) received 200 units of bovine PTH. The CAMP response to l-38 hPTH was remeasured in patient 2 of the PsH group, after an interval of nine months, following a four-week period of mild hypercalcaemia. All patients were studied after an overnight fast, except that usual treatment with thyroxine and vitamin D was administered with water at 0730. All other medications were omitted. Hydration was maintained throughout the test by the oral administration of water (200 ml/h) from 0730 until 1530. Urine was collected by voiding hourly from 0800 until 1600, except for the hour after PTH administration when two 30-min collections were made. Calcium, phosphate, creatinine, sodium, and CAMP were measured on all samples. Blood was taken at the midpoint of all the urine collections for the determination of calcium, phosphate, creatinine, and albumin. Serum calcium values were adjusted for fluctuations in serum albumin (Kanis & Yates 1985). On a separate occasion, all patients underwent a standard

Table II. Clinical details of patients with hypoparathyroidism

Age/sex

Diagnosis

Ca (mmoV1)

10 11 12 13 14 15 16 17 18

42 M 50 M 39 F 56 F 36 F 63 F 69 F 62 F 65 F

TPTX: Ca thyroid TPTX: Ca larynx Idiopathic TX: thyrotoxic TX: thyrotoxic TX: thyrotoxic TX: thyrotoxic TX: thyrotoxic TX: thyrotoxic

2.05 2.27 2.31 2.25 2.21 2.12 2.22 2.14 2.24

0.89 1.16 1.30 1.15 1.11 1.33 0.88 1.29 1.20

Mean SE Normal range

53.7 4.1

2.20 0.03

1.15 0.07

97.4 8.6

2.2-2.6

0.8-1.4

60-120

Case

TmPGdGFR (mnlol/l)

Current daily treatment

Great

(wmY1) 103 156 82 81 74 106 95 93 87

Vitamin D

Thyroxine (pg)

Other

Calcitriol 1.0 pg Calcitriol 0.5 kg Calcitriol 1.0 *g Calcitriol 1.0 pg CalcitriolO.75 kg Calciferol 2.5 mg Calcitriol 1.0 kg Calcitriol 1.0 pg Calcitriol 1.0 kg

150 100 200 50 150 150

BFz (5) At (100) BFZ (5) Ca (26) BFz (5) BFZ (5) At (100) At (SO) -

TPTX = thyroparathyroidectomy,TX = thyroidectomy,BP2 = Bendrofluazide(dose in mg), At = Atenolol (dose in mg), Ca = elemental calcium (dose in mmol).

M. D. Stone et al.: Renal response to PTH in treated pseudohypoparathyroidism

729

calcium infusion ter;t (Peacock & Nordin 1968) during which 80 ml of 10% calcium gluconate (20 mm01 elemental calcium) diluted in 500 ml 5% dextrose was administered intravenously over 4 h. Hourly urine samples (for calcium, creatinine, sodium, and phosphate) and midpoint blood samples (for calcium, phosphate, cteatinine, and albumin) were obtained during and for 4 h after the calcium infusion. Hydration was maintained throughout the test as described above. Calcium, phosphate, creatinine, sodium, and albumin were measured by standard autoanalyser techniques. CAMP in urine was measured by a competitive protein binding assay (Brown et al. 1971). Urinary cAMP was expressed as nmol/l glomerular filtrate (LGF). The setting of renal tubular phosphate (TmPOd GFR) and notional calcium (TmCa/GFR) reabsorption in relation to GFR were calculated from nomograms (Walton & Bijvoet 1975; Nordin 197611.The tubular reabsorption of phosphate (TRP) was calculated as % TRP: urine phosphate serum phosphate

X

A v

l

PTH<55

serum creatinine

Intact PTH in serum was measured using a commercial kit (Incstar Corporation, Stillwater, MN): The reference range for this assay is 10-55 rig/l.. All results are expressed as means + SE unless otherwise indicated. For the calcium infusion data, comparison between the PsH and HP groulps was made by fitting a generalised linear model with one covariate (serum calcium). All other data were analysed by the two-tailed Student’s t test and analysis of variance for repeated measures with Newman-Keuls multiple comparisons if the F test was significant at the 0.05 level. Data for calcium excretion rate and clearance of calcium relative to sodium were positively skewed and were logarithmically transformed before data analysis. For statistical analysis of the PsH type I patients, data from the subject tested with bovine PTH was only included where indicated.

PsH

HP

r-0.76

~‘0.046

Results

The urinary CAMP res,ponses to mH are shown in Fig. 1 (top) and summarised in Table III. Peak values of CAMP were achieved within 30 min of the infusion of PTH with only two exceptions (one patient with PsH type I and the patient with PsH type II) where the maximum response was delayed by 30 min. These responses clearly separate the patients with PsH type I from those with HP. The patient with PsH type II had a peak response which fell into the low normal range for the HP group. The greatest responses to exogenous PTH in the PsH type I patients occurred in those who had endogenous PTH levels within or below the normal range, except for the patient who received 200 units of bovine PTH, equivalent to half the dose of l-38 hPTH (Fig. 1, top). The patient whose CAMP response was tested twice showed a larger increase after the second test, when endogenous PTH levels had been suppressed further by treatment to below the lower limit of normal (< 10 ng/l), and serum calcium levels were correspondingly high (Table I). The correlation between the maximum increase in urinary CAMP and endogenous PTH, which just achieves statistical significance, is shown in the bottom panel of Fig. 1. The correlation between the CAMP response and baseline serum calcium was very similar (r = 0.74; p = 0.037). Phosphaturic responses were expressed as percent reduction in TmPO,/GFR from baseline and the fall in % TRP. They are summarised in Fig. 2 (top) and Table III. For the PsH type I group as a whole, there was a significantly smaller phosphaturic response than that seen in the HP patients. However, for those

I

I

I

10

100

1000

serum

PTH

(ng/Ll

Fig. 1. (Top) Cyclic AMP response to 35 pg 1-38 hPTH. The shaded area represents the mean 2 2 SD for the HP group. The data points marked 1 and 2 represent the first and second tests for patient 2 in the PsH group. (Bottom) Relationship between the cyclic AMP response to 35 pg 1-38 hPTH and endogenous serum PTH concentrations in patients with PsH type I. The data through which the regression line is drawn do not include the data point of the patient tested with bovine PTH.

patients with PsH type I whose endogenous PTH levels were normal (including the patient tested with bovine PTH), the phosphaturic response came within the lower part of the normal range for the HP group and was statistically indistinguishable. Table III shows that very similar results were obtained when the phosphaturic response was expressed as the absolute increment in phosphate excretion after PTH infusion (APO,; mmoV2 h). Figure 2 (bottom) shows that the phosphaturic response was strongly dependent upon the prevailing endogenous PTH level in PsH type I. A very similar relationship was seen between serum calcium and the percent decrease in TmpO,/GFR (r = 0.95; p = 0.001) in the same patients. In the single patient with PsH type II, the phosphaturic response was low despite normal PTH levels. A good correlation was also found between APO, and endogenous PTH levels (r = 0.90; p = 0.006).

M. D. Stone et al.: Renal response to PTH in treated pseudohypoparathyroidism

730 Table III.

Summary

of urinary responses

to l-38 hF’TH Psedohypoparathyroid

Response Urinary CAMP (mmol!LGF) TmP/GFR (mmol/l) 8 fall in TmP/GFR (all patients) % fall in TmP/GFR (PTH < 55) 8 TRP (all patients) 8 TRP (PTH < 55) APO., (mmoU2 h, all patients) APO., (mmoY2 h, PTH < 55) Urinary calcium (I*moUmin) TmWGFR (mmoY1) Sodium-independent TmWGFR (mmoY1) Urinary sodium: NaE (mmol/LGF) WC,* GFR (ml/min)

Basal

(type 1)

Max. change

25.1 * 2.2 1.45 -c 0.1 -

+ 175 -0.37 28.8 35.4

93.7 k 1.5 90.5 f 0.73 -

- 15.9 2 5.2 -20.3 2 6.4

2.26 1.78 1.74 0.94 1.60 89.6

+ 2 I? 2 k 2

0.5 0.05 0.03 1.28 0.58 17

1.32 1.73 - 1.53 +0.18 +0.17 + 1.76 +2.20 38.5

Figure 3 shows that there was a close agreement between endogenous PTH and serum calcium levels in patients with PsH prior to administration of l-38 hPTH. The renal handling of calcium and sodium is shown in Figs. 4-6 and summarised in Table III. Neither the patient tested with bovine PTH nor the patient with type II PsH differed significantly from the rest of the PsH group, and they have been combined under the term PsH. However, these two patients have been separately identified in Figs. 4-6. Bendrofluazide did not affect the setting of TmCa/GFR nor did NaE, and responses have not been segregated for this variable. In the basal state, the two hypoparathyroid groups had similar levels of serum calcium (Tables I and II). Those with PsH were characterised by a lower absolute calcium excretion and a higher setting of TmCa/GFR, which was maintained after correction for sodium excretion (Table III). The response of both groups to PTH infusion was similar in that there was an immediate and transient increase in calcium and sodium excretion, with a small decrease in TmCa/GFR (Fig. 4). Subsequently there was a slow rise in TmCa/GFR, whilst sodium excretion quickly returned to baseline. However, 120 min after PTH injection, calcium excretion was slightly below baseline, and consequently there was a significant fall in the clearance of calcium relative to the clearance of sodium (Fig. 5). The changes in sodium-independent TmCa/GFR were very similar to those of TmCa/GFR, except that after correction for sodium excretion the early transient fall in TmCa!GFR was lost. The changes in calcium and sodium excretion were not dependent on endogenous serum PTH levels (r < 0.10; p > 0.80). Calcium excretion rates in the two groups of hypoparathyroid patients were also compared during a standard intravenous calcium infusion (Fig. 6). It can be seen that the relationship between serum and urinary calcium (expressed as CaE) lies substantially within the normal range in PsH, but is shifted to the left @ < 0.001) in HP except for those patients with a low sodium excretion rate (NaE < 1 mmol/LGF) . For a given serum calcium concentration the corresponding CaE value was higher (p = 0.008) for the PsH Ia patients (n = 2) than for the type Ib subjects (n = 6). The ratio of fasting CaE/serum calcium was closely related to the endogenous PTH concentration (Fig. 7). There was a small but significant rise in GFR at 30 min after PTH injection in both the HP @ = 0.023) and PsH @ = 0.011) groups that returned to baseline by 120 min. There was no significant difference in response between the two groups (Table III).

? 2 2 f

6.4 0.04 3.8 2.4

rf: 0.30 2 0.47 ” 0.33 2 0.04 * 0.03 ” 0.37 2 0.47 f 14

Hypoparathyroid Basal

Max. change

25.6 2 3.0 1.15 2 0.07 80.5 5 3.4 I,

+3,521 k 515 -0.47 ” 0.05 4323.5 ,, -26.4 f 4.4 ,I 2.55 2 0.29 ,, - 1.8 f 0.46 +0.14 2 0.04 +0.15 f 0.03 + 1.60 k 0.27 -2.27 + 0.47 23.2 k 5.5

5.48 1.58 1.52 1.51 2.79 91.8

2 2 2 -+ 2 -t

0.81 0.02 0.03 0.12 0.48 8.2

P (PHP vs. HP) Basal 0.91 0.02 0.01 0.02 0.02 < 0.001 < 0.001 0.58 0.09 0.91

Max. change < 0.0001 0.18 0.013 0.16 0.14 0.43 0.01 0.16 0.52 0.60 0.65 0.73 0.89 0.29

Discussion The present study has shown that the urinary CAMP and phosphaturic responses to exogenous l-38 hPTH are dependent upon the prevailing endogenous serum PTH levels in PsH type I. This relationship was particularly striking for the effect on phosphate excretion, which was expressed as percent reduction in TmPGd GFR since this has been shown by others to be the best discriminator between HP and PsH patients (Mallette et al. 1988). The mean fall in TmPO,/GFR (35%) seen in the PsH type I patients with normal serum PTH levels is slightly greater than that previously reported in normal subjects (28%) (Roelen et al. 1989), whilst the mean response seen in the HP group (43%) was very similar to that seen after 200 units of l-34 hPTH (40%) (Mallette et al. 1988). The original data describing TmP/GFR were measured under conditions that were closer to a steady state than the rapidly changing conditions of the present study. Phosphate excretion was therefore also expressed as absolute changes in % TRP, and the results were very similar to those using TmPG,/ GFR. In fact, our results confirm the previous finding (Mallette et al. 1988) that the response of % TRP to infused PTH is a slightly poorer discriminator between HP and PsH patients than changes in TmPO,/GFR. Although we did not study normal controls, it is likely that we have seen a normal phosphaturic response in our PsH type I patients with endogenous serum PTH levels in the normal range. This finding corroborates previous single case reports of restoration of the phosphaturic response to exogenous PTH after treatment with vitamin D (Suh et al. 1970; Stogman & Fisher 1975). Other workers have reported modest improvements in phosphate excretion following treatment but have not related these findings to prevailing endogenous PTH or serum calcium levels (Yamamoto et al. 1989). In addition to the apparent dependency upon endogenous PTH levels, the phosphaturic response to PTH injection was similarly related to baseline serum calcium. This is not surprising in view of the close correlation between serum calcium and PTH seen in the present study. We did not measure 1,25(OH),D levels, but it is possible that this would have had the same influence on the response to exogenous PTH. All PsH patients with a normal serum calcium had a normal PTH value, which contrasts with the previous finding that although these two parameters are correlated in PsH, the setpoint at which calcium inhibits PTH secretion is raised (Allgrove et al. 1984; Kruse & Kracht 1987), perhaps reflecting lower 1,25(OH),D levels for a given serum calcium value or differ-

M. D. Stone et al.: Renal response to PTH in treated pseudohypoparathyroidism

70

731

1

PsH

.

v

PTHx55

l

PTH>55

A l

HP

PsH type

‘I bovine

OPsH

II

PTH

HP

50 A

40 -

“\\\

A

30 -

A

10

A

20 -

A

10 -

I

I

I

A

p-0.00

,“I

serum

1

I

100

10

1000

r--0.95

(vbovinsl

O-

100

serum PTH hg/LJ

PTH

I

rnrl

1000

hg/L)

Fig. 2.

(Top) The percent reduction in TmPO,/GFR and fall in % TRP (inset) in response to 35 (~g l-38 hPTH. The shaded area represents the mean f 2 SD for the HP group. (Bottom) Relationship between the percent reduction in TmPO,/GFR and fall in % TRP (inset) in response to 35 p,g 1-38 hPTH and endogenous serum PTH concentrations in patients with PsH type I. The data through which the regression lines are drawn do not include the data points of the patient tested with bovine PTH.

ences in duration of treatment. The length of time on treatment may be important, since other studies have shown that serum PTH levels will only fall to normal after prolonged treatment courses, despite rapid attainment of normal serum calcium concentrations (Stogman & Fisher 1975; Drezner & Neelon 1983). At the present time, there is evidence both for (Eisenburg 1965; Rodriguez et al. 1974) and against (Suh et al. 1970; Schwille et al. 1977; Lcwin et al. 1978; Goltzman et al. 1989) serum calcium per se mlodulating the phosphaturic response to PTH infusion. It is unlikely that serum calcium has any important influence on the CAMP response to exogenous PTH, since this is normal in HP patknts presenting with severe hypocalcae-

mia (Lewin et al. 1978). The evidence for the potential role of secondary hyperparathyroidism is more compelling (Goltzman et al. 1989; Nagant de Deuxchaisnes et al. 1982; Lewin et al. 1982). Although there is very little information regarding the independent effect of 1,25(OH),D, work on animals has demonstrated a specific enhancement of PTH action on calcium reabsorption (Yamamoto et al. 1984). Several investigators have suggested the existence of a PTH inhibitor in the plasma of patients with PsH (Nagant de Deuxchaisnes et al. 1981; Loveridge et al. 1982; Allgrove et al. 1984). It is possible that suppression of this putative aberrant PTH molecule (Goltzman et al. 1989) is crucial in enhancing

132

M. D. Stone et al.: Renal response to PTH in treated pseudohypoparathyroidism 2.6 -

reaches that of the normal range for 35 pg l-38 hPTH established by others (>700 nmol/LGF) (Roelen et al. 1989), despite suppression of endogenous PTH to a subnormal concentration. Nevertheless, this magnitude of response is severalfold greater than that reported previously (107 nmol/LGF). Although not statistically pure, it is of interest that the projected CAMP response for a serum PTH suppressed to 1.0 rig/l is 1047 nmol/ LGF, which lies in the normal range defined above. The single patient tested with 200 units of bovine PTH showed a normal phosphaturic response but a blunted CAMP response compared to the other PsH type I patients who were tested with l-38 hPTH. This is what one would expect, since the peak phosphaturic response is reached at lower doses of exogenous PTH than the maximum CAMP increase (Kaminsky et al. 1970). The renal handling of calcium in response to l-38 hPTH was the same in both the HP and PsH groups, with the expected rise in sodium-independent TmWGFR together with the fall in C,J C Na, typical of PTH-stimulated distal tubular reabsorption of calcium (Massry et al. 1968; Agus et al. 1973). This confirms the findings of other work using l-34 hPTH (Yamamoto et al. 1988). The response to a standard intravenous calcium infusion (Peacock & Nordin 1968) was also normal in the PsH group, demonstrating that the renal tubular reabsorption of calcium was normal over a wide range of serum calcium values, including baseline. As expected, the relationship between serum and urinary calcium was shifted to the left in the HP group (Peacock et al. 1969), except for the patients with low (< 1 mmol/LGF) rates of sodium excretion (Kerr et al. 1990). These findings contrast with the previous report that the distal reabsorption of calcium was abnormal in PsH (Moses et al. 1976). Their apparently discrepant results might be due to methodological differences. For example, if the C&/C,, values are logarithmically transformed, then three of their five patients responded normally. The other problem was that their sodium excretion responses were very variable, in contrast to the con-

2.4 2.3 2.2 2.1 2.0 I* PtH type II

I

1

I

10

100

1000

serum

PTH hg/Ll

Relationship between serum calcium and endogenous serum PTH concentrations in patients with PsH. The regression line is drawn through all the data Points shown. Fig. 3.

PTH-stimulated phosphate excretion and might explain the very close relationship between immunoreactive endogenous PTH and percent reduction in TmPO,/GFR which continues well into the normal range for PTH. It is interesting to note the failure of restoration of phosphaturic response in the patient with PsH type II, despite normal serum PTH and calcium levels. This implies irreversibility in contradistinction to the type I patients, but clearly more patients with type II PsH need to be studied before any firm conclusions can be made. For the first time we have demonstrated that the CAMP response to exogenous PTH in PsH type I is dependent on endogenous PTH levels. However, unlike the influence on phosphaturia, the maximum CAMP increase seen (427 nmol/LGF) never PTH

PTH

I

2

2.25

2.25

B E

2.00

2.00

E

1.75

1.75

Q 2

1.50

1so

f

1.25

1.25

7.5

7.5

60-

6.0

5

4.5

4.5

d

3.0

3.0

Y z

1.5

1.5

0

0

*

* 0 - PTH > 55 A - bovine PTH

z

ii0

i

0

60

120

160

minutes (~sEuDoHYPoPARATHYROID]

Fig. 4. Change in calcium and sodium excretion after 35 p,g 1-38 to the mean pre-FTH value.

*

0

*

60

120

Ii0

minutes IHYPOPARATHYROID)

WTH. *P < 0.05 for the difference between the mean at each time point with respect

M. D. Stone et al.: Ronal response to lTH in treated pseudohypoparathyroidism PTH

PTH

1

103

**

x

*

1

103

*

**

o - PTH > 65

*

A - bovine

1

1

$

733

l~$szgs

PTH

1:

0.1 -

0.1 -

0

60

120

160

I

I

I

f

0

60

120

160

minutes

minutes lPSEUDOHYPOPARATHYROlD/

Fig. 5. Changes in calcium excretion rate expressed as clearance (Cc&J

sistent effects on NaE in the present study. It is also possible that

nous PTH levels are important in the steady state. It is important to note that the relatively higher CaE values for a given serum calcium in the PsH type Ia patients compared to the type Ib subjects is a finding exactly the opposite of previous reports (Mizunashi et al. 1990), and suggests that there is no a priori difference in calcium handling between these two types of PsH. The similar rise in GPR in the PsH and HP patients implies that the response of the glomexular receptors or renal haemodynamics is relatively normal in our PsH group (Agus et al. 1981). Although our results are consistent with the proposal that the main site of PTH resistance in PsH is in the proximal nephron

bovine PTH may not be as effective as hPTH, although this seems unlikely in view of the normal response seen in our patient tested with bovine PTH. The renal handling of calcium and sodium in response to exogenous PTH was independent of prevailing endogenous semm PTH levels, and this implies heterogeneity of PTH receptors at different sites along the nephron with respect to structure, sensitivity, or mechanism of action (Hruska et al. 1987; Hosking & Kerr 1988). In contrast, the close correlation between fasting GE/serum calcium and endogenous PTH suggests that endoge-

1.6

2.0

corrected

2.4

serum

2.6

calcium

(mmol/L)

PSEUDOHYPOPARATHYROID

and in absolute terms (pmol/min) after 35 p,g 1-38 hPTH.

3.2

1.6

2.0

corrected

2.4

serum (mmol/Ll

2.6

3.2

calcium

HYPOPARATHYROID

Fig. 6. Relationship between calcium excretion and serum calcium during an intravenous calcium infusion for the PsH and HP groups of patients.

M. D. Stone et al.: Renal response to PTH in treated pseudohypoparathyroidism

I=

_ A

A

r-0.90 A

pxo.0

A

1

\

A

, lb

, 100

,

, 1000

serum PTH (ng/L) Fig. 7. Relationship of fasting calcium excretion divided by fasting serum calcium with endogenous PTH concentrations in the PsH type I patients. The regression line is drawn through all the data points. et al. 1988), they have nevertheless indicated that some proximal tubular functions such as sodium and phosphorus excretion may be normal during treatment with vitamin D or its metabolites. It is tempting to suggest that the crucial abnormality in PsH may be defective stimulation of 1,25(OH), production by the PTH-adenylate cyclase system (Drezner et al. 1975). In summary, we have shown that the CAMP and phosphaturic responses to exogenous PTH infusion in treated PsH type I are dependent upon the prevailing concentration of endogenous serum PTH and calcium; the interactive role of 1,25(OH), remains unclear. Complete restoration of the phosphaturic response and marked enhancement of the CAMP response towards normal as serum PTH is progressively suppressed emphasises the important modulatory role of the biochemical abnormalities in PsH type I. We have also demonstrated, by analysis of several different parameters, that renal calcium and sodium handling appears normal in both type I and type II PsH patients. (Yamamoto

We wish to thank all the staff of the Metabolic Unit without whose help this study would not have been possible. We should also like to thank Dr. Colin Selby for the serum PTH measurements and Bissendorf Peptides for provision of l-38 hPTH.

Acknowledgments:

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Date Received: August 20, 1992 Date Revised: November 26, 1992 Dale Accepted: March 23, 1993