Eur Respir J 1990, 3, 447-449

The tubular maximum for calcium reabsorption in patients with chronic active thoracic sarcoidosis

P.D. Broulik*, V. Votava**, V. Pacovsky*

The tubular maximum for c.alcium reabsorption in patients with chronic active thoracic sarcoidosis. P.D. Broulik, V. Votava, V. Pacovsky.

* Third Dept of Internal Medicine and ** First Dept of Tuberculosis and Respiratocy Diseases, Charles University, Faculty of Medicine, Prague, Czechoslovakia.

ABSTRACT: The tubular maximum for calcium reabsorption (TmCa) was evaluated in 52 patients with chronic active thoracic sarcoidosis. Hypercal­caemia was found In five patients (9.6%). The mean serum calcium value of 2.54±0.18 mmoH"1 in patients with sarcoidosis was significantly higher than that obtained In the control group (2.42±0.11 mmol·l"1

). The mean TmCa In patients with sarcoidosis (2.11±0.26 mmol·t1 glomerular filtrate (GF)) was not statistically different from the mean TmCa for the group of healthy subjects (2.18±0.23 mmoH"1 GF). Urinary sodium corrected TmCa In both groups or patients was affected In a similar way. Our study demonstrates for the first time that there Is no Increase In TmCa in patients with chronic active thoracic sarcoidosis. Hypercalcaemia is not a result of an Increased TmCa.

Correspondence: P.D. Broulik, 3rd Internal Clinic, Prague 2, Czechoslovakia.

Keywords: Calcium metabolism; sarcoidosis; tubular maximum for calcium reabsorption.

Received: April 1989; accepted after revision November 2, 1989.

Eur Respir J., 1990, 3, 447-449.

Hypercalcaemia, with or without hypercalciuria, is a well-known complication of sarcoidosis. The reported incidence of hypercalcaemia associated with sarcoidosis varies from 2-63% [1]. Hypercalcaemia tends to be tran­sient in subacute sarcoidosis, but in chronic sarcoidosis, depending on the activity of the disease, the serum level of calcium may fluctuate [2). Hypercalciuria is consid­erably more common [3]. Absorptive hypercalciuria is related to the development of sarcoidosis and can be explained by high free 1 ,25-dihydroxy vitamin D 3 (1, 25(0H)p3). Resorptive hypercalciuria seems to be linked with disease extension [4, 5].

The plasma calcium concentration is determined by the relationship between three factors: 1) the rate of flow of calcium into the extracellular space from gut or bone; 2) the rate of filtration of calcium through the glomeruli; and 3) the rate of tubular reabsorption of calcium. In spite of the growing knowledge about sarcoidosis the mechanism of hypercalcaemia has rarely been investigated.

We have used a method which has been developed for measuring the tubular maximum for calcium in man [6]. The tubular maximum relative to the glomerular filtra­tion rate (GFR) can be calculated in any subject [7] based on the known relationship between the plasma and urine calcium before and during calcium infusions in normal subjects.

The purpose of the present study was to examine the tubular maximum for calcium in an unselected group of patients with chronic active thoracic sarcoidosis.

Patients and methods

The subjects were 52 patients with chronic thoracic sarcoidosis (25 men and 27 women, aged 20-71 yrs) who had been followed-up for varying periods (mean 4.2 yrs). The diagnosis of sarcoidosis was based on clinical, radiographic and laboratory features consistent with the disease and was supported by a tissue biopsy showing noncaseating epitheliod-cell granulomas. Diagnosis of thoracic active sarcoidosis was related to presence of prolonged respiratory symptoms and to duration of find­ings on chest X-ray pulmonary examination (more than two years) with a slow progression. The biological marker of activity that was considered was the lymphocyte percentage, i.e. the percentage of lymphocytes in bronchoalveolar lavage fluid. No subjects in either the observation or the control group used any medical treat­ment to affect calcium and phosphorous metabolism. No patient was taking corticosteroids at the time of the investigations.

To minimize dietary influences the patients were fasted overnight and urine samples (collected over 2 h) and blood samples were obtained. Each sample was analysed for calcium, phosphate, sodium and creatinine content. The calcium/creatinine ratio was calculated according to NoRDIN [8]. Fasting calcium excretion (C~) was calcu­lated from the formula: C~ = Uc. X (P er·Uc,). The tubular maximum for calcium reabsorption was calculated according to NEED et al. [6], from the formula: TmCa = ((0.56 P c.)-C~)-(1-0.08 logc(0.56 P c;C~)) mmol·Z·1

448 P.D. BROULIK, V. VOTAVA, V. PACOVSKY

glomerular filtrate (GF). The term (0.56 Pc.) is an ap­proximation to the plasma ultrafiltrable concentration. The tubular maximum for calcium reabsorption was also calculated after correction for urinary sodium [6]. The renal phosphate threshold concentration (TmPO/GFR) was calculated using the nomogram of W ALTON and BINOET [9]. Inorganic phosphate in the serum and urine was determined photometrically [10]. Serum and urine creatinine were measured by the method of HARE [11]. Serum and urine calcium were determined by a complexometric method [12]. A control group matched for age and sex was selected from the original health screening register. Group data are expressed as mean±sn and a comparison made using Students t-test for unpaired data [13].

Table 1. - Mean values±so of measured variables in fasting blood and urine collected from 52 patients with sarcoidosis and 40 healthy subjects

Sarcoidosis Controls n=52 n=40

Age yrs 45.6±13 44.5±8 Serum calcium mmoH1 2.54±0.18• 2.42±0.11 Serum creatinine mmoH1 0.08±0.013 0.08±0.011 Urine Ca/Cr mmol·mmol·1 0.31±0.28 0.28±0.11 C~ mmoH1 GFR 0.027±0.019 0.025±0.011 N~ mmoH1 GFR 1.08±0.84 0.89±0.45 TmCa mmoH1 GFR 2.11±0.26 2.18±0.23 TmCa/Na corr. mmoH1 GFR 2.40±0.25 2.44±0.20 TmP04

mmoH1 GFR 1.16±0.28* 1.01±0.14

Ca: calcium; Cr: creatinine; C~: calcium excretion; N~: sodium excretion; GFR: glomerular filtration rate; TmCa: tubular maximum for calcium reabsorption; TmCa/Na corr.: sodium corrected TmCa; TmP0

4: tubular maximum for phosphate

reabsorption; •: p<O.Ol.

Results

The mean values of the measured variables are shown in table 1. At the time of investigation all 52 patients had chronic active thoracic sarcoidosis. The mean serum calcium value of 2.54±0.18 mmoH1 in patients with sarcoidosis was significantly higher than that obtained in the group of healthy subjects (2.42±0.11 mmoH1). Five patients were unmistakably hypercalcaemic. Hypercalcaemia was diagnosed if serum calcium levels were equal to or greater than the mean of the control values plus three standard deviations. The mean tubular maximum for calcium reabsorption (TmCa) in patients with sarcoidosis, 2.11±0.26 mmol·l·' GF (range 1.72-2.64), was not statistically different from the mean TmCa for the group of healthy subjects, 2.18±0.23 mmoH1 GF (range 1.72-2.64). The range is mean±2sn. The range of TmCa was reduced by taking urinary sodium into account. Thus urinary sodium corrected TmCa in patients with sarcoidosis was affected in a similar way to TmCa uncorrected. The values were within the normal range without significant differences between the means of the groups.

Renal function as measured by the serum creatinine was normal in all of the patients with sarcoidosis. In seven patients the fasting urinary calcium/creatinine ratios were increased above the normal range 0.40. Measurement of this ratio minimizes dietary influences. Increased values indicate either, increased bone resorption of calcium or, less commonly, decreased renal tubular reabsorption of calcium.

The mean TmPO /(JFR in sarcoidosis was significantly higher than in controls (p<0.01), but still within the normal range for TmPO/GFR (0.8-1.25 mmoH' GF). Fourteen patients with sarcoidosis had functional hypoparathyroidism as measured by the renal phosphate threshold concentration, the TmPO/GFR was increased above the normal range 1.25 mmol-1-1 GF (1.34±0.24 mmoH1 GF).

Discussion

The present study revealed abnormal calcium metabo­lism in 12 (23%) patients. Five patients were hypercal­caemic and seven patients showed an abnormal calcium/ creatinine ratio. The present data concerning the frequency of hypercalcaemia (9.6%) in sarcoidosis are consistent with those of LEBACQ et al. [14]. However, the whole group of patients with sarcoidosis had significantly higher plasma calcium levels than the group of healthy subjects. The bulk of calcium studies in sarcoidosis was essen­tially dedicated to the dearrangement of vitamin D metabolism. In this respect, two major steps were the demonstration that the serum 1,25(0H)p3 level is ele­vated in sarcoidosis [ 15] and the evidence that sarcoid granulomas are able to elaborate 1,25(0H)p

3 or 1 alpha

hydroxylase [16]. In spite of this growing knowledge, no attempts have been made to examine the tubular maximum for calcium reabsorption in patients with sar­coidosis. · Increased TmCa is one of three variables which can contribute to the pathogenesis of hypercalcaemia. Using a very sensitive method, a range for TmCa in patients with sarcoidosis has been established for the first time. Our range of TmCa in the control group is in good correlation with the work of NEED et al. [6]. Because urinary sodium excretion has been reported to influence urinary calcium excretion we determined the effect of sodium excretion on tubular reabsorption of calcium and derived a corrected TmCa in patients with sarcoidosis which takes into account the urinary sodium. Correcting the TmCa for urinary sodium excretion reduced the range ofTmCa.

If hypercalcaemia is associated with a normal TmCa it must be due to increased entry of calcium into the plasma or a reduced glomerular filtration rate. In all of our patients with sarcoidosis renal functions were normal. From our results, it is obvious that there is no increase in TmCa in patients with chronic active thoracic sarcoidosis. Even the five patients with elevated serum calcium levels had normal TmCa. Thus, increased TmCa does not contrib­ute to the pathogenesis of hypercalcaemia in sarcoidosis.

In seven patients the fasting urinary calcium/creatinine ratios were elevated. Mean TmCa of these seven patients

CALCIUM REABSORPTION IN CHRONIC SARCOIDOSIS 449

(1.95±0.37 mmol-/·1 GF) was statistically different from mean TmCa for the group of healthy subjects (2.18±0.23 mmol-I-1 GF); but still within the normal range for TmCa.

The mechanism for abnormal calcium metabolism remains very complex. Among factors which might cause hypercalcaemia in sarcoidosis, parathyroid hyperplasia does not play a role [15]. When the data for all of our patients with sarcoidosis were considered as a whole, the mean TmPOiGFR was within the normal range. Only 14 of these patients had functional hypoparathyroidism as measured by the TmP04 ; the TmPOiGFR was increased to 1.34±0.24 mmol·l-1 GF. However, from TmPOiGFR it is very difficult to assess whether serum parathormone (PTH) levels are in the low-normal range or renal phosphate excretion is augmented in response to the elevation of the serum calcium concentration. Any additional influence of PTH on the tubular handling of calcium in the majority of our patients with sarcoidosis remained negligible.

At present the factors causing the inappropriate eleva­tion of I ,25(0H)zD3 in serum are sarcoid granulomas which are able to elaborate 1,25(0H)2D3 or 1 alpha hydroxylase [16]. Whereas the effects of 1,25(0H)p3 on the skeleton and intestine have been well documented (17], the intrinsic effects of vitamin D on the kidney remain unclear [18].

Ninety nine per cent of the calcium filtered by the kidney is reabsorbed even in vitamin D deficiency, rendering any influence of vitamin D on calcium reab­sorption of questionable physiological importance [19]. Our data support evidence that circulating active vitamin D metabolites have 1iule or no influence on the TmCa.

Hypercalcaemia in patients with chronic thoracic active sarcoidosis is not a result of an increased tubular reabsorption of calcium.

References

1. Studdy PR, Bird R, Nevil!e E. James DG.- Biochemical findings in sarcoidosis. J Clin Pathol, 1980, 33, 528-533. 2. Sharma OP. - Hypercalcemia in sarcoidosis. Arch /rl!ern Med, 1985, 145, 626- 627. 3. Singer F. Adams J. - Abnormal calcium homeostasis in sarcoidosis. N Engl J Med, 1986, 315, 755- 757. 4. Meyrier A, Valeyre D. Bouillon R, Paillard F, Battesti JP, Georges R. - Resorptive versus absorptive hypercalciuria in sarcoidosis: correlations with 25-hydroxy vitamin D, and 1,25-di.hydroxy vitamin D, and parameters of disease activity. Q J Med, 1985, 54, 269- 281. 5. Meyricr A, Valeyre D, Bouillon R, Paillard F, Battesti JP, Gcorgcs R. - Different mechanisms of hypercalciuria in sarcoidosis. Ann N Y Acad Sci, 1986, 465, 575- 586. 6. Weed AG, Guerin MD, Pain RW, Hartley TF, Nordin BECh. - The tubular maximum for calcium reabsorption: normal range and correction for sodium excretion. Clin Chim Acta, 1985, 150, 87-93.

7. Marshal! DH. - Calcium and phosphate kinetics. In: Calcium phosphate and magnesium metabolism. B.E.Ch. Nordin ed., Churchill Livingstone, Edinburgh, 1976, p. 281. 8. Nordin BECh. - Assessment of calcium excretion from the urinary/creatinine ratio. Lancet, 1959, ii, 368-371. 9. Walton RJ, Bijvoet OLM.- Nomogram for derivation of renal threshold phosphate concentration. Lancet, 1975, ii, 309. 10. Kraml MA. - A semiautomated determination of phospholipids. Clin Chim Acta, 1966, 13, 442-448. 11. Hare RS. - Endogenous creatinine in serum and urine. Proc Soc Exper Bioi Med, 1950, 74, 148-150. 12. Gitelman HJ. - An improved automated procedure for the determination of calcium in biological specimens. Anal Biochem, 1967, 18, 521-531. 13. Finney DJ. - In: Statistical method in biological assay. 2nd edn. Griffin, London, 1967. 14. Lebacq EG, Verhaegen H, Desmet V. - Renal involve­ment in sarcoidosis. Postgrad Med J, 1970, 46, 526-529. 15. Koide Y, Kugai N, Kimura S, Fujita T, Yamashita N, Hiramoto T, Sukegawa I, Ogata E. Kamashita K. - Increased 1,25 dihydroxycholecalciferol as a cause of abnormal calcium metabolism in sarcoidosis. J Clin Endocrinol Metab, 1981, 52, 494-498. 16. Adams JS, Sharma OP, Gacod MA, Singer FR. -Metabolism of 25 hydroxyvitamin D, by cultured pulmonary alveolar macrophages in sarcoidosis. J Clin Invest, 1983, 72, 1856- 1860. 17. Bouillon R.- Vitamin D and the kidney. A short review. Contr Nephrol, 1988, 64, 24-33. 18. Yamamoto M, Kawanobe Y, Ogata E. - In vivo renal calcium transport in vitamin D-deficient rats. In: Abs. Vlllth Int Conf Calcium Reg, Kobe, Japan, 1983, p. 123. 19. Haussler MR, McCain TA.- Basic and clinical concepts related to vitamin D metabolism and action. N Engl J Med, 1977, 297, 974-983.

Le maximum tubulaire pour la reabsorption calcique chez les patients aJteints de sarcoidose thoracique chronique active. P. Broulik, V. Votava, V. Pacovsky. RESUME: Le maximum tubulaire de reabsorption calcique (fmCa) a ete evalue chez 52 patients atteints de sarcoi"dose thoracique chronique active. Unc hypercalcemie a ete trouvee chez 5 patients (9.6%). La valeur moyenne du calcium serique de 2.54±0.18 m.mol-11 chez les patients atteints de sarcoldose, s'avcre significativement plus elevee que celle obtenue dans le groupe controle (2.42±0.11 m.moH1

). La TmCa moyenne chez les patients aueints de sarcoi"dose (2.11±0.26 mmoH1 GF) n'etait pas statistiquement differente de la TmCa moyenne dans le groupe des sujets sains (2.18±0.23 mmol·t1 GF). La TmCa corrigce pour le sodium urinaire, a ete affectee de fa~on similaire dans les deux groupes. Notre etude dcmontre pour la premiere fois que chez les patients atteints de sarcoi:dose thoracique chronique active, il n'y a pas d'augmentation de TmCa. L'hypercalcemie n'est done pas la consequence d'une augmentation de TmCa. Eur Respir J., 1990, 3, 447-449