British Journal of Urology (1977), 49, 1-10

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Seasonal Variations in Urinary Excretion of Calcium and Oxalate in Normal Subjects in Patients with Idiopathic Hypercalciuria P.

c. HALLSON,

G. P. KASIDAS

and

G. ALAN ROSE

St Peter’s Hospitals and Institute of Urology, London

(Received 9 July 1976; accepted for publication 29 September 1976)

It was reported by Robertson et al. (1974, 1975) that urinary calcium values of normal subjects and of patients with idiopathic stone formation were higher in the summer than in the winter. The magnitude of the changes was considerable; thus, for males with idiopathic stones the mean urinary calcium was 5.7 mmo1/24 hours in December and 9-3 mmo1/24 hours in July. It seems surprising that changes of such a size had not been noticed previously and it was therefore decided to see if those results observed in Leeds could be confirmed in London. 2 separate studies of urinary calcium have been undertaken. The first study was retrospective and was based upon urinary calcium values observed over a 9-year period in a single metabolic stone clinic where the same patients with idiopathic hypercalciuria had attended and brought 24-hour urine collections repeatedly for many years. All of the patients were observed at first untreated, but many were subsequently treated either with thiazide diuretics or cellulose phosphate. The data was therefore not only viewed as a whole but also subdivided according to the treatment. Many of these patients have been the subject of a previous report (Rose and Harrison, 1974). The second study was prospective and based upon a group of normal individuals each of whom collected a single 24-hour specimen of urine every month for 13 consecutive months. A new enzymatic method for the measurement of urinary oxalate was reported from these laboratories recently (Hallson and Rose, 1974). Since this method is specific and accurate within the normal range, it was thought of interest to extend the study of seasonal variations in urinary calcium to include oxalate. Accordingly, urinary oxalate was measured on every urine sample in the prospective study, and a 2-year study was also made of urinary oxalate in the patients with idiopathic hypercalciuria. Methods All urine collections were made as out-patients. The patients received written instructions on how to make the collections. Containers issued to patients contained 5 ml Conc. HCI prior to issue, and were normally returned to the laboratory on the day that the collection was completed. Creatinine was invariably measured and by AutoAnalyser. Calcium was measured by emission flame photometry (MacIntyre, 1957), except that during the last few months of the study a change was made to atomic absorption flame photometry. It was demonstrated that this change in method did not alter values obtained for urinary calcium. Oxalate was determined by the enzymatic method of Hallson and Rose (1974). Diagnosis of idiopathic hypercalciuria was as previously described by Rose and Harrison (1974). The thiazide diuretic used was almost invariably bendrofluazide, the dose was usually 5 mg per day, sometimes rising to 10 mg 4911-A 1

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Number of estimations

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Fig. 1. Monthly variation in values for 24-hour urinary calcium of all male patients (treated or untreated) with idiopathic hypercalciuria. Thin vertical lines indicate S.E.M. The mean number of estimations per patient was 9.75.

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Fig. 2. Monthly variation in values for 24-hour urinary calcium of male patient with idiopathic hypercalciuria while on treatment with thiazides. Thin vertical lines indicate S.E.M. The mean number of estimations per patient was 16.9.

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SEASONAL CHANGES I N URINE CALCIUM AND OXALATE

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Fig. 3. Bimonthly variation in values of 24-hour urinary calcium of male patients with idiopathic hypercalciuria while o n treatment wlth cellulose phosphate. Thin vertical lines indicate S.E.M. Mean number of estimations per patient was 11.6.

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Fig. 4. Bimonthly variations in values for 24-hour urinary calcium of male patients with idiopathic hypercalciuria who were either untreated or treated only with mild calcium restriction. Thin vertical lines indicate S.E.M. Mean number of estimations per patient was 5.8.

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per day. Cellulose phosphate was administered in the sodium form in a dose of 10 t o 30 g per day and taken with meals.

Information on hours of sunshine and mean daily temperature for each month were obtained from the London Weather Centre.

Results The monthly variation in urinary calcium values for all patients with idiopathic hypercalciuria, whether treated or not, is shown in Figure 1. In Figure 2 the same data is shown but restricted to

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Fig. 5. Prospective study of 24-hour urinary calcium and oxalate values measured each month in a srnail group of normal volunteers. Thin vertical lines indicate S.E.M.

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SEASONAL CHANGES IN URINE CALCIUM A N D OXALATE

those patients receiving thiazide diuretics at the time. Figure 2 shows the data for patients undergoing treatment with cellulose phosphate, and Figure 4 shows the data for patients without treatment at the time. In Figure 3 and 4 it has been necessary to plot as 2-month periods, rather than as 1-month periods, because of the smaller number of samples available. It is clear, however, that no significant seasonal variations in urinary calcium can be observed in any of these figures. Results from the prospective study are shown in Figure 5. It can be seen that there is no significant change in urinary calcium values obtained from the normal volunteers over the 13th month period. Changes in urinary oxalate are very small, with a slight rise in the 4 summer months which does not, however, achieve statistical significance. Figure 6 shows that the urinary oxalate values of the patients with idiopathic hypercalciuria did show seasonal changes with values rising appreciably in the summer months. Results from normal subjects and patients are contrasted in Figure 8, which shows that there is a statistical difference between results from summer and winter months only in the case of the patients with idiopathic hypercalciuria. Figure 7 shows that

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Fig. 6. Bimonthly values in urinary oxalate of male patients with idiopathic hypercalciuria, mean air temperature. and hours of sunshine for 24 successive months. Thin vertical lines indicate S.E.M.

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Fig. 7. Same data as in Figure 6 plotted to show correlations and regression lines. For oxalic and mean temperature R = 0.89; for oxalic and hours o f sunshine R = 0.80.

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SEASONAL CHANGES IN URINE CALCIUM AND OXALATE

the correlation coefficient between bi-monthly urinary oxalate values and mean monthly temperature is 0.89, slightly better than the correlation coefficient of 0.80 between bi-monthly urinary oxalate and hours of sunshine, although the difference between these two correlation coefficients does not achieve statistical significance. Discussion

It has been conclusively shown that in a clinic serving the London area and the surrounding region there are no seasonal changes in urinary calcium. Neither were there any such changes in a group of normal volunteers. Admittedly, the numbers in the latter group were small, but nevertheless the result is so clear-cut that it seems unlikely that an increase in the numbers could have altered the result. The lack of change of urinary calcium with season comes as no surprise because it is felt that any change of the magnitude described by the Leeds group would have been noticed a long time ago had it occurred in London. The question now arises is why such different results should be reported in London and Leeds. First, the 2 studies need careful examination to see if they are comparable. It must be noted that the London retrospective study is a longitudinal study in which each patient was observed on many occasions, whereas the Leeds study was of

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the cross-sectional type in which each patient contributed once only. The cross-sectional study can be influenced by extraneous factors unwittingly introduced. Thus if any factor was at work which caused hypercalciuric patients to present in the summer rather than the winter, then it would appear that hypercalciuria was more common in the summer whereas this might not be so. That such factors were at work seems rather likely. Thus, it was found by Black (1945) that oxaluria was most common in the British Army in India during the hot months. Also, Pierce and Bloom (1945) reported that the incidence of renal stones amongst US troops in the desert was greatest in the hot months. Furthermore, Robertson et al. (1975) themselves clearly show that the incidence of spontaneous passage of stones in their patients was highest in the summer months, perhaps because the urine collections were made soon after these episodes. Hence I possible cause of bias clearly exists and there could be others of which we are unaware. Secondly, however, the possibility must be considered that there is in fact a true difference between the populations of the Leeds and London areas respectively. If this is so, is the difference occurring in the summer, or the winter, or in both? Comparison of the data from the 2 studies shows that the summer values for urinary calcium agree in the 2 areas and that it is in the winter that the differences occur, the London patients failing to show the fall from the summer levels of urinary calcium shown by the Leeds patients. Robertson et al. (1974) have attributed the seasonal changes they observed, at least in part, to changes in exposure to sunlight. If this view is correct, it would follow that in London the level of exposure to sunlight does not change appreciably between summer and winter in contrast to Leeds. Although Leeds is 180 miles north of London, this proposition does not seem likely to be true, and indeed it could be argued that the absolute difference in exposure to sunlight between summer and winter is greater for London than in Leeds. At the outset of this study we were unaware of any other observations of seasonal variations for urinary oxalate. Recently, however, Robertson et al. (1975) confirmed our preliminary report (Rose and Hallson, 1975) that patients with idiopathic calcium stone formation show rises in urinary oxalate during the summer months. These authors did not, however, study normal individuals. It has been shown here that in a small group of normal subjects there was no difference in urinary oxalate values between the summer and winter months. On the other hand, the patients with idiopathic hypercalciuria, in a longitudinal 2-year study, showed a rise in urinary oxalate in the summer months which was seen in each of the 2 successive years. I possible cause of the rise in urinary oxalate in the summer months might be that it is related in some way to vitamin D obtained from sunlight. Since, however, it has been shown above that urinary calcium is unchanged between summer and winter, this explanation is rendered unlikely. Furthermore, Figure 7 shows that the correlation between urinary oxalate and hours of sunshine is not as good as that between urinary oxalate and mean temperature. This suggests that an increase in oxalate in the diet for the summer months might be a more likely explanation, and certain known facts support this theory. Firstly, some of the oxalate-rich foods, namely rhubarb, spinach and beetroot, are seasonal and consumed more in the summer than in the winter. Secondly, Archer et al. (1957) found that when healthy normal volunteers received standard sodium oxalate supplements to their diet, the rise in urinary oxalate accounted for 3% of the oxalate given. Marshall, Cochran and Hodgkinson (1972) found that the rise in urinary oxalate produced by a standard oxalate load was increased to 8.1 % by a low calcium diet and reduced to 3 6 % by a high calcium diet. Similar results were reported by Villarino et al. (1972). It should be noted here that all the patients with idiopathic hypercalciuria had been prescribed a low calcium diet with restrictions of milk, cheese and related foods. Hence there is a ready explanation for the fact that the patients, but not normal subjects, showed a rise in urinary oxalate in the summer. To see this rise, not only must there be an increase in intake, but the individuals must have a low faecal calcium. Such a low faecal calcium results from a low calcium diet together with relative hyperabsorption of dietary calcium. It is of interest that these seasonal changes in urinary oxalate have been observed only very recently. 2 possible explanations for this may be offered. Firstly, the measurement of urinary

SEASONAL CHANGES IN URINE CALCIUM AND OXALATE

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oxalate has been tedious and lacking in precision and accuracy so that few estimations have been undertaken in the past and the results are of doubtful value. On the other hand, using the enzymatic method described, it has been possible to undertake large numbers of measurements and obtain reliable results within the normal range, so revealing the facts described. Secondly, it should be noted that there are in the literature some suggestions that urinary oxalate may be raised in idiopathic hypercalciuria or idiopathic stone formation (RevGsova, Zvara and Gratzlova, 1971 ; Thomas et al., 1973), without however clear indication of the season of the year or whether the patients were on normal or low calcium intake. It is therefore possible that seasonal variations have been seen but not recognised. It is clearly important in future work that both the season of the year and the diet should be clearly identified. Summary

A longitudinal 9-year retrospective study of 24-hour urinary calcium values has been made in a metabolic stone clinic amongst patients with idiopathic hypercalciuria. No seasonal variations could be observed in contrast to a previous study from Leeds. A prospective longitudinal study was made of 24-hour urinary calcium values in a small group of normal subjects. No seasonal variation could be observed. In the prospective study no seasonal variations in urinary oxalate could be observed. In a 2-year longitudinal study of stone patients with idiopathic hypercalciuria, urinary oxalate was found to be higher in the summer than in the winter. This was attributed to the combination of a higher intake of oxalate-rich foods in the summer, and the low calcium diet with which they were treated. This work was financed by a grant from the St Peter’s Research Trust.

References ARCHER, H. E., DORMER, A. E., SCOWEN, E. F. and WATTS,R. W. E. (1957). Studies on the urinary excretion of oxalate by normal subjects. Clinical Science, 16, 405-41 1 BLACK,J. M. (1945). Oxaluria in British troops in India. British Medical Journal, 1, 590-592. P. C. and ROSE,G. A. (1974). A simplified and rapid enzymatic method for determination of urinary HALLSON, oxalate. Clinica Chimica Acta, 55, 29-39. MACINTYKE, I. (1957). The flame-spectrophotometric determination of calcium in biological fluids and an isotopic analysis of the errors in the Kramer-Tisdall procedure. Biochemical Journal, 67, 164-172. M. and HODGKINSON, A. (1972). Relationships between calcium and oxalic acid MARSHALL, R. W., COCHRAN, intake in the diet and their excretion in the urine of normal and renal-stone-forming subjects. Clinical Science, 43, 91-99. PIERCE,L. W. and BLOOM, B. (1945). Observations on urolithiasis amongst American troops in a desert area. Journal of Urology, 54, 466-470. J. (1971). Urinary oxalate excretion in patients with urolithiasis. R E V I ~ O VV., A , ZVARA,V. and GRATZLOV,~, Urologia Internationalis, 26, 277-282. ROBERTSON, W. G., GALLAGHER, J. C., MARSHALL, D. H., PEACOCK, M. and NORDIN,B. E. C. (1974). Seasonal variations in urinary excretion of calcium. British Medical Journal, 4, 436-437. M., MARSHALL, R. W., SPEED,R. and NORDIN, B. E. C. (1975). Seasonal variations ROBERTSON, W. G., PEACOCK, in the composition of urine in relation to calcium stone formation. Clinical Science, 49, 597-602. ROSE,G. A. and HALLSON,P. (1975). Idiopathic hypercalciuria+ffect of treatment upon urinary calcium and oxalate. Pathogenese, und Klinik der Harnsteine I V . Symposium in Bonn 1974. Darmstadt. A. R. (1974). The incidence, investigation and treatment of idiopathic hypercalciuria. ROSE,G. A. and HARRISON, British Journal of Urology, 46, 261-274. THOMAS,J., MELON,J. M., THOMAS, E., STEG,A. and ABOULKER, P. (1973). The role of oxalic acid in oxalic nephrolithiasis. In : Urinary calculi. Proceedings of the International Symposium on Renal Stone Research, Ed. L. Cifuentes-Delatte. Madrid, 1972. Basel: Karger, 57-66. J. A,, RAPADO, A., TRABA, M. L. and MENDOZA, H. H. (1972). La determinacion de acido oxalica en la VILLARINO, orina y su influencia por la dieta. Revista Chimica Espariola, 125, 19-26.

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The Authors P. C. Hallson, MPhil, Research Biochemist, Institute of Urology. G. P. Kasidas, MSc, Research Technician, St Peter’s Hospital. G. Alan Rose, FRCP, MRCPath, Consultant Chemical Pathologist, St Peter’s Hospital. Correspondence to Dr G . Alan Rose, St Paul’s Hospital, Endell Street, London, WC2.