International Urology and Nephrology 9 (3), pp. 213--216 (1977)
Urolithiasis Associated with Hypercalciuria A. WEINBERGER, O. SPERLING, J. SCHECHTER, U. A. LIBERMAN, J. PINKHAS, A. DE VRIES Metabolic Unit, Department of Medicine D, Rogoff-Wellcome Medical
Research Institute, Tel-Aviv, University Medical School, Beilinson Medical Center, Petah Tikva, Israel (Received August 30, 1976)
Fifty male patients with urolithiasis (UL), associated with idiopathic hyper-
calciuria (IH), were studied in comparison to a group of 18 male normocalcemic patients with inactive calcium stone disease of unknown etiology. In the group of IHUL, in addition to hypercalciuria, statistically significant hyperphosphaturia with decreased tubular reabsorption of phosphate and hyperuricemia were observed; there was a tendency to hypophosphatemia although non-significant. In 36% of the IH-UL patients the first episode of renal colic appeared at age 40 to 50. Thirty-eight per cent of the IH-UL patients had recurrent stone formation. Twenty per cent of the IH-UL patients had a family history of urolithiasis. Forty-six per cent of all stones contained oxalate in addition to calcium, and 25 ~ of the stones contained oxalate and phosphate. The term idiopathic hypercalciuria has been assigned to normocalcemic hypercalciuria of unknown etiology. The syndro me is characterized by an abnormally high renal excretion of calcium, norm ocalcemia, normo- or hypophosphatemia and high frequency o f renal calcium stones [1 ]. The mechanism underlying the hypercalciuria in I H is not known with certainty and three different abnormalities have been proposed as the primary cause: intestinal hyperabsorption, decreased tubular reabsorption of calcium, and increased catabolism of bone [2, 3]. Elevated serum levels of parathyroid hormone have been observed in I H by several investigators and considered by some to reflect secondary hyperparathyroidism as a response to renal calcium loss [4], and by others " n o r m o calcemic" primary hyperparathyroidism [5, 6 ]. The genetic aspect of I H has as yet not been sufficiently evaluated. There is no information on familial occurrence of the disease. In this communication we present clinical and biochemical observations on a large series of patients with I H and urolithiasis (IH-UL). Material and methods Fifty adult patients aged 24 to 65 years with I H - U L were studied. Their age distribution is shown in Table 1. All patients were admitted for a period of 14 days to the metabolic ward and placed on a diet containing 900 mg calcium/day. Having been on this diet for 2
International Urology and Nephrology 9, 1977
214
Weinberyer et al. : Urolithiasis and hypercalciuria Table 1 Age distribution of 50 males with idiopathic hypercalciuria at the time of diagnosis Years
No, of patients
20--29 30--39 40--49 50--59 60--69
5 9 18 14 4
at least 3 days, all patients had subsequently a urinary calcium excretion of above 300 rag/day (a value higher than the upper limit of normal [7]) on at least 8 days out of 10 daily examinations. Hypercalciuric conditions such as sarcoidosis, renal tubular acidosis, multiple myeloma, Cushing's syndrome and various malignancies were excluded during hospitalization. According to accepted clinical and biochemical criteria [8, 9] none of the patients had primary hyperparathyroidism: neither bone pain, peptic ulcer, chronic pancreatitis, mental disturbances nor subperiostal resorption, hypercalcemia or decreased tubular reabsorption of phosphate (under 85 %) were found in any of them. Biochemical investigations included measurement of serum and urinary calcium, inorganic phosphorus, uric acid and creatinine, all determined by the Technicon AutoAnalyzer. In 6 patients serum parathyroid hormone level was determined by radioimmunoassay and found to be elevated in 5 [10]. Plain abdominal film, intravenous pyelogram and skeletal X-ray survey were performed on each patient. Renal calculi, when available, were analyzed chemically using the method of Winer and Mattice [11 ]. Statistical analysis was performed with the Student t-test [12]. Results
The diagnosis of IH was made in 50 patients at an average age of 45.5 years. Renal colic or stone expulsion appeared for the first time at an average age of 31.5 years, i. e. 14 years before the diagnosis was made. Twenty per cent of the patients with IH-UL had a family history of urolithiasis. In 91% of these patients renal colic or stone expulsion was the presenting symptom that led to the diagnosis of IH. Nine per cent of the IH-UL patients were investigated because of hypercalciuria and/or hyperuricosuria detected before urolithiasis was known. Nineteen of the patients (38%) had recurrent stone formation and 17 patients (34%) underwent surgical intervention for urolithiasis. The initial biochemical data on the 50 patients with IH-UL and on 18 subjects of the control group (UL) are shown in Table 2. In the group of IH-UL, in addition to hypercalciuria, statistically significant hyperphosphaturia with decreased tubular reabsorption of phosphate (TRP) and hyperuricemia were observed; there was a tendency to hypophosphatemia, although non-significant. International Urology and l'4ephrology 9; 1977
Weinberyer et al. : Urolithiasis and hypercalciuria
215
Table 2 Serum and urinary calcium, phosphorus and uric acid in patients with idiopathic hypercalciuria and urolithiasisa Patients
Urine (mg/24 hr)
i
Serum (rag%)
Ca
P
UA
Ca
Control UL c
168 7.8
764 35.5
589 14.4
9.91 0.03
3.56 0.05
IH-UL e
394 8.5
987 48.5
656 24.3
10.02 0.04
< 0.001
< 0.025
>0.05
>0.05
TR.P ( %)b
P
UA 5.70 0.09
93.45 a 0.25
3.32 0.05
6.20 0.15
90.41 f 0.61
>0.05
< 0.02
I
p
< 0.05
a Values represent mean (upper) standard error (lower). p >0.05 non-significant b Tubular reabsorption of phosphate e 18 controls with normocalciuria and urolithiasis a 13 patients only e 50 male patients with hypercalciuria and urolithiasis 44 patients only Forty-eight stones from 48 patients were chemically examined; 4 6 ~ of them were composed of calcium oxalate, 25 % of calcium oxalate and phosphate, the remainder being mixed stones containing urate, carbonate and ammonium in addition to calcium. Discussion
The average age at which the diagnosis of IH was made (45.5 years)does not differ from the average age of 42.3 years found by others [I 3 ]. The age distribution of 83 patients with IH in Rose's series [13] is the same as found by us. The relatively high incidence of a positive family history of urolithiasis (20 %) in the group of IH-UL patients is noteworthy. Also Coe and Kavalach [14] mentioned that there appeared to be a strong family history trend of stone disease among patients with IH. In the family of one of the IH-UL patients in our series hypercalciuria and renal stones appeared in 3 generations [15]. These observations lead to the assumption that IH may be genetically determined. The overall picture of metabolic and surgical stone activity in this series of patients with IH-UL is not different from that reported by other investigators [16, 17]. Furthermore, the composition of the stones of our patients is similar to that found by others [18]. The biochemical data found in the IH-UL patients are consistent with those reported by Hennemanet al. [1] and Yendt et al. [19]. The increased level of circulating parathyroid hormone, found in 5 out of the 6 IH-UL patients in whom it was measured, is consistent with the findings of Coe et al. [4] and presumed by them, on the basis of normocalcemia and suppressible parathormone levels, to 2*
International Urology and Nephrology 9, 1977
216
Weinberger et al. : Urolithiasis and hypercalciuria
reflect s e c o n d a r y h y p e r p a r a t h y r o l d i s m . However, the finding o f elevated ionized s e r u m calcium in the presence o f n o r m o c a l c e m i a a n d elevated p a r a t h o r m o n e levels led M u l d o w n e y et al. [6] to diagnose in such cases n o r m o c a l c e m i c p r i m a r y h y p e r p a r a t h y r o i d i s m which they c o u l d confirm o n surgery in several patients. T h e possibility o f n o r m o c a l c e m i c p r i m a r y h y p e r p a r a t h y r o i d i s m in s o m e o f o u r patients c a n n o t be excluded with certainty, a l t h o u g h the decrease in T R P was less striking t h a n generally f o u n d in p r i m a r y h y p e r p a r a t h y r o i d i s m .
References 1. Henneman, P. H., Forbers, A. P., Benedicts, P. H., Dudley, H. R.: Idiopathic hypercalciuria. New Enyl. J. Med., 259, 805 (1958). 2. Milhaud, G., Aubert, J. P. : l~tude du metabolisme du calcium chez l'homme ~t l'aide de Caas: l'hypercalciuria et la lithiase r6nale oxalique. Rev. Med., 22, 1 (1962). 3. Jackson, W. P. U., Dancaster, C.: A consideration of the hypercalciuria in sarcoidosis, idiopathic hypercalciuria and that produced by vitamin D. A new suggestion regarding calcium metabolism. J. Clin. Endocrin., 19, 658 (1959). 4. Coe, F. L., Canterbury, J. M., Firpo, J. J., Reiss, E. E.: Evidence for secondary hyperparathyroidism in idiopathic hypercalciuria. J. Clin. Invest., 52, 134 (1973). 5. Pak, C. Y. C., Ohata, M., Lawrence, E. C., Snyder, W.: The hypercalciurias. Causes, parathyroid functions and diagnostic criteria. J. Clin. Invest., 54, 387 (1974). 6. Muldowney, F. P., Freaney, R., McMullin, J. P., Towers, R. P., Spillane, A., O'Connor, P., O'Donohve, P., Moloney, M.: Serum ionized calcium and parathyroid hormone in renal stone disease. Quart. J. Med. New Series XLV, 75 (1976). 7. Hodgkinson, A., Pyrah, L. N.: The urinary excretion of calcium and inorganic phosphate in 344 patients with calcium stone of renal origin. Brit. J. Sury., 46, 10 (1958). 8. Strott, C. A., Nugent, C. A.: Laboratory tests in the diagnosis of hyperparathyroidism in hypercalcemic patients. Ann. Intern. Med., 68, 188 (1968). 9. Purnell, D. C., Smith, L. H., Scholz, D. A., Elveback, L. R., Arnaud, D. C.: Primary hyperparathyroidism: A prosPective clinical study. Amer. J. Med., 50, 670 (1971). 10. Weinberger, A., Shainkin, R., Oliver, I., Sperling, O., Berlyne, G. M., de Vries, A.: Parathyroid hormone and calcitonin in idiopathic hypercalciuria. Biomedicine Exp., 21, 459 (1974). 11. Winer, J. H., Mattice, M. R. : Analysis of urinary calculi. Hepler Manual of Clinical Laboratory Methods. Thomas, Springfield, Ill. 1953. 12. Ipsen, J., Feigl, P.: Bancroft's Introduction to Biostatistics. Harper and Row, New York 1970. 13. Rose, G. A., Harrison, A. R.: The incidence, investigation and treatment of idiopathic hypercalciuria. Brit. J. Urol., 46, 261 (1974). 14. Coe, F. L., Kavalach, A. G. : Hypercalciuria and hyperuricosuria in patients with calcium nephrolithiasis. New Enyl. J. Med., 291, 1344 (1974). 15. Unpublished data. 16. Smith, L. H., Thomas, W. C., Jr., Arnaud, C. D. : Orthophosphate therapy in calcium renal lithiasis. Urinary calculi. Int. Symp. Renal Stone Res. Karger, Basel 1973. 17. Yendt, E. R., Guary, G. F., Garcia, D. A. : The use of thiazides in the prevention of renal calculi. Canad. Med. Ass. J., 102, 614 (1970). 18. Pak, C. Y.C., Delea, A. B., Bartler, F. C. : Successful treatment of recurrent nephrolithiasis (calcium stones) with cellulose phospate. New En#l. J. Med., 290, 178 (1974). 19. Yendt, E. R., Gagne, R. J. A., Cohanim, M.: The effect of thiazides in idiopathic hypercalciuria. J. Med. Sci 251, 107 (1966). ]International Urology and Nephrology9, 1977
Urolithiasis Associated with Hypercalciuria A. WEINBERGER, O. SPERLING, J. SCHECHTER, U. A. LIBERMAN, J. PINKHAS, A. DE VRIES Metabolic Unit, Department of Medicine D, Rogoff-Wellcome Medical
Research Institute, Tel-Aviv, University Medical School, Beilinson Medical Center, Petah Tikva, Israel (Received August 30, 1976)
Fifty male patients with urolithiasis (UL), associated with idiopathic hyper-
calciuria (IH), were studied in comparison to a group of 18 male normocalcemic patients with inactive calcium stone disease of unknown etiology. In the group of IHUL, in addition to hypercalciuria, statistically significant hyperphosphaturia with decreased tubular reabsorption of phosphate and hyperuricemia were observed; there was a tendency to hypophosphatemia although non-significant. In 36% of the IH-UL patients the first episode of renal colic appeared at age 40 to 50. Thirty-eight per cent of the IH-UL patients had recurrent stone formation. Twenty per cent of the IH-UL patients had a family history of urolithiasis. Forty-six per cent of all stones contained oxalate in addition to calcium, and 25 ~ of the stones contained oxalate and phosphate. The term idiopathic hypercalciuria has been assigned to normocalcemic hypercalciuria of unknown etiology. The syndro me is characterized by an abnormally high renal excretion of calcium, norm ocalcemia, normo- or hypophosphatemia and high frequency o f renal calcium stones [1 ]. The mechanism underlying the hypercalciuria in I H is not known with certainty and three different abnormalities have been proposed as the primary cause: intestinal hyperabsorption, decreased tubular reabsorption of calcium, and increased catabolism of bone [2, 3]. Elevated serum levels of parathyroid hormone have been observed in I H by several investigators and considered by some to reflect secondary hyperparathyroidism as a response to renal calcium loss [4], and by others " n o r m o calcemic" primary hyperparathyroidism [5, 6 ]. The genetic aspect of I H has as yet not been sufficiently evaluated. There is no information on familial occurrence of the disease. In this communication we present clinical and biochemical observations on a large series of patients with I H and urolithiasis (IH-UL). Material and methods Fifty adult patients aged 24 to 65 years with I H - U L were studied. Their age distribution is shown in Table 1. All patients were admitted for a period of 14 days to the metabolic ward and placed on a diet containing 900 mg calcium/day. Having been on this diet for 2
International Urology and Nephrology 9, 1977
214
Weinberyer et al. : Urolithiasis and hypercalciuria Table 1 Age distribution of 50 males with idiopathic hypercalciuria at the time of diagnosis Years
No, of patients
20--29 30--39 40--49 50--59 60--69
5 9 18 14 4
at least 3 days, all patients had subsequently a urinary calcium excretion of above 300 rag/day (a value higher than the upper limit of normal [7]) on at least 8 days out of 10 daily examinations. Hypercalciuric conditions such as sarcoidosis, renal tubular acidosis, multiple myeloma, Cushing's syndrome and various malignancies were excluded during hospitalization. According to accepted clinical and biochemical criteria [8, 9] none of the patients had primary hyperparathyroidism: neither bone pain, peptic ulcer, chronic pancreatitis, mental disturbances nor subperiostal resorption, hypercalcemia or decreased tubular reabsorption of phosphate (under 85 %) were found in any of them. Biochemical investigations included measurement of serum and urinary calcium, inorganic phosphorus, uric acid and creatinine, all determined by the Technicon AutoAnalyzer. In 6 patients serum parathyroid hormone level was determined by radioimmunoassay and found to be elevated in 5 [10]. Plain abdominal film, intravenous pyelogram and skeletal X-ray survey were performed on each patient. Renal calculi, when available, were analyzed chemically using the method of Winer and Mattice [11 ]. Statistical analysis was performed with the Student t-test [12]. Results
The diagnosis of IH was made in 50 patients at an average age of 45.5 years. Renal colic or stone expulsion appeared for the first time at an average age of 31.5 years, i. e. 14 years before the diagnosis was made. Twenty per cent of the patients with IH-UL had a family history of urolithiasis. In 91% of these patients renal colic or stone expulsion was the presenting symptom that led to the diagnosis of IH. Nine per cent of the IH-UL patients were investigated because of hypercalciuria and/or hyperuricosuria detected before urolithiasis was known. Nineteen of the patients (38%) had recurrent stone formation and 17 patients (34%) underwent surgical intervention for urolithiasis. The initial biochemical data on the 50 patients with IH-UL and on 18 subjects of the control group (UL) are shown in Table 2. In the group of IH-UL, in addition to hypercalciuria, statistically significant hyperphosphaturia with decreased tubular reabsorption of phosphate (TRP) and hyperuricemia were observed; there was a tendency to hypophosphatemia, although non-significant. International Urology and l'4ephrology 9; 1977
Weinberyer et al. : Urolithiasis and hypercalciuria
215
Table 2 Serum and urinary calcium, phosphorus and uric acid in patients with idiopathic hypercalciuria and urolithiasisa Patients
Urine (mg/24 hr)
i
Serum (rag%)
Ca
P
UA
Ca
Control UL c
168 7.8
764 35.5
589 14.4
9.91 0.03
3.56 0.05
IH-UL e
394 8.5
987 48.5
656 24.3
10.02 0.04
< 0.001
< 0.025
>0.05
>0.05
TR.P ( %)b
P
UA 5.70 0.09
93.45 a 0.25
3.32 0.05
6.20 0.15
90.41 f 0.61
>0.05
< 0.02
I
p
< 0.05
a Values represent mean (upper) standard error (lower). p >0.05 non-significant b Tubular reabsorption of phosphate e 18 controls with normocalciuria and urolithiasis a 13 patients only e 50 male patients with hypercalciuria and urolithiasis 44 patients only Forty-eight stones from 48 patients were chemically examined; 4 6 ~ of them were composed of calcium oxalate, 25 % of calcium oxalate and phosphate, the remainder being mixed stones containing urate, carbonate and ammonium in addition to calcium. Discussion
The average age at which the diagnosis of IH was made (45.5 years)does not differ from the average age of 42.3 years found by others [I 3 ]. The age distribution of 83 patients with IH in Rose's series [13] is the same as found by us. The relatively high incidence of a positive family history of urolithiasis (20 %) in the group of IH-UL patients is noteworthy. Also Coe and Kavalach [14] mentioned that there appeared to be a strong family history trend of stone disease among patients with IH. In the family of one of the IH-UL patients in our series hypercalciuria and renal stones appeared in 3 generations [15]. These observations lead to the assumption that IH may be genetically determined. The overall picture of metabolic and surgical stone activity in this series of patients with IH-UL is not different from that reported by other investigators [16, 17]. Furthermore, the composition of the stones of our patients is similar to that found by others [18]. The biochemical data found in the IH-UL patients are consistent with those reported by Hennemanet al. [1] and Yendt et al. [19]. The increased level of circulating parathyroid hormone, found in 5 out of the 6 IH-UL patients in whom it was measured, is consistent with the findings of Coe et al. [4] and presumed by them, on the basis of normocalcemia and suppressible parathormone levels, to 2*
International Urology and Nephrology 9, 1977
216
Weinberger et al. : Urolithiasis and hypercalciuria
reflect s e c o n d a r y h y p e r p a r a t h y r o l d i s m . However, the finding o f elevated ionized s e r u m calcium in the presence o f n o r m o c a l c e m i a a n d elevated p a r a t h o r m o n e levels led M u l d o w n e y et al. [6] to diagnose in such cases n o r m o c a l c e m i c p r i m a r y h y p e r p a r a t h y r o i d i s m which they c o u l d confirm o n surgery in several patients. T h e possibility o f n o r m o c a l c e m i c p r i m a r y h y p e r p a r a t h y r o i d i s m in s o m e o f o u r patients c a n n o t be excluded with certainty, a l t h o u g h the decrease in T R P was less striking t h a n generally f o u n d in p r i m a r y h y p e r p a r a t h y r o i d i s m .
References 1. Henneman, P. H., Forbers, A. P., Benedicts, P. H., Dudley, H. R.: Idiopathic hypercalciuria. New Enyl. J. Med., 259, 805 (1958). 2. Milhaud, G., Aubert, J. P. : l~tude du metabolisme du calcium chez l'homme ~t l'aide de Caas: l'hypercalciuria et la lithiase r6nale oxalique. Rev. Med., 22, 1 (1962). 3. Jackson, W. P. U., Dancaster, C.: A consideration of the hypercalciuria in sarcoidosis, idiopathic hypercalciuria and that produced by vitamin D. A new suggestion regarding calcium metabolism. J. Clin. Endocrin., 19, 658 (1959). 4. Coe, F. L., Canterbury, J. M., Firpo, J. J., Reiss, E. E.: Evidence for secondary hyperparathyroidism in idiopathic hypercalciuria. J. Clin. Invest., 52, 134 (1973). 5. Pak, C. Y. C., Ohata, M., Lawrence, E. C., Snyder, W.: The hypercalciurias. Causes, parathyroid functions and diagnostic criteria. J. Clin. Invest., 54, 387 (1974). 6. Muldowney, F. P., Freaney, R., McMullin, J. P., Towers, R. P., Spillane, A., O'Connor, P., O'Donohve, P., Moloney, M.: Serum ionized calcium and parathyroid hormone in renal stone disease. Quart. J. Med. New Series XLV, 75 (1976). 7. Hodgkinson, A., Pyrah, L. N.: The urinary excretion of calcium and inorganic phosphate in 344 patients with calcium stone of renal origin. Brit. J. Sury., 46, 10 (1958). 8. Strott, C. A., Nugent, C. A.: Laboratory tests in the diagnosis of hyperparathyroidism in hypercalcemic patients. Ann. Intern. Med., 68, 188 (1968). 9. Purnell, D. C., Smith, L. H., Scholz, D. A., Elveback, L. R., Arnaud, D. C.: Primary hyperparathyroidism: A prosPective clinical study. Amer. J. Med., 50, 670 (1971). 10. Weinberger, A., Shainkin, R., Oliver, I., Sperling, O., Berlyne, G. M., de Vries, A.: Parathyroid hormone and calcitonin in idiopathic hypercalciuria. Biomedicine Exp., 21, 459 (1974). 11. Winer, J. H., Mattice, M. R. : Analysis of urinary calculi. Hepler Manual of Clinical Laboratory Methods. Thomas, Springfield, Ill. 1953. 12. Ipsen, J., Feigl, P.: Bancroft's Introduction to Biostatistics. Harper and Row, New York 1970. 13. Rose, G. A., Harrison, A. R.: The incidence, investigation and treatment of idiopathic hypercalciuria. Brit. J. Urol., 46, 261 (1974). 14. Coe, F. L., Kavalach, A. G. : Hypercalciuria and hyperuricosuria in patients with calcium nephrolithiasis. New Enyl. J. Med., 291, 1344 (1974). 15. Unpublished data. 16. Smith, L. H., Thomas, W. C., Jr., Arnaud, C. D. : Orthophosphate therapy in calcium renal lithiasis. Urinary calculi. Int. Symp. Renal Stone Res. Karger, Basel 1973. 17. Yendt, E. R., Guary, G. F., Garcia, D. A. : The use of thiazides in the prevention of renal calculi. Canad. Med. Ass. J., 102, 614 (1970). 18. Pak, C. Y.C., Delea, A. B., Bartler, F. C. : Successful treatment of recurrent nephrolithiasis (calcium stones) with cellulose phospate. New En#l. J. Med., 290, 178 (1974). 19. Yendt, E. R., Gagne, R. J. A., Cohanim, M.: The effect of thiazides in idiopathic hypercalciuria. J. Med. Sci 251, 107 (1966). ]International Urology and Nephrology9, 1977
