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Clinical Relationships Among Urinary Calcium Excretion and Blood Urea Nitrogen Levels, Urinary Volume and Ureteral Catheterization
THE J OUR,,.AL OF UROLOGY Vol. 91, No. 6 June 1964 Copyright© 1964 by The Williams & Wilkins Co. Printed in U.S.A.
CLINICAL RELATIONSHIPS AMONG URINARY CALCIUM EXCRETION AND BLOOD UREA NITROGEN LEVELS, URINARY VOLUl\fE AND URETERAL CATHETERIZATION J. ERNEST LATHEM, WILLIAM H. BOYCE
AND
J. STANTON KING, JR.
From the Department of Urology, Bowman Gray School of Medicine, Winston-Salem, North Carnlina
The urinary excretion of calcium has large fluctuations, for reasons that are as yet incompletely clear.1. 2 The following report summarizes clinical observations of 3 factors related to urinary calcium excretion: 1) blood urea nitrogen (BUN), 2) urinary volume, and 3) ureteral catheterization. Urinary calcium excretion is generally expected to decrease as renal damage approaches the point of azotemia. If this is true, the clinician might expect to see an inverse relation between increased BUN, which is a rough index of the degree of renal damage 3 and decreased calcium excretion. This expectation was examined, while looking also for any indication that prolonged hypercalcinuria is injurious to the kidney. Secondly, it has been shown that experimental polyuria is accompanied by increased urinary calcium excretion. 4 - 6 This observation has been reported in clinical situations. 7 • 8 If consistently
true, the increased fluid intake popularly recommended to decrease urinary calcium concentration in renal stone-forming patients may be unhelpful or detrimental. Finally, separate collections of urine from each kidney are occasionally useful in experimental and diagnostic studies. We have obtained data. indicating that ureteral catheterization may affect the urinary excretion of calcium. METHODS
Accepted for publication December 13, 1963. Supported by grants A-259 and K3-I6,620, National Institute of Arthritis and Metabolic Diseases, National Institute of Health, United States Public Health Service and the John A. Hartford Foundation. 1 Heaton, F. W. and Hodgkinson, A.: External factors affecting diurnal variation in electrolyte excretion with particular reference to calcium and magnesium. Clin. Chim. Acta, 8: 46, 1963. 2 Lathem, J.E. and King, J. S., Jr.: Patterns of urinary calcium excretion in normal subjects and in renal calculous disease. J. Urol., 89: 541, 1963. 3 De Wardner, H. E. : The Kidney. Boston: Little, Brown and Co., 1961, pp. 26, 27, 179, 192. 4 Goff art, H. and Brull, L.: Debit urinaire du calcium et polyurie par ingestion d'eau. Compt. rend soc. biol., 118: 1630, 1935. 5 Brull, L., Poverman, R. and Goffart, H.: Recherches sur le metabolisme mineral. Arch. internat. physiol., 43: 238, 1936. 6 Causeret, J.: Influence de la consommation d'eau sur ]'elimination intestinale et renale du calcium. Compt. rend. Acad. Sci., 237: 664, 1953. 7 Mertz, D. P.: Untersuchungen i.iber die physiologiscben renalen Ausscheidungs-Verhaltnisse von Magnesium und Calcium. Klin. Wchnschr., 35: 1171. 1957. 8 Cottet, J.: Le syndrome biochimique des lithiases urinaires. In: Encyclopedia of Urology, Berlin: Springer-Verlag. Edited by C. E. Alken, V. W. Dix, H. M. Weyrauch and E. Wildbolz, 1961, vol. 10, p. 410.
Urinary calcium: BUN. Data covering periods of 12 to 84 months were obtained on 50 patients with renal calculous disease. BUN 9 and urinary calcium10 were determined at irregular intervals. Urinary calcium: Volume. One hundred fortythree stone formers, who had a minimum of three 24-hour urinary calcium determinations during the past 2 years, were the subject of this study. ·water intake was ad libitum. The calcium excretions and urinary volumes for each patient were averaged and graphed. Urinary calcium: Ureteral catheterization. 'Urine was collected from catheters inserted into one or both ureters. Collection intervals were 1 to 4 hours, usually for a total of 8 to 24 hours but for 5 days in 1 patient. When excretion of opposite kidneys was compared, a No. 5 woven or polyethylene ureteral catheter was inserted into one ureter and a Foley catheter into the bladder. The position of the tip of the ureteral catheter at the ureteropelvic junction was confirmed by x-ray. Twelve patients were studied in this manner. The proportionally equal volumes obtained from the 2 catheters indicated adequate drainage. The results for 4 further patients were excluded from this study because the volume of urine obtained from the catheterized kidney was markedly lower than the opposite one, indicating a technically
681
9 Koch, F. C.: A stable and convenient urease reagent and a modified blood urea method. J. Lab. & Clin. Med., 11: 774, 1926. 10 Clark, E. P. and Collip, J.B.: A study of the Tisdal] method for the determination of blood serum calcium, with a suggested modification. J. Biol. Chem., 63: 461, 1925.
682
LATHEM, BOYCE AND KING, JR.
inadequate experiment; however, one patient (case 3) is included who excreted a notably larger volume from the catheterized kidney. Patients in this group varied from the normal (who had a previously questionable excretory urogram, thus requiring a retrograde pyelogram) to the severe bilateral recurrent stone former.
4500 4000 3500 3000 ~
~
" ..,' ,,.
2500
!;
:',
RESULTS
BUN. The degree of relationship found between urinary calcium excretion and BUN is illustrated in figure 1. The excretion rate of calcium never exceeded 300 mg./24 hr. in a patient with an elevated BUN. Three patients were followed 48 to 84 months, with urinary calcium determined several times a year. All three had mild to moderate hypercalcinuria (the individual averages ranged from 177 to 219 mg./ 24 hr. over the entire observation period). The BUN at the end of these periods was 15 mg./ 100 ml. blood for 2 patients and 17 for the other. Volume. The lack of relationship between urinary calcium excretion and volume is seen in figure 2. ·while many stone-formers have an unusually high urinary volume, this is not necessarily accompanied by a high calcium excretion (and vice versa). Only one urinary calcium exceeded 215 mg./24 hr. when the urinary volume exceeded 3 liters. Conversely, a urine volume of one liter/day was accompanied by an excretion of over 300 mg. calcium in two of the 143 patients. Catheterization. In 7 of 12 patients, calcium 36
""i
•01.
32
2000
'"
1500 I 000
.... ,·. ••
•
••
I
.. ::• ..:: : \
•
•
.r
'
500 0
200
100
300
400
24 hr. Urinary Ca. (mg.)
Fm. 2. Relationship between urinary volume and urinary calcium in 143 calculous disease patients. Each dot represents average of three or more specimens. 1. Urinary calcium excretion in patients showing differences in urine voliime from catheterized kidney (A) and bladder (B)
TABLE
Ca (mg)
Volume (ml)
Ca (mg.%)
Subject No. B B A B A A ------ --- - - --- --- ---
1 2 3 4 5 6 7
14.6 5.6 13.9 24.2 1.1 508 13.2
62.6 26.5 49.7 55.4 10.3 720 28.4
506 562 1122 1077 201 3749 455
496 497 498 849 154 3714 534
2.9 1.0 1.2 2.3 0.6 13.5 2.8
12.6 5.3 10.0 6.5 6.7 19.3 5.3
28 ~ 24
t
20
;,, :::,
16
"'
12 8
·• -----. ---- .---------------------------------------
4
o~---1~0~0---~20~0~--~3~0~0---~400 24 hr. Urinary Ca (mg.)
Fm. 1. Relationship between BUN and urinary calcium in 50 calculous disease patients. Broken lines indicate normal range established by clinical laboratory at this institution.
excretion by the catheterized kidney decreased, while the urinary volume was unchanged (table 1). The excretion of phosphate and sodium was bilaterally equal in one subject in whom these were determined. In 5 patients, the calcium excretion was unaffected, as were phosphate, sodium, hydrogen ion, creatinine and uric acid in all cases where these were determined. An additional patient with bilateral ureteral catheterization (with a Foley catheter in the bladder to confirm the absence of leakage around the ureteral catheters) excreted only 11 mg. calcium from one kidney and 6 mg. from the other, during a 24-hour period when he excreted 1440 ml.
FACTORS RELATED '1'0 URINARY CALCIUM
urine. A pre-test 24-hour specimen contained 76 mg. calcium. There was no obvious relationship between the results and the patients' disorders or clinical condition. DISCUSSION
The relationship of renal failure to calcium excretion has been primarily centered around situations in which hypercalcinuria secondary to hypercalcemia was associated with renal damage.11 Renal tubular acidosis is the only intrinsic renal disease that is known to cause a great increase in urinary calcium excretion. 3 The patient with calculous disease who consistently excretes more than 300 mg. calcium per day in the urine is obviously uncommon (figs. 1 and 2). The present studies give no indication that increased urinary calcium excretion rates produce injury to the kidney in the absence of concomitant hypercalcemia, which is generally recognized as being nephrotoxic. 11 Gill and Bartter feel that hypercalcinuria per se may be sufficient to cause impairment of urine concentration.12 Normocalcemic stone disease patients, averaging up to 220 mg. urinary calcium per day for as much as 7 years, still had normal BUN levels. It is also clear that significant renal damage, as indicated by a moderately elevated BUN,1 is infrequently accompanied by a subnormal calcium excretion, if the normal is considered to be 140 ± 50 (standard deviation) mg. Ca/day. 2 For practical clinical purposes, the two are not usefully related until the BUN is excessively high, 13 at which time there is a decreased calcium excretion. 11 Schreiner, G. E. and Maher, J. F.: Uremia: Biochemistry, Pathogenesis and Treatment. Springfield: C. C. Thomas, 1961, pp. 186-189. 12 Gill, J. R., Jr. and Bartter, F. C.: On the impairment of renal concentrating ability in prolonged hypercalcemia and hypercalciuria in man. J. Clin. Invest., 40: 716, 1961. 13 Kaye, IVI., Pritchard, J. E., Halpenny, G. W. and Light, W.: Bone disease in chronic renal fail-
68:3
The studies of Boyarsky on ureteral catheterization suggest that a reflex interference with renal function is the most likely cause of de-· creased calcium excretion from kidneys with catheters in the ureters. 14 The work of duMont and :iVIarggraff is also pertinent to the present study. 15 These investigators compared urine specimens collected simultaneously from each kidney by bilateral eatheterization. This precluded observation of the effect of ureteral catheterization per se. However, one (calculous disease) patient, from whom urine was collected for a 2-day period in the same manner as we have clone, showed a gradual decline in the urinary calcium concentration from the ureteral catheter as compared with urine from the other kidney. Those investigators also demonstrated that the calcium concentration of the urine from one kidney can differ from that of the contralateral kidney, and that such variation can be independent of variations in other parameters, such as rate of dye excretion, pH, and concentration of P, NH 3 , uric acid or urea. The contralateral kidney is therefore not as adequate a control as one could wish. SUMMARY
In calculous disease patients, no consistent relationships were seen between urinary calcium excretion and either moderately elevated BUN levels or urinary volume. No evidence was obtained that prolonged hypercalcinuria is in jurious to the kidney. Ureteral catheterization produced a decreased calcium excretion in a ma-j ority of patients. ure with particular reference to osteosclerosis . Medicine, 39: 157, 1960. 14 Boyarsky, S. and .Martinez, J.: Ureteral peristaltic pressures in dogs with changing urine flows. J. Urol., 87: 25, 1962. 15 DuMont, H. L. and Marggraff, A.: Studies on separate kidney urine. Z. Urol. 53: 401, 1960.
CLINICAL RELATIONSHIPS AMONG URINARY CALCIUM EXCRETION AND BLOOD UREA NITROGEN LEVELS, URINARY VOLUl\fE AND URETERAL CATHETERIZATION J. ERNEST LATHEM, WILLIAM H. BOYCE
AND
J. STANTON KING, JR.
From the Department of Urology, Bowman Gray School of Medicine, Winston-Salem, North Carnlina
The urinary excretion of calcium has large fluctuations, for reasons that are as yet incompletely clear.1. 2 The following report summarizes clinical observations of 3 factors related to urinary calcium excretion: 1) blood urea nitrogen (BUN), 2) urinary volume, and 3) ureteral catheterization. Urinary calcium excretion is generally expected to decrease as renal damage approaches the point of azotemia. If this is true, the clinician might expect to see an inverse relation between increased BUN, which is a rough index of the degree of renal damage 3 and decreased calcium excretion. This expectation was examined, while looking also for any indication that prolonged hypercalcinuria is injurious to the kidney. Secondly, it has been shown that experimental polyuria is accompanied by increased urinary calcium excretion. 4 - 6 This observation has been reported in clinical situations. 7 • 8 If consistently
true, the increased fluid intake popularly recommended to decrease urinary calcium concentration in renal stone-forming patients may be unhelpful or detrimental. Finally, separate collections of urine from each kidney are occasionally useful in experimental and diagnostic studies. We have obtained data. indicating that ureteral catheterization may affect the urinary excretion of calcium. METHODS
Accepted for publication December 13, 1963. Supported by grants A-259 and K3-I6,620, National Institute of Arthritis and Metabolic Diseases, National Institute of Health, United States Public Health Service and the John A. Hartford Foundation. 1 Heaton, F. W. and Hodgkinson, A.: External factors affecting diurnal variation in electrolyte excretion with particular reference to calcium and magnesium. Clin. Chim. Acta, 8: 46, 1963. 2 Lathem, J.E. and King, J. S., Jr.: Patterns of urinary calcium excretion in normal subjects and in renal calculous disease. J. Urol., 89: 541, 1963. 3 De Wardner, H. E. : The Kidney. Boston: Little, Brown and Co., 1961, pp. 26, 27, 179, 192. 4 Goff art, H. and Brull, L.: Debit urinaire du calcium et polyurie par ingestion d'eau. Compt. rend soc. biol., 118: 1630, 1935. 5 Brull, L., Poverman, R. and Goffart, H.: Recherches sur le metabolisme mineral. Arch. internat. physiol., 43: 238, 1936. 6 Causeret, J.: Influence de la consommation d'eau sur ]'elimination intestinale et renale du calcium. Compt. rend. Acad. Sci., 237: 664, 1953. 7 Mertz, D. P.: Untersuchungen i.iber die physiologiscben renalen Ausscheidungs-Verhaltnisse von Magnesium und Calcium. Klin. Wchnschr., 35: 1171. 1957. 8 Cottet, J.: Le syndrome biochimique des lithiases urinaires. In: Encyclopedia of Urology, Berlin: Springer-Verlag. Edited by C. E. Alken, V. W. Dix, H. M. Weyrauch and E. Wildbolz, 1961, vol. 10, p. 410.
Urinary calcium: BUN. Data covering periods of 12 to 84 months were obtained on 50 patients with renal calculous disease. BUN 9 and urinary calcium10 were determined at irregular intervals. Urinary calcium: Volume. One hundred fortythree stone formers, who had a minimum of three 24-hour urinary calcium determinations during the past 2 years, were the subject of this study. ·water intake was ad libitum. The calcium excretions and urinary volumes for each patient were averaged and graphed. Urinary calcium: Ureteral catheterization. 'Urine was collected from catheters inserted into one or both ureters. Collection intervals were 1 to 4 hours, usually for a total of 8 to 24 hours but for 5 days in 1 patient. When excretion of opposite kidneys was compared, a No. 5 woven or polyethylene ureteral catheter was inserted into one ureter and a Foley catheter into the bladder. The position of the tip of the ureteral catheter at the ureteropelvic junction was confirmed by x-ray. Twelve patients were studied in this manner. The proportionally equal volumes obtained from the 2 catheters indicated adequate drainage. The results for 4 further patients were excluded from this study because the volume of urine obtained from the catheterized kidney was markedly lower than the opposite one, indicating a technically
681
9 Koch, F. C.: A stable and convenient urease reagent and a modified blood urea method. J. Lab. & Clin. Med., 11: 774, 1926. 10 Clark, E. P. and Collip, J.B.: A study of the Tisdal] method for the determination of blood serum calcium, with a suggested modification. J. Biol. Chem., 63: 461, 1925.
682
LATHEM, BOYCE AND KING, JR.
inadequate experiment; however, one patient (case 3) is included who excreted a notably larger volume from the catheterized kidney. Patients in this group varied from the normal (who had a previously questionable excretory urogram, thus requiring a retrograde pyelogram) to the severe bilateral recurrent stone former.
4500 4000 3500 3000 ~
~
" ..,' ,,.
2500
!;
:',
RESULTS
BUN. The degree of relationship found between urinary calcium excretion and BUN is illustrated in figure 1. The excretion rate of calcium never exceeded 300 mg./24 hr. in a patient with an elevated BUN. Three patients were followed 48 to 84 months, with urinary calcium determined several times a year. All three had mild to moderate hypercalcinuria (the individual averages ranged from 177 to 219 mg./ 24 hr. over the entire observation period). The BUN at the end of these periods was 15 mg./ 100 ml. blood for 2 patients and 17 for the other. Volume. The lack of relationship between urinary calcium excretion and volume is seen in figure 2. ·while many stone-formers have an unusually high urinary volume, this is not necessarily accompanied by a high calcium excretion (and vice versa). Only one urinary calcium exceeded 215 mg./24 hr. when the urinary volume exceeded 3 liters. Conversely, a urine volume of one liter/day was accompanied by an excretion of over 300 mg. calcium in two of the 143 patients. Catheterization. In 7 of 12 patients, calcium 36
""i
•01.
32
2000
'"
1500 I 000
.... ,·. ••
•
••
I
.. ::• ..:: : \
•
•
.r
'
500 0
200
100
300
400
24 hr. Urinary Ca. (mg.)
Fm. 2. Relationship between urinary volume and urinary calcium in 143 calculous disease patients. Each dot represents average of three or more specimens. 1. Urinary calcium excretion in patients showing differences in urine voliime from catheterized kidney (A) and bladder (B)
TABLE
Ca (mg)
Volume (ml)
Ca (mg.%)
Subject No. B B A B A A ------ --- - - --- --- ---
1 2 3 4 5 6 7
14.6 5.6 13.9 24.2 1.1 508 13.2
62.6 26.5 49.7 55.4 10.3 720 28.4
506 562 1122 1077 201 3749 455
496 497 498 849 154 3714 534
2.9 1.0 1.2 2.3 0.6 13.5 2.8
12.6 5.3 10.0 6.5 6.7 19.3 5.3
28 ~ 24
t
20
;,, :::,
16
"'
12 8
·• -----. ---- .---------------------------------------
4
o~---1~0~0---~20~0~--~3~0~0---~400 24 hr. Urinary Ca (mg.)
Fm. 1. Relationship between BUN and urinary calcium in 50 calculous disease patients. Broken lines indicate normal range established by clinical laboratory at this institution.
excretion by the catheterized kidney decreased, while the urinary volume was unchanged (table 1). The excretion of phosphate and sodium was bilaterally equal in one subject in whom these were determined. In 5 patients, the calcium excretion was unaffected, as were phosphate, sodium, hydrogen ion, creatinine and uric acid in all cases where these were determined. An additional patient with bilateral ureteral catheterization (with a Foley catheter in the bladder to confirm the absence of leakage around the ureteral catheters) excreted only 11 mg. calcium from one kidney and 6 mg. from the other, during a 24-hour period when he excreted 1440 ml.
FACTORS RELATED '1'0 URINARY CALCIUM
urine. A pre-test 24-hour specimen contained 76 mg. calcium. There was no obvious relationship between the results and the patients' disorders or clinical condition. DISCUSSION
The relationship of renal failure to calcium excretion has been primarily centered around situations in which hypercalcinuria secondary to hypercalcemia was associated with renal damage.11 Renal tubular acidosis is the only intrinsic renal disease that is known to cause a great increase in urinary calcium excretion. 3 The patient with calculous disease who consistently excretes more than 300 mg. calcium per day in the urine is obviously uncommon (figs. 1 and 2). The present studies give no indication that increased urinary calcium excretion rates produce injury to the kidney in the absence of concomitant hypercalcemia, which is generally recognized as being nephrotoxic. 11 Gill and Bartter feel that hypercalcinuria per se may be sufficient to cause impairment of urine concentration.12 Normocalcemic stone disease patients, averaging up to 220 mg. urinary calcium per day for as much as 7 years, still had normal BUN levels. It is also clear that significant renal damage, as indicated by a moderately elevated BUN,1 is infrequently accompanied by a subnormal calcium excretion, if the normal is considered to be 140 ± 50 (standard deviation) mg. Ca/day. 2 For practical clinical purposes, the two are not usefully related until the BUN is excessively high, 13 at which time there is a decreased calcium excretion. 11 Schreiner, G. E. and Maher, J. F.: Uremia: Biochemistry, Pathogenesis and Treatment. Springfield: C. C. Thomas, 1961, pp. 186-189. 12 Gill, J. R., Jr. and Bartter, F. C.: On the impairment of renal concentrating ability in prolonged hypercalcemia and hypercalciuria in man. J. Clin. Invest., 40: 716, 1961. 13 Kaye, IVI., Pritchard, J. E., Halpenny, G. W. and Light, W.: Bone disease in chronic renal fail-
68:3
The studies of Boyarsky on ureteral catheterization suggest that a reflex interference with renal function is the most likely cause of de-· creased calcium excretion from kidneys with catheters in the ureters. 14 The work of duMont and :iVIarggraff is also pertinent to the present study. 15 These investigators compared urine specimens collected simultaneously from each kidney by bilateral eatheterization. This precluded observation of the effect of ureteral catheterization per se. However, one (calculous disease) patient, from whom urine was collected for a 2-day period in the same manner as we have clone, showed a gradual decline in the urinary calcium concentration from the ureteral catheter as compared with urine from the other kidney. Those investigators also demonstrated that the calcium concentration of the urine from one kidney can differ from that of the contralateral kidney, and that such variation can be independent of variations in other parameters, such as rate of dye excretion, pH, and concentration of P, NH 3 , uric acid or urea. The contralateral kidney is therefore not as adequate a control as one could wish. SUMMARY
In calculous disease patients, no consistent relationships were seen between urinary calcium excretion and either moderately elevated BUN levels or urinary volume. No evidence was obtained that prolonged hypercalcinuria is in jurious to the kidney. Ureteral catheterization produced a decreased calcium excretion in a ma-j ority of patients. ure with particular reference to osteosclerosis . Medicine, 39: 157, 1960. 14 Boyarsky, S. and .Martinez, J.: Ureteral peristaltic pressures in dogs with changing urine flows. J. Urol., 87: 25, 1962. 15 DuMont, H. L. and Marggraff, A.: Studies on separate kidney urine. Z. Urol. 53: 401, 1960.