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Regulation of plasma calcium in man McPherson, George Duncan 1959

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REGULATION OP PLASMA CALCIUM IN MAN BY GEORGE DUNCAN McPHERSON M.D., U n i v e r s i t y o f W e s t e r n O n t a r i o , 1956 A T H E S I S SUBMITTED I N PARTIAL FULFILMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE i n t h e D e p a r t m e n t o f PHYSIOLOGY We a c c e p t t h i s t h e s i s a s c o n f o r m i n g t o t h e r e q u i r e d s t a n d a r d . THE UNIVERSITY OF B R I T I S H COLUMBIA O c t o b e r , 1959 ABSTRACT The k i n e t i c s o f p l a s m a c a l c i u m r e g u l a t i o n i n man were s t u d i e d b y n o t i n g t h e r e s p o n s e t o i n t r a v e n o u s i n j e c t i o n o f c a l c i u m a s g l u c o n a t e g i v e n a t t h e r a t e o f 10 mg/kg/hr. T w e n t y - n i n e i n f u s i o n t e s t s were c a r r i e d o u t on 20 a d u l t m a l e s u b j e c t s . The s e r i e s c o m p r i s e d n o r m a l s , c a s e s o f h y p o p a r a t h y r o i d i s m , h y p e r p a r a t h y r o i d i s m , P a g e t ' s D i s e a s e , a n d o s t e o p o r o s i s . A l l were h o s p i t a l i z e d a t t h e t i m e o f t h e s t u d y . The c h a n g e s i n l e v e l s o f p l a s m a c a l c i u m , p h o s p h o r u s and c i t r a t e were f o l l o w e d b y f r e q u e n t b l o o d s a m p l i n g . E x c r e t i o n o f c a l c i u m , p h o s p h o r u s a n d c i t r a t e b y t h e k i d n e y was a l s o d e t e r m i n e d . I n a l l c a s e s , p l a s m a c a l c i u m l e v e l s r o s e i n r e s p o n s e t o t h e i n f u s i o n and d e c l i n e d s l o w l y a f t e r i t h a d e n d e d , r e t u r n i n g t o n o r m a l s e v e r a l h o u r s l a t e r . P l a s m a p h o s p h a t e a n d c i t r a t e a l s o r o s e s l i g h t l y , b u t more s l o w l y t h a n t h e p l a s m a c a l c i u m , a n d r e m a i n e d e l e v a t e d a s l o n g a s p l a s m a c a l c i u m was a b o v e n o r m a l . The i n c r e a s e i n t h e c a l c i u m e x c r e t i o n r a t e was d i r e c t l y p r o p o r t i o n a l t o t h e p l a s m a c a l c i u m d u r i n g t h e p e r i o d o f h y p e r c a l c e m i a . From t h i s l i n e a r r e l a t i o n s h i p i t was p o s s i b l e t o e s t i m a t e a t u b u l a r maximum (Tm) f o r r e a b s o r p t i o n o f c a l c i u m b y t h e r e n a l t u b u l e s . The v a l u e o b t a i n e d f o r c a l c i u m Tm i n t h i s s e r i e s o f 8 n o r m a l s u b j e c t s was 4.97 - 0.27 mg/min ( r a n g e 5.60 - 5-80). I n t h e one c a s e o f o s t e o p o r o s i s s t u d i e d , t h e Tm a p p e a r e d t o be i n c r e a s e d f o l l o w i n g c o r r e c t i o n o f a h y p e r c h l o r e m i c a c i d o s i s . The i n c r e a s e d c a l c i u m e x c r e t i o n d u r i n g h y p e r c a l c e m i a i s a most i m p o r t a n t h o m e o s t a t i c f a c t o r i n r e s t o r i n g t h e p l a s m a l e v e l t o n o r m a l . The r a p i d i t y o f t h e e x c h a n g e b e t w e e n t h e b o n e a n d t h e s o f t t i s s u e c a l c i u m c o m p a r t m e n t s a p p e a r e d t o be much g r e a t e r i n t h e c a s e s o f P a g e t ' s d i s e a s e , a s m i g h t be p r e d i c t e d f r o m t h e h i g h r a t e o f bone b l o o d f l o w c h a r a c t e r i s t i c o f t h i s d i s e a s e . I n p r e s e n t i n g t h i s t h e s i s i n p a r t i a l f u l f i l m e n t o f t h e r e q u i r e m e n t s f o r an a d v a n c e d d e g r e e a t t h e U n i v e r s i t y o f B r i t i s h C o l u m b i a , I a g r e e t h a t t h e L i b r a r y s h a l l make i t f r e e l y a v a i l a b l e f o r r e f e r e n c e and s t u d y . I f u r t h e r a g r e e t h a t p e r m i s s i o n f o r e x t e n s i v e c o p y i n g o f t h i s t h e s i s f o r s c h o l a r l y p u r p o s e s may be g r a n t e d by t h e Head o f my Department o r by h i s r e p r e s e n t a t i v e s . I t i s u n d e r s t o o d t h a t c o p y i n g o r p u b l i c a t i o n o f t h i s t h e s i s f o r f i n a n c i a l g a i n s h a l l n o t be a l l o w e d w i t h o u t my w r i t t e n p e r m i s s i o n . Department o f PHYSIOLOGY  The U n i v e r s i t y o f B r i t i s h C o l u m b i a , V a n c o u v e r 8, Canada. D a t e S e p t e m b e r 24. 1959 TABLE OF CONTENTS CHAPTER PAGE I INTRODUCTION 1 II METHODS 11 Subjects 11 Administration of Calcium 12 Diet 12 Collection of Samples 13 Observation of Patients 13 Analytical Methods 14 III RESULTS 15 Observation of the Subjects 15 Plasma Calcium 15 Urine Calcium 16 Phosphorus 17 Citrate 18 Treatment of Data 18 Plasma Calcium Curves . . . 20 IV DISCUSSION 21 V APPENDIX 28 CASE HISTORIES 28 SAMPLE CALCULATIONS 30 VI TABLES . 31 VII FIGURES 41 VIII BIBLIOGRAPHY 50 ACKNOWLEDGEMENTS The a u t h o r w i s h e s t o t h a n k D r . D.H. Copp, H e a d o f t h e D e p a r t m e n t o f P h y s i o l o g y , f o r h i s e n c o u r a g e m e n t , d i r e c t i o n , a n d s p o n s o r s h i p o f t h i s r e s e a r c h ; D r . H. M c i n t o s h f o r h i s c o u n s e l ; M r s . N. W i l s o n f o r h e r e x p e r t t e c h n i c a l a s s i s t a n c e ; Mr. K. Henze f o r p r e p a r a t i o n o f t h e g r a p h s ; t h e many o t h e r s o f t h e s t a f f s o f t h e D e p a r t m e n t o f P h y s i o l o g y a n d S h a u g h n e s s y H o s p i t a l f o r t h e i r c o o p e r a t i o n and h e l p f u l s u g g e s t i o n s ; a n d t h e N a t i o n a l R e s e a r c h C o u n c i l o f C a n a d a f o r f i n a n c i a l s u p p o r t o f t h i s p r o j e c t . i i i 1 INTRODUCTION The p u r p o s e o f t h i s s t u d y was t o i n v e s t i g a t e t h e e f f e c t s o f a c u t e i n t r a v e n o u s c a l c i u m l o a d i n g i n man, I t was h o p e d t h a t f r e q u e n t s a m p l i n g o f p l a s m a and u r i n e w o u l d g i v e i n s i g h t i n t o t h e k i n e t i c s o f c a l c i u m r e g u l a t i o n , b o t h i n n o r m a l s u b j e c t s , a n d i n t h o s e w i t h known d i s t u r b a n c e s o f m i n e r a l m e t a b o l i s m . The l a t t e r c o n s i s t e d o f h y p o p a r a t h y r o i d i s m o f b o t h i d i o p a t h i c a n d p o s t - s u r g i c a l t y p e s , h y p e r p a r a t h y r o i d i s m b e f o r e a n d a f t e r s u r g e r y , a n d c a s e s o f w i d e s p r e a d P a g e t ' s d i s e a s e o f bone ( o s t e i t i s d e f o r m a n s ) . The p l a s m a c a l c i u m l e v e l i s one o f t h e most c l o s e l y r e g u l a t e d b o d y c o n s t a n t s . The m e c h a n i s m s w h e r e b y t h i s c o n s t a n c y i s p r e s e r v e d r e m a i n p o o r l y u n d e r s t o o d d e s p i t e i n t e n s i v e i n v e s t i g a t i o n i n t o t h e many a s p e c t s o f c a l c i u m m e t a b o l i s m . The a s s o c i a t i o n o f h y p e r - o r h y p o c a l c e m i a w i t h many d i s e a s e s t a t e s , w h e t h e r a s a c a u s e o r a n e f f e c t , makes a s t u d y o f t h e n o r m a l r e g u l a t i o n o f p l a s m a c a l c i u m i m p o r t a n t . H y p e r c a l c e m i a a c c o m p a n i e s s u c h d i v e r s e c o n d i t i o n s a s p r i m a r y and s e c o n d a r y b one t u m o u r s , h y p e r p a r a t h y r o i d i s m , a d v a n c e d n e p h r i t i s and u r e m i a , P a g e t ' s d i s e a s e , a n d i m m o b i l i z a t i o n o f p a r t s o f t h e b o d y a s i n t h e t r e a t m e n t o f f r a c t u r e s . ( 2 9 ) . H y p o c a l c e m i a , on t h e o t h e r h a n d , i s a s s o c i a t e d w i t h d e f e c t s i n two o r g a n s - t h e p a r a t h y r o i d g l a n d and t h e k i d n e y . H y p o p a r a t h y r o i d i s m , w h e t h e r o f t h e p r i m a r y , p o s t - s u r g i c a l t y p e , o r o f t h e i d i o p a t h i c t y p e , l e a d s t o a f a l l o f p l a s m a c a l c i u m w h i c h may be s u f f i c i e n t t o c a u s e t e t a n y w i t h i t s s t r i k i n g c l i n i c a l s i g n s . R e n a l d e f e c t s may c a u s e h y p o c a l c e m i a b y a n e x c e s s i v e l o s s o f c a l c i u m a s i n 2 renal acidosis, renal rickets, and the Fanconi syndrome. (30,59,62). In the normal adult man, the concentration of calcium i n the plasma i s between 9 and 11 mg%. A 70 kilogram man has about 280 mg. of calcium i n the circulating plasma, of which 140 mg. i s i n the form of calcium ions. This ionized portion i s i n free and rapid exchange with the estimated 500 mg. of ionized calcium i n the 10 l i t r e s of i n t e r s t i t i a l f l u i d . (45). Isotopic studies show that as much as 52% to 80% of the plasma calcium exchanges with calcium of the i n t e r s t i t i a l f l u i d each minute. (3,64). McLean ca l l s the extracellular f l u i d calcium, the "calcium compartment", and states that i t amounts to 20% of the body weight, containing 700 mg. of calcium ions i n a 70 kilogram man.(45). The soft tissues contain considerable calcium. Muscle contains as much as 8-10 mg./lOO gms. wet weight.(21,28). However, much of this i s believed to be related to membranes, and McLean states that the contents of c e l l s are v i r t u a l l y free of calcium and do not participate i n the rapid exchange between the "calcium compartment" and bone. The calcium of body fluids i s divided into three chief forms: the freely ionized, the protein-bound, and the complexed, diffusible fraction. McLean and Hastings, i n 1935, (44) related the total calcium to the total protein and formulated a nomogram which relates the percentage of protein-bound calcium dire c t l y to total plasma protein levels. It has been accepted generally, 3 u n t i l r e c e n t l y , t h a t t h e p r o p o r t i o n s o f t h e two f r a c t i o n s r e m a i n c o n s t a n t a t a l l l e v e l s o f t o t a l c a l c i u m , i f o t h e r c o n d i t i o n s s u c h a s pH, a n d p l a s m a p r o t e i n l e v e l , a r e c o n s t a n t . However, t h e u l t r a f i l t r a t i o n s t u d i e s o f L l o y d a n d R ose ( 4 0 ) S u g g e s t t h a t t h e p r o t e i n - b o u n d f o r m i s s t a b l e , a n d t h a t t h e i o n i z e d f r a c t i o n v a r i e s w i t h t h e t o t a l l e v e l o f c a l c i u m . B e c a u s e o f t h e d i f f i c u l t y i n s e p a r a t i n g t h e s e f r a c t i o n s , most w o r k e r s h a d t o d e p e n d u p o n t o t a l c a l c i u m d e t e r m i n a t i o n s . The t o t a l c a l c i u m c o n t e n t o f a 70 k i l o g r a m a d u l t h a s b e e n a c c e p t e d a s 1200-1400 grams. Of t h i s , 11 grams a r e i n t h e s o f t t i s s u e s , a b o u t h a l f o f t h i s i n l i g a m e n t s and t e n d o n s (54-), a n d l e s s t h a n one gram i n t h e e x t r a c e l l u l a r f l u i d . T h u s , l e s s t h a n 1% o f t h e t o t a l b o d y c a l c i u m i s i n t h e b o d y f l u i d a n d s o f t t i s s u e s ; t h e r e s t f o r m s a r e s e r v e , i m p o r t a n t n o t o n l y a s p a r t o f t h e s u p p o r t i n g s t r u c t u r e o f bone b u t a l s o f u n c t i o n i n g a s a m i n e r a l b a n k t h a t c a n be d r a w n u p o n t o p r e s e r v e c a l c i u m l e v e l s i n t i m e s o f n e e d . ( 8 , 2 6 ) . The m e c h a n i s m o f c a l c i u m e x c h a n g e b e t w e e n b o d y f l u i d s and t h i s bone r e s e r v e h a s b e e n i n v e s t i g a t e d e x t e n s i v e l y b y i s o t o p e t e c h n i q u e s w h i c h h a v e c o n f i r m e d t h e p r e s e n c e o f a n e x c h a n g e a b l e f r a c t i o n o f t h e bone m i n e r a l i n e q u i l i b r i u m w i t h c a l c i u m i n b o d y f l u i d s . (5»4-2,25,60,11) . The c a l c i u m o f bone i s l a i d down i n c r y s t a l s o f c o l l o i d a l s i z e , 200 - 3 0 0 b y 20 - 5 0 A ° , i n w h i c h t h e c a l c i u m t o p h o s p h o r u s r a t i o i s b e t w e e n 1 . 3 a n d 2 . 0 . ( 5 0 ) . The c r y s t a l s a r e o r i e n t e d i n t h e l o n g a x i s o f t h e c o l l a g e n f i b r e s o f t h e o r g a n i c m a t r i x o f b o n e . The s m a l l s i z e o f t h e c r y s t a l s r e s u l t s i n a t r e m e n d o u s 4 surface area, estimated at 100 M2/gm of inorganic material (8,48,18). The exchangeable or l a b i l e form of calcium i s held on the surface of the bone crystals i n the hydration layer proposed by Neuman ( 5 0 ) . This fraction, estimated at 1-4% of the total bone calcium, i s readily available to buffer any sudden change of plasma calcium (10) by i t s contact with the plasma flowing through bone. Blood to bone exchange of mineral appears to be governed largely by a physico-chemical exchange on this surface (43). In addition, there are deeper reactions between the hydration layer and the crystal, and a recrystallization within the l a t t i c e i t s e l f . Accretion and resorption processes also modify the exchange, especially i n the period of active growth of bone (4,50,5 54-9). Parathyroid hormone i s believed to maintain the constant calcium level i n plasma by exerting some control over the blood-bone equilibrium of calcium. The means whereby this control i s exerted has not yet been established. McLean postulated that chemical dynamics of the l a b i l e fraction maintain blood levels up to 7 mg%, but that the f i n a l regulation i s due to a feedback mechanism of parathyroid stimulation i n response to hypocalcemia, serving to mobilize more calcium from bone (43). Patt and Luckhardt (53) showed that the parathyroid gland responded to changing calcium levels, so a feedback appears possible. Howard (34) supported this view, stating that a gradient exists at the blood-bone interface to preserve a high blood calcium level, under the influence of the parathyroids. 5 Neuman (19) has postulated that the mechanism of the ion-gradient on the bone surface i s the production of citrate by-c e l l s l o c a l l y under the influence of parathyroid hormone. Citrate i s present i n bone i n large amounts - 1% of the fresh weight of bone (15). C i t r i c acid i s capable of chelating calcium; i t i s readily produced at the bone surface, and i s metabolized elsewhere, chiefly i n the kidney, so i t may well be the mechanism for maintaining the bone-blood gradient (37)' The other proposed site of action of parathyroid hormone i s the kidney. In 1929, Albright (2) advanced the theory that parathyroid hormone caused phosphaturia and a secondary rise i n blood calcium by lowering the Ca x P product. This has not been supported. Jahan and P i t t s , i n 1948, (36) concluded that the hypercalcemia and hypercalcuria produced by administration of parathyroid hormone were dependent upon an extrarenal action of the hormone i n mobilizing calcium from the body stores, not upon any specific depression of renal tubular reabsorption of either phosphorus or calcium. Handler and Conn have shown that the phosphaturic effect of parathyroid hormone seemed to depend upon experimental conditions and the means by which the parathyroid hormone was administered (24). Calcium loading techniques have been widely used to study calcium regulation. A good deal of the pertinent work has been directed toward studying the response of blood and urine phosphate levels to calcium loading as an estimation of parathyroid activity, rather than to study calcium kinetics 6 directly (27,35,38). While the kidney i s prominent i n the regulation of other electrolytes, i t s role regarding calcium has not been emphasized. If the diffusible fraction i s 60% of the total plasma calcium, then the f i l t e r e d load per day i s 180 l i t r e s x 60 mg. or 10.8 gms. Since normal excretion i s less than 300 mg/day, the reabsorptive mechanism must be very effici e n t (45). The presence of a tubular reabsorption maximum (Tm) for calcium would help to explain the minute to minute constancy of plasma levels. While a high Tm would raise blood levels, a lowered Tm might not be reflected i n lower blood levels as long as mobilization of calcium from the bones was e f f i c i e n t . Since there i s a tremendous reserve, this d e f i c i t could be compensated for a long time. Investigation into the relation between plasma levels of calcium and renal excretion rates, which are necessary to calculate the tubular maximum, have been done by several workers (57,52,66,31)• Their clearance periods have often been short, or else plasma levels have not been well defined, so that conclusive results were not obtained. In 19^-9, Wolff and B a l l (66), working on dogs given an intravenous calcium load, stated that there was no effective threshold for retention of calcium, and that the plasma level of calcium was apparently not regulated appreciably by renal function. Freedman et a l (20), i n 1958, stated that only a small fraction of the calculated increase i n the f i l t e r e d 7 l o a d o f c a l c i u m was e x c r e t e d . W i l l i a m s o n a n d F r e e m a n ( 6 5 ) s t a t e d t h a t c a l c i u m r e a b s o r p t i o n v a r i e d d i r e c t l y w i t h t h e f i l t e r e d c a l c i u m l o a d . P o u l o s , i n 1 9 5 7 , ( 5 5 ) o b s e r v e d e x c r e t i o n r a t e s i n d o g s g i v e n i n t r a v e n o u s c a l c i u m , a n d c o u l d n o t d e m o n s t r a t e a t u b u l a r maximum f o r c a l c i u m . He s t u d i e d p l a s m a l e v e l s a s h i g h a s 3 7 mg% w h i c h w e r e above t h e p h y s i o l o g i c a l r a n g e . C h e n an d Keuman ( 1 2 ) were a l s o u n a b l e t o d e m o n s t r a t e , a f t e r i n t r a v e n o u s c a l c i u m l o a d i n g i n d o g s , t h a t c a l c i u m e x h i b i t e d a Tm. On t h e o t h e r h a n d , A l b r i g h t ( 1 ) , i n 1 9 2 9 , o b s e r v e d a " r e n a l t h r e s h o l d " f o r c a l c i u m e x c r e t i o n a t 8 . 5 mg% i n a h y p o p a r a t h y r o i d p a t i e n t g i v e n i n t r a v e n o u s c a l c i u m . McCance and Widdowson, i n 1 9 3 9 (4-1) gave i n t r a v e n o u s c a l c i u m t o p e r s o n s on a c o n t r o l l e d b a l a n c e s t u d y and n o t e d i t s r a p i d e x c r e t i o n i n t h e u r i n e . T h e y s t a t e d t h a t , t h e k i d n e y must be v e r y s e n s i t i v e t o c h a n g e s i n p l a s m a c a l c i u m l e v e l s . The f i r s t r e f e r e n c e t o a Tm f o r c a l c i u m i s b y Goldman and B a s s e t t , i n 1 9 5 4 ( 2 3 ) who n o t e d t h e r e s p o n s e o f t h r e e p a t i e n t s w i t h h y p o p a r a t h y r o i d i s m t o i n t r a v e n o u s c a l c i u m . A t h r e s h o l d o f e x c r e t i o n was n o t e d i n e a c h , and t h e r e seemed t o be a l i n e a r r e l a t i o n s h i p b e t w e e n c a l c i u m e x c r e t i o n r a t e s a n d t h e p l a s m a l e v e l , a b o v e t h e " r e n a l t h r e s h o l d " . A n y l o a d i n g t e c h n i q u e u s i n g i n t r a v e n o u s c a l c i u m must c o n s i d e r t h e p o s s i b l e r e s p o n s e o f t h e g a s t r o - i n t e s t i n a l t r a c t . The k i d n e y i s known t o r e s p o n d b y i n c r e a s e d e x c r e t i o n , b u t most e v i d e n c e s u g g e s t s t h a t t h e r e i s no a c t i v e e x c r e t i o n o f 8 calcium into the gastro-intestinal tract i n response to raised blood levels. Christiansen, i n 1937, (13) , using rabbits, rats, and goats, could find no active gastrointestinal excretion on intravenous calcium loads. McCance and Widdowson (41), i n their balance study on men given additional intravenous calcium load, noted that excretion of the calcium was via the urine rather than the feces. Baylor, et a l (7) gave intravenous calcium and observed fecal and urinary excretion. They found no change in the fecal calcium content. Having considered b r i e f l y the general responses of the kidney versus the gastrointestinal tract to intravenous calcium, loads, we turn to the question of the fate of intravenous calcium, and i n particular, i t s retention in the body. In 1924, Salvesen and Hastings (56) noted the retention of calcium following intravenous loading. Greville, in 1931 (22) noted the rapid disappearance of calcium following intravenous injection and found that this rapid disappearance from the blood occured even in eviscerated and nephrectomized dogs, and concluded that the i n i t i a l rapid f a l l of blood calcium was due to uptake into the skeleton. More recently, many authors have used calcium infusions and have noted the recovery in the urine over the next 24 hours as measured above the control excretion. Recovery has ranged from 20% - 60% of the dose i n various series (38 ,52,31 ,9) . Laszlo, i n 1951 (57) related urine calcium recovery to bone metabolism, stating that high recovery indicated osteolytic processes, low recovery, osteoblastic processes. Others have used the calcium tolerance 9 t e s t a s a g e n e r a l i n d i c a t o r o f bone m e t a b o l i s m , p a r t i c u l a r l y i n r e g a r d t o o s t e o p o r o s i s a n d o s t e o m a l a c i a (61,58). I t h a s b e e n s u g g e s t e d t h a t r e t e n t i o n may be due t o a l a y i n g down o f new b one m i n e r a l a t t h e h i g h l e v e l s o f p l a s m a c a l c i u m e x i s t i n g f o r a s h o r t t i m e d u r i n g t h e s e t e s t s (33). The s t u d y r e p o r t e d i n t h i s t h e s i s was an e x t e n s i o n o f i n v e s t i g a t i o n s o n c a l c i u m k i n e t i c s done b y Copp e t a l ( 1 4 ) o n d o g s an d p i g s . U s i n g c o n t r o l l e d , r a p i d i n f u s i o n r a t e s o f c a l c i u m g l u c o n a t e , w i t h f r e q u e n t s a m p l i n g o f p l a s m a c a l c i u m , t h e s e w o r k e r s were a b l e t o f o l l o w t h e r e s p o n s e o f t h e p l a s m a c a l c i u m l e v e l . T h i s work h a s shown t h a t e x c r e t i o n b y t h e k i d n e y i s i m p o r t a n t i n r e s t o r i n g t h e p l a s m a c a l c i u m l e v e l t o n o r m a l a f t e r an i n t r a v e n o u s c a l c i u m l o a d . F u r t h e r a n a l y s i s o f t h e c u r v e s s u g g e s t e d t h a t t h e m i x i n g r a t e b e t w e e n t h e c a l c i u m " c o m p a r t m e n t " o f e x t r a c e l l u l a r f l u i d a n d t h e bone m i g h t be d e r i v e d a s a m easure o f b o n e - b l o o d f l o w . I t was h o p e d t h a t t h e a d a p t a t i o n o f t h i s a c u t e i n t r a v e n o u s i n f u s i o n t e s t t o man m i g h t g i v e i n f o r m a t i o n o n t h e f a c t o r s r e g u l a t i n g t h e n o r m a l p l a s m a l e v e l i n b o t h n o r m a l s u b j e c t s a n d i n s u b j e c t s w i t h p a r a t h y r o i d d i s e a s e s . The c a s e s o f P a g e t ' s d i s e a s e were c h o s e n b e c a u s e o f t h e known h i g h b l o o d f l o w f o u n d c l i n i c a l l y i n t h i s c o n d i t i o n ( 1 7 ) . F r e q u e n t p l a s m a and u r i n e s a m p l i n g was done i n an a t t e m p t t o e s t a b l i s h t h e r o l e o f t h e k i d n e y i n t h e e x c r e t i o n o f t h e l o a d ; and t o s t u d y t h e e x t r a - r e n a l m echanism w h i c h i s r e s p o n s i b l e f o r t h e r e t e n t i o n o f p a r t o f t h e d o s e , p r e s u m a b l y b y s k e l e t a l u p t a k e . A t t h e same 10 t i m e , t h e c h a n g e s i n p h o s p h o r u s a n d c i t r a t e c o u l d "be f o l l o w e d a n d m i g h t be r e l a t e d i n t i m e a n d a m p l i t u d e t o t h e c h a n g e s i n p l a s m a c a l c i u m l e v e l s . 11 METHODS S u b j e c t s : The e x p e r i m e n t a l s e r i e s c o m p r i s e d 20 a d u l t , m a l e p a t i e n t s , r a n g i n g i n age f r o m n i n e t e e n t o e i g h t y - t h r e e y e a r s . A l l were a m b u l a t o r y a n d i n g o o d g e n e r a l c o n d i t i o n a t t h e t i m e o f t h e s t u d y . C a s e s number 13, 15 a n d 18 were h o s p i t a l i z e d on t h e M e t a b o l i c w a r d o f t h e V a n c o u v e r G e n e r a l H o s p i t a l . The o t h e r s w ere p a t i e n t s i n t h e C l i n i c a l I n v e s t i g a t i o n U n i t a t S h a u g h n e s s y H o s p i t a l , V a n c o u v e r . R e p e a t i n f u s i o n t e s t s were done on n i n e s u b j e c t s , a t i n t e r v a l s r a n g i n g f r o m n i n e d a y s t o s e v e r a l months f o l l o w i n g t h e i n i t i a l i n f u s i o n . O f t h e s e r i e s , e i g h t s u b j e c t s were c o n s i d e r e d t o be n o r m a l i n r e g a r d t o m i n e r a l m e t a b o l i s m . F i v e s u b j e c t s s u f f e r e d f r o m w i d e s p r e a d P a g e t ' s d i s e a s e o f bone ( O s t e i t i s d e f o r m a n s ) c o n f i r m e d b y X - r a y . C a s e 11 h a d d e v e l o p e d h y p o p a r a t h y r o i d i s m f o l l o w i n g t h y r o i d e c t o m y , a n d c a s e 13 h a d i d i o p a t h i c h y p o p a r a t h y r o i d i s m . C a s e 18 was s t u d i e d b e f o r e a n d a f t e r r e m o v a l o f a p a r a t h y r o i d adenoma. C a s e 14 was d i a g n o s e d a s o s t e o p o r o s i s o n X - r a y . D e t a i l s o f t h e c a s e s a r e g i v e n on p a g e s 28 a n d 29. 12 Administration of Calcium: Calcium was given as calcium gluconate 10% (Nadeau) and the dosage was calculated as 10 mg. calcium per kg. body weight. The 10% solution contained 9*3 mg. Ca per cc. The required amount of calcium gluconate was made up to a standard volume of 180 cc. with d i s t i l l e d water, and was mixed thoroughly. The solution was administered intravenously into the antecubital vein at a constant rate of 3 cc per minute from a graduated burette, to make a standard infusion rate of 10 mg. Ca/Kg/hr. for one hour. In most cases, the infusion was carried out between 9:30 and 10:30 a.m. In two cases, numbers 11(b) and 13, a two hour infusion was done, using double the dose and volume, but the same rate of flow, and running from 9:30 a.m. to 11:30 a.m. Diet: The earlier tests were done i n the fasting state: that i s , patients were allowed water ad libitum on the day of the test, but did not eat u n t i l five or six hours after the infusion - at about 3:00 p.m., when they resumed a standard hospital diet. Case 5 was studied both on high (1500 mg calcium per day) and on low (150 mg calcium per day) calcium diet. Later cases consumed a standard hospital diet at the normal meal times on the day of the test, the calcium content being approximately 500 mg. per day and being the same on the control days before and after the test. 13 C o l l e c t i o n o f S a m p l e s : 5 c c . b l o o d s a m p l e s were c o l l e c t e d i n d r y s y r i n g e s b y v e n i p u n c t u r e i n t h e arm o p p o s i t e t o t h e i n f u s i o n , u s u a l l y f r o m a s i n g l e v e i n . B l o o d was t r a n s f e r r e d , a t o n c e , t o d r y h e p a r i n i z e d c e n t r i f u g e t u b e s and c e n t r i f u g e d . The p l a s m a was t h e n t r a n s f e r r e d t o c l e a n , d r y s p e c i m e n t u b e s w h i c h w e r e s e a l e d w i t h p a r a f i l m . C a r e was t a k e n t o n o t e t h e e x a c t t i m e o f e a c h b l o o d s a m p l e . P o u r c o n t r o l s a m p l e s b e f o r e t h e i n f u s i o n , t h e n f o u r 15 m i n u t e s a m p l e s d u r i n g t h e i n f u s i o n h o u r , w e r e f o l l o w e d b y 30 m i n u t e a n d one h o u r s a m p l e s f o r t h e s i x o r s e v e n h o u r s f o l l o w i n g t h e i n f u s i o n . F u r t h e r s a m p l e s were t a k e n , i n some c a s e s , d u r i n g t h e f o l l o w i n g 18 h o u r s . A l l b l o o d s a m p l e s were a n a l y z e d f o r t o t a l c a l c i u m , i n o r g a n i c p h o s p h a t e a n d c i t r a t e . The p a t i e n t s v o i d e d i n t o c l e a n u r i n e b o t t l e s a t t i m e i n t e r v a l s o f one h o u r b e f o r e , d u r i n g , and f o r f i v e o r s i x h o u r s f o l l o w i n g t h e i n f u s i o n . C o l l e c t i o n s were c a r r i e d o u t a t l o n g e r i n t e r v a l s t o c o m p l e t e a 24 h o u r p e r i o d a f t e r t h e s t a r t o f t h e t e s t . N e a r l y a l l c a s e s h a d a f r a c t i o n a t e d c o n t r o l 24 h o u r u r i n e c o l l e c t i o n p r i o r t o t h e t e s t d a y . The e x a c t t i m e o f v o i d i n g was m a r k e d o n t h e b o t t l e . A l l u r i n e s a m p l e s w e r e a n a l y z e d f o r c o n t e n t o f c a l c i u m , p h o s p h a t e and c i t r a t e . O b s e r v a t i o n o f P a t i e n t s : The p a t i e n t s were o b s e r v e d c a r e f u l l y f o r a n y s u b j e c t i v e o r o b j e c t i v e r e s p o n s e t o h y p e r c a l c e m i a . ECG t r a c i n g s were done b e f o r e a n d a t t h e end o f i n f u s i o n i n t h e f i r s t t e n c a s e s . 14 Analytical Methods: Plasma calcium was analyzed "by the Copp modification of the photometric t i t r a t i o n method of Lehmann (39). Urine calcium was determined i n the same manner after precipitation of the phosphate and protein by Horner's method (32). Plasma and urine inorganic phosphates were determined according to the method of Taussky and Shorr (63). Plasma and urine citrates were determined according to the method of Natelson, Pincus and Lugovoy (46). In some cases, glomerular f i l t r a t i o n rate was measured independently using the i n u l i n clearance procedure. 15 RESULTS O b s e r v a t i o n o f t h e S u b j e c t s : The p a t i e n t s were o b s e r v e d c a r e f u l l y d u r i n g a n d a f t e r t h e i n f u s i o n . T h e r e w e r e no u n t o w a r d r e a c t i o n s t o t h e i n d u c e d h y p e r c a l c e m i a , a s i d e f r o m a s e n s a t i o n o f " l i g h t h e a d e d n e s s " i n two o f t h e n o r m a l s u b j e c t s n e a r t h e e n d o f t h e i n f u s i o n . I t was i n t e r e s t i n g t o n o t e i n t h e two c a s e s o f h y p o p a r a t h y r o i d i s m , t h e d i s a p p e a r a n c e o f o b j e c t i v e s i g n s o f n e u r o m u s c u l a r i r r i t a b i l i t y ( C h v o s t e k ' s a n d T r o u s s e a u ' s s i g n s ) , a n d t h e g e n e r a l f e e l i n g o f w e l l - b e i n g d u r i n g t h e t i m e t h a t t h e p l a s m a c a l c i u m was e l e v a t e d a b o v e 8 mg%. ECG t r a c i n g s , done b e f o r e t h e i n f u s i o n a n d n e a r t h e end o f t h e i n f u s i o n i n 10 c a s e s , d i d n o t show a n y c a r d i a c e f f e c t due t o h y p e r c a l c e m i a . P l a s m a C a l c i u m : C o n t r o l c a l c i u m l e v e l s i n n o r m a l s u b j e c t s r e m a i n e d c o n s t a n t a t 9*4-9 - 0.0? mg%, w i t h l i t t l e v a r i a t i o n when r e -t e s t e d weeks l a t e r ( T a b l e I ) . However, i n t h e c a s e s o f P a g e t 1 s d i ' s e a s e , t h e c o n t r o l l e v e l s v a r i e d c o n s i d e r a b l y i n s u b s e q u e n t t e s t s . The a v e r a g e r e s t i n g l e v e l was 8.83 - 0.36 mg% ( T a b l e I I ) . The two c a s e s o f h y p o p a r a t h y r o i d i s m h a d c a l c i u m l e v e l s a s l o w a s 5*65 a n d 6.55 mg%. The one c a s e o f h y p e r p a r a t h y r o i d i s m h a d a c o n t r o l l e v e l o f 13-90 mg%, w h i c h f e l l t o 9-35 mg% p o s t -o p e r a t i v e l y . D e s p i t e t h e v a r i a t i o n i n l e v e l s i n t h e d i f f e r e n t t y p e s o f c a s e s , t h e c o n t r o l p l a s m a c a l c i u m l e v e l s o f e a c h p a t i e n t d i d n o t v a r y s i g n i f i c a n t l y on t h e d a y o f t h e t e s t . 16 The u n i f o r m r e s p o n s e o f a l l c a s e s t o a n i n f u s e d l o a d o f c a l c i u m was a r i s e i n t h e p l a s m a c a l c i u m t h r o u g h o u t t h e i n f u s i o n p e r i o d , r e a c h i n g a p e a k a t t h e end o f t h e i n f u s i o n , a n d f a l l i n g o f f r a p i d l y t h e r e a f t e r . I n t h e n o r m a l s , t h e p e a k r a n g e d f r o m 3.05 mg% t o 4 .15 mg% a b o v e t h e c o n t r o l l e v e l ( T a b l e s I a n d I I I ) . I n P a g e t ' s d i s e a s e , t h e r i s e a v e r a g e d 1.84 - 0.25 mg% ( T a b l e I I ) . The h y p o p a r a t h y r o i d c a s e s showed a r i s e o f 5.25 mg% a n d 6.20 mg% i n r e s p o n s e t o a t w o - h o u r i n f u s i o n o f 20 mg. Ca/Kg. The p l a s m a c a l c i u m l e v e l i n t h e h y p e r p a r a t h y r o i d s u b j e c t r o s e 3.00 mg%. D u r i n g a s e c o n d i n f u s i o n g i v e n one week a f t e r r e m o v a l o f a p a r a t h y r o i d adenoma, t h e p l a s m a c a l c i u m r o s e 3.10 mg%. F o l l o w i n g t h e i n f u s i o n , t h e i n i t i a l d r o p i n t h e p l a s m a c a l c i u m was r a p i d f o r a b o u t one and a h a l f h o u r s , a n d t h e r e a f t e r f e l l more s l o w l y , r e t u r n i n g t o n o r m a l s i x t o t w e n t y - f o u r h o u r s a f t e r t h e i n f u s i o n . A t no t i m e d i d t h e p l a s m a c a l c i u m l e v e l f a l l b e l o w t h e s u b j e c t ' s c o n t r o l l e v e l . The c u r v e s a p p e a r e d t o be smooth. T y p i c a l p a t t e r n s f o r t h e p l a s m a c a l c i u m r e s p o n s e t o t h e i n f u s i o n emerged, a s shown i n t h e c u r v e s f o r n o r m a l , P a g e t ' s d i s e a s e , h y p o p a r a t h y r o i d a n d h y p e r p a r a t h y r o i d c a s e s ( F i g u r e s 1, 2, 3, 4 ) . U r i n e C a l c i u m : R a t e s o f u r i n e e x c r e t i o n were m e a s u r e d i n mg/min f o r t h e c o n t r o l and p o s t - i n f u s i o n h o u r l y c o l l e c t i o n p e r i o d s . The r a t e o f u r i n e c a l c i u m e x c r e t i o n i n c r e a s e d a s t h e p l a s m a c a l c i u m l e v e l r o s e a b o v e t h e " t h r e s h o l d " p l a s m a l e v e l , w h i c h was a b o u t 10 mg% i n t h e n o r m a l c a s e s ( T a b l e I ) . I n c r e a s e d u r i n e c a l c i u m 17 excretion was not observed i n cases of Paget's disease where the rise in plasma calcium level was very small. (Figures 6, 7, 8) (Table II). The net retention of calcium by the body was determined by subtracting from the infusion dose the excess excretion of the test day above that of the control day. Results were expressed as percentage of dose retained. In normal cases, the retention varied from 37-64%. Some cases of Paget*s disease and of hypoparathyroidism showed almost complete retention. Phosphorus: In the normal subjects, the control level of plasma phosphorus was 3.24 - 0.14 mg%. Patients with Paget's disease had control levels averaging 3*15 - 0.18 mg%, which was not significantly different from the normals. The two hypoparathyroid cases had control phosphorus levels of 5*13 -0.60 mg%. The hyperparathyroid subject had a control plasma phosphorus of 2.20 mg% pre-operatively and 3.50 mg% one week after the parathyroid adenoma had been removed. Plasma phosphorus rose in response to the calcium infusion but the rise was always delayed 1/2 - 1 hour i n comparison to the rise i n calcium l e v e l . In normals, the rise averaged 1.00 - 0.08 mg% while i n Paget's disease the rise was only 0.18 - 0.13 mg%. There was l i t t l e or no peak observed in the normal plasma phosphorus curve; but i n cases of hypoparathyroidism the plasma phosphorus rose to a definite peak 2.40 mg% above the 18 c o n t r o l l e v e l a n d t h e n r e t u r n e d t o n o r m a l . I n some c a s e s no c h a n g e i n p h o s p h o r u s l e v e l was n o t e d . The e x c r e t i o n o f p h o s p h o r u s r o s e a s c a l c i u m e x c r e t i o n i n c r e a s e d , a n d r e t u r n e d t o n o r m a l a s t h e c a l c i u m l e v e l i n p l a s m a a p p r o a c h e d n o r m a l l e v e l s . The e x c r e t i o n r a t e o f p h o s p h o r u s d i d n o t show a l i n e a r r e l a t i o n t o p l a s m a p h o s p h o r u s l e v e l s . C i t r a t e , : C o n t r o l p l a s m a c i t r a t e c o n c e n t r a t i o n was 1 .65 - 0 .20 mg% i n t h e n o r m a l s u b j e c t s , 3 .58 - 0.24 mg% i n t h e p a t i e n t s w i t h P a g e t ' s d i s e a s e , a n d 1 .63 - 0 .09 mg% i n h y p o p a r a t h y r o i d c a s e s . P l a s m a c i t r a t e r o s e i n r e s p o n s e t o t h e c a l c i u m i n f u s i o n - r i s i n g 0 . 3 5 - 0.14 mg% i n n o r m a l s , 0 .15 - 0 .15 mg% i n P a g e t ' s d i s e a s e , a n d 0 .98 - 0 .03 mg% i n t h e h y p o p a r a t h y r o i d s u b j e c t s . The r a t e o f c i t r a t e e x c r e t i o n r o s e d u r i n g and f o l l o w i n g t h e i n f u s i o n b u t d i d n o t show a l i n e a r r e l a t i o n t o p l a s m a c i t r a t e l e v e l s . T r e a t m e n t o f D a t a : A s a m p l e c a l c u l a t i o n o f t h e d a t a f r o m p a t i e n t n o . 2 h a s b e e n w o r k e d o u t o n p a g e 30 » When e x c r e t i o n r a t e s i n mg/min (UY) were p l o t t e d a g a i n s t t h e mean p l a s m a l e v e l ( P ) o v e r t h e c o r r e s p o n d i n g t i m e i n t e r v a l , a s t r a i g h t l i n e was o b t a i n e d . S i n c e u r i n e c o l l e c t i o n s were made o v e r h o u r l y p e r i o d s f o r a t l e a s t f i v e h o u r s a f t e r t h e i n f u s i o n e n d e d , a t l e a s t f i v e c l e a r a n c e p e r i o d s c o u l d be s t u d i e d . The p e r i o d s were s u f f i c i e n t l y l o n g so t h a t t h e l a g f r o m t h e k i d n e y t o b l a d d e r c o u l d b e n e g l e c t e d . 19 Where incomplete emptying of the bladder was suspected, i t was usually found that the following period compensated for the low value. This was checked by calculating excretion rate vs. plasma calcium level on overlapping two hourly clearance periods. The linear relationship of UV vs P was a constant finding i n a l l cases where the plasma calcium had risen above a "threshold" le v e l . The slope of the line ku = UV/P i s dependent upon the GFR and upon the diffusible fraction of the plasma calcium, that i s , the f i l t e r e d load of calcium. In the later cases, where GFR was determined by the inu l i n clearance technique, the diffusible fraction was found to be 50 - 60% of the total plasma calcium. The above can be summarized by the equation: UV = GFR x P x d - Tm where UV = excretion rate in mg/min. GFR = glomerular f i l t r a t i o n rate (Ml/min) = inulin clearance (Cin). P = mean plasma calcium over each time period i n mg%. d = diffusible fraction of total plasma calcium. Tm = a constant = tubular reabsorption maximum (Mg. Ca/min). The dependence of excretion of calcium upon the plasma calcium concentration suggested a definite tubuler reabsorption maximum. This appeared to correspond to the normal plasma concentration i n the normal subjects, but i n the cases with a 20 l o w c o n t r o l c a l c i u m l e v e l ( P a g e t ' s d i s e a s e a n d h y p o p a r a t h y r o i d i s m ) t h e Tm was n o t e x c e e d e d u n l e s s t h e p l a s m a c a l c i u m was r a i s e d a b o v e a p p r o x i m a t e l y 10 mg%. P l a s m a C a l c i u m C u r v e s : The f a c t t h a t a l l t h e p l a s m a c a l c i u m c u r v e s showed a smo o t h d e c l i n e , r a p i d a t f i r s t , t h e n much s l o w e r a s n o r m a l c a l c i u m l e v e l s were a p p r o a c h e d , s u g g e s t e d t h a t t h e r a t e o f d e c l i n e m i g h t be r e l a t e d t o t h e p l a s m a c a l c i u m l e v e l s , a s d e m o n s t r a t e d b y i n t e g r a t i n g t h i s o v e r f i n i t e t i m e i n t e r v a l s . P l o t t i n g t h e r a t e o f d e c r e a s e o f p l a s m a c a l c i u m (A P / ^ t ) v e r s u s t h e i n t e g r a t e d mean p l a s m a c a l c i u m (Pm) o v e r s h o r t f i n i t e t i m e i n t e r v a l s g a v e a s t r a i g h t l i n e w h i c h " b r o k e " a t a p l a s m a l e v e l ( P x ) a b o u t 1 mg% a b o v e t h e n o r m a l p l a s m a l e v e l ( F i g u r e 9). I f one assumes t h a t t h e f u r t h e r d e c l i n e i n p l a s m a c a l c i u m l e v e l b e l o w P x i s due e n t i r e l y t o c a l c i u m e x c r e t i o n i n u r i n e , i t i s p o s s i b l e t o e s t i m a t e t h e s i z e o f t h e b o d y c a l c i u m p o o l f r o m w h i c h t h i s w o u l d be drawn. I n t h e n o r m a l s u b j e c t s s t u d i e d t h i s was f o u n d t o be 18 - 25 mg. Ca/Kg. b o d y w e i g h t . 21 DISCUSSION F o r t h e p u r p o s e o f d i s c u s s i o n , i t i s c o n v e n i e n t t o c o n s i d e r a s i m p l i f i e d c o m p a r t m e n t s y s t e m f o r c a l c i u m movement. T h i s h a s b e e n h e l p f u l i n t h e a n a l y s i s o f c a l c i u m t r a n s p o r t a n d e x c h a n g e u s i n g r a d i o i s o t o p e s (6). However, l o a d i n g w i t h c a l c i u m a l t e r s t h e m o d e l c o n c e p t somewhat b e c a u s e we a r e c o n c e r n e d w i t h e f f e c t s on t o t a l c o n c e n t r a t i o n a n d n o t so much w i t h r a t e s o f e x c h a n g e o c c u r i n g w i t h i n t h e s u b d i v i s i o n s o f t h e c o m p a r t m e n t . The m o d e l p r o p o s e d i s made up o f a " c a l c i u m c o m p a r t m e n t " c o r r e s p o n d i n g t o t h e " c a l c i u m c o m p a r t m e n t " o f M c L e a n (45), a n d c o m p r i s i n g t h e c a l c i u m i n b o d y f l u i d s a n d s o f t t i s s u e s . T h i s c ompartment i s i n e q u i l i b r i u m w i t h t h e e x c h a n g e a b l e f r a c t i o n o f bone c a l c i u m , a n d i s d r a i n e d b y e x c r e t i o n . The p l a s m a c a l c i u m c o n c e n t r a t i o n i s assumed t o r e p r e s e n t t h e o v e r a l l c o n c e n t r a t i o n i n t h i s c o m p a r t m e n t . T h i s i s a n o v e r s i m p l i f i e d e x p l a n a t i o n . P l a s m a c a l c i u m i s p a r t i a l l y p r o t e i n b o u n d , t h e r e m a i n d e r b e i n g c h i e f l y i o n i z e d , w i t h a s m a l l c o m p l e x d i f f u s i b l e f r a c t i o n . T h e r e f o r e , t h e c o n c e n t r a t i o n o f c a l c i u m i n t h e i n t e r s t i t i a l f l u i d w i l l be d e p e n d e n t u p o n t h e Donnan membrane e q u i l i b r i u m a n d i s u s u a l l y g i v e n a s 70% o f t h e t o t a l p l a s m a c o n c e n t r a t i o n (45). I n a d d i t i o n t o t h e f l u i d p o r t i o n , c a l c i u m o f t h e s o f t t i s s u e s i s b ound t o m u s c l e , t e n d o n and membranes i n g e n e r a l . T h e s e d i v e r s e p o o l s o f c a l c i u m h a v e b e e n g r o u p e d t o g e t h e r a s a s i n g l e " c a l c i u m c o m p a r t m e n t " f o r t h e p u r p o s e o f t h i s d i s c u s s i o n . T h a t t h e r e i s some d e l a y i n t h e m i x i n g b e t w e e n p l a s m a a n d o t h e r c o m ponents o f t h e p o o l i s t o be e x p e c t e d . S t u d i e s o n t h e 22 e x c h a n g e o f r a d i o c a l c i u m b e t w e e n p l a s m a a n d e x t r a c e l l u l a r f l u i d h a v e i n d i c a t e d t h a t m i x i n g i s v e r y r a p i d and t h i s d e l a y i s s m a l l ( 3 , 6 4 ) . I n t h i s d i s c u s s i o n , i t i s assumed t h a t t h e p l a s m a and t i s s u e c a l c i u m make up a s i n g l e c o m p a r t m e n t , and t h a t a n y l a g due t o m i x i n g may be i g n o r e d . The r i s e a nd f a l l o f t h e c a l c i u m c o n c e n t r a t i o n i n t h i s c o mpartment h a s b e e n o b s e r v e d a s m e a s u r e d b y t h e c h a n g e s i n p l a s m a c a l c i u m c o n c e n t r a t i o n i n r e s p o n s e t o a r a p i d i n f u s i o n . I t was a p p a r e n t t h a t t h e l o s s f r o m t h i s " c a l c i u m c o m p a r t m e n t " o c c u r r e d i n a t l e a s t two ways. One was b y e x c r e t i o n t h r o u g h t h e k i d n e y , and t h e o t h e r was b y r e t e n t i o n o f p a r t o f t h e i n f u s e d l o a d o f c a l c i u m b y t h e b o d y , p r e s u m a b l y i n t h e s k e l e t o n . The c o n c e n t r a t i o n i n t h e compartment a t a n y t i m e r e p r e s e n t s t h e c o n c e n t r a t i o n i n t h e p l a s m a f l o w i n g t h r o u g h t h e k i d n e y a n d t h r o u g h t h e b o n e s . The e f f e c t o f e x c r e t i o n b y t h e k i d n e y c o u l d be d e t e r m i n e d f r o m t h e l i n e a r r e l a t i o n b e t w e e n e x c r e t i o n r a t e (UV) a n d p l a s m a l e v e l s ( P ) . T h i s g a v e a d e f i n i t e m e a s u r e o f t h e r a t e o f e x c r e t i o n f r o m t h e " c a l c i u m c o m p a r t m e n t " a t a n y g i v e n p l a s m a l e v e l a b o v e t h e r e n a l t h r e s h o l d . U n l e s s t h e t u b u l a r r e a b s o r p t i o n maximum was e x c e e d e d , p r a c t i c a l l y a l l t h e f i l t e r e d l o a d was r e a b s o r b e d d e s p i t e a c o n s i d e r a b l e c h a n g e i n p l a s m a l e v e l ( n o t e 1 1a, 1 0 a , 10b i n T a b l e s I I a n d I I I ) . The p r e s e n c e o f a t u b u l a r r e a b s o r p t i o n maximum a p p e a r s t o be i m p o r t a n t i n t h e r e s t o r a t i o n o f n o r m a l p l a s m a l e v e l s a f t e r i n t r a v e n o u s c a l c i u m l o a d i n g . The r e n a l t h r e s h o l d a p p e a r s 23 to be i n the range of 8.5 t o 10.0 mg% i n the cases s t u d i e d . The normal s u b j e c t s had a c o n s i s t e n t t h r e s h o l d a t , o r v e r y c l o s e to t h e i r normal plasma l e v e l . Some o f the Paget's d i s e a s e c a s e s , and the two cases of h y p o p a r a t h y r o i d i s m had plasma l e v e l s a p p a r e n t l y below r e n a l t h r e s h o l d s i n c e i n c r e a s e d e x c r e t i o n was not observed u n t i l plasma l e v e l s exceeded 8.5 t o 10.0 mg%. The h y p e r p a r a t h y r o i d p a t i e n t appeared t o have the same Tm f o r c a l c i u m when determined b e f o r e and a f t e r removal o f the p a r a t h y r o i d tumour. T h i s case suggests t h a t the Tm f o r c a l c i u m may be independent o f p a r a t h y r o i d f u n c t i o n . The case o f o s t e o p o r o s i s had a low Tm on the f i r s t t e s t . A f t e r treatment t o c o r r e c t h y p e r c h l o r e m i c a c i d o s i s , an i n c r e a s e i n the Tm was observed. T h i s suggests t h a t h i s low plasma c a l c i u m l e v e l and h y p e r c a l c u r i a may have been due t o i n t e r f e r e n c e w i t h normal t u b u l a r r e a b s o r p t i o n of c a l c i u m . I t i s suggested t h a t the h i g h v a l u e o f Ku i n cases 7 ( a ) and 9 ( a ) may be accounted f o r by a h i g h GPR w i t h a d i f f u s i b l e f r a c t i o n o f t o t a l c a l c i u m l e v e l much h i g h e r than the 0.6 t h a t appeared to b e : t y p i c a l f o r the normal s u b j e c t s . In a s u b j e c t w i t h a normal g l o m e r u l a r f i l t r a t i o n r a t e and a d i f f u s i b l e f r a c t i o n o f 0.6. of t o t a l plasma c a l c i u m , 10.8 gms of c a l c i u m i s f i l t e r e d p e r day at a plasma c a l c i u m l e v e l o f 10 mg%. I f t h i s l e v e l i s r a i s e d above the r e n a l t h r e s h o l d , a l a r g e e x t r a l o a d can be e x c r e t e d i n a day, i n d i c a t i n g the c a p a c i t y o f a r e n a l mechanism to d i s p o s e of excess c a l c i u m . A lowered t u b u l a r maximum, as i n r e n a l d i s e a s e s o r a c i d o s i s (as shown i n case 14), can cause a h i g h e x c r e t i o n ; 24 y e t t h e n o r m a l p l a s m a l e v e l may he p r e s e r v e d f o r a l o n g p e r i o d b y m o b i l i z a t i o n f r o m t h e l a r g e s k e l e t a l r e s e r v e o f c a l c i u m . T h i s l o w e r e d Tm may a c c o u n t f o r c a s e s o f h y p e r c a l c u r i a when p l a s m a c a l c i u m l e v e l s a r e n o r m a l . The f a l l i n g p l a s m a c a l c i u m c u r v e a p p r o a c h e d t h e c o n t r o l l e v e l g r a d u a l l y , a n d t h e r e were no o v e r s w i n g s p a s t t h e c o n t r o l l e v e l . The s i z e o f t h e " c a l c i u m c o m p a r t m e n t " m e n t i o n e d p r e v i o u s l y was i n v e s t i g a t e d . The a s s u m p t i o n s were made t h a t no n e t a c c r e t i o n was o c c u r r i n g d u r i n g t h e p e r i o d a f t e r p l a s m a c a l c i u m l e v e l s h a d f a l l e n b e l o w Px, t h e p o i n t where t h e p l a s m a c a l c i u m c u r v e b r o k e . I n c a s e s where Tm was e x c e e d e d , i t was p o s s i b l e t o e s t i m a t e t h e s i z e o f t h e c o mpartment i n t e r m s o f b o d y w e i g h t . T h i s was done b y d i v i d i n g t h e d e c r e a s e i n c o n c e n t r a t i o n o f p l a s m a c a l c i u m i n t o t h e o b s e r v e d e x c e s s e x c r e t i o n s o c c u r r i n g i n e a c h o f t h e c l e a r a n c e p e r i o d s ( s e e c a l c u l a t i o n s ) . The c o m p a r t m e n t was e s t i m a t e d t o be 18 - 25 mg. Ca p e r k g . b o d y w e i g h t f o r p l a s m a l e v e l s b e t w e e n Px a n d c o n t r o l l e v e l . T h i s a p p e a r e d t o be a r e a s o n a b l e v a l u e f o r t h e s o f t t i s s u e a n d f l u i d " c a l c i u m c o m p a r t m e n t " . The c a l c i u m n o t e x c r e t e d i n t h e u r i n e was a s s u m e d t o be r e t a i n e d i n t h e b o d y s i n c e e x c r e t i o n i n t o t h e g a s t r o i n t e s t i n a l t r a c t i n r e s p o n s e t o h i g h p l a s m a c a l c i u m l e v e l s h a s n o t b e e n d e m o n s t r a t e d ( 4 1 , 7 , 1 3 ) - I t i s s u g g e s t e d t h a t t h e o t h e r f a c t o r r e m o v i n g c a l c i u m f r o m t h e " c a l c i u m c o m p a r t m e n t " i s bone u p t a k e . A n a l y s i s o f t h e f a l l o f p l a s m a c u r v e s h a s shown a c h a n g e i n t h e r a t e o f f a l l , a t a l e v e l P x a b o u t 1 mg% a b o v e t h e c o n t r o l l e v e l . T h i s b r e a k - p o i n t ( P x ) was n o t e d i n r e l a t i o n t o r e n a l t h r e s h o l d s 25 a n d n o r m a l p l a s m a l e v e l s . The s i g n i f i c a n c e o f t h i s p o i n t i s o p e n t o q u e s t i o n . The f o l l o w i n g i s a d v a n c e d a s a p o s s i b l e e x p l a n a t i o n . I n n o r m a l c a s e s , r e n a l l o s s o c c u r s a t a l l l e v e l s o f p l a s m a c a l c i u m a b o v e t h e r e n a l t h r e s h o l d a n d i s d i r e c t l y d e p e n d e n t u p o n t h e p l a s m a c a l c i u m l e v e l . A n a l y s i s o f t h e c u r v e shows t h a t a n o t h e r r e m o v a l p r o c e s s may a f f e c t t h e c a l c i u m i n t h e " c a l c i u m c o m p a r t m e n t " a t l e v e l s a b o v e Px, a n d t h a t i t s r a t e o f r e m o v a l i s a l s o d i r e c t l y d e p e n d e n t u p o n t h e p l a s m a c a l c i u m l e v e l . W h a t e v e r t h e s i g n i f i c a n c e o f t h e Px l e v e l , i t a p p e a r s t h a t t h e r a t e o f movement f r o m t h e f l u i d " c a l c i u m c o m p a r t m e n t " i n t o t h e bone s h o u l d be d e p e n d e n t u p o n t h e b l o o d f l o w r a t e i n b o n e , i n t h e same way t h a t e x c r e t i o n d e p e n d s on GFR. A h i g h r a t e o f f l o w w o u l d t e n d t o d i s t r i b u t e t h e c a l c i u m l o a d q u i c k l y i n t o t h e b o n e , and w o u l d r e s u l t i n a l o w e r p e a k l e v e l . T h i s was o b s e r v e d i n a l l t h e c a s e s o f P a g e t ' s d i s e a s e s t u d i e d , a n d a g r e e s w i t h t h e v i e w s o f o t h e r w o r k e r s t h a t P a g e t ' s d i s e a s e i s a c c o m p a n i e d b y a v e r y h i g h bone b l o o d f l o w - up t o t w e n t y t i m e s t h e n o r m a l r a t e i n a g i v e n bone ( 1 7 ) . T h a t t h e d i s e a s e i s s u b j e c t t o p e r i o d s o f q u i e s c e n c e a n d a c t i v i t y i s r e f l e c t e d i n t h e g e n e r a l r e s p o n s e o f t h e c a s e s o f P a g e t ' s d i s e a s e . T e s t i n g , a t i n t e r v a l s o f a f e w weeks t o m onths, r e v e a l e d q u i t e d i f f e r e n t c o n t r o l p l a s m a c a l c i u m l e v e l s and a l s o c h a n g e s i n t h e p a t t e r n o f r e s p o n s e t o t h e i n f u s i o n ( T a b l e I I ) . T h u s f a r , o n l y t h e c h a n g e s i n p l a s m a c a l c i u m i n r e s p o n s e t o c a l c i u m l o a d i n g h a v e b e e n c o n s i d e r e d . The p h o s p h a t e a n d 26 c i t r a t e l e v e l s i n t h e p l a s m a a n d t h e i r e x c r e t i o n r a t e s i n u r i n e were a l s o d e t e r m i n e d . I t was h o p e d t h a t t h i s m i g h t a l s o show a d e f i n i t e p a t t e r n o f r e s p o n s e . However, i t a p p e a r e d t h a t t h e r e s p o n s e was n e i t h e r m a r k e d n o r c o n c l u s i v e ( T a b l e s V, V I , V I I ) . I n a l l c a s e s , t h e e x c r e t i o n o f p h o s p h a t e and c i t r a t e r o s e w i t h c a l c i u m e x c r e t i o n r a t e s a n d t h e n f e l l t o n o r m a l a t a b o u t t h e same t i m e a s c a l c i u m e x c r e t i o n r e t u r n e d t o n o r m a l . The r i s e o f p h o s p h a t e a n d c i t r a t e i n p l a s m a was n o t s t r i k i n g e x c e p t i n t h e c a s e s o f h y p o p a r a t h y r o i d i s m where t h e p l a s m a p h o s p h o r u s r o s e b y 2.40 mg%, r e a c h i n g a p e a k a n d t h e n f a l l i n g t o i t s c o n t r o l l e v e l . I n a l l c a s e s , t h e i n i t i a l r i s e i n p l a s m a p h o s p h o r u s was d e l a y e d u n t i l n e a r t h e e n d o f t h e i n f u s i o n ; t h e n i n a l l e x c e p t t h e h y p o p a r a t h y r o i d c a s e s , t h e r e was a r i s e t o a p l a t e a u l e v e l w h i c h was m a i n t a i n e d u n t i l t h e p l a s m a c a l c i u m l e v e l s r e a c h e d n o r m a l a g a i n . The same d e l a y e d r i s e t o a p l a t e a u was s e e n i n t h e p l a s m a c i t r a t e l e v e l s , f o l l o w e d b y a r e t u r n t o n o r m a l when t h e p l a s m a c a l c i u m r e t u r n e d t o n o r m a l . No d e f i n i t e c o n c l u s i o n s c o u l d be drawn from t h e s e o b s e r v a t i o n s . The k i d n e y a p p e a r s t o a c t u p o n a " c a l c i u m c o m p a r t m e n t " o f l e s s t h a n one gram o f c i r c u l a t o r y c a l c i u m i n t h e b o d y f l u i d s a n d s o f t t i s s u e s . T h i s s m a l l " c a l c i u m c o m p a r t m e n t " i s i n e q u i l i b r i u m w i t h a t r e m e n d o u s r e s e r v e o f c a l c i u m i n bone m i n e r a l , w h i c h i s a v a i l a b l e t o o p p o s e w i d e v a r i a t i o n s i n p l a s m a c a l c i u m , e i t h e r b y s t o r a g e o f c a l c i u m i n h y p e r c a l c e m i a , o r m o b i l i z a t i o n o f c a l c i u m i n h y p o c a l c e m i a ( 1 4 ) . The bone b l o o d f l o w i s one o f t h e l i m i t i n g f a c t o r s i n t h e r e s p o n s e o f t h i s b one c a l c i u m c ompartment t o a c u t e c h a n g e s i n p l a s m a l e v e l s . I n n o r m a l 27 s u b j e c t s , t h e k i d n e y p l a y s a n i m p o r t a n t r o l e i n t h e r e s t o r a t i o n o f n o r m a l l e v e l s o f p l a s m a c a l c i u m a f t e r i n f u s i o n . The Tm f o r c a l c i u m a p p e a r s t o be i n d e p e n d e n t o f t h e p a r a t h y r o i d f u n c t i o n i n t h e c a s e s s t u d i e d . W . P . Neuman (47) e x p l a i n s t h e i m p o r t a n c e o f b o n e a n d e x c r e t i o n i n c a l c i u m h o m e o s t a s i s as f o l l o w s : Bone c a n n o t be c o n s i d e r e d a s t a b l e s y s t e m i n w h i c h t h e i n o r g a n i c p h a s e i s i n e r t . The t i s s u e f l u i d s o f a n a d u l t man l i t e r a l l y f l o w o v e r a c r e s o f a c t i v e i n o r g a n i c s u r f a c e . I t i s n o t s u r p r i s i n g t h a t t h e i n o r g a n i c c o m p o s i t i o n o f t h e b o d y f l u i d s v a r i e s o n l y s l i g h t l y . The a p p a r e n t s t a b i l i t y o f t h e s k e l e t o n c a n be a t t r i b u t e d o n l y t o e x t r e m e l y e f f i c i e n t e x c r e t o r y mechanisms w h i c h a u t o m a t i c a l l y b a l a n c e v a r i a t i o n s i n i n o r g a n i c i n t a k e . 28 C A S E H I S T O R I E S : HI. G . S . S . 27 y e a r o l d a i r m a n w i t h , d u o d e n a l u l c e r , o n a h i g h c a l c i u m d i e t ( g a s t r i c 2) f o r t w o w e e k s p r i o r t o t e s t o n J u l y 21, 1958. H2. J . B . A . A 37 y e a r o l d m a n w i t h n e g a t i v e i n v e s t i g a t i o n o f a l c o h o l i c c i r r n h o s i s , o n n o r m a l d i e t , t e s t e d J u l y 23,1958. H3. T . R . A g e 60. A l c o h o l i c . N o r m a l d i e t , t e s t e d A u g u s t 6 a n d N o v e m b e r 25, 1958. H4. J . E . L . A g e 49. R e c u r r e n t r e n a l c a l c u l i . L o w c a l c i u m d i e t f o r o n e w e e k (150 m g / d a y ) p r i o r t o t e s t o n A u g u s t 24, 1958. H5. V . J . S . A g e 27. A c r o m i o - c l a v i c u l a r s e p a r a t i o n . T e s t e d a f t e r o n e w e e k o n l o w c a l c i u m d i e t (150 m g / d a y ) o n S e p t e m b e r 5, 1958 a n d a f t e r o n e w e e k o n h i g h c a l c i u m d i e t (1500 m g / d a y ) o n S e p t e m b e r 15, 1958. H6. E . O . B . A g e 77* W i d e s p r e a d P a g e t ' s d i s e a s e o f f e m o r a , p e l v i s , k n o w n f o r 20 y e a r s . G a s t r e c t o m y 1954. N o r m a l d i e t b e f o r e t e s t o n S e p t e m b e r 19, 1958. A l k a l i n e p h o s p h a t a s e 38 K T J . H"7. H . J . M . A g e 63* W i d e s p r e a d P a g e t ' s d i s e a s e f o r 16 y e a r s . 1 N o r m a l d i e t b e f o r e t e s t o n N o v e m b e r 10, 1958 a n d N o v e m b e r ' 21, 1958. A l k a l i n e p h o s p h a t a s e 97 K U . H8. W . L . B . 83 y e a r s . P a g e t ' s d i s e a s e k n o w n f o r 16 y e a r s . L o w s a l t d i e t b e f o r e t e s t o n N o v e m b e r 17 a n d N o v e m b e r 27, 1958. 2 g m D i u r i l / d a y . H9. H . W . E . A g e 74. P a g e t ' s d i s e a s e o f t h e p e l v i s a n d t i b i a . B r o n c h o g e n i c c a n c e r d i s c o v e r e d a t t i m e o f t e s t a n d l a t e r r e m o v e d b y t h o r a c o t o m y . N o r m a l d i e t , d i u r i l , d i g i t a l i s , b e n e m i d , a n d c o l c h i c i n e b e f o r e t e s t o n J a n u a r y 9, 1959; n o r m a l d i e t a n d b e n e m i d b e f o r e t e s t o f A p r i l 20, 1959-H10. E.G.F. Age 75« W i d e s p r e a d P a g e t ' s d i s e a s e known f o r 25 y e a r s . N o r m a l d i e t b e f o r e t e s t o n F e b r u a r y 10, a n d F e b r u a r y 1 9 , 1 9 5 8 . A l k a l i n e p h o s p h a t a s e was 1 5 8 KU. H l l . M.B. Age 30. H y p o p a r a t h y r o i d . S u b t o t a l t h y r o i d e c t o m y F e b r u a r y 1 9 , 1959 l o r t o x i c h y p e r t h y r o i d i s m . S i g n s o f h y p o p a r a t h y r o i d i s m w e r e o b s e r v e d f i v e d a y s l a t e r . One h o u r i n f u s i o n F e b r u a r y 2 5 , 1959 . Two h o u r i n f u s i o n M a r c h 4, 1959-H12. A.D.M. Age 44. N o r m a l . N o r m a l d i e t b e f o r e t e s t o n M a r c h 2, 1 9 5 9 . H13. T . J . Age 42. I d i o p a t h i c h y p o p a r a t h y r o i d i s m . Two h o u r i n f u s i o n o n M a r c h 6, 1959 . H14. R.H.B. Age 48. O s t e o p o r o s i s . H y p e r c h l o r e m i c a c i d o s i s . N o r m a l d i e t f o r two d a y s p r i o r t o t e s t , t h e n l o w c a l c i u m (150 mg) o n d a y o f t e s t - J u n e 1 , 1959 . R e t e s t e d on J u l y 2 3 , 1959 a f t e r t h e r a p y . H 1 5 . H.M. Age 39- F r a c t u r e d i s l o c a t i o n o f t h e h i p t h r e e months p r e v i o u s l y . N o r m a l d i e t when t e s t e d o n J u l y 2, 1959 . H16. E l l i o t t . Age 18. N o r m a l . N o r m a l d i e t b e f o r e t e s t o n J u l y 8, 1959 . H17. W a g s t a f f e . Age 4 5 . N o r m a l d i e t b e f o r e t e s t o n J u l y 1 5 , 1 9 5 9 . H18. S i m p s o n . Age 48. H y p e r p a r a t h y r o i d . N o r m a l d i e t b e f o r e t e s t on J u l y 24, 1959 . R e t e s t e d on A u g u s t 7 , 1959 a f t e r r e m o v a l o f p a r a t h y r o i d g l a n d adenoma o n A u g u s t 1, 1959* H 1 9 . L u t z . Age 30 . N o r m a l d i e t b e f o r e t e s t o n A u g u s t 4, 1959 . H20. C o l e . Age 20. N o r m a l d i e t b e f o r e t e s t o n A u g u s t 1 7 , 1 9 5 9 . SAMPLE CALCULATIONS: Sample C a l c u l a t i o n - IL-, D e t e r m i n a t i o n o f Ku a n d Tm The s l o p e o f t h e l i n e UV v s . P was d e t e r m i n e d f r o m t h e g r a p h ( F i g u r e 6) and e x p r e s s e d i n mg/min/mg%. F o r H-2 t h e v a l u e o f t h i s s l o p e ( Ku) was 0.610 mg/min/mg%. To d e t e r m i n e Tm, t h e e q u a t i o n b e l o w was u s e d , a n d t h e a p p r o p r i a t e v a l u e s were s u b s t i t u t e d . UV = GFR x P x d - Tm UV = 1.00 Mg/min when P = 11.15 Ku = GFR x d = 0.610 Mg/min/Mg% d = The d i f f u s i b l e o r f i l t e r e d f r a c t i o n o f p l a s m a c a l c i u m GFR = G l o m e r u l a r f i l t r a t i o n r a t e GFR a n d d were n o t m e a s u r e d o n t h i s s u b j e c t . .*. The e q u a t i o n b e c o m e s : 1.00 = 0.6;10 x 11.15 - Tm Tm = 5 * 8 0 Mg/min GFR I f t h e d i f f u s i b l e f r a c t i o n ( d ) i s assumed t o be 6 0 % o f t h e t o t a l p l a s m a c a l c i u m , t h e n , u s i n g Ku = GFR x d , GFR = x 100 = 102 M l / m i n . T A B L E I: C A L C I U M V A L U E S F O R NORMAL S U B J E C T S P l a s m a C a (mg%) C o n t r o l I n f u s i o n P l a s m a S u b j e c t D o s e , mg L e v e l P e a k R i s e " P x " C o n t r o l 24 H o u r E x c r e t i o n T e s t D a y 24 h o u r % D o s e E x c r e t i o n R e t a i n e d Ku = R e n a l G F R x d Tm G-FR T h r e s h o l d m ^ / m i n / M g / m i n M l / m i n Mg M g 2 616 9.55 13.10 3-55 10.85 240 620 37 9.55 .610 . 5.80 102 3(a) 547 9.70 13.85 4 . 1 5 9.80 1 7 0 475 44 9.70 .600 5.60 100 3 ( b ) 565 9.65 13.60 3.95 11.35 340 635 47 1 0 . 3 0 • 545 5.40 91 4 616 9.55 12.90 3.35 11.75 290 570 54 1 0 . 2 5 .378 3-60 63 5 ( a ) 7 1 5 9.40 12.45 3.05 10.95 210 570 50 10.00 .560 5.30 94 5 ( b ) 7 1 7 9.35 13.20 3.85 10.95 360 645 60 1 0 . 2 5 .560 5.35 94 12 691 9 . 7 0 13.60 3.90 11.90 200 4 5 0 64 10.75 • 375 3.75 63 16 762 9-90 13.20 3.30 10.60 342 670 57 9.90 . 6 5 0 6 . 0 5 108 19 670 8.85 12.20 3 . 3 5 1 0 . 6 5 258 6 3 5 45 8.85 .540 4.55 90 20 7 1 0 9.50 12.80 3.30 1 0 . 3 5 3 1 0 600 59 9 . 5 0 .485 4.30 81 M e a n 9.49 1 3 . 0 9 3.58 1 0 . 9 2 2 7 2 587 5 2 9 - 9 1 0 . 5 3 0 4.97 89 ± S . E . M . ± 0 . 0 7 ±0.16 ±0.10 ±0.18 ±18 ±23 ±3 ± 0 . 1 5 ±0.029 ± 0 . 2 7 S . E . M . = S t a n d a r d e r r o r o f t h e m e a n f—1 TABLE I I : CALCIUM VALUES FOR SUBJECTS WITH PAGET'S DISEASE Plasma Ca (mg%) Subject Infusion Dose, mg Control Plasma Level Peak Rise "Px" Control 24 Hour Excretion Test Day 24 Hour Excretion % Dose Retained Renal Threshold Ku = GFRxd Tm GFR ml/min/ Mg/min Ml/ah 6 5^7 9.05 10.90 1.85 10.50 wig 100 s5f 60 10.50 .475 4.2 79 7(a) 886 10.95 12.85 1.90 11.80 125 200 91 11.75 1.25 14.5 210 7(b) 886 9.15 11.85 2.70 10.45 110 150 95 10.00 .350 3.4 59 8(a) 585 7.00 8.35 1.35 7.95 150 120 100 8.35 - - -8(b) 554 8.35 9.90 1.55 8.70 440 330 100 9.90 - - -9(a) 756 9.50 11.10 1.60 10.75 625 1165 27 9.50 2.16 20.0 360 9(b) 715 8.20 11.55 3.35 9.20 45 72 95 8.20 - - -10(a) 736 8.65 9.60 0.95 8.95 35 80 93 8.65 - - -10(b) 750 8.65 10.00 1.35 9.20 85 100 98 8.65 - - -Mean 8.83 10.68 1.84 3.15 191 282 84 1.06 10.5 177 ±S.E.M. ±0.36 ±0.45 ±0.25 ±0.18 ±67 ±115 ±8 ±0.42 ±1.3 ±69 ro TABLE III: CALCIUM VALUES EOR SUBJECTS WITH HYPOPARATHYROIDISM, HYPERPARATHYROIDISM, OR OSTEOPOROSIS Plasma Ca (mg%)  Control Control Test Day Ku = Infusion Plasma 24 Hour 24 Hour % Dose Renal GFRxd Tm GER Case No. Dose, mg Level Peak Rise "Px" Excretion Excretion Retained Threshold ml/min/ Mg/min Ml/min Hypoparathyroid Mg Mg 11(a) 750 6.60 9.55 2.95 8.00 55 92 95 8.50 - - -* 11(b) 1500 6.55 11.80) 5.25) 8.50 40 183) 95 8.50 .300 2.40 50 * 13 1300 5.65 11.85) 6.20)10.00 65 440) 71 10.00 .920 8.90 153 Mean 6.27 11.83 5.73 8.83 53 312 87 9.00 0.610 5.65 is.E.M. ±0.29 ±0.02 ±0.44 ±0.61 ±8 ±128 ±8 ±0.50 Hyperparathyroid 18(a) (Pre-Op) 740 13.90 16.90 3.00 14.85 555 1030 36 9-70 .150 1.35 25 18(b) . (Post-Op) 740 9.35 12.45 3.10 9.30 78 145 91 9.30 .150 1.35 25 Osteoporosis 14(a) 726 9.30 11.60 2.30 10.75 420 675 50 8.60 .575 5.00 96 14(b) 726 9.80 12.90 3.10 11.05 143 500 50 10.55 .575 5.80 96 9.55 ±0.25 12.25 ±0.65 2.70 10.90 ±0.40 ±0.15 +282 -138 588 ±86 50 9.58 ±0.95 .575 5.40 ±0.40 96 * Dose was 10 Mg/kg/hr for two hours. VN TABLE IV: PHOSPHORUS AND CITRATE VALUES FOR NORMAL SUBJECTS PHOSPHORUS CITRATE Control Case No. Control Plasma Level Maximum Rise Mg% Control 24 Hour Excretion Test Day 24 Hour Excretion Plasma Level ' Mpf/o Maximum Rise Mg% Control 24 Hour Excretion Test : 24 Ho-Excre' Mg% mg mg mg mg 2 3.60 1.00 360 495 1.45 0.55 140 160 3(a) 2.85 0.85 360 525 1.00 0.00 360 430 3(b) 2.50 0.80 870 680 - - - -4 3.40 1.10 480 510 2.50 0.00 660 620 5(a) 3-50 1.25 710 650 1.60 0.60 660 600 5(b) 3.60 0.90 1490 1375 1.75 0.00 950 700 12 3.80 1.00 1366 965 1.60 0.40 358 254 16 3.50 0.70 1250 2584 - - - -19 2.75 0.75 560 452 - - - -20 2.90 1.60 830 242 - - - -Hean 3.24 1.00 828 848 1.65 0.35 521 461 ts.E.I a.±0.14 ±0.08 ±151 ±216 ±.20 ±0.14 ±118 ±88 TABLE V: PHOSPHORUS AND CITRATE VALUES FOR SUBJECTS WITH PAGET1S DISEASE PHOSPHORUS CITRATE Control Case Plasma No. Level Maxim-urn Rise Control 24 Hour Excretion Test Day 24 Hour Excretion Control Plasma Level Maximum Rise Control 24 Hour Excretion Test Day 24 Hour Excretion 6 7(a) 7(b) 8(a) 8(b) 9(a) 9(b) 10(a) 10(b) 4.00 2.75 3.00 2.10 3.00 3.50 3.10 3.20 3.70 -1.00 0.65 0.70 0.55 -0.40 0.00 0.40 0.00 0.00 0.18 Mean 3.15 ±S.E.M.±0.18 ±0.13 Mg 885 710 400 622 680 400 800 560 632 ±62 Mg 610 415 370 270 415 830 370 577 430 476 ±56 4.50 3.50 3.25 2.80 3.00 4.25 3.75 3.58 ±0.24 0.30 0.25 0.15 -0.55 0.00 1.00 0.0 0.15 ±.15 465 210 110 367 350 300 ±63 300 280 170 145 436 230 260 ±43 TABLE VI: PHOSPHORUS AND CITRATE VALUES POR SUBJECTS WITH HYPOPARATHYROIDISM, HYPOPARATHYROIDISM, OSTEOPOROSIS PHOSPHORUS CITRATE Control Maximum Control Test Day Control Maximum Control Test Day Plasma Rise 24 Hour 24 Hour Plasma Rise 24 Hour 24 Hour Level Mg% Excretion Excretion Level Mg% Excretion Excretion Hypoparathyroidism 11(a) 6.30 1.40 620 873 0.90 0.85 202 291 * 1Kb) 5.75) 3.35) 1010 982) 1.50 0.90) 327 403) * 13 4.50) 2.45) 575 1117) 1.75 1.05) 132 290) Mean .5.13 2.90 735 1050 1.63 0.98 220 347 ±S.E.M. -0.60 ±0.45 ±138 ±64 ±0.09 ±0.03 ±57 ±55 Hyperparathyroidism 18(a)(Pre-Op) 2.20 0.10 860 1020 - - - -18(b)(Post-OP) 3.50 0.70 700 52 - - - -Osteoporosis 14(a) 2.90 0.50 600-1000 830 3.70 0.80 720 600-800 14(b) 3.00 0.75 800 610 - - - -Mean 2.95 0.63 720 ± S.E.M. ±0.05 ±0.11 ±110 * Infused dose was 10 Mg/k/hr for two hours. S.E.M.: Standard error of the mean. VN 0^  37 TABLE V I I : DETAILED PLASMA DATA FROM A NORMAL SUBJECT - H2 P l a s m a T o t a l Time T o t a l C a Mg% T o t a l P C i t r a t e Mpf/o 8:00 a.m. 9-72 3.58 1.77 8:30 9.50 3.91 1.29 9:00 9-55 3.83 1.29 9:30 9.50 3.70 1.62 9:45 10.31 3.61 1.45 10:00 11.29 3.53 1.29 10:15 11.97 3.58 -10:30 13.11 3.95 1.62 11:00 12.45 4.33 2.09 11:30 11.50 4.61 1.94 12:00 11.10 4.68 1.94 1:00 10.80 5.10 -2:00 10.47 4-.57 4.03 3:00 10.28 - 1.45 38 TABLE VIII: DETAILED URINE DATA FROM A NORMAL SUBJECT - H2 T o t a l T o t a l T o t a l C a P C i t r a t e Time Ca Mg P Mg C i t r a t e Mg/min Mg/min Mg/min Ms 7:30-8:30 6.5 13.0 6.9 0.101 0.217 0.115 8:30-9:30 8.0 11.2 7.1 0.133 0.187 0.118 9:30-10:30 121.0 39.7 17.0 2.017 0.662 0.283 10:30-11:30 76.5 39.1 10.3 1.275 0.652 0.172 11:30-12:30 74.2 46.1 6.3 1.238 0.768 0.105 12:30-1:30 46.6 27.8 6.0 0.776 0.596 0.100 1:30-2:30 41.1 22.2 6.1 0.686 0.371 0.102 2:30-3:30 18.0 12.6 4.7 0.300 0.210 0.078 3:30-6:00 69.0 41.4 23-2 0.460 0.275 0.154 6:00-12:00 117-0 118.0 51.0 0.325 0.328 0.141 12:00-8:00 57.1 135.5 21.3 0.119 0.282 0.044 TABLE IX: ANALYSIS OF PLASMA CALCIUM CURVE - H2 Time Pmg% At(hxs) Z\Pmg% A P mg% A t P mean ' 9:30 9-55 10:30 13-11 10:45 12.57 •54 2.16 12.84 11:00 12.10 .47 1.88 12.34 11:15 11.75 .35 1.40 11.93 11:30 11.50 .25 1.00 11.63 11:45 11.30 % .20 .80 11.40 12:00 11.13 % .17 .68 11.22 12:15 11.00 % .13 .52 11.07 12:30 10.90 .10 .40 10.95 1:00 10.78 .12 .24 10.84 1:30 10.66 % .12 .24 10.72 2:30 10.42 i .24 .24 10.54 3:30 10.25 i .07 .17 10.30 T A B L E X: DETERMINATION OF DILUTION VOLUME E x c e s s Ca A. D i l u t i o n Time E x c r e t i o n - m g mg% Volume ( c c ) 1 0 : 3 0 - 1 1 : 3 0 6 9 . 5 1 . 6 5 4 , 2 0 0 1 1 : 3 0 - 1 2 : 3 0 6 7 - 2 .60 1 1 , 2 0 0 1 2 : 3 0 - 1 : 3 0 3 9 - 6 . 2 5 15,800 1 : 3 0 - 2 : 3 0 3 4 . 1 . 2 2 1 5 , 5 0 0 2 : 3 0 - 6 : 0 0 6 5 . 0 . 4 5 1 5 , 5 0 0 Normal Ca mg.% Time in Hours. F i g u r e 1: P l a s m a c a l c i u m , p h o s p h o r u s a n d c i t r a t e f o r a n o r m a l s u b j e c t Paget's Disease. H - 10 (o) Ca mg,% 10 8 6 4 2 i 1 ' 1 Renal Threshold r 1 • 1 • J _ P * _ Calcium | 1 1 I 1 1 1 1 x ' * - - x — X - Citrate A , / " X \ ' X ^ • o>- O O'' ' o c . • ° - - . ' Phosphorus 'O' • . Q. • 1 I 10 mg. /kg. /hr . Wi • 0 1 2 1 4 i • i i 6 8 Time in Hours. F i g u r e 2: P l a s m a c a l c i u m , p h o s p h o r u s a n d c i t r a t e f o r a s u b j e c t w i t h P a g e t ' s d i s e a s e ( R e n a l t h r e s h o l d was e s t i m a t e d o n l y ) F i g u r e 3: P l a s m a c a l c i u m , p h o s p h o r u s a n d c i t r a t e f o r a s u b j e c t w i t h h y p o p a r a t h y r o i d i s m ( P x was e q u a l t o t h e r e n a l t h r e s h o l d . The l i n e d rawn a t 8.30 Mg% was t h e l e v e l t o w h i c h t h e p l a s m a v a l u e s r e t u r n e d ) Hyperporathyroidism. (Pre-Op) H -18 (o) F i g u r e 4: P l a s m a c a l c i u m a n d p h o s p h o r u s f o r a s u b j e c t w i t h h y p e r p a r a t h y r o i d i s m ( P r e - o p e r a t i v e ) Hyperparathyroidism - (Post -Op . ) H - 18 (b) Ca mg. % Calcium 4 6 Time in Hours. F i g u r e 5: P l a s m a c a l c i u m and p h o s p h o r u s f o r a s u b j e c t w i t h h y p e r p a r a t h y r o i d i s m ( P o s t - o p e r a t i v e ) Normal H - 2 Ca mg./min. MU V" 1.5 -\ Ca mg. % " P " F i g u r e 6: V a r i a t i o n o f r a t e o f u r i n a r y c a l c i u m e x c r e t i o n w i t h p l a s m a c a l c i u m c o n c e n t r a t i o n i n a n o r m a l s u b j e c t 47 Hypoparathyroidism. Ca mg./min. u 1-2 • u v . Q J L i l . 2.0 n 1.5 -1.0 -0.5 -F i g u r e 7: V a r i a t i o n o f r a t e o f u r i n a r y c a l c i u m e x c r e t i o n w i t h p l a s m a c a l c i u m c o n c e n t r a t i o n i n a s u b j e c t w i t h h y p o p a r a t h y r o i d i s m ( Dose was 10 Mg/Kg/Hr. f o r two h o u r s ) H -18 Ca mg./min. 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