Study of intestinal absorption of calcium in patients with renal failure

Kidney International, Vol. 3 (1973), p. 264—272

Study of intestinal absorption of calcium in patients with renal failure JACK W. COBURN, MARCELO H. KOPPEL, ARNOLD S. BRICKMAN and SHAUL G. MASSRY Medical Service, Veterans Administration Wadsworth Hospital Center and the Departments of Medicine, Cedars-Sinai Medical Center and the UCLA School of Medicine, Los Angeles, California

assesses true absorption and shows good reproducibility in

périodique a été observée, mais dans l'ensemble les valeurs sont demeurées subnormales. La transplantation a ramcné l'absorption a la normale sauf chez les malades dont Ia crdatinine était

256 subjects, including 47 normal, 16 with early renal failure (serum creatinines 2.5 mg/100 ml), 96 with advanced renal failure (serum creatinines >2.5 mg/tOO ml), 58 undergoing regular hemodialysis, and 39 renal transplant recipients. In

testinale vraie de calcium est nettement diminuée par l'insuff isance rénale quoiquc le deficit ne puisse être détecté au cours de

Study of intestinal absorption of calcium in patients with renal failure. Absorption of 47Ca was measured with a method which

supérieure a 2.0 mg/100 ml ct l'absorption était invcrsement corrélée a la posologie de la Prednisone. Ainsi l'absorption in-

normal subjects 47Ca absorption varied inversely with previous

l'insuffisancc rénale modérée. La ration alimentaire de ces

habitual dietary calcium intake, and absorption did not differ

maladcs conticnt pcu de calcium, ce qui contribue probablement a l'hypocalcémie des malades urémiques. Le deficit d'absorption de calcium est discuté en tenant compte du role du rein dans Ia

from normal in patients with early renal failure. In patients with advanced renal failure and in those treated with hemodialysis, 47Ca absorption was below normal; deviation below normal was greater when dietary calcium intake was considered. In individual patients, calcium absorption often increased slightly with initiation

production du I ,25-dihydroxycholecalciférol, Ia forme active présumée de Ia vitamine D.

of regular hemodialysis, but values generally remained subnormal. Renal transplantation restored absorption to normal, but absorption was reduced in those with serum creatinine >2.0 mg/100 ml and was inversely related to prcdnisone dosage. Thus true intestinal calcium absorption is clearly impaired with renal failure although the defect cannot be detected with mild renal failure. The diets of these patients contain tow quantities

In patients with chronic renal failure, impaired intestinal absorption of radiocalcium has been reported by a number of investigators [1—7]. However, considerable overlap be-

tween values obtained in uremic patients and those in normal subjects has been found with use of isotopic me-

of calcium, probably contributing to hypocalcemia in uremic patients. The impaired calcium absorption is discussed in relation to the kidney's role in producing I ,25-dihydroxycholecalciferol, the presumed active form of vitamin D.

thods which measure the actual calcium absorption [2, 3, 7]. Such variability could be related to variations in the degree of impairment of renal function in the populations studied

consideration. Chez certains malades une augmentation modérée

or to differences in the levels of previous habitual dietary intake of calcium, a factor which clearly affects the absorption of calcium in man [8—11]. In one study, the relation between calcium absorption to the previous dietary calcium intake was given for only 11 uremic patients [7]. It is not known when in the course of progressive renal failure the abnormality of calcium absorption first becomes apparent. Also, reports dealing with the effect of improving the uremic state on intestinal absorption of calcium are conflicting. Genuth, Vertes and Leonards [4] found no improvement of calcium absorption following initiation of therapy with regular hemodialysis, while Messner et al [5] and Reeker and Saville [7] reported slight improvement

de l'absorption contemporaine du debut de l'hémodialyse

toward normal after initiation of therapy with regular

Received for publication August 14, 1972; accepted in revised form November 7, 1972. © 1973, by the International Society of Nephrology.

hemodialysis. The influence of renal transplantation on intestinal absorption of calcium has not been systematically evaluated.

Etude de l'absorption intestinale de calcium chez des malades atteints d'insuffisance rénale. L'absorption de 47Ca a été mesurée par une méthode qui determine l'absorption vraie et posséde une bonnc reproductibilité chez 256 sujets, dont 47 sujets normaux, 16 au stade initial de l'insuffisance rénale (créatinines plasmatiques <2.5 mg/tOO ml), 96 atteints d'insuffisance rénale sévére (créatinines plasmatiques >2.5 mg/100 ml), 58 soumis a l'hémo-

dialyse périodique et 39 transplantés. Chez les normaux l'absorption de 47Ca vane en fonction inverse des habitudes alimentaires antéricures, elle n'est pas différente de celle des sujets au stade initial de l'insuffisance rénale. Chez les malades atteints

d'insuffisance rénale avancée et ceux traités par hémodialyse l'absorption de 47Ca était inférieure a Ia normale et l'écart était plus grand quand l'ingestion de calcium était prise en

264

265

Intestinal absorption of calcium in rena/failure Table 1. Clinical and biochemical data and results of intestinal absorption of calcium

Chronic renal failure Observation

Normal

MildModerate

Advanced Scr> 2.5 mgI

S1a2.5mg/

lOOm!

Total Group

Renal transplant recipients

Patients treated with regular hemodialysis

Total Group

58 (48/10)

39

28

11

(36/3)

(26/2)

(10/1)

SCr 2.0 mg/ Sr> 2.0 mg/ 100 ml 100 ml

100 ml

Patients, total no. (male/female) Age, years Range Fraction of 47Ca absorbed Dietary calcium intake, mg/day mg/lOU ml

S, mg/lOU ml Sca, mg/lOOm! SMg, mg/lOOml

Duration of treatment, mos Dose of prednisone, mg/day

46± 10

112 (103/9) 46± 11

40.0± 11

36±9

37±9

32±8

(19—65)

(19—75)

(19—64)

(21—52)

(21—52)

(21—43)

(0.18—0.36)

(0.07—0.40)

(0.07—0.40)

(0.11—0.41)

(0.08—0.38)

795± 350

475±270

300±240

325±250

500±235

1125±740

1170± 770 1015±690

(400—1600)

(170—1150)

(130—1150)

(130—1150)

(200—1250) (175—3250)

(175—3250) (390—2800)

12.7±7.0 6.6±2.4

11.1±7.6

10.5±3.4

6.0±2.6

8.6± 1.3

8.7± 1.2

3.0±0.7

2.9±0.7

6.0± 1.7 9.3± 1.0 3.5± 1.2

47

16

96

(14/2)

(89/7)

(29/18) 37± lOb

46± 13

(20—57)

(19—75)

(0.14—0.35)

0.25±0.06 0.25±0.05

1.1±0.2 3.4±0.6 9.8±0.5 2.6±0.2 — —

1.7±0.5 2.9±0.6 9.2±0.7 2.5±0.3

0.17±0.06 0.18±0.07 0.19±0.05 0.21±0.07 0.22±0.08 0.18±0.07

—

— —

—

—

13.1

11.4

(1—44) —

1.8±0.8 2.8±0.8 9.8±0.8 2.5±0.3 12.1

11.7

(1—41)

27± 14.2 (5—70)

(0.09—0.38)

1.4±0.3 2.8±0.6 9.9±0.8 2.5±0.3 11.3

11.0

(1—38)

27± 15.9 (5—70)

(0.08—0.30)

2.8±0.7 2.8± 1.3

9.5±0.5 2.7±0.4 13.6 (1-41) 28± 10.2

14.1

(12.5—45)

a Sr= serum creatinine; S= serum phosphorus; SCa= serum calcium; SMg= serum magnesium. b Data are expressed as mean SD; numbers in parentheses represent the range.

In the present study, 300 determinations of fractional absorption of calcium were carried out utilizing 47Ca in 256 subjects, including 47 normal subjects, 16 patients with early and 96 with advanced renal failure, 58 patients being treated with regular hemodialysis, and 39 renal transplant

recipients. The effect of therapy with vitamin D3 (cholecalciferol) was also evaluated. Calcium absorption was determined utilizing a method [12] which takes into account the poo1 size and turnover of radiocalcium and permits the estimation of true absorption. The results were interpreted in relation to the previous habitual dietary intake of calcium.

Methods

The normal subjects were ambulatory hospital and laboratory employees who were free of known diseases affecting calcium metabolism. The patients were taken from

the outpatient or inpatient population of our hospitals. The ages and sex distribution of the subjects are shown in Table 1. All patients had an established diagnosis of primary renal disease. They included those with mild-to-moderate renal failure (serum creatinine 2.5 mg/100 ml), patients with advanced renal failure (serum creatinine >2.5 mg/ 100 ml), patients treated with regular hemodialysis, and renal transplant recipients. The patients treated with hemodialysis were studied from 1 to 44 months after initiation of treatment. The dialyses were carried out 2 to 3 times/week in the inpatient units or in the patient's home, utilizing a coil-type dialyzer for 6 to 9 hr on each occasion, or a Kiil dialyzer for 10 to 12 hr. The concentration of calcium in dialysate was 6 mg/100 ml in most patients, although six patients were treated with dialysate containing 8 mg of

calcium/l00 ml for 12 to 18 months before the study of absorption [13]. Aluminum hydroxide gel was prescribed for the patients treated with hemodialysis, but the degree of adherence to this therapy was variable. All patients received one multivitamin capsule containing 400 I. U. of vitamin D2 each day.

The renal transplant recipients were studied 1 to 41 months after surgery, when dietary intake and immunosuppressive therapy were relatively constant. The details of the management of these patients have been described elsewhere [14].

Intestinal absorption of calcium was measured in the first 62 studies in a manner identical to that described by Curtis, Fellows and Rich t121 using a large volume scintilla-

tion counter (Armac, Packard Instrument Co.). Between 9 and 10 a. m. on the first day, a control measurement of arm radioactivity was made. Each individual then received intravenously a measured dose of 47Ca (') 0.90 to 1.10 liCi, with 0.1 mg of CaC12 in I ml of saline. The subjects fasted after midnight, and on the second day, 23 hours after

the intravenous dose, the radioactivity in the arm was measured (A1); then they received by mouth 25 ml of a solution containing 20 jiCi of 47Ca (1) and 200 mg of stable calcium as calcium gluconate. The container was rinsed twice with 20 ml of distilled water which the subject

also swallowed. Two hours later, they ate their usual breakfast. At 25 and 49 hr after the oral dose, on days 3 and 4, radioactivity in the forearm was again measured, A2 and A3, respectively. For measurement of the forearm radioactivity, the subject was seated in a special chair carefully positioned on one side of the counting chamber with his body shielded from the detector. The forearm was insert-

26i

Coburn et al

ed into the chamber, with its position standardized by having the individual firmly grasp a bar located deep within the counting chamber. Measurement of body-background was made with the subject seated in exactly the same position

with the arm withdrawn from the chamber. Forearm and background radioactivity was measured over 3 to 5 mm,

0.30

• Chronic uremia • Hemodialysis Kidney transplants £ Normal • Miscellaneous

providing total counts sufficient to give an error of less than 2%. The radioactivity from 47Ca was separated from that

of the daughter isotope, 47Sc, by adjusting the spectrophotometer to measure only emissions above 1.0mev.

0.20

Calculations were made assuming that the distribution of

the absorbed isotope within the arm after 23 hr is similar to the distribution of the intravenously administered dose. Thus, the forearm radioactivity measured 25 hr after

the oral dose (A2) represents the fraction absorbed (cc) multiplied by the fraction of the intravenous dose present in the forearm (A1/[). However, residual counts remain

0.10

from the intravenous dose; this activity decays according to the biologic turnover (/3), which can be assessed from the change in radioactivity from day 3 to day 4 (A3/A2).

Thus, A2=cc l0(A1/10)+A1 or, cc = (A2/A i — A3/A2)(t/I,) The results of the first 62 studies revealed the mean value of /3 to be 0.92, which is almost identical to that reported by Curtis et al [11]. Since a change in value of /3 of 15% affects cc by only 1 to 3%, /1 can be assumed to be 0.92, and it is not necessary to count radioactivity in the arm on the third day, and the formula becomes: cc' =(A2/A1 —0.92) (1/1)

0.10

from the two calculations are nearly identical; therefore,

the latter method of calculation of cc as a measure of absorption was employed for all the present data, To further validate the arm-counting method, intestinal absorption of calcium was simultaneously determined in ten subjects by measuring fecal recovery of 47Ca after its oral administration. Subjects received by mouth 1.5 g of BaSO4, as a nonabsorbable fecal marker on the day before ingestion of the 47Ca. Stools were collected and pooled for 5 to 6 days, and then the feces were collected separately on each day; when the radioactivity in the daily specimens fell below 1 % of the ingested dose, stool collections were discontinued. Total fecal radioactivity and the quantity of BaSO4 were determined [15]. Only determinations with recovery of BaSO4 within 5% of the administered dose were

considered valid. Absorption of 47Ca was calculated from the formula:

Absorption 1 —

radioactivity recovered in feces total administered radioactivity

The values of calcium absorption determined simultaneously by forearm counting and by fecal recovery fell near the

line of identity (Fig. 2); these results are similar to those reported by Curtis et al [121 and Wills et al [16].

0.30

0.40

Fig. 1. A comparison of calcium absorption utilizing the abbreviated method (cc') and the more complete protocol (cc). Each point represents the observations in a separate individual. -a a 0.6

aso

• 0.5 a 0.4

To test the validity of this assumption, calculated values of cc' are compared with cc in the 62 patients (Fig. 1); the results

0.20

-a

..a I- 0.3 0 Ct

L)

0.2

r=0.96 P<0.0o1

C.-

0

a 0.1

0 U

cc

0.1

0.2

0.3

0.4

0.5

0.6

0.7

Fraction of 47Ca absorbed — Fecal recovery method Fig. 2. A comparison of the fraction of 47Ca absorbed measured by the arm-counting method with simultaneously measured 47Ca absorption determined from the fecal recovery method. Each point represents a different patient. The patients represented by closed symbols (.) are from the present study; those by the open symbols (0) were studied by Curtis et al [11], and those by the x 's,

by Wills et al [161. The data from one patient from the latter group, with fractional absorption rates of 0.84 and 0.82 by the two methods, were omitted from this illustration.

The total quantity of 47Ca necessary for the performance of the test was substantially reduced by first giving an oral dose of 7 to 8 jsCi of 47Ca, followed by an intravenous dose of 1.5 to 2.0 jsc 5 to 14 days later. Forearm radioactivity

267

Intestinal absorption of calcium in renalfailure

was measured 23 to 25 hours after administration of both the oral and intravenous doses of 47Ca, and c' was calculated using the principles described above in a manner described by Wills et al [16]. The lower quantity of radioisotope made the test more economical and permitted performance of the test at more frequent intervals on the same patient. In ten normal subjects, 16 patients with renal failure, and 4 with other disorders, the absorption of 47Ca was measured

on two occasions, separated by periods ranging between one and 25 months. The results demonstrated good reproducibility in the same subject (Fig. 3). In 15 normal and nine uremic patients undergoing therapy with hemodialysis, the intestinal absorption of calcium was

measured before and seven days after the daily oral administration of 1 mg (40,000 I. U.) of vitamin D3.

The previous habitual dietary intake of calcium was estimated from a detailed interview performed by the same dietitian in a manner described elsewhere [17]. Serum concentrations of creatinine, phosphorus, calcium and magnesium were measured by methods previously reported [18].

The following parameters were considered in the statistical evaluation of the data: fractional absorption of calcium (a'), dietary intake of calcium, serum levels of creatinine, calcium, phosphorus, and magnesium and the age of the subject. The duration after initiation of hernodialysis or a renal transplantation as well as the daily dosage of prednisone therapy in the transplant recipients were also considered. Possible associations were assessed by the corre-

lation coefficients between the various factors utilizing standard statistical methods [19].

Results

A summary of results, showing the characteristics of all subjects, including age, sex, dietary calcium intake, fractional absorption of calcium and plasma biochemical findings, is given in Table 1. There was a significant inverse relation between the fractional absorption of the test dose of

47Ca in the normal subjects and the previous habitual dietary calcium intake (Fig. 4), but the fractional absorption was not related to the age or sex of the subjects. In patients with mild or moderate renal failure, the mean absorption of 47Ca was not different from that of normal, and most values were in the normal range when evaluated

in relation to the previous calcium intake (Fig. 5). In patients with advanced renal failure, the fractional absorption of calcium was significantly below normal; the dietary intake of calcium was generally low in this group with a mean value well below normal. The difference between the calcium absorption observed in this group and normal subjects is amplified when the previous dietary intake

of calcium is taken into consideration, with only 41 of 96

patients within the normal range (Fig. 6). For the total group of patients with renal failure, there was an inverse correlation between calcium absorption and the levels of serum creatinine, r = —0.22, P <0.05. in the uremic patients, calcium absorption was unrelated to either serum calcium level or the previous dietary intake of calcium. The mean fractional absorption of calcium in patients treated with hemodialysis was not different from that observed in patients with advanced renal failure although the dietary intake of calcium was higher in the former. When dietary calcium intake is taken into consideration, 37 of the 58 patients had values in the normal range (Fig. 7). In 0.40

o Normal

• Uremia 0.4

X

•

-u

a Hemodialysis Other

.•0

.••

o.-._

__.-•..__

0.30

1)

a

0

0.3

U

a

.5

0 0.2

020 0

y= 1.08x+0,013

r=088

0.10.

0.1

y=O.30— 0.066 x

r= —0.39 P <0.01 0.5

0.2

0.3

0.4

0.5

Initial measurement Fig. 3. A comparison of the fraction of 47Ca absorbed when the

same subject was studied on two separate occasions, the two studies separated by 1 to 25 months; the previous dietary intake of calcium did not differ significantly in each individual patient.

1.0

1.5

Calcium intake, g/day Fig. 4. The relationship between the fraction of 47Ca absorbed and the previous habitual dietary intake of calcium in normal subjects.

Each point represents a separate individual; males (.), females (a); the interrupted lines encompass the 95% confidence limits for individual values.

Coburn et al

268 0.40

0.40 S S

__S_.

S

0.30

S-S_S_S

0

-e 0.30—

a Cl,

-

Cs

c_)

o

C-

0.20

I

O—___

-S_S

•

•.O. ••

.

o 0.20 —

a

a —5-

-

C.) Cs

I__5_ S_-S

0.10

SS —

o

0

0.10

•. •

.

•0

.

0•

..

.•

. S

S.—

•

——S

1 1.5

1.0

0.5

Calcium intake, g/day Fig. 5. The fraction of 47Ca absorbed in patients with mild-tomoderate renal failure (serum creatinine 2.5 mg/100 ml) in relation to the previous dietary intake of calcium. The symbols are similar to those in Fig. 4. The normal range is superimposed.

. i0.30:

a 0.20-

aa

-

Cs I-

1.0

1.5

Fig. 7. The fraction of 47Ca absorbed in uremic patients under-

going treatment with regular hemodialysis in relation to their previous dietary intake of calcium. Symbols are as in Fig. 4.

Moreover, when the renal transplant recipients were divided into those with serum creatinine 2.0 and those with serum

0.40

C.)

0.5

Calcium intake, g/day

ijo'. •.. ..

0.10

S

S

-S. S S

.

-.-

creatinine > 2.0 mg/l00 ml, the mean calcium absorption in the latter was lower than those in normal subjects and in transplant recipients with serum creatinine 2.0 mg/I 00 ml, despite similar doses of prednisone and levels of dietary calcium intake. In ten of 15 patients who were studied both before and 1 to 12 months after renal transplantation, the absorption of calcium either improved or remained within the normal range. There was a small but significant increase in the fractional absorption of 47Ca following treatment with cholecalciferol in both normal subjects and in patients treated with hemodialysis. In these normal subjects, fractional absorption increased from 0.25 0.012 (sa) to 0.28 0.016

and in the uremic patients, from 0.17±0.015 to 0.19± 0.5

110

Calcium intake, g/day Fig 6. The fraction of 47Ca absorbed in patients with advanced rena/failure (serum creatinine >2.5 mg/100 ml) in relation to the previous dietary intake of calcium. Symbols are similar to those

in Fig.4. eight of 11 patients, there was a small but definite increase toward normal when 47Ca absorption was measured before and after initiation of hemodialysis (Fig. 8). In the renal transplant recipients, fractional absorption

0.0 12. Utilizing the paired t test, the changes in both groups were statistically significant, but the increments in the two groups did not differ from each other. Discussion

In the intestine, part of ingested calcium is absorbed, i. e., transported from the lumen into the blood, while at the same time an amount of calcium passes from the blood into the gut, the so-called endogenous fecal calcium [20, 211; net absorption of calcium represents the difference

was in the normal range in most of the patients (Fig. 9). In four patients the absorption was higher than normal;

between these two parameters. When radiocalcium is given

one of them had persistent hypercalcemia and other evidence of secondary hyperparathyroidism. There was a significant

inverse relationship between the fractional absorption of

diluted in a large miscible pool of stable calcium, causing the specific activity to be very low in blood; therefore the fraction of the absorbed radiocalcium which returns to the

47Ca and the daily dosage of prednisone, r= —0.36, P= 0.02.

gut via endogenous secretion is quite small. Failure to

by mouth, the fraction absorbed from the intestine is

269

Intestinal absorption of calcium in renalfailure

• Hemodialysis

[ o No Dialysis

Male Female •

1

s

• V0

0.40

0.40

2.0mg %

s2.0mg% Cr 2700

—

2000 —

0.30

•

U

•• •.

'5 0.20

U

aa

0.30

C.)

a -u C) I-

•D

2800

a a

0.10•

.

.•

•— —

0.5

U

Calcium intake, g/day

0.20

•

.

0 a

a

•

3250

1.0

1.5

Fig. 9. Fraction of 47Ca absorbed in renal transplant recipients in relation to their previous dietary intake of calcium. The symbols are as in Fig. 4.

a aa C)

a

double isotope method and employed a similar quantity of

stable calcium as a carrier [7]. The values of fractional absorption found in our normal subjects are lower than

0.10

those reported by others who gave radiocalcium with food [11] or with a smaller quantity of stable calcium as carrier [2, 3].

Our data confirm previous observations [8—111 showing

0

0.5

1.0

Calcium intake, g/day Fig. 8. Fraction of 47Ca absorbed in 11 uremic patients who were studied before and after initiation of therapy with regular hemodialysis. The open symbols (0) indicate values obtained before therapy was initiated while the closed circles indicate those after

treatment was begun. The lines connect values obtained in the same patient. The shaded area is the normal range.

an inverse relation between the fraction of radiocalcium absorbed and the previous habitual dietary intake of calcium in normal subjects. Among our normal group, the fractional absorption of calcium did not vary with age; this observation differs from previous reports which include more subjects in younger or older age groups and show an

inverse relation between calcium absorption and age [24, 25]. The narrower age range of our subjects may account for this discrepancy.

The results of the present study clearly indicate that intestinal absorption of calcium in patients with mild to

correct the measured absorption for such losses resulted in

moderate renal failure is not different from normal but it is

an average error of only 3% [221. The combined use of

impaired in patients with advanced uremia. Several in-

intravenous and oral doses of 41Ca circumvents differences due to variations in the size of the miscible pooi of calcium,

vestigators have reported reduced mean values of calcium absorption in patients with renal failure with the use of various methods which estimate true absorption of calcium f2, 3, 7]; however, considerable overlap exists between results found in normal subjects and uremic patients. Ogg found values within his normal range in 16 of 23 azotemic patients [31 and Recker and Saville reported results in the lower part of the normal range in most uremic patients [7]. The overlap between uremic patients and normal subjects

since the distribution of the absorbed fraction of the oral dose of the isotope is similar to the distribution of the intravenous dose, with identical fractions appearing in the arm [12]. Moreover, the similarity between the values of intestinal absorption obtained when the same individual was tested on more than one occasion indicates that this method yields reproducible results; these observations are similar to previous reports demonstrating little variability in intestinal absorption of calcium on repeated testing in the same individual [22, 23]. The present results of the fractional absorption of calcium

in normal subjects agree quantitatively with the mean absorption of 22

8.1

% in normal individuals reported by

Recker and Saville, who measured absorption using a

could be related to variations in the degree of renal insufficiency, failure to relate calcium absorption to the previous dietary intake of calcium, and the occurrence of the same wide variation in absorption from one azotemic patient to another, as exists in normal subjects. The correlation between calcium absorption and the serum creatinine level suggests that absorption may be worse as renal func-

2O

Coburn et al

tion decreases. Reeker and Saville also noted such a relationship in azotemic patients with blood urea nitrogen

serum calcium was significantly lower than normal (Table 1).

(BUN) concentrations under 150 mg/l00 ml, although they

This mild hypocalcemia occurred despite a mean frac-

found radiocalcium absorption to be increased above

tional absorption of calcium which was not different from normal and a mean level of serum phosphorus which was significantly lower than that of normal. These observations suggest that factors other than hyperphosphatemia [33] or defective intestinal calcium absorption may underlie the mild hypocalcemia observed in these patients with mild-tomoderate renal failure. The observation that intestinal absorption of calcium, viewed in relation to previous dietary intake of calcium, is within the normal range in most renal transplant recipients indicates that the defect in calcium absorption is reversed when renal function is restored to normal; however, intestinal absorption of calcium remains abnormal if renal function is not adequately improved after renal transplantation. Short term treatment with glucocorticoids impairs calcium absorption [20, 34, 35], and our observations in renal transplant recipients suggest that such an effect from prednisone may be dose-related during its long-term administration. The mechanisms underlying impaired calcium absorption in chronic renal failure remain obscure [36]. Metabolic studies showing that large pharmacological doses of vitamin D can overcome defective absorption of calcium in chronic

normal in two of five patients with BUN levels exceeding

lSOmgflOOml. The levels of BUN were not routinely measured in the present patients, and most patients in the present population either received protein restricted diets or treatment with hemodialysis before azotemia of this degree developed. Also, the intestinal absorption of calcium involves several distinct processes, including active transport against a chemical gradient and passive diffusion down

a chemical gradient, which may or may not be facilitated [261. it is possible that uremia or kidney disease may impair only a single component of the transport process, and there could be different degrees of compensatory increases in the unaffected mechanisms resulting in variability in total ab-

sorption from one patient to another. The present study does not permit differentiation between these possibilities. The present observations in patients treated with hemodialysis are similar to previous reports of others who found little [5, 7] or no improvement [4] in calcium absorption in

uremic patients treated with hemodialysis. However, a larger fraction of our patients had results within the low normal range when the results are evaluated in relation to previous dietary intake, suggesting that there may be partial reversal of the defect of intestinal calcium absorption after regular hemodialysis. Among both patients with chronic renal failure and those treated with hemodialysis, there was no relationship between the fraction of radiocalcium absorbed and the previous dietary intake of calcium. The distribution of dietary calcium intake in these patients was skewed toward the low range, which could account for this lack of relationship. Alternatively, it is plausible that renal failure may impair mechanisms by which the organism modifies absorption of calcium in response to changes in dietary intake of this ion. Indeed, there is some support for

the latter possibility from data derived from metabolic studies in patients with renal failure. Uremic patients are usually in negative balance for calcium, with fecal losses equal to or greater than dietary intake when they ingest their usual low calcium diet [27—29]; with ingestion of larger quantities of calcium, fecal losses do not increase proportionately and they remain in positive balance for this ion [30—32].

In the patients with mild renal failure, the mean level of

renal failure led to the postulate that uremia causes a vitamin D-resistant state [27—29]. It has been shown that I ,25-dihydroxycholecalciferol (1 ,25-(OH)2-CC), the most active known form of the vitamin [37, 38] is produced only in the kidney (39), raising the possibility that decreased production of 1,25-(OH)2-CC by the diseased kidney could

lead to impaired calcium absorption and the apparent vitamin D-resistance found in uremia. In support of this possibility, observations in our laboratory indicate that 1,25-(OH)2-CC may be more than 400 times more potent than cholecalciferol in stimulating calcium absorption and elevating serum calcium in uremic patients [40]. Our failure

to restore calcium absorption to normal following the improvement of uremia by hemodialysis is also consistent with this view. On the other hand, calcium absorption was, slightly improved following treatment with hemodialysis, findings consistent with those in experimental animals which suggest that uremia, per se, contributes to reduced intestinal absorption of calcium [36, 41—43].

The diets ingested by uremic patients in the present population contained very low quantities of calcium; this was not due to selection of one specific group of patients, since these patients were managed by many different physicians in the Los Angeles area. This reduced dietary intake of calcium is probably related to the ingestion of proteinrestricted diets by these patients. The intake of diets containing a limited amount of calcium and defective intestinal calcium absorption probably both contribute significantly and compound each other in leading to deranged calcium homeostasis in patients with chronic renal failure.

Acknowledgments

This work was presented, in part, before the Annual Meeting of the American Society of Nephrology, Washing-

ton, D. C., December 2, 1969. It was supported, in part, by Contract 43-68-1040 with the United States Public Health

Service. Drs. M. H. Koppel and A. S. Brickman carried out the work while they were Research and Education Associates of the Veterans Administration. Dr. Massry is an Established Investigator of the American Heart Asso-

271

Intestinal absorption of calcium in renalfailure

ciation. Mrs. Alice Kumamoto, Mrs. Sonia Soghomonian, Mr. Robert Adachi and Mr. Dale Johnson provided tech-

nical assistance. We are particularly indebted to Miss Molly Sorensen who carried out each of the dietary interviews. Mr. Robert Seltzer provided assistance with the statistical analysis. The physicians referring their patients to us for study include: Drs. Keith Agre, John DePalma, James Drinkard, Marshall Fichman, Stanley Franklin, Richard Glassock, Harvey Gonick, Arthur Gordon, Thomas Gral, Charles Kleeman, Joel Kopple, David Lee, Morton Maxwell, Martin Rosenblatt, Milton Rubini, Bernard Salick, Alvin Sellers and James Shinaberger. Reprint requests to Dr. Jack W. Coburn, Nephrology Section, Wadsworth VA Hospital, Wilshire & Sawtelle Blvds., Los Angeles, Calif. 90073, U.S.A.

17:118—124, 1971 14. REEVE CE, MARTIN HC, GONICK HC, KAUFMAN JJ, RUBINI ME, MIMMS MM, GOODWIN WE, KOPPEL MH, KOPPLE JD,

GOLDMAN R: Kidney transplantation: A comparison of results using cadavers and related living donors. Am J Med 47:410—420, 1969 15. FIGUEROA WG, JORDAN T, BASSETT SH: Use of barium sul-

fate as an unabsorbable fecal marker. Am J C/in Nutr 21: 1239—1245, 1968 16. WILLS MR, ZISMAN E, WORTSMAN J, EVENS RG, PAK CYC,

BARTTER FC: The measurement of intestinal calcium absorption by external radioisotope counting: Application to study of nephrolithiasis. C/in Sci 39:95—106, 1970 17. SORENSEN MK, KOPPLEJD: Assessment of adherence to a

uremia. Am J C/in Nutr 21:631—637, 1968

1. Ruii'ii ME, COHEN MB, GONICK HC, COBURN JW: Calcium

absorption and turnover in chronic renal failure. Proc Second Cong Nephrol, Prague, 1963, pp. 727—731

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