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The effect of subtotal parathyroidectomy and renal transplantation on mineral balance and secondary hyperparathyroidism in chronic renal failure
The Effect of Subtotal Parathyroidectomy and Renal Transplantation on Mineral Balance and Secondary Hyperparathyroidism
in Chronic Renal Failure
By JAMES W. JOHNSON,AMNON WACHMAN, ADRIAN I. KATZ, DANIEL S. BERNSTEIN, CONSTANTINEL. HAMPERS, ROBERT S. HATTNER, RICHARDE. WILSON, ANDJOHNP. MERRILL
Subtotal parathyroidectomy results in improvement of bone disease and metastatic calcification present in some uremic patients. This improvement is not associated with any consistent changes in external mineral balance. Calcium balance may be quite negative in both the dialyzed and undialyzed uremic patient, probably due to defective intestinal absorption, and is not altered in any cous&tent manner by subtotal parathyroidsuccessful renal ectomy. Following transplantation the manifestations of hyperparathyroidism may resolve spontaneously and calcium balance usually becomes positive. Although both im-
From Brigham Boston,
the Departments Hospital;
and
of Medicine
provements follow the restoration of renal function they may not be mutually dependent or even related. The improved calcium balance appears to depend upon the correction of defective gastrointestinal absorption. In patients in whom external calcium balance does not become positive, resolution of parathyroid induced bone disease and metastatic calcification may result from the resorption of endogenous calcium from ectopic sites with redeposition into bone, a process presumably made possible by the decrease in plasma parathyroid hormone consequent to renal transplantation.
and Surgery,
the Department
Harvard
of Nutrition,
Medical
Harvard
School;
School
Peter
of Public
Bent
Health,
Mass.
Received
for publication
October
14, 1970.
Supported by NIH Grants 5-MOI-FR-31, 5-TOI-AI-00301, and AM-03967, the Fund for Research and Teaching, Department of Nutrition, Harvard School of Public Health; and the Massachusetts Heart Association. JAMES W. JOHNSON,M.D.: Research Fellow in Medicine, Harvard Medical School, Assistant in Medicine, Peter Bent Brigham Hospital, Boston, Mass. AMNONWACHMAN, M.D.: Research Associate, Department of Nutrition, Harvard School of Public Health, Boston, Mass. ADRIAN I. KATZ, M.D.: Research Associate in Medicine, Harvard Medical School; Assistant in Medicine, Peter Bent Brigham Hospital, Boston, Mass. DANIEL S. BERNSTEIN, M.D.: Assistant Professor of Medicine, Harvard Medical School; Senior Associate in Medicine,
Peter
Instructor
in Medicine,
Hospital:
Bent Brigham
Director,
sistant in Medicine, Associate Medical
School;
Howard
Hughes
Fellow
School:
of Surgery,
Mass.
in Nutrition, Hospital,
Harvard
Medical
Peter
in Medicine,
Bent
Brigham
Hospital,
Harvard
Boston,
Medical
Mass. JOHN P. MERRILL, M.D.: Physician,
CONSTANTINE L. HAMPERS, M.D.:
Associate
Peter Bent Brigham
Peter Bent Brigham
Professor Boston,
Boston,
Medical
Dialysis Facilities,
S. HAITNER, M.D.: Research
Hospital,
Hospital,
Harvard
School
Peter Bent Brigham
Boston,
Mass. ROBERT
of Public
Health;
As-
Mass. RICHARD E. WILSON, M.D.:
School;
Surgeon,
Associate
Professor
Hospital,
Boston,
Bent
Brigham
of Medicine,
Peter
Harvard
Mass.;
investigator,
Institute,
MFTABOLISM, VOL. 20, No. 5 (MAY),
1971
487
488
JOHNSON ET AL.
THE
PATHOGENESIS OF RENAL OSTEODYSTROPHY is complex and probably involves abnormalities of vitamin D, parathyroid function, pH, ionized calcium and end-organ responsiveness. The net result is a profound alteration in calcium homeostasis with a redistribution of skeletal mineral and the appearance of metastatic mineral deposits. Spotty sclerosis of bones as well as measurable, although not necessarily grossly visible, increases in skin calcium may be present. 1 This peculiar redistribution as well as a possible overall net loss of calcium in chronic renal failure (CRF) can be reversed at least in part by successful renal transplantation .2.3,4Although arterial calcification may not resolve following the restoration of renal function, remineralization of the skeleton occurs, subperiosteal resorption resolves, and subcutaneous calcium deposits disappear. In association with this clinical improvement, responsiveness to vitamin D is restored and hyperparathyroidism resolves.5,6 Since hemodialysis is not as effective as successful renal transplantation in effecting these changes, 5~~attempts have been made in the dialyzed patient with CRF to overcome vitamin D resistance by administration of large doses of vitamin Ds and to decrease plasma parathyroid hormone (PTH) by subtotal parathyroidectomy (sPTX) .9~0 The place of sPTX in CRF remains controversial and the indications for sPTX are not unanimously agreed upon. In order to determine the therapeutic role as well as the timing of sPTX in CRF, the following studies have been performed to assess metabolic changes which occur following sPTX and successful transplantation as reflected in the overall mineral balance. MATERIALS
AND METHODS
Nine patients with CRF and associated secondary hyperparathyroidism were studied in the Clinical Research Center, Peter Bent Brigham Hospital, Boston, Mass., before (period I) and after sPTX (period II). Three of these patients were again restudied following successful renal transplantation (period III). Two additional patients with secondary hyperparathyroidism who did not undergo sPTX were studied prior to (period I) and again following successful renal transplantation (period III). The patients’ clinical data are given in Table 1. Two patients had not yet required hemodialysis at the time of period I, while the remainder had been hemodialyzed three times weekly for 2 to 13 months. Following sPTX, however, D.F. developed further deterioration of renal function requiring the initiation of hemodialysis before period II. Thus, only one patient was studied without dialysis in both periods I and II. The indications for sPTX in the nine patients who underwent this procedure were: repeated episodes of hypercalcemia in five, severe progressive hyperparathyroid bone disease in three and intractable pruritus in one patient. Although episodes of hypercalcemia were repeatedly demonstrated in the five patients in whom sPTX was performed for this reason, elevated levels were not constantly present as shown by the mean serum concentrations during the period I study (Table 2). A liquid diet utilizing purified soy-bean protein was used as the exclusive source of nutrient throughout the balance studies. 11 Each 100 g of soy-bean powder contained 86.5 280 mg calcium, 980 mg phosphate and 84 mg g of protein, 2.0 g of carbohydrates, magnesium. Multivitamins (not including vitamin D), ferrous gluconate and calcium lactate tablets at constant doses (sufficient to raise the daily calcium intake to 434 to 681 mg) were given daily. The diet was prepared by blending a weighed amount of soy-bean powder with distilled water. Dextrose, corn oil, flavoring (usually vanilla), amino acids, methylcellulose, sodium and potassium salts were added and the entire mixture was blended to a liquid consistency. Each individual serving and all unconsumed portions were accurately weighed to determine the intake precisely.
F
F
53
18
16
24
N.U.
Without sPTX S.G.
glomerulonephritis.
B.S.
D. Fi.
* Chronic
M
M Alport’s syndrome CGN
cancer of solitary kidney chronic pyelonephritis
4
3
17
‘/z
18
CGN
F
37
D.F.
11
CGN
F
28
E.T.
4
CGN
F
24
J.P.
3 1% 6
nephrosclerosis CGN CGN
M
M F M
47 21 30
G.S. E.M. J.M.
(Years)
Known Duration of Disease
16
Diaanosis
of Hyperparathyroidism
progressive cystic changes of distal ulna subperiosteal resorption of phalanges and distal clavicles
severe progressive X-ray changes in secondary hyperparathyroidism serum calcium of 14 m&100 ml intractable pruritus serum calcium of 12.0 mg/lOO ml severe progressive X-ray changes of secondary hyperparathyroidism serum calcium of 12.0 mg/lOO ml, mild band keratopathy serum calcium of 12.4 mg/lOO ml, progressive X-ray changes of secondary hyperparathyroidism serum calcium of 12.4 mg/lOO ml, mild band keratopathy severe progressive X-ray changes of secondary hyperparathyroidism
Evidence of HyDerDarathyroidism
Features and Evidence
CGN *
45
S.F.
Sex
A%
Patient with sPTX
Table l.-Clinical
4
10
4
-
-
-
-
-
-
-
-
-L
-
+
2
+
+ + +
13 12 12
4
+
Skeletal Pain
+
Pruritus
2
Duration of Nemodialysis (months)
490
JOHNSON ET AL.
While on the metabolic ward each patient was allowed to equalibrate on the diet for at least 3 days during which hemodialysis was performed prior to initiation of the balance studies. These consisted of either two 4 day balance periods for the patients on hemodialysis separated by a day for dialysis or a single 6 day period for those not on dialysis. While longer equilibration and balance periods are preferable, patient tolerance of the monotonous formula diet and reluctance to withold hemodialysis for longer than 4 consecutive days limited the study to periods as described. Since hemodialysis immediately preceded each of the two 4 day balance periods, equivalent effects would be anticipated. Following period I, sPTX was performed in nine patients. The four parathyroid glands were identified and all tissue except for l/3 to l/2 of the smallest gland was excised. Period II was carried out 8 days to 9 months following sPTX. In the five patients who underwent renal homotransplantation, period III was carried out 3 to 5 months following restoration of renal function. Since none were on hemodialysis at this time, a single 6-day balance period was employed for all. Balance studies were initiated and terminated using carmine red stool markers. In addition, 500 mg of chromium sesquioxide was given three times daily as a continuous stool marker for correction of fecal losses .rs,ls Chromium was determined in triplicate and results showing less than 5 per cent variation were accepted. Feces were dried, weighed, homogenized and ashed prior to determination of chromium,14 calcium,15 phosphate,16 and magnesium.17 Twenty-four hour urine specimens were collected (where applicable) under toluene and refrigerated. Determinations performed on daily 24 hour urine collections included calcium,15 phosphate16 and magnesium.17 During each balance period, arterial blood calcium, phosphate, magnesium and pH were determined daily while alkaline and acid phosphatase, creatinine, urea nitrogen, sodium, potassium and chloride were measured on alternate days by routine methods of the clinical laboratory in the Peter Bent Brigham Hospital. Heparinized plasma was collected and frozen during each balance period for assay of PTH. These assays were performed by Dr. Rosalyn Yalow and Dr. Solomon Berson, Bronx V.A. Hospital, New York, N.Y., utilizing antisera 273 which may detect, in addition to native PTH, biologically active metabolic fragments peculiar to CRF.18 A complete radiological skeletal survey, which included films of the skull, shoulders, hands, spine, pelvis and knees, was obtained preoperatively and periodically thereafter. Unless otherwise indicated, tests of significance between mean values were calculated by the paired t-test.19 RESULTS
Calcium balance data for periods I and II are shown in Table 2. All the patients studied were in negative calcium balance in Period I (range -83 mg/day to - 549 mg/day) , primarily as a result of fecal excess. Urinary calcium losses were inconsequential since only three patients were not anephric (in preparation for transplantation) and even in these patients urinary calcium levels were low (range: 18 to 95 mg/day). In all patients except N.U. fecal losses exceeded intake. In comparing periods I and II, calcium balance improved in five patients and became more negative in four. Fecal calcium remained the major determinant of the negative balance. Urinary calcium fell after surgery in the three patients with kidneys (range: 3 to 7 mg/day). Mean calcium balance did not change significantly following sPTX. In those patients who were studied by two 4 day balance periods (those on hemodialysis, that is, all except N.U. and D.F. during period I and N.U. alone during period II) there were no consistent differences between the balance results of the first and second 4 day period. Therefore, mean values for the two periods were used for analysis. The mean period I phosphate balance of -389 mg/day did not differ sig-
S.F. G.S. E.M. J.M. J.P. E.T. D.F. B.S. N.U. Mean SEM ‘-c
Patient
SF. G.S. E.M. J.M. J.P. E.T. D.F. B.S. N.U. Mean SEM -c
I
-504 -263 -539 -403 -414 -241 -351 -543 -243 -389 41
I
569 573 542 434 513 536 474 449 526 513 17
I
584 582 549 536 482 510 474 489 612 535 17
II
Dietary Calciupme$dg/day)
1076 671 771 983 985 945 722 713 609 831 56
I
1446 972 896 744 555 914 572 807 402 812 101
II
Total Calcium Excretgl(omdg/day)
-813 -359 -425 -267 - 220 -398 -291 - 363 + 245 -321 91
II
522 465 429 451 404 451 236 288 413 407 30 ~____
I
II
557 564 451 451 297 360 236 288 663 430 49
Dietary Phosphg.e~oy/dau)
1026 728 968 854 818 692 587 831 656 796 48
I
1370 923 876 718 517 758 527 6.51 418 751 9.5 _~ _____
II
Total Phosphate Excret;;AF$/day)
3.9 5.0 5.3 9.0 5.5 5.8 7.4 6.8 8.2 6.3 0.3
I
2.5 3.4 2.9 7.2 5.0 2.2 4.4 6.0 6.2 4.4 0.6
II
Mean Serum Phospha;e$mAOO
ml)
II
5.6 9.6 7.2 9.9 6.8 8.8 7.3 9.9 6.4 7.9 0.5
I
10.4 10.2 10.0 10.5 8.6 10.2 9.5 10.2 9.2 9.9 0.2
Mean Serum CalciumP~qnlOO ml)
Data for Nine Patients With CRF Before (Period I) and After (Period II) sPTX
Balance Data for Nine Patients With CRF Before (Period I) and After (Period II) @TX
-862 -390 - 347 -208 - 73 -404 - 98 -318 +210 -277 98
Phosphate Balancpee;imJday )
Table 3.-Phosphate
-507 - 98 - 229 - 549 -472 - 409 - 248 -264 - 83 -318 58
II
Balance
Calcium BalanFe;,Tj/day)
Table 2.-Calcium
JOHNSON ET AL. +60,
I
Fig. l.-Mean magnesium balance in nine patients before (period I) and after (period II) subtotal parathyroidectomy. There is no significant change in magnesium balance, dietary magnesium, or magnesium excreted.
from the mean period II balance of - 321 mg/day (Table 3). Phosphate balance between periods I and II improved in six patients and worsened in three. Excessive fecal loss remained the major determinant of the overall negative balances although there was a decrease in phosphaturia in the three patients with kidneys between period I (range: 24 to 222 mg/day) and periods II (range: 7 to 78 mg/day). The mean magnesium balance of periods I and II did not differ significantly (Fig. 1). Following sPTX, magnesium balance improved in seven patients and worsened in two. Urinary magnesium decreased following sPTX. Fecal magnesium remained the principal cause of the negative balances. Figure 2 illustrates the effect of sPTX on mean serum concentrations of calcium, phosphate and magnesium. Total serum calcium fell significantly (p < 0.005) between periods I and II. A similar fall in serum phosphate (p < 0.001) and magnesium (p < 0.05) was seen. There were no significant nificantly
Fig. 2.-Mean
total serum calcium, phosphate and magnesium fell significantly following subtotal parathyroidectomy in nine patients with chronic renal failure and secondary hyperparathyroidism.
2 $ 2 ’
:
4
\\:
6 !
F -‘-.,P_o~ --._
4
pcOOOl
I -----.-._.-
!
”
MQ
l
2
NC
peooo5,
I
pcoo5
I
I
I
/
I
PERIOD
I
PERIOD
II
10.5
> 100
> 2oi.g
moderate
severe hypertrophy
mild hypertrophy severe hypertrophy
E.T.
D.F.
B.S. N.U.
* Plasma parathyroid
hormone
hypertrophy
34.0
severe hypertrophy
J.P.
in ~1 eq/ml
6.2
moderate hypertrophy moderate hypertrophy moderate hypertrophy
I
G.S. E.M. J.M.
-
severe hypertrophy
S.F.
0
*
(normal
0.95 3.7
9.4
2.7
7.6
-
II -
PTH Concentrations
Contractions
of phalanges
and
bone demineraliz-
normal subperiosteal resorption of phalanges and distal clavicles, demineralization of skull and spine
generalized ation resorption clavicles
subperiosteal resorption of phalanges and distal clavicles, demineralization of skull and spine
and Metastatic
improvement in phalanges and clavicles 2i% months following sPTX normal normal remineralization of skull after 1% years improvement in hands after 1 improved month: clavicles after 3 months: remineralization of skull and spine after 3 months bone remineralization after 6% months phalanges improvement in after 3% months: improvement in clavicles after 5 months normal phalanges improved after 2 months: clavicles much improved after 5 months: remineralization of skull and spine after 5 months
Radiographic Changes Post-sPTX
X-Ray Abnormalities
marked subperiosteal resorption of phalanges and distal clavicles normal normal mild demineralization of skull
Bone Radiographs Pre-sPTX
Hormone
< 4Fl eq/ml).
of sPTX on Parathyroid
Parathyroid Gland Size
Table 4 .-Effects
Patient
vascular
none carotid arteries
subcutaneous about shoulder: aortic
none
extensive subcutaneous and vascular
none none none
widespread
Metastatic Calcification
Calcification
494
JOHNSON
ET AL.
changes in mean blood pH, pCOz, sodium, potassium, CO2 chloride, alkaline and acid phosphatase, creatinine and urea nitrogen. PTH determinations are available in six of the nine patients (Table 4). All six had elevated values prior to sPTX and all fell afterwards. In two patients PTH concentrations remained elevated during period II, but subsequently became normal. X-ray skeletal abnormalities improved in the months following sPTX in all patients. Subcutaneous soft tissue calcium deposits resolved rapidly in the two patients who had these deposits. Vascular calcification remained unchanged even after many months. WOPruritus improved shortly after sPTX in the seven patients so afflicted (Table 1).20,21 Bone pain disappeared 1 month after sPTX in J.P., and after 6 months in S.F., but then only after high oral doses of vitamin D. Five patients comprise those studied after successful renal transplantation. Two had not had sPTX while three were studied both in periods I and II. Calcium balance data for the sPTX patients in shown in Fig. 3. In two of these three patients the calcium balance improved, becoming positive following transplantation while the other became more negative. Calcium balance also improved after transplantation in the two patients whose parathyroids had been left intact (Fig. 4). Table 5 shows PTH levels and total serum calcium concentrations during period III. All PTH and serum calcium values were normal in the posttransplant state in the three sPTX patients. Neither of the non-sPTX patients developed hypercalcemia, but an elevated PTH value persisted in S.G. Unfortunately, posttransplant PTH values for D. Fi. whose pretransplant values were quite high were not obtained. In these two patients the X-ray abnormalities of one (D. Fi.) who had phalangeal and clavicular erosions significantly improved in the 3 months following renal transplantation, but the other (S.G.) showed no radiological improvement of the distal ulna cystic changes at the time of period III.
BAL4NCE
-549 -206 '56
-472 -73 t343
-264 -316-494
D/iv
434 536 681
513 462 587
449 469 540
EXCRETED
983 744 625
965 555 244
713 007 1042
I
Fig. 3.-Calcium
nm
I
lIm
1
n
i i
m
balance in three uremic patients prior to subtotal parathyroidectomy (period I), following parathyroid surgery (period II) and after successful renal transplantation (period III). Calcium balance became positive in two following restoration of renal function, but in the other it worsened.
SUBTOTAL
PARATHYROIDECTOMY
Fig. 4.-Calcium
balance
495
in two
uremic patients with secondary hyperparathyroidism before (period i) and after successful renal transplantation (period III). Balance improved in both patients. Neither had subtotal parathyroidectomy.
3 i G :
I
-*oar -‘loo -1500 t
EXCRETED 1
474 I
Table 5.-PTH Patients With sPTX
J.M. J.P. B.S.
Without sPTX S.G. D. Fi.
435
2040
861
I
m
m
and Serum Calcium Concentration in Five Transplanted Patients PTH * PI w/ml
Perior I MeEzA
6.2
10.5
34.0 4.8
8.6 10.2
14
9.7 10.2
17.5
+
PTH
Period II
PI w/ml
0 1.6 0.95
*Ez*
9.9 6.8 9.9
PTH
Period III
~1w/ml
M::~A
4.0 3.0 1.5
9.4 9.0 9.6
12 -
9.4 10.6
* Normal < 4 pl eq/ml. f Normal 9.0-11.0 mg/lOO ml. DISCUSSION
Variable Additional to Subtotal Parathyroidectomy and Renal Transplantation
The classic studies of Liu and Chu22 on five patients with CRF constitute the earliest data on mineral balances in uremia. Their data as well as that of others”3,24n25have demonstrated that changes in pH, dietary calcium and vitamin D related compounds can influence calcium balance in CRF. In order to prevent any changes in mineral balance resulting from dietary variations, calcium intake was maintained between 400 and 700 mg/day throughout the present studies. This range approximates the content of calcium in the 70 g protein diet followed by many dialysis patients. Vitamin D administration may have influenced the mineral balances of D.F. and N.U. (Tables 1 and 2)) who required large doses of vitamin D and calcium in the immediate post-sPTX period because of hypocalcemic tetany. One month elapsed between the last dose of vitamin D and the period II balance studies of D.F. and N.U. This interval may not be sufficient to preclude changes between periods I and II partially due to vitamin D.23 Blood pH changed in only one patient (D-F.) and followed the initiation of hemodialysis. The acidosis (arterial pH = 7.30) present during period I had been corrected by dialysis (arterial pH = 7.45) during period II. Although this was the only patient in whom hemodialysis was initiated between periods I and II, net transfer of calcium during this procedure was not necessarily constant in
496
JOHNSON
ET AL.
the remaining eight patients since the fall in serum calcium following sPTX influenced the gradient between dialysate (2.6 meq per liter) and blood. In the five patients studied after transplantation the discontinuation of hemodialysis probably contributed to the changes in calcium balance in Period III (Figs. 3 and 4). In addition, all were taking prednisone (20 to 45 mg/day) and azathioprine (150 to 225 mg/day). Whereas azathioprine may or may not have influenced the results, glucocorticoids are known to decrease intestinal absorption of calcium.20 Thus, changes observed following sPTX may reflect not only decreased PTH, but also correction of metabolic acidosis and the initiation of dialysis (in D.F.) , vitamin D effects (in D.F. and N.U.), and an unknown ionic flux during dialysis (in all nine patients). Following transplantation, in addition to the restoration of renal function, the cessation of dialysis and the administration of glucocorticosteroids probably also contributed to the change observed. Ef/ect of Subtotal Parathyroidectomy on Calcium Balance Stanbury et aLZ3 have reported that dietary and fecal calcium were approximately equal in a group of 39 patients with CRF and net absorption of calcium was nil in these undialyzed uremic individuals. The abnormal intestinal absorption of calcium in renal failure is probably due to an acquired resistance to vitamin D and/or abnormal vitamin D metabolism.jc7 Using tracer techniques,7 it was shown that calcium absorption is abnormally low in hemodialysis patients, and does not differ significantly from patients with CRF who are not being treated with hemodialysis. In addition, the abnormalities in vitamin D metabolism demonstrated by Avioli in uremia, while corrected following successful renal transplantation, are not improved by hemodialysis.” The present data that show that fecal calcium exceeded dietary calcium support the presence of a persistent impairment in absorption of calcium from gastrointestinal secretions and diet in the dialyzed patient. The marked negative calcium balances demonstrated in our dialyzed patients, compared to the smaller negative balances found in undialyzed uremics,23 may reflect unmeasured calcium which is transferred to the patient during dialysis and later secreted into the gut but not reabsorbed. The smaller negative calcium balances in N.U. and D.F. who were not on dialysis, compared to the mean negative balance of the group, support this concept. In addition, the relatively low calcium intake used throughout our study, may have also contributed to the negative balances.“‘t”j Following sPTX no consistent change in mineral balance was demonstrated. In a preliminary report10 an apparent improvement in calcium balance was noted, but after additional patients were studied, this trend did not prove to be consistent. The improvement in calcium balance demonstrated in five patients was offset by greater negative balances in the other four, so that the mean calcium balance decreased only from - 3 18 mg/day to - 277 mg/day (Table 2)) which was not statistically significant. The one patient whose balance actually became positive had been treated with large doses of vitamin D following sPTX and, even though the treatment was discontinued 1 month prior to the study, the positive balance may partially reflect the effect of vitamin D.23 There were no differences in initial serum calcium concentrations or the fall
SUBTOTAL
PARATHYROIDECTOMY
495
Fig. 4.-Calcium balance in two uremic patients with secondary hyperparathyroidism before (period I) and after successful renal transplantation (period III). Balance improved in both patients. Neither had subtotal parathyroidectomy. BALANCE DIET EXCRETED
Table 5.-PTH Patients With sPTX
+71
I
-1491
476
506
1
549
614
474
435
2040
661
I
m
I
m
-247
and Serum Calcium Concentration in Five Transplanted Patients PTH * PI q/ml
Perior I
J.M.
6.2
J.P. B.S.
34.0 4.8
Without sPTX S.G. D. Fi.
+4
14 175
“=tS*
10.5 8.6 10.2
t
Period II PTH Mean CA mg% pl eqlml
0 7.6 0.95
9.7 10.2
PTH
Period III
H earn1
M%%A
9.9
4.0
9.4
6.8 9.9
3.0 1.5
9.0 9.6
12 -
9.4 10.6
* Normal < 4 pl eq/ml. t Normal 9.0-11.0 mg/lOO ml. DISCUSSION
Variable Additional to Subtotal Parathyroidectomy and Renal Transplantation The classic studies of Liu and Chuz2 on five patients with CRF constitute the earliest data on mineral balances in uremia. Their data as well as that of others23*24,25 have demonstrated that changes in pH, dietary calcium and vitamin
D related compounds can influence calcium balance in CRF. In order to prevent any changes in mineral balance resulting from dietary variations, calcium intake was maintained between 400 and 700 mg/day throughout the present studies. This range approximates the content of calcium in the 70 g protein diet followed by many dialysis patients. Vitamin D administration may have influenced the mineral balances of D.F. and N.U. (Tables 1 and 2), who required large doses of vitamin D and calcium in the immediate post-sPTX period because of hypocalcemic tetany. One month elapsed between the last dose of vitamin D and the period II balance studies of D.F. and N.U. This interval may not be sufficient to preclude changes between periods I and II partially due to vitamin D.23 Blood pH changed in only one patient (D.F.) and followed the initiation of hemodialysis. The acidosis (arterial pH = 7.30) present during period I had been corrected by dialysis (arterial pH = 7.45) during period II. Although this was the only patient in whom hemodialysis was initiated between periods I and II, net transfer of calcium during this procedure was not necessarily constant in
SUBTOTAL
PARATHYROIDECTOMY
497
in serum calcium after sPTX between patients whose balance improved and those in whom it did not. Changes in calcium balance did not appear to be related in any consistent manner either to the severity of hyperparathyroidism or to the time that had elapsed between sPTX and the period II study. Stanbury reported a similar, but undialyzed, patient who was in negative calcium balance and whose phalangeal erosions and metastatic calcifications improved following sPTX without a change in the negative calcium balance.23 He attributed this improvement to a transfer of mineral from the soft tissue back to bone and remarked that the remineralization of the skeleton depends upon an endogenous source of mineral present in areas of obvious ectopic calcification. We agree that the improvement may be mediated by a transfer of endogenous ectopic mineral back to bone. However, the improvement in osteodystrophy in our patients was not invariably related to resolution of grossly demonstrable ectopic calcium deposits following sPTX. Only two of our patients had ectopic subcutaneous calcium deposits which disappeared following surgery. Although two additional patients had vascular calcification, this did not change appreciably while their bones improved dramatically (Table 4). The bone disease in two other patients without any demonstrable ectopic calcifications improved as well. Since the calcium content of the skin in uremic patients with renal osteodystrophy has been shown to be higher than in normals or in uremic patients without bone disease,l it appears reasonable to assume that a considerable reservoir of calcium exists extraskeletally in these patients as well as abnormally in bone as localized sclerotic lesions. Although not obvious clinically or radiographically, these ectopic deposits may provide the endogenous source of mineral for bone repair. Without an improvement in the negative balances, the ultimate development of other forms of metabolic bone disease might be anticipated. Any influence of a reduction in PTH concentrations on this occurrence remains to be defined. EfJect
of Rend Transplantation of Calcium Balance
Calcium balance became positive after transplantation in two of the three patients who had previously had sPTX and healing of their bone lesions continued (Fig. 3 and Table 5). It should be noted that PTH concentrations were normal in all three sPTX patients and had not changed appreciably since period II (Table 5). Thus, the transition to a positive calcium balance following transplantation in two of these patients probably was caused by factors other than PTH changes. We cannot explain the worsening of calcium balance which occurred in B.S. Unfortunately, this patient died 2 months later of disseminated aspergillosis, precluding further studies. It is likely that this infection was latent at the time of the balance studies, possibly influencing the results. Only two patients who had not been subjected to sPTX were studied following transplantation (Fig. 4 and Table 5). Although there was an improvement in calcium balance in S.G. 5 months following renal transplantation, there was little change in PTH and no improvement in the radiological bone lesions. The failure of PTH to fall appreciably may have been due to less than optimal renal function (serum creatinine 3.0 mg/lOO ml) and again illustrates the apparent independence of external mineral balance from PTH and bone improvement. D. Fi., who showed a marked negative balance during period II ( - 1491 mg/day)
498
JOHNSONETAL.
improved (-247 mg/day) in period III. Of note is the initiation of healing in the clavicular and phalangeal erosions, which was evident by 2% months posttransplant. At this time external calcium balance was still negative although much less so than during period II. These observations lend further support for the concept that an endogenous source of mineral is utilized for bone repair. Unfortunately, no PTH values were obtained on D. Fi. following transplantation but the radiographic improvement may reflect a decline from the previously markedly elevated value of 175 ~1 eq per milliliter. The improvement in calcium balance seen in four of the five transplanted patients, in spite of the known depressive effect of glucocorticosteroids on calcium absorption, was clearly due to reduced fecal losses (Figs. 3 and 4). This change in calcium balance probably resulted from correction of the intestinal absorptive defect following restoration of renal function, as well as the effects of the cessation of dialysis. Changes in Phosphate and Magnesium Balance
Mean phosphate balance did not change significantly following sPTX, although it improved in six and worsened in only three patients (Table 3). The unmeasured phosphate losses during hemodialysis were probably substantial since an effective gradient for its dialytic removal is created by its absence from the dialysate. The validity of the phosphate balance is, therefore, doubtful. As with calcium, fecal loss of phosphate was high and was the principal cause of the negative balance (Table 3)) again, probably due to abnormal absorption. Urinary phosphate excretion fell after sPTX as expected. Paradoxically, serum phosphate concentrations fell, probably reflecting decreased bone resorption ensuing the decreases in PTH which counterbalanced the impaired phosphaturic response of the severely diseased kidney to a decrease in PTH. In period III phosphate balance worsened in two and improved in three patients. These changes showed no apparent correlation with either parathyroid status or changes in calcium balance. Serum phosphate fell dramatically in all patients following transplantation. Although magnesium balance improved in seven patients, and worsened in only two following sPTX, the mean balance did not change significantly (Fig. 1) . The fall in mean serum magnesium concentration following sPTX probably reflects decreased mobilization of magnesium from bone as was true for both serum calcium and phosphate (Fig. 2). Following transplantation magnesium balance improved in three and worsened in two, and was unrelated to changes in either calcium or phosphate balance or in parathyroid status. Serum magnesium fell in all patients with restoration of renal function. CONCLUSIONS
Subtotal parathyroidectomy results in an improvement in the manifestations of hyperparathyroidism in patients with CRF without any consistent changes in measured external mineral balances. This improvement is probably a consequence of a fall in PTH and may reflect shifts in the internal calcium pools. Renal transplantation appears to correct the intestinal absorptive defect for
500 Glenview,
JOHNSON
Ill. Scott & Foresman,
1968, p.
.m
IL.
20. Hampers, C. L., Katz, A. I., Wilson, R. E., and Merrill, J. P.: Disappearance of “uremic” itching after subtotal parathyroidectomy. New Eng. .I. Med. 279:695, 1968. 21. Massry, S. G., Popovtzer, M. M., Coburn, J. W., Makoff, D. L., Maxwell, M. H., and Kleeman, C. R.: Intractable pruritus as a manifestation of secondary hypcrparathyroidism in uremia. New Eng. J. Med. 279:697, 1968. 22. Liu, S. H., and Chu, H. I.: Studies of calcium and phosphate metabolism with special reference to pathogenesis and effects of dihydrotachysterol and iron. Medicine 22: 103, 1943. 23. Stanbury, S. W., Lumb, G. A., and
ET AL.
Mawer, E. B.: Osteodystrophy developing spontaneously in the course of chronic renal failure. Arch. Intern. Med. (Chicago) 124: 274, 1969. 24. Litzow, J. R., Lemann, J., and non, E. J.: The effect of treatment of osis on calcium balance in patients chronic axotemic renal disease. J. Invest. 46:280, 1967.
Lenacidwith Clin.
25. Spencer, H., Levin, I., Fowler, J., and Samachson, J.: Influence of dietary calcium intake on Cad7 absorption in man. Amer. J. Med. 46:197, 1969. 26. Kimberg, D. V.: Effects of vitamin D and steroid hormones on the active transport of calcium by the intestine. New Eng. J. Med. 280:1396, 1969.
in Chronic Renal Failure
By JAMES W. JOHNSON,AMNON WACHMAN, ADRIAN I. KATZ, DANIEL S. BERNSTEIN, CONSTANTINEL. HAMPERS, ROBERT S. HATTNER, RICHARDE. WILSON, ANDJOHNP. MERRILL
Subtotal parathyroidectomy results in improvement of bone disease and metastatic calcification present in some uremic patients. This improvement is not associated with any consistent changes in external mineral balance. Calcium balance may be quite negative in both the dialyzed and undialyzed uremic patient, probably due to defective intestinal absorption, and is not altered in any cous&tent manner by subtotal parathyroidsuccessful renal ectomy. Following transplantation the manifestations of hyperparathyroidism may resolve spontaneously and calcium balance usually becomes positive. Although both im-
From Brigham Boston,
the Departments Hospital;
and
of Medicine
provements follow the restoration of renal function they may not be mutually dependent or even related. The improved calcium balance appears to depend upon the correction of defective gastrointestinal absorption. In patients in whom external calcium balance does not become positive, resolution of parathyroid induced bone disease and metastatic calcification may result from the resorption of endogenous calcium from ectopic sites with redeposition into bone, a process presumably made possible by the decrease in plasma parathyroid hormone consequent to renal transplantation.
and Surgery,
the Department
Harvard
of Nutrition,
Medical
Harvard
School;
School
Peter
of Public
Bent
Health,
Mass.
Received
for publication
October
14, 1970.
Supported by NIH Grants 5-MOI-FR-31, 5-TOI-AI-00301, and AM-03967, the Fund for Research and Teaching, Department of Nutrition, Harvard School of Public Health; and the Massachusetts Heart Association. JAMES W. JOHNSON,M.D.: Research Fellow in Medicine, Harvard Medical School, Assistant in Medicine, Peter Bent Brigham Hospital, Boston, Mass. AMNONWACHMAN, M.D.: Research Associate, Department of Nutrition, Harvard School of Public Health, Boston, Mass. ADRIAN I. KATZ, M.D.: Research Associate in Medicine, Harvard Medical School; Assistant in Medicine, Peter Bent Brigham Hospital, Boston, Mass. DANIEL S. BERNSTEIN, M.D.: Assistant Professor of Medicine, Harvard Medical School; Senior Associate in Medicine,
Peter
Instructor
in Medicine,
Hospital:
Bent Brigham
Director,
sistant in Medicine, Associate Medical
School;
Howard
Hughes
Fellow
School:
of Surgery,
Mass.
in Nutrition, Hospital,
Harvard
Medical
Peter
in Medicine,
Bent
Brigham
Hospital,
Harvard
Boston,
Medical
Mass. JOHN P. MERRILL, M.D.: Physician,
CONSTANTINE L. HAMPERS, M.D.:
Associate
Peter Bent Brigham
Peter Bent Brigham
Professor Boston,
Boston,
Medical
Dialysis Facilities,
S. HAITNER, M.D.: Research
Hospital,
Hospital,
Harvard
School
Peter Bent Brigham
Boston,
Mass. ROBERT
of Public
Health;
As-
Mass. RICHARD E. WILSON, M.D.:
School;
Surgeon,
Associate
Professor
Hospital,
Boston,
Bent
Brigham
of Medicine,
Peter
Harvard
Mass.;
investigator,
Institute,
MFTABOLISM, VOL. 20, No. 5 (MAY),
1971
487
488
JOHNSON ET AL.
THE
PATHOGENESIS OF RENAL OSTEODYSTROPHY is complex and probably involves abnormalities of vitamin D, parathyroid function, pH, ionized calcium and end-organ responsiveness. The net result is a profound alteration in calcium homeostasis with a redistribution of skeletal mineral and the appearance of metastatic mineral deposits. Spotty sclerosis of bones as well as measurable, although not necessarily grossly visible, increases in skin calcium may be present. 1 This peculiar redistribution as well as a possible overall net loss of calcium in chronic renal failure (CRF) can be reversed at least in part by successful renal transplantation .2.3,4Although arterial calcification may not resolve following the restoration of renal function, remineralization of the skeleton occurs, subperiosteal resorption resolves, and subcutaneous calcium deposits disappear. In association with this clinical improvement, responsiveness to vitamin D is restored and hyperparathyroidism resolves.5,6 Since hemodialysis is not as effective as successful renal transplantation in effecting these changes, 5~~attempts have been made in the dialyzed patient with CRF to overcome vitamin D resistance by administration of large doses of vitamin Ds and to decrease plasma parathyroid hormone (PTH) by subtotal parathyroidectomy (sPTX) .9~0 The place of sPTX in CRF remains controversial and the indications for sPTX are not unanimously agreed upon. In order to determine the therapeutic role as well as the timing of sPTX in CRF, the following studies have been performed to assess metabolic changes which occur following sPTX and successful transplantation as reflected in the overall mineral balance. MATERIALS
AND METHODS
Nine patients with CRF and associated secondary hyperparathyroidism were studied in the Clinical Research Center, Peter Bent Brigham Hospital, Boston, Mass., before (period I) and after sPTX (period II). Three of these patients were again restudied following successful renal transplantation (period III). Two additional patients with secondary hyperparathyroidism who did not undergo sPTX were studied prior to (period I) and again following successful renal transplantation (period III). The patients’ clinical data are given in Table 1. Two patients had not yet required hemodialysis at the time of period I, while the remainder had been hemodialyzed three times weekly for 2 to 13 months. Following sPTX, however, D.F. developed further deterioration of renal function requiring the initiation of hemodialysis before period II. Thus, only one patient was studied without dialysis in both periods I and II. The indications for sPTX in the nine patients who underwent this procedure were: repeated episodes of hypercalcemia in five, severe progressive hyperparathyroid bone disease in three and intractable pruritus in one patient. Although episodes of hypercalcemia were repeatedly demonstrated in the five patients in whom sPTX was performed for this reason, elevated levels were not constantly present as shown by the mean serum concentrations during the period I study (Table 2). A liquid diet utilizing purified soy-bean protein was used as the exclusive source of nutrient throughout the balance studies. 11 Each 100 g of soy-bean powder contained 86.5 280 mg calcium, 980 mg phosphate and 84 mg g of protein, 2.0 g of carbohydrates, magnesium. Multivitamins (not including vitamin D), ferrous gluconate and calcium lactate tablets at constant doses (sufficient to raise the daily calcium intake to 434 to 681 mg) were given daily. The diet was prepared by blending a weighed amount of soy-bean powder with distilled water. Dextrose, corn oil, flavoring (usually vanilla), amino acids, methylcellulose, sodium and potassium salts were added and the entire mixture was blended to a liquid consistency. Each individual serving and all unconsumed portions were accurately weighed to determine the intake precisely.
F
F
53
18
16
24
N.U.
Without sPTX S.G.
glomerulonephritis.
B.S.
D. Fi.
* Chronic
M
M Alport’s syndrome CGN
cancer of solitary kidney chronic pyelonephritis
4
3
17
‘/z
18
CGN
F
37
D.F.
11
CGN
F
28
E.T.
4
CGN
F
24
J.P.
3 1% 6
nephrosclerosis CGN CGN
M
M F M
47 21 30
G.S. E.M. J.M.
(Years)
Known Duration of Disease
16
Diaanosis
of Hyperparathyroidism
progressive cystic changes of distal ulna subperiosteal resorption of phalanges and distal clavicles
severe progressive X-ray changes in secondary hyperparathyroidism serum calcium of 14 m&100 ml intractable pruritus serum calcium of 12.0 mg/lOO ml severe progressive X-ray changes of secondary hyperparathyroidism serum calcium of 12.0 mg/lOO ml, mild band keratopathy serum calcium of 12.4 mg/lOO ml, progressive X-ray changes of secondary hyperparathyroidism serum calcium of 12.4 mg/lOO ml, mild band keratopathy severe progressive X-ray changes of secondary hyperparathyroidism
Evidence of HyDerDarathyroidism
Features and Evidence
CGN *
45
S.F.
Sex
A%
Patient with sPTX
Table l.-Clinical
4
10
4
-
-
-
-
-
-
-
-
-L
-
+
2
+
+ + +
13 12 12
4
+
Skeletal Pain
+
Pruritus
2
Duration of Nemodialysis (months)
490
JOHNSON ET AL.
While on the metabolic ward each patient was allowed to equalibrate on the diet for at least 3 days during which hemodialysis was performed prior to initiation of the balance studies. These consisted of either two 4 day balance periods for the patients on hemodialysis separated by a day for dialysis or a single 6 day period for those not on dialysis. While longer equilibration and balance periods are preferable, patient tolerance of the monotonous formula diet and reluctance to withold hemodialysis for longer than 4 consecutive days limited the study to periods as described. Since hemodialysis immediately preceded each of the two 4 day balance periods, equivalent effects would be anticipated. Following period I, sPTX was performed in nine patients. The four parathyroid glands were identified and all tissue except for l/3 to l/2 of the smallest gland was excised. Period II was carried out 8 days to 9 months following sPTX. In the five patients who underwent renal homotransplantation, period III was carried out 3 to 5 months following restoration of renal function. Since none were on hemodialysis at this time, a single 6-day balance period was employed for all. Balance studies were initiated and terminated using carmine red stool markers. In addition, 500 mg of chromium sesquioxide was given three times daily as a continuous stool marker for correction of fecal losses .rs,ls Chromium was determined in triplicate and results showing less than 5 per cent variation were accepted. Feces were dried, weighed, homogenized and ashed prior to determination of chromium,14 calcium,15 phosphate,16 and magnesium.17 Twenty-four hour urine specimens were collected (where applicable) under toluene and refrigerated. Determinations performed on daily 24 hour urine collections included calcium,15 phosphate16 and magnesium.17 During each balance period, arterial blood calcium, phosphate, magnesium and pH were determined daily while alkaline and acid phosphatase, creatinine, urea nitrogen, sodium, potassium and chloride were measured on alternate days by routine methods of the clinical laboratory in the Peter Bent Brigham Hospital. Heparinized plasma was collected and frozen during each balance period for assay of PTH. These assays were performed by Dr. Rosalyn Yalow and Dr. Solomon Berson, Bronx V.A. Hospital, New York, N.Y., utilizing antisera 273 which may detect, in addition to native PTH, biologically active metabolic fragments peculiar to CRF.18 A complete radiological skeletal survey, which included films of the skull, shoulders, hands, spine, pelvis and knees, was obtained preoperatively and periodically thereafter. Unless otherwise indicated, tests of significance between mean values were calculated by the paired t-test.19 RESULTS
Calcium balance data for periods I and II are shown in Table 2. All the patients studied were in negative calcium balance in Period I (range -83 mg/day to - 549 mg/day) , primarily as a result of fecal excess. Urinary calcium losses were inconsequential since only three patients were not anephric (in preparation for transplantation) and even in these patients urinary calcium levels were low (range: 18 to 95 mg/day). In all patients except N.U. fecal losses exceeded intake. In comparing periods I and II, calcium balance improved in five patients and became more negative in four. Fecal calcium remained the major determinant of the negative balance. Urinary calcium fell after surgery in the three patients with kidneys (range: 3 to 7 mg/day). Mean calcium balance did not change significantly following sPTX. In those patients who were studied by two 4 day balance periods (those on hemodialysis, that is, all except N.U. and D.F. during period I and N.U. alone during period II) there were no consistent differences between the balance results of the first and second 4 day period. Therefore, mean values for the two periods were used for analysis. The mean period I phosphate balance of -389 mg/day did not differ sig-
S.F. G.S. E.M. J.M. J.P. E.T. D.F. B.S. N.U. Mean SEM ‘-c
Patient
SF. G.S. E.M. J.M. J.P. E.T. D.F. B.S. N.U. Mean SEM -c
I
-504 -263 -539 -403 -414 -241 -351 -543 -243 -389 41
I
569 573 542 434 513 536 474 449 526 513 17
I
584 582 549 536 482 510 474 489 612 535 17
II
Dietary Calciupme$dg/day)
1076 671 771 983 985 945 722 713 609 831 56
I
1446 972 896 744 555 914 572 807 402 812 101
II
Total Calcium Excretgl(omdg/day)
-813 -359 -425 -267 - 220 -398 -291 - 363 + 245 -321 91
II
522 465 429 451 404 451 236 288 413 407 30 ~____
I
II
557 564 451 451 297 360 236 288 663 430 49
Dietary Phosphg.e~oy/dau)
1026 728 968 854 818 692 587 831 656 796 48
I
1370 923 876 718 517 758 527 6.51 418 751 9.5 _~ _____
II
Total Phosphate Excret;;AF$/day)
3.9 5.0 5.3 9.0 5.5 5.8 7.4 6.8 8.2 6.3 0.3
I
2.5 3.4 2.9 7.2 5.0 2.2 4.4 6.0 6.2 4.4 0.6
II
Mean Serum Phospha;e$mAOO
ml)
II
5.6 9.6 7.2 9.9 6.8 8.8 7.3 9.9 6.4 7.9 0.5
I
10.4 10.2 10.0 10.5 8.6 10.2 9.5 10.2 9.2 9.9 0.2
Mean Serum CalciumP~qnlOO ml)
Data for Nine Patients With CRF Before (Period I) and After (Period II) sPTX
Balance Data for Nine Patients With CRF Before (Period I) and After (Period II) @TX
-862 -390 - 347 -208 - 73 -404 - 98 -318 +210 -277 98
Phosphate Balancpee;imJday )
Table 3.-Phosphate
-507 - 98 - 229 - 549 -472 - 409 - 248 -264 - 83 -318 58
II
Balance
Calcium BalanFe;,Tj/day)
Table 2.-Calcium
JOHNSON ET AL. +60,
I
Fig. l.-Mean magnesium balance in nine patients before (period I) and after (period II) subtotal parathyroidectomy. There is no significant change in magnesium balance, dietary magnesium, or magnesium excreted.
from the mean period II balance of - 321 mg/day (Table 3). Phosphate balance between periods I and II improved in six patients and worsened in three. Excessive fecal loss remained the major determinant of the overall negative balances although there was a decrease in phosphaturia in the three patients with kidneys between period I (range: 24 to 222 mg/day) and periods II (range: 7 to 78 mg/day). The mean magnesium balance of periods I and II did not differ significantly (Fig. 1). Following sPTX, magnesium balance improved in seven patients and worsened in two. Urinary magnesium decreased following sPTX. Fecal magnesium remained the principal cause of the negative balances. Figure 2 illustrates the effect of sPTX on mean serum concentrations of calcium, phosphate and magnesium. Total serum calcium fell significantly (p < 0.005) between periods I and II. A similar fall in serum phosphate (p < 0.001) and magnesium (p < 0.05) was seen. There were no significant nificantly
Fig. 2.-Mean
total serum calcium, phosphate and magnesium fell significantly following subtotal parathyroidectomy in nine patients with chronic renal failure and secondary hyperparathyroidism.
2 $ 2 ’
:
4
\\:
6 !
F -‘-.,P_o~ --._
4
pcOOOl
I -----.-._.-
!
”
MQ
l
2
NC
peooo5,
I
pcoo5
I
I
I
/
I
PERIOD
I
PERIOD
II
10.5
> 100
> 2oi.g
moderate
severe hypertrophy
mild hypertrophy severe hypertrophy
E.T.
D.F.
B.S. N.U.
* Plasma parathyroid
hormone
hypertrophy
34.0
severe hypertrophy
J.P.
in ~1 eq/ml
6.2
moderate hypertrophy moderate hypertrophy moderate hypertrophy
I
G.S. E.M. J.M.
-
severe hypertrophy
S.F.
0
*
(normal
0.95 3.7
9.4
2.7
7.6
-
II -
PTH Concentrations
Contractions
of phalanges
and
bone demineraliz-
normal subperiosteal resorption of phalanges and distal clavicles, demineralization of skull and spine
generalized ation resorption clavicles
subperiosteal resorption of phalanges and distal clavicles, demineralization of skull and spine
and Metastatic
improvement in phalanges and clavicles 2i% months following sPTX normal normal remineralization of skull after 1% years improvement in hands after 1 improved month: clavicles after 3 months: remineralization of skull and spine after 3 months bone remineralization after 6% months phalanges improvement in after 3% months: improvement in clavicles after 5 months normal phalanges improved after 2 months: clavicles much improved after 5 months: remineralization of skull and spine after 5 months
Radiographic Changes Post-sPTX
X-Ray Abnormalities
marked subperiosteal resorption of phalanges and distal clavicles normal normal mild demineralization of skull
Bone Radiographs Pre-sPTX
Hormone
< 4Fl eq/ml).
of sPTX on Parathyroid
Parathyroid Gland Size
Table 4 .-Effects
Patient
vascular
none carotid arteries
subcutaneous about shoulder: aortic
none
extensive subcutaneous and vascular
none none none
widespread
Metastatic Calcification
Calcification
494
JOHNSON
ET AL.
changes in mean blood pH, pCOz, sodium, potassium, CO2 chloride, alkaline and acid phosphatase, creatinine and urea nitrogen. PTH determinations are available in six of the nine patients (Table 4). All six had elevated values prior to sPTX and all fell afterwards. In two patients PTH concentrations remained elevated during period II, but subsequently became normal. X-ray skeletal abnormalities improved in the months following sPTX in all patients. Subcutaneous soft tissue calcium deposits resolved rapidly in the two patients who had these deposits. Vascular calcification remained unchanged even after many months. WOPruritus improved shortly after sPTX in the seven patients so afflicted (Table 1).20,21 Bone pain disappeared 1 month after sPTX in J.P., and after 6 months in S.F., but then only after high oral doses of vitamin D. Five patients comprise those studied after successful renal transplantation. Two had not had sPTX while three were studied both in periods I and II. Calcium balance data for the sPTX patients in shown in Fig. 3. In two of these three patients the calcium balance improved, becoming positive following transplantation while the other became more negative. Calcium balance also improved after transplantation in the two patients whose parathyroids had been left intact (Fig. 4). Table 5 shows PTH levels and total serum calcium concentrations during period III. All PTH and serum calcium values were normal in the posttransplant state in the three sPTX patients. Neither of the non-sPTX patients developed hypercalcemia, but an elevated PTH value persisted in S.G. Unfortunately, posttransplant PTH values for D. Fi. whose pretransplant values were quite high were not obtained. In these two patients the X-ray abnormalities of one (D. Fi.) who had phalangeal and clavicular erosions significantly improved in the 3 months following renal transplantation, but the other (S.G.) showed no radiological improvement of the distal ulna cystic changes at the time of period III.
BAL4NCE
-549 -206 '56
-472 -73 t343
-264 -316-494
D/iv
434 536 681
513 462 587
449 469 540
EXCRETED
983 744 625
965 555 244
713 007 1042
I
Fig. 3.-Calcium
nm
I
lIm
1
n
i i
m
balance in three uremic patients prior to subtotal parathyroidectomy (period I), following parathyroid surgery (period II) and after successful renal transplantation (period III). Calcium balance became positive in two following restoration of renal function, but in the other it worsened.
SUBTOTAL
PARATHYROIDECTOMY
Fig. 4.-Calcium
balance
495
in two
uremic patients with secondary hyperparathyroidism before (period i) and after successful renal transplantation (period III). Balance improved in both patients. Neither had subtotal parathyroidectomy.
3 i G :
I
-*oar -‘loo -1500 t
EXCRETED 1
474 I
Table 5.-PTH Patients With sPTX
J.M. J.P. B.S.
Without sPTX S.G. D. Fi.
435
2040
861
I
m
m
and Serum Calcium Concentration in Five Transplanted Patients PTH * PI w/ml
Perior I MeEzA
6.2
10.5
34.0 4.8
8.6 10.2
14
9.7 10.2
17.5
+
PTH
Period II
PI w/ml
0 1.6 0.95
*Ez*
9.9 6.8 9.9
PTH
Period III
~1w/ml
M::~A
4.0 3.0 1.5
9.4 9.0 9.6
12 -
9.4 10.6
* Normal < 4 pl eq/ml. f Normal 9.0-11.0 mg/lOO ml. DISCUSSION
Variable Additional to Subtotal Parathyroidectomy and Renal Transplantation
The classic studies of Liu and Chu22 on five patients with CRF constitute the earliest data on mineral balances in uremia. Their data as well as that of others”3,24n25have demonstrated that changes in pH, dietary calcium and vitamin D related compounds can influence calcium balance in CRF. In order to prevent any changes in mineral balance resulting from dietary variations, calcium intake was maintained between 400 and 700 mg/day throughout the present studies. This range approximates the content of calcium in the 70 g protein diet followed by many dialysis patients. Vitamin D administration may have influenced the mineral balances of D.F. and N.U. (Tables 1 and 2)) who required large doses of vitamin D and calcium in the immediate post-sPTX period because of hypocalcemic tetany. One month elapsed between the last dose of vitamin D and the period II balance studies of D.F. and N.U. This interval may not be sufficient to preclude changes between periods I and II partially due to vitamin D.23 Blood pH changed in only one patient (D-F.) and followed the initiation of hemodialysis. The acidosis (arterial pH = 7.30) present during period I had been corrected by dialysis (arterial pH = 7.45) during period II. Although this was the only patient in whom hemodialysis was initiated between periods I and II, net transfer of calcium during this procedure was not necessarily constant in
496
JOHNSON
ET AL.
the remaining eight patients since the fall in serum calcium following sPTX influenced the gradient between dialysate (2.6 meq per liter) and blood. In the five patients studied after transplantation the discontinuation of hemodialysis probably contributed to the changes in calcium balance in Period III (Figs. 3 and 4). In addition, all were taking prednisone (20 to 45 mg/day) and azathioprine (150 to 225 mg/day). Whereas azathioprine may or may not have influenced the results, glucocorticoids are known to decrease intestinal absorption of calcium.20 Thus, changes observed following sPTX may reflect not only decreased PTH, but also correction of metabolic acidosis and the initiation of dialysis (in D.F.) , vitamin D effects (in D.F. and N.U.), and an unknown ionic flux during dialysis (in all nine patients). Following transplantation, in addition to the restoration of renal function, the cessation of dialysis and the administration of glucocorticosteroids probably also contributed to the change observed. Ef/ect of Subtotal Parathyroidectomy on Calcium Balance Stanbury et aLZ3 have reported that dietary and fecal calcium were approximately equal in a group of 39 patients with CRF and net absorption of calcium was nil in these undialyzed uremic individuals. The abnormal intestinal absorption of calcium in renal failure is probably due to an acquired resistance to vitamin D and/or abnormal vitamin D metabolism.jc7 Using tracer techniques,7 it was shown that calcium absorption is abnormally low in hemodialysis patients, and does not differ significantly from patients with CRF who are not being treated with hemodialysis. In addition, the abnormalities in vitamin D metabolism demonstrated by Avioli in uremia, while corrected following successful renal transplantation, are not improved by hemodialysis.” The present data that show that fecal calcium exceeded dietary calcium support the presence of a persistent impairment in absorption of calcium from gastrointestinal secretions and diet in the dialyzed patient. The marked negative calcium balances demonstrated in our dialyzed patients, compared to the smaller negative balances found in undialyzed uremics,23 may reflect unmeasured calcium which is transferred to the patient during dialysis and later secreted into the gut but not reabsorbed. The smaller negative calcium balances in N.U. and D.F. who were not on dialysis, compared to the mean negative balance of the group, support this concept. In addition, the relatively low calcium intake used throughout our study, may have also contributed to the negative balances.“‘t”j Following sPTX no consistent change in mineral balance was demonstrated. In a preliminary report10 an apparent improvement in calcium balance was noted, but after additional patients were studied, this trend did not prove to be consistent. The improvement in calcium balance demonstrated in five patients was offset by greater negative balances in the other four, so that the mean calcium balance decreased only from - 3 18 mg/day to - 277 mg/day (Table 2)) which was not statistically significant. The one patient whose balance actually became positive had been treated with large doses of vitamin D following sPTX and, even though the treatment was discontinued 1 month prior to the study, the positive balance may partially reflect the effect of vitamin D.23 There were no differences in initial serum calcium concentrations or the fall
SUBTOTAL
PARATHYROIDECTOMY
495
Fig. 4.-Calcium balance in two uremic patients with secondary hyperparathyroidism before (period I) and after successful renal transplantation (period III). Balance improved in both patients. Neither had subtotal parathyroidectomy. BALANCE DIET EXCRETED
Table 5.-PTH Patients With sPTX
+71
I
-1491
476
506
1
549
614
474
435
2040
661
I
m
I
m
-247
and Serum Calcium Concentration in Five Transplanted Patients PTH * PI q/ml
Perior I
J.M.
6.2
J.P. B.S.
34.0 4.8
Without sPTX S.G. D. Fi.
+4
14 175
“=tS*
10.5 8.6 10.2
t
Period II PTH Mean CA mg% pl eqlml
0 7.6 0.95
9.7 10.2
PTH
Period III
H earn1
M%%A
9.9
4.0
9.4
6.8 9.9
3.0 1.5
9.0 9.6
12 -
9.4 10.6
* Normal < 4 pl eq/ml. t Normal 9.0-11.0 mg/lOO ml. DISCUSSION
Variable Additional to Subtotal Parathyroidectomy and Renal Transplantation The classic studies of Liu and Chuz2 on five patients with CRF constitute the earliest data on mineral balances in uremia. Their data as well as that of others23*24,25 have demonstrated that changes in pH, dietary calcium and vitamin
D related compounds can influence calcium balance in CRF. In order to prevent any changes in mineral balance resulting from dietary variations, calcium intake was maintained between 400 and 700 mg/day throughout the present studies. This range approximates the content of calcium in the 70 g protein diet followed by many dialysis patients. Vitamin D administration may have influenced the mineral balances of D.F. and N.U. (Tables 1 and 2), who required large doses of vitamin D and calcium in the immediate post-sPTX period because of hypocalcemic tetany. One month elapsed between the last dose of vitamin D and the period II balance studies of D.F. and N.U. This interval may not be sufficient to preclude changes between periods I and II partially due to vitamin D.23 Blood pH changed in only one patient (D.F.) and followed the initiation of hemodialysis. The acidosis (arterial pH = 7.30) present during period I had been corrected by dialysis (arterial pH = 7.45) during period II. Although this was the only patient in whom hemodialysis was initiated between periods I and II, net transfer of calcium during this procedure was not necessarily constant in
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PARATHYROIDECTOMY
497
in serum calcium after sPTX between patients whose balance improved and those in whom it did not. Changes in calcium balance did not appear to be related in any consistent manner either to the severity of hyperparathyroidism or to the time that had elapsed between sPTX and the period II study. Stanbury reported a similar, but undialyzed, patient who was in negative calcium balance and whose phalangeal erosions and metastatic calcifications improved following sPTX without a change in the negative calcium balance.23 He attributed this improvement to a transfer of mineral from the soft tissue back to bone and remarked that the remineralization of the skeleton depends upon an endogenous source of mineral present in areas of obvious ectopic calcification. We agree that the improvement may be mediated by a transfer of endogenous ectopic mineral back to bone. However, the improvement in osteodystrophy in our patients was not invariably related to resolution of grossly demonstrable ectopic calcium deposits following sPTX. Only two of our patients had ectopic subcutaneous calcium deposits which disappeared following surgery. Although two additional patients had vascular calcification, this did not change appreciably while their bones improved dramatically (Table 4). The bone disease in two other patients without any demonstrable ectopic calcifications improved as well. Since the calcium content of the skin in uremic patients with renal osteodystrophy has been shown to be higher than in normals or in uremic patients without bone disease,l it appears reasonable to assume that a considerable reservoir of calcium exists extraskeletally in these patients as well as abnormally in bone as localized sclerotic lesions. Although not obvious clinically or radiographically, these ectopic deposits may provide the endogenous source of mineral for bone repair. Without an improvement in the negative balances, the ultimate development of other forms of metabolic bone disease might be anticipated. Any influence of a reduction in PTH concentrations on this occurrence remains to be defined. EfJect
of Rend Transplantation of Calcium Balance
Calcium balance became positive after transplantation in two of the three patients who had previously had sPTX and healing of their bone lesions continued (Fig. 3 and Table 5). It should be noted that PTH concentrations were normal in all three sPTX patients and had not changed appreciably since period II (Table 5). Thus, the transition to a positive calcium balance following transplantation in two of these patients probably was caused by factors other than PTH changes. We cannot explain the worsening of calcium balance which occurred in B.S. Unfortunately, this patient died 2 months later of disseminated aspergillosis, precluding further studies. It is likely that this infection was latent at the time of the balance studies, possibly influencing the results. Only two patients who had not been subjected to sPTX were studied following transplantation (Fig. 4 and Table 5). Although there was an improvement in calcium balance in S.G. 5 months following renal transplantation, there was little change in PTH and no improvement in the radiological bone lesions. The failure of PTH to fall appreciably may have been due to less than optimal renal function (serum creatinine 3.0 mg/lOO ml) and again illustrates the apparent independence of external mineral balance from PTH and bone improvement. D. Fi., who showed a marked negative balance during period II ( - 1491 mg/day)
498
JOHNSONETAL.
improved (-247 mg/day) in period III. Of note is the initiation of healing in the clavicular and phalangeal erosions, which was evident by 2% months posttransplant. At this time external calcium balance was still negative although much less so than during period II. These observations lend further support for the concept that an endogenous source of mineral is utilized for bone repair. Unfortunately, no PTH values were obtained on D. Fi. following transplantation but the radiographic improvement may reflect a decline from the previously markedly elevated value of 175 ~1 eq per milliliter. The improvement in calcium balance seen in four of the five transplanted patients, in spite of the known depressive effect of glucocorticosteroids on calcium absorption, was clearly due to reduced fecal losses (Figs. 3 and 4). This change in calcium balance probably resulted from correction of the intestinal absorptive defect following restoration of renal function, as well as the effects of the cessation of dialysis. Changes in Phosphate and Magnesium Balance
Mean phosphate balance did not change significantly following sPTX, although it improved in six and worsened in only three patients (Table 3). The unmeasured phosphate losses during hemodialysis were probably substantial since an effective gradient for its dialytic removal is created by its absence from the dialysate. The validity of the phosphate balance is, therefore, doubtful. As with calcium, fecal loss of phosphate was high and was the principal cause of the negative balance (Table 3)) again, probably due to abnormal absorption. Urinary phosphate excretion fell after sPTX as expected. Paradoxically, serum phosphate concentrations fell, probably reflecting decreased bone resorption ensuing the decreases in PTH which counterbalanced the impaired phosphaturic response of the severely diseased kidney to a decrease in PTH. In period III phosphate balance worsened in two and improved in three patients. These changes showed no apparent correlation with either parathyroid status or changes in calcium balance. Serum phosphate fell dramatically in all patients following transplantation. Although magnesium balance improved in seven patients, and worsened in only two following sPTX, the mean balance did not change significantly (Fig. 1) . The fall in mean serum magnesium concentration following sPTX probably reflects decreased mobilization of magnesium from bone as was true for both serum calcium and phosphate (Fig. 2). Following transplantation magnesium balance improved in three and worsened in two, and was unrelated to changes in either calcium or phosphate balance or in parathyroid status. Serum magnesium fell in all patients with restoration of renal function. CONCLUSIONS
Subtotal parathyroidectomy results in an improvement in the manifestations of hyperparathyroidism in patients with CRF without any consistent changes in measured external mineral balances. This improvement is probably a consequence of a fall in PTH and may reflect shifts in the internal calcium pools. Renal transplantation appears to correct the intestinal absorptive defect for
500 Glenview,
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Ill. Scott & Foresman,
1968, p.
.m
IL.
20. Hampers, C. L., Katz, A. I., Wilson, R. E., and Merrill, J. P.: Disappearance of “uremic” itching after subtotal parathyroidectomy. New Eng. .I. Med. 279:695, 1968. 21. Massry, S. G., Popovtzer, M. M., Coburn, J. W., Makoff, D. L., Maxwell, M. H., and Kleeman, C. R.: Intractable pruritus as a manifestation of secondary hypcrparathyroidism in uremia. New Eng. J. Med. 279:697, 1968. 22. Liu, S. H., and Chu, H. I.: Studies of calcium and phosphate metabolism with special reference to pathogenesis and effects of dihydrotachysterol and iron. Medicine 22: 103, 1943. 23. Stanbury, S. W., Lumb, G. A., and
ET AL.
Mawer, E. B.: Osteodystrophy developing spontaneously in the course of chronic renal failure. Arch. Intern. Med. (Chicago) 124: 274, 1969. 24. Litzow, J. R., Lemann, J., and non, E. J.: The effect of treatment of osis on calcium balance in patients chronic axotemic renal disease. J. Invest. 46:280, 1967.
Lenacidwith Clin.
25. Spencer, H., Levin, I., Fowler, J., and Samachson, J.: Influence of dietary calcium intake on Cad7 absorption in man. Amer. J. Med. 46:197, 1969. 26. Kimberg, D. V.: Effects of vitamin D and steroid hormones on the active transport of calcium by the intestine. New Eng. J. Med. 280:1396, 1969.