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Role of 1,25(OH)2D in the genesis of secondary hyperparathyroidism of early renal failure and its use in the prevention of this abnormality
Role of 1,25(OH),D in the Genesis of Secondary Hyperparathyroidism of Early Renal Failure and Its Use in the Prevention of This Abnormality Shaul G. Massry To clarify secondary
the mechanisms
of hypocalcemia
hyperparathyroidism
phosphate restriction
in these
with
on divalent ion metabolism
male patients with stable mild renal insufficiency with
those
of other
hyperparathyroidism
studies
that
indicate
as well as other
therapy
of 1,25(OH),D,
with 1,25(OH),D,
patients with creatinine the management
that
phosphate
abnormalities
(calcitriol).
clearances
conducted
in divalent
production
of 15 to 55 mL/min.
hyperparathyroidism
clearances
restriction
to examine
hormone
the effect
ion metabolism.
to reverse
Because
an alternative
study was conducted
of
of dietary
The study was conducted on four
of 56 to 80 mL/min.
is adequate
of 1,25(OH),D,
To test this, another
Our results correspond and correct
secondary
phosphate
restriction
dietary
therapeutic evaluating
(PTH) and on various parameters
approach would be the effect
of l-year
of bone pathology
in
Our results showed that the use of calcitriol is safe and effective
in
and bone disease in patients with moderate
renal failure.
Company.
P
ATIENTS WITH renal insufficiency have secondary hyperparathyroidism and elevated blood levels of parathyroid hormone (PTH)re3 and histological evidence of bone disease.4*5This secondary hyperparathyroidism is observed early in the course of renal insufficiency when creatinine clearance decreases to 70 mL/min or less,‘,2 and it has been attributed to transient and recurrent or sustained hypocalcemia. Three hypotheses have been proposed to explain the pathogenesis of this hypocalcemia, including phosphate retention,6-9 skeletal resistance to the calcemic action of PTH,“-I2 and altered vitamin D metabolism. However, these pathogenetic mechanisms may not be mutually exclusive, but rather interrelated and together may provide a unified and integrated explanation for the pathogenesis of the hypocalcemia of renal insufficiency. In order to clarify the mechanisms of this hypocalcemia, we examined the effect of dietary phosphate restriction on divalent ion metabolism in patients with early renal insufficiency to delineate the contribution of the various factors described above to the genesis of the hypocalcemia.‘3 Four patients with stable mild renal insufficiency were studied in a metabolic ward for a period of 85 days. All were males, age 46, 48, 50, and 56 years, and their creatinine clearances were 55, 62, 66, and 65 mL/min, respectively. The causes of renal insufficiency were chronic glomerulonephritis in two, interstitial nephritis in one, and benign nephrosclerosis in the fourth. The patients were studied in a Clinical Research Center. They were placed on a diet comparable to their habitual dietary intake providing 600 + 35 g of calcium per day and 1,236 + 97 g/d of phosphorus for a period of 10 days (equilibration phase) followed by an additional 15 days on a similar diet (control phase). During the control phase the following studies were performed twice per week: (1) measurements of the serum concentration of inorganic phosphorus, of total and ionized calcium, and of creatinine and PTH; and (2) estimations of the urinary excretion of phosphorus, calcium creatinine, and CAMP. Also, every patient had measurements of 25(OH)D, 24,25(OH),D, and 1,25(OH),D in blood, estimation of intestinal absorption of calcium, and received a PTH infusion to evaluate the calcemic response to the hormone. Metabolism, Vol39,
and to gain more insight into the mechanisms
study was
in patients with early renal insufficiency.
on blood levels of parathyroid
of secondary
o 1990 by W.B. Saunders
an 85-day
who had creatinine
appears to exert its effect through the increased supplementation
renal insufficiency
patients,
No 4, Suppl 1 (April), 1990: pp 13-17
At the end of the control phase, the patients received a similar diet except for phosphorus intake. The latter was reduced in proportion to the decrease in creatinine clearance. During this period, the diet provided 600 + 35 g/d of calcium and 7 19 k 127 g/d of phosphorus. Serum and urine biochemical parameters were evaluated frequently during this phase of the study and measurements of the blood levels of 25(OH)D, 24,25(OH),D, and 1,25(OH),D, intestinal absorption of calcium, and the calcemic response to PTH infusion were repeated at the end of the phosphate restriction period. The details of the techniques for the measurement of these various parameters have been previously published from our laboratories.13 The results showed that all patients had elevated blood levels of PTH (330 + 19 pg/mL), reduced tubular reabsorption of phosphate (TRP) (60% + 4.3%) and hypocalciuria (24 t 5 mg/24 h). The serum concentration of total calcium (9.3 f 0.13 mg/dL) was within the normal range, but that of ionized calcium (3.70 + 0.10 mg/dL) was significantly (P .Z .Ol) lower than that determined in 11 normal subjects (4.02 c 0.08 mg/dL). The serum concentration of phosphorus was 2.3 * 0.07 mg/dL and urinary excretion of this ion was 688 + 84 mg/24 h. Urinary CAMP excretion was 1.36 t 0.1 nmol/min. During dietary phosphate restriction, the concentration of total and ionized calcium in serum tended to increase and the concentrations of serum phosphorus did not change. The serum levels of PTH began to decrease during phosphate restriction and reached normal values within 2 weeks of this
From the Division of Nephrology and The Department of Medicine, University of Southern California School of Medicine, Los Angeles, CA. Supported by Grant No. 29955 of The National Institute of Diabetes and Digestive and Kidney Diseases and by a grant from Hoffmann-La Roche. Address reprint requests to Shaul G. Massry. MD, Chief, Division of Nephrology, University of Southern California, School of Medicine, 2025 Zonal Ave. Los Angeles, CA 90033. B 1990 by W.B. Saunders Company. 00260495/90/3904-1009$3.00/O
13
SHAUL
14
maneuver. The decrease in serum PTH was accompanied by a significant (P < .Ol) increase in TRP to values between 80% and 90% (88% + l.S%), and a significant (P < .Ol) decline in urinary CAMP (0.53 + 0.13 nmol/min). Urinary phosphate excretion decreased, while urinary excretion of calcium increased. The chronology of all these changes is depicted in Fig 1. Fractional intestinal absorption of calcium during the control period was either overtly low or in the lower normal range. Its mean value was 18.3% + 1.1% which is significantly (P < .Ol) lower than that (25.0% + 0.06%) reported by us in normal subjects.14 Dietary phosphate restriction was associated with a significant increase in the values of this parameter in all patients, with the mean value (24.3% k 1.67%) being significantly (P < .Ol) higher than that in the control period and not different from that in normal subjects (Fig 2). The infusion of PTH during the control period produced an increase in serum calcium levels from 9.14 + 0.13 to 10.40 + 0.22 mg/dL, with the mean increase being 1.26 + 0.11 mg/dL. After dietary phosphate restriction, PTH infusion caused a significantly (P < .Ol) greater increase in the concentrations of total calcium (2.05 f 0.08 mg/dL) from 9.40 + 0.17 to 11.45 k 0.23 mg/dL, with a mean increment of 2.05 t 0.08 mg/dL (Fig 3).
G. MASSRY
Before phosphate restriction, the blood levels of 1,25(OH),D (108, 104, 124, and 178 pmol/L) were normal or modestly elevated. There were significant (P < .Ol) increments in the blood levels of this vitamin D metabolite after dietary phosphate restriction to 180, 184, 182, and 200 pmol/L, respectively. The blood levels of 25(OH)D and 24,25(OH),D were normal and not affected by dietary phosphate restriction. The data of the present study demonstrate that patients with early renal failure display a multitude of abnormalities in divalent ion metabolism. They have elevated blood levels of PTH, modest hypophosphatemia, reduced blood levels of ionized calcium, reduced calcemic response to PTH, and impaired intestinal absorption of calcium. Since calcium transport by the intestineI and the calcemic response to PTH’6-‘8 are largely dependent on vitamin D, the finding that these functions are impaired in our patients suggests that an absolute or relative deficiency of vitamin D exists in these patients. Further support for such a possibility is found in the data of Malluche et al,4 who demonstrated that patients with early renal failure have defective mineralization of osteoid, a function that also requires vitamin D. However, the blood levels of all vitamin D metabolites were normal in our patients. Similar observations were reported by Slatopolsky et a1,19Cheung et al,*’ and Massry et
O_l
T
T
T
T
3 40]] 15
20
4.5 DAYS
60
75
15
45
30
60
75
DAYS
Fig 1. The changes in the serum concentrations of (A) total and ionized calcium, inorganic phosphorus, and immunoreactive parethyroid hormone (iPTH1; end (6) tubular reabsorption of phosphate (TRPL urinary excretion of cyclic AMP WcAMPV) and calcium WcaVI, and creatinine clearance (Ccrj during the control and phosphate restriction periods. Each data point represents the mean of four studies and the brackets denote + 1 SE. (Reprinted with permission.“)
15
Fig 2. Intestinel absorption of calcium before and after phosphate restriction. Each line represents one patient. (Reprinted with permission.“)
a12’ who found either normal or elevated blood level of 1,25(OH),D in patients with moderate renal failure. Thus, the demonstration of disturbances in the functional integrity of the target organs for vitamin D in the face of normal blood levels of its metabolites suggests that a state of vitamin D resistance exists in these patients. It should also be mentioned that other investigators reported low blood levels of 1,25(OH),D in adults’* and in children22*23with moderate renal failure. Therefore, it appears that absolute deficiency of and/or resistance to vitamin D develops early in the course of renal insufficiency and such derangements contribute to many of the abnormalities of divalent ion metabolism in such patients, It is intriguing that despite the presence of adequate functioning renal mass in patients with moderate renal insufficiency, the production of 1,25(OH),D is not increased adequately to meet the needs of the target organs for vitamin D. Since the regulation of the renal lo-hydroxylase, the enzyme responsible for the production of 1,25(OH),D, is influenced by alterations in phosphate homeostasis, it is possible that the phosphate retention that may develop with declining renal function plays a major role in the disturbances in 1,25(OH),D production. The data of the present study are consistent with this hypothesis. Dietary phosphate restriction was associated with a significant increase (44%) in the blood levels of 1,25(OH),D and with biological evidence for the normalization of the target organs’ response to vitamin D. Indeed, dietary phosphate restriction was accompanied by significant improvement or normalization of intestinal absorption of calcium, calcemic response to PTH, and of serum concentrations of ionized calcium and PTH. Data reported by Portale et al23on the effect of dietary phosphate restriction in children with renal insufficiency are in agreement with our results.
Our data in adults and those reported by Portale et al23 in children allow a new formulation for the mechanism of secondary hyperparathyroidism in renal insufficiency. It appears that phosphate retention, which may develop as renal insufficiency ensues, may interfere with the ability of the patient to augment the renal production of 1,25(OH),D to meet increased need. A state of absolute or relative vitamin D deficiency develops, leading to defective intestinal absorption of calcium and impaired calcemic response to PTH. These two abnormalities produce hypocalcemia and, subsequently, secondary hyperparathyroidism. Although this formulation still assigns an important role for phosphate retention in the genesis of secondary hyperparathyroidism in early renal failure, the pathway through which such phosphate retention mediates its effect is different from that originally proposed by Bricker et al.’ The postulate of these investigators implied that phosphate retention in early renal failure causes an increase in serum phosphorus and a consequent decrease in serum calcium, which, in turn, stimulates the parathyroid gland activity. Our data are consistent with the notion that a relative or absolute deficiency of 1,25(OH),D may play a major role in the genesis of secondary hyperparathyroidism of renal insufficiency. Such a proposition is also supported by many observations demonstrating an interaction between this metabolite of vitamin D and the parathyroid glands. Prolonged exposure to 1,25(OH),D, both in vivo24 or in vitro*’ may directly suppress the parathyroid gland activity. Also, available data suggest that 1,25(OH),D, may render the parathyroid glands more susceptible to the suppressive action of ionized calcium.26.27 Thus, it is possible that deficiency of 1,25(OH),D may initiate secondary hyperparathyroidism, even in the absence of overt hypocalcemia. This postulate is in agreement with observations by Lopez et al28 who found
I
l
BEFORE
O
WITH
,
6 a.m.
PO4 PO4
RESTRICTION
RESTRICTtON
I
I
II 0.m.
3
p.m.
I
,
6p.m
6pm
HOURS Fig 3. The changes in the serum concentration of total calcium during psrathyroid extract infusion given between 8:oO AM and 8~00 PM to four patients before and after phosphate restriction. Each data point represents the mean value and the brackets denote + 1 SE. (Reprinted with permission.“)
16
SHAUL G. MASSRY
that secondary hyperparathyroidism developed in dogs with 70% decrease in glomerular filtration rate and in which serum calcium was maintained at normal levels. The results of our studies clearly indicate that phosphate restriction in proportion to the decrease in glomerular filtration rate in patients with early renal failure is adequate to reverse and correct secondary hyperparathyroidism, as well as other abnormalities in divalent ion metabolism. However, achieving the proper and adequate dietary phosphate restriction and successful patient compliance with the dietary regimen may prove difficult. Since the available data indicate that dietary phosphate restriction exerts its effect through the increased production of 1,25(OH),D, it is obvious that an alternative therapeutic approach would be supplementation of 1,25(OH),D,. To test this latter possibility, we conducted a double-blind randomized study to evaluate the effect of 1 year of treatment of patients with creatinine clearances of 15 to 55 mL/min with 1,25(OH),D, (17 patients) or placebo (16 patients) on blood levels of PTH and on various parameters of bone pathology evaluated by morphometric and dynamic studies of bone biopsies. The results showed that almost all patients had elevated blood levels of PTH. Low blood levels of 1,25(OH),D were found in those with creatinine clearances of less than 35
mL/min. Bone biopsies showed evidence of bone resorption (elevated osteoclast index and increased surface density of bone-osteoclast interface), as well as of osteomalacia (increased density of osteoid and of percent osteoid area and prolonged mineralization lag time). One year of therapy with 1,25(OH),D produced a progressive increase in serum concentrations of calcium and a decrease in blood levels of PTH; these changes were inversely correlated. The blood levels of PTH at the end of therapy were about 50% of the values before treatment. Also, the therapy with this vitamin D metabolite resulted in a complete reversal or marked improvement in the indices of bone resorption and of the defective mineralization. Therapy with placebo was without effect on any of these parameters. Hypercalcemic episodes occurred during therapy with 1,25(OH),D,, but were easily controlled either by reducing the dose of the metabolite or by temporary cessation of its administration. We found no adverse effects of 1,25(OH),D, therapy on renal function as evaluated by monthly measurements of creatinine clearance. Therefore, we conclude that treatment of patients with moderate renal failure with 1,25(OH),D, is safe and effective in the management of secondary hyperparathyroidism and bone disease in these patients. Our data are in agreement with those of Baker et al,29 who reported similar results in a smaller number of patients.
REFERENCES
1. Reiss E, Canterbury JM, Bdgahl RH: Experiencewith radioimmunoassay of parathyroid hormone in human sera. Trans Assoc Am Physicians 8 1:104, 1968 2. Massry SG, Coburn JW, Peacock M, et al: Turnover of endogenous parathyroid hormone in uremic patients and those undergoing hemodialysis. Trans Am Sot Artif Int Organs 18:416, 1972 3. Arnaud CL: Hyperparathyroidism and renal failure. Kidney Int 489, 1973 4. Malluche HH, Ritz E, Lange HP, et al: Bone histology in incipient and advanced renal failure. Kidney Int 9:355, 1976 5. Bricker NS, Slatopolsky E, Reiss E, et al: Calcium, phosphorus and bone in renal disease and transplantation. Arch Intern Med 123543, 1969 6. Healy M, Malluche HH, Goldstein DS, et al: Effects of long-term therapy with 1,25(OH),D, in patients with moderate renal failure. Arch Intern Med 140: 1030, 1980 7. Slatopolsky E, Caglar S, Pennell JP, et al: On the pathogenesis of hyperparathyroidism in chronic and experimental renal insufficiency in the dog. J Clin Invest 50:492, 1971 8. Slatopolsky E, Cagler S, Gradowska L, et al: On the prevention of secondary hyperparathyroidism in experimental chronic renal disease using “proportional reduction” of dietary phosphorus intake. Kidney Int 2:147, 1972 9. Slatopolsky E, Bricker NS: The role of phosphorus restriction in the prevention of secondary hyperparathyroidism in chronic renal disease. Kidney Int 4:141,1973 10. Massry SG, Coburn JW, Lee DBN, et al: Skeletal resistance to parathyroid hormone in renal failure: Study in 105 human subjects. Ann Intern Med 78:357, 1973 11. Massry SG, Arieff AI, Coburn JW, et al: Divalent ion metabolism in patients with acute renal failure: Studies on mechanism of hypccalcemia. Kidney Int 5:437, 1974 12. Llach F, Massry SG, Singer FR, et al: Skeletal resistance to endogenous parathyroid hormone in patients with early renal failure:
A possible cause for secondary hyperparathyroidism.
J Clin Endocrinol Metab 41:339, 1975 13. Llach F, Massry SG: On the mechanism of secondary hyperparathyroidism in moderate renal insufficiency. J Clin Endocrinol Metab 61:601, 1985 14. Coburn JW, Koppel JH, Brickman AS, et al: Study of intestinal absorption of calcium in patients with renal failure. Kidney Int 3:264, 1973 15. Coburn JW, Hartenbower DL, Massry SG: Intestinal absorption of calcium and the effect of renal insufficiency. Kidney Int 4:96, 1973 16. Arnaud C, Rassumussen H, Anast C: Further studies on inter-relationship between parathyroid hormone and vitamin D. J Clin Invest 45:1955,1966 17. Massry SG, Stein R, Garty J, et al: Skeletal resistance to the calcemic action of parathyroid hormone in uremia: Role of 1,25(OH),D,. Kidney Int 9:467, 1976 18. Wilson L, Felsenfeld A, Drezner MK, et al: Altered divalent ion metabolism in early renal failure: Role of 1,25(OH),D. Kidney Int 27:77, 1985 19. Slatopolsky E, Gray R, Adams ND, et al: Low serum levels of 1,25(OH),D are not responsible for the development of secondary hyperparathyroidism in early renal failure. Kidney Int 14:733A, 1978 20. Cheung AK, Magnolagas SC, Catherwood BD, et al: Determinations of serum 1,25(OH),D levels in renal disease. Kidney Int 24:104,1983 21. Massry SG, Gruber H, Rizvi AS, et al: Use of 1,25(OH),D, in the treatment of renal osteodystrophy in patients with moderate renal failure, in France B, Potts JT Jr (eds): Clinical Disorders of Bone and Mineral Metabolism. Excerpta Medica, 1983, pp 260-262 22. Chesney RW, Hamstra AJ, Mazess RB, et al: Circulating vitamin D metabolite concentration in childhood renal disease. Kidney Int 21:65, 1982 23. Portale AA, Booth BE, Halldran BP, et al: Effect of dietary
17
phosphorus on circulating concentrations of 1,2Sdihydroxyvitamin D and immunoreactive parathyroid hormone in children with moderate renal insufficiency. J Clin Invest 73:1580, 1984 24. Slatopolsky E, Weerts C, Thielan G, et al: Marked suppression of secondary hyperparathyroidism (SH) by intravenous l,ZS(OH),D, in uremic patients, in Frame B, Potts JT Jr (eds): Clinical Disorders of Bone and Mineral Metabolism. Excepta Medica, 1983, pp 267-270 25. Chan W, McKay C, Dye E, et al: The effects of 1,25(OH),D, on PTH secretion by monolayer cultures of bovine parathyroid (PT) cells. Proc Am Sot Nephrol 17:13A, 1984 26. Oldham SB, Smith R, Hartenbower DO, et al: The acute
effects of 1,25-dihydroxycholelciferol on serum immunoreactive parathyroid hormone in the dog. Endocrinology 104:248, 1979 27. Madsen S, Olgaard K, Ladefoged J: Suppressive effect of 1,25-dihydroxyvitamin D, on circulating parathyroid hormone in acute renal failure. J Clin Endocrinol Metab 53:823, 1981 28. Lopez S, Galceran T, Chan W, et al: Hypocalcemia may not be the cause of the development of secondary hyperparathyroidism. Proc Am Sot Nephrol 17:24A, 1984 29. Baker LRI, Abrams SML, Roe CJ, et al: 1,25(OH),D, administration in moderate renal failure: A prospective double-blind trial. Kidney Int 35:661, 1989
the mechanisms
of hypocalcemia
hyperparathyroidism
phosphate restriction
in these
with
on divalent ion metabolism
male patients with stable mild renal insufficiency with
those
of other
hyperparathyroidism
studies
that
indicate
as well as other
therapy
of 1,25(OH),D,
with 1,25(OH),D,
patients with creatinine the management
that
phosphate
abnormalities
(calcitriol).
clearances
conducted
in divalent
production
of 15 to 55 mL/min.
hyperparathyroidism
clearances
restriction
to examine
hormone
the effect
ion metabolism.
to reverse
Because
an alternative
study was conducted
of
of dietary
The study was conducted on four
of 56 to 80 mL/min.
is adequate
of 1,25(OH),D,
To test this, another
Our results correspond and correct
secondary
phosphate
restriction
dietary
therapeutic evaluating
(PTH) and on various parameters
approach would be the effect
of l-year
of bone pathology
in
Our results showed that the use of calcitriol is safe and effective
in
and bone disease in patients with moderate
renal failure.
Company.
P
ATIENTS WITH renal insufficiency have secondary hyperparathyroidism and elevated blood levels of parathyroid hormone (PTH)re3 and histological evidence of bone disease.4*5This secondary hyperparathyroidism is observed early in the course of renal insufficiency when creatinine clearance decreases to 70 mL/min or less,‘,2 and it has been attributed to transient and recurrent or sustained hypocalcemia. Three hypotheses have been proposed to explain the pathogenesis of this hypocalcemia, including phosphate retention,6-9 skeletal resistance to the calcemic action of PTH,“-I2 and altered vitamin D metabolism. However, these pathogenetic mechanisms may not be mutually exclusive, but rather interrelated and together may provide a unified and integrated explanation for the pathogenesis of the hypocalcemia of renal insufficiency. In order to clarify the mechanisms of this hypocalcemia, we examined the effect of dietary phosphate restriction on divalent ion metabolism in patients with early renal insufficiency to delineate the contribution of the various factors described above to the genesis of the hypocalcemia.‘3 Four patients with stable mild renal insufficiency were studied in a metabolic ward for a period of 85 days. All were males, age 46, 48, 50, and 56 years, and their creatinine clearances were 55, 62, 66, and 65 mL/min, respectively. The causes of renal insufficiency were chronic glomerulonephritis in two, interstitial nephritis in one, and benign nephrosclerosis in the fourth. The patients were studied in a Clinical Research Center. They were placed on a diet comparable to their habitual dietary intake providing 600 + 35 g of calcium per day and 1,236 + 97 g/d of phosphorus for a period of 10 days (equilibration phase) followed by an additional 15 days on a similar diet (control phase). During the control phase the following studies were performed twice per week: (1) measurements of the serum concentration of inorganic phosphorus, of total and ionized calcium, and of creatinine and PTH; and (2) estimations of the urinary excretion of phosphorus, calcium creatinine, and CAMP. Also, every patient had measurements of 25(OH)D, 24,25(OH),D, and 1,25(OH),D in blood, estimation of intestinal absorption of calcium, and received a PTH infusion to evaluate the calcemic response to the hormone. Metabolism, Vol39,
and to gain more insight into the mechanisms
study was
in patients with early renal insufficiency.
on blood levels of parathyroid
of secondary
o 1990 by W.B. Saunders
an 85-day
who had creatinine
appears to exert its effect through the increased supplementation
renal insufficiency
patients,
No 4, Suppl 1 (April), 1990: pp 13-17
At the end of the control phase, the patients received a similar diet except for phosphorus intake. The latter was reduced in proportion to the decrease in creatinine clearance. During this period, the diet provided 600 + 35 g/d of calcium and 7 19 k 127 g/d of phosphorus. Serum and urine biochemical parameters were evaluated frequently during this phase of the study and measurements of the blood levels of 25(OH)D, 24,25(OH),D, and 1,25(OH),D, intestinal absorption of calcium, and the calcemic response to PTH infusion were repeated at the end of the phosphate restriction period. The details of the techniques for the measurement of these various parameters have been previously published from our laboratories.13 The results showed that all patients had elevated blood levels of PTH (330 + 19 pg/mL), reduced tubular reabsorption of phosphate (TRP) (60% + 4.3%) and hypocalciuria (24 t 5 mg/24 h). The serum concentration of total calcium (9.3 f 0.13 mg/dL) was within the normal range, but that of ionized calcium (3.70 + 0.10 mg/dL) was significantly (P .Z .Ol) lower than that determined in 11 normal subjects (4.02 c 0.08 mg/dL). The serum concentration of phosphorus was 2.3 * 0.07 mg/dL and urinary excretion of this ion was 688 + 84 mg/24 h. Urinary CAMP excretion was 1.36 t 0.1 nmol/min. During dietary phosphate restriction, the concentration of total and ionized calcium in serum tended to increase and the concentrations of serum phosphorus did not change. The serum levels of PTH began to decrease during phosphate restriction and reached normal values within 2 weeks of this
From the Division of Nephrology and The Department of Medicine, University of Southern California School of Medicine, Los Angeles, CA. Supported by Grant No. 29955 of The National Institute of Diabetes and Digestive and Kidney Diseases and by a grant from Hoffmann-La Roche. Address reprint requests to Shaul G. Massry. MD, Chief, Division of Nephrology, University of Southern California, School of Medicine, 2025 Zonal Ave. Los Angeles, CA 90033. B 1990 by W.B. Saunders Company. 00260495/90/3904-1009$3.00/O
13
SHAUL
14
maneuver. The decrease in serum PTH was accompanied by a significant (P < .Ol) increase in TRP to values between 80% and 90% (88% + l.S%), and a significant (P < .Ol) decline in urinary CAMP (0.53 + 0.13 nmol/min). Urinary phosphate excretion decreased, while urinary excretion of calcium increased. The chronology of all these changes is depicted in Fig 1. Fractional intestinal absorption of calcium during the control period was either overtly low or in the lower normal range. Its mean value was 18.3% + 1.1% which is significantly (P < .Ol) lower than that (25.0% + 0.06%) reported by us in normal subjects.14 Dietary phosphate restriction was associated with a significant increase in the values of this parameter in all patients, with the mean value (24.3% k 1.67%) being significantly (P < .Ol) higher than that in the control period and not different from that in normal subjects (Fig 2). The infusion of PTH during the control period produced an increase in serum calcium levels from 9.14 + 0.13 to 10.40 + 0.22 mg/dL, with the mean increase being 1.26 + 0.11 mg/dL. After dietary phosphate restriction, PTH infusion caused a significantly (P < .Ol) greater increase in the concentrations of total calcium (2.05 f 0.08 mg/dL) from 9.40 + 0.17 to 11.45 k 0.23 mg/dL, with a mean increment of 2.05 t 0.08 mg/dL (Fig 3).
G. MASSRY
Before phosphate restriction, the blood levels of 1,25(OH),D (108, 104, 124, and 178 pmol/L) were normal or modestly elevated. There were significant (P < .Ol) increments in the blood levels of this vitamin D metabolite after dietary phosphate restriction to 180, 184, 182, and 200 pmol/L, respectively. The blood levels of 25(OH)D and 24,25(OH),D were normal and not affected by dietary phosphate restriction. The data of the present study demonstrate that patients with early renal failure display a multitude of abnormalities in divalent ion metabolism. They have elevated blood levels of PTH, modest hypophosphatemia, reduced blood levels of ionized calcium, reduced calcemic response to PTH, and impaired intestinal absorption of calcium. Since calcium transport by the intestineI and the calcemic response to PTH’6-‘8 are largely dependent on vitamin D, the finding that these functions are impaired in our patients suggests that an absolute or relative deficiency of vitamin D exists in these patients. Further support for such a possibility is found in the data of Malluche et al,4 who demonstrated that patients with early renal failure have defective mineralization of osteoid, a function that also requires vitamin D. However, the blood levels of all vitamin D metabolites were normal in our patients. Similar observations were reported by Slatopolsky et a1,19Cheung et al,*’ and Massry et
O_l
T
T
T
T
3 40]] 15
20
4.5 DAYS
60
75
15
45
30
60
75
DAYS
Fig 1. The changes in the serum concentrations of (A) total and ionized calcium, inorganic phosphorus, and immunoreactive parethyroid hormone (iPTH1; end (6) tubular reabsorption of phosphate (TRPL urinary excretion of cyclic AMP WcAMPV) and calcium WcaVI, and creatinine clearance (Ccrj during the control and phosphate restriction periods. Each data point represents the mean of four studies and the brackets denote + 1 SE. (Reprinted with permission.“)
15
Fig 2. Intestinel absorption of calcium before and after phosphate restriction. Each line represents one patient. (Reprinted with permission.“)
a12’ who found either normal or elevated blood level of 1,25(OH),D in patients with moderate renal failure. Thus, the demonstration of disturbances in the functional integrity of the target organs for vitamin D in the face of normal blood levels of its metabolites suggests that a state of vitamin D resistance exists in these patients. It should also be mentioned that other investigators reported low blood levels of 1,25(OH),D in adults’* and in children22*23with moderate renal failure. Therefore, it appears that absolute deficiency of and/or resistance to vitamin D develops early in the course of renal insufficiency and such derangements contribute to many of the abnormalities of divalent ion metabolism in such patients, It is intriguing that despite the presence of adequate functioning renal mass in patients with moderate renal insufficiency, the production of 1,25(OH),D is not increased adequately to meet the needs of the target organs for vitamin D. Since the regulation of the renal lo-hydroxylase, the enzyme responsible for the production of 1,25(OH),D, is influenced by alterations in phosphate homeostasis, it is possible that the phosphate retention that may develop with declining renal function plays a major role in the disturbances in 1,25(OH),D production. The data of the present study are consistent with this hypothesis. Dietary phosphate restriction was associated with a significant increase (44%) in the blood levels of 1,25(OH),D and with biological evidence for the normalization of the target organs’ response to vitamin D. Indeed, dietary phosphate restriction was accompanied by significant improvement or normalization of intestinal absorption of calcium, calcemic response to PTH, and of serum concentrations of ionized calcium and PTH. Data reported by Portale et al23on the effect of dietary phosphate restriction in children with renal insufficiency are in agreement with our results.
Our data in adults and those reported by Portale et al23 in children allow a new formulation for the mechanism of secondary hyperparathyroidism in renal insufficiency. It appears that phosphate retention, which may develop as renal insufficiency ensues, may interfere with the ability of the patient to augment the renal production of 1,25(OH),D to meet increased need. A state of absolute or relative vitamin D deficiency develops, leading to defective intestinal absorption of calcium and impaired calcemic response to PTH. These two abnormalities produce hypocalcemia and, subsequently, secondary hyperparathyroidism. Although this formulation still assigns an important role for phosphate retention in the genesis of secondary hyperparathyroidism in early renal failure, the pathway through which such phosphate retention mediates its effect is different from that originally proposed by Bricker et al.’ The postulate of these investigators implied that phosphate retention in early renal failure causes an increase in serum phosphorus and a consequent decrease in serum calcium, which, in turn, stimulates the parathyroid gland activity. Our data are consistent with the notion that a relative or absolute deficiency of 1,25(OH),D may play a major role in the genesis of secondary hyperparathyroidism of renal insufficiency. Such a proposition is also supported by many observations demonstrating an interaction between this metabolite of vitamin D and the parathyroid glands. Prolonged exposure to 1,25(OH),D, both in vivo24 or in vitro*’ may directly suppress the parathyroid gland activity. Also, available data suggest that 1,25(OH),D, may render the parathyroid glands more susceptible to the suppressive action of ionized calcium.26.27 Thus, it is possible that deficiency of 1,25(OH),D may initiate secondary hyperparathyroidism, even in the absence of overt hypocalcemia. This postulate is in agreement with observations by Lopez et al28 who found
I
l
BEFORE
O
WITH
,
6 a.m.
PO4 PO4
RESTRICTION
RESTRICTtON
I
I
II 0.m.
3
p.m.
I
,
6p.m
6pm
HOURS Fig 3. The changes in the serum concentration of total calcium during psrathyroid extract infusion given between 8:oO AM and 8~00 PM to four patients before and after phosphate restriction. Each data point represents the mean value and the brackets denote + 1 SE. (Reprinted with permission.“)
16
SHAUL G. MASSRY
that secondary hyperparathyroidism developed in dogs with 70% decrease in glomerular filtration rate and in which serum calcium was maintained at normal levels. The results of our studies clearly indicate that phosphate restriction in proportion to the decrease in glomerular filtration rate in patients with early renal failure is adequate to reverse and correct secondary hyperparathyroidism, as well as other abnormalities in divalent ion metabolism. However, achieving the proper and adequate dietary phosphate restriction and successful patient compliance with the dietary regimen may prove difficult. Since the available data indicate that dietary phosphate restriction exerts its effect through the increased production of 1,25(OH),D, it is obvious that an alternative therapeutic approach would be supplementation of 1,25(OH),D,. To test this latter possibility, we conducted a double-blind randomized study to evaluate the effect of 1 year of treatment of patients with creatinine clearances of 15 to 55 mL/min with 1,25(OH),D, (17 patients) or placebo (16 patients) on blood levels of PTH and on various parameters of bone pathology evaluated by morphometric and dynamic studies of bone biopsies. The results showed that almost all patients had elevated blood levels of PTH. Low blood levels of 1,25(OH),D were found in those with creatinine clearances of less than 35
mL/min. Bone biopsies showed evidence of bone resorption (elevated osteoclast index and increased surface density of bone-osteoclast interface), as well as of osteomalacia (increased density of osteoid and of percent osteoid area and prolonged mineralization lag time). One year of therapy with 1,25(OH),D produced a progressive increase in serum concentrations of calcium and a decrease in blood levels of PTH; these changes were inversely correlated. The blood levels of PTH at the end of therapy were about 50% of the values before treatment. Also, the therapy with this vitamin D metabolite resulted in a complete reversal or marked improvement in the indices of bone resorption and of the defective mineralization. Therapy with placebo was without effect on any of these parameters. Hypercalcemic episodes occurred during therapy with 1,25(OH),D,, but were easily controlled either by reducing the dose of the metabolite or by temporary cessation of its administration. We found no adverse effects of 1,25(OH),D, therapy on renal function as evaluated by monthly measurements of creatinine clearance. Therefore, we conclude that treatment of patients with moderate renal failure with 1,25(OH),D, is safe and effective in the management of secondary hyperparathyroidism and bone disease in these patients. Our data are in agreement with those of Baker et al,29 who reported similar results in a smaller number of patients.
REFERENCES
1. Reiss E, Canterbury JM, Bdgahl RH: Experiencewith radioimmunoassay of parathyroid hormone in human sera. Trans Assoc Am Physicians 8 1:104, 1968 2. Massry SG, Coburn JW, Peacock M, et al: Turnover of endogenous parathyroid hormone in uremic patients and those undergoing hemodialysis. Trans Am Sot Artif Int Organs 18:416, 1972 3. Arnaud CL: Hyperparathyroidism and renal failure. Kidney Int 489, 1973 4. Malluche HH, Ritz E, Lange HP, et al: Bone histology in incipient and advanced renal failure. Kidney Int 9:355, 1976 5. Bricker NS, Slatopolsky E, Reiss E, et al: Calcium, phosphorus and bone in renal disease and transplantation. Arch Intern Med 123543, 1969 6. Healy M, Malluche HH, Goldstein DS, et al: Effects of long-term therapy with 1,25(OH),D, in patients with moderate renal failure. Arch Intern Med 140: 1030, 1980 7. Slatopolsky E, Caglar S, Pennell JP, et al: On the pathogenesis of hyperparathyroidism in chronic and experimental renal insufficiency in the dog. J Clin Invest 50:492, 1971 8. Slatopolsky E, Cagler S, Gradowska L, et al: On the prevention of secondary hyperparathyroidism in experimental chronic renal disease using “proportional reduction” of dietary phosphorus intake. Kidney Int 2:147, 1972 9. Slatopolsky E, Bricker NS: The role of phosphorus restriction in the prevention of secondary hyperparathyroidism in chronic renal disease. Kidney Int 4:141,1973 10. Massry SG, Coburn JW, Lee DBN, et al: Skeletal resistance to parathyroid hormone in renal failure: Study in 105 human subjects. Ann Intern Med 78:357, 1973 11. Massry SG, Arieff AI, Coburn JW, et al: Divalent ion metabolism in patients with acute renal failure: Studies on mechanism of hypccalcemia. Kidney Int 5:437, 1974 12. Llach F, Massry SG, Singer FR, et al: Skeletal resistance to endogenous parathyroid hormone in patients with early renal failure:
A possible cause for secondary hyperparathyroidism.
J Clin Endocrinol Metab 41:339, 1975 13. Llach F, Massry SG: On the mechanism of secondary hyperparathyroidism in moderate renal insufficiency. J Clin Endocrinol Metab 61:601, 1985 14. Coburn JW, Koppel JH, Brickman AS, et al: Study of intestinal absorption of calcium in patients with renal failure. Kidney Int 3:264, 1973 15. Coburn JW, Hartenbower DL, Massry SG: Intestinal absorption of calcium and the effect of renal insufficiency. Kidney Int 4:96, 1973 16. Arnaud C, Rassumussen H, Anast C: Further studies on inter-relationship between parathyroid hormone and vitamin D. J Clin Invest 45:1955,1966 17. Massry SG, Stein R, Garty J, et al: Skeletal resistance to the calcemic action of parathyroid hormone in uremia: Role of 1,25(OH),D,. Kidney Int 9:467, 1976 18. Wilson L, Felsenfeld A, Drezner MK, et al: Altered divalent ion metabolism in early renal failure: Role of 1,25(OH),D. Kidney Int 27:77, 1985 19. Slatopolsky E, Gray R, Adams ND, et al: Low serum levels of 1,25(OH),D are not responsible for the development of secondary hyperparathyroidism in early renal failure. Kidney Int 14:733A, 1978 20. Cheung AK, Magnolagas SC, Catherwood BD, et al: Determinations of serum 1,25(OH),D levels in renal disease. Kidney Int 24:104,1983 21. Massry SG, Gruber H, Rizvi AS, et al: Use of 1,25(OH),D, in the treatment of renal osteodystrophy in patients with moderate renal failure, in France B, Potts JT Jr (eds): Clinical Disorders of Bone and Mineral Metabolism. Excerpta Medica, 1983, pp 260-262 22. Chesney RW, Hamstra AJ, Mazess RB, et al: Circulating vitamin D metabolite concentration in childhood renal disease. Kidney Int 21:65, 1982 23. Portale AA, Booth BE, Halldran BP, et al: Effect of dietary
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phosphorus on circulating concentrations of 1,2Sdihydroxyvitamin D and immunoreactive parathyroid hormone in children with moderate renal insufficiency. J Clin Invest 73:1580, 1984 24. Slatopolsky E, Weerts C, Thielan G, et al: Marked suppression of secondary hyperparathyroidism (SH) by intravenous l,ZS(OH),D, in uremic patients, in Frame B, Potts JT Jr (eds): Clinical Disorders of Bone and Mineral Metabolism. Excepta Medica, 1983, pp 267-270 25. Chan W, McKay C, Dye E, et al: The effects of 1,25(OH),D, on PTH secretion by monolayer cultures of bovine parathyroid (PT) cells. Proc Am Sot Nephrol 17:13A, 1984 26. Oldham SB, Smith R, Hartenbower DO, et al: The acute
effects of 1,25-dihydroxycholelciferol on serum immunoreactive parathyroid hormone in the dog. Endocrinology 104:248, 1979 27. Madsen S, Olgaard K, Ladefoged J: Suppressive effect of 1,25-dihydroxyvitamin D, on circulating parathyroid hormone in acute renal failure. J Clin Endocrinol Metab 53:823, 1981 28. Lopez S, Galceran T, Chan W, et al: Hypocalcemia may not be the cause of the development of secondary hyperparathyroidism. Proc Am Sot Nephrol 17:24A, 1984 29. Baker LRI, Abrams SML, Roe CJ, et al: 1,25(OH),D, administration in moderate renal failure: A prospective double-blind trial. Kidney Int 35:661, 1989