Reversal of hyperparathyroidism in response to dietary phosphorus restriction in the uremic dog

Kidney International, Vol. 15 (1979), pp. 43-48

Reversal of hyperparathyroidism in response to dietary phosphorus restriction in the uremic dog MICHAEL A. KAPLAN, JANET M. CANTERBURY, JACQUES J. B0uRG0IGNIE, GASTON VELIZ, GEORGE GAVELLAS, ERIC REiss, and NEAL S. BRICKER Department of Medicine, Divisions of Nephrology and Endocrinology, University of Miami School of Medicine, Miami,

Florida

84 mg. Pendant PRS-P GFR et S n'ont pas été modifies (17 mllmin et 4,3 mgldl, respectivement). 5Ica a augmente significativement a partir du 2ème jour pour atteindre un plateau au 4ème, a 5,13 0,20 mg/di. La PTH a diminué progressivement

Reversal of hyperparathyroidism in response to dietary phosphorus restriction in the uremic dog. The role of phosphorus in the genesis of uremic hyperparathyroidism is well established. Prophylactic reduction of dietary phosphorus intake (PRS-P) in exact proportion to GFR reduction prevents renal hyperparathy-

pendant les i6jours de PRS-Pjusqu'a 170 49 sl Eq/mi. Up4V a diminué des le premier jour jusqu'au plateau atteint le 2ème

roidism, but its effects on established hyperparathyroidism, serum calcium and phosphate concentration, and phosphorus balance are not known. Seven chronically uremic dogs (2 to

jour. L'excrétion fécale de phosphore a été de 43% de I'apport. L'excrétion totale de phosphore (urine et selies) n'était pas significativement différente de l'apport mesuré. La reabsorption tubulaire maximum de phosphate/GFR était en moyenne de 2,7 0,4 mg/100 ml avant PRS-P et a augmenté significativement a 4,9 0,2 mg/100 ml aprês i8jours. En résumé, PRS-P paraIt une méthode efficace non seulement pour empécher i'hyperparathyroidisme mais aussi pour obtenir sa reversion. Du fait de l'accumulation des preuves que Ia PTH est une toxine urémique,

5 months) were housed in metabolic cages and maintained on a controlled phosphorus intake of 1,200 mg/day. After a control period of 10 days, the dogs were subjected to PRS-P. Control

GFR averaged 16 4 mllmin; serum phosphate concentration (Se), 4.3 0.2 mg/dl; serum ionized calcium concentration 4.67 0.29 mg/di; parathyroid hormone level (PTH), 610 91 pi Eq/mi; and 24-hr urine phosphate excretion (U04V), 845 84 mg. During PRS-P, no change in GFR or S occurred (17 mI/mm and 4.3 mg/dl, respectively). Sica increased significantly by day 2 and plateaued by day 4 at 5.13 0.20 mg/dl. PTH fell progres-

PRS-P pourrait étre un élément important dans le traitement futur de i'insuffisance rénale chronique.

sively over the 16 days of PRS-P to 170 49 pd Eq/mi. Upo4V fell on day 1 of PRS-P and plateaued by day 2. Stool phosphorus excretion averaged 43% of intake. Total phosphorus excretion (urine plus stool) did not differ significantly from measured intake. Tubular maximum phosphate reabsorptionlGFR averaged 2.7 0.4 mg/lOO ml before PRS-P and increased significantly to 4.9 0.2 mg/tOO ml after 18 days of PRS-P. In summary, dietary therapy with PRS-P appears to be an effective method, not only for preventing uremic hyperparathyroidism, but for reversing established uremic hyperparathyroidism. In view of the growing evidence that PFH may be a major "uremic toxin," PRS-P could represent an important element in the future therapy of chronic renal failure.

As kidney function declines during the course of

chronic progressive renal disease, the need for maintaining phosphorus homeostasis is met by an

everincreasing rate of phosphate excretion per nephron [1-4]. It has been proposed that this physiologic adaptation, which contributes importantly to life maintenance, may account also, at least in part, for the hyperparathyroidism of uremia [5]. In the dog and rat, it has been possible to obviate

prophylactically the need for an ever-increasing fractional excretion of phosphate as renal function declines by reducing dietary phosphorus in exact proportion to the fall in GFR [6-9]. This dietary therapy is associated with the maintenance of nor-

Reversion de I'hyperparathyroidisme en réponse a Ia restriction alimentaire de phosphate cnez le chien urémique. Le role du phosphore dans Ia génése de i'hyperparathyroidisme est bien étabii.

La reduction prophylactique de l'apport alimentaire de phosphore (PRS-P) dans La méme proportion que celie du debit de filtration glomerulaire empéche i'hyperparathyroidisme mais son effet sur l'hyperparathyroidisme installé, sur les concentra-

mal parathyroid hormone (PTH) levels over a period of many months.

tions plasmatiques de calcium et de phosphore et sur le bilan de

phosphore, ne sont pas connus. Sept chiens urémiques chroniques (2 a 5 mois) ont été installés dans des cages metaboliques et maintenus a un apport de 1200 mg de phosphore/jour. Après

une période contrôie de 10 jours les chiens ont été soumis a PRS-P. Le debit de filtration glomérulaire pendant Ia période 4 mi/mm; le phosphate plasniatique (Si.) de

Received for publication March 3, 1978 and in revised form May 30, 1978.

4,3 0,2 mg/dl; le calcium ionisé du plasma (Sica) de 4,67 0,29 mg/di; l'hormone parathyroidienne (PTH) de 610 91 jl . Eq/ ml; l'excrétion urinaire quotidienne de phosphate (U04V) de 845

© 1979 by the International Society of Nephrology

contrOle était de 16

0085—2538/79/0015—0043 $01.20

43

Kaplan et at

44

The possibility that a dietary regimen may obviate uremic hyperparathyroidism is of more than academic interest. There is mounting evidence that PTH may represent an important "uremic toxin" with adverse effects that go beyond the bone disease [10-241. The present study was designed to evaluate the effects of reducing dietary phosphorus intake in exact proportion to the fall in GFR on PTH levels, serum calcium and phosphate concentration,

and phosphorus balance in the chronically uremic dog with established uremic hyperparathyroidism. More specifically, does it lead to reversal of hyperparathyroidism; and does this dietary therapy trade osteitis fibrosis cystica for negative phosphorus balance (and thus increase the risk of osteomalacia)? Methods

Seven adult female mongrel dogs (weight range, 13 to 18 kg) were made uremic by ligation of the majority of the branches of the left renal artery and removal of the right kidney. Three of the animals

marker 72 hours apart. All stool specimens were collected from the first apperance of the dye up to but not including the second appearance of the dye [25].

In four dogs, phosphate titration studies were performed at the beginning of the 10-day control period while they were on the CSI regimen and again

after they had been on the PRS-P regimen for 18 days. The titration studies were done in the morning with the animals in the unanesthetized state, standing in a supporting sling, and fasted overnight. They had free access to water until the time of the experiment. A urinary catheter was inserted into the bladder for quantitative urine collection. Venous catheters were placed in the inferior vena cava through a hind limb vein for infusion and blood sampling. After injection of a priming dose of creatinine, a solution of 0.45% saline containing creatinine was infused at a rate of 0.3 mllmin. After a 60-mm period of equilibration, three 20-

mm control clearance periods were obtained. Thereafter, a solution of neutral sodium phosphate

were studied during the third month and four during the sixth month of experimental uremia. From the initiation of uremia, the dogs received

(Na3HPO4, 44 g/liter; NaH2PO4, 10.7 g/liter) was infused at a rate of 0.4 mllmin. Eight 30-mm clearance periods then were obtained. At the midpoint of each

400 g of a fibrin-base low phosphorus diet (ICN Pharmaceuticals, Cleveland, Ohio) daily, to which 1,200 mg of phosphorus as neutral sodium phosphate (designated as "constant solute intake", CSI) was added. The daily intake of calcium was 1,700 mg, and that of magnesium was 240 mg. The protocol was as follows: The dogs, which as indicated were chronically uremic, were transferred to indi-

period, a sample of blood was collected. At the end of each period, the bladder was washed with 30 ml of sterile water to ensure complete urine collection. The 72-hour stool collections were blended with distilled water to a fixed volume. Duplicate l0-ml aliquots were alkalinized to a pH of 10 with 3 N sodium carbonate and dried at 1000 C for 24 hours. The samples were then ashed at 615° C for 24 hours.

vidual metabolic cages but maintained on the 1,200 mg/day phosphorus intake for a control period of 10

The ash was digested with 10 ml of concentrated

days. Thereafter, their phosphorus intake was "proportionally" reduced using the formula: 1,200

mg x GFR uremialGFR initial. Both values for GFR were measured, the "uremia" value during the 10-day control period and the "initial" value prior to the induction of renal insufficiency. Phosphorus intake thereby was reduced in exact proportion to the measured reduction in GFR (designated as "proportional reduction of solute-phosphorus", PRS-P). Body weight in all dogs remained stable throughout the metabolic study. Urine collections were begun and terminated at the same time each day. A single feeding by orogastric intubation was given at 2:00 P.M. Blood samples were collected anaerobically at 9:00 A.M. from

an anterior limb vein. Three-day stool collections were performed during the second week of phos-

phorus reduction. Carmine (Alum Lake, Fisher Scientific), 0.6 g, was given as an intermittent stool

hydrochloric acid for 24 hours. The digest was then made up to 50 ml with distilled water and analyzed.

Phosphate and creatinine were measured by a modified autoanalyzed method (Technicon Auto Analyzer II). Serum ionized calcium was determined with a flow-through electrode system (Orion Biomedical, model SS-20). Serum PTH was quantitated by radioimmunoassay using antiserum CH71 at a final dilution of 1:125,000 [5, 2611. This antiserum cross-reacts with intact hormone as well as NH2- and COOH-terminal fragments. Each sample was measured in duplicate at two widely varying dilutions. The coefficient of variation of replicate assays was 9%; samples showing a larger variation

were reassayed. PTH levels are reported in arbitrary units (d . Eq/ml), relating the potency of the test serum to that of a standard hyperparathyroid serum obtained from a dog with experimentally induced chronic renal failure. Data are expressed as means SEM. Statistical

45

Uremic hyperparathyroidism and phosphorus

Table 1. Serum and urine values during constant solute intake (CSI) and 16 days of proportional reduction of solute-phosphorus

(PRSP)a During PRS-P

During CS!

GFR,ml/min Sre ,mg/dl

S,,mg/d1

UV,mg/duy PTH,.d Eq/mi

4

26

4.3 4.67 845 610

Day 2 14

0.2

4.2

0.29

5.O1

84

l77

9!

504

Day 4

3 35 112

2

13

0.4 0.17

Day 7

4.0 5.13e 135k

4l5

0.2 0.20 40 104

4

17

4.0

16

0.4 0.18 50

5.l5

t57 375

Day II

Day 9

104

3

19

4.3

0.3

4.0

S.22

0.04

5.22k

1l2

31ff

Day 16

Day 14

4

II

t02'

0.3 0.20 IS

97

267

91

4

17

4.1 S.24

0.3 0.15

4

17

4.3

0.2 0.14

5.l9

t37

20

l38

22

234

78

17ff

49

Values are the mean SEM for 7 dogs. Abbreviations are serum phosphate concentration; S, serum ionized calcium concentration; excretion; and PTH, parathyroid hormone level. Significantly different from control value (P < 0.05) Significantly different from control and preceeding value (P < 0.05)

24-hour urine phosphate

PRS-P, phosphate excretion fell within 1 day and plateaued by day 2. All dogs had marked hyperparathyroidism before the PRS-P regimen was initiated. The mean PTH

analyses were performed with standard programs for Student's t tests for paired and unpaired data on a Wang 700 calculator.

level during the control period was 610

Results

91 pJ .

Eq/

ml with a range of 300 to 900 pi . Eq/ml (normal range, 40 to 100 l Eq/ml). PTH levels fell steadily

Before producing experimental uremia, the mean

normal GFR was 84 mI/mm. Table 1 shows the

and significantly each day over the 16 days of PRSP to 170 49 l Eq/ml. By the 16th day of study, four dogs had normal PTH levels, but the remaining

mean values for GFR, serum phosphate and serum

ionized calcium concentrations, 24-hour urinary phosphate excretion rates, and PTH levels during the control period on the CS! regimen and during a 16-day period on the PRS-P regimen. GFRs re-

three dogs had values which were somewhat elevated. These three dogs had the highest PTH levels at the outset. Table 2 presents the phosphate balance data of six dogs obtained during the second week of the

mained stable throughout, averaging 16 4 mllmin during the control period and 17 4 mllmin on day 16 of the PRS-P therapy. Serum phosphate concentrations averaged 4.3 0.2 mIld! during CSI and did not change significantly over the 16 days of PRS-P. When the dogs were on CSI, their serum ionized calcium values averaged 4.67 0.29 mg/dl. After only 2 days of PRS-P, the mean value had risen significantly to 5.01 0.17 mg/dl, and the value continued to rise significantly through day 4, at which time it plateaued at 5.13 0.20 mg/dl.

PRS-P regimen. Stool and urine phosphate excretion averaged 43 6% and 53 6% of intake, respec-

tively. For the group, total excretion (urine plus feces) was not significantly different from intake. The results of the phosphate titration studies are shown in Table 3. The values for tubular maximum reabsorption of phosphate per GFR (Tm04/GFR) are derived at a steady-state serum phosphate concentration between 8 and 10 mg/dl. During CSI, the Tm04/GFR averaged 2.7 0.4 mg/tOO ml. After 18 days of PRS-P, the Tm04/GFR had increased significantly to 4.9 0.2 mg/100 ml.

With 1,200 mg of phosphorus per day, urinary 84 mg/day. With phosphate excretion was 845

Table 2. Three-day phosphorus balance while on proportiona 1 reduction of solute-phosphorus (PRS-P)

Stool phosphate

.

Dietary

— % of

% of

phosphorus

Total excretion

mg/72 hr

mg172 hr

intake

mg172 hr

intake

mg172 hr

540

154

29

380

70

534

540 900

637

35 33 71

630 720

231 365

383 243 317 299 388

71 41 35 47 54

574

600

191 196

37 51

Mean SEM

Urinary phosphate

655

56

296

74

43 6

335

24

53

439 954

530 753

6

631

77

Kaplan et al

46

Table 3. Tm04/GFR (mg/100 ml) during CSI and after 18 days of

PRSPa CS!

PRS-P

2.9 3.6

4.7 4.7 5.5

2.5

4.6

1.8

Mean SCM

a See b

2.7

04b

4.9

0.2

Table 1 for abbreviations.

Significantly different from PRS (P < 0.001)

Discussion

Hyperparathyroidism is an almost universal concomitant of chronic renal failure [201. Although the etiology of uremic hyperparathyroidism is multifactorial, the role of dietary phosphorus appears to be well established [5—9].

The sequence of events may be an exaggerated hyperphosphatemia after eating, causing prolonged hypocalcemia with subsequent sustained stimulation of PTH secretion [9, 271. It has also been suggested that phosphate may limit the production of 1,25 dihydroxycholecalciferol [28]. The low concentration of this active metabolite of vitamin D in uremia is at least partially responsible for the impaired intestinal calcium absorption of chronic renal

failure and the skeletal resistance to exogenous PTH [20, 21]. The dog with experimental uremia manifests uremic hyperparathyroidism similar to the patient with

chronic renal failure [5]. The uremic hyperparathyroid animal has been shown to develop skeletal

changes of increased osteoclastic reabsorptive surface area within 6 months of the induction of renal failure [8]. This skeletal abnormality correlated

with the concentration of circulating PTH. It has been possible to largely prevent uremic hyperparathyroidism [6-9] and parathyroid-induced bone disease [8] in the experimental animal by prophylactically decreasing dietary phosphorus intake in ex-

act proportion to the decrease in GFR at the in-

ception of renal insufficiency. Whether this dietary therapy can reverse the established hyperparathyroidism of advanced chronic renal insufficiency is an important question for patient management.

A major theoretical limitation of a low-phos-

phorus diet would be the development of phosphate depletion with all its adverse effects. Previous stud-

ies with PRS-P have not dealt with this question, but hypophosphatemia has not been observed. Recently, animals with PRS-P have been shown to

have physiologic responses inconsistent with phosphate depletion. The phosphaturic response to exogenous PTH is exaggerated in the uremic rat [29] and dog [30]. Phosphate depletion, in contrast, is associated with a blunted response [31, 32]. In the uremic dog, a phosphorus load is excreted similarly whether the diet is CSI or PRS-P [9]. In contrast,

phosphate depletion is associated with a blunted phosphaturia following a phosphorus load [33, 34]. The present study shows that external phosphorus balance is well maintained throughout the period of PRS-P. The percentage of absorbed dietary phosphorus in the present animals is in good agreement

with those observed in more extensive studies in uremic man on higher phosphorus intake [21]. A study of uremic man on a low-protein (and thus lowphosphorus) diet, showed negative phosphorus bal-

ance but is not comparable because of the protein restriction [35]. Previous studies have suggested that a slight but

significant increase in the concentration of serum ionized calcium develops in the uremic dog treated with PRS-P [9, 30]. The development of this rise in

serum ionized calcium concentration is clearly documented in this study. The value for serum ionized calcium was significantly elevated by day 2 of PRS-P, and increased further through day 4, and remained elevated thereafter. The cause of the hyper-

calcemia is unclear, but it is not caused by phosphate depletion. It could conceivably relate to the change in calcium:phosphorus product in the diet making more calcium available for absorption. Another more likely possibility would be a change in hormonal status due to PRS-P. A reduction in phosphorus intake is known to increase 1,25 dihydroxycholecalciferol production in the normal state [28]. It is conceivable that PRS-P increased this vitamin D analog and thus calcium absorption. PTH levels in each dog fell progressively during the period of PRS-P. By the 16th day of study, four

dogs had normal PTH levels, but the remaining three dogs' values were still somewhat elevated. There is a clear dissociation between the rapid decline in urinary phosphate excretion and the protracted fall in PTH levels. These parameters cannot be compared because of the nature of the PTH assay which measures both NH2- and COOH-terminal fragments. Many of these PTH metabolites have a prolonged half-life in uremic dog and man [36-40].

The major observation, though, is that the established hyperparathyroidism of uremia is reversible by PRS-P. Tm04/GFR was low, as expected, when the dogs

Uremic hyperparathyroidism and phosphorus

were on the CSI regimen with high levels of circulating PTH [9, 30]. After 18 days of PRS-P, when the circulating levels of PTH had by and large returned to normal, the Tmp04/GFR had risen significantly to values similar to those reported previously in a prophylactic PRS-P protocol and similar to levels found in normal dogs [9, 30]. Although the level

of parathyroid activity may be implicated in the change in Tm04/GFR [41], other data suggest that dietary phosphorus intake itself can reset the level of tubular reabsorption [34]. The present experimental design can not differentiate these factors. In summary, dietary therapy with PRS-P appears to be a potential method for reversing established uremic hyperparathyroidism, although the degree of chronicity is probably critical as evidenced by the slowness of regression of hyperparathyroidism in many patients following successful renal transplantation. In a preliminary report, PRS-P has been shown to reverse uremic hyperparathyroidism in patients with mild chronic renal failure [42]. In the

present short-term studies, PRS-P is associated with the maintenance of phosphate balance and with the return of PTH levels to or towards the normal range. With the evolving evidence that implicates PTH as a major "uremic toxin," PRS-P may represent an important future therapeutic modality, as well as a major experimental investigative tool. Acknowledgments

This work was presented in part at the national meeting of the American Society of Clinical Research, San Francisco, California, April 1978, and was supported by N.I.H. grants AM-16768 and 7

47

6. SLATOPOLSKY E, CAGLAR S, GRADOWSKI L, CANTERBURY

JM, REiss E, BRICKER NS: On the prevention of secondary hyperparathyroidism in experimental chronic renal disease using proportional reduction of dietary phosphorus intake. Kidney mt 2:147, 1972 7. KAYE M: The effects in the rat of varying intakes of dietary

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