80 Farrell et al.

12. Quarks LD, Lobaugh B, Murphy G: Intact parathyroid hormone overestimates the presence and seventy of parathyroid-mediated os- seous abnormalities in uremia. J Clin Endocrinol Merab 75: 145-150, 1992

13. Cohen-Solal ME, Sebert JL, Boudailliez B, Mane A, Moriniere P, Gueris J , Bouillon R, Fournier A: Comparison of intact, midregion, and carboxy-terminal assays of parathyroid hormone for the diagnosis of bone disease in hemodialyzed patients. J Clin Endocrinol Merab 73516-524, 1991

14. Goodman WG, Ramirez JA, Belin TR, Chon Y, Gales B, Segre GV, Salusky IB: Development of adynamic bone in patients with second- ary hyperparathyroidism after intermittent calcitriol therapy. Kidney Inr 46: 1160-1 166, 1994

IS. Ott SM, Maloney NA, Coburn JW, Alfrey AC, Sherrard DJ: The prevalence of bone aluminum deposition in renal osteodystrophy and its relation to the response to calcitriol therapy. N Engl J Med 307: 709-713, 1982

16. Brickman AS, Sherrard DJ, Jowsey J, Singer FR, Baylink DJ, Mal- oney N , Massry SG, Norman AW, Coburn JW: 1.25-Dihydroxy- cholecalciferol: Effect on skeletal lesions and plasma parathyroid hor- mone levels in uremic osteodystrophy. Arch Intern Med 134:883-888, 1974

17. Berl T, Bems AS, Huffer WE, Hammill K. Alfrey AC, Arnaud CD, Schrier RW: 1,25-Dihydroxycholecalciferol effects in chronic dialy- sis. A double-blind controlled study. Ann Intern Med 88:774-780, 1978

18. Slatopolsky E, Weerts C, Thielan J , Horst RL, Harter H , Martin KJ: Marked suppression of secondary hyperparathyroidism by intrave- nous administration of 1,25-dihydroxycholecalciferol in uremic pa- tients. J Clin Invest 74321362143, 1984

19. Quarks LD, Yohay DA, Carroll BA, Spntzer CE, Minda SA, Bar- tholomay D, Lobaugh BA: Prospective trial of pulse oral versus in-

travenous calcitriol treatment of hyperparathyroidism in ESRD. Kid- ney Inr 45:1710-1721, 1994

20. Martin KJ, Bullal HS, Domoto DT, Blalock S, Weindel M: Pulse oral calcitriol for the treatment of hyperparathyroidism in patients on con- tinuous ambulatory peritoneal dialysis: Preliminary observations. A m J Kidney Dis 19:540-545, 1992

21. Tsukamoto Y, Nomura M, Takahashi Y, Takagi Y, Yoshida A, Na- goaka T , Togashi K, Kikawada R. Marurno F: The “oral 1.25- dihydroxyvitamin D, pulse therapy” in heinodialysis patients with severe secondary hyperparathyroidism. Nephron 57:23-27, 1991

22. Fukagawa M, Kitaoka M, Kaname S, Okazaki R, Matsumoto T , Ogata E. Hoshino M, Inada T, Sekine T, Kurokawa K Suppression of parathyroid gland hyperplasia by 1.25(OH)2D, pulse therapy. N Engl J Med 315:421422, 1990

23. Szabo A, Merke J , Beier E, Mall G, Ritz E: 1,25(OH), vitamin D, inhibits parathyroid cell proliferation in experimental uremia. Kidney In t 35:1049-1056, 1989

24. Fukuda N, Tanaka H, Tominaga Y. Fukagawa M, Kurokawa K, Seino Y: Decreased 1,2S-dihydroxyvitamin D, receptor density is as- sociated with a more severe form of parathyroid hyperplasia in chronic uremic patients. J Clin Invest 92:1436-1443, 1993

25. Delmez JA, Slatopolsky E: Hyperphosphatemia: Its consequences and treatment in patients with chronic renal disease. Am J Kidney Dis 19:30>317, 1992

26. Chesney RW, Moorthy AV, Eisman JA, Tax DK. Mazess RB, De Luca HF: Increased growth after long-term oral 1,25-vitamin Dl in childhood renal osteodystrophy. N Engl J Med 298:238-242. 1978

27. Chan JCM, McEnery PT, Chinchilli VM, Abitbol CL, Boineau FG, Friedman AL, Lum GM, Roy 111 S. Ruley EJ, Strife CF: A prospec- tive, double-blind study of growth failure in children with chronic renal insufficiency and the effectiveness of treatment with calcitriol versus dihydrotachysterol. J Pediatr 124520-528, 1994

John Farrell, Esther A. Gonzaiez, and Kevin J. Martin Division of Nephroiogy, Department of Internal Medicine, St. Louis University School of Medicine, St. Louis, Missouri

A major goal in the management of all patients with renal impairment is the prevention of renal os- teodystrophy. Over the last two decades, there have been many advances in our knowledge of the pathophysiology of renal osteodystrophy including an improved delineation of the role that secondary hyperparathyroidism (HPT) and low calcitriol lev- els play in its development. This has led to the use of vitamin D metabolites to prevent or control HPT and to suppress PTH secretion in established HPT. It is hoped that with early treatment, we can pre- vent the development of the serious manifestations of this condition. Vitamin D therapy, however, is only part of a treatment regimen for renal osteo- dystrophy. Other therapies include dietary phos- phate restriction, phosphate binders, calcium sup- plementation, and control of metabolic acidosis.

There are many different types of vitamin D ste- rols available, but to date there have been no con- trolled studies on their relative efficacy in renal os- teodystrophy. The principal therapeutic agents in use today are la-hydroxycholecalciferol (alfacalci- dol), and 1,25-dihydroxycholecalciferol (calcitriol).

Address correspondence to: Kevin J. Martin, MB, BCh, FACP, Di- vision of Nephrology, St. Louis Universily Medical Center, 3635 Vlsta Avenue at Grand Boulevard, St. Louis, MO 63110-0250. Seminars in Dialysis-Voi 8. No 2 [Mar-Apr] 1995 pp 80-82

Currently, in this country, calcitriol, the naturally occurring biologically active form of vitamin D, is the most widely used.

As renal function deteriorates, calcitriol synthe- sis decreases. Many factors contribute to this, in- cluding loss of functioning renal mass, phosphate retention and hyperphosphatemia, and the develop- ment of metabolic acidosis. Originally, it was be- lieved that the major effect of calcitriol was to in- crease intestinal calcium absorption, and to a lesser extent, phosphate absorption. However, it is now obvious that it plays a more important role. There is evidence that calcitriol can do the following:

cause suppression of parathyroid hormone (PTH) release by decreasing the levels of pre- pro-PTHmRNA (1). This is brought about by regulation at the transcriptional level due to ac- tions of the vitamin D receptor on the 5‘ flank- ing sequence of the PTH gene;

0 increase the number of vitamin D receptors on the parathyroid glands. In secondary hyperpar- athyroidism due to renal impairment, there is a decrease in parathyroid vitamin D receptor density, which is believed to be secondary to a combination of low calcitriol levels, high plasma PTH, and uraemic toxins. There may also be a defect in calcitriol receptor function, leading to additional calcitriol resistance (2);

0 alter parathyroid cell proliferation (3);

ViTAMIN D 81 regulate the set point at which plasma calcium

modulate the peripheral response to PTH at the

The primary goal of calcitriol therapy should be the prevention of secondary hyperparathyroidism as it has been shown that while calcitriol is able to prevent gland hyperplasia, it will not completely re- verse hyperplasia once this had occurred. It is therefore important to commence therapy as soon as possible according to the scheme outlined in Fig- ure 1. Calcitriol levels begin to fall when the GFR is less than 50 mL/min, and reach very low levels in patients with end-stage renal failure. Even when calcitriol levels are normal in early renal insuffi- ciency, these may still be inappropriately low since the level of PTH, which stimulates calcitriol pro- duction, is already increased. In children and pa- tients with slowly deteriorating renal function, there may be significant secondary HPT prior to the onset of dialysis. All patients with chronic renal impair- ment should have regular measurements of PTH levels. While there are presently many different PTH assays available, the most widely used are the two-site assays which measure intact PTH (intact PTH-IRMA or intact PTH-ICMA). It is important to use the same assay to follow hyperparathy- roidism in a given patient and to know the charac- teristics of the assay in renal insufficiency.

Even if the patient is not hyperphosphataemic, dietary phosphorus restriction should be started and therapy with calcitriol should be considered for all patients with impaired renal function and a plasma intact PTH that is greater than 3-5 times normal, particularly if the level is increasing. If PTH is more than 5 times the upper limit of normal, therapy with calcitriol should be initiated. The goal is to achieve a PTH level of between 2-3 times the upper limit of normal, as it is now known that pa- tients with advanced renal insufficiency require a higher PTH level to avoid low bone turnover and ensure normal bone remodeling. Therapy may be commenced with calcitriol 0.25 pg daily or 0.5 pg

suppresses PTH release (4);

level of bone.

*use of calcitriol in chronic renal failure.

*

*calcium Carbonate or acetate *

.Treat acidosis *

.Monitor PTH *

Intact PTH > 3 times normal FTlOsDHOms < 6 mgtdl

Calcitrlol 0.25 Swaav or 0.5 #g tnrlceiweek Monltor Ca. PI. FTH

- HemOdlalySlS use I.V. CaIcltrio1 0.5.3 pg oost dialysis

- U P 0 use oral calcltrlol 0.5- 3 Sg twice or thrlcehveek

Adjust alalvsate calclum Monitorca. PI. PTH

FIG. 1. Use of calcitriol in chronic renal failure.

three times per week. This will increase intestinal calcium absorption, correct hypocalcemia, and sup- press PTH secretion. Regular measurements of PTH levels allow for the follow-up of the response to therapy. It is very important that hypercalcemia and hyperphosphataemia be avoided. If they should occur, an elevated calcium phosphate product may result, which if >70 may cause metastatic calcifica- tion and could accelerate renal damage and neces- sitate an earlier institution of dialysis therapy. Phos- phate control may be initially achieved by dietary methods, but if this is unsuccessful, one may add calcium based phosphate binders given with meals. These have the additional benefit of providing a cal- cium source for the patient. Calcitriol also impairs creatinine secretion by the renal tubule, leading to a reversible increase in serum creatinine which should be monitored closely. Once the patient is dialysis dependent, the method of calcitriol admin- istration will depend on the clinical situation. In pa- tients with established or developing HPT, pulse administration of calcitriol should be administered. Slatopolsky et al. demonstrated that it was possible to suppress PTH release in dialysis patients with supraphysiologic intravenous doses of calcitriol ad- ministered thrice weekly after each dialysis (5 ) . Such pulse therapy has been shown to improve os- teitis fibrosa in patients refractory to conventional oral therapy and may also reduce parathyroid gland hyperplasia. It is now accepted that pulse oral ther- apy is as effective as intravenous therapy (6) and, thus, this route of administration may be advanta- geous in CAPD patients. Although whether pulse therapy confers an advantage over regular daily oral doses is still debated, there is evidence to suggest that the high peak calcitriol levels achieved by pulse administration may better suppress PTH produc- tion than a lower steady-state level. Intermittent ad- ministration may also result in less hypercalcemia and hyperphosphatemia. Low-dose continuous oral therapy acts mainly by increasing calcium and phosphate absorption and, when administered in this way, undergoes significant intestinal and he- patic metabolism, so little may be available for PTH suppression.

A major side effect of calcitriol therapy is hyper- calcemia, and the increased use of calcium-based phosphate binders has aggravated this problem. De- creasing the dialysate calcium concentration from 3.5 mEq/L to 2.5 mEq/L, may allow for the contin- ued use of high doses of calcitriol and calcium bind- ers. However, this may not be desirable in noncom- pliant patients, who may therefore lose a source of calcium supplementation. When indicated in hemo- dialysis patients, pulse intravenous calcitriol ther- apy should be used to ensure patient compliance and should be administered after each dialysis ses- sion. The usual starting dose is 0.5 Kg, and, after this, the dose is titrated at monthly intervals accord- ing to calcium, phosphate, and PTH levels. A serum PTH level is obtained every three months, and one aims to achieve an intact PTH value of 2-3 times the

82 Farrell et al.

upper limit of normal, a serum calcium of not greater than 10.5 mg/dL, and serum phosphate less than 6.0 mg/dL. The usual doses required range from 0.5 pg to as high as 4.0 pg thrice weekly. If the serum phosphate is greater than 6.0 mg/dL or the serum calcium is above 11.5 mg/dL therapy, should be withheld. Once the calcium level returns to nor- mal, therapy may be restarted at 0.5 pg less than the previous dose. A typically responsive patient should show a significant decrease in PTH level over a three- to six-month period. It must be em- phasized that the prevention of hyperphosphatemia is extremely important, as this will result in further stimulation of PTH release making it more difficult to control secondary HPT.

The fact that some patients fail to respond to cal- citriol may be due to a combination of factors in- cluding severe established parathyroid hyperplasia with a large parathyroid mass, vitamin D receptor deficiency, and an inability to tolerate the required doses of calcitriol without hypercalcemia. Mono- clonal proliferation of autonomous parathyroid se- creting cells has also been described (7). These pa- tients may require parathyroidectomy for disease control. One should administer oral calcitriol (0.5- 1.0 pg) daily or i.v. calcitriol 1.5-2.0 pg at every dialysis session for two to six days prior to surgery to maximize intestinal calcium absorption postop- eratively. With this regimen, the severity of the “hungry bones” syndrome may be lessened.

Future prospects for improvements in the treat- ment of secondary HPT include the use of less cal- cemic calcitriol analogs such as 22 oxacalcitriol. This compound has a low affinity for vitamin D binding protein and has little effect on intestinal cal- cium or phosphate absorption. However, it is able to block PTH secretion (8). Additional future ave- nues of therapy may be derived from the cloning of cDNA that encodes an extracellular calcium recep- tor in the parathyroid, which may allow the devel- opment of agents that would potentiate the activa- tion of this receptor in the parathyroid gland (9).

Currently, a worrisome feature in dialysis pa- tients is the apparent increased development of se-

vere metastatic calcification. This is a major prob- lem in a group of patients already at increased risk for severe vascular disease. It is possible that over- treatment of hyperparathyroidism with calcitriol and calcium supplementation could aggravate this important phenomenon. It would be very advanta- geous if a more effective and safer phosphate binder could be developed. Although calcitriol therapy has allowed us to achieve better control of hyperpara- thyroidism, it is important to recognize the potential risks and limitations of this therapy and to realize that it is only one component of a comprehensive treatment for renal osteodystrophy and the other factors which play a role in the pathogenesis of hy- perparathyroidism should be continuously moni- tored and treated.

I .

2.

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4.

5.

6.

7.

8 .

9.

References Silver J, Russell J. Shenvood LM: Regulation by vitamin D metabo- lites of messenger RNA for pre-proparathyroid hormone in isolated bovine parathyroid cells. Proc Nut/ Acod Sci 82:427&4273, 1985 Fukuda N, Tanaka H, Tominaga Y, Fukagawa M, Kurokawa K, Seino Y: Decreased 1.25-dihydroxyvitamin D3 receptor density is associated with a more severe form of parathyroid hyperplasia in chronic uremic patients. J Clin Invest 92:14361443. 1993 Kremer R. Bolivar I , Goltzman D, Hendy GN: Influence of calcium and 1,25-dihydroxycholecalciferol on proliferation and proto- oncogene expression in primary cultures of bovine parathyroid cells. Endocrinology 125:935-941, 1989 Delmez JA. Tindira C, Grooms P. Dusso A, Windus DW, Slatopolsky E: Parathyroid hormone suppression by intravenous 1.25-dihydroxy- vitamin D: A role for increased sensitivity to calcium. J C/in Invest 83:3349-1355, 1989 Slatopolsky E. Weerts C. Thielan J, Horrt R, Harter H, Martin KJ: Marked suppression of secondary hyperparathyroidism by intrave- nous administration of 1,25-dihydroxycholecalciferol in uremic pa- tients. J Clin Invest 74:213&2143, 1984 Quarks LD. Yohay DA. Carroll BA, Spritzer CE, Minda SA. Bar- tholomay D, Lobaugh BA: Prospective double-blind placebo con- trolled trial of pulse oral versus intravenous calcitriol treatment of hyperparathyroidism in ESRD. Kidney Int 45: 1710-1721, 1994 Falchetti A. Bale AE. Amorosi A, BordiC, Cicchi P. Bandini S , Mar% SJ, Brandi ML: Progression of uremic hyperparathyroidism involves allelic loss of chromosome 11. J Clin Endocrind Merub 76:139-144. 1993 Brown AJ, Finch J, Grieff M, Ritter C, Kubodera N, Nishii Y , Slatopolsky E: The mechanism for the disparate actions of calcitriol and 22-oxacalcitriol in the intestine. Endocrinology 133: 1158-1 164, 1993 Brown EM, Gamba G, Riccardi D, Lombardi M, Butters R, Klfor 0, Sun A, Hediger MA. Lytton I , Hebert SC: Cloning and characteriza- tion of an extracellular calcium sensing receptor from bovine para- thyroid. Nature 366575-580. 1993

Klaus Schaefer Medlcal Department 11, Saint Joseph Hospital and the Free University of Berlin, Berlin, Germany

Even if there is no doubt that the reduced syn- thesis of 1,25-dihydroxyvitamin D3( 1 ,25[OHI2D3, calcitriol) plays a decisive pathogenic role in the development of secondary hyperparathyroidism,

the therapeutic use of calcitriol should always be preceded by careful consideration. This reservation is based not only on the potential side effects of the therapy with 1,25(OH),D, but also on the fact that the spectrum of renal- bone disease has changed over the last decade (1). Malluche and Monier- Faugere (1) have recently analyzed the t c S J h of 2,357 bone biopsies. In only 20% of the selected

Address correspondence to: Prof. Dr. Klaus Schaefer. St. Joseph- Krankenhous, Medizinische Abteilung II, Bdumerplan 24, D-12101 Berlin, Germany. Seminars in Dialysis-Vol 8, No 2 (Mar-Apr) 1995 pp 82-85 patients was there a (calcitriol-requiring) predomi-