Acute Changes in Serum Calcium after Renal Transplantation

Acute Changes in Serum Calcium after Renal Transplantation

Vol. THE JOURNAL OF UROLOGY Copyright © 1972 by The Williams & Wilkins Co. Printed ACUTE CHANGES IN SERUM CALCIUM AFTER RENAL TRANSPLANTATION SHER...

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Vol.

THE JOURNAL OF UROLOGY

Copyright © 1972 by The Williams & Wilkins Co.

Printed

ACUTE CHANGES IN SERUM CALCIUM AFTER RENAL TRANSPLANTATION SHERMAN J. SILBER, JOHN KONNAK

AND

FRANKLIN D. MCDONALD

From the Section of Urology, Department of Surgery and the Renal Unit, Department of Internal Medicine, The University of Michigan Medical Center, Ann Arbor, Michigan

Despite significant advances in the treatment of chronic renal failure with hemodialysis, the abnormalities of calcium, phosphorus and bone metabolism remain an enigma. Eventually 80 per cent of patients undergoing chronic hemodialysis have osteomalacia or osteitis fibrosa cystica. 1 The hyperparathyroidism of uremia is thought to be caused by an initial alteration in the serum calcium or phosphorus levels related to impairment of renal excretory function. In chronic renal failure, resistance to vitamin D causes decreased intestinal absorption of calcium, and the resulting hypocalcemia stimulates parathyroid hypersecretion. 2- 5 In addition, impaired phosphate excretion with attendant hyperphosphatemia causes a depression of serum calcium, and this likewise increases parathyroid hormone. 5- 9 However, inconsistencies in the literature and observations made on patients undergoing chronic hemodialysis followed by renal transplantation suggest that other factors may also be involved. CASE REPORTS

Case 1. A 17-year-old man had glomerulonephritis and progressive azotemia in January 1968. In

Accepted for publication 7, 1971. 1 Kleeman, C.R., Massry, S. , Coburn, J. W. and Popovtzer, M. M.: The problem and unanswered questions. Renal osteodystrophy, soft tissue calcification, and disturbed divalent ion metabolism in chronic renal failure. Arch. Intern. Med., 124: 262, 1969. 2 Dent, C. E., Harper, C. M" and Philpot, G. R.: The treatment of renal-glomerular osteodystrophy. Quart,. J. Med., 30: 1, 1961. 3 Friis, T., Hahnemann, S. and Weeke, E. : Serum calcium and serum phosphorus in uraemia during administration of sodium and aluminum hy, 497, 1968. droxide. Acta Med. 4 Avioli, L. V., Birge, S., Lee, S. W. and Slatopolsky, E.: The metabolic fate of vitamin D 3 - 3H in chronic renal failure. J. Clin. Invest., 47: 2239, 1968. 5 Liu, S. H. and Chu, H. I.: Studies of calcium and phosphorus metabolism with special reference to pathogenesis and effects of dihydrotachysterol (A.T. 10) and iron. Medicine, 22: lil43. 6 Kleeman, C. R., Better, Massry, S. G. and M. H.: Divalent ion metabolis1L and osteoin chronic renal failure. Yale J. Biol Med., 7 N. S., Ogden, D. A., Schreiner, G. E. and Walser, M.: Invited discussion. Arch. Intern. Med., 124: 292, 1969. 8 Slatopolsky, E., Caglar, S., Pennell, J.P., TagD., Canterbury, J.M., Reiss, E. and Bricker, : Pathogenesis of hyperparathyroidism in chronic renal disease. J. Clin. Invest., abst. 285, 49:

89a, 1970. 9 Reiss, E., Canterbury, J.M. and Kanter, A.: Circulating parathyroid hormone concentration in chronic renal insufficiency. Arch. Intern. Med., 124:

417, 1969.

JVIarch 1969 he presented with pruritus, soft tissue calcifications in the hands, vasa deferentia and seminal vesicles, and diffuse bony demineralization Thrice weekly hemodialysis was begun. On 6 he received a renal allograft from his mother and underwent simultaneous bilateral,,-,~·"·-~ He was oliguric and required regular for the next 4 weeks. However, by had recovered good renal function and charged from the hospital. He never had bone pain. He did have hypercalcemia before receiving the However, he has been normocalcemic and pruritus since the transplant, even during the weeks of severe oliguria. This patient's calcium and phosphorus values are summarized in Case 2. A 24-year-old man had tis in 1964. In December 1965 chronic uv,u~·~""~"·' was begun. A bilateral nephrectomy was in May 1966. In 1968 foot, leg and hip veloped, and he had spontaneous rib fractures and a fracture of the neck of the left femur. The serum calcium values were 13.2, 12.4 and 12.9 mg. per 100 ml; the serum phosphorus values were and 2.7 mg. per 100 ml. Radiographic examination showed diffuse osteoporosis, subperiosteal about the hands and feet, healed rib healed fracture of the left hip and demineralization of the clavicles. In October 1969 a sub-total parathyroidectomy was performed with no in the symptoms. The serum calcium at 11 to 12 mg. per 100 ml. On January 15, 1970 the patient received a renal. transplant from a cadaveric donor. severe oliguria, the serum calcium level returned to norma.i one day postoperatively and remained normal. On March 12 a renal biopsy caused profuse requiring a nephrectomy. He was then inadvertently placed on vitamin D 50,000 units and the serum calcium became elevated calcium and phosphorus values are summarized in figure 2. Case 3. A 27-year-old man had glomerulonephritis in ~Iarch 1967. He was first admitted to l:niversity Hospital in March 1969, with severe uremia. He was maintained on intermittent dialysis until late June when thrice weekly hemodialysis was begun. There were no clinical or radiologic signs of bone disease and the serum calcium and alkaline phosphatase levels were normal. On August 5 the serum calcium was noted to be and it reached 14.8 mg. per 100 ml. by The serum alkaline phosphatase was 10.2 King3 Armstrong units. On August 533

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Fm. 1. Case 1. Patient was hypercalcemic until receiving renal transplant, after which he became normocalcemic immediately despite negligible excretory function.

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March 1970 parathyroidectomy but became normocalexcretory function.

containing no calcium. Despite this the serum calcium was consistently 11 to 12 mg. per 100 ml. On October 25 the patient received a cadaveric renal allograft and underwent simultaneous bilateral nephrectomy. There was good function immediately. Henceforth he had persistent hypocalcemia with a

ACUTE CHANGES IN SERUM CALCIUM AFTER RENAL TRANSPLANTATION

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July Aug. Sept. Oct. Nov. Dec. 1969 !969 1969 1969 1969 1969 Fm. 3. Case 3. Patient remained hypercalcemic after parathyroidectomy but became severely hypocalcemic and had hypoparathyroidism immediately after renal transplant, which exhibited good excretory function immediately. ·

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normal alkaline phosphatase (consistently less than 10 King-Armstrong units), indicating severe hypoparathyroidism. The patient's calcium and phosphorus values are summarized in figure 3. Case 4- A 35-year-old man had glomerulonephritis in 1956 and became uremic in 1966. Six months later chronic hemodialysis was begun. In June 1968 he began to have skeletal demineralization and progressively severe bone pain in the ankles, knees, shoulders and ribs. Eventually he could ambulate only with a walker. The serum calcium was between 9.0 and 9.5 mg. per 100 ml. In the summer of 1969 he was given a trial of vitamin D (50,000 units per day) for 3 months. The serum calcium rose to 11.0 mg. per 100 ml. but there was no clinical improvement. By February 1970 he was confined to a wheelchair because of intolerable pain on standing. The serum phosphorus was constantly maintained at less than 4.0 mg. per 100 ml. The serum calcium never exceeded 11.0 mg. per 100 ml. These values are summarized in figure 4. X-rays showed advancing demineralization of the fingers, wrists, feet and stippled areas in both femoral necks. On May 11, 1970 he received a cadaveric renal allograft and underwent simultaneous bilateral nephrectorny. He was severely oliguric until May 29, and hemodialysis was continued until May 30, when improvement of excretory function was sustained. However, by May 15 he had noticed lessening of bone pain and by May 25 was able to walk with a cane. Eventually there was complete resolution of the bone disease which, however, had begun to improve before the new kidney had any measurable excretory function. DISCUSSIOK

All of our patients had severe hypercalcemia or bone disease and were receiving chronic hernodialysis therapy. Each patient was receiving alu-

minurn hydroxide gel from the time of the initial consultation. A dialysis bath with 5.0 mg. per 100 ml. of calcium was used routinely (except for the brief period mentioned in case 3). Parathyroidectorny did not resolve the symptoms. Despite severe oliguria for 4 to 6 weeks, serum calci urn levels returned to normal immediately following renal transplantation in 2 of these patients. In case 3 there was severe hypoparathyroidisrn after transplantation. In case 4 there was no hypercalcemia but the severe bone pain began to improve before the transplanted kidney had developed excretory function. All 4 patients demonstrate that return of renal excretory function is not the only mechanism whereby the bone disease of uremia is ameliorated after transplantation. Possible role of corticosteroids. All patients were placed on prednisone postoperatively. Adrenal corticosteroids correct hypercalcernia which is not associated with high parathyroid hormone levels. Hyperparathyroidisrn (primary or tertiary) responds. However, exceptions to this rule have been reported in 2 cases. 10 Adrenal steroids have been shown to antagonize the effect of exogenous parathyroid extract on bone and kidney in patients with hypoparathyroidisrn.11 However, in norrnal patients with intact parathyroid glands there was no clinical or chemical evidence of hypoparathyroidisrn after corticosteroid adrninistration. 12 10 Dent, C. E. and Watson, L.: The hydrocortisone test in primary and tertiary hyperparathyroidism. Lancet, 2: 662, 1968. 11 Eliel, L. P., Thomsen, C. and Chanes, R.: Antagonism between parathyroid extract and adrenal cortical steroids in man. J. Clin. Endocr., 26: 457,

1965.

12 Elie!, L. P., Chanes, R. and Hawrylko, J.: Urinary excretion of parathyroid hormone in man: effects of calcium loads, protein-free diets, adrenal cortical steroids and neoplastic disease. J. Clin. Endocr., 25: 445, 1965.

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Fm. 4. Case 4. Patient had severe bone disease despite normocalcemia. High doses of vitamin D did not improve bone disease. After renal transplantation bone disease improved prior to any measurable renal excretory function.

Hyperphosphatemia and vitamin D resistance. Investigators have found that in mild renal failure parathyroid hormone levels are always elevated. The reduction of serum phosphorus by the administration of aluminum hydroxide gel or restriction of phosphorus intake caused parathyroid hormone levels to return to normal.7, 8 However, these approaches have neither reversed the autonomous hyperparathyroidism of end-stage renal disease nor brought symptomatic relief of bone pain. 9 Friis and associates demonstrated that vitamin D resistance and negative calcium balance are earlier causes of hyperparathyroidism than phosphorus retention. 3 Stanbury and associates 13 and Pendras 14 report that large doses of vitamin D cures bone disease in their uremic patients with hypocalcemia. But Stanbury's uremic patients in England are more prone to early osteomalacia than uremic patients in America ,.and have low serum calcium levels, possibly because of their lower dietary intake of vitamin D.13 Patients in this country usually do not become symptomatic with bone pain or have metastatic calcification until the parathyroid glands have become so hyperplastic that the serum calcium reaches normal or persistently high levels despite a normal or high serum 13 Stanbury, S. W., Lumb, G. A. and Mawer, E. B.: Osteodystrophy developing spontaneously in the course of chronic renal failure. Arch. Intern. Med.: 124: 274, 1969. 14 Pendras, J.P.: Parathyroid disease in long-term maintenance hemodialysis. Arch. Intern. Med., 124: 312, 1969.

phosphorus. In these cases even Stanbury does not recommend vitamin D. 13 Vitamin D actually potentiates the effect of parathyroid hormone and increases calcium resorption from bone. 15 In osteomalacia vitamin D therapy increases the total available calcium for deposition in bone by increasing intestinal absorption. However, when the serum levels of calcium are already high, vitamin D would not only aggravate the effects of hyperparathyroidism on bone metabolism but also increase the risk of diffuse metastatic calcification in soft tissues and vessels. The half life of vitamin D in serum is about 6 months, and once vitamin D intoxication is reached, there is no easy retreat. 13 , 14 It is known that even in far-advanced vitamin D-deficient rickets unrelated to renal disease, hypercalcemia does not develop. 16 These patients have secondary hyperparathyroidism but not the massive hyperplasia and autonomy of renal failure. Therefore, the phenomenon we observe in patients receiving chronic dialysis therapy does not appear to be caused simply by vitamin D resistance. Other theories. Goldsmith and associates noted 15 Raisz, L. G.: Physiologic pharmacologic regulation of bone resorption. New Engl. J. Med., 282: 909, 1970. 16 Potts, J. T., Jr. and Deftos, L. J.: Parathyroid hormone, thyrocalcitonin, vitamin D, bone and bone mineral metabolism. In: Duncan's Diseases of Metabolism: Endocrinology and Nutrition, 6th ed. Edited by P. K. Bondy. Philadelphia: W. B. Saunders Co., p. 1050, 1969.

ACUTE CHANGES IN SERUM CALCIUM AFTER RENAL TRANSPLANTATION

little radiographic bone disease when the dialysate calcium concentration was kept at more than 5.7 mg. per 100 ml. for 6 months. 17 They further noted that parathyroid hormone levels could be substantially reduced if the serum phosphorus was kept low and the dialysate calcium concentration was as high as 6.5 mg. per 100 ml.1 7 However, their findings do not explain the bone disease of patients with hypercalcemia. Parfitt has shown how secondary parathyroid hyperplasia, that is an increased number of cells, can produce excessive parathyroid hormone even though each individual cell produces only an amount of hormone appropriate to the elevation in serum calcium. 18 However, hypercalcemia should inh,bit the stimulus to further parathyroid hyperplasia and prevent further elevations in serum calcium, unless each cell has begun to recognize a new serum calcium level as normal and has secreted more parathyroid hormone for a given level of serum calcium. Parathyroidectomy and transplantation. Subtotal parathyroidectomy may lower the serum calcium and provide symptomatic relief but success is not always achieved and the parathyroid hormone levels still may not be lowered to normal.13· 14 , 19 For the paLent with no prospect of transplantation, total parathyroidectomy with vitamin D replacement may be more permanently effective even though being unphysiological.2°, 21 Successful renal transplantation will produce dramatic improvement within weeks, with complete relief of symptoms, healing of bone and rernlution of hypercalcemia in 6 to 18 months in almost all cases. 22 • 23 The reason why a new kidney 17 Goldsmith, R. S., Fournier, A., Johnson, W. J· and Arnaud, C. D.: Etiologic role of dialysis in stimu la ting hyperparathyroidism during chronic hemo dialysis. J. Clin. Invest., abst. 113, 49: 35a, 1970i 18 Parfitt, A. M.: Relation between parathyroid eel mass and plasma calcium concentration in normal and uremic subjects. A theoretical model with an analysis of the concept of autonomy, and speculations on the mechanism of parathyroid hyperplasia. Arch. Intern. Med., 124: 269, 1969. 19 Johnson, J. W., Berstein, D. S., Wachman, A., Katz, A. I., Hampers, C. L., Wilson, R. E. and Merrill, J. P.: Bone metabolism after subtotal parathyroidectomy in chronic renal failure. Clin. Res., 17: 433, 1969. 2° Castleman, B. and B. U.: Case records Hos pi ta!. Weekly of the Massachusetts clinicopathological exercises. New Engl. J. Med., 282: 1028, 1970. 21 Round table discussion. Arch. Intern. Med., 124: 670, 1969. 22 Alfrey, A. C., Jenkins, D., Groth, C. G., Schorr, W. S., Gecelter, L. and Ogden, D. A.: Resolution of hyperparathyroidism, renal osteodystrophy and metastatic calcification after renal homotransplantation. New Engl. J. Med., 279: 1349, 1968. 23 Hampers, C. L., Katz, A. I., Wilson, R. E. and Merrill, J. P.: Calcium metabolism and osteodystrophy after renal transplantation. Arch. Intern. Med., 124: 282, 1969.

should reverse this otherwise progressive deterioration of bone metabolism is not clear. The view that post-transplant hypophosphatemia with elevation of serum calcium depresses secretion does not explain why only renal tramplantation can resolve parathyroid and bone disease in these patients, are kept hypophosphatemic with amphogel intensive dialysis prior to transplantation. 7 , 9 Renal anti-parathyroid effect. These observations could be explained if one that a renal anti-parathyroid effect in the regulation of calcium, phosphorus metabolism. It has been shown that hormone-like activity is reduced in vitro immersion with slices of kidney tissue. 24 Since this was first written DeLuca and others have shown that the kidney helps produce the active metabolites of vitamin D. 25 Thus in uremic patients who have not yet had kidney transplant, the absence of normal roid antagonism would explain why subtotal parathyroidectomy is often ineffective. The presence this renal anti-parathyroid effect immediately after transplantation of a normal kidney could the rapid healing of severe bone lesions, the resolution of bone pain and the rapid fall in serum thyroid hormone levels even in the absence of hypercalcemia or previous parathyroidectomy. It is well known that the kidney regulates red blood cell and renin production. 26 It would not be surprising to discover a new non-excretory function of the kidney: control of calcium, phosphorus bone metabolism. As with the anemia of renal failure, perhaps only successful transplantation wiJl restore this function completely to normal. SUMMARY

Successful renal transplantation 1s most effective way to treat bone disease in with renal failure receiving hemodialysis. A group of cases is presented which demonstrates tlmt return of renal excretory function may not be the method whereby transplantation cures the bone disease. Available data from the literature on calcium, phosphorus and bone metabolism in renal failure are reviewed and the inadequacies of theories are discussed. The postulate of a parathyroid effect is presented, that is the kidney its products may play an endocrinologic role in normal calcium, phosphorus and bone metabolism. 2 4 Orimo, H., Fujita, T., Morii, H. and Inactivation in vitro of parathyroid hormone bv kidney slices. Endocrinology, 76: 255, 1965. 25 DeLuca, H. F.: Role of kidney tissue in mctabolism of vitamin D. New Engl. J. Med. 284: 1971. 20 Hamburger, J., Richet, G., J., Brentano, J .. L., Antoine, B., Ducrot, H., . and de Montera, H.: N ephrology. Ph1ladelphrn: Saunders Co., p. 92, 1968. e