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Hypocalcemia following bilateral nephrectomy
HYPOCALCEMIA BILATERAL JHOONG ALBERT
FOLLOWING
NEPHRECTOMY*
S. CHEIGH, L. RUBIN,
KURT
H.
STENZEL,
JOHN
C. WHITSELL,
M.D. M.D. M.D. M.D.
From the Rogosin Kidney Center, Departments of Surgery and Biochemistry, The New York Hospital-Cornell Medical Center, New York, New York
ABSTRACT-A patient with polycystic kidney disease, secondary hyperparathyroidism, and relative hypercalcemia developed severe symptomatic hypocalcemia following bilateral nephrectomy. Acute depletion of 1,25dihydroxycholecalciferol is proposed as a possible cause of the hypocalcemia.
1,25-dihydroxycholecalciferol (1,25( OH)zD3) has recently been shown to be the most potent form of vitamin D3 in stimulating intestinal calcium and skeletal calcium mobilization.3 absorptior? Kidney tissue is the only apparent site of synthesis of 1,25(OH)2D3 from its precursor 25hydroxycholecalciferol (25( OH)D3), ’and anephric animals as well as uremic patients are incapable of producing 1,24(0H)2D3.2*4s5 It has therefore been suggested that bilateral nephrectomy in patients with end-stage kidney disease might adversely affect calcium homeostasis and renal osteodystrophy.2*6 Although the anemia of uremia often is made worse by bilateral nephrectomy, 7 the effects of this procedure on calcium homeostasis and the subsequent clinical course of renal osteodystrophy have not yet been clinically determined. We here report the case of a patient with polycystic kidney disease, secondary hyperparaand relative hypercalcemia, who thyroidism, developed acute hypocalcemia following bilateral nephrectomy. Case Report A forty-seven-year-old woman was found to have polycystic kidney disease at age thirty-nine, *This study was supported in part by The New York State Kidney Disease Institute and the Kidney Foundation of New York.
UROLOGY
/ AUGUST
1973 / VOLUME
II, NUMBER
2
following episodes of recurrent urinary tract infection and hematuria. In 1969, she was admitted for the first time to The New York Hospital complaining of weakness and easy fatigability. The clinical diagnosis of polycystic kidney disease was confirmed with renal arteriograms and intravenous and occlusive retrograde pyelograms. Markedly decreased renal function was noted (serum creatinine 6.4 mg. per 100 ml.; creatinine clearance 14 ml. per minute; blood urea nitrogen 67 mg., serum calcium 10.1 mg., and serum phosphorus 5.6 mg. per IO0 ml.; serum alkaline phosphatase 9.3 Bodansky units; and hematocrit 30). Her renal function gradually decreased over the following three years, and became endstage by early 1972. Serum calcium, however, remained above 9 mg. per 100 ml. in spite of high serum phosphorus (over 7 mg. per 100 ml,), and the serum alkaline phosphatase was elevated (over 200 milliunits per ml.). Bone x-ray films, iliac crest bone biopsy, as well as serum parathormone i.mmunoassay (4.5 ng. per ml. when serum calcium was 9.6 mg. per 100 ml.) done in March, 1972, were consistent with secondary hyperparathyroidism. In April, 1972, the patient was placed on fivehour, thrice-weekly hemodialysis treatments. On May 11, 1972, she underwent bilateral nephrectomy because of recurrent hematuria, urinary tract infection, and flank pain. One day before nephrectomy, her serum calcium was 9.2 mg.
121
and phosphorus 7.8 mg. per 100 ml.; alkaline phosphatase 217 milliunits per ml.; albumin 5 Gm. and globulin 2.7 Gm. per 100 ml.; and creatinine 8 mg. per 100 ml. The postoperative course was uneventful, and she was discharged on May 24,1972; therapy included multivitamins, folic acid, and aluminum hydroxide tablets. On May 31,1972, during one of her hemodialysis visits, she complained of generalized numbness, weakness, anorexia, postural dizziness, and emotional instability. On physical examination, she had mild postural hypotension (130/70 supine and 100/60 standing), without any changes in body weight, and Chvostek’s and Trousseau’s signs were negative. Prehemodialysis blood tests revealed serum calcium 3.1 mg., creatinine 11 mg., and phosphorus 3.8 mg. per 100 ml.; alkaline phosphatase 432 milliunits per ml.; and albumin 3.8 Gm. (globulin 2.5 Gm. per 100 ml.). Hepatic enzymes were within the normal range. During hemodialysis, she received a total of 7 Gm. calcium gluconate intravenously, and postdialysis serum calcium was 6.7 mg. per 100 ml. While she was receiving hemodialysis (elementary calcium 5 mg. per 100 ml. in bath) and intravenous calcium supplementation, a blood specimen was obtained to assay parathormone level which was subsequently reported as 1.05 ng. per ml. Her symptoms disappeared following dialysis when the serum calcium was 6.7 mg. per 100 ml. Repeat bone x-ray films and posterior iliac crest bone biopsy again revealed advanced osteodystrophy but with no further progression when compared to the studies done three months earlier. She was subsequently treated with oral calcium gluconate 8 Gm., dihydrotachysterolO.6 mg., aluminum hydroxide tablets daily, and five hours of thrice-weekly hemodialysis with 8 mg. per 100 ml. elementary calcium in the bath. Over the next several months, while receiving calcium supplementation and dihydrotachysterol, alkaline phosphatase gradually decreased below 400 milliunits per ml. (Fig. 1). Comment Bilateral nephrectomy in uremic patients with end-stage kidney disease might adversely affect calcium homeostasis and renal osteodystrophy,2,6 because of the role of the kidne*ys in the synthesis of the active form of vitamin D3.2~4 The kidneys in end-stage renal disease do not have significant glomerular or tubular function, but they maintain some endocrine function, producing both renin and possibly erythropoietin.s Renin production is indicated by the cure of
122
renin-dependent hypertension following bilateral nephrectomys and erythropoietin-like activity by the exacerbation of uremic anemia following this procedure.’ If diseased kidneys were able to produce even small amounts of 1,2~5(OH)~D3, as Boyle et al2 suggest, then nephrectomy could further decrease intestinal calcium absorption and skeletal calcium mobilization. This would result in hypocalcemia, unless parathormone secretion was increased enough to overcome these factors. Other events that could potentially cause hypocalcemia after major surgery include infarction of the parathyroid glands, hyperphosphatemia secondary to insufficient dialysis, insufficient dosages of binding gels, and hypercatabolism. This patient had chronic renal failure with renal secondary hyperparatbyroidism and osteodystrophy and acute hypocalcemia developed after bilateral nephrectomy. Severe and symptomatic hypocalcemia was first recognized three weeks after the surgical procedure, although hypocalcemia had begun within one week after the nephrectomy. The serum phosphorus was normal, but serum alkaline phosphatase was markedly elevated, and serum parathormone level was moderately elevated. AvailabIe laboratory data ruled out the possibility of parathyroid gland infarction or hyperphosphatemia as a cause of hypocalcemia. Although we do not have any data regarding 1,25(OH)zD3 1evels before and after nephrectomy, the available data are consistent with an acute deficiency of 1,25(OH),D3 causing decreased calcium mobilization from dietary sources and bone as a cause of this patient’s hypocalcemia. This phenomenon may be more apparent in patients with polycystic kidney disease. Other types of disease often lead to gradual fibrosis of the renal parenchyma and a gradual loss of ability to produce 1,25(OH)zD3. In these cases nephrectomy may not be a significant factor in further altering calcium absorption and utilization. Polycystic kidneys, however, may retain more functioning parenchymal cells and may continue to produce significant amounts of 1,25(OH)zD3 despite loss of excretory function. Depletion of 1,25(OH)2D3 storage apparently comes quite early in the postoperative period since serum calcium was significantly decreased by the fifth postoperative day. At this stage, very high serum parathormone levels would be expected. Our patient, however, had only moderately elevated serum parathormone, probably because of intravenous calcium infusion as well as high
UROLOGY
/ AUGUST
1973
/
VOLUME
II, NUMBER
2
10
f
86414
10 CREATININE 8 6
PHOSPHORUS
ALKALINE
ALBUMIN
4 3
Calcium
Aluminum hydroxide
m
gluconate .:<.x. .........)...). .ofr .a.. .d>... ..>>:,A ty
Ca in dialysate Ca Ici ” m gl “conate,
months
FIGURE
PHOSPHATASE
1.
dgmlday ......~. .......:::. :..:.:.:.:.::: :.:::.:..>> ,.,. ~~ 4 po ~1:ili:‘.‘:‘:I~si~~:~:~~:‘~:~~:‘.’~~~i,:-II:.,. .,.:.,.~~~:3
221 23
preop DIALYSIS NEPHRECTOMIES
days postop
Graphic summary of course of hypocalcemia
in patient following
bilateral nephrectomy.
calcium concentration in the dialysis bath. The serum parathormone levels may have been higher before calcium supplementation therapy, as reflected by an extremely high serum alkaline phosphatase. Serum calcium may not be brought back to prenephrectomy levels even with higher serum parathormone if the calcium mobilizing effect of parathormone is lessened by
UROLOGY
/ AUGUST
1973 / VOLUME
II, NUMBER
2
poor skeletal calcium content (hungry bone) or decreased vitamin D3 activity-l0 The over-all incidence and severity of postnephrectomy hypocalcemia is unknown. Prospective studies on this subject are now under way, and we have found a significant incidence of hypocalcemia in the first three cases. These were, however, associated with hyperphosphatemia in
123
spite of pure parenteral glucose feeding and continuation of thrice-weekly maintenance hemodialysis. Two of these patients, who had histories of seizure disorders, developed prolonged grand ma1 seizures during hemodialysis in the immediate postoperative period, while they were hypocalcemic, and in spite of maintenance anticonvulsant drug therapy. Although hypocalcemia itself may not cause grand ma1 seizures with postictal amnesia, it may act as an initiating factor, exacerbating a preexisting seizure disorder. Patients with end-stage kidney disease undergoing bilateral nephrectomy should be carefully evaluated in terms of calcium metabolism and bone disease to avoid complications and to determine the over-all incidence and causes of postnephrectomy hypocalcemia and the subsequent course of renal osteodystrophy. 525 East 68th Street New York, New York 10021 (DR. CHEIGH) References Biological activity of 1,25-dihydroxy1. OMDAHL,J.,~~UZ.: cholecalciferol, Biochemistry lo:2935 (1971).
124
2. BOYLE I. T., et al.: The response of intestinal calcium transport to 25-hydroxy and 1,25-dihydroxy vitamin D in nephrectomized rats, Endocrinology 90: 605 (1972). 3. TANAKA, Y., and DELUCA, H. F.: Bone mineral mobilization activity of 1,25-dihydroxy-cholecalciferol, a metabolite of vitamin D, Arch. Biochem. Biophys. 146: 574 (1972). 4. FRASER, D. R., and KODICEK, E.: Unique biosynthesis by kidney of a biologically active vitamin D metabolite, Nature 228: 764 (1970). 5. MAWER, E. B., et al.: Failure of formation of I,25dihydroxycholecalciferol in chronic renal insufficiency, Lancet 1: 626 (1973). 6. MOORE, F. D.: Kidney-parathyroid loop and nephrectomy, N. Engl. J. Med. 287: 67 (1972). 7. VAN YPERSELE DE STRIHOU, C., and STRAGIER, A.: Effect of bilateral nephrectomy on transfusion requirements of patients undergoing chronic dialysis, Lancet 2: 705 (1969). 8. KOTCHEN, T. A., et al.: A study of the renin-angiotensin system in patients with severe chronic renal insufficiency, Nephron 7: 317 (1970). 9. VERTES, V., et al.: Hypertension in end-stage renal disease, N. Engl. J. Med. 280: 978 (1969). 10. DELUCA, H. F., MORII, F. H., and MELANCON, M. J., JR.: The interaction of vitamin D, parathyroid hormone and thyrocalcitonin, parathyroid hormone and thyrocalcitonin (calcitonin), in Talmage, Ft. V., and Belanger, L. F., Eds.: Proceedings of the Third Parathyroid Conference (International Congress Series No. 159); abstracted, Excerpta Medica, 1968, p. 448.
UROLOGY
/
AUGUST
1973
/
VOLUME
II, NUMBER
2
FOLLOWING
NEPHRECTOMY*
S. CHEIGH, L. RUBIN,
KURT
H.
STENZEL,
JOHN
C. WHITSELL,
M.D. M.D. M.D. M.D.
From the Rogosin Kidney Center, Departments of Surgery and Biochemistry, The New York Hospital-Cornell Medical Center, New York, New York
ABSTRACT-A patient with polycystic kidney disease, secondary hyperparathyroidism, and relative hypercalcemia developed severe symptomatic hypocalcemia following bilateral nephrectomy. Acute depletion of 1,25dihydroxycholecalciferol is proposed as a possible cause of the hypocalcemia.
1,25-dihydroxycholecalciferol (1,25( OH)zD3) has recently been shown to be the most potent form of vitamin D3 in stimulating intestinal calcium and skeletal calcium mobilization.3 absorptior? Kidney tissue is the only apparent site of synthesis of 1,25(OH)2D3 from its precursor 25hydroxycholecalciferol (25( OH)D3), ’and anephric animals as well as uremic patients are incapable of producing 1,24(0H)2D3.2*4s5 It has therefore been suggested that bilateral nephrectomy in patients with end-stage kidney disease might adversely affect calcium homeostasis and renal osteodystrophy.2*6 Although the anemia of uremia often is made worse by bilateral nephrectomy, 7 the effects of this procedure on calcium homeostasis and the subsequent clinical course of renal osteodystrophy have not yet been clinically determined. We here report the case of a patient with polycystic kidney disease, secondary hyperparaand relative hypercalcemia, who thyroidism, developed acute hypocalcemia following bilateral nephrectomy. Case Report A forty-seven-year-old woman was found to have polycystic kidney disease at age thirty-nine, *This study was supported in part by The New York State Kidney Disease Institute and the Kidney Foundation of New York.
UROLOGY
/ AUGUST
1973 / VOLUME
II, NUMBER
2
following episodes of recurrent urinary tract infection and hematuria. In 1969, she was admitted for the first time to The New York Hospital complaining of weakness and easy fatigability. The clinical diagnosis of polycystic kidney disease was confirmed with renal arteriograms and intravenous and occlusive retrograde pyelograms. Markedly decreased renal function was noted (serum creatinine 6.4 mg. per 100 ml.; creatinine clearance 14 ml. per minute; blood urea nitrogen 67 mg., serum calcium 10.1 mg., and serum phosphorus 5.6 mg. per IO0 ml.; serum alkaline phosphatase 9.3 Bodansky units; and hematocrit 30). Her renal function gradually decreased over the following three years, and became endstage by early 1972. Serum calcium, however, remained above 9 mg. per 100 ml. in spite of high serum phosphorus (over 7 mg. per 100 ml,), and the serum alkaline phosphatase was elevated (over 200 milliunits per ml.). Bone x-ray films, iliac crest bone biopsy, as well as serum parathormone i.mmunoassay (4.5 ng. per ml. when serum calcium was 9.6 mg. per 100 ml.) done in March, 1972, were consistent with secondary hyperparathyroidism. In April, 1972, the patient was placed on fivehour, thrice-weekly hemodialysis treatments. On May 11, 1972, she underwent bilateral nephrectomy because of recurrent hematuria, urinary tract infection, and flank pain. One day before nephrectomy, her serum calcium was 9.2 mg.
121
and phosphorus 7.8 mg. per 100 ml.; alkaline phosphatase 217 milliunits per ml.; albumin 5 Gm. and globulin 2.7 Gm. per 100 ml.; and creatinine 8 mg. per 100 ml. The postoperative course was uneventful, and she was discharged on May 24,1972; therapy included multivitamins, folic acid, and aluminum hydroxide tablets. On May 31,1972, during one of her hemodialysis visits, she complained of generalized numbness, weakness, anorexia, postural dizziness, and emotional instability. On physical examination, she had mild postural hypotension (130/70 supine and 100/60 standing), without any changes in body weight, and Chvostek’s and Trousseau’s signs were negative. Prehemodialysis blood tests revealed serum calcium 3.1 mg., creatinine 11 mg., and phosphorus 3.8 mg. per 100 ml.; alkaline phosphatase 432 milliunits per ml.; and albumin 3.8 Gm. (globulin 2.5 Gm. per 100 ml.). Hepatic enzymes were within the normal range. During hemodialysis, she received a total of 7 Gm. calcium gluconate intravenously, and postdialysis serum calcium was 6.7 mg. per 100 ml. While she was receiving hemodialysis (elementary calcium 5 mg. per 100 ml. in bath) and intravenous calcium supplementation, a blood specimen was obtained to assay parathormone level which was subsequently reported as 1.05 ng. per ml. Her symptoms disappeared following dialysis when the serum calcium was 6.7 mg. per 100 ml. Repeat bone x-ray films and posterior iliac crest bone biopsy again revealed advanced osteodystrophy but with no further progression when compared to the studies done three months earlier. She was subsequently treated with oral calcium gluconate 8 Gm., dihydrotachysterolO.6 mg., aluminum hydroxide tablets daily, and five hours of thrice-weekly hemodialysis with 8 mg. per 100 ml. elementary calcium in the bath. Over the next several months, while receiving calcium supplementation and dihydrotachysterol, alkaline phosphatase gradually decreased below 400 milliunits per ml. (Fig. 1). Comment Bilateral nephrectomy in uremic patients with end-stage kidney disease might adversely affect calcium homeostasis and renal osteodystrophy,2,6 because of the role of the kidne*ys in the synthesis of the active form of vitamin D3.2~4 The kidneys in end-stage renal disease do not have significant glomerular or tubular function, but they maintain some endocrine function, producing both renin and possibly erythropoietin.s Renin production is indicated by the cure of
122
renin-dependent hypertension following bilateral nephrectomys and erythropoietin-like activity by the exacerbation of uremic anemia following this procedure.’ If diseased kidneys were able to produce even small amounts of 1,2~5(OH)~D3, as Boyle et al2 suggest, then nephrectomy could further decrease intestinal calcium absorption and skeletal calcium mobilization. This would result in hypocalcemia, unless parathormone secretion was increased enough to overcome these factors. Other events that could potentially cause hypocalcemia after major surgery include infarction of the parathyroid glands, hyperphosphatemia secondary to insufficient dialysis, insufficient dosages of binding gels, and hypercatabolism. This patient had chronic renal failure with renal secondary hyperparatbyroidism and osteodystrophy and acute hypocalcemia developed after bilateral nephrectomy. Severe and symptomatic hypocalcemia was first recognized three weeks after the surgical procedure, although hypocalcemia had begun within one week after the nephrectomy. The serum phosphorus was normal, but serum alkaline phosphatase was markedly elevated, and serum parathormone level was moderately elevated. AvailabIe laboratory data ruled out the possibility of parathyroid gland infarction or hyperphosphatemia as a cause of hypocalcemia. Although we do not have any data regarding 1,25(OH)zD3 1evels before and after nephrectomy, the available data are consistent with an acute deficiency of 1,25(OH),D3 causing decreased calcium mobilization from dietary sources and bone as a cause of this patient’s hypocalcemia. This phenomenon may be more apparent in patients with polycystic kidney disease. Other types of disease often lead to gradual fibrosis of the renal parenchyma and a gradual loss of ability to produce 1,25(OH)zD3. In these cases nephrectomy may not be a significant factor in further altering calcium absorption and utilization. Polycystic kidneys, however, may retain more functioning parenchymal cells and may continue to produce significant amounts of 1,25(OH)zD3 despite loss of excretory function. Depletion of 1,25(OH)2D3 storage apparently comes quite early in the postoperative period since serum calcium was significantly decreased by the fifth postoperative day. At this stage, very high serum parathormone levels would be expected. Our patient, however, had only moderately elevated serum parathormone, probably because of intravenous calcium infusion as well as high
UROLOGY
/ AUGUST
1973
/
VOLUME
II, NUMBER
2
10
f
86414
10 CREATININE 8 6
PHOSPHORUS
ALKALINE
ALBUMIN
4 3
Calcium
Aluminum hydroxide
m
gluconate .:<.x. .........)...). .ofr .a.. .d>... ..>>:,A ty
Ca in dialysate Ca Ici ” m gl “conate,
months
FIGURE
PHOSPHATASE
1.
dgmlday ......~. .......:::. :..:.:.:.:.::: :.:::.:..>> ,.,. ~~ 4 po ~1:ili:‘.‘:‘:I~si~~:~:~~:‘~:~~:‘.’~~~i,:-II:.,. .,.:.,.~~~:3
221 23
preop DIALYSIS NEPHRECTOMIES
days postop
Graphic summary of course of hypocalcemia
in patient following
bilateral nephrectomy.
calcium concentration in the dialysis bath. The serum parathormone levels may have been higher before calcium supplementation therapy, as reflected by an extremely high serum alkaline phosphatase. Serum calcium may not be brought back to prenephrectomy levels even with higher serum parathormone if the calcium mobilizing effect of parathormone is lessened by
UROLOGY
/ AUGUST
1973 / VOLUME
II, NUMBER
2
poor skeletal calcium content (hungry bone) or decreased vitamin D3 activity-l0 The over-all incidence and severity of postnephrectomy hypocalcemia is unknown. Prospective studies on this subject are now under way, and we have found a significant incidence of hypocalcemia in the first three cases. These were, however, associated with hyperphosphatemia in
123
spite of pure parenteral glucose feeding and continuation of thrice-weekly maintenance hemodialysis. Two of these patients, who had histories of seizure disorders, developed prolonged grand ma1 seizures during hemodialysis in the immediate postoperative period, while they were hypocalcemic, and in spite of maintenance anticonvulsant drug therapy. Although hypocalcemia itself may not cause grand ma1 seizures with postictal amnesia, it may act as an initiating factor, exacerbating a preexisting seizure disorder. Patients with end-stage kidney disease undergoing bilateral nephrectomy should be carefully evaluated in terms of calcium metabolism and bone disease to avoid complications and to determine the over-all incidence and causes of postnephrectomy hypocalcemia and the subsequent course of renal osteodystrophy. 525 East 68th Street New York, New York 10021 (DR. CHEIGH) References Biological activity of 1,25-dihydroxy1. OMDAHL,J.,~~UZ.: cholecalciferol, Biochemistry lo:2935 (1971).
124
2. BOYLE I. T., et al.: The response of intestinal calcium transport to 25-hydroxy and 1,25-dihydroxy vitamin D in nephrectomized rats, Endocrinology 90: 605 (1972). 3. TANAKA, Y., and DELUCA, H. F.: Bone mineral mobilization activity of 1,25-dihydroxy-cholecalciferol, a metabolite of vitamin D, Arch. Biochem. Biophys. 146: 574 (1972). 4. FRASER, D. R., and KODICEK, E.: Unique biosynthesis by kidney of a biologically active vitamin D metabolite, Nature 228: 764 (1970). 5. MAWER, E. B., et al.: Failure of formation of I,25dihydroxycholecalciferol in chronic renal insufficiency, Lancet 1: 626 (1973). 6. MOORE, F. D.: Kidney-parathyroid loop and nephrectomy, N. Engl. J. Med. 287: 67 (1972). 7. VAN YPERSELE DE STRIHOU, C., and STRAGIER, A.: Effect of bilateral nephrectomy on transfusion requirements of patients undergoing chronic dialysis, Lancet 2: 705 (1969). 8. KOTCHEN, T. A., et al.: A study of the renin-angiotensin system in patients with severe chronic renal insufficiency, Nephron 7: 317 (1970). 9. VERTES, V., et al.: Hypertension in end-stage renal disease, N. Engl. J. Med. 280: 978 (1969). 10. DELUCA, H. F., MORII, F. H., and MELANCON, M. J., JR.: The interaction of vitamin D, parathyroid hormone and thyrocalcitonin, parathyroid hormone and thyrocalcitonin (calcitonin), in Talmage, Ft. V., and Belanger, L. F., Eds.: Proceedings of the Third Parathyroid Conference (International Congress Series No. 159); abstracted, Excerpta Medica, 1968, p. 448.
UROLOGY
/
AUGUST
1973
/
VOLUME
II, NUMBER
2