Acta Med Scand 201: 35-39, 1977
H ypercalcemia and Parathyroid Function after Renal Transplantation Merete Sanvig Christensen, Hans Egon Nielsen and Susanne Tarring From First Medical University Clinic, Arhus Kommunehospital. and the Institute of Pharmacology, Arhus Universitet, Arhus, Denmark
ABSTRACT. Hypercalcemia after renal transplantation (post-T hypercalcemia) has been detected in 29 (16.7%) of 174 long-term survivors. The mean time of onset of hypercalcemia was 69 days after renal transplantation (range 3-210). In 18 patients the hypercalcemia was mild and resolved spontaneously (transient)from 2-65 months (mean 19) after onset. In 4 patients serum calcium normalized concurrently with rejection episodes. In 7 patients the hypercalcemia was more pronounced (permanent), being terminated by subtotal parathyroidectomy in 5 and persisting in 2 recipients. The hypercalcemia was asymptomatic except in one patient, who developed calculi in the graft and a fall in graft function, all of which disappeared after parathyroidectomy. At operation the parathyroid glands showed hyperplasia, except in one case with an adenoma in one of the hyperplastic glands. Serum phosphorus was markedly decreased, to the same extent in transiently and permanently hypercalcemic recipients. Serum parathyroid hormone (S-PTH) was increased in all of 5 patients with permanent and in 3 of 8 with transient post-T hypercalcemia. In normocalcemic and in transiently hypercalcemic recipients the mean S-PTH was identical, but significantly lower than in the permanently hypercalcemic recipients. S-PTH was suppressed to the same extent during an i.v. calcium infusion in patients with post-T hypercalcemia and with primary hyperparathyroidism. The occurrence of hypercalcemia after successful renal transplantation (RT) was first reported in 1964 (20), and has since been described by several authors (2, 6, 10, 14, 17, 19, 24). The reported incidence of hypercalcemia in kidney recipients has varied considerably and different opinions as to the clinical significance and the need for subtotal parathyroidectomy have been presented. We have
therefore performed an analysis of the incidence and clinical course of hypercalcemia among the patients who received renal allografts in this hospital. PATIENTS AND METHODS During the years 1964-74, 291 patients (aged ! L 6 5 years) received kidney allografts and 174 were alive with a creatinine concentration in serum at or below 2 mg/lOO ml 6 months after RT. The incidence of post-transplantation (post-T) hypercalcemia among the 174 long-term survivors is reported here. Immunosuppressive therapy was carried out with azathioprine and prednisone, with minor changes in dosage schedule over the years. Two months after RT the daily dose of prednisone was normally about 30 mg. Antacid therapy with aluminum hydroxide gel in moderate doses was given during the period when prednisone exceeded 40 mg/day, i.e. for about 4-5 weeks. Serum concentrations of calcium, phosphorus and alkaline phosphatase were measured at weekly intervals for the first 4-8 weeks after R T and later at intervals of 2-3 months. Normal range for serum calcium (S-Ca) is 9.010.8 mg/IOO mi, for serum phosphorus 2.74.7 mg/lOO ml and for alkaline phosphatase 8CL220 U/I. Hypercalcemia is here defined as serum calcium concentration above 10.8 mg/lOO ml and hypophosphatemia as serum concentration of phosphorus below 2.7 mg/IOO mi in two consecutive blood samples. The serum concentration of parathyroid hormone (S-PTH) was measured by a radioimmunoassay after extraction of the hormone from serum by adsorption to and elution from a microfine precipitated silica (Quso G 32), providing a hormone concentration 3.2 times higher in extract than in serum ( 5 ) . The antibody used was anti-bovine PTH AS 21 1/32. Bovine PTH was used for 'ZSI-labeling. The coefficient of variation in per cent was 6 for measurements above and 16 for measurements within the normal range (30-105 pglml bovine equivalents. MRC bPTH standard 71/324). The sensitivity of the assay was 10 pg bPTH present in the incubation mixture. Calcium infusion with simultaneous measurement of S-PTH was performed in 3 patients with permanent
36
M . S . Christensen et al.
Table I. Yearly incidence of hypercalcemia after renal transplantation and mean duration of dialysis Recipients
At
1964-67 1968 1969 1970 1971 1972 1973 1974 1%4-74
risk
21 23 23 31 25 19 21 11
174
Mean duration of dialysis
With
for all 174
hypercalcemia
recipients
7 (33.3%) 3 (13.0%) 3 (13.0%) 4 (7.8%) 4 (16.0%) 6 (3 1.6%) 2 (9.5%) 0 (0.070) 29(16.7%)
3.3 4.0 5.3 5.9 6.0 7.0 9.0 8.2 5.8
(mo.1
post-T hypercalcemia and in 3 patients with primary hyperparathyroidism with comparable serum values of calcium and PTH. I.v. infusion of 12 mg calcium/kg b.wt. (as calcium laevulate) was given between 9 and 12 a.m. Blood samples were taken before, each hour during and 2 and 20 hours after the infusion. Statistical evaluation. For comparison of the incidence of post-T hypercalcemia in different groups, a Xz-test was used. For comparison of differences of group means, Student's t-test was used. RESULTS Post-T hypercalcemia developed in 29 (16.7%) of 174 long-term surviving recipients. The incidence of post-T hypercalcemia decreased insignificantly over the 11 years (Table I), was not correlated with the age or sex of the recipients, with the type of primary kidney disease or with the duration of dialysis before R T (Table I). In 7 patients the hypercalcemia was permanent, that is terminated by subtotal parathyroidectomy (5 patients) or persisting (2 patients). In 4 patients normalization of S-Ca occurred concurrently with rejection episodes and increased prednisone doses. In 18 patients the hypercalcemia was transient and resolved spontaneously. The onset of hypercalcemia could not be established exactly in 4 patients. In 2 patients hypercalcemia was present at the time of RT, but aggravated considerably after RT. In the rest of the patients hypercalcemia was first detected 3-2 10 days (mean 69) after RT. There was no difference in the mean time of onset between the permanently and transiently hypercalcemic recipients. The mean duration of the transient hypercalcemia was 19 months (range 2-65). None of the tranAclti
Med Scund 201
siently hypercalcemic recipients had symptoms ascribable to hypercalcemia and no treatment was given. In 5 patients subtotal parathyroidectomy was performed after 4-45 months of the hypercalcemia. In one recipient a decreasing graft function and calculi in the graft developed simultaneously with severe hypercalcemia. Subtotal parathyroidectomy induced normalization of all abnormalities. In the other 4 patients subtotal parathyroidectomy was performed because of long-standing elevation of S-Ca at or above 11.5 mg/lOO ml. At operation the parathyroid glands showed chief cell hyperplasia, but in one case an adenoma was found within one of the hyperplastic glands. The weight of the excised 3 1 glands varied between 0.7 and 1.6 g. On X-rays none of the hypercalcernic recipients displayed bone lesions suggesting classical osteitis fibrosa. Aseptic necrosis or spontaneous fractures were found in 4 of 18 transiently and in 2 of 7 permanently hypercalcemic recipients. The incidence of these bone lesions was not higher than in the normocalcemic long-term survivors (22). Biochemical findings. The mean maximal S-Ca was 12.6 mgl100 ml in the permanently and 11.5 mg/ 100 ml in the transiently hypercalcemic patients @
H ypercalcemia and Parathyroid Function after Renal Transplantation Merete Sanvig Christensen, Hans Egon Nielsen and Susanne Tarring From First Medical University Clinic, Arhus Kommunehospital. and the Institute of Pharmacology, Arhus Universitet, Arhus, Denmark
ABSTRACT. Hypercalcemia after renal transplantation (post-T hypercalcemia) has been detected in 29 (16.7%) of 174 long-term survivors. The mean time of onset of hypercalcemia was 69 days after renal transplantation (range 3-210). In 18 patients the hypercalcemia was mild and resolved spontaneously (transient)from 2-65 months (mean 19) after onset. In 4 patients serum calcium normalized concurrently with rejection episodes. In 7 patients the hypercalcemia was more pronounced (permanent), being terminated by subtotal parathyroidectomy in 5 and persisting in 2 recipients. The hypercalcemia was asymptomatic except in one patient, who developed calculi in the graft and a fall in graft function, all of which disappeared after parathyroidectomy. At operation the parathyroid glands showed hyperplasia, except in one case with an adenoma in one of the hyperplastic glands. Serum phosphorus was markedly decreased, to the same extent in transiently and permanently hypercalcemic recipients. Serum parathyroid hormone (S-PTH) was increased in all of 5 patients with permanent and in 3 of 8 with transient post-T hypercalcemia. In normocalcemic and in transiently hypercalcemic recipients the mean S-PTH was identical, but significantly lower than in the permanently hypercalcemic recipients. S-PTH was suppressed to the same extent during an i.v. calcium infusion in patients with post-T hypercalcemia and with primary hyperparathyroidism. The occurrence of hypercalcemia after successful renal transplantation (RT) was first reported in 1964 (20), and has since been described by several authors (2, 6, 10, 14, 17, 19, 24). The reported incidence of hypercalcemia in kidney recipients has varied considerably and different opinions as to the clinical significance and the need for subtotal parathyroidectomy have been presented. We have
therefore performed an analysis of the incidence and clinical course of hypercalcemia among the patients who received renal allografts in this hospital. PATIENTS AND METHODS During the years 1964-74, 291 patients (aged ! L 6 5 years) received kidney allografts and 174 were alive with a creatinine concentration in serum at or below 2 mg/lOO ml 6 months after RT. The incidence of post-transplantation (post-T) hypercalcemia among the 174 long-term survivors is reported here. Immunosuppressive therapy was carried out with azathioprine and prednisone, with minor changes in dosage schedule over the years. Two months after RT the daily dose of prednisone was normally about 30 mg. Antacid therapy with aluminum hydroxide gel in moderate doses was given during the period when prednisone exceeded 40 mg/day, i.e. for about 4-5 weeks. Serum concentrations of calcium, phosphorus and alkaline phosphatase were measured at weekly intervals for the first 4-8 weeks after R T and later at intervals of 2-3 months. Normal range for serum calcium (S-Ca) is 9.010.8 mg/IOO mi, for serum phosphorus 2.74.7 mg/lOO ml and for alkaline phosphatase 8CL220 U/I. Hypercalcemia is here defined as serum calcium concentration above 10.8 mg/lOO ml and hypophosphatemia as serum concentration of phosphorus below 2.7 mg/IOO mi in two consecutive blood samples. The serum concentration of parathyroid hormone (S-PTH) was measured by a radioimmunoassay after extraction of the hormone from serum by adsorption to and elution from a microfine precipitated silica (Quso G 32), providing a hormone concentration 3.2 times higher in extract than in serum ( 5 ) . The antibody used was anti-bovine PTH AS 21 1/32. Bovine PTH was used for 'ZSI-labeling. The coefficient of variation in per cent was 6 for measurements above and 16 for measurements within the normal range (30-105 pglml bovine equivalents. MRC bPTH standard 71/324). The sensitivity of the assay was 10 pg bPTH present in the incubation mixture. Calcium infusion with simultaneous measurement of S-PTH was performed in 3 patients with permanent
36
M . S . Christensen et al.
Table I. Yearly incidence of hypercalcemia after renal transplantation and mean duration of dialysis Recipients
At
1964-67 1968 1969 1970 1971 1972 1973 1974 1%4-74
risk
21 23 23 31 25 19 21 11
174
Mean duration of dialysis
With
for all 174
hypercalcemia
recipients
7 (33.3%) 3 (13.0%) 3 (13.0%) 4 (7.8%) 4 (16.0%) 6 (3 1.6%) 2 (9.5%) 0 (0.070) 29(16.7%)
3.3 4.0 5.3 5.9 6.0 7.0 9.0 8.2 5.8
(mo.1
post-T hypercalcemia and in 3 patients with primary hyperparathyroidism with comparable serum values of calcium and PTH. I.v. infusion of 12 mg calcium/kg b.wt. (as calcium laevulate) was given between 9 and 12 a.m. Blood samples were taken before, each hour during and 2 and 20 hours after the infusion. Statistical evaluation. For comparison of the incidence of post-T hypercalcemia in different groups, a Xz-test was used. For comparison of differences of group means, Student's t-test was used. RESULTS Post-T hypercalcemia developed in 29 (16.7%) of 174 long-term surviving recipients. The incidence of post-T hypercalcemia decreased insignificantly over the 11 years (Table I), was not correlated with the age or sex of the recipients, with the type of primary kidney disease or with the duration of dialysis before R T (Table I). In 7 patients the hypercalcemia was permanent, that is terminated by subtotal parathyroidectomy (5 patients) or persisting (2 patients). In 4 patients normalization of S-Ca occurred concurrently with rejection episodes and increased prednisone doses. In 18 patients the hypercalcemia was transient and resolved spontaneously. The onset of hypercalcemia could not be established exactly in 4 patients. In 2 patients hypercalcemia was present at the time of RT, but aggravated considerably after RT. In the rest of the patients hypercalcemia was first detected 3-2 10 days (mean 69) after RT. There was no difference in the mean time of onset between the permanently and transiently hypercalcemic recipients. The mean duration of the transient hypercalcemia was 19 months (range 2-65). None of the tranAclti
Med Scund 201
siently hypercalcemic recipients had symptoms ascribable to hypercalcemia and no treatment was given. In 5 patients subtotal parathyroidectomy was performed after 4-45 months of the hypercalcemia. In one recipient a decreasing graft function and calculi in the graft developed simultaneously with severe hypercalcemia. Subtotal parathyroidectomy induced normalization of all abnormalities. In the other 4 patients subtotal parathyroidectomy was performed because of long-standing elevation of S-Ca at or above 11.5 mg/lOO ml. At operation the parathyroid glands showed chief cell hyperplasia, but in one case an adenoma was found within one of the hyperplastic glands. The weight of the excised 3 1 glands varied between 0.7 and 1.6 g. On X-rays none of the hypercalcernic recipients displayed bone lesions suggesting classical osteitis fibrosa. Aseptic necrosis or spontaneous fractures were found in 4 of 18 transiently and in 2 of 7 permanently hypercalcemic recipients. The incidence of these bone lesions was not higher than in the normocalcemic long-term survivors (22). Biochemical findings. The mean maximal S-Ca was 12.6 mgl100 ml in the permanently and 11.5 mg/ 100 ml in the transiently hypercalcemic patients @
