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Hypercalcemia in renal transplant patients with tuberculosis
Hypercalcemia in Renal Transplant Patients With Tuberculosis W.C. Yang, I.T. Chang, and B.L. Tsai
H
YPERCALCEMIA is frequently seen in the early posttransplant period. The incidence is 9% to 33%. It is generally regarded as benign and transient, but may be prolonged in about 50% of these patients, depending on the degree of secondary hyperparathyroidism before transplantation.1 A persistent hypercalcemia is usually due to sustained tertiary hyperparathyroidism. However, hypercalcemia occurring after more than 2 years posttransplant should raise the suspicion of an underlying malignant lesion or granulomatous disease. We present such a case.
sputum smear and culture for TB being negative on two occasions; and an increase of serum 1,25(OH)2D3 120 pg/mL (normal value, 16.4 ⫾ 15.8 pg/mL), a decrease in intact parathyroid hormone (PTH) 13.21 pg/mL (normal value, ⬍35.3 pg/mL), and a normal value of 25(OH)D3 23.31 ng/mL (normal value, 25.7 ⫾ 15.8 ng/mL). He was then successfully treated with 300 mg/d isoniazid, 450 mg/d rifampin, 800 mg/36 hours of ethambutol, 500 mg/48 hours of pyrazinamide, and 280 mg/d ganciclovir. While the pulmonary TB lesion resolved, renal graft function improved. Hypercalcemia and the associated increase of serum 1,25 (OH)2D3 and decrease of intact PTH gradually returned to normal values. The temporal and parallel profiles of renal function and hormonal parameters are shown in Fig 1.
CASE PRESENTATION A 32-year-old uremic patient with chronic glomerulonephritis received a renal transplant 7 years earlier. He had stable graft function with serum blood urea nitrogen (BUN) and creatinine (Cr) levels of around 43 and 1.9 mg/dL, respectively, in the ensuing 6 years. The maintenance immunosuppressive agents included 5 mg/d prednisolone, 50 mg/d azathioprine, and 200 mg/d Sandimmune Neoral. Over the previous year, he developed two episodes of grade II acute tubulointerstitial rejection. Focal mesangial proliferative glomerulonephritis with moderate IgA deposits and mild focal interstitial fibrosis, presumably due to IgA nephropathy, was also found on graft biopsy. There was no evidence of cyclosporine (CyA) vasculopathy. The second episode occurred 2 months prior to the current hospitalization, during which he required two courses of antithymocyte globulin 150 mg/d for 10 days because pulse methylprednisolone therapy failed. Preemptive ganciclovir 100 mg/d was given during antithymocyte globulin therapy. His serum Cr level increased and remained at 2.8 to 3.3 mg/dL. One month later, he manifested a high spiking fever, weight loss, nausea, and vomiting. The anti-cytomegalovirus (CMV) IgG and IgM assays were both positive. The C-reactive protein level was 17.3 mg/dL. BUN and serum Cr levels further rose to 60 to 115 mg/dL and 3.8 to 4.7 mg/dL, respectively. A chest film disclosed diffuse reticulonodular lesions on both lung fields, which were suspected to be CMV pneumonia. However, hypercalcemia with a serum total Ca level of 12.6 to 14.0 mg/dL and a free Ca2⫹ level of 7.7 to 7.9 mg/dL made the pulmonary changes highly suspicious of granulomatous lesions. The diagnosis of miliary pulmonary tuberculosis (TB) was then made based on the following examinations: a high-resolution computed tomographic (CT) scan of the chest further confirmed the changes of diffuse finely nodular lesions on both lung fields; a positive test for polymerase chain reaction (PCR) assay of mycobacteria from serum and transbronchoscopic brushings despite the
DISCUSSION
We have demonstrated that a renal transplant patient developed miliary pulmonary TB and hypercalcemia after antirejection therapy 7 years posttransplant. The mechanism of hypercalcemia in such a case is now known due to increased calcitriol production, resulting from increased macrophagic 1␣-hydroxylase activity in granulomatous lesions.2–7 The increased serum calcitriol level can enhance intestinal Ca reabsorption and bone reabsorption and then lead to hypercalcemia. However, hypercalcemia only occurs or is aggravated in the following settings: increased dietary Ca intake, exposure to ultraviolet light, and decrease in glomerular filtration rate. During the episode of miliary pulmonary TB the impaired renal function due to graft dysfunction in this case may exaggerate the severity of hypercalcemia. The resultant hypercalcemia then further jeopardizes the graft function. TB infection is not considered to be an important problem in transplant recipients. The incidence is about 2%, but it may be as high as 12% in endemic areas of TB infection.8 A literature review reported that disseminated infection may occur in fewer than 40% of patients.9 Thus, prophy-
From the Division of Nephrology, Department of Medicine, Veterans General Hospital-Taipei, and College of Medicine, National Yang-Ming University, Taipei, Taiwan, Republic of China. Address reprint requests to Wu-Chang Yang, MD, Division of Nephrology, Department of Medicine, Veterans General Hospital-Taipei, 201 Shih-Pai Rd, Section 2, Taipei, Taiwan 11217 ROC.
0041-1345/00/$–see front matter PII S0041-1345(00)01475-5
© 2000 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
1882
Transplantation Proceedings, 32, 1882–1883 (2000)
HYPERCALCEMIA IN RENAL TRANSPLANT PATIENTS
1883
lactic anti-TB therapy may be indicated in patients with a previous history of TB, regardless of whether or not treatment was required.10 The main hazard of TB infection in transplant patients is the potential induction of allograft rejection. This could be due to either a reduction of immunosuppressive agents for the fear of disseminated infection or to the drug interaction with anti-TB treatment, eg, reduction of CyA blood level resulting from induction by rifampin of liver P450 system. In conclusion, granulomatous lesions should be considered in the differential diagnosis of hypercalcemia occurring in patients with long-term renal transplants.
REFERENCES
Fig 1. Temporal changes in renal function, Ca, and Ca-regulating hormones in a renal transplant patient with hypercalcemia due to TB infection.
1. Gonzalez MT, Gonzalez C, Grino JM, et al: Transplant Proc 22:1407, 1990 2. Bell NH, Stern PH, Pantzer E, et al: J Clin Invest 64:218, 1979 3. Papapoulos SE, Fraher LJ, Sandler LM, et al: Lancet i:627, 1979 4. Adams JS, Sharma OP, Gacad MA, et al: J Clin Invest 72:1856, 1983 5. Gkonos PJ, London R, Hendler ED: N Engl J Med 311:1683, 1984 6. Barbour GL, Coburn JW, Slatopolsky E, et al: N Engl J Med 305:440, 1981 7. Reichel H, Koeffler HP, Norman AW: N Engl J Med 320:980, 1989 8. Malhotra KK, Dash SC, Dhawan IK, et al: Postgrad Med J 62:359, 1986 9. Quinibi WY, Al-Sibai MB, Taher S, et al: Q J Med 77:1039, 1990 10. Higgins RM, Cahn AP, Porter D, et al: Q J Med 78:145, 1991
H
YPERCALCEMIA is frequently seen in the early posttransplant period. The incidence is 9% to 33%. It is generally regarded as benign and transient, but may be prolonged in about 50% of these patients, depending on the degree of secondary hyperparathyroidism before transplantation.1 A persistent hypercalcemia is usually due to sustained tertiary hyperparathyroidism. However, hypercalcemia occurring after more than 2 years posttransplant should raise the suspicion of an underlying malignant lesion or granulomatous disease. We present such a case.
sputum smear and culture for TB being negative on two occasions; and an increase of serum 1,25(OH)2D3 120 pg/mL (normal value, 16.4 ⫾ 15.8 pg/mL), a decrease in intact parathyroid hormone (PTH) 13.21 pg/mL (normal value, ⬍35.3 pg/mL), and a normal value of 25(OH)D3 23.31 ng/mL (normal value, 25.7 ⫾ 15.8 ng/mL). He was then successfully treated with 300 mg/d isoniazid, 450 mg/d rifampin, 800 mg/36 hours of ethambutol, 500 mg/48 hours of pyrazinamide, and 280 mg/d ganciclovir. While the pulmonary TB lesion resolved, renal graft function improved. Hypercalcemia and the associated increase of serum 1,25 (OH)2D3 and decrease of intact PTH gradually returned to normal values. The temporal and parallel profiles of renal function and hormonal parameters are shown in Fig 1.
CASE PRESENTATION A 32-year-old uremic patient with chronic glomerulonephritis received a renal transplant 7 years earlier. He had stable graft function with serum blood urea nitrogen (BUN) and creatinine (Cr) levels of around 43 and 1.9 mg/dL, respectively, in the ensuing 6 years. The maintenance immunosuppressive agents included 5 mg/d prednisolone, 50 mg/d azathioprine, and 200 mg/d Sandimmune Neoral. Over the previous year, he developed two episodes of grade II acute tubulointerstitial rejection. Focal mesangial proliferative glomerulonephritis with moderate IgA deposits and mild focal interstitial fibrosis, presumably due to IgA nephropathy, was also found on graft biopsy. There was no evidence of cyclosporine (CyA) vasculopathy. The second episode occurred 2 months prior to the current hospitalization, during which he required two courses of antithymocyte globulin 150 mg/d for 10 days because pulse methylprednisolone therapy failed. Preemptive ganciclovir 100 mg/d was given during antithymocyte globulin therapy. His serum Cr level increased and remained at 2.8 to 3.3 mg/dL. One month later, he manifested a high spiking fever, weight loss, nausea, and vomiting. The anti-cytomegalovirus (CMV) IgG and IgM assays were both positive. The C-reactive protein level was 17.3 mg/dL. BUN and serum Cr levels further rose to 60 to 115 mg/dL and 3.8 to 4.7 mg/dL, respectively. A chest film disclosed diffuse reticulonodular lesions on both lung fields, which were suspected to be CMV pneumonia. However, hypercalcemia with a serum total Ca level of 12.6 to 14.0 mg/dL and a free Ca2⫹ level of 7.7 to 7.9 mg/dL made the pulmonary changes highly suspicious of granulomatous lesions. The diagnosis of miliary pulmonary tuberculosis (TB) was then made based on the following examinations: a high-resolution computed tomographic (CT) scan of the chest further confirmed the changes of diffuse finely nodular lesions on both lung fields; a positive test for polymerase chain reaction (PCR) assay of mycobacteria from serum and transbronchoscopic brushings despite the
DISCUSSION
We have demonstrated that a renal transplant patient developed miliary pulmonary TB and hypercalcemia after antirejection therapy 7 years posttransplant. The mechanism of hypercalcemia in such a case is now known due to increased calcitriol production, resulting from increased macrophagic 1␣-hydroxylase activity in granulomatous lesions.2–7 The increased serum calcitriol level can enhance intestinal Ca reabsorption and bone reabsorption and then lead to hypercalcemia. However, hypercalcemia only occurs or is aggravated in the following settings: increased dietary Ca intake, exposure to ultraviolet light, and decrease in glomerular filtration rate. During the episode of miliary pulmonary TB the impaired renal function due to graft dysfunction in this case may exaggerate the severity of hypercalcemia. The resultant hypercalcemia then further jeopardizes the graft function. TB infection is not considered to be an important problem in transplant recipients. The incidence is about 2%, but it may be as high as 12% in endemic areas of TB infection.8 A literature review reported that disseminated infection may occur in fewer than 40% of patients.9 Thus, prophy-
From the Division of Nephrology, Department of Medicine, Veterans General Hospital-Taipei, and College of Medicine, National Yang-Ming University, Taipei, Taiwan, Republic of China. Address reprint requests to Wu-Chang Yang, MD, Division of Nephrology, Department of Medicine, Veterans General Hospital-Taipei, 201 Shih-Pai Rd, Section 2, Taipei, Taiwan 11217 ROC.
0041-1345/00/$–see front matter PII S0041-1345(00)01475-5
© 2000 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
1882
Transplantation Proceedings, 32, 1882–1883 (2000)
HYPERCALCEMIA IN RENAL TRANSPLANT PATIENTS
1883
lactic anti-TB therapy may be indicated in patients with a previous history of TB, regardless of whether or not treatment was required.10 The main hazard of TB infection in transplant patients is the potential induction of allograft rejection. This could be due to either a reduction of immunosuppressive agents for the fear of disseminated infection or to the drug interaction with anti-TB treatment, eg, reduction of CyA blood level resulting from induction by rifampin of liver P450 system. In conclusion, granulomatous lesions should be considered in the differential diagnosis of hypercalcemia occurring in patients with long-term renal transplants.
REFERENCES
Fig 1. Temporal changes in renal function, Ca, and Ca-regulating hormones in a renal transplant patient with hypercalcemia due to TB infection.
1. Gonzalez MT, Gonzalez C, Grino JM, et al: Transplant Proc 22:1407, 1990 2. Bell NH, Stern PH, Pantzer E, et al: J Clin Invest 64:218, 1979 3. Papapoulos SE, Fraher LJ, Sandler LM, et al: Lancet i:627, 1979 4. Adams JS, Sharma OP, Gacad MA, et al: J Clin Invest 72:1856, 1983 5. Gkonos PJ, London R, Hendler ED: N Engl J Med 311:1683, 1984 6. Barbour GL, Coburn JW, Slatopolsky E, et al: N Engl J Med 305:440, 1981 7. Reichel H, Koeffler HP, Norman AW: N Engl J Med 320:980, 1989 8. Malhotra KK, Dash SC, Dhawan IK, et al: Postgrad Med J 62:359, 1986 9. Quinibi WY, Al-Sibai MB, Taher S, et al: Q J Med 77:1039, 1990 10. Higgins RM, Cahn AP, Porter D, et al: Q J Med 78:145, 1991