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1,25-Dihydroxyvitamin D-Mediated Hypercalcemia in a Renal Transplant Recipient
Case Report 1,25-Dihydroxyvitamin D-Mediated Hypercalcemia in a Renal Transplant Recipient MURALlKRISHNA
S. GOLCONDA, M.D.,* TIMOTHY S. LARSON, M.D., LISA
G. KOLB,
M.D.,t
AND RAJIV KUMAR, M.B.,B.S.
Hypercalcemia occurs in 10 to 30% of renal transplant recipients and is most often due to persistent hyperparathyroidism. Herein we describe a patient with a history of hyperparathyroidism who sought medical assessment because of recurrence of hypercalcemia 7 years after a successful renal transplantation. The hypercalcemia was associated with a normal serum phosphate level, a low to normal parathyroid hormone level, virtually undetectable levels of parathyroid hormone-related protein, and increased 1,25dihydroxyvitamin D levels. Further assessment led to
the diagnosis of an underlying lymphoma. To our knowledge, this is the first report of 1,25-dihydroxyvitamin D-mediated hypercalcemia in a renal transplant recipient with lymphoma. The possibility of an underlying Iymphoproliferative disorder should be considered in the differential diagnosis of hypercalcemia in a renal transplant recipient. (Mayo Clin Proc 1996; 71:32-36)
= computed tomography; PTH = parathyroid hormone; PTHrP =parathyroid hormone-related peptide
CT
Hypercalcemia after renal transplantation was first described 3 decades ago. I During the first year after successful renal transplantation, up to a third of patients will have hypercalcemia due to persistent hyperparathyroidism." Posttransplantation hypercalcemia due to hyperparathyroidism should be distinguished from hypercalcemia due to other causes, including vitamin D intoxication attributable to use of vitamin D analogues,' hypophosphatemia as a result of continued ingestion of phosphate binders;' granulomatous diseases associated with increased 1,25-dihydroxyvitamin D production.t" and malignant lesions. Malignancy-associated hypercalcemia can be classified into three major categories: hypercalcemia due to osteolytic metastatic disease; humoral hypercalcemia associated with malignant lesions, which is often mediated by parathyroid hormone-related peptide (PTHrP); and hypercalcemia caused by dysregulated production of 1,25-dihydroxyvitamin D. Almost all patients with Hodgkin's disease and most patients with non-Hodgkin's lymphoma complicated
by hypercalcemia have increased 1,25-dihydroxyvitamin D levels.' A few cases of hypercalcemia have been reported in patients with non-Hodgkin's lymphoma associated with increased levels of PTHrp. 7 In this report, we describe a patient in whom, 7 years after a successful cadaveric renal transplantation, hypercalcemia developed due to increased plasma 1,25-dihydroxyvitamin D concentrations associated with an underlying lymphoma.
REPORT OF CASE A 61-year-old woman who had received a cadaveric renal transplant in May 1986 was admitted to the Mayo Medical Center in January 1993 because of a l-month history of anorexia and increasing fatigue and a 2-week history of nausea, vomiting, and diarrhea. Primary hyperparathyroidism had been diagnosed in 1963 after the patient had had a trochanteric fracture of the right femur. Laboratory studies elsewhere had revealed hypercalcemia (total serum calcium, 15.7 mg/dL) and impaired renal function (blood urea nitrogen, 44 mg/dL). Further examination at that time had disclosed nephrocalcinosis in a solitary kidney. Exploration of the neck had revealed an adenoma in the right inferior parathyroid gland; after the adenoma was excised, serum calcium concentrations returned to normal. The patient's renal function gradually deteriorated, and in 1985, she initially received continuous ambulatory perito-
From the Division of Nephrology and Internal Medicine, Mayo Clinic Rochester, Rochester, Minnesota. *Current address: Portland, Oregon. tCurrent address: Internal Medicine Consultants, Jefferson City, Missouri. This study was supported in part by Grants DK 25409 and DK 42971 from the National Institutes of Health, Public Health Service. Address reprint requests to Dr. T. S. Larson, Division of Nephrology, Mayo Clinic Rochester, 200 First Street SW, Rochester, MN 55905.
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© 1996 Mayo Foundation/or Medical Education and Research
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
Mayo Clin Proc, January 1996, Vol 71
neal dialysis and subsequently received maintenance hemodialysis therapy. In May 1986, she received a cadaveric renal transplant (one HLA-DR mismatch) at another institution. Neither the recipient nor the donor had undergone Epstein-Barr virus serologic testing before transplantation. Maintenance immunosuppressive therapy consisted of prednisone (12 mg/day), cyclosporine (350 mg/ day), and azathioprine (100 mg/day). She experienced no rejection episodes and received no monoclonal or polyclonal antilymphocyte preparations at any time. Graft function was excellent, and her posttransplantation course was remarkable only for hypercalcemia, which was first noted in December 1986, 7 months after transplantation. The hypercalcemia was attributed to persistent hyperparathyroidism; in October 1988, she underwent parathyroidectomy, and two identifiable hyperplastic parathyroid glands were excised. An examination revealed glandular hyperplasia with histologic features suggestive of an adenoma in one of the parathyroid glands. Serum calcium levels returned to normal postoperatively and remained normal during subsequent follow-up until a few days before the current admission when the serum calcium level was noted to be increased (11.2 mg/dL). Physical examination of the patient at our institution in January 1993 revealed that she was lethargic and had dry mucous membranes and diminished skin turgor. No lymphadenopathy was evident. An abdominal examination was remarkable only for a nontender renal allograft. Initial laboratory studies revealed severe hypercalcemia (total calcium, 18.4 mg/dL; albumin, 2.9 g/dL; and ionized calcium, 8.8 mg/dL), normophosphatemia (4.1 mg/dL), and impaired renal function (urea, 125 mg/dL; creatinine, 1.6 mg/dL). Roentgenographic studies of the chest and abdomen were nondiagnostic. Saline was administered to treat the hypercalcemia. During a 3-day period, the serum calcium concentration decreased to 10.4 mg/dL, and the serum creatinine decreased to 1.1 mg/dL. The patient was ingesting no medications that could cause the hypercalcemia. Serum immunoelectrophoresis revealed a small monoclonal IgG K protein, but no monoclonal protein was detected on urine immunoelectrophoresis. Bone marrow aspirate and biopsy disclosed slightly increased plasma cells, and immunohistochemical studies showed polyclonal staining for K and Iv light chains. The trabeculae were normal, and the number of osteoclasts was not increased. A skeletal survey and a bone scan showed no evidence of skeletal metastatic disease. No localized solid tumor masses were evident on computed tomography (CT) of the abdomen, pelvis, and chest nor on high-resolution CT of the head. No parathyroid adenomas were detected on ultrasound examination of the neck. On two occasions, plasma intact parathyroid hormone (PTH) levels were measured with the immunochemiluminometric
HYPERCALCEMIA IN A RENAL TRANSPLANT RECIPIENT
33
assay;" results were 1.0 and 0.1 pmol/L, respectively (normal, 1 to 5). On both occasions, the concomitantly measured serum calcium level was increased (15 and 12.8 mg/dL, respectively). On the second occasion, 1,25-dihydroxyvitamin D and 25-hydroxyvitamin D levels were also measured. The 1,25-dihydroxyvitamin D concentration was increased (110 pg/mL; normal, 15 to 60) in the presence of a normal level of 25-hydroxyvitamin D (21 ng/mL; normal, 14 to 42). The concentration of PTHrP measured by a radioimmunoassay? was less than 2 pmol/L (normal, 2 to 5). The angiotensin-converting enzyme level was normal. CT of the abdomen and pelvis revealed ascites and extensive thrombosis in the right common femoral vein. CT of the chest showed the presence of pulmonary emboli in both the main and the lower lobe pulmonary arteries. Anticoagulant therapy with heparin was commenced. Abdominal paracentesis yielded straw-colored fluid, which had the biochemical characteristics of an exudate. Microscopy revealed the presence of large atypical cells that were subsequently identified as malignant lymphoma cells. Molecular genetic studies disclosed the presence ofT-cell receptor gene rearrangements. After the diagnosis of lymphoma was confirmed, use of cyclosporine and azathioprine was discontinued, and the dosage of prednisone was increased. The patient's hospital course was complicated by cytomegalovirus viremia, leukopenia, Staphylococcus aureus and Escherichia coli bacteremia with septic shock, upper gastrointestinal bleeding due to esophageal and gastric erosions, and progressive obtundation. She died 1 month after admission. Permission for a postmortem examination was denied. DISCUSSION Since the first reported case of hypercalcemia after transplantation in 1964,1 various series have reported a prevalence that varies between 8.5% and 71%.10,11 In a series of95 renal transplant recipients in whom total calcium and ionized calcium levels were measured, the prevalence of hypercalcemia was 10,5% and 49.5%, respectively.'? Posttransplantation hypercalcemia usually manifests in one of three variants: transient hypercalcemia, the most common type, which generally resolves within 1 year; subacute hypercalcemia, which usually manifests within 3 months and may cause allograft dysfunction and calciphylaxis; and persistent mild hypercalcemia, which gradually resolves within 2 to 5 years.' Persistent hyperparathyroidism is the most common cause of posttransplantation hypercalcemia, and its frequency has been correlated with the duration of dialysis therapy before transplantation. 12 Other causes of hypercalcemia after renal transplantation include mobilization of calcium from soft tissue calcium-phosphate deposits,
For personal use, Mass reproduce only with permission from Mayo Clinic Proceedings,
34
HYPERCALCEMIA IN A RENAL TR ANSPLANT RECIPIENT
vitamin 0 intoxication, and phosphate depletion due to continued inge stion of dietary pho sphate binders and increased renal pho sphate clearance (Table 1). In the renal transplant recipient, hypophosphatemia may unmask the persistent secondary hyperparathyroidism that is pre sent at the time of transplantation.P Granulomatous diseases associated with increased 1,25-dihydroxyvitamin 0 production and malignant lesions are additional diagnoses that should be considered. "? Measuring serum pho sphate, PTH, PTHrP, 25hydroxyvitamin D, and 1,25-dihydroxyvitamin D levels can help to identify these diverse causes of hypercalcemia. Malignancy-associated hypercalcemia can be classified into three categories: local osteolytic hypercalcemia, which is caused by bone resorption by activated osteoclasts in the vicinity of metastatic deposits in the bones; humoral hypercalcemia associated with malignant lesions, which is usuall y mediated by PTHrP; and 1,25-dihydroxyvitam in Dmedi ated hypercalcemia. Local osteolytic hypercalcemia is typically noted in the setting of solid tumors, such as carci noma of the lung and breast met astatic to the bone , and with multiple myeloma. Humoral hypercalcemia associated with malign ant disease occurs in the setting of epidermoid carcinom a, renal cell carcinoma, and carcinoma of the breast in the absence of pronounced bon y metastatic involvement, and it is mediated by increased level s of PTH rP , which act systemically to increase osteoclastic bone resorption and tubular reabsorption of calcium. 1,25-D ihydroxyvitamin D-mediated hypercalcemia is the most frequent cause of hypercalcemia in patients with Hodgkin's disease and nonHodgkin's lymphoma. In a recent report, 55% of patients with hypercalcemia and non-Hodgkin's lymphoma had increased 1,25-dihydroxyvitamin 0 levels." Hypercalcemia results from enhanced inte stinal calcium absorption and osteoclastic bone resorption and seems to be related to dy sregulated extrarenal production of 1,25-dihydroxyvitamin D. Whether the lymphoma cells or the infiltrating host monocytes and macrophages are the primary source is unclear. Indeed, macrophages are known to have substantial l o-hydroxylase activity, and strong evidence impli cates them as the source of 1,25-dihydroxyvitamin D in the hypercalcemia that complicates granulomatous disease such as sarcoidosis and tuberculosis." Th ese three categories of malignancy -associated hypercalcemia can be distinguished from one another by their characteri stic biochemical profiles (Table 2). Our patient had a remote history of primary hyperparathyroidism and had undergone excision of a parathyroid adenoma, after which serum calcium levels had returned to normal. Seven months after she received a cadaveric renal transplant, hypercalcemia recurred, and she underwent excision of two identifiable hyperplastic parathyroid glands. Her serum calcium levels had remained normal
Mayo Clin Proc, January 1996, Vol 71
Table I.-Differential Diagnosis of Posttransplantation Hypercalcemia Early posttransplantation period Persistent hyperparathyroidism Vitamin D intoxication Resorptionof metastatic calcium-phosphate deposits Hypophosphatemia Malignantlesions Chronic granulomatous diseases Several years after transplantation Malignant disease Chronic granulomatous diseases
until ju st before her final admi ssion. Her biochemical profile was characterized by hypercalcemia associated with a normal serum pho sphate level , a low to normal PTH level , virtually undetectable PTHrP level s, and increased con centrations of 1,25-dihydroxyvitamin 0 in the presence of normal level s of 25-hydroxyvitamin D. The cau se of her hypercalcemia became evident after she underwent diagnostic abdominal paracentesis, which revealed the pre sence of malignant lymphoma cell s. Since an increased incidence of lymphomas in ren al tran splant recipients was first noted in 1969,14 evidence has continued to accumulate that org an transplantation and subsequent chronic immunosuppressive therapy are associated with an increased incidence of cert ain cancers. Anal ysi s of the Cincinnati tumor regi stry data has shown that various cancers that are uncommon in the general population occur often in transplant recipients. This increased incidence is particularly true in the case of lymphomas, which account for 21 % of cancers in transpl ant recipients ; 93 % of po sttran splantation lymphoma s are non-Hodgkin's lymphomas (in comparison with 65 % in the general population), and the vast majority are B-cell tumors. Tumors ofTcell origin account for 14%, and less than 1% are of null cell origin. IS The incidence of hypercalcemia in patients with lymphomas after tran splantation is unknown. Impaired immune surveillance, chronic antigenic stimulation from the allograft, Ep st ein-Barr virus-induced Iymphoproliferation, oncogenic effects of the immunosuppres sive agents, or a combination of these factors is thought to be responsible for the pathogenesis of posttransplantation lymphoproliferative disorders." An increased incidence of pos ttransplantation Iymphoproliferative disorders has been reported with the addition of cyclo sporine to conventional immunosuppressive protocols' ? and with use of potent antilymphocyte preparations. v" however, a high degree of overall immunosuppression with multiple powerful agents may be responsible for the pathogenesis of lymphopro/iferative disorders. IS
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HYPERCALCEMIA IN A RENAL TRANSPLANT RECIPIENT
Mayo Clin Proc, January 1996, Vol 71
35
Table 2.-Biochemical Factors That Are Helpful in the Differential Diagnosis of Malignancy-Associated Hypercalcemia *
Factors
Local osteolytic hypercalcemia
Humoral hypercalcemia
Calcitriolmediated hypercalcemia
Current case
Serum phosphatelevels PTH levels PTHrP levels Calcitriollevels
Normal Decreased Undetectable Decreased
Decreased Decreased Increased Decreased
Normal to increased Decreasedto normal Undetectable Increased
Normal Normal Undetectable Increased
*PTH = parathyroidhormone; PTHrP = parathyroidhormone-related peptide. Modifiedfrom Seymourand Gagel.' By permission.
Posttransplantation non-Hodgkin's lymphomas differ from those in the general population in several respects: extranodal involvement is more common, as is central nervous system involvement often in the absence of involvement of other organs, and involvement of the allograft itself by the lymphoproliferative process." The last-mentioned factor may manifest as allograft dysfunction and must be excluded histologically before treating presumed rejection. 19 Our patient sought medical assessment 7 years after cadaveric renal transplantation in which the posttransplantation course had been uneventful except for hypercalcemia due to persistent hyperparathyroidism, which had resolved after parathyroidectomy. Her immunosuppressive therapy consisted of prednisone, cyclosporine, and azathioprine, but she received no antilymphocyte preparations. The posttransplantation lymphoproliferative disorder was diagnosed after lymphoma cells were detected in the abdominal paracentesis fluid. Imaging studies revealed no evidence of lymphoma in the abdomen, chest, or brain. A biopsy of the renal allograft was not performed because she had no evidence of persistent allograft dysfunction. Possibly, a postmortem examination may have revealed small foci of lymphoma in the abdomen, beyond the resolution of the CT scan. Initial management of posttransplantation lymphoproliferative disorders has been to decrease or discontinue use of immunosuppressive therapy. In patients who experience no response, additional therapeutic measures may be indicated, ranging from local irradiation or surgical excision (or both) for patients with localized disease to combination chemotherapy for patients with extensive disease. Response to therapy, however, is less common in transplant recipients than in immunocompetent hosts." In patients with extensive disease, antiviral therapy with acyclovir-'-" has been successful, especially in patients with polyclonal B-cell proliferation. Ganciclovir," interferon alfa and intravenous immunoglobulin therapy," and anti-B-cell monoclonal antibodies" have also been used to treat patients with posttransplantation lymphoproliferative disorders.
CONCLUSION To our knowledge, this is the first report of 1,25dihydroxyvitamin D-mediated hypercalcemia in a renal transplant recipient with malignant lymphoma. The possibility of an underlying lymphoproliferative disorder should be considered in the differential diagnosis of hypercalcemia in a renal transplant recipient.
REFERENCES 1. McPhaul JJ, McIntosh DA, Hammond WS, Park OK. Autonomous secondary(renal) parathyroidhyperplasia. N Engl J Med 1964; 271:1342-1345 2. Julian BA, Quarles LD, Niemann KM. Musculoskeletal complications after renal transplantation: pathogenesis and treatment. Am J Kidney Dis 1992; 19:99-120 3. Alfrey AC, Jenkins D, Groth CG, Schorr WS, Gecelter L, Ogden DA. Resolution of hyperparathyroidism, renal osteodystrophy and metastatic calcification after renal homotransplantation. N Engl J Med 1968; 279:13491356 4. BarbourGL, CoburnJW, Slatopolsky E, NormanAW, Horst RL. Hypercalcemia in an anephric patient with sarcoidosis: evidencefor extrarenal generationof 1,25-dihydroxyvitamin D. N Engl J Med 1981; 305:440-443 5. Gkonos PJ, London R, Hendler ED. Hypercalcemia and elevated 1,25-dihydroxyvitamin D levels in a patient with end-stage renal disease and active tuberculosis. N Engl J Med 1984;311:1683-1685 6. KantarjianHM, Saad MF, Estey EH, Sellin RV, SamaanNA. Hypercalcemia in disseminated candidiasis. Am J Med 1983; 74:721-724 7. SeymourJF, GagelRF. Calcitriol: the majorhumoralmediator of hypercalcemia in Hodgkin's disease and nonHodgkin's lymphomas. Blood 1993; 82:1383-1394 8. Klee GG, Preissner CM, Schryver PG, Taylor RL, Kao PC. Multisite immunochemiluminometric assay for simultaneously measuring whole-molecule and amino-terminal fragments of human parathyrin. Clin Chern 1992; 38:628635 9. Kao PC, Klee GG, Taylor RL, Heath H III. Parathyroid hormone-related peptide in plasma of patients with
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10.
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14. 15. 16. 17.
18.
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hypercalcemia and malignant lesions. Mayo Clin Proc 1990; 65:1399-1407 Pletka PG, Strom TB, Hampers CL, Griffiths H, Wilson RE, Bernstein DS, et al. Secondary hyperparathyroidism in human kidney transplant recipients. Nephron 1976; 17:371381 McIntosh DA, Peterson EW, McPhaul JJ Jf. Autonomy of parathyroid function after renal homotransplantation. Ann Intern Med 1966; 65:900-907 Conceicao SC, Wilkinson R, Feest TG, Owen JP, Dewar J, Kerr DN. Hypercalcemia following renal transplantation: causes and consequences. Clin Nephrol 1981; 16:235244 Seymour JF, Gagel RF, Hagemeister FB, Dimopoulos MA, Cabanillas F. Calcitriol production in hypercalcemic and norrnocalcemic patients with non-Hodgkin lymphoma. Ann Intern Med 1994; 121:633-640 Penn I, Hammond W, Brettschneider L, Starzl TE. Malignant lymphomas in transplantation patients. Transplant Proc 1969; 1:106-112 Penn I. Cancers complicating organ transplantation [editorial]. N Engl J Med 1990; 323:1767-1769 Hanto DW, Frizzera G, Gajl-Peczalska KJ, Simmons RL. Epstein-Barr virus, immunodeficiency, and B cell Iymphoproliferation. Transplantation 1985; 39:461-472 Wilkinson AH, Smith JL, Hunsicker LG, Tobacman J, Kapelanski DP, Johnson M, et al. Increased frequency of posttransplant lymphomas in patients treated with cyclosporine, azathioprine, and prednisone. Transplantation 1989; 47:293-296 Swinnen LJ, Constanzo-Nordin MR, Fisher SG, O'Sullivan EJ, Johnson MR, Heroux AL, et al. Increased incidence of
19.
20. 21. 22.
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lymphoproliferative disorder after immunosuppression with the monoclonal antibody OKT3 in cardiac-transplant recipients. N Engl J Med 1990; 323:1723-1728 Cockfield SM, Preiksaitis JK, Jewell LD, Parfrey NA. Posttransplant Iymphoproliferative disorder in renal allograft recipients: clinical experience and risk factor analysis in a single center. Transplantation 1993; 56:88-96 Opelz G, Henderson R. Incidence of non-Hodgkin lymphoma in kidney and heart transplant recipients. Lancet 1993; 342:1514-1516 Morrison VA, Dunn DL, Manivel JC, Gajl-Peczalska KJ, Peterson BA. Clinical characteristics of post-transplant Iymphoproliferative disorders. Am J Med 1994; 97:14-24 Hanto DW, Frizzera G, Gajl-Peczalska KJ, Sakamoto K, Purtilo DT, Balfour HH Jr, et al. Epstein-Barr virus-induced B-cell lymphoma after renal transplantation: acyclovir therapy and transition from polyclonal to monoclonal B-cell proliferation. N Engl J Med 1982; 306:913-918 Pirsch JD, Stratta RJ, Sollinger HW, Hafez GR, D' Alessandro AM, Kalayoglu M, et al. Treatment of severe Epstein-Barr virus-induced Iymphoproliferative syndrome with ganciclovir: two cases after solid organ transplantation. Am J Med 1989; 86:241-244 Shapiro RS, Chauvenet A, McGuire W, Pearson A, Craft AW, McGlave P, et al. Treatment of B-cell Iymphoproliferative disorders with interferon alfa and intravenous gamma globulin [letter]. N Engl J Med 1988; 318:1334 Fischer A, Blanche S, Le Bidois J, Bordigoni P, Gamier JL, Niaudet P, et al. Anti-B-cell monoclonal antibodies in the treatment of severe B-celllymphoproliferative syndrome following bone marrow and organ transplantation. N Engl J Med 1991; 324:1451-1456
TEXT BITESFROMOTHER JOURNALS Infective endocarditis in intravenous drug users affects the right and left sides of the heart with approximately equal frequency. At present, more than 90% of cases of infective endocarditis in intravenous drug users in Chicago are caused by staphylococci or streptococci.
-Arch Intern Med 1995; I55:1641-I648 Dental erosion is a common finding in patients with gastroesophageal reflux disease and should be considered an atypical manifestation of this disease.
-Ann Intern Med I995; 122:809-815 The association between brain tumors and multiple colorectal adenomas [Turcot's syndrome] can result from two distinct types of germ-line defects: mutation of the APe [adenomatous polyposis coli] gene or mutation of a mismatch-repair gene.
-N Engl J Med I995; 332:839-847
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
S. GOLCONDA, M.D.,* TIMOTHY S. LARSON, M.D., LISA
G. KOLB,
M.D.,t
AND RAJIV KUMAR, M.B.,B.S.
Hypercalcemia occurs in 10 to 30% of renal transplant recipients and is most often due to persistent hyperparathyroidism. Herein we describe a patient with a history of hyperparathyroidism who sought medical assessment because of recurrence of hypercalcemia 7 years after a successful renal transplantation. The hypercalcemia was associated with a normal serum phosphate level, a low to normal parathyroid hormone level, virtually undetectable levels of parathyroid hormone-related protein, and increased 1,25dihydroxyvitamin D levels. Further assessment led to
the diagnosis of an underlying lymphoma. To our knowledge, this is the first report of 1,25-dihydroxyvitamin D-mediated hypercalcemia in a renal transplant recipient with lymphoma. The possibility of an underlying Iymphoproliferative disorder should be considered in the differential diagnosis of hypercalcemia in a renal transplant recipient. (Mayo Clin Proc 1996; 71:32-36)
= computed tomography; PTH = parathyroid hormone; PTHrP =parathyroid hormone-related peptide
CT
Hypercalcemia after renal transplantation was first described 3 decades ago. I During the first year after successful renal transplantation, up to a third of patients will have hypercalcemia due to persistent hyperparathyroidism." Posttransplantation hypercalcemia due to hyperparathyroidism should be distinguished from hypercalcemia due to other causes, including vitamin D intoxication attributable to use of vitamin D analogues,' hypophosphatemia as a result of continued ingestion of phosphate binders;' granulomatous diseases associated with increased 1,25-dihydroxyvitamin D production.t" and malignant lesions. Malignancy-associated hypercalcemia can be classified into three major categories: hypercalcemia due to osteolytic metastatic disease; humoral hypercalcemia associated with malignant lesions, which is often mediated by parathyroid hormone-related peptide (PTHrP); and hypercalcemia caused by dysregulated production of 1,25-dihydroxyvitamin D. Almost all patients with Hodgkin's disease and most patients with non-Hodgkin's lymphoma complicated
by hypercalcemia have increased 1,25-dihydroxyvitamin D levels.' A few cases of hypercalcemia have been reported in patients with non-Hodgkin's lymphoma associated with increased levels of PTHrp. 7 In this report, we describe a patient in whom, 7 years after a successful cadaveric renal transplantation, hypercalcemia developed due to increased plasma 1,25-dihydroxyvitamin D concentrations associated with an underlying lymphoma.
REPORT OF CASE A 61-year-old woman who had received a cadaveric renal transplant in May 1986 was admitted to the Mayo Medical Center in January 1993 because of a l-month history of anorexia and increasing fatigue and a 2-week history of nausea, vomiting, and diarrhea. Primary hyperparathyroidism had been diagnosed in 1963 after the patient had had a trochanteric fracture of the right femur. Laboratory studies elsewhere had revealed hypercalcemia (total serum calcium, 15.7 mg/dL) and impaired renal function (blood urea nitrogen, 44 mg/dL). Further examination at that time had disclosed nephrocalcinosis in a solitary kidney. Exploration of the neck had revealed an adenoma in the right inferior parathyroid gland; after the adenoma was excised, serum calcium concentrations returned to normal. The patient's renal function gradually deteriorated, and in 1985, she initially received continuous ambulatory perito-
From the Division of Nephrology and Internal Medicine, Mayo Clinic Rochester, Rochester, Minnesota. *Current address: Portland, Oregon. tCurrent address: Internal Medicine Consultants, Jefferson City, Missouri. This study was supported in part by Grants DK 25409 and DK 42971 from the National Institutes of Health, Public Health Service. Address reprint requests to Dr. T. S. Larson, Division of Nephrology, Mayo Clinic Rochester, 200 First Street SW, Rochester, MN 55905.
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© 1996 Mayo Foundation/or Medical Education and Research
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
Mayo Clin Proc, January 1996, Vol 71
neal dialysis and subsequently received maintenance hemodialysis therapy. In May 1986, she received a cadaveric renal transplant (one HLA-DR mismatch) at another institution. Neither the recipient nor the donor had undergone Epstein-Barr virus serologic testing before transplantation. Maintenance immunosuppressive therapy consisted of prednisone (12 mg/day), cyclosporine (350 mg/ day), and azathioprine (100 mg/day). She experienced no rejection episodes and received no monoclonal or polyclonal antilymphocyte preparations at any time. Graft function was excellent, and her posttransplantation course was remarkable only for hypercalcemia, which was first noted in December 1986, 7 months after transplantation. The hypercalcemia was attributed to persistent hyperparathyroidism; in October 1988, she underwent parathyroidectomy, and two identifiable hyperplastic parathyroid glands were excised. An examination revealed glandular hyperplasia with histologic features suggestive of an adenoma in one of the parathyroid glands. Serum calcium levels returned to normal postoperatively and remained normal during subsequent follow-up until a few days before the current admission when the serum calcium level was noted to be increased (11.2 mg/dL). Physical examination of the patient at our institution in January 1993 revealed that she was lethargic and had dry mucous membranes and diminished skin turgor. No lymphadenopathy was evident. An abdominal examination was remarkable only for a nontender renal allograft. Initial laboratory studies revealed severe hypercalcemia (total calcium, 18.4 mg/dL; albumin, 2.9 g/dL; and ionized calcium, 8.8 mg/dL), normophosphatemia (4.1 mg/dL), and impaired renal function (urea, 125 mg/dL; creatinine, 1.6 mg/dL). Roentgenographic studies of the chest and abdomen were nondiagnostic. Saline was administered to treat the hypercalcemia. During a 3-day period, the serum calcium concentration decreased to 10.4 mg/dL, and the serum creatinine decreased to 1.1 mg/dL. The patient was ingesting no medications that could cause the hypercalcemia. Serum immunoelectrophoresis revealed a small monoclonal IgG K protein, but no monoclonal protein was detected on urine immunoelectrophoresis. Bone marrow aspirate and biopsy disclosed slightly increased plasma cells, and immunohistochemical studies showed polyclonal staining for K and Iv light chains. The trabeculae were normal, and the number of osteoclasts was not increased. A skeletal survey and a bone scan showed no evidence of skeletal metastatic disease. No localized solid tumor masses were evident on computed tomography (CT) of the abdomen, pelvis, and chest nor on high-resolution CT of the head. No parathyroid adenomas were detected on ultrasound examination of the neck. On two occasions, plasma intact parathyroid hormone (PTH) levels were measured with the immunochemiluminometric
HYPERCALCEMIA IN A RENAL TRANSPLANT RECIPIENT
33
assay;" results were 1.0 and 0.1 pmol/L, respectively (normal, 1 to 5). On both occasions, the concomitantly measured serum calcium level was increased (15 and 12.8 mg/dL, respectively). On the second occasion, 1,25-dihydroxyvitamin D and 25-hydroxyvitamin D levels were also measured. The 1,25-dihydroxyvitamin D concentration was increased (110 pg/mL; normal, 15 to 60) in the presence of a normal level of 25-hydroxyvitamin D (21 ng/mL; normal, 14 to 42). The concentration of PTHrP measured by a radioimmunoassay? was less than 2 pmol/L (normal, 2 to 5). The angiotensin-converting enzyme level was normal. CT of the abdomen and pelvis revealed ascites and extensive thrombosis in the right common femoral vein. CT of the chest showed the presence of pulmonary emboli in both the main and the lower lobe pulmonary arteries. Anticoagulant therapy with heparin was commenced. Abdominal paracentesis yielded straw-colored fluid, which had the biochemical characteristics of an exudate. Microscopy revealed the presence of large atypical cells that were subsequently identified as malignant lymphoma cells. Molecular genetic studies disclosed the presence ofT-cell receptor gene rearrangements. After the diagnosis of lymphoma was confirmed, use of cyclosporine and azathioprine was discontinued, and the dosage of prednisone was increased. The patient's hospital course was complicated by cytomegalovirus viremia, leukopenia, Staphylococcus aureus and Escherichia coli bacteremia with septic shock, upper gastrointestinal bleeding due to esophageal and gastric erosions, and progressive obtundation. She died 1 month after admission. Permission for a postmortem examination was denied. DISCUSSION Since the first reported case of hypercalcemia after transplantation in 1964,1 various series have reported a prevalence that varies between 8.5% and 71%.10,11 In a series of95 renal transplant recipients in whom total calcium and ionized calcium levels were measured, the prevalence of hypercalcemia was 10,5% and 49.5%, respectively.'? Posttransplantation hypercalcemia usually manifests in one of three variants: transient hypercalcemia, the most common type, which generally resolves within 1 year; subacute hypercalcemia, which usually manifests within 3 months and may cause allograft dysfunction and calciphylaxis; and persistent mild hypercalcemia, which gradually resolves within 2 to 5 years.' Persistent hyperparathyroidism is the most common cause of posttransplantation hypercalcemia, and its frequency has been correlated with the duration of dialysis therapy before transplantation. 12 Other causes of hypercalcemia after renal transplantation include mobilization of calcium from soft tissue calcium-phosphate deposits,
For personal use, Mass reproduce only with permission from Mayo Clinic Proceedings,
34
HYPERCALCEMIA IN A RENAL TR ANSPLANT RECIPIENT
vitamin 0 intoxication, and phosphate depletion due to continued inge stion of dietary pho sphate binders and increased renal pho sphate clearance (Table 1). In the renal transplant recipient, hypophosphatemia may unmask the persistent secondary hyperparathyroidism that is pre sent at the time of transplantation.P Granulomatous diseases associated with increased 1,25-dihydroxyvitamin 0 production and malignant lesions are additional diagnoses that should be considered. "? Measuring serum pho sphate, PTH, PTHrP, 25hydroxyvitamin D, and 1,25-dihydroxyvitamin D levels can help to identify these diverse causes of hypercalcemia. Malignancy-associated hypercalcemia can be classified into three categories: local osteolytic hypercalcemia, which is caused by bone resorption by activated osteoclasts in the vicinity of metastatic deposits in the bones; humoral hypercalcemia associated with malignant lesions, which is usuall y mediated by PTHrP; and 1,25-dihydroxyvitam in Dmedi ated hypercalcemia. Local osteolytic hypercalcemia is typically noted in the setting of solid tumors, such as carci noma of the lung and breast met astatic to the bone , and with multiple myeloma. Humoral hypercalcemia associated with malign ant disease occurs in the setting of epidermoid carcinom a, renal cell carcinoma, and carcinoma of the breast in the absence of pronounced bon y metastatic involvement, and it is mediated by increased level s of PTH rP , which act systemically to increase osteoclastic bone resorption and tubular reabsorption of calcium. 1,25-D ihydroxyvitamin D-mediated hypercalcemia is the most frequent cause of hypercalcemia in patients with Hodgkin's disease and nonHodgkin's lymphoma. In a recent report, 55% of patients with hypercalcemia and non-Hodgkin's lymphoma had increased 1,25-dihydroxyvitamin 0 levels." Hypercalcemia results from enhanced inte stinal calcium absorption and osteoclastic bone resorption and seems to be related to dy sregulated extrarenal production of 1,25-dihydroxyvitamin D. Whether the lymphoma cells or the infiltrating host monocytes and macrophages are the primary source is unclear. Indeed, macrophages are known to have substantial l o-hydroxylase activity, and strong evidence impli cates them as the source of 1,25-dihydroxyvitamin D in the hypercalcemia that complicates granulomatous disease such as sarcoidosis and tuberculosis." Th ese three categories of malignancy -associated hypercalcemia can be distinguished from one another by their characteri stic biochemical profiles (Table 2). Our patient had a remote history of primary hyperparathyroidism and had undergone excision of a parathyroid adenoma, after which serum calcium levels had returned to normal. Seven months after she received a cadaveric renal transplant, hypercalcemia recurred, and she underwent excision of two identifiable hyperplastic parathyroid glands. Her serum calcium levels had remained normal
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Table I.-Differential Diagnosis of Posttransplantation Hypercalcemia Early posttransplantation period Persistent hyperparathyroidism Vitamin D intoxication Resorptionof metastatic calcium-phosphate deposits Hypophosphatemia Malignantlesions Chronic granulomatous diseases Several years after transplantation Malignant disease Chronic granulomatous diseases
until ju st before her final admi ssion. Her biochemical profile was characterized by hypercalcemia associated with a normal serum pho sphate level , a low to normal PTH level , virtually undetectable PTHrP level s, and increased con centrations of 1,25-dihydroxyvitamin 0 in the presence of normal level s of 25-hydroxyvitamin D. The cau se of her hypercalcemia became evident after she underwent diagnostic abdominal paracentesis, which revealed the pre sence of malignant lymphoma cell s. Since an increased incidence of lymphomas in ren al tran splant recipients was first noted in 1969,14 evidence has continued to accumulate that org an transplantation and subsequent chronic immunosuppressive therapy are associated with an increased incidence of cert ain cancers. Anal ysi s of the Cincinnati tumor regi stry data has shown that various cancers that are uncommon in the general population occur often in transplant recipients. This increased incidence is particularly true in the case of lymphomas, which account for 21 % of cancers in transpl ant recipients ; 93 % of po sttran splantation lymphoma s are non-Hodgkin's lymphomas (in comparison with 65 % in the general population), and the vast majority are B-cell tumors. Tumors ofTcell origin account for 14%, and less than 1% are of null cell origin. IS The incidence of hypercalcemia in patients with lymphomas after tran splantation is unknown. Impaired immune surveillance, chronic antigenic stimulation from the allograft, Ep st ein-Barr virus-induced Iymphoproliferation, oncogenic effects of the immunosuppres sive agents, or a combination of these factors is thought to be responsible for the pathogenesis of posttransplantation lymphoproliferative disorders." An increased incidence of pos ttransplantation Iymphoproliferative disorders has been reported with the addition of cyclo sporine to conventional immunosuppressive protocols' ? and with use of potent antilymphocyte preparations. v" however, a high degree of overall immunosuppression with multiple powerful agents may be responsible for the pathogenesis of lymphopro/iferative disorders. IS
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HYPERCALCEMIA IN A RENAL TRANSPLANT RECIPIENT
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Table 2.-Biochemical Factors That Are Helpful in the Differential Diagnosis of Malignancy-Associated Hypercalcemia *
Factors
Local osteolytic hypercalcemia
Humoral hypercalcemia
Calcitriolmediated hypercalcemia
Current case
Serum phosphatelevels PTH levels PTHrP levels Calcitriollevels
Normal Decreased Undetectable Decreased
Decreased Decreased Increased Decreased
Normal to increased Decreasedto normal Undetectable Increased
Normal Normal Undetectable Increased
*PTH = parathyroidhormone; PTHrP = parathyroidhormone-related peptide. Modifiedfrom Seymourand Gagel.' By permission.
Posttransplantation non-Hodgkin's lymphomas differ from those in the general population in several respects: extranodal involvement is more common, as is central nervous system involvement often in the absence of involvement of other organs, and involvement of the allograft itself by the lymphoproliferative process." The last-mentioned factor may manifest as allograft dysfunction and must be excluded histologically before treating presumed rejection. 19 Our patient sought medical assessment 7 years after cadaveric renal transplantation in which the posttransplantation course had been uneventful except for hypercalcemia due to persistent hyperparathyroidism, which had resolved after parathyroidectomy. Her immunosuppressive therapy consisted of prednisone, cyclosporine, and azathioprine, but she received no antilymphocyte preparations. The posttransplantation lymphoproliferative disorder was diagnosed after lymphoma cells were detected in the abdominal paracentesis fluid. Imaging studies revealed no evidence of lymphoma in the abdomen, chest, or brain. A biopsy of the renal allograft was not performed because she had no evidence of persistent allograft dysfunction. Possibly, a postmortem examination may have revealed small foci of lymphoma in the abdomen, beyond the resolution of the CT scan. Initial management of posttransplantation lymphoproliferative disorders has been to decrease or discontinue use of immunosuppressive therapy. In patients who experience no response, additional therapeutic measures may be indicated, ranging from local irradiation or surgical excision (or both) for patients with localized disease to combination chemotherapy for patients with extensive disease. Response to therapy, however, is less common in transplant recipients than in immunocompetent hosts." In patients with extensive disease, antiviral therapy with acyclovir-'-" has been successful, especially in patients with polyclonal B-cell proliferation. Ganciclovir," interferon alfa and intravenous immunoglobulin therapy," and anti-B-cell monoclonal antibodies" have also been used to treat patients with posttransplantation lymphoproliferative disorders.
CONCLUSION To our knowledge, this is the first report of 1,25dihydroxyvitamin D-mediated hypercalcemia in a renal transplant recipient with malignant lymphoma. The possibility of an underlying lymphoproliferative disorder should be considered in the differential diagnosis of hypercalcemia in a renal transplant recipient.
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TEXT BITESFROMOTHER JOURNALS Infective endocarditis in intravenous drug users affects the right and left sides of the heart with approximately equal frequency. At present, more than 90% of cases of infective endocarditis in intravenous drug users in Chicago are caused by staphylococci or streptococci.
-Arch Intern Med 1995; I55:1641-I648 Dental erosion is a common finding in patients with gastroesophageal reflux disease and should be considered an atypical manifestation of this disease.
-Ann Intern Med I995; 122:809-815 The association between brain tumors and multiple colorectal adenomas [Turcot's syndrome] can result from two distinct types of germ-line defects: mutation of the APe [adenomatous polyposis coli] gene or mutation of a mismatch-repair gene.
-N Engl J Med I995; 332:839-847
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