- Email: [email protected]
Evaluation of Thyroid Disease in Kidney Transplantation Candidates: Management and Follow-up
Evaluation of Thyroid Disease in Kidney Transplantation Candidates: Management and Follow-up M. Veroux, G. Giuffrida, M. Gagliano, A. Giaquinta, T. Tallarita, M. Sorbello, D. Corona, D. Zerbo, D. Vizcarra, V. Scriffignano, M.A. Cannizzaro, and P. Veroux ABSTRACT Introduction. Diagnosis of thyroid disease is fundamental in the evaluation of patients awaiting kidney transplantation. We analyzed the incidence of thyroid disease in patients with end-stage renal disease (ESRD) and evaluated its evolution before and after kidney transplantation. Patients and Methods. Between January 2000 and May 2008, we evaluated 323 candidates for kidney transplantation. In all patients, serum concentrations of free triiodothyronine, free thyroxine, and thyroid-stimulating hormone were determined and a ultrasonography of the neck was performed. Patients with thyroid cancer were considered eligible for kidney transplantation after at least 2 years since treatment. Results. One-hundred-four patients with ESRD (44%) had functional or morphologic changes in the thyroid gland. Forty-one patients (17.4%) underwent fine-needle aspiration cytology; 3 demonstrated showed papillary carcinoma; 3, follicular adenomas; 8, uncertain cytologic lesions; and 27, a nodular goiter. Seventeen patients underwent surgery. Six of 11 patients with thyroid cancer underwent transplantation: two patients underwent laterocervical lymph node dissection because of local recurrence within 2 years after successful transplantation; the other 4 patients are alive with a functioning graft. Of the 184 transplant recipients, 10 underwent surgery to treat thyroid disease: 8 with multinodular goiter, 1 with micropapillary carcinoma, and 1 with follicular adenoma. All 10 patients are alive with a well-functioning graft and no signs of disease recurrence. Conclusions. Thyroid diseases are common in patients with ESRD. Early diagnosis and treatment significantly decreased morbidity and mortality in patients awaiting transplantation. LARGE SPECTRUM of disturbances of thyroid function and morphologic features is common in patients with end-stage renal disease (ESRD). These patients demonstrate an increased prevalence of subclinical and overt hypothyroidism, primarily from an autoimmune cause. The most frequently observed changes in thyroid function in patients with ESRD is so-called nonthyroidal illness, a condition defined as an alteration of thyroid hormone levels with no demonstrable thyroid disorder. In these patients, alteration of thyroid hormone levels is primarily due to the effects of uremia and altered hormone excretion, transport, and degradation. Hormonal changes may include elevated serum levels of thyroid-stimulating hormone (TSH), low TSH response to thyrotropin-releasing hormone, impaired TSH clearance, decreased serum levels
A
of free triiodothyronine (FT3) and free thyroxine (FT4) in the absence of increased TSH and abnormal serum-binding protein levels.1,2 Lower serum FT3 levels may be significantly associated with serum markers of inflammation and endothelial activation in patients with ESRD.3,4 Rotondi et al4 demonstrated a negative correlation between pretransplantation serum FT3 levels and serum creatinine concenFrom the Department of Surgery, Transplantation and Advanced Technologies, Vascular Surgery and Organ Transplant Unit, University Hospital of Catania, Catania, Italy. Address reprint requests to Massimiliano Veroux, MD, PhD, Department of Surgical Sciences, Transplantation and Advanced Technologies, Organ Transplant Unit, University Hospital, Via S. Sofia 86, 95123 Catania, Italy. E-mail: [email protected]
0041-1345/09/$–see front matter doi:10.1016/j.transproceed.2009.03.014
© 2009 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
1142
Transplantation Proceedings, 41, 1142–1144 (2009)
THYROID DISEASE IN TRANSPLANTATION CANDIDATES
tration after kidney transplantation, which may be a predictor of greater risk of graft failure. Diagnosis of thyroid disease is fundamental in the evaluation of patients awaiting kidney transplantation. We analyzed the incidence of thyroid disease in patients with ESRD and evaluated the evolution of this disturbance before and after kidney transplantation.
1143
One-hundred-eighty-four of 236 patients (77.9%) who were kidney transplantation candidates received a graft during the study period. Ten recipients underwent surgery to treat thyroid disease: 8 with multinodular goiter, 1 with micropapillary carcinoma, and 1 with follicular adenoma. All of these patients are alive with a well-functioning graft and no signs of disease recurrence.
PATIENTS AND METHODS This retrospective study included 323 patients with ESRD who were evaluated for kidney transplantation between January 2000 and May 2008. After clinical evaluation, 87 patients were considered ineligible for transplantation because of severe cardiovascular disease, neoplasm, or active infection. All patients who were eligible for kidney transplantation underwent ultrasonography of the neck and complete assessment of thyroid function according to serum levels of FT3, FT4, and TSH. All patients with an isoechogenic solid thyroid nodule greater than 1 cm in diameter underwent fine-needle aspiration cytology (FNAc). All patients with high levels of FT3 and FT4, low levels of TSH, and clinical signs or symptoms of hyperfunction of the thyroid gland (eg, tachycardia, flushing, or anxiety) underwent scintigraphy with iodine 131. Surgical treatment was performed in patients with a diagnosis of thyroid cancer or an uncertain diagnosis at FNAc, follicular adenoma, Plummer adenoma, or multinodular goiter and compressive symptoms on adjacent organs. Patients with benign disease, cystic lesions, or thyroid nodules smaller than 1 cm were followed up for 6 months to evaluate thyroid function and perform ultrasonography. Patients with a diagnosis of thyroid cancer were considered eligible for kidney transplantation after at least 2 years of negative follow-up.
RESULTS
One hundred four patients with ESRD (44%) demonstrated functional or morphologic changes in the thyroid gland. Sixty-one patients (25.8%) had single or multiple nodular lesions less than 1 cm in diameter, Forty-one patients (17.4%) underwent FNAc; 3 had papillary carcinoma, 3 had follicular adenomas, 8 had uncertain cytologic lesions, and 27 had a nodular goiter. Three patients with clinical signs of hyperthyroidism at 131 I scintigraphy had a hyperfunctional goiter and underwent left lobectomy. Seventeen patients underwent surgery. Six patients with a preoperative diagnosis of cancer underwent total thyroidectomy; 8 with an undefined diagnosis underwent an intraoperative histologic examination that demonstrated the presence of papillary cancer in 5 patients (total thyroidectomy) or a benign nodular goiter in 3 patients (lobectomy). No patient with ESRD with thyroid cancer exhibited lymphatic metastases at surgery. Six of 11 patients with a diagnosis of thyroid cancer underwent transplantation after a waiting time of 2 years from successful treatment. Two of these patients underwent laterocervical lymph node dissection because of local recurrence at 2 years after successful transplantation; the other 4 patients are alive with a functioning graft without signs of local recurrence or distant metastases at a median follow-up of 13 months.
DISCUSSION
It is widely accepted that immunosuppression after organ transplantation is associated with a markedly increased risk of cancer. However, the most frequently occurring malignant tumors in the general population, such as carcinoma of the colon, rectum, breast, and prostate gland, are not found with increased frequency after renal transplantation.5 This observation could be explained because the most frequent posttransplant neoplasms are related to oncogenic viruses such as human herpesvirus-8 or Epstein-Barr virus, which may be activated by chronic immunosuppression and may evolve in lymphoproliferative disorders. In contrast, cancers that are more frequently observed in the general population are not related to virus oncogenicity; therefore, their incidence is not higher in kidney transplant recipients.6,7 Cancer incidence is only slightly increased during dialysis, although dialysis and uremia may facilitate the occurrence of cancer due to nutritional deficiencies or metabolic changes, retention of carcinogenic compounds, and immune dysfunction.8 A recent study performed by Serraino et al9 evaluated the risk of cancer after solid-organ transplantation in southern Europe and demonstrated that after 15 years of immunosuppression, approximately 15% of transplant recipients developed cancer. Other series have confirmed that renal transplant recipients are at least 3 to 5 times more likely to develop cancer compared with the general population.10 The occurrence of thyroid cancer in the renal transplant population has been rarely reported. In a recent study performed in Australia and New Zealand,11 23 patients (0.22%) were diagnosed with thyroid cancer among a cohort of 10,689 renal transplant recipients. The median age in the renal transplant group with thyroid cancer was 48.2 years (age range, 23– 67 years). In that study, 48% of male patients had thyroid cancer compared with 26% of male patients in the general population (p ⫽ .02). Ten patients (43%) were found to have lymphatic metastases, present in 8 patients at the time of the primary diagnosis. The risk ratio was 5.2 (95% confidence interval, 2.0 –16.6), with an attributable risk of 17.4 cases per 10,000 population. There were 2 cancer-related deaths, for a survival probability of 89% at 5, 10, and 15 years. Although thyroid cancers may occur more frequently many years after kidney transplantation, recent studies have demonstrated that they can occur early in the posttransplantation follow-up. Their histologic behavior is often more aggressive than in the general population.5,11,12
1144
The incidence of thyroid disease and nodular lesions is common in patients with ESRD, and the incidence of thyroid cancer may be higher than in the general population. Considering the aggressiveness and the poor outcome of cancer after transplantation, there is a clear need for pretransplantation and posttransplantation screening to detect malignant lesions at an earlier stage to achieve a successful outcome. We analyzed our series of patients with ESRD to evaluate the incidence of thyroid disease and the progression of thyroid disease in transplant recipients. The rate of thyroid disease was quite high (44%) in the population with ESRD awaiting kidney transplantation; however, only a minority of these patients had cancer. A similar incidence of cancer has been observed in transplant recipients; however, in these patients the cancer exhibited more aggressive patterns with frequent local recurrence and lymphatic metastases. We suggest complete investigation of thyroid disease every 6 months in kidney transplantation candidates using ultrasonography of the neck and determining serum concentrations of FT3, FT4, and TSH. Fine-needle aspiration cytology should be reserved for patients with single or multiple nodular lesions greater than 1 cm in diameter. Surgery may be indicated for all multinodular goiters with compressive symptoms on adjacent organs or in cases of cancer or suspected lesions at cytologic examination. Renal transplant recipients should be followed up every 6 months, with early referral to surgery those with neoplastic lesions. In conclusion, thyroid diseases are common in patients with ESRD and transplant recipients. Thyroid disease may evolve after transplantation, probably as a consequence of immunosuppression. A complete evaluation of thyroid disease is mandatory in patients with ESRD and transplant recipients because early diagnosis and appropriate treat-
VEROUX, GIUFFRIDA, GAGLIANO ET AL
ment of nodular lesions significantly decreases morbidity and mortality in these patients. REFERENCES 1. Rotondi M, Netti GS, Rosati A, et al: Pretransplant serum FT3 levels in kidney graft recipients are useful for identifying patients with higher risk for graft failure. Clin Endocrinol (Oxf) 68:220, 2008 2. Carrero JJ, Qureshi AR, Axelsson J, et al: Clinical and biochemical implications of low thyroid hormone levels (total and free forms) in euthyroid patients with chronic kidney disease. J Intern Med 262:690, 2007 3. Lo JC, Chertow GM, Go AS, et al: Increased prevalence of subclinical and clinical hypothyroidism in persons with chronic kidney disease. Kidney Int 67:1047, 2005 4. Malyszko J, Malyszko JS, Pawlak K, et al: Possible relations between thyroid function, endothelium, and kidney and liver function in kidney allograft recipients. Transplant Proc 38:3509, 2006 5. Peen I. De novo cancers in organ allograft recipients. Curr Opin Organ Transplant 3:188, 1998 6. Winter P, Schoeneich G, Miersch WD, et al: Tumor induction as a consequence of immunosuppression after renal transplantation. Int Urol Nephrol 29:701, 1997 7. Vajdic CM, McDonald SP, McCredie MR, et al: Cancer incidence before and after kidney transplantation. JAMA 296: 2823, 2006 8. Vamvakas S, Bahner U, Heidland A: Cancer in end-stage renal disease: potential factors involved. Am J Nephrol 18:89, 1998 9. Serraino D, Piselli P, Busnach G, et al: Immunosuppression and Cancer Study Group: Risk of cancer following immunosuppression in organ transplant recipients and in HIV-positive individuals in southern Europe. Eur J Cancer 43:2117, 2007 10. Wong G, Chapman JR. Cancers after renal transplantation. Transplant Rev 22:141, 2008 11. Pond F, Serpell JW, Webster A: Thyroid cancer in the renal transplant population: epidemiological study. A NZ J Surg 75:106, 2005 12. Veroux M, Puliatti C, Fiamingo P, et al: Early de novo malignancies after kidney transplantation. Transplant Proc 36:718, 2004
A
of free triiodothyronine (FT3) and free thyroxine (FT4) in the absence of increased TSH and abnormal serum-binding protein levels.1,2 Lower serum FT3 levels may be significantly associated with serum markers of inflammation and endothelial activation in patients with ESRD.3,4 Rotondi et al4 demonstrated a negative correlation between pretransplantation serum FT3 levels and serum creatinine concenFrom the Department of Surgery, Transplantation and Advanced Technologies, Vascular Surgery and Organ Transplant Unit, University Hospital of Catania, Catania, Italy. Address reprint requests to Massimiliano Veroux, MD, PhD, Department of Surgical Sciences, Transplantation and Advanced Technologies, Organ Transplant Unit, University Hospital, Via S. Sofia 86, 95123 Catania, Italy. E-mail: [email protected]
0041-1345/09/$–see front matter doi:10.1016/j.transproceed.2009.03.014
© 2009 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
1142
Transplantation Proceedings, 41, 1142–1144 (2009)
THYROID DISEASE IN TRANSPLANTATION CANDIDATES
tration after kidney transplantation, which may be a predictor of greater risk of graft failure. Diagnosis of thyroid disease is fundamental in the evaluation of patients awaiting kidney transplantation. We analyzed the incidence of thyroid disease in patients with ESRD and evaluated the evolution of this disturbance before and after kidney transplantation.
1143
One-hundred-eighty-four of 236 patients (77.9%) who were kidney transplantation candidates received a graft during the study period. Ten recipients underwent surgery to treat thyroid disease: 8 with multinodular goiter, 1 with micropapillary carcinoma, and 1 with follicular adenoma. All of these patients are alive with a well-functioning graft and no signs of disease recurrence.
PATIENTS AND METHODS This retrospective study included 323 patients with ESRD who were evaluated for kidney transplantation between January 2000 and May 2008. After clinical evaluation, 87 patients were considered ineligible for transplantation because of severe cardiovascular disease, neoplasm, or active infection. All patients who were eligible for kidney transplantation underwent ultrasonography of the neck and complete assessment of thyroid function according to serum levels of FT3, FT4, and TSH. All patients with an isoechogenic solid thyroid nodule greater than 1 cm in diameter underwent fine-needle aspiration cytology (FNAc). All patients with high levels of FT3 and FT4, low levels of TSH, and clinical signs or symptoms of hyperfunction of the thyroid gland (eg, tachycardia, flushing, or anxiety) underwent scintigraphy with iodine 131. Surgical treatment was performed in patients with a diagnosis of thyroid cancer or an uncertain diagnosis at FNAc, follicular adenoma, Plummer adenoma, or multinodular goiter and compressive symptoms on adjacent organs. Patients with benign disease, cystic lesions, or thyroid nodules smaller than 1 cm were followed up for 6 months to evaluate thyroid function and perform ultrasonography. Patients with a diagnosis of thyroid cancer were considered eligible for kidney transplantation after at least 2 years of negative follow-up.
RESULTS
One hundred four patients with ESRD (44%) demonstrated functional or morphologic changes in the thyroid gland. Sixty-one patients (25.8%) had single or multiple nodular lesions less than 1 cm in diameter, Forty-one patients (17.4%) underwent FNAc; 3 had papillary carcinoma, 3 had follicular adenomas, 8 had uncertain cytologic lesions, and 27 had a nodular goiter. Three patients with clinical signs of hyperthyroidism at 131 I scintigraphy had a hyperfunctional goiter and underwent left lobectomy. Seventeen patients underwent surgery. Six patients with a preoperative diagnosis of cancer underwent total thyroidectomy; 8 with an undefined diagnosis underwent an intraoperative histologic examination that demonstrated the presence of papillary cancer in 5 patients (total thyroidectomy) or a benign nodular goiter in 3 patients (lobectomy). No patient with ESRD with thyroid cancer exhibited lymphatic metastases at surgery. Six of 11 patients with a diagnosis of thyroid cancer underwent transplantation after a waiting time of 2 years from successful treatment. Two of these patients underwent laterocervical lymph node dissection because of local recurrence at 2 years after successful transplantation; the other 4 patients are alive with a functioning graft without signs of local recurrence or distant metastases at a median follow-up of 13 months.
DISCUSSION
It is widely accepted that immunosuppression after organ transplantation is associated with a markedly increased risk of cancer. However, the most frequently occurring malignant tumors in the general population, such as carcinoma of the colon, rectum, breast, and prostate gland, are not found with increased frequency after renal transplantation.5 This observation could be explained because the most frequent posttransplant neoplasms are related to oncogenic viruses such as human herpesvirus-8 or Epstein-Barr virus, which may be activated by chronic immunosuppression and may evolve in lymphoproliferative disorders. In contrast, cancers that are more frequently observed in the general population are not related to virus oncogenicity; therefore, their incidence is not higher in kidney transplant recipients.6,7 Cancer incidence is only slightly increased during dialysis, although dialysis and uremia may facilitate the occurrence of cancer due to nutritional deficiencies or metabolic changes, retention of carcinogenic compounds, and immune dysfunction.8 A recent study performed by Serraino et al9 evaluated the risk of cancer after solid-organ transplantation in southern Europe and demonstrated that after 15 years of immunosuppression, approximately 15% of transplant recipients developed cancer. Other series have confirmed that renal transplant recipients are at least 3 to 5 times more likely to develop cancer compared with the general population.10 The occurrence of thyroid cancer in the renal transplant population has been rarely reported. In a recent study performed in Australia and New Zealand,11 23 patients (0.22%) were diagnosed with thyroid cancer among a cohort of 10,689 renal transplant recipients. The median age in the renal transplant group with thyroid cancer was 48.2 years (age range, 23– 67 years). In that study, 48% of male patients had thyroid cancer compared with 26% of male patients in the general population (p ⫽ .02). Ten patients (43%) were found to have lymphatic metastases, present in 8 patients at the time of the primary diagnosis. The risk ratio was 5.2 (95% confidence interval, 2.0 –16.6), with an attributable risk of 17.4 cases per 10,000 population. There were 2 cancer-related deaths, for a survival probability of 89% at 5, 10, and 15 years. Although thyroid cancers may occur more frequently many years after kidney transplantation, recent studies have demonstrated that they can occur early in the posttransplantation follow-up. Their histologic behavior is often more aggressive than in the general population.5,11,12
1144
The incidence of thyroid disease and nodular lesions is common in patients with ESRD, and the incidence of thyroid cancer may be higher than in the general population. Considering the aggressiveness and the poor outcome of cancer after transplantation, there is a clear need for pretransplantation and posttransplantation screening to detect malignant lesions at an earlier stage to achieve a successful outcome. We analyzed our series of patients with ESRD to evaluate the incidence of thyroid disease and the progression of thyroid disease in transplant recipients. The rate of thyroid disease was quite high (44%) in the population with ESRD awaiting kidney transplantation; however, only a minority of these patients had cancer. A similar incidence of cancer has been observed in transplant recipients; however, in these patients the cancer exhibited more aggressive patterns with frequent local recurrence and lymphatic metastases. We suggest complete investigation of thyroid disease every 6 months in kidney transplantation candidates using ultrasonography of the neck and determining serum concentrations of FT3, FT4, and TSH. Fine-needle aspiration cytology should be reserved for patients with single or multiple nodular lesions greater than 1 cm in diameter. Surgery may be indicated for all multinodular goiters with compressive symptoms on adjacent organs or in cases of cancer or suspected lesions at cytologic examination. Renal transplant recipients should be followed up every 6 months, with early referral to surgery those with neoplastic lesions. In conclusion, thyroid diseases are common in patients with ESRD and transplant recipients. Thyroid disease may evolve after transplantation, probably as a consequence of immunosuppression. A complete evaluation of thyroid disease is mandatory in patients with ESRD and transplant recipients because early diagnosis and appropriate treat-
VEROUX, GIUFFRIDA, GAGLIANO ET AL
ment of nodular lesions significantly decreases morbidity and mortality in these patients. REFERENCES 1. Rotondi M, Netti GS, Rosati A, et al: Pretransplant serum FT3 levels in kidney graft recipients are useful for identifying patients with higher risk for graft failure. Clin Endocrinol (Oxf) 68:220, 2008 2. Carrero JJ, Qureshi AR, Axelsson J, et al: Clinical and biochemical implications of low thyroid hormone levels (total and free forms) in euthyroid patients with chronic kidney disease. J Intern Med 262:690, 2007 3. Lo JC, Chertow GM, Go AS, et al: Increased prevalence of subclinical and clinical hypothyroidism in persons with chronic kidney disease. Kidney Int 67:1047, 2005 4. Malyszko J, Malyszko JS, Pawlak K, et al: Possible relations between thyroid function, endothelium, and kidney and liver function in kidney allograft recipients. Transplant Proc 38:3509, 2006 5. Peen I. De novo cancers in organ allograft recipients. Curr Opin Organ Transplant 3:188, 1998 6. Winter P, Schoeneich G, Miersch WD, et al: Tumor induction as a consequence of immunosuppression after renal transplantation. Int Urol Nephrol 29:701, 1997 7. Vajdic CM, McDonald SP, McCredie MR, et al: Cancer incidence before and after kidney transplantation. JAMA 296: 2823, 2006 8. Vamvakas S, Bahner U, Heidland A: Cancer in end-stage renal disease: potential factors involved. Am J Nephrol 18:89, 1998 9. Serraino D, Piselli P, Busnach G, et al: Immunosuppression and Cancer Study Group: Risk of cancer following immunosuppression in organ transplant recipients and in HIV-positive individuals in southern Europe. Eur J Cancer 43:2117, 2007 10. Wong G, Chapman JR. Cancers after renal transplantation. Transplant Rev 22:141, 2008 11. Pond F, Serpell JW, Webster A: Thyroid cancer in the renal transplant population: epidemiological study. A NZ J Surg 75:106, 2005 12. Veroux M, Puliatti C, Fiamingo P, et al: Early de novo malignancies after kidney transplantation. Transplant Proc 36:718, 2004