- Email: [email protected]
Thyroid function and morphology in kidney transplant recipients, hemodialyzed, and peritoneally dialyzed patients
Thyroid Function and Morphology in Kidney Transplant Recipients, Hemodialyzed, and Peritoneally Dialyzed Patients U. Łebkowska, J. Malyszko, and M. Mys´liwiec ABSTRACT Disturbances in thyroid function are common among patients on renal replacement therapy. The aim of the present study was to compare thyroid stimulating hormone (TSH) and thyroid morphology among patients on hemodialysis (HD), peritoneal dialysis (CAPD), and after kidney transplantation. The study was performed on three groups of patients: 48 transplant recipients (Tx) (receiving cyclosporine, azathioprine, and prednisone); 32 HD, and 26 CAPD patients. The control group included 40 healthy volunteers. Thyroid examinations were performed with a 7.5-MHz probe and the thyroid volume was calculated. Among Tx patients the thyroid volume was 25.16 ⫾ 12.27mL; 21.60 ⫾ 10.33mL in HD; 19.70 ⫾ 8.46 mL in CAPD; and 16.34 ⫾ 5.46mL in the healthy volunteers. Serum TSH was within the normal range in each group. Goiter was diagnosed in the majority of Tx, most HD patients, and some CAPD patients. Single and multiple nodules were found in 21 Tx, 12 HD, and 2 CAPD patients. Moreover, parathyroid glands were visualized on sonography in 10 Tx, 12 HD, and 8 CAPD subjects. In Tx observed correlations were positive between thyroid volume and creatinine, negative between thyroid volume and TSH. The time after transplantation correlated negatively with TSH. No correlation between TSH, thyroid volume, and time on dialysis was observed. The prevalence in patients on renal replacement therapy was higher than that in the general population. These findings suggest that screening for abnormal thyroid morphology should be performed in kidney patients and that iodide supplementation should be considered in Tx patients.
T
HE KIDNEY plays an important role in the metabolism, degradation, and excretion of several thyroid hormones. It contributes to the clearance of iodide, primarily by glomerular filtration. Chronic renal failure is associated with multiple disturbances in thyroid metabolism although generally the serum TSH is normal and most patients are euthyroid. Advanced renal failure is associated with decreased iodide excretion, subsequent elevations of plasma inorganic iodide, and initially an increment in thyroidal iodide uptake.1 Elevated total body inorganic iodide can potentially block thyroid hormone synthesis (the Wolff-Chaikoff effect), which may explain the slightly higher frequency of goiter and hypothyroidism in patients with renal failure.2 In contrast, the subtle changes in thyroid hormone metabolism are not sufficient to produce these disorders. The exact reasons for an increased thyroid gland volume are not known. Potential pathogentic factors include enhanced iodide trapping by the thyroid gland3 and the possibility of accumulation of
an unidentified goitrogen or strumigenic substance in uremic plasma.4 It has been reported that goiter prevalence in end-stage renal disease varies from 0% in Great Britain and Austria to 58% in Utah, USA, suggesting geographic differences.5 Goiter has been observed more frequently (50%) in patients on hemodialysis for more than 1 year than among those dialyzed less than 1 year or not at all (39%).5 Its frequency has not been related to age, diabetes mellitus, thyroid stimulating hormone (TSH), or PTH.5 Patients with chronic renal failure may have a slightly higher frequency of thyroid nodules and thyroid carcinoma.6 But the reasons From the Department of Radiology (U.L.) Department of Nephrology and Transplantology (J.M., M.M.), Medical University, Bialystok, Poland. Address reprint requests to Jolanta Malyszko, Department of Nephrology & Transplantology, Zurawia 14, Bialystock 15-540, Poland. E-mail: [email protected]
© 2003 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/03/$–see front matter doi:10.1016/j.transproceed.2003.10.066
Transplantation Proceedings, 35, 2945⫺2948 (2003)
2945
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are unknown. The presence of thyroid nodules has not been related to age, duration of hemodialysis, PTH, or TSH.7 However, it has been suggested that secondary hyperparathyroidism could also play a role.6 It should be stressed that majority of data deal with hemodialyzed patients, and that the literature concerning continuous ambulatory peritoneal dialysis (CAPD) patients and kidney transplant recipients are insufficient to compare the impact of different modes of renal replacement therapies on thyroid function and morphology. Thus, the aim of our study was to examine thyroid hormone concentrations and morphology among patients on various forms of renal replacement therapy: hemodialysis, CAPD, and kidney transplantation. MATERIALS AND METHODS The study was performed on three groups of patients on renal replacement therapy: group I consisted of kidney transplant recipients, group II consisted of chronically hemodialyzed (HD) patients, and group III consisted of 26 peritoneal dialysis patients on CAPD. The 48 kidney transplant recipients (aged 26 – 64 years) displayed stable graft function (serum creatinine 1.75 ⫾ 0.59 mg/dL) without any infection (C-reactive protein within the normal ranges), and in the absence of a known family history of thyroid diseases. The immunosuppressive agents were cyclosporine, azathioprine, and prednisone. The average dose of cyclosporine was 280 ⫾ 80 mg/day (doses ranging from 175 to 425 mg/day). The mean trough concentration, as measured using the AxSYM system with polarized fluorescence, was 144 ⫾ 60 ng/mL. The average dose of prednisone was 7.5 mg/day. The mean azathioprine (Imuran) dose averaged 100 mg/day, (range between 50 and 150 mg/day). Patients had been engrafted for 9 months to 10 years (average 47 ⫾ 37 months). The average time on dialysis before transplantation was 37 months (range 10 – 80 months). The underlying renal pathology in these patients was chronic glomerulonephritis (n ⫽ ⫺29), pyelonephritis (n ⫽ 9), adult polycystic kidney disease (n ⫽ 5), and unknown (n ⫽ 5). The causes of renal failure among HD patients included chronic glomerulonephritis (n ⫽ 20), chronic interstitial nephritis (n ⫽ 9), polycystic kidney disease (n ⫽ 2), and unknown causes (n ⫽ 1). For HD patients blood was drawn in the morning between 8 and 9 AM to avoid circadian variations before the onset of the dialysis session and heparin administration. Ultrasonography of the thyroid gland was performed on a day between dialyses. All patients underwent regular hemodialyses for 4 to 5 hours a day three times a week. Blood flow was usually 180 to 230 mL/min, with a dialysate flow rate of 500 mL/min. Ultrafiltration varied according to the patient’s weight. Among CAPD patients, the renal failure was due to glomerulonephritis (n ⫽ 14), chronic interstitial nephritis (n ⫽ 5), polycystic kidney disease (n ⫽ 4), or other or unknown causes (n ⫽ 3). Blood samples were drawn in the morning when subjects, receiving their normal diet, appeared for routine assessment of dialysis therapy after an overnight oral fast. On the same day thyroid gland sonography was performed. All CAPD patients were performing four 2-L exchanges using a Baxter Twin-Bag system or Fresenius Andy Plus system. Dwell times were generally 4 to 6 hours during the day and 8 hours overnight. The osmotic pressure of the CAPD fluid was adjusted in accord with the extent of required ultrafiltration. Twenty-seven HD and 16 CAPD patients were treated with rHuEPO (Eprex, Janssen-Cilag, Switzerland-HD, NeoRecormon, Roche, Switzerland), using doses ranging from 2000 to 8000 U/week.
Patient height and weight were recorded for all groups. All patients were informed about the aim of the study and gave their consent. The study was approved by the local ethics committee. The control group consisted of 40 healthy volunteers without known thyroid pathology recruited from the medical staff members and their families. The thyroid evaluation employed various techniques of ultrasonography (B-mode, color Doppler-CD, power Doppler-PD), using a 7.5MHz probe. Three consecutive measurements were performed for each thyroid lobe, and these after the thyroid volume was calculated using the formula V ⫽ a ⫻ b ⫻ c ⫻ /6, where a,b, and c were the longitudinal, the transverse, and the antero-posterior dimensions of the thyroid lobes. The total thyroid volume was calculated as the sum of the lobe volumes. A healthy thyroid is visualized by ultrasound as homogenous. Cases in which at least one clearly (or slightly) delineated focus was observed, were classified as nonhomogenous. Due to unclear clinical and sonographic symptoms of benign versus malignant lesions (mainly cancer), a sonographically guided fine-needle aspiration biopsy (FNAB) was performed on suspected thyroid nodules. In addition, the following laboratory tests were performed hemoglobin, red blood cell count, total protein, albumin, cholesterol, triglycerides, urea (in HD patients before and after HD), TSH (MEIA) using standard laboratory methods. Intact PTH was estimated by a radioimmunoassay method using commercially available kits from Cis, France. Semiquantitative measurement of urine iodide was performed with Urojod test (Merck, Germany).
RESULTS
The biochemical characteristics of patients on renal replacement therapy are presented in Table 1 The patients were similar with regard to age, sex, underlying renal pathology, dialysis duration, and body mass index. The erythrocyte count, hemoglobin, serum cholesterol, and triglyceride levels were significantly higher among CAPD than HD subjects. Kidney transplant recipients showed significantly higher levels of serum cholesterol and triglycerides than hemodialyzed patients as well as higher total protein and albumin, with lower urea concentrations than peritoneally dialyzed patients. Serum PTH was significantly higher among dialyzed patients compared with control or kidney transplant recipients. The serum PTH content was significantly higher among kidney transplant recipients than healthy volunteers. There were no statistically significant differences in serum TSH between dialyzed patients, kidney transplant recipients (Table 1), and healthy volunteers (1.97 ⫾ 0.96 mU/mL). In all healthy volunteers except four, urine iodide was over 100 g/L. Only four CAPD and five kidney transplant recipients exhibited ioduria over 100 g/L. In five CAPD patients, eight Tx, and four healthy volunteers, urine iodide was between 50 and 100 g/L. The rest of the Tx and the CAPD patients as well as all of the HD patients shared urine iodide below 30 g/L. Thyroid nodules were found on sonography in 21 kidney allograft recipients (9 patients -single and 12 -multiple), in 12 HD patients (4-single, 8-multiple), and only two CAPD patients (multiple nodules). All of the nodules were smaller than 2 cm in diameter. Among kidney transplant recipients, 7 nodules were cystic, 21 solid/hypoechic, and 27 nonhomogenous.
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Table 1. Clinical Characteristics of the Hemodialyzed Patients, Peritoneally Dialyzed Patients and Kidney Transplant Recipients
Age (yrs) BMI (kg/m2) Duration of dialyses (months)/time after Tx Thyroid stimulating hormone (mU/mL) Hemoglobin (g/L) Erythrocyte count (mln/mm3) Cholesterol (mg/dL) Triglycerides (mg/dL) Total protein (g/L) Albumin (g/L) Urea before HD (mg/dL) urea in CAPD, Tx PTH (pg/mL)
HD n ⫽ 32
CAPD n ⫽ 26
TX n ⫽ 48
56 ⫾ 18 24.0 ⫾ 4.1 34 ⫾ 27 1.42 ⫾ 0.97 9.55 ⫾ 1.86### 3.12 ⫾ 0.61### 178.4 ⫾ 44.9### 110.1 ⫾ 52.6## 6.46 ⫾ 0.61 3.95 ⫾ 0.44 120.9 ⫾ 29.7# 332 ⫾ 310
51 ⫾ 11 23.2 ⫾ 3.6 31 ⫾ 24 1.46 ⫾ 0.86 10.42 ⫾ 2.41* 3.73 ⫾ 0.75* 219.2 ⫾ 45.1*** 156.7 ⫾ 72.7** 6.28 ⫾ 0.65* 3.45 ⫾ 0.54** 105.4 ⫾ 28.5 301 ⫾ 277
44 ⫾ 12 24.9 ⫾ 3.8 47 ⫾ 27 1.41 ⫾ 0.89 12.91 ⫾ 2.91°° 4.24 ⫾ 1.09°°° 213.8 ⫾ 40.6 137.1 ⫾ 51.7 6.80 ⫾ 0.66°° 4.14 ⫾ 0.48°°° 70.7 ⫾ 35.0° 204 ⫾ 115°
HD: hemodialysis; CAPD: continuous ambulatory peritoneal dialysis; Tx: transplant. Values given are means ⫾ SD. *P ⬍ .05, **P ⬍ .01, ***P ⬍ .001 HD vs CAPD. #P ⬍ .05, ##P ⬍ .01, ###P ⬍ .001 HD vs Tx. °P ⬍ .05, °°P ⬍ .01,
Among HD patients 3 nodules were solid, 2 normoechoic, and 15 hypoechoic. Among CAPD patients, all nodules were hypoechoic. Among six kidney transplant recipients papillary or follicular tumors were diagnosed on sonigraphically guided FNAB The rest of the kidney transplant recipients or the dialyzed patients showed benign goiters. In addition, 10 kidney transplant recipients, 12 HD patients, and 8 CAPD patients showed visualization of parathyroid glands on sonography. The thyroid volumes were 25.16 ⫾ 12.27 mL in Tx, 21.60 ⫾ 10.33 mL in HD, 19.70 ⫾ 8.46 mL in CAPD, and 16.34 ⫾ 5.46 mL in healthy volunteers. Thyroid volumes were largest in kidney transplant recipients, namely, statistically higher than those in CAPD patients or healthy volunteers. The difference in thyroid volume between kidney transplant recipients and HD patients almost reached statistical significance (P ⫽ .09), as well as between CAPD and healthy volunteers (P ⫽ .06). Thyroid volume in HD patients was not significantly higher than CAPD (P ⫽ .25). A positive correlation was observed between thyroid volume and creatinine (r ⫽ 0.44, P ⬍ .05), and (negative association between thyroid volume and TSH in Tx (r ⫽ 0.48, P ⬍ .05). The time after transplantation correlated negatively with TSH (r ⫽ ⫺0.5, P ⬍ .05). No correlation between TSH, thyroid volume, and time on dialysis was observed. DISCUSSION
Patients with end-stage renal disease exhibit multiple disturbances in thyroid hormone metabolism in the absence of concurrent thyroid disease. The described alterations includes those in serum thyroid hormones, namely, elevated basal TSH values, blunted TSH response to TRH, diminished or absent TSH diurnal rhythm, altered TSH glycosylation, and impaired TSH and TRH clearance rates.8 –11 In addition, serum total and free T3 and T4 values may be reduced and free rT3 levels elevated. In contrast, total values are normal, while serum binding protein concentrations may be altered.8 –11 Dialysis therapy minimally affects
°°°
P ⬍ .001 CAPD vs TX.
thyroid hormone metabolism,11 which normalizes following successful renal transplantation.12 However, data about thyroid hormone metabolism are limited. Premises reports have dealt mainly with hemodialyzed patients.6,11,13,14 Few Data with regard to thyroid hormones and morphology are available comparing the three methods of renal replacement therapy: HD, CAPD and kidney transplantation. We sought to address the question of whether these three methods affect TSH, thyroid morphology, and ioduria. We observed that TSH was within the lower normal range in all three groups of patients, not differing significantly from healthy volunteers. In contrast, urine iodide excretion, which was normal in healthy volunteers, was near normal in kidney transplant recipients but significantly reduced among dialyzed, particularly HD, subjects. It has been reported that due to reduced renal excretion of iodide, serum iodide levels are increased among patients with end-stage renal failure, despite decreased dietary iodide intake. Although inorganic iodide is removed by both HD and CAPD, serum iodide has been reported to be increased in CAPD and HD patients.15 Use of povidone-iodine for disinfecting arteriovenous fistulas for HD or Tenckhoff peritoneal cathethers may contribute to the rise in serum iodide in some dialyzed patients.15 Decreased urine iodide excretion and thus increased serum iodide may result in thyroid gland enlargement and subsequent goiter formation. The incidence of goiter in patients with renal failure has been reported to be higher5,6,11 than in general population. In our study, the prevalence of goiter was 100% in Tx, 50% in HD, and 25% in CAPD patients (according to WHO classification of goiter.16 Also, goiter frequency is related to the duration of hemodialysis. However, in our study, CAPD and HD patients did not differ significantly concerning time on dialysis. Time on dialysis prior to transplantation was also similar to the time on HD or CAPD. However, goiter was diagnosed in all Tx patients. In addition to urine iodide excretion, which was abnormal except in four cases, we sought other factors that might
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2948
contribute to goiter formation, including duration of uremia before renal transplantation, residual renal function of the native kidneys, graft function, episodes of graft rejection, modulation of secretion, transport and degradation of hormones, or altered target organ responsiveness to hormones induced by immunosuppressive drugs (steroids, cyclosporine, azathioprine). In our study patients with episodes of acute graft rejection were excluded because these episodes are thought to produce alterations of the endocrine system similar to those seen in patients with acute or chronic renal failure.17 Successful kidney transplantation has been reported to improve renal function and to restore some thyroid function tests to normal, while the associated medications, such as high-dose steroids, may produce other abnormalities.12,18,19 Moreover, a high prevalence of thyroid nodules was observed in Tx. As reported previously,20 higher concentrations of cyclosporine were observed in patients having nodules, suggesting that immunosuppresion may contribute to the development of goiter as well as to nodule development. It has been reported that the presence of thyroid nodules is not related to age, duration of dialysis, PTH, or TSH.7 Our data corroborate these findings. However, it has been suggested that secondary hyperparathyroidism could also play a role.6 Therefore, we assessed PTH levels, observing that PTH was significantly higher among HD and CAPD patients compared to Tx and healthy volunteers. PTH was also significantly higher in Tx than control subjects but did not correlate with TSH, thyroid volume, or the presence of nodules. In conclusion, patients on dialysis or after renal transplantation have an increased frequency of goiter and thyroid nodules. Goiter in patients on renal replacement therapy may be induced by reduced renal iodide excretion. Screening for thyroid function goiter, and nodules should
be considered, particularly among patients on immunosuppressive therapy. REFERENCES 1. Kaptein EM, Finstein EI, Massry SG: Contrib Nephrol 33: 122, 1982 2. Sato K, Okamura K, Yoshinari M, et al: Acta Endocrinol (Copenhagen) 126:253, 1992 3. Beckers C, van Ipersele de Strihou C, Coche E, et al: J Clin Endocrinol Metab 29:293, 1969 4. Hegedus L, Andersen JR, Poulsen LR, et al: Nephron 40:171, 1985 5. Kaptein EM, Quion-Verde H, Chooljian CJ, et al: Medicine (Baltimore) 67:187, 1988 6. Kaptein EM: Endocr Rev 17:45, 1996 7. Miki H, Oshimo K, Inoue H, et al: J Surg Oncol 54:216, 1993 8. Lee PC, Tang MJ, Song CM, et al: Transplant Proc 26:184, 1994 9. Tessler FN, Tublin ME: Am J Roentgenol 173:37, 1999 10. Hardy MJ, Ragbeer SS, Nasimento L: J Clin Endocrinol Metabol 66:33, 1988 11. Lim VS: Am J Kidney Dis 38(Suppl 1):S80, 2001 12. Vaziri ND, Gvinup C, Martin D, et al: Clin Nephrol 15:131, 1981 13. Yonemura K, Nakajima T, Suzuki T, et al: Nephrol Dial Transplant 15:668, 2000 14. Lin CC, Chen TW, Ng YY, et al: Perit Dial Int 18:16, 1998 15. Gardner DF, Mars DR, Thomas RG, et al: Am J Kidney Dis 7:471, 1986 16. Indicators for Assessing Iodine Deficiency Disorders and Their Control Through Salt Iodization. World Health Organization. WHO/NUT/94.6 17. Kokot F, Grzeszczak W, Zukowska-Szczechowska E, et al: Blood Purif 8:76, 1990 18. Kaptein EM, Levitan D, Feinstein EI, et al: Am J Nephrol 1:138, 1981 19. Wartofsky L, Burman KD: Endocr Rev 3:164, 1982 20. Lebkowska U, Malyszko J, Brzosko S, et al: Transplant Proc 34:596, 2002
T
HE KIDNEY plays an important role in the metabolism, degradation, and excretion of several thyroid hormones. It contributes to the clearance of iodide, primarily by glomerular filtration. Chronic renal failure is associated with multiple disturbances in thyroid metabolism although generally the serum TSH is normal and most patients are euthyroid. Advanced renal failure is associated with decreased iodide excretion, subsequent elevations of plasma inorganic iodide, and initially an increment in thyroidal iodide uptake.1 Elevated total body inorganic iodide can potentially block thyroid hormone synthesis (the Wolff-Chaikoff effect), which may explain the slightly higher frequency of goiter and hypothyroidism in patients with renal failure.2 In contrast, the subtle changes in thyroid hormone metabolism are not sufficient to produce these disorders. The exact reasons for an increased thyroid gland volume are not known. Potential pathogentic factors include enhanced iodide trapping by the thyroid gland3 and the possibility of accumulation of
an unidentified goitrogen or strumigenic substance in uremic plasma.4 It has been reported that goiter prevalence in end-stage renal disease varies from 0% in Great Britain and Austria to 58% in Utah, USA, suggesting geographic differences.5 Goiter has been observed more frequently (50%) in patients on hemodialysis for more than 1 year than among those dialyzed less than 1 year or not at all (39%).5 Its frequency has not been related to age, diabetes mellitus, thyroid stimulating hormone (TSH), or PTH.5 Patients with chronic renal failure may have a slightly higher frequency of thyroid nodules and thyroid carcinoma.6 But the reasons From the Department of Radiology (U.L.) Department of Nephrology and Transplantology (J.M., M.M.), Medical University, Bialystok, Poland. Address reprint requests to Jolanta Malyszko, Department of Nephrology & Transplantology, Zurawia 14, Bialystock 15-540, Poland. E-mail: [email protected]
© 2003 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/03/$–see front matter doi:10.1016/j.transproceed.2003.10.066
Transplantation Proceedings, 35, 2945⫺2948 (2003)
2945
ŁEBKOWSKA, MALYSZKO AND MYS´ LIWIEC
2946
are unknown. The presence of thyroid nodules has not been related to age, duration of hemodialysis, PTH, or TSH.7 However, it has been suggested that secondary hyperparathyroidism could also play a role.6 It should be stressed that majority of data deal with hemodialyzed patients, and that the literature concerning continuous ambulatory peritoneal dialysis (CAPD) patients and kidney transplant recipients are insufficient to compare the impact of different modes of renal replacement therapies on thyroid function and morphology. Thus, the aim of our study was to examine thyroid hormone concentrations and morphology among patients on various forms of renal replacement therapy: hemodialysis, CAPD, and kidney transplantation. MATERIALS AND METHODS The study was performed on three groups of patients on renal replacement therapy: group I consisted of kidney transplant recipients, group II consisted of chronically hemodialyzed (HD) patients, and group III consisted of 26 peritoneal dialysis patients on CAPD. The 48 kidney transplant recipients (aged 26 – 64 years) displayed stable graft function (serum creatinine 1.75 ⫾ 0.59 mg/dL) without any infection (C-reactive protein within the normal ranges), and in the absence of a known family history of thyroid diseases. The immunosuppressive agents were cyclosporine, azathioprine, and prednisone. The average dose of cyclosporine was 280 ⫾ 80 mg/day (doses ranging from 175 to 425 mg/day). The mean trough concentration, as measured using the AxSYM system with polarized fluorescence, was 144 ⫾ 60 ng/mL. The average dose of prednisone was 7.5 mg/day. The mean azathioprine (Imuran) dose averaged 100 mg/day, (range between 50 and 150 mg/day). Patients had been engrafted for 9 months to 10 years (average 47 ⫾ 37 months). The average time on dialysis before transplantation was 37 months (range 10 – 80 months). The underlying renal pathology in these patients was chronic glomerulonephritis (n ⫽ ⫺29), pyelonephritis (n ⫽ 9), adult polycystic kidney disease (n ⫽ 5), and unknown (n ⫽ 5). The causes of renal failure among HD patients included chronic glomerulonephritis (n ⫽ 20), chronic interstitial nephritis (n ⫽ 9), polycystic kidney disease (n ⫽ 2), and unknown causes (n ⫽ 1). For HD patients blood was drawn in the morning between 8 and 9 AM to avoid circadian variations before the onset of the dialysis session and heparin administration. Ultrasonography of the thyroid gland was performed on a day between dialyses. All patients underwent regular hemodialyses for 4 to 5 hours a day three times a week. Blood flow was usually 180 to 230 mL/min, with a dialysate flow rate of 500 mL/min. Ultrafiltration varied according to the patient’s weight. Among CAPD patients, the renal failure was due to glomerulonephritis (n ⫽ 14), chronic interstitial nephritis (n ⫽ 5), polycystic kidney disease (n ⫽ 4), or other or unknown causes (n ⫽ 3). Blood samples were drawn in the morning when subjects, receiving their normal diet, appeared for routine assessment of dialysis therapy after an overnight oral fast. On the same day thyroid gland sonography was performed. All CAPD patients were performing four 2-L exchanges using a Baxter Twin-Bag system or Fresenius Andy Plus system. Dwell times were generally 4 to 6 hours during the day and 8 hours overnight. The osmotic pressure of the CAPD fluid was adjusted in accord with the extent of required ultrafiltration. Twenty-seven HD and 16 CAPD patients were treated with rHuEPO (Eprex, Janssen-Cilag, Switzerland-HD, NeoRecormon, Roche, Switzerland), using doses ranging from 2000 to 8000 U/week.
Patient height and weight were recorded for all groups. All patients were informed about the aim of the study and gave their consent. The study was approved by the local ethics committee. The control group consisted of 40 healthy volunteers without known thyroid pathology recruited from the medical staff members and their families. The thyroid evaluation employed various techniques of ultrasonography (B-mode, color Doppler-CD, power Doppler-PD), using a 7.5MHz probe. Three consecutive measurements were performed for each thyroid lobe, and these after the thyroid volume was calculated using the formula V ⫽ a ⫻ b ⫻ c ⫻ /6, where a,b, and c were the longitudinal, the transverse, and the antero-posterior dimensions of the thyroid lobes. The total thyroid volume was calculated as the sum of the lobe volumes. A healthy thyroid is visualized by ultrasound as homogenous. Cases in which at least one clearly (or slightly) delineated focus was observed, were classified as nonhomogenous. Due to unclear clinical and sonographic symptoms of benign versus malignant lesions (mainly cancer), a sonographically guided fine-needle aspiration biopsy (FNAB) was performed on suspected thyroid nodules. In addition, the following laboratory tests were performed hemoglobin, red blood cell count, total protein, albumin, cholesterol, triglycerides, urea (in HD patients before and after HD), TSH (MEIA) using standard laboratory methods. Intact PTH was estimated by a radioimmunoassay method using commercially available kits from Cis, France. Semiquantitative measurement of urine iodide was performed with Urojod test (Merck, Germany).
RESULTS
The biochemical characteristics of patients on renal replacement therapy are presented in Table 1 The patients were similar with regard to age, sex, underlying renal pathology, dialysis duration, and body mass index. The erythrocyte count, hemoglobin, serum cholesterol, and triglyceride levels were significantly higher among CAPD than HD subjects. Kidney transplant recipients showed significantly higher levels of serum cholesterol and triglycerides than hemodialyzed patients as well as higher total protein and albumin, with lower urea concentrations than peritoneally dialyzed patients. Serum PTH was significantly higher among dialyzed patients compared with control or kidney transplant recipients. The serum PTH content was significantly higher among kidney transplant recipients than healthy volunteers. There were no statistically significant differences in serum TSH between dialyzed patients, kidney transplant recipients (Table 1), and healthy volunteers (1.97 ⫾ 0.96 mU/mL). In all healthy volunteers except four, urine iodide was over 100 g/L. Only four CAPD and five kidney transplant recipients exhibited ioduria over 100 g/L. In five CAPD patients, eight Tx, and four healthy volunteers, urine iodide was between 50 and 100 g/L. The rest of the Tx and the CAPD patients as well as all of the HD patients shared urine iodide below 30 g/L. Thyroid nodules were found on sonography in 21 kidney allograft recipients (9 patients -single and 12 -multiple), in 12 HD patients (4-single, 8-multiple), and only two CAPD patients (multiple nodules). All of the nodules were smaller than 2 cm in diameter. Among kidney transplant recipients, 7 nodules were cystic, 21 solid/hypoechic, and 27 nonhomogenous.
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Table 1. Clinical Characteristics of the Hemodialyzed Patients, Peritoneally Dialyzed Patients and Kidney Transplant Recipients
Age (yrs) BMI (kg/m2) Duration of dialyses (months)/time after Tx Thyroid stimulating hormone (mU/mL) Hemoglobin (g/L) Erythrocyte count (mln/mm3) Cholesterol (mg/dL) Triglycerides (mg/dL) Total protein (g/L) Albumin (g/L) Urea before HD (mg/dL) urea in CAPD, Tx PTH (pg/mL)
HD n ⫽ 32
CAPD n ⫽ 26
TX n ⫽ 48
56 ⫾ 18 24.0 ⫾ 4.1 34 ⫾ 27 1.42 ⫾ 0.97 9.55 ⫾ 1.86### 3.12 ⫾ 0.61### 178.4 ⫾ 44.9### 110.1 ⫾ 52.6## 6.46 ⫾ 0.61 3.95 ⫾ 0.44 120.9 ⫾ 29.7# 332 ⫾ 310
51 ⫾ 11 23.2 ⫾ 3.6 31 ⫾ 24 1.46 ⫾ 0.86 10.42 ⫾ 2.41* 3.73 ⫾ 0.75* 219.2 ⫾ 45.1*** 156.7 ⫾ 72.7** 6.28 ⫾ 0.65* 3.45 ⫾ 0.54** 105.4 ⫾ 28.5 301 ⫾ 277
44 ⫾ 12 24.9 ⫾ 3.8 47 ⫾ 27 1.41 ⫾ 0.89 12.91 ⫾ 2.91°° 4.24 ⫾ 1.09°°° 213.8 ⫾ 40.6 137.1 ⫾ 51.7 6.80 ⫾ 0.66°° 4.14 ⫾ 0.48°°° 70.7 ⫾ 35.0° 204 ⫾ 115°
HD: hemodialysis; CAPD: continuous ambulatory peritoneal dialysis; Tx: transplant. Values given are means ⫾ SD. *P ⬍ .05, **P ⬍ .01, ***P ⬍ .001 HD vs CAPD. #P ⬍ .05, ##P ⬍ .01, ###P ⬍ .001 HD vs Tx. °P ⬍ .05, °°P ⬍ .01,
Among HD patients 3 nodules were solid, 2 normoechoic, and 15 hypoechoic. Among CAPD patients, all nodules were hypoechoic. Among six kidney transplant recipients papillary or follicular tumors were diagnosed on sonigraphically guided FNAB The rest of the kidney transplant recipients or the dialyzed patients showed benign goiters. In addition, 10 kidney transplant recipients, 12 HD patients, and 8 CAPD patients showed visualization of parathyroid glands on sonography. The thyroid volumes were 25.16 ⫾ 12.27 mL in Tx, 21.60 ⫾ 10.33 mL in HD, 19.70 ⫾ 8.46 mL in CAPD, and 16.34 ⫾ 5.46 mL in healthy volunteers. Thyroid volumes were largest in kidney transplant recipients, namely, statistically higher than those in CAPD patients or healthy volunteers. The difference in thyroid volume between kidney transplant recipients and HD patients almost reached statistical significance (P ⫽ .09), as well as between CAPD and healthy volunteers (P ⫽ .06). Thyroid volume in HD patients was not significantly higher than CAPD (P ⫽ .25). A positive correlation was observed between thyroid volume and creatinine (r ⫽ 0.44, P ⬍ .05), and (negative association between thyroid volume and TSH in Tx (r ⫽ 0.48, P ⬍ .05). The time after transplantation correlated negatively with TSH (r ⫽ ⫺0.5, P ⬍ .05). No correlation between TSH, thyroid volume, and time on dialysis was observed. DISCUSSION
Patients with end-stage renal disease exhibit multiple disturbances in thyroid hormone metabolism in the absence of concurrent thyroid disease. The described alterations includes those in serum thyroid hormones, namely, elevated basal TSH values, blunted TSH response to TRH, diminished or absent TSH diurnal rhythm, altered TSH glycosylation, and impaired TSH and TRH clearance rates.8 –11 In addition, serum total and free T3 and T4 values may be reduced and free rT3 levels elevated. In contrast, total values are normal, while serum binding protein concentrations may be altered.8 –11 Dialysis therapy minimally affects
°°°
P ⬍ .001 CAPD vs TX.
thyroid hormone metabolism,11 which normalizes following successful renal transplantation.12 However, data about thyroid hormone metabolism are limited. Premises reports have dealt mainly with hemodialyzed patients.6,11,13,14 Few Data with regard to thyroid hormones and morphology are available comparing the three methods of renal replacement therapy: HD, CAPD and kidney transplantation. We sought to address the question of whether these three methods affect TSH, thyroid morphology, and ioduria. We observed that TSH was within the lower normal range in all three groups of patients, not differing significantly from healthy volunteers. In contrast, urine iodide excretion, which was normal in healthy volunteers, was near normal in kidney transplant recipients but significantly reduced among dialyzed, particularly HD, subjects. It has been reported that due to reduced renal excretion of iodide, serum iodide levels are increased among patients with end-stage renal failure, despite decreased dietary iodide intake. Although inorganic iodide is removed by both HD and CAPD, serum iodide has been reported to be increased in CAPD and HD patients.15 Use of povidone-iodine for disinfecting arteriovenous fistulas for HD or Tenckhoff peritoneal cathethers may contribute to the rise in serum iodide in some dialyzed patients.15 Decreased urine iodide excretion and thus increased serum iodide may result in thyroid gland enlargement and subsequent goiter formation. The incidence of goiter in patients with renal failure has been reported to be higher5,6,11 than in general population. In our study, the prevalence of goiter was 100% in Tx, 50% in HD, and 25% in CAPD patients (according to WHO classification of goiter.16 Also, goiter frequency is related to the duration of hemodialysis. However, in our study, CAPD and HD patients did not differ significantly concerning time on dialysis. Time on dialysis prior to transplantation was also similar to the time on HD or CAPD. However, goiter was diagnosed in all Tx patients. In addition to urine iodide excretion, which was abnormal except in four cases, we sought other factors that might
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contribute to goiter formation, including duration of uremia before renal transplantation, residual renal function of the native kidneys, graft function, episodes of graft rejection, modulation of secretion, transport and degradation of hormones, or altered target organ responsiveness to hormones induced by immunosuppressive drugs (steroids, cyclosporine, azathioprine). In our study patients with episodes of acute graft rejection were excluded because these episodes are thought to produce alterations of the endocrine system similar to those seen in patients with acute or chronic renal failure.17 Successful kidney transplantation has been reported to improve renal function and to restore some thyroid function tests to normal, while the associated medications, such as high-dose steroids, may produce other abnormalities.12,18,19 Moreover, a high prevalence of thyroid nodules was observed in Tx. As reported previously,20 higher concentrations of cyclosporine were observed in patients having nodules, suggesting that immunosuppresion may contribute to the development of goiter as well as to nodule development. It has been reported that the presence of thyroid nodules is not related to age, duration of dialysis, PTH, or TSH.7 Our data corroborate these findings. However, it has been suggested that secondary hyperparathyroidism could also play a role.6 Therefore, we assessed PTH levels, observing that PTH was significantly higher among HD and CAPD patients compared to Tx and healthy volunteers. PTH was also significantly higher in Tx than control subjects but did not correlate with TSH, thyroid volume, or the presence of nodules. In conclusion, patients on dialysis or after renal transplantation have an increased frequency of goiter and thyroid nodules. Goiter in patients on renal replacement therapy may be induced by reduced renal iodide excretion. Screening for thyroid function goiter, and nodules should
be considered, particularly among patients on immunosuppressive therapy. REFERENCES 1. Kaptein EM, Finstein EI, Massry SG: Contrib Nephrol 33: 122, 1982 2. Sato K, Okamura K, Yoshinari M, et al: Acta Endocrinol (Copenhagen) 126:253, 1992 3. Beckers C, van Ipersele de Strihou C, Coche E, et al: J Clin Endocrinol Metab 29:293, 1969 4. Hegedus L, Andersen JR, Poulsen LR, et al: Nephron 40:171, 1985 5. Kaptein EM, Quion-Verde H, Chooljian CJ, et al: Medicine (Baltimore) 67:187, 1988 6. Kaptein EM: Endocr Rev 17:45, 1996 7. Miki H, Oshimo K, Inoue H, et al: J Surg Oncol 54:216, 1993 8. Lee PC, Tang MJ, Song CM, et al: Transplant Proc 26:184, 1994 9. Tessler FN, Tublin ME: Am J Roentgenol 173:37, 1999 10. Hardy MJ, Ragbeer SS, Nasimento L: J Clin Endocrinol Metabol 66:33, 1988 11. Lim VS: Am J Kidney Dis 38(Suppl 1):S80, 2001 12. Vaziri ND, Gvinup C, Martin D, et al: Clin Nephrol 15:131, 1981 13. Yonemura K, Nakajima T, Suzuki T, et al: Nephrol Dial Transplant 15:668, 2000 14. Lin CC, Chen TW, Ng YY, et al: Perit Dial Int 18:16, 1998 15. Gardner DF, Mars DR, Thomas RG, et al: Am J Kidney Dis 7:471, 1986 16. Indicators for Assessing Iodine Deficiency Disorders and Their Control Through Salt Iodization. World Health Organization. WHO/NUT/94.6 17. Kokot F, Grzeszczak W, Zukowska-Szczechowska E, et al: Blood Purif 8:76, 1990 18. Kaptein EM, Levitan D, Feinstein EI, et al: Am J Nephrol 1:138, 1981 19. Wartofsky L, Burman KD: Endocr Rev 3:164, 1982 20. Lebkowska U, Malyszko J, Brzosko S, et al: Transplant Proc 34:596, 2002