Low Triiodothyronine: A New Facet of Inflammation in
End-Stage Renal Disease
      Carmine Zoccali, Giovanni Tripepi, Seba...
2790         Journal of the American Society of Nephrology                                                   J Am Soc Neph...
J Am Soc Nephrol 16: 2789 –2795, 2005                                                      fT3 and Inflammation in ESRD   ...
2792        Journal of the American Society of Nephrology                                         J Am Soc Nephrol 16: 278...
J Am Soc Nephrol 16: 2789 –2795, 2005                                                         fT3 and Inflammation in ESRD...
2794       Journal of the American Society of Nephrology                                          J Am Soc Nephrol 16: 278...
J Am Soc Nephrol 16: 2789 –2795, 2005                                                           fT3 and Inflammation in ES...
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  1. 1. Low Triiodothyronine: A New Facet of Inflammation in End-Stage Renal Disease Carmine Zoccali, Giovanni Tripepi, Sebastiano Cutrupi, Patrizia Pizzini, and Francesca Mallamaci CNR-IBIM, Clinical Epidemiology and Pathosphysiology of Renal Diseases and Hypertension, Ospedali Riuniti, Calabria, Italy Because inflammation influences thyroid function, it was hypothesized that low plasma free triiodothyronine (fT3) in ESRD may be an unsuspected expression of the inflammatory state of these patients. This study investigated (1) the steady-state relationship between fT3 and inflammation markers (IL-6 and C-reactive protein) and markers of endothelial activation (intercellular adhesion molecule-1 [ICAM-1] and vascular cellular adhesion molecule-1 [VCAM-1]) in 200 hemodialysis (HD) patients and (2) the effect of intercurrent acute inflammatory/infectious processes on plasma fT3 in a group of 17 patients with chronic kidney disease (CKD). HD patients displayed lower (P < 0.001) plasma fT3 than healthy subjects (n 31) and clinically euthyroid patients with chronic diseases and normal renal function (n 262). When HD patients were subdivided into IL-6 tertiles, fT3 was progressively lower across tertile increments (P < 0.001). Accordingly, regression analysis showed strong and inverse associations (P < 0.002) between fT3 and IL-6, C-reactive protein, ICAM-1, and VCAM-1, and, with the exception of the ICAM–fT3 relationship, these associations remained highly significant (P < 0.004) in multiple regression analyses adjusting for demographic variables, risk factors, and other potential confounders. In patients who had CKD and were studied during intercurrent inflammatory/infectious processes, fT3 was significantly lower (P 0.008) at the zenith of inflammation than after its resolution. Low circulating fT3 is frequently observed in inflammatory illnesses, and the same association exists in patients with CKD and in ESRD. This association may entail a causal link because fT3 is acutely and reversibly suppressed in patients with CKD during inflammatory processes triggered by intercurrent infections. J Am Soc Nephrol 16: 2789 –2795, 2005. doi: 10.1681/ASN.2005040356 C hronic renal failure is a widely recognized cause of on chronic dialysis (5–13), the hypothesis that low fT3 in pa- nonthyroidal illness (1,2), i.e., alterations in thyroid tients with ESRD can be explained in part by inflammation has hormones in the absence of underlying intrinsic thy- not been considered. This hypothesis has a solid rationale in roid disorder. Low levels of the active form of the thyroid that several lines of evidence indicate that cytokines have a role hormone, free triiodothyronine (fT3), is the hallmark of this in developing nonthyroidal illness. Serum IL-6 is often elevated disturbance, which is interpreted as a finalistic adaptation in nonthyroidal illness (14), and the plasma concentration of aimed at maintaining energy balance and minimizing protein this cytokine is inversely related to that of T3 (14 –16). Bolus wasting. Approximately one fourth of patients with ESRD dis- infusion of recombinant TNF- in humans produces a well- play low fT3, thyroid dysfunction being an emerging problem defined decrease in serum T3 (16), and chronic administration also in patients with moderate to severe chronic kidney dis- of IL-6 reduces serum T3 in patients with renal cancer (17). eases (3). Chronic renal failure apart, much interest has recently Furthermore, the role of this cytokine in nonthyroidal illness is been focused on the reduced fT3 plasma concentration ob- epitomized by observations in IL-6 knockout mice, in which served in various clinical conditions such as acute and chronic acutely induced illness is much less pronounced than in wild- infections; diabetes; and cardiovascular (CV) diseases, includ- type mice (18). Although mechanisms whereby cytokines per- ing myocardial infarction and heart failure (4), and this finding turb thyroid function are still poorly defined, the prevailing is now perceived as an alteration that is less innocent than view is that nonthyroidal illness is an acute-phase response previously thought (2). generated by activation of the cytokine network (19). Notwithstanding that the malnutrition-inflammation syn- In this study, we investigated the steady-state relationships drome is one of the most investigated issues in patients who are between IL-6 and C-reactive protein (CRP), i.e., two solidly established markers of the malnutrition-inflammation syn- drome 5,6 and the most metabolically active hormone (free T3) Received April 5, 2005. Accepted June 27, 2005. in hemodialysis patients. Furthermore, we examined the dy- Published online ahead of print. Publication date available at www.jasn.org. namic relationship between inflammatory markers and thyroid Address correspondence to: Prof. Carmine Zoccali, CNR-IBIM, Istituto di Bio- hormones during the evolution of inflammatory-infectious medicina, Epidemiologia Clinica e Fisiopatologia, Ospedali Riuniti, 89124 Reggio Calabria, Italy. Phone: 39-0965-397010; Fax: 39- 0965-397000; E-mail: complications in a series of patients with chronic renal insuffi- carmine.zoccali@tin.it ciency. Copyright © 2005 by the American Society of Nephrology ISSN: 1046-6673/1609-2789
  2. 2. 2790 Journal of the American Society of Nephrology J Am Soc Nephrol 16: 2789 –2795, 2005 Materials and Methods globin measurements were made by standard methods in the routine The protocol conformed to the ethical guidelines of our institution, clinical laboratory. fT3 and fT4 were measured by a commercially and informed consent was obtained from each participant. The steady- available RIA kit (Byk-Sangtek Diagnostica, Dietzenbach, Germany) state relationship between thyroid hormones and inflammation was and TSH by a sensitive IRMA (Byk-Sangtek Diagnostica). The intra- investigated in a survey in 200 hemodialysis patients with ESRD (105 assay coefficient of variation of these hormones ranged from 2.8 to men and 95 women, aged 61 15 yr). These patients were being treated 4.7%; and the interassay coefficient of variation was from 6.5 to 7.1%. in two dialysis centers that shared the same practice pattern. To be The upper limit of TSH of this assay is 3 mIU/L. We elected to use CRP included in the study, patients had to be free of intercurrent illnesses (Behring, Scoppito, Italy) and IL-6 as inflammation markers because in (infectious diseases, cardiocirculatory congestion, cancer, and any other a previous study we demonstrated that these compounds are the disease requiring hospitalization) and off drugs that may affect the strongest predictors of death among inflammatory proteins (11). Like- plasma concentration of thyroid hormones. Eighteen patients were wise, we measured the two major adhesion molecules, intercellular excluded from the study because they were taking -blockers. No adhesion molecule-1 (ICAM-1) and vascular cellular adhesion mole- patient was taking lithium, amiodarone, or other drugs that may inter- cule-1 (VCAM-1; R&D Systems Inc., Minneapolis, MN), as markers of fere with thyroid function. endothelial activation because these substances are associated with Patients were being treated thrice weekly with standard bicarbonate inflammation, malnutrition, and death in patients with CKD (20). dialysis (138 mmol/L Na, 35 mmol/L HCO3, 1.5 mmol/L K, 1.25 mmol/L Ca, and 0.75 mmol/L Mg) by cuprophane or semisynthetic Statistical Analyses membranes (dialysis filters surface area 1.1 to 1.7 m2). Dry weight was Data are reported as mean SD, median and interquartile range, or targeted in each case to achieve a normotensive edema-free state. The percentage frequency, as appropriate, and comparisons among more average urea Kt/V in these patients was 1.20 0.26. Seventy-one than two groups were made by one-way ANOVA followed by a P for patients were habitual smokers (22 16 cigarettes/d). A total of 107 trend test. Within-patient comparisons were made by the paired t test patients were on treatment with erythropoietin. Sixty patients were on (normally distributed data) or by Wilcoxon test (nonnormally distrib- antihypertensive treatment (48 on monotherapy with angiotensin-con- uted data). Relationships between continuous variables were analyzed verting inhibitors, AT1 antagonists, or calcium channel blockers and 12 by standard Pearson correlation analysis. Continuous variables with on double or triple therapy with various combinations of these drugs). positively skewed distribution were log transformed (lg10) before the We formed two control groups: One composed of 31 healthy indi- correlation study. viduals (recruited from the clinical and laboratory staff and from a To analyze the independent link between inflammation and fT3, we series of healthy senior members of an association that supports our divided patients into tertiles on the basis of the plasma concentration of institution) who were matched accurately (by 5-yr categories) to pa- IL-6. Tested covariates included thyroid hormones as well as a series of tients for gender and age (15 men, 16 women, average age 61 yr). traditional risk factors (age, male gender, previous CV events, smoking, Furthermore, for fT3 measurement only, we formed an additional diabetes, arterial pressure, heart rate, antihypertensive treatment, and control group that comprised 262 clinically euthyroid individuals (av- cholesterol), risk factors peculiar to dialysis patients (albumin, hemo- erage age 55 yr; range 20 to 85 yr; 136 men and 126 women) who had globin, calcium and phosphate, and homocysteine), and other markers normal renal function (creatinine 1.2 mg/dl) and were referred con- of inflammation or endothelial activation (CRP, ICAM-1, and VCAM- secutively to an internal medicine clinic for hypertension, gastrointes- 1). The independent association between plasma fT3 and IL-6, CRP, and tinal diseases, or osteoporosis. ICAM-1 and VCAM-1 was analyzed further by simple and multiple linear regression analyses. In this analysis, we included all covariates that differed among IL-6 tertiles as well as all correlates of plasma fT3 Thyroid Hormones Response to Inflammation-Infection in (with P 0.10). Data are expressed as correlation coefficients (r) or as Chronic Kidney Disease standardized regression coefficients ( ) and P values. All calculations These studies were performed in 17 consecutive patients who had were made using a standard statistical package (SPSS for Windows chronic kidney disease (CKD; age 55.8 19.7 yr; six women and 11 Version 9.0.1, Chicago, IL). men) and were admitted to our hospital because of high fever and markedly raised serum CRP. The median GFR in these patients was 25 ml/min per 1.73 m2 (interquartile range 8 to 33 ml/min per 1.73 m2). Results The cause of inflammation/infection was represented by systemic sep- The main demographic, somatometric, clinical, and biochem- sis triggered by bronchopulmonary or urinary infections in eight cases, ical characteristics of patients included in the study are detailed septic arthritis in two, limb abscess in two, influenza in two, infected in Table 1. A total of 102 patients had had at least one CV event. central catheters in one, brucellosis in one, and lupus erythematosus In particular, 52 patients had had one CV event (myocardial reactivation in one. infarction in six cases, ECG documented anginal episodes in 27 Blood sampling in these cases was performed at the outset of the cases, peripheral artery diseases in 12 cases, arrhythmia in three inflammatory-infectious process and repeated when the process was either much attenuated or resolved. In this study, we measured plasma cases, transient ischemic attacks in two cases, and stroke in two CRP, IL-6, fT3, free thyroxine (fT4), and serum thyrotropin (TSH). case), and the remaining 50 patients had had two or three (n 43) or more than three (n 7) CV complications. Laboratory Measurements All blood tests in hemodialysis patients were performed between Steady-State Relationship between fT3 and Inflammation 8:00 and 10:00 a.m. midweek, during the dialysis interval. After 20 to 30 Markers min of quiet resting in semirecumbent position, samples were taken Patients who were on chronic hemodialysis (3.3 0.8 pg/ml) into chilled EDTA Vacutainers, placed immediately on ice, and centri- had lower fT3 (P 0.001) than healthy subjects (3.7 1.0 fuged within 30 min at 4°C, and the plasma was stored at 80°C pg/ml) and clinically euthyroid patients with normal renal before assay. Serum lipids, albumin, calcium, phosphate, and hemo- function (3.6 0.8 pg/ml). fT4 did not differ between hemo-
  3. 3. J Am Soc Nephrol 16: 2789 –2795, 2005 fT3 and Inflammation in ESRD 2791 Table 1. Main demographic, clinical, and biochemical data of dialysis patients (n 200)a IL-6 P for Trend I Tertile II Tertile III Tertile ( 3.0 pg/ml; n 68) (3.1 to 7.0 pg/ml; n 67) ( 7 pg/ml; n 65) Age (yr) 54 16 60 13 67 12 0.001 Male gender (n % ) 38 (57%) 31 (46%) 36 (55%) 0.94 Dialysis vintage (mo) 30 (14 to 77) 55 (25 to 124) 41 (24 to 96) 0.49 Smoker (n % ) 26 (39%) 23 (34%) 22 (34%) 0.60 Diabetes (n % ) 12 (18%) 10 (15%) 13 (20%) 0.73 On antihypertensive (n % ) 20 (30%) 25 (37%) 15 (23%) 0.44 With previous CV events (n % ) 26 (39%) 34 (51%) 42 (65%) 0.002 Systolic pressure (mmHg) 133 22 128 26 130 23 0.52 Diastolic pressure (mmHg) 75 9 72 15 72 12 0.12 Pulse pressure (mmHg) 63 20 61 18 67 19 0.32 Heart rate (beats/min) 79 10 81 11 82 12 0.13 Hemoglobin (g/L) 108 18 108 18 107 20 0.69 Albumin (g/L) 43 4 42 5 39 4 0.001 Calcium phosphate (mmol2/L2) 4.51 1.04 4.44 1.28 4.47 0.95 0.83 Homocysteine ( mol/L) 28.9 (19.2 to 50.4) 24.3 (20.8 to 32.7) 29.0 (20.2 to 43.5) 0.53 Cholesterol (mmol/L) 5.38 1.72 5.42 1.20 5.35 1.40 0.92 CRP (mg/L) 3.5 (3.4 to 9.6) 7.0 (3.4 to 14.7) 15.6 (4.7 to 28.8) 0.001 IL-6 (pg/ml) 2.3 (1.3 to 2.8) 4.8 (3.9 to 6.1) 11.4 (9.3 to 17.2) 0.001 ICAM-1 (pg/ml) 243 (208 to 283) 260 (227 to 324) 304 (257 to 374) 0.001 VCAM-1 (ng/ml) 1026 (823 to 1281) 1101 (959 to 1415) 1260 (931 to 1548) 0.02 fT3 (pg/ml) 3.7 0.8 3.5 0.7 2.8 0.7 0.001 fT4 (ng/100 ml) 1.1 (1.0 to 1.4) 1.2 (1.1 to 1.3) 1.2 (1.0 to 1.4) 0.56 TSH (mIU/L) 1.3 (0.9 to 2.0) 1.5 (1.0 to 2.3) 1.5 (0.8 to 2.1) 0.79 a Data are expressed as mean SD, median and interquartile range, or percentage frequency, as appropriate. CV, cardiovascular; CRP, C-reactive protein; ICAM-1, intercellular adhesion molecule-1; VCAM-1, vascular cellular adhesion molecule-1; fT3, free triiodothyronine; fT4, free thyroxine; TSH, thyrotropin. dialysis patients (1.23 0.25 ng/100 ml) and healthy control independently associated with fT3 (P 0.004). Of note, a com- subjects (1.25 0.22 ng/100 ml). Fifteen hemodialysis patients plementary analysis correlating fT3 and previous CV events (7.5%) had TSH above the upper limit (cutoff 3 mIU/L) of the revealed a graded inverse relationship (P 0.001) between the normal range. number of past CV events and the plasma concentration of fT3 When hemodialysis patients were subdivided into three ter- (Figure 2). tiles on the basis of the plasma IL-6 concentration, it emerged that those in the third tertile were older and had a higher Thyroid Hormone Response to Inflammation-Infection proportion of background CV complications. Patients in the in CKD third tertile displayed lower albumin than those in the other As shown in Figure 3, at the peak of intercurrent inflamma- two tertiles (Table 1). Remarkably, fT3 was progressively lower tory processes, both CRP and IL-6 were very high and fell from the first tertile of IL-6 onward, and overall 43 and 11% of substantially after the resolution of these processes (P 0.001). patients displayed fT3 values 90th percentile of the distribu- fT3 was significantly lower (P 0.008) at the zenith of inflam- tion of fT3 in healthy subjects and clinically euthyroid control mation than after its resolution, and the magnitude of such patients with normal renal function, respectively. The associa- suppression was independent of the GFR (fT3 change versus tion between IL-6 and fT3 that emerged in this categorical GFR, r 0.13, P 0.62). Likewise, inflammation-induced sup- analysis was confirmed in analyses that considered IL-6 as a pression of fT3 was independent of age, gender, smoking, continuous variable. Indeed, fT3 correlated inversely with IL-6 cholesterol, arterial pressure, hemoglobin, and other variables as well as with CRP, ICAM-1, and VCAM-1 and directly with listed in Table 1 (P ranging from 0.12 to 0.97). No changes were albumin (Figure 1). Importantly, associations between fT3 with observed in plasma fT4 and TSH. all inflammation markers but ICAM-1 remained significant also in multiple regression analyses adjusting for demographic vari- Discussion ables, risk factors, and other potential confounders (Table 2). This study shows that thyroid function, as characterized on Indeed, in this analysis, IL-6, CRP, and VCAM-1 remained the basis of the plasma concentration of the active form of the
  4. 4. 2792 Journal of the American Society of Nephrology J Am Soc Nephrol 16: 2789 –2795, 2005 Figure 1. Relationships between free triiodothyronine (fT3) and IL-6, C-reactive protein (CRP), intercellular adhesion molecule-1 (ICAM-1), vascular cellular adhesion molecule-1 (VCAM-1), and albumin. Data are correlation coefficients and P values. Table 2. Multiple regression analysis of plasma fT3a P Age 0.14 0.03 Background CV complications 0.006 0.92 Albumin 0.29 0.001 Smoking 0.03 0.54 Diabetes 0.13 0.03 Pulse pressure 0.08 0.21 Hemoglobin 0.03 0.54 IL-6 0.25 0.001 CRP 0.17 0.004 ICAM-1 0.04 0.51 VCAM-1 0.17 0.004 Figure 2. Relationship between plasma fT3 and number of back- a Data are expressed as standardized regression coefficient ground cardiovascular (CV) complications. ( ) and P value. Dependent variable: plasma fT3. Multiple R 0.67, R2 0.45, P 0.001. Intensive studies in the 1980s and 1990s revealed that renal insufficiency affects thyroid function in multiple ways, includ- thyroid hormone (fT3), is associated with markers of inflam- ing altered peripheral hormone metabolism, disturbed binding mation and endothelial activation in stable patients with ESRD. to proteins, reduction in tissue thyroid hormone content, and This association may entail a causal link because we also found iodine accumulation in thyroid glands (1). Furthermore, uremic that fT3 is suppressed during inflammatory processes that are patients have a variety of nonrenal, nonthyroidal disorders that triggered by intercurrent infections and that it reverts to normal affect thyroid hormone metabolism, such as diabetes, infec- as inflammation resolves. tions, and malnutrition, and they are often treated by drugs that
  5. 5. J Am Soc Nephrol 16: 2789 –2795, 2005 fT3 and Inflammation in ESRD 2793 and perhaps any severe illness (2). A reduction in plasma fT3 is the most precocious alteration signaling thyroid dysfunction while a more complex syndrome, characterized also by reduced plasma fT4, develops as the severity of illness and the associ- ated malnutrition progress. The association between inflamma- tion markers and thyroid dysfunction in nonthyroidal illness has been investigated intensively, and the hypothesis that cy- tokines may be instrumental in reducing circulating thyroid hormones now has solid support (2,14,15). Indeed, deranged thyroid function in nonthyroidal illness is currently considered as an acute-phase response generated by activation of a cyto- kine network, with IL-6 playing a fundamental role (15). High plasma IL-6 is an important feature of nonthyroidal illness, and it is well established that in this syndrome, circulating IL-6 mirrors T3 levels. A causal involvement of IL-6 in nonthyroidal illness is suggested by the observation that chronic administra- tion of this cytokine produces clear-cut suppression of plasma T3 (17). The role of IL-6 in thyroid dysfunction is also sup- ported by data in the IL-6 knockout mice. Indeed, in this experimental model, the administration of bacterial endotoxin causes a much less pronounced reduction in plasma T3 than in wild-type mice (18). Studies in patients with hypothyroidism and in the general population revealed consistent and intriguing links between biomarkers of inflammation and thyroid hormones. CRP levels are overtly elevated in patients with either subclinical or clini- cal hypothyroidism (23). fT4 levels are negatively correlated with those of fibrinogen (24), and it was speculated that down- regulation of thyroid function may be a mechanism whereby Figure 3. Relationship between acute inflammation/infection inflammatory processes induce CV damage. By the same token, (zenith versus nadir) and circulating levels of IL-6, CRP, and fT3 is known to be subnormal in approximately 30% of hospi- fT3. IL-6 and CRP are reported as median and interquartile talized patients with heart failure (4), i.e., a disease associated range and fT3 as mean SD. with high IL-6 plasma levels (25). It has been hypothesized that low fT3 in heart failure may specifically contribute to myocar- diopathy, and some advocate the therapeutic use of T3 in interfere with thyroid function (1). In ESRD, both plasma fT3 patients with subnormal plasma concentration of this hormone and T3 are often reduced, and this alteration is attributed to (26,27). To our knowledge, our study is the first to investigate impaired extrathyroidal T4 to T3 conversion, whereas T4 and the relationship between inflammation markers and thyroid fT4 are much less frequently depressed in these patients (21). hormones in ESRD. Remarkably, we found consistent and in- The different behavior of fT4 and fT3 in ESRD may depend on dependent inverse associations between IL-6 and CRP and an the fact that the depression of T3 is much greater than that of T4 indicator of endothelial activation/dysfunction (VCAM-1) and and/or that, T3 being less tightly bound to thyroid-binding fT3 in these patients. Besides these steady-state associations, we globulin than T4, alterations in thyroid hormone binding in found that fT3 was reduced to an important extent during ESRD are more apt to disturb the interpretation of T4 assays intercurrent inflammatory processes and that this alteration than those of T3 (2). resolved as inflammation faded away. This phenomenon doc- The malnutrition-inflammation complex is a major clinical uments that like in other clinical situations, inflammation problem in patients with ESRD. This complex is not only the acutely interferes with thyroid function in patients with CKD hallmark of a negative protein-energy balance but also a fun- and that this interference is fully reversible and independent of damental risk factor implicated in the high mortality and in CV the GFR. Homocysteine, another risk factor that has previously complications of the dialysis population (5–9). Notwithstand- been associated with inflammation, is increased in hypothy- ing that malnutrition was suspected as a possible cause of roidism. In this study, homocysteine was unrelated to IL-6 and disturbed thyroid function in ESRD in 1996 (22), the issue CRP or to fT3. whether inflammation is implicated in low fT3 has received no The risk for CV events increases in parallel with IL-6 levels attention so far. Nonthyroidal illness is a clinical syndrome both in the general population (28) and in the ESRD population characterized by a disturbance in thyroid function of increasing (10,11). Our finding that low fT3 is closely associated with IL-6 severity that may occur in disparate stressful conditions such as and CRP seems to be of relevance. Individuals with subclinical starvation/malnutrition, sepsis, surgery, myocardial infarction, carotid atherosclerosis display lower fT4 levels than those who
  6. 6. 2794 Journal of the American Society of Nephrology J Am Soc Nephrol 16: 2789 –2795, 2005 present with normal arteries (29), and it is interesting to note C: Inflammation enhances cardiovascular risk and mortal- that a relationship exists between arterial intima-media thick- ity in hemodialysis patients. Kidney Int 55: 648 – 658, 1999 ness and CRP in patients with ESRD (12). Given the potentially 9. Ikizler TA, Wingard RL, Harvell J, Shyr Y, Hakim RM: important role of low fT3 in CV diseases (30), depressed fT3 in Association of morbidity with markers of nutrition and ESRD may be an unsuspected player in the high risk associated inflammation in chronic hemodialysis patients: A prospec- tive study. Kidney Int 55: 1945–1951, 1999 with inflammation in these patients, an issue that clearly de- 10. Pecoits-Filho R, Barany P, Lindholm B, Heimburger O, serves to be explored in more extensive and specifically de- Stenvinkel P: Interleukin-6 is an independent predictor of signed studies. mortality in patients starting dialysis treatment. Nephrol Our study has limitations. Although very consistent, the Dial Transplant 17: 1684 –1688, 2002 multiple associations between inflammation markers and fT3 11. Tripepi G, Mallamaci F, Zoccali C: Inflammation markers, may not entail a causal link, and the direction of causality, if adhesion molecules, and all-cause and cardiovascular mor- any, remains unresolved. In this regard, it is worth noting that tality in patients with ESRD: Searching for the best risk the links between inflammation and thyroid function may be marker by multivariate modeling. J Am Soc Nephrol complex and perhaps bidirectional. Indeed, lipoprotein(a), a 16[Suppl 1]: S83–S88, 2005 pro-atherogenic protein and an acute-phase reactant that is 12. Zoccali C, Benedetto FA, Mallamaci F, Tripepi G, Fermo I, strongly associated with CRP in ESRD (31), is significantly Foca A, Paroni R, Malatino LS: Inflammation is associated reduced by d-thyroxin treatment in clinically euthyroid ESRD with carotid atherosclerosis in dialysis patients. Creed In- vestigators. Cardiovascular Risk Extended Evaluation in patients (32). The observation that acute inflammation causes a Dialysis Patients. J Hypertens 18: 1207–1213, 2000 reversible decrease in fT3 is compatible with the hypothesis 13. Kalantar-Zadeh K, Block G, McAllister CJ, Humphreys that this relationship is causal and that inflammation is the MH, Kopple JD: Appetite and inflammation, nutrition, trigger of low fT3 in these patients. However, further studies anemia, and clinical outcome in hemodialysis patients. are needed in steady-state ESRD patients to determine whether Am J Clin Nutr 80: 299 –307, 2004 pharmacologic interventions aimed at reducing inflammation 14. 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