Pretransplant serum FT3 levels in kidney graft ... - Wiley Online Library

Clinical Endocrinology (2008) 68, 220–225

doi: 10.1111/j.1365-2265.2007.03022.x

ORIGINAL ARTICLE

Pretransplant serum FT3 levels in kidney graft recipients are useful for identifying patients with higher risk for graft failure Blackwell Publishing Ltd

Mario Rotondi*, Giuseppe Stefano Netti†, Alberto Rosati‡, Benedetta Mazzinghi†, Flavia Magri*, Elisa Ronconi†, Francesca Becherucci†, Fabio Pradella§, Maurizio Salvadori‡, Mario Serio†, Paola Romagnani† and Luca Chiovato* *Unit of Internal Medicine and Endocrinology, Fondazione Salvatore Maugeri I.R.C.C.S., University of Pavia, Pavia, †Excellence Center for Research, Transfer and High Education (DENOThe), University of Florence, Florence, ‡Center for Nephrology, Dialysis and Transplantation, Azienda Ospedaliera di Careggi, Florence, §Immunogenetics Unit, Azienda Ospedaliera di Careggi, Florence, Italy

Summary Objective End-stage renal disease (ESRD) is a condition associated with thyroid disturbances both in function and morphology. Recent studies demonstrated that serum free triiodothyronine 3 (FT3) levels are negatively correlated with serum markers of inflammation and endothelial activation in patients with ESRD. However, no previous research evaluated serum thyroid function parameters in relation to kidney graft outcome, as we aim to do so in this study. Design Serum FT3, free thyroxine 4 (FT4) and TSH levels were measured before transplantation in 196 kidney graft recipients. Results The graft survival rate at 5 years for all patients was 92·3%. Kidney graft recipients with normally functioning grafts showed serum pretransplant thyroid parameters similar to patients who experienced graft failure. Life-time analysis was performed after stratification of patients according to pretransplant serum FT3 levels < 3·1 pmol/l or > 3·1 pmol/l. A significantly different 5-year death-censored graft survival rate (93·9% vs. 76·5% for patients with normal or low FT3 levels, respectively; P < 0·01) and similar survival rate (death of patients with functioning grafts) (21·1% vs. 5·9%; P = 0·288) were observed. No similar feature was found for FT4 or TSH, suggesting that the effect is not related to hypothyroidism but rather dependent upon inappropriately low FT3 levels. Pretransplant serum FT3 levels were similar in patients who experienced early acute rejections as compared with nonrejector patients. Conclusions The results of this study demonstrate that among patients with ESRD undergoing kidney transplantation, those displaying lower pretransplant serum FT3 levels are at higher risk for subsequent graft failure. The demonstration of a predictive value of serum FT3 levels for graft survival suggests that measurement of pretransplant serum FT3 levels might represent a clinically

Correspondence: Prof. Luca Chiovato, Chair of Endocrinology, Unit of Internal Medicine and Endocrinology, Fondazione Salvatore Maugeri I.R.C.C.S. University of Pavia, Via S. Maugeri 10, I-27100 Pavia, Italy. Tel: +39-0382-592240; Fax: +39-0382-592692; E-mail: [email protected]

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useful parameter to identify patients with increased risk for graft failure. (Received 17 April 2007; returned for revision 24 April 2007; finally revised 17 May 2007; accepted 19 July 2007)

Introduction End-stage renal disease (ESRD) is a condition associated with a wide spectrum of thyroid disturbances, both in function and morphology.1 The thyroidal repercussions of ESRD are mostly due to the effects of uraemia and altered excretion, transport and degradation of thyroid hormones. Hormonal changes may include elevated serum TSH levels, blunted TSH response to TRH, impaired TSH clearance rate, reduced serum free triiodothyronine 3 (FT3) and free thyroxine 4 (FT4) levels in the absence of TSH elevation and abnormal serum binding protein levels.1 In patients with end-stage renal disease, the most frequently observed alteration of circulating thyroid parameters is the so-called nonthyroidal illness, a condition defined as an alteration of thyroid hormones levels in the absence of intrinsic thyroid disorder. The hallmark of such a condition is a low circulating concentration of FT3, which is viewed as an adaptive change aimed at reducing energy expenditure and protein wasting.2 Apart from nonthyroidal illness, patients with ESRD show an increased prevalence of subclinical and overt hypothyroidism, mainly due to an autoimmune cause.3 The fact that reduced FT3 concentrations are also found in many other chronic conditions, including diabetes, and the fact that diabetic patients account for more than 40% of ESRD patients waiting for a transplant, has raised awareness of the issue of kidney transplantation in endocrinologists.4,5 Recent studies have focused attention on low serum FT3 levels in patients with end-stage renal disease, demonstrating that this parameter is significantly associated with serum markers of inflammation and endothelial activation in patients with ESRD.6 A negative correlation between serum FT3 and creatinine has been reported in patients undergoing kidney transplantation.7 Thus, © 2007 The Authors Journal compilation © 2007 Blackwell Publishing Ltd

Serum FT3 and kidney graft outcome 221 serum triiodothironine concentrations correlate with the function of the renal graft. The above reported findings suggested that alterations in the serum levels of FT3 may have important repercussions on transplant function. Given the fact that allograft failure is one of the most common cause of ESRD, it is clear that surrogate measures are needed for the prediction of graft survival at the earliest stage of transplantation in order to guide effective therapeutic approaches. Recently clinical studies have demonstrated that high pretransplant serum levels of CXCL10, a CXC chemokine, are significantly related to a lower rate of graft survival and to a higher occurrence of acute rejection (AR) in kidney graft recipients.8 However, there are no published results in which thyroid function parameters have been evaluated before transplantation and related to graft outcome. The aim of this study was to correlate pretransplant serum levels of thyroid hormones and TSH with the graft outcome in kidney graft recipients. Evaluating thyroid parameters in relation to the graft outcome may be useful to identify, before transplantation, those patients who carry a higher risk for graft failure. This could be helpful for establishing more effective therapeutic strategies aimed at prolonging graft survival.

Patients and methods This retrospective study was performed by collecting a total of 196 cadaveric kidney transplants carried out at the Florence Transplant Centre, between January 1991 and June 2001. Included in the study were all patients for whom pretransplant sera samples were available. All patients were on haemodialysis before transplant and underwent measurements of main haematochemical parameters every 6 months. All patients were on active transplant waiting list, which implies that all of them were in good physical and psychiatric health with no systemic infections, cancer, HIV positivity or other life-threatening conditions with life expectancy lower than 2 years. Furthermore, they were not taking corticosteroids or other immunosuppressive drugs. Pretransplant serum thyroid function parameters (FT3, FT4 and TSH) were retrospectively measured and related to the graft outcome. Serum thyroid parameters were assayed in an aliquot of the serum specimen which had been used for final cytotoxic cross-match at the time of transplantation (within 1 month before transplantation). All the recipients were Caucasians. The following are the demographic characteristics of the recipients (see also Table 1): age: 47·0 ± 11·4 years, gender Male/Female: 121/75, duration of dialysis age: 36·1 ± 30·1 months, original disease: glomerulopathies 37·8%, autosomal dominant polycystic kidney disease 23·5%, interstitial nephritis 17·3%, nephroangiosclerosis 15·8%, and others 5·6%. Ninety-five percent of the patients received cyclosporin-based immunosuppression, while the remaining 5% received tacrolimus-based immunosuppression. Human leucocyte antigen (HLA) typing and panel reactive lymphocytotoxic antibody determinations were performed at the Tissue Typing Laboratory of Azienda Ospedaliera Careggi in Florence. Patients with 5% antibody reactivity against a randomly chosen lymphocyte test panel were categorized as sensitized and represented 15% of all subjects. The number of HLA-A + B + DR mismatches was < 3 in 43% and ≥ 3 in 57% of patients. Donor age was 45·1 ± 15·9 years, and cold ischaemia

Table 1. Clinical characteristics of the kidney transplant recipients in relation to graft outcome Survived N Sex (Male/Female) Age at transplantation (years) Time on dialysis (months) Type of dialysis (haemodialysis vs. peritoneal dialysis) Panel reactivity Ab ≥ 5% Total mismatch (HLA-A, -B, -DR) Donor sex (Male/Female) Donor age (years) Cold ischaemia time (hours) Delayed graft function Acute rejection CXCL10 (ng/l) FT3 (pmol/l) FT4 (pmol/l) TSH (mIU/l)

Failed

181 110/71 46·9 ± 0·8 36·1 ± 2·3 153/28

15 11/4 48·9 ± 2·9 34·9 ± 6·1 12/3

28/153 2·64 ± 0·72 101/80 44·5 ± 1·2 19·8 ± 0·48 39/142 37/144 119·8 ± 8·0 4·17 ± 0·60 13·7 ± 0·25 1·56 ± 0·13

2/13 2·33 ± 0·29 7/8 51·9 ± 3·97 21·5 ± 1·1 5/10 6/9 253·3 ± 46·3 3·86 ± 0·36 14·07 ± 0·48 0·91 ± 0·13

P-value

0·42 0·52 0·88 0·71 0·83 0·25 0·49 0·82 0·31 0·33 0·07 0·00002 0·17 0·71 0·16

Data are presented as mean ± SEM. FT3, free triiodothyronine 3; FT4, free thyroxine 4. The parameters showing significant differences are in bold characters.

time was 19·9 ± 6·3 h. Information on graft function and patient survival were collected at 1, 3 and 6 months and at 1, 2, 3, 4 and 5 years. The mean follow-up time after transplant, including patients who experienced graft failure, was 88·8 ± 36·6 months. Informed consent, concerning the future use of serum samples and clinical-pathological data for research purposes, was obtained from all patients included in the present study. This was in accordance with the guidelines laid down by the Regional Ethics Committee on human experimentation. All acute rejection (AR) episodes were biopsy proven and were classified according to Banff classification9 and treated with steroids. Serum assays Serum concentrations of FT3 (normal range 2·3–6·3 pmol/l), FT4 (normal range 10·3–24·4 pmol/l) and TSH (normal range 0·4 –4·0 mIU/l) were measured using immunochemoluminiscent assays by an automated analyser (Immulite 2000, DPC Cirrus, Los Angeles, CA) employing commercially available kits (all from Diagnostic Products Corporation, Los Angeles, CA). The intra-assay coefficient of variation for these hormones ranged, respectively, from 8·4% to 4·3% for FT3, 7·5% to 5·2% for FT4 and 12·5% to 5·1% for TSH, while the interassay coefficient of variation ranged, respectively, from 10·0% to 5·4% for FT3, 9·0% to 7·7% for FT4 and 12·5% to 6·4% for TSH. The analytical sensitivities were, respectively, 1·5 pmol/l for FT3, 3·8 pmol/l for FT4 and 0·004 mIU/l for TSH (third generation TSH assay). Serum CXCL10 levels were assayed by a quantitative sandwich immunoassay using a commercially available kit (R & D Systems, Minneapolis, MN), with a mean minimum detectable dose of 1·67 ng/l and a maximum detectable dose of 500 ng /l. The intra- and interassay coefficients of variation were 3%

© 2007 The Authors Journal compilation © 2007 Blackwell Publishing Ltd, Clinical Endocrinology, 68, 220–225

222 M. Rotondi et al.

Fig. 1 Pretransplant serum free triiodothyronine 3 (FT3) levels at the lower limit of the normal range are associated with an increased rate of allograft failure. Recipients with serum FT3 levels lower than the 10th centiles (< 3·1 pmol/l; N = 17; solid line) showed a significantly lower 5-year death censored rate of graft survival than recipients with serum FT3 levels above the 10th centiles (> 3·1 pmol/l; N = 179; broken line); (76·5% vs. 93·9%, respectively). In this analysis, death with a functioning graft was not counted as graft failure (Kaplan-Meier life-time analysis and log-rank test; P < 0·01).

and 6·1%, respectively. Samples were assayed in duplicate. Quality control pools at low, normal and high concentrations for all parameters were present in each assay, respectively. Statistical analysis Statistical analysis was performed using SPSS software (SPSS Inc, Evanston, IL). Serum parameters were compared between groups by means of Student’s t-test for unpaired data and Mann–Whitney U-test owing to normal or nonparametric distribution. Correlation between two variables was ascertained by Pearson and Spearman’s correlation tests as appropriate. To test the independent effects of different variables on kidney allograft survival, Cox regression analysis was used and partial correlation coefficients were computed. Kaplan-Meier estimates were used to generate an overall survival curve for transplanted grafts and differences among groups were assessed by log-rank test. Graft failure was defined as the need to return to dialysis. Frequencies of allograft failure were compared among groups by χ2-test. A P-value < 0·05 was considered statistically significant. Results are expressed in the text as mean ± SEM unless otherwise stated.

Results The clinical characteristics of patients are shown in Table 1. The graft survival rate for all patients after a 5-year follow-up period was 92·3%. No significant difference in pretransplant serum thyroid hormones and TSH were found in kidney graft recipients according to subsequent graft outcome. Life-time analysis performed after the assignment of all patients to two groups according to their pretransplant serum FT3 levels above or below the 10th centiles of the values found in the whole study group (3·1 pmol/l) showed a significant difference in 5-year

Fig. 2 Pretransplant serum levels of free triiodothyronine 3 (FT3) and CXCL10. Pretransplant serum FT3 and serum CXCL10 levels are not significantly correlated with each other in kidney graft recipients.

death censored graft survival rate for patients displaying normal FT3 levels as compared with those with serum FT3 levels below 3·1 pmol/l (93·9% vs. 76·5%; P < 0·01) (Fig. 1). Such a result was specifically related to serum FT3 as no significant influence on graft survival rate could be demonstrated for FT4 and TSH. Three of five patients with circulating FT3 concentrations below the lower limit of the normal range (median 1·76 pmol/l, range 1·54–2·17 pmol/l) experienced graft loss accounting for a very low 5-year death censored graft survival rate (40%). Pretransplant parameters which might influence graft outcome such as donor age, cold ischaemia time, total number of HLA mismatches, time on dialysis and pretransplant serum CXCL10 were similar in patients with pretransplant serum FT3 levels < 10th centile and > 10th centile values. Life-time analysis for patient survival (death of patients with functioning grafts) was performed on the same groups of patients. Similar death rates were observed for patients with serum FT3 levels > 10th centiles compared with patients with serum FT3 levels < 10th centiles (21·1% vs. 5·9%; P = 0·288). Previous studies demonstrated a significant role for serum CXCL10 levels on graft survival8 and such results were confirmed in this study (Table 1). No correlation was found between pretransplant serum FT3 and CXCL10 levels in our series of patients (Fig. 2). In order to further discriminate between the effect of circulating FT3 and CXCL10, the two parameters were entered into two separate Cox regression analysis models, using graft failure as dependent variable and FT3 and CXCL10 as covariates. The results demonstrated that when FT3 and CXCL10 were entered as continuous variables, only CXCL10 significantly influenced graft survival (Table 2). On the other hand, when FT3 and CXCL10 were entered as dichotomous variables (< 10th centile and > 10th centile for FT3 and < 150 ng/l or > 150 ng/l for CXCL10) both variables were significantly and independently related to graft survival (Table 2). The cut-off of


Serum FT3 and kidney graft outcome 223

Fig. 3 Combined effect of pretransplant serum free triiodothyronine 3 (FT3) and CXCL10 on kidney graft survival. Kidney graft recipients exhibit significantly different 5-year death censored graft survival rates after stratification for the presence of risk factors for graft loss. Recipients with pretransplant serum FT3 levels > 3·1 pmol/l and CXCL10 and < 150 ng/l (no risk factor, N = 141; solid thick line) display a very high graft survival rate (97·2%). Patients carrying either one of the risk factors (FT3 < 3·1 pmol/l and CXCL10 < 150 ng/l, N = 13; solid thin line, or FT3 > 3·1 pmol/l and CXCL10 > 150 ng/l, N = 38; broken thin line) had similar graft survival rate (84·6%, vs. 81·6%). Patients with pretransplant serum FT3 levels < 3·1 pmol/l and CXCL10 levels > 150 ng/l (both risk factors, N = 4; broken thick line) showed extremely high rate of graft loss (50·0%). In this analysis, death with a functioning graft was not counted as graft failure. (Kaplan-Meier life-time analysis and log-rank test; P < 0·0001.)

8,10

150 ng/l for CXCL10 was choosen according to previous results. The effect of the two combined parameters was also investigated and found to be additive. Indeed, life-time analysis performed after the assignment of all patients to four groups in relation to the combined effect of the two parameters (CXCL10 > 150 ng/l and < 150 ng/l; FT3 < 10th centile and > 10th centile) revealed significant differences (P < 0·0001) in 5-year survival rates for the four groups (Fig. 3). In detail, an extremely high survival rate (97·2%) for patients with normal FT3 and low CXCL10 contrasted with the similar rates observed in patients carrying either one of the two risk factors, 81·6% and 84·6% for the subgroup showing normal FT3 and high CXCL10 and for patients with low FT3 and CXCL10 < 150 ng/l,

Table 2. Relative risks for graft failure according to two separate Cox regression analysis models in which the covariates free triiodothyronine 3 (FT3) and CXCL10 were entered as continuous or dichotomic variable 95% CI

FT3 (pmol/l) CXCL10 (ng/l) FT3 < 3·1 pmol/l CXCL10 > 150·0 ng/l

P-value

Relative risk

Lower

Upper

0·250 0·001 0·016 0·001

0·711 1·004 4·093 5·700

0·397 1·002 1·300 2·023

1·272 1·006 12·885 16·056

The parameters showing significant influences on graft survival are in bold characters.

Fig. 4 Pretransplant serum free triiodothyronine 3 (FT3) levels and occurrence of early acute rejection in patients receiving kidney transplant. Pretransplant serum FT3 levels are similar in kidney graft recipients irrespective of the occurrence of rejection episodes within the first month after transplantation. (Mann–Whitney U-test.) Data are expressed as median and 25th and 75th percentiles in boxes and 5th and 95th percentiles as whiskers.

respectively. Patients carrying both risk factors, although their number was limited to four cases, showed a much lower survival rate (50%). In order to evaluate the mechanisms by which FT3 and CXCL10 lead to graft failure, the occurrence of AR episodes was taken into account. In line with previous findings, the 43 patients who developed early acute rejections had significantly higher pretransplant median serum levels of CXCL10, 116·0 ng/l (25·2–895·9) as compared with 87·9 ng/l (4·7–438·2) for the 153 nonrejector patients (P < 0·05). The circulating concentrations of FT3 were similar in patients developing early acute rejection as compared with patients not experiencing this clinical event. No trend within the range of FT3 values for increased rejection was observed (Fig. 4). These results suggested that unlike CXCL10, whose role in determining graft failure is closely related to its action on immune-mediated events, other mechanisms should be proposed to explain the effect of low serum FT3 levels. The fact that among thyroid function parameters only FT3, but not FT4 and TSH, significantly influenced graft survival suggested that this effect was unrelated to thyroid function but rather dependent upon inappropriately low FT3 levels. For this reason patients displaying a serum concentration of FT3 < 10th centile were evaluated with regard to their FT4/FT3 ratio. Interestingly, patients experiencing graft loss had significantly higher FT4/FT3 ratio as compared to patients with normally functioning grafts (6·8 ± 1·9 vs. 4·8 ± 1·0; P < 0·05). On the other hand, patients with pretransplant serum FT3 > 10th centile levels showed similar FT4/FT3 ratios, irrespective of graft outcome.


224 M. Rotondi et al.

Discussion The results of this study demonstrate that pretransplant serum FT3 levels in the lower normal range are associated with an increased risk of graft failure in patients receiving kidney transplant for ESRD. No such a relationship was observed for FT4 and TSH. Furthermore, among patients with low FT3, those who experienced graft loss showed a significantly higher FT4/FT3 ratio as compared with those with normal functioning grafts. Taken together, these findings support the hypothesis that low pretransplant triiodothyronine plays a role when it reflects the clinical picture of the ‘low total triiodothyronine 3 (T3) syndrome’ rather than hypothyroidism. This finding is particularly relevant in that it would not support treatment with levothyroxine (L-T4) in ESRD patients, a therapeutic strategy proposed by some authors.7 The specificity of the association between low pretransplant serum FT3 levels and graft outcome is further confirmed by the finding that no relationship was found between the circulating concentrations of FT3 and all cause mortality. This finding might seem to contradict previous reports demonstrating that low triiodothyronine levels are a significant short-term predictor of death in various diseases, including patients with ESRD.11–13 The different cut-off level used in these studies for defining low serum levels of FT3 (pathological concentrations or concentrations in the lower 10th centiles), as well as the different length of the surveillance period may both account for the discrepancy. Furthermore, in the current study, the serum levels of FT3 were measured before transplantation in order to estimate their predictive value on graft outcome. Thus, serum FT3 levels were not influenced by surgery and/or post-transplant immunosuppressive treatments, which are known to profoundly affect serum thyroid function parameters and particularly FT3·14,15 Growing evidence suggests that CXCL10, a chemokine of the CXC 16 17,18 family, is important for the immune response to transplant. The action of CXCL10 seems to be mostly dependent upon its ability to promote more frequent and severe Th-1 immune-mediated reactions19 such as AR episodes, which are a major cause of morbidity in transplanted patients and predisposed to graft loss.17 In line with previous findings,8,10 CXCL10 was significantly higher in patients experiencing early AR as compared to nonrejector patients. On the contrary, pretransplant serum FT3 levels were similar in kidney recipients irrespective of the development of AR. A previous study reported decreased circulating concentrations of total T3 and FT3 in the course of acute graft failure and AR.15 Another peculiarity of the serum levels of FT3 as compared with CXCL10 in determining graft loss is provided by the results of the Cox regression model. When the two parameters were entered as continuous variables, only CXCL10 was significantly related to graft outcome while a significant and independent effect of both CXCL10 and FT3 was demonstrated when they were entered as dichotomic variables. Unlike CXCL10 which exerts its action in ‘a dose dependent manner’,8 FT3 seems to be a significant parameter influencing graft outcome only when below a certain cut-off. The above reported findings suggest that the mechanisms by which the two variables act on graft outcome are profoundly different. This observational study does not permit conclusions with regards to the mechanism by which low levels of serum FT3 would facilitate

graft loss. As far as it is possible to speculate, previous experimental evidence may provide a clue for the interpretation of the above reported results. Malnutrition/inflammation syndrome has been widely investigated in ESRD patients.6 The hypothesis that low FT3 in these patients can be explained at least in part by inflammation is based upon the solid rationale that cytokines have a role in the development of nonthyroidal illness.2 It has been recently demonstrated that in kidney graft recipients, serum FT3 levels are inversely correlated with circulating markers of inflammation such as CRP and IL-6.6 Circulating IL-6 concentrations are also inversely correlated with serum thyroid hormones levels in patients with nonthyroidal illness.20,21 This is in line with the view that nonthyroidal illness is an acute-phase response generated by activation of the cytokine network.2,22 The low T3 syndrome is characterized by depressed cardiac function and elevated systemic vascular resistance.23 Moreover, a recent study performed in humans has demonstrated that T3 exerts direct and acute effects on the resistance vessels by enhancing endothelial function and norepinephrineinduced vasoconstriction24 Taken together these data may help to clarify the vascular impact of the low T3 syndrome and may sustain its role in mediating the impairment of endothelial fuction.24,25 Endothelial dysfunctions and consequent transplant atherosclerosis are commonly observed in kidney graft recipients and are responsible for graft loss.25 Therefore, it seems reasonable to hypothesize the existence of a link between thyroid status, endothelial damage, inflammation and graft loss, and which deserve further investigation.25 In conclusion, the results of this study demonstrate that among patients with ESRD undergoing kidney transplantation, those displaying lower pretransplant serum FT3 levels have a significantly higher risk for subsequent graft failure. A second finding emerging from this study is that serum FT3 levels have been assayed pretransplant, thus constituting the first demonstration of a predictive value of serum FT3 levels for graft survival.

Acknowledgements The experiments reported in this paper were supported in part by funds from the TRESOR Research Project of the Tuscany Region (Italy) and by Progetto di Ricerca Finalizzata ex art.12, del D.Lgs.502/ 92–2005.

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