A Correlation Analysis of Serum Creatinine Based eGFR and Serum Cystatin C Based eGFR with Thyroid

(1)

pISSN 1738-3544 eISSN 2288-1662

A Correlation Analysis of Serum Creatinine Based eGFR and Serum Cystatin C Based eGFR with Thyroid

Dysfunction Patients

Gu Lim ^1,2,3 , Hyung-Doo Park ³ , Ho Joong Sung ^1,2

1

Department of Biomedical Laboratory Sciences, College of Health Science, Eulji University, Seongnam, Korea

2

BK21 Plus Program, Department of Senior Healthcare, Graduate School, Eulji University, Daejeon, Korea

3

Department of Laboratory Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

갑상선기능이상 환자에서 크레아티닌과 시스타틴을 이용한 사구체여과율 검사결과의 상관성 연구

임 구 ^1,2,3 , 박형두 ³ , 성호중 ^1,2

1

을지대학교 보건과학대학 임상병리학과,

²

을지대학교 대학원 시니어헬스케어학과,

³

성균관대학교 의과대학 삼성서울병원 진단검사의학교실

Serum creatinine-based eGFR and serum cystatin C-based eGFR are the most popular methods for measuring renal function. Thyroid hormone is known to affect serum creatinine-based eGFR and serum cystatin C-based eGFR; however, the clinical significance of thyroid dysfunctional patients of renal function evaluation has not been fully elucidated to date. This study examined the effect of thyroid hormone on serum creatinine-based eGFR and serum cystatin C-based eGFR. Moreover, we also evaluated the correlation analysis between serum creatinine-based eGFR and serum cystatin C-based eGFR in patients with thyroid dysfunction. A total of 442 patients with hypothyroidism and 284 patients with hyperthyroidism were investigated. A correlation analysis between thyroid hormone and serum creatinine- (and cystatin C-) based eGFR was performed. A correlation analysis between thyroid hormone and serum cystatin-C based eGFR indicated that serum cystatin-C based eGFR is more of an independent biomarker than serum creatinine-based eGFR in thyroid dysfunction patients. Therefore, serum cystatin C-based eGFR more accurately reflects renal function than serum creatinine-based eGFR in thyroid dysfunction patients.

Key words: Creatinine, Cystatin C, eGFR, Thyroid dysfunction

Corresponding author: Hyung-Doo Park Department of Laboratory Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Korea

Tel: 82-2-3410-0290 Fax: 82-2-3410-2719

E-mail: hyungdoo.park@samsung.com Co-Corresponding author: Ho Joong Sung Department of Biomedical Laboratory Sciences, College of Health Science, Eulji University, 553 Sanseong-daero, Soojeong-gu, Seongnam 13135, Korea Tel: 82-31-740-7306

Fax: 82-31-740-7425 E-mail: hjsung@eulji.ac.kr

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Received: July 25, 2017 Revised 1^st: July 31, 2017 Revised 2^nd: August 2, 2017 Accepted: August 2, 2017

INTRODUCTION

Thyroid dysfunction is an endocrine disease that shows various clinical features and can be diagnosed by laboratory findings such as thyroid hormone and thyroid stimulating hormone (TSH)[1]. Thyroid dysfunction is one

of the most common endocrine diseases caused by

synthesis, transport and metabolism of thyroid hormone

and impaired hormone activity. Thyroid dysfunction is

classified into overt hypothyroidism and overt hyperthy-

roidism. In general, the most reliable method of diagnosing

overt hypothyroidism and overt hyperthyroidism is to

(2)

measure TSH and thyroid hormone.

Overt hypothyroidism is characterized by increase of TSH concentration and decrease of thyroid hormone concentration in blood. Overt hyperthyroidism can be defined as decrease of TSH concentration and increase of thyroid hormone [2,3]. Thyroid hormone affects the physiology and function of the kidneys in various ways. In overt hypothyroidism, renal perfusion is affected by hemodynamic changes due to decrease of renal blood flow (RBF), decrease of cardiac output, decrease of renin angiotension system (RAS) activity, decrease of atrial natriuretic factor (ANF), etc., resulting in decrease of glomerular filtration rate (GFR). Conversely, in overt hyperthyroidism, blood volume and glomerular filtration pressure increase due to increase of cardiac output, RAS activation and increase of RBF, resulting in increase of GFR [4-8]. Best known method of measuring GFR is to directly administer external markers like Inulin, Iohexol,

¹²⁵

I-labele- dIothalamate,

⁵¹

Cr-ethylenediaminetetraacetic acid (EDTA), etc. on the patient and measure removal rate in the kidneys, but this method requires much time and effort.

Due to difficulty of having to directly administer markers on the patient, GFR is evaluated quickly and easily using a formula based on internal markers like serum creatinine, cystatin C, etc [9-11]. Thyroid dysfunction is known to play an important role in renal function changes. Over hypothyroidism and overt hyperthyroidism affect GFR, RBF, renal tubular function, electrolyte balance, and structural function of the kidneys [12]. Serum creatinine and cystatin C used as indicators of renal function are also affected by thyroid dysfunction. It is known that overt hypothyroidism results in high level of serum creatinine and low level of cystatin C. On the contrary, overt hyperthyroidism is associated with high level of serum creatinine and low level of cystatin C [13]. Change of serum creatinine according to thyroid dysfunction can be explained by the effect of thyroid hormone on GFR.

Cystatin C increases with increasing GFR in overt hyper- thyroidism, indicating that thyroid hormone is involved in the production of cystatin C in the general metabolic process. Therefore, when evaluating renal function using

serum creatinine and cystatin C, the condition of the thyroid gland must be considered. Therefore, this study aims to analyze the correlation of serum creatinine-based e-GFR and cystatin C-based e-GFR with general charac- teristics such as age, height, weight, sex, hypertension and diabetes, thyroid hormone, and TSH of patients with overt hypothyroidism and overt hyperthyroidism, to find the correlation of renal function indicators with thyroid dysfunction in Koreans, and to analyze usefulness of serum creatinine-based eGFR and cystatin C-based eGFR as renal function indicators.

MATERIALS AND METHODS

1. Subjects

The subjects of this study were 761 patients aged 14 years or older who were diagnosed with overt hypo- thyroidism and overt hyperthyroidism at Samsung Medical Center from 2012 to 2015. Among 761 patients, 442 patients were diagnosed with overt hypothyroidism, including 175 men (39.59%) and 267 women (60.41%), 276 patients with hypertension (62.4%), and 173 patients with diabetes (39.1%). Out of 284 patients diagnosed with overt hyperthyroidism, there were 131 men (46.10%) and 153 women (53.87%), 171 patients with hypertension (60.21%), and 89 patients with diabetes (31.34%). This study was approved by the Institutional Review Board (IRB) of Samsung Medical Center, and approval number is SMC 2016-03-133.

2. Measurement method

Blood samples were collected using vacuum blood

collection tube (BD Korea, Seoul, Korea), which is coated

with slice particles to facilitate coagulation of blood, and

centrifuged at 3,500 rpm for 5 minutes within 2 hours to be

examined on the same day. Thyroid hormone and TSH

were tested by chemoluminescence assay using ADVIA

CENTAUR XP (Simens Healthcare Diagnostics, Massachusetts,

USA). Reference value ranges of thyroid hormone are T

3

:

60∼181 ng/dL, T

4

: 3.2∼12.6  g/dL, free T4: 0.89∼1.8

ng/dL, and TSH: 0.55∼4.78  IU/mL. Serum creatinine was

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Table 1. Correlation among age, height, weight, sex, hypertension, and diabetes of patients with overt hypothyroidism

Variable N Correlation p -value

Serum creatinine based eGFR Age 410 −0.266 ＜0.001

Height 183 0.080 0.283

Weight 243 0.076 0.237

Sex 410 −0.020 0.681

HTN 410 −0.342 ＜0.001

DM 410 −0.270 ＜0.001

Serum cystatin C based eGFR Age 41 −0.222 0.164

Height 17 −0.077 0.768

Weight 24 0.177 0.409

Sex 41 −0.068 0.673

HTN 41 −0.544 ＜0.001

DM 41 −0.310 0.049

Abbreviations: eGFR, Estimated glomerular filtration rate; HTN, hypertension; DM, Diabetes.

analyzed by the Kinetic Jaffe reaction using Roche Modular (Roche Diagnostic GmbH, Mannheim, Germany) equipment.

The reference value range is 0.6∼1.3 mg/dL. Cystatin C was analyzed by immunology turbidimetric assay using Roche Modular (Roche Diagnostic GmbH, Mannheim, Germany) and Gentian Cystatin C Immunoassay Reagent (Gentian AS, Moss, Norway). The reference value range is 0.51∼1.05 mg/dL.

3. Glomerular filtration rate calculation formula

In this study, serum creatinine glomerular filtration rate was calculated using the MDRD formula used at Samsung Medical Center. The formula is as follows.

eGFRcr=175×(serum creatinine)

^−1.154

×(age)

^−0.203

(in case of women×0.742) [14]. Glomerular filtration rate of Cytatin C was calculated using the formula recommended by the reagent manufacturer. Based on comparison of the correlation between cystatin C and iohexol clearance test, the formula showed high correlation of R

²

=0.956. The formula is as follows. eGFRcys=79.901×(Cystatin C)

^−1.4389

[15,16]

4. Analysis method

Analysis was done by dividing groups into overt hypo- thyroidism, overt hyperthyroidism, other thyroid diseases and control. We analyzed the correlation among height, age, weight, gender, presence of hypertension, presence of diabetes, thyroid hormone, TSH and regional hormone of the subjects, serum creatinine-based eGFR, and cystatin

C-based eGFR. Statistical analysis was performed using SAS 9.4 (SAS Institute, Cary, NC) and R 3.3.1 (Vienna, Austria), and statistical significance level was p＜0.05.

RESULTS

1. Correlation among age, height, weight, sex, hypertension, and diabetes of patients with overt hypothyroidism

As a result of analyzing the correlation among age, height, weight, sex, hypertension, and diabetes, serum creatinine-based eGFR was significantly correlated with age, hypertension, and diabetes and cystatin C-based eGFR was correlated with hypertension and diabetes.

Hypertension and diabetes commonly showed significant results, indicating that serum creatinine-based eGFR and cystatin C-based eGFR measurements are affected by hypertension and diabetes. Only serum creatinine-based eGFR was significantly associated with age. This suggests that cystatin C-based eGFR is not affected by age as an independent factor compared to serum creatinine-based eGFR (Table 1, Figure 1A, 1B).

2. Correlation among T

3

, T

4

, free T

4

, and TSH in patients with overt hypothyroidism

As a result of analyzing the correlation with different

hormones, serum creatinine-based eGFR was significantly

correlated with T

3

, free T

4

, and TSH, and cystatin C-based

eGFR only showed significant correlation with T

3

. Corre-

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Figure 1. Correlation among age, height, weight, sex, hypertension, and diabetes of patients with overt hypothyroidism. (A) Correlation analysis between age, height, weight, sex, hypertension, diabetes and creatinine based eGFR with overt hypothyroidism patients, (B) Correlation analysis between age, height, weight, sex, hypertension, diabetes and cystatin C based eGFR with overt hypothyroidism patients (eGFR unit: mL/min/1.73 m

²

).

Table 2. Correlation among T

3

, T

4

, free T

4

, and TSH in patients with overt hypothyroidism

Variable N Correlation p -value

Serum creatinine based eGFR T

3

409 0.339 ＜0.001

T

4

269 0.061 0.3171

Free T

4

140 0.200 0.018

TSH 409 −0.105 0.034

Serum cystatin C based eGFR T

3

41 0.445 0.004

T

4

20 0.043 0.858

Free T

4

21 0.300 0.186

TSH 41 0.080 0.622

Abbreviations: T3, Triiodothyronine; T4, Thyroxine; Free T4, Free Thyroxine; TSH, Thyroid Stimulating Hormone.

lation analysis revealed that T

3

, free T

4

, and TSH influence measurement of creatinine-based eGFR and T

3

influences measurement of cystatin C-based eGFR in patients with overt hypothyroidism. These results suggest that cystatin C-based eGFR is a more independent measure of renal function for thyroid hormone and TSH than serum

creatinine-based eGFR during measurement of GFR for

evaluating renal function of patients with overt hypo-

thyroidism (Table 2, Figure 2A, 2B).

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Figure 2. Correlation among T

3

, T

4

, free T

4

, and TSH in patients with overt hypothyroidism. (A) Correlation analysis between T

3

, T

4

, Free T

4

, TSH and creatinine based eGFR with overt hypothyroidism patients, (B) Correlation analysis between T

3

, T

4

, Free T

4

, TSH and cystatin C based eGFR with overt hypothyroidism patients (eGFR unit: mL/min/1.73 m

²

).

Table 3. Correlation with thyroid hormone and TSH of patients with overt hypothyroidism in each interval

Variable N Correlation p -value

Serum creatinine based eGFR T

3

Low 122 0.078 0.391

Normal 284 0.196 ＜0.001

High 3 −0.500 0.667

T

4

Low 14 −0.040 0.893

Normal 250 −0.038 0.549

High 5 0.700 0.188

Free T

4

Low 43 0.026 0.869

Normal 92 0.105 0.320

High 5 0.100 0.873

TSH Low 57 −0.262 0.049

Normal 232 −0.019 0.769

High 120 −0.204 0.025

Serum cystatin C based eGFR T

3

Low 18 0.267 0.284

Normal 23 0.045 0.839

High 0 . .

T

4

Low 0 . .

Normal 19 −0.008 0.974

High 1 . .

Free T

4

Low 5 −0.200 0.747

Normal 16 0.135 0.617

High 0 . .

TSH Low 7 0.607 0.148

Normal 20 0.323 0.164

High 14 −0.059 0.840

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Figure 3. Correlation with thyroid hormone and TSH of patients with overt hypothyroidism in each interval. (A) Correlation analysis between T

3

and creatinine based eGFR with overt hypothyroidism patients in each interval, (B) Correlation analysis between and creatinine based eGFR with overt hypothyroidism patients in each interval, (C) Correlation analysis between Free and creatinine based eGFR with overt hypothyroidism patients in each interval, (D) Correlation analysis between and creatinine based eGFR with overt hypothyroidism patients in each interval (eGFR unit: mL/min/1.73 m

²

).

3. Correlation with thyroid hormone and TSH of patients with overt hypothyroidism in each interval Thyroid hormone and TSH levels of patients with overt hypothyroidism were divided into sections by upper limit value, normal value and lower limit value based on the range of reference values used at Samsung Medical Center, and the correlation of each interval with serum crea- tinine-based eGFR and cystatin C-based eGFR was analyzed. Serum creatinine-based eGFR showed significant results with normal value of T

3

and lower and upper limits of TSH, and cystatin C-based eGFR was insignificant in all intervals of each hormone. Statistical significance could

not be verified for some intervals because the number of subjects was too small (Table 3, Figure 3A∼3D).

4. Correlation with age, height, weight, sex, hypertension and diabetes of patients with overt hyperthyroidism

As a result of analyzing the correlation of serum

creatinine-based eGFR with age, height, weight, sex,

hypertension and diabetes, significant results were shown

by age, height, hypertension and diabetes. On the

contrary, none of them was significantly correlated with

cystatin C-based eGFR. In patients with overt hyper-

thyroidism, measurement of serum creatinine-based eGFR

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Figure 4. Correlation with age, height, weight, sex, hypertension and diabetes of patients with overt hyperthyroidism. (A) Correlation analysis between age, height, weight, sex, hypertension, diabetes and creatinine based eGFR with overt hyperthyroidism patients, (B) Correlation analysis between age, height, weight, sex, hypertension, diabetes and cystatin C based eGFR with overt hyperthyroidism patients (eGFR unit: mL/min/1.73 m

²

).

Table 4. Correlation with age, height, weight, sex, hypertension and diabetes of patients with overt hyperthyroidism

Variable N Correlation p -value

Serum creatinine based eGFR Age 272 −0.423 ＜0.001

Height 115 0.203 0.030

Weight 189 −0.072 0.328

Sex 272 0.101 0.097

HTN 272 −0.496 ＜0.001

DM 272 −0.269 ＜0.001

Serum cystatin C based eGFR Age 19 −0.013 0.957

Height 7 0.000 1.000

Weight 11 0.515 0.105

Sex 19 −0.156 0.524

HTN 19 −0.387 0.101

DM 19 −0.438 0.061

was significantly correlated with age, height, hypertension and diabetes, and measurement of cystatin C-based eGFR was not affected by these variables (Table 4, Figure 4A, 4B).

Therefore, when assessing kidney function of patients

with overt hyperthyroidism, cystatin C-based eGFR can be

described as an indicator that more accurately reflects

(8)

Table 5. Correlation with T

3

, T

4

, free T

4

and TSH of patients with overt hyperthyroidism

Variable N Correlation p -value

Serum creatinine based eGFR T

3

271 0.385 ＜0.001

T

4

210 0.281 ＜0.001

Free T

4

61 0.064 0.625

TSH 271 −0.323 ＜0.001

Serum cystatin C based eGFR T

3

19 −0.072 0.770

T

4

15 −0.452 0.091

Free T

4

4 0.800 0.200

TSH 19 0.309 0.198

Figure 5. Correlation with T

3

, T

4

, free T

4

and TSH of patients with overt hyperthyroidism. (A) Correlation analysis between T

3

, T

4

, Free T

4

, TSH and creatinine based eGFR with overt hyperthyroidism patients, (B) Correlation analysis between T

3

, T

4

, Free T

4

, TSH and cystatin C based eGFR with overt hyperthyroidism patients (eGFR unit: mL/min/1.73 m

²

).

renal function, independent of age, height, weight, sex, hypertension and diabetes, than serum creatinine-based eGFR.

5. Correlation with T

3

, T

4

, free T

4

and TSH of patients with overt hyperthyroidism

As a result of analyzing the correlation of serum creatinine-based eGFR with each hormone, significant results were shown by T

3

, T

4

, and TSH. The correlation of cystatin C-based eGFR with all hormones was insignificant.

When measuring GFR of patients with overt hyperthyroidism,

serum creatinine-based eGFR is affected by T

3

, T

4

and TSH

and is not affected by free T

4

. On the other hand, cystatin

C-based eGFR is not affected by thyroid hormone and

TSH. As a result, cystatin C-based eGFR in patients with

overt hyperthyroidism is an indicator of renal function

more independent of thyroid hormone and TSH than

serum creatinine-based eGFR (Table 5, Figure 5A, 5B).

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Table 6. Correlation with thyroid hormone and TSH of patients with overt hyperthyroidism in each interval

Variable N Correlation p -value

Serum creatinine based eGFR T3 Low 29 0.187 0.332

Normal 212 0.191 0.005

High 30 0.498 0.005

T4 Low 1 . .

Normal 178 0.101 0.179

High 31 0.341 0.060

Free T4 Low 5 −0.500 0.391

Normal 43 0.220 0.156

High 13 0.190 0.535

TSH Low 88 −0.235 0.027

Normal 155 −0.043 0.595

High 28 0.269 0.167

Serum cystatin C based eGFR T3 Low 6 −0.200 0.704

Normal 11 0.118 0.729

High 2 1.000 .

T4 Low 2 1.000 .

Normal 12 −0.179 0.579

High 1 . .

Free T4 Low 0 . .

Normal 3 0.500 0.667

High 1 . .

TSH Low 5 0.8 0.104

Normal 11 0.277 0.502

High 3 0.500 0.667

6. Correlation with thyroid hormone and TSH of patients with overt hyperthyroidism in each interval Thyroid hormone and TSH levels of patients with overt hyperthyroidism were divided into sections by upper limit value, normal value and lower limit value based on the range of reference values used at Samsung Medical Center, and the correlation of each interval with serum crea- tinine-based eGFR and cystatin C-based eGFR was analyzed. Serum creatinine-based eGFR showed significant results with normal value and upper limit of T3 and lower limit of TSH, and cystatin C-based eGFR was insignificant in all intervals of each hormone. Statistical significance could not be verified for some intervals because the number of subjects was too small (Table 6, Figure 6A∼6D).

DISCUSSION

This study was conducted based on previous studies that serum creatinine-based eGFR and cystatin C-based eGFR change according to change of thyroid hormone in

thyroid dysfunction [17].

Patients with thyroid dysfunction who were hospitalized at Samsung Medical Center from 2012 to 2015 were selected as the subjects, and thyroid dysfunction was classified into overt hypothyroidism, overt hyperthyroidism.

The correlation of serum creatinine-based eGFR and cystatin C-based eGFR with age, height, weight, sex, hypertension and diabetes of the thyroid dysfunction patients was analyzed. The correlation of serum crea- tinine-based eGFR and cystatin C-based eGFR with levels of thyroid-related hormones that appear in thyroid dysfunction was also analyzed. The conclusions of this study can be summarized as below. First, in patients with thyroid dysfunction, cystatin C-based eGFR is an indicator that better assesses renal function, independent of age, height, weight, sex, hypertension and diabetes of the subjects, compared to serum creatinine-based eGFR.

Second, in patients with thyroid dysfunction, cystatin

C-based eGFR is an indicator that better assesses renal

function, independent of thyroid hormone and TSH,

compared to serum creatinine-based eGFR. A more

(10)

Figure 6. Correlation with thyroid hormone and TSH of patients with overt hyperthyroidism in each interval. (A) Correlation analysis between T

3

and creatinine based eGFR with overt hyperthyroidism patients in each interval, (B) Correlation analysis between T

4

and creatinine based eGFR with overt hyperthyroidism patients in each interval, (C) Correlation analysis between Free T

4

and creatinine based eGFR with overt hyperthyroidism patients in each interval, (D) Correlation analysis between TSH and creatinine based eGFR with overt hyperthyroidism patients in each interval (eGFR unit: mL/min/1.73 m

²

).

in-depth study must be carried out with greater number of subjects in the future. Summarizing the results, in order to accurately assess renal function of patients with thyroid dysfunction, it would be necessary to calculate GFR using cystatin C, which has more statistically insignificant items and therefore can assess renal function more independently compared to serum creatinine, which has many statistically significant items. As for limitations of this study, since this study used examination results of patients who were diagnosed with overt hypothyroidism and overt hyper- thyroidism, medicines and treatments were not taken into consideration. However, this study is the very first study that verified significance of biomarkers for renal function assessment by performing correlation analysis of serum

creatinine-based eGFR and cystatin C-based eGFR, renal function indicators of patients with thyroid dysfunction, using clinical data.

요 약

혈청 크레아티닌 기반 eGFR과 혈청 Cystatin C 기반 eGFR

을 측정하는 것은 신장기능을 평가하기 위하여 가장 널리 이용

되는 방법이다. 갑상선호르몬은 혈청 크레아티닌 기반 eGFR과

혈청 Cystatin C 기반 eGFR에 영향을 미치는 것으로 알려져 있

다. 갑상선기능이상 환자에게서 신장기능평가에 대한 위의 두

마커의 임상적 의미는 아직 명료하게 밝혀지지 않았다. 이에 본

연구에서는 갑상선기능이상 환자에서 혈청 크레아티닌 기반

eGFR과 혈청 Cystatin C 기반 eGFR에 대한 갑상선호르몬의

(11)

영향과 상관성에 대하여 알아보고자 한다. 442명의 갑상선기능 저하 환자와 284명의 갑상선기능항진 환자를 대상으로 갑상선 호르몬과 혈청 크레아티닌 기반 eGFR, 혈청 Cystatin C 기반 eGFR과의 상관관계 분석을 하였다. 상관관계 분석 결과는 갑상 선기능이상 환자들에서 갑상선호르몬과 혈청 Cystatin C 기반 eGFR이 갑상선호르몬과 혈청 크레아티닌 기반 eGFR보다 독 립적으로 신장기능을 평가할수 있는 지표로 나타났다. 결론적 으로 갑상선기능이상 환자에서 혈청 Cystatin C 기반 eGFR이 혈청 크레아티닌 기반 eGFR보다 정확하게 신장의 기능을 반영 할 수 있는 지표인 것을 알 수 있다.

Acknowledgements: This research was supported by the Bio & Medical Technology Development Program of the National Research Foundation (NRF) & funded by the Korean government (MSIP&MOHW) (No. 2016M3A9B6904244).

Funding: None

Conflict of interest: None

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A Correlation Analysis of Serum Creatinine Based eGFR and Serum Cystatin C Based eGFR with Thyroid

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