Relation of Thyroid Disfunction, Thyroid Autoantibodies, and Renal Function

Abstract

Fifty-eight patients with thyroid dysfunction were included, comparing 27 healthy subjects to evaluate the relationship between thyroid autoimmunity, thyroid functional status, and renal function. Regardless of clinical status, hypothyroidism was defined as T3–T4 < normal limits and TSH>upper limit of normal, and hyperthyroidism was defined as T3–T4>normal limits and TSH < 0.1 mcU/mL. In all participants, serum antithyroperoxidase level, serum antithyroglobulin level, creatinine clearance (CC), and urinary albumin excretion rate (UAER) in 24-h urine collections were measured. Of 85 persons, 41 patients ages 20 to 71 years (median; 44) had hypothyroidism, 17 patients ages 22 to 56 years (median; 32) had hyperthyroidism, and 27 subjects ages 20 to 67 years (median; 50) were normal. Regarding thyroid autoantibody positiveness, the positive group had a higher UAER than the negative group (30.2 mg/day, 20.8 mg/day, respectively; p = 0.05). In hypothyroid patients, UAER was significantly higher than in hyperthyroid patients and control subjects (30.1 mg/day, 11.8 mg/day, 10.5 mg/day, respectively; p < 0.001). In the hypothyroid population, with regard to UAER and CC, we could not find a significant difference between the thyroid autoantibody positive and negative groups. In view of CC, hypothyroid patients had significantly lower CC than the hyperthyroid group (79.0 mL/min, 86.5 mL/min, respectively; p < 0.01). A careful control of the renal function in thyroid diseases should be evaluated. Renal dysfunction seems to be secondary to hypothyroidism rather than thyroid autoimmunity.

• renal function
• thyroid autoimmunity
• thyroid dysfunction
• thyroid autoantibodies

Introduction

Thyroid hormone plays an important role in kidney growth and in the maintenance of many of its functions.[1&2] The hyperthyroid state is characterized by a hyperdynamic circulation with elevated cardiac output, diminished peripheral vascular resistance, and intrarenal vasodilation.[3] Overall renal function is preserved in thyrotoxicosis because glomerular filtration rate (GFR), renal plasma flow (RPF), and tubular reabsorptive and secretory ability are usually increased. In hyperthyroid patients, mean creatinine clearance was 62% higher than that of euthyroid patients.[2] In hypothyroidism, cardiac output decreases, peripheral vascular resistance increases, and intrarenal vasoconstriction occurs.[3] Therefore, effective RPF and GFR in hypothyroid patients are approximately one-third lower than the respective values in euthyroid individuals.[2] The defect, which is corrected by administration of thyroid hormone,[4] is frequently subtle and difficult to diagnose because most patients have normal or slightly increased blood urea nitrogen and serum creatinine levels, and clearance measurements are not routinely performed.[5] Serious hypothyroidism can also be accompanied by morphologic changes in the glomeruli, such as thickening of the glomerular basement membrane, as well as increased mesangial matrix, thickening of the tubular basement membrane, and cytoplasmic inclusions in renal tubular epithelial cells.[2], [6] An increased transcapillary leaking of the plasma proteins such as albumin has also been reported in hypothyroid patients, which can lead to mild proteinuria, generalized edema, pleural and pericardial effusions, and ascites in these patients.[7&8] Mild proteinuria has been reported in approximately 30% of patients with autoimmune thyroid disease. The proteinuria did not appear to be related to thyroid status and persisted after treatment.[9]

Herein, the effect of thyroid autoimmunity on renal functions, which involved in urinary albumin excretion rate (UAER) and creatinine clearance (CC), was investigated in patients with hypothyroidism and hyperthyroidism by comparing them with healthy subjects. To the best of our knowledge, this is the first investigation that includes hypo- and hyperthyroid patients in the same study.

Material and Method

Forty-one untreated patients with hypothyroidism ages 20 to 71 years (median; 44), 17 untreated patients with hyperthyroidism ages 22 to 56 years (median, 32), and 27 healthy patients ages 20 to 67 years (median, 50) were included. Persons were excluded who were pregnant; who had urinary infection, nephrotoxic medications, acute severe disease, chronic renal insufficiency, and diabetes mellitus; or who had disorders in addition to thyroid dysfunction that might have affected renal function.

Ethical approval was obtained, and each subject gave written informed consent following an explanation as to the nature and purpose of the study.

In all patients, the thyroid dysfunction was diagnosed by measurement of the serum levels of thyroid hormones and thyrotropin. Regardless of clinical status, hypothyroidism was defined as T3–T4 < normal limits and TSH>upper limit of normal, hyperthyroidism was defined as T3–T4>normal limits, and TSH < 0.1 mcU/mL. Causes of hypothyroidism were Hashimoto thyroiditis (n = 21) and postablative hypothyroidism (n = 20), and hyperthyroidism included Graves' disease (n = 3) and toxic nodule(s) (n = 14).

In all participants, serum antithyroperoxidase (anti-TPO) level, serum antithyroglobulin (anti-Tg) level, serum and urinary creatinine level, and UAER in 24-h urine collections were measured. CC in 24-h urine samples was used for estimating GFR. The level of UAER of 30 to 300 mg/day was accepted as microalbuminuria, the more levels were taken as macroalbuminuria. None of the participants was investigated for anti-TSH-receptor antibody.

Statistical analysis was performed by the chi-square test. In addition, to compare multiple groups, we used Krsukall-Wallis nonparametric test with post hoc Mann-Whitney U test to evaluate significance of the differences. Statistical significance was assumed at p < 0.05.

Results

The characteristics of the subjects were detailed in Table 1. Thyroid autoantibody (anti-TPO and anti-Tg) was positive in 28 (35.9%) patients. The prevalence of thyroid autoantibody positiveness was higher in hypothyroid patients (46.3%) than in hyperthyroid patients (17.6%), but this difference was not significant.

Table 1. Characteristics of patients

	Hypothyroidism	Hyperthyroidism	Control subjects
No. of patients	41	17	27
Mean of age	43.5 ± 12.3	34.4 ± 9.5	48.7 ± 11.9
Male	7	9	13
Female	34	8	14

In thyroid autoantibody positive group, UAER had higher than negative group (30.2 mg/day, 20.8 mg/day, respectively; p = 0.05), but both levels were almost in normal range. Besides, the prevalence of microalbuminuria in the thyroid autoantibody positive population was 31.8%, whereas that in the antibody negative one was 22.2%. The difference between these groups was not significant (Table 2). However, mean CC in the antibody positive group was not significantly different than in the negative one. Regarding thyroid autoantibody positiveness, the differences between UAER and CC in the positive group and those in the negative group were not significant.

Table 2. Association of thyroid autoantibody with UAER and CC

	TAA positive	TAA negative	P value
Mean UAER (mg/day)	30.2	20.8	= 0.05
Mean CC (mL/min)	79.8	82.1	NS
Prevalence of microalbuminuria	31.8%	22.2%	NS

TAA, thyroid autoantibodies; UAER, urinary albumin excretion rate; CC, creatinine clearance; NS, not significant.

Mean UAER was significantly higher in the hypothyroid group (30.1 mg/day) than in the hyperthyroid (11.8 mg/dL) and control (10.5 mg/dL) groups (p < 0.001), but these three results were almost in normal range. The overall difference in UAER and CC among three groups was significant (p < 0.001, p = 0.02; respectively). In addition, mean CC value was significantly lower in hypothyroid patients (79.0 mL/min) when compared with hyperthyroid group (86.5 mL/min) (p < 0.01), but the CC value difference between hypothyroid patients and control subjects was not significant. The values of UAER and CC were slightly increased in hyperthyroid patients compared with the control group, but the differences were not significant. The prevalence of microalbuminuria in the hypothyroid population was 36.6%, whereas microalbuminuria was not present in the hyperthyroid and control groups (p < 0.01; Table 3). None of the participants had macroalbuminuria.

Table 3. Relation between thyroid functional status with UAER and CC

	Hypothyroidism	Hyperthyroidism	Control	P value
Mean UAER (mg/day)	30.1,#	11.8	10.5	< 0.001
Mean CC (mL/min)	79.0**	86.5	84.1	= 0.02
Prevalence of microalbuminuria	36.6%	0%	0%

UAER, urinary albumin excretion rate; CC, creatinine clearance.

^#p < 0.001 for the comparison with control.

*p < 0.001 vs. hyperthyroid patients.

**p < 0.01 vs. hyperthyroid patients.

In the hypothyroid population, in view of UAER and CC, we also could not find a significant difference between the thyroid autoantibody positive and negative groups (Table 4).

Table 4. Association of thyroid autoantibody (TAA) with UAER and CC in hypothyroid population

	TAA positive	TAA negative	P value
Mean UAER (mg/day)	32.9	27.9	NS
Mean CC (mL/min)	79.3	78.8	NS
Prevalence of microalbuminuria	46.7%	53.3%	NS

TAA, thyroid autoantibodies; UAER, urinary albumin excretion rate; CC, creatinine clearance; NS, not significant.

Discussion

Thyroid hormones have extensive effects on renal functions. Metabolic rate set by thyroid hormones is one of the major determinants of GFR.[1] Although hyperthyroidism can cause hyperfiltration in the kidneys along with a hyperdynamic physiology, hypothyroidism can result in the impairment of GFR.[2] The measurement of CC is an acceptable method for the assessment of GFR.[10] Weetman et al. claimed that mild proteinuria was present in 29.8% of the patients with thyroid autoimmune disease.[9] In a few patients with thyroid autoimmune disease, kidney damage and nephrotic syndromes have been reported.[11] There are few data about thyroid autoantibody effects on renal functions independently from thyroid hormone metabolic status. Therefore, we investigated thyroid autoantibody effects on renal functions. Glomerular injury secondary to immune complexes, as postulated by Weetman et al.,[9] seems a less likely cause in the majority of patients. In our study, the prevalence of microalbuminuria was found in 31.8% of patients with thyroid autoantibody positiveness, and this result was consistent with the literature.

Although the increase of UAER was mildly significant in patients who had thyroid autoantibody positiveness compared with those with autoantibody negative, most patients with autoantibody positive were hypothyroid. Furthermore, among the hypothyroid population, differences between values of UAER and CC in the autoantibody positive group and those in the negative group were not significant. In this situation, we consider that albuminuria probably is due mainly to hypothyroidism rather than to thyroid autoimmunity.

Both GFR and RPF are low in the hypothyroid states and return to normal values after thyroxine therapy.[1&2], [5], [8], [12] The mechanism(s) of the decrease in GFR is unknown. This rapid improvement suggests that renal changes in the hypothyroid state are functional, reversible, and do not cause permanent histologic damage.[5] It may be related to the decrease in the circulating atrial natriuretic factor, which is known to increase GFR,[12] or to an adaptive preglomerular vasoconstriction to avoid a filtrate overload of the tubular system as a consequence of a deficiency of sodium and water reabsorption in the proximal tubule.[13] In experimental studies, overt hypothyroidism is commonly associated with increased sCr.[14] Our study was similar with some literature[1], [8], [15] that CC in hypothyroid patients was less than the control group, but not statistically significant.

The transcapillary escape rate of albumin in subclinical hypothyroid condition increases.[7] Advanced hypothyroidism was reported to be associated with increased intraglomerular pressure and glomerulopathy resulting in albuminuria.[5] Karanikas et al. showed by using radiopharmaceutical agents that the tubular function is less impaired than the glomerular function during hypothyroidism.[16] In our study, UAER in hypothyroid patients was significantly higher than in control group and hyperthyroid patients. We consider that in thyroid hormone deficiency, albuminuria has been developed earlier than the decrease of the GFR.

In hyperthyroid patients, both renal blood flow and the capacity of the renal tubules to carry out active transport are increased.[17&18] Ford et al. found that the total protein/creatinine ratio was increased in random urine specimens from hyperthyroid patients. In addition, they observed significant elevations in the values for albumin/creatinine in hyperthyroid patients compared with the same patients when they became euthyroid.[18] In our study, both UAER and CC were slightly elevated in hyperthyroid patients compared with control group, but there were no significant differences. However, both UAER and CC values in hyperthyroid patients were significantly higher than in hypothyroid patients.

In conclusion, according to our study, renal dysfunction seems to be secondary to hypothyroidism rather than thyroid autoimmunity; therefore, a careful control of the renal function in thyroid disease should be evaluated.