Albuminuria is an independent risk factor of T4 elevation in chronic kidney disease

www.nature.com/scientificreports OPEN Albuminuria is an independent risk factor of T4 elevation in chronic kidney disease received: 10 August 2016 Xin Du1,*, Binbin Pan1,*, Wenwen Li2, Yonghua Zou3, Xi Hua1, Wenjuan Huang1, Xin Wan1 & Changchun Cao1 accepted: 19 December 2016 Published: 24 January 2017 This study was to explore the association between thyroid dysfunction and albuminuria. 581 cases with chronic kidney disease (CKD) were included in this study. The clinical characteristics consisted of sex, age, serum creatinine, urinary albumin-to-creatinine ratio (ACR), thyroid function were recorded. Estimated glomerular filtration rate (eGFR) was calculated by CKD-EPI four-level race equation. Prevalence of different thyroid diseases was calculated by chi-square test. Levels of thyroid hormone were compared among different albuminuria groups by Kruskal-Wallis test. Spearman’s correlation was used to assess the association between albuminuria and thyroid hormone. Our study showed that total T4 and free T4 were significantly different among ACR < 30 mg/g, 30–300 mg/g and >300 mg/g (P < 0.001 and =0.007, respectively). Positive correlation between T4 (total T4 and free T4) and albuminuria was evaluated by correlation analysis (P = 0.001 and <0.001, respectively). Albuminuria was an independent influence factor of T4 after adjustment for age, sex, serum creatinine, albumin, hs-CRP, smoking status, systolic blood pressure, diabetes mellitus, medication use for diabetes mellitus, eGFR, LDL-cholesterol, triglycerides, hypertension, and medication use for hypercholesterinemia. In conclusion, T4 was positively correlated with albuminuria, and it was completely not consistent with our anticipation. Further study is needed to elucidate the causation association between albuminuria and T4. Chronic kidney disease (CKD) is a global public health problem, affecting 10–16% of the adult population worldwide1. CKD is characterised by low estimated glomerular filtration rate (eGFR) and high albuminuria1, persistent for more than three months1, and is associated with adverse outcomes, irrespective of hypertension2, diabetes3, age4, and sex5. Persistent proteinuria and/or albuminuria for more than three months is a hallmark of CKD6. It is well established that the kidney is capable of participating in all aspects of peripheral thyroid hormone (TH) metabolism. Intact THs are filtered, reabsorbed and secreted by the kidney. A major route of iodide elimination is by urinary excretion7. Nephrotic syndrome is associated with changes in serum TH levels8. Urinary losses of binding proteins, such as thyroxine binding globulin (TBG), transthyretin or pre-albumin, albumin, and TH binded to them, result in a reduction in serum total thyroxine (TT4) and, sometimes, in total triiodothyronine (TT3) levels9. These hormonal changes are related both to the degree of proteinuria and to serum albumin levels10. Patients often remain euthyroid, because free T4 (FT4) and free T3 (FT3) levels are usually normal10. Thyroid is able to compensate for hormonal urinary losses keeping the patient euthyroid. However, in patients with low thyroid reserve, clinical hypothyroidism (or overt hypothyroidism) can develop11. Similarly, nephrotic syndrome may increase the needs of exogenous levothyroxine in patients with hypothyroidism. It is well known that serum TT4 and sometimes FT4 were both decreased in nephrotic syndrome7–12. Serum TT4 and FT4 were negatively correlated with massive proteinuria. However, the association of albuminuria and thyroid dysfunction is unknown. Our research was to explore the associations between thyroid dysfunction and albuminuria. It is hypothesized that serum TT4 and FT4 would be also negatively correlated with albuminuria. 1 Department of Nephrology, Nanjing First Hospital, Nanjing Medical University, Nanjing, PR China. 2Department of Nephrology, Sir Run Run Hospital, Nanjing Medical University, Nanjing, PR China. 3Outpatient Department, Nanjing Medical University, Nanjing, PR China. *These authors contributed equally to this work. Correspondence and requests for materials should be addressed to C.C. (email: ) Scientific Reports | 7:41302 | DOI: 10.1038/srep41302 1 www.nature.com/scientificreports/ Sex Serum Creatinine Level, μmol/L (mg/dL) Equation Female ≤62 (≤0.7) >  62 (>0.7) 151 ×  (0.993)Age ×  (Scr/0.7)−0.328 151 ×  (0.993)Age ×  (Scr/0.7)−1.210 Male ≤80 (≤0.9) >  80 (>0.9) 149 ×  (0.993)Age ×  (Scr/0.9)−0.412 149 ×  (0.993)Age ×  (Scr/0.9)−1.210 Table 1. The CKD-EPI four-level race GFR estimation equation (Asian people). Methods Study population. We performed a cross-sectional analysis on the database of the Laboratory Information System of the Clinical Chemistry Laboratory at Nanjing First Hospital of Nanjing Medical University to retrieve results of urinary albumin to creatinine ratio, serum creatinine, and thyroid function tests, which have been performed on 1689 inpatient adults (≥18 yr of age) consecutively referred by nephrology practitioners for routine blood testing over the last 7 yr (from August 2009 to August 2016). Different albuminuria groups were set by the level of albumin to creatinine ratio in urine (ACR) and eGFR according to the KDIGO guideline1. We excluded subjects who were younger than 18 years of age, women who were pregnant (given potential pregnancy-related changes in thyroid function), subjects with urinary traction infection (given potential trasient albuminuria, N = 15), subjects with previous thyroid disease (N = 3), subjects who have a history of thyroid disease or who were receiving concurrent treatment with drugs that could effect on thyroid function (lithium, amiodarone, iodine, methimazole or propylthiouracil, N = 1). We also excluded subjects in which thyrotropin (or thyroid-stimulating hormone, TSH), total T3, free T3, total T4 and free T4 levels were not available (N = 1089). Thus, this study analyzes the remaining 581 patients. Only 15 patients tested anti-thyroid antibody, 16 patients tested reverse T3, so we did not analyze them in the study. Proteinuria was performed in only 72 patients, and the association of proteinuria and thyroid dysfunction was well studied7–12, thus, we did not analyze proteinuria in the study. The study was performed in accordance with the Declaration of Helsinki and was approved by the Institutional Review Board at Nanjing First Hospital affiliated to Nanjing Medical University (IRB no. 86-025-52271039-21). Informed consents were obtained from all participants when they were admitted to the hospital. Laboratory measures. Thyroid function and urinary albumin were tested by using electrochemiluminescence assay (Siemens ADVIA Centaur XP, NY, USA). The reference ranges of serum TT4, FT4, TT3, FT3 and TSH in our institute are as follows: for TSH is 0.55–4.78 mIU/L, for TT4 58.1–140.6 mmol/L, for FT4 11.5–22.7 pmol/L, for TT3 0.92–2.79 mmol/L, for FT3 3.5–6.5 pmol/L, respectively. The reference ra (...truncated)