| Abstract|| |
Chronic renal failure is often associated with multiple organ co-morbidities, including thyroid dysfunction. This has been associated with poorer prognosis, particularly in patients with end-stage renal disease. This study aimed to examine the relationship between renal failure and thyroid dysfunction in an outpatient setting at the King Abdulaziz University Hospital, Saudi Arabia, from January 2011 to June 2012. Demographic and biochemical data were extracted from medical records. Differences in the levels of thyroid hormones and lipids between the four renal function groups were analyzed using the chi-square test for categorical variables and Kruskal- Wallis test for binomial variables. A total of 486 patients were included in the study population, of whom approximately half were female, and the median (range) age was 61 (17-90) years. According to creatinine measurements, renal function was normal in 48 participants, 290 had mild renal failure, 122 had moderate renal failure and 26 had severe renal failure. No significant relationships were observed between renal failure and cardiac or pulmonary dysfunction. Free triiodothyronine (FT3) levels were significantly reduced (P = 0.005) and both free thyroxin (FT4; P = 0.034) and parathyroid hormone (PTH; P = 0.028) significantly increased with increasing severity of renal failure. Patients with moderate to severe renal failure displayed reduced hemoglobin levels and were significantly more likely to be anemic (P <0.001). Highly significant increases in alkaline phosphatase (P <0.001), uric acid (P <0.001) and low-density lipoprotein-cholesterol (P = 0.014) levels were also observed with increasing renal dysfunction. To conclude, it was observed that renal dysfunction is associated with notable changes to other organ systems, including the thyroid. Further studies may investigate the association of multiple organ co-morbidities with prognosis in patients with chronic renal failure.
|How to cite this article:|
Ahmed MM. Association of renal failure with thyroid dysfunction: A retrospective cohort study. Saudi J Kidney Dis Transpl 2014;25:1017-25
|How to cite this URL:|
Ahmed MM. Association of renal failure with thyroid dysfunction: A retrospective cohort study. Saudi J Kidney Dis Transpl [serial online] 2014 [cited 2020 Sep 20];25:1017-25. Available from: http://www.sjkdt.org/text.asp?2014/25/5/1017/139902
| Introduction|| |
The kidney plays a central role in maintaining whole body homeostasis, regulating acid-base balance, electrolyte concentrations, extracellular fluid volume and blood pressure through the production and metabolism of a variety of hormones and excretion of a variety of waste products. As a result, chronic renal failure can affect almost all body systems, with patients often presenting with several co-morbidities including thyroid dysfunction, anemia, pulmonary and cardiac pathology and lipid abnormalities.
Chronic renal failure has been shown to induce a variety of hormonal and metabolic changes,  with studies suggesting that such changes may contribute to a worsening of the overall clinical condition of the patient.  However, the effect of chronic renal failure on thyroid function is still not entirely clear, with some studies suggesting hyperthyroidism in uremic patients and others demonstrating hypothyroidism and, also, euthyroid state.
Cardiovascular disease is the major cause of morbidity and mortality in end-stage renal disease, with a 120-fold increase in the death rate for patients aged 25-34 years receiving dialysis compared with the general population.  Hyperlipidemia is one of the leading risk factors for cardiovascular disease, both in end-stage renal patients  and in patients with other conditions. , Studies have found that patients with chronic renal failure often display increased levels of triglycerides, although total cholesterol levels remain unchanged. This high triglyceride level in dialysed patients has been shown to predict the presence of coronary heart disease independent of other factors,  with patients with both renal failure and cardiovascular disease having 50-times the level of triglycerides than those with renal failure alone. 
There have been very few studies examining chronic renal failure and the association with multiple co-morbid pathologies, particularly thyroid, in Saudi Arabia. The aim of this study was to examine the association of renal dysfunction with thyroid dysfunction, pulmonary and cardiac dysfunction, lipid abnormalities and anemia.
| Methods|| |
Patients and data extraction
This was a retrospective study of patients attending the outpatient department of the King Abdul Aziz University Hospital, Saudi Arabia. Data were extracted from the medical notes of all patients meeting the inclusion/ exclusion criteria who attended the medical out patient department from January 2011 to June 2012. Patients were excluded from the study if they were on dialysis or had heart failure, if they had previous thyroid disease or were on thyroxine treatment.
The following demographic data were extracted from the medical notes: Age, sex and nationality. In addition, the following biochemical data were extracted from the medical notes: Creatinine, urea, uric acid, hemoglobin (Hb), hematocrit, platelets, vitamin D, calcium, parathyroid hormone (PTH), alkaline phospha-tase, thyroid-stimulating hormone (TSH), free thyroxin (FT4), free tri-iodothyronine (FT3), cholesterol, triglyceride (TG), low-density lipo-protein (LDL) and high-density lipoprotein (HDL). Presence of pulmonary hypertension, diastolic dysfunction, grade of diastolic dysfunction, systolic dysfunction, ejection fraction and left ventricular hypertrophy were also noted. Renal function was classified according to creatinine levels as normal (<150 μmol/mL), mild (150-500 μmol/mL), moderate (500-1000 μmol/mL) and severe (>1000 μmol/mL). Anemia was defined as hemoglobin less than 13 g/dL in men and less than 11.5 g/dL in women. Vitamin D3 deficiency was defined as less than 8 ng/mL.
| Statistical Methods|| |
Data were entered in Microsoft Excel and analyzed using SPSS v19.0 for Windows (SPSS, Chicago, IL, USA). Demographic characteristics are presented for continuous variables as means and standard deviations and categorical variables as frequencies and percentages. Differences in the levels of thyroid hormones and lipids between the four renal function groups were analyzed using the chi-square test for categorical variables and the Kruskal-Wallis test for binomial variables. Non-normal lipid variables were analyzed by logarithmic transformation and are expressed as anti-logarithmic transformation to facilitate understanding. Significance was set at the 0.05 level.
| Results|| |
A total of 486 patients met the inclusion criteria and were included in the study population. The demographic characteristics of the study population are presented in [Table 1]. Approximately half of them were females. The median age (range) was 61 (17-90) years. Approximately one-third of the participants were of Saudi nationality. Of those of non-Saudi nationality, the most common nationalities were Yemeni, Palestinian, Pakistani and Sudanese.
According to creatinine measurements, renal function was normal in 48 participants [Table 2]. Of the remaining participants, 290 had mild renal failure, 122 had moderate renal failure and 26 had severe renal failure. There were no significant differences in the distribution of men and women across the four renal function groups or in the distribution of Saudi and non-Saudi nationals. Those with normal kidney function or mild renal failure were more likely to be older than those with moderate or severe renal failure [mean ± standard error (s. e.) age: Normal, 59.17 ± 2.51; mild, 60.14 ± 0.91; moderate, 54.76 ± 1.54; severe, 47.88 ± 3.5; P <0.001].
|Table 2: Relationship between renal dysfunction and cardiac and pulmonary pathologies.|
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Relationship between renal failure and cardiac dysfunction
Systolic dysfunction was observed in approximately one-quarter of participants in the study (n = 119; 24.4%), while over half (n = 263; 53.9%) had diastolic dysfunction [Table 2]. Of the latter, the majority had grade 1 (51.7%) or grade 2 (25.5%) diastolic dysfunction. Patients with systolic dysfunction had significantly reduced ejection fractions (mean ± s. e.: 36.35 ± 0.97) compared with those with normal systolic function (61.45 ± 0.46; P <0.001). Diastolic dysfunction was also associated with reduced ejection fractions, particularly in grades 3 and 4 (Grade 1: 56.54 ± 1.09; Grade 2: 53.69 ± 1.46; Grade 3: 42.89 ± 1.99; Grade 4: 20.00 ± 2.89; P <0.001). Left ventricular hypertrophy was found in 33% of patients. No significant difference was detected in ejection fraction for patients with or without left ventricular hypertrophy.
Although there were trends for an increased prevalence of cardiac and pulmonary pathologies in patients with severe renal failure, these did not reach significance [Table 2]. Similarly, while the mean ejection fraction was reduced in patients with severe renal failure compared with controls, this result did not reach significance in this study population.
Relationship between renal failure and thyroid dysfunction
The association of thyroid hormone levels with severity of renal failure was analyzed in all patients to further understand the relationship between uremia and thyroid dysfunction. There was a significant reduction in free tri-iodothyronine (FT3) levels with increasing severity of renal failure [Table 3]; P = 0.005), while both free thyroxine (FT4) and PTH were increased in severe renal failure compared with normal patients (P = 0.034 and P = 0.028). No changes were ob-served in thyroid-stimulating hormone (TSH) levels with increasing renal impairment. Given the role of PTH in mediating serum calcium concentration and in converting vitamin D3 to its active form, we also analyzed the calcium and vitamin D3 levels in our population. No relationship was found between renal dysfunction and vitamin D3 or calcium levels, although there was a trend toward a reduction in vitamin D3 in patients with severe renal dysfunction compared with those with normal renal function. When stratified according to the clinical definition of vitamin D3 deficiency (vitamin D3 <8 ng/mL), patients who were vitamin D3 deficient had significantly increased creatinine levels (521.50 ± 101.18) compared with those with normal vitamin D3 levels (354.43 ± 21.43; P = 0.027), although no differences in urea levels were observed.
|Table 3: Association of renal abnormality with hematological and biochemical results.|
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Lipid abnormality in relation to severity of renal failure
The association of renal failure with lipid levels was analyzed in all patients. A significant increase in LDL-C levels was observed with increasing renal failure [Table 3], P = 0.014), although no relationship was detected with HDL-C, triglyceride or cholesterol.
Anemia in relation to renal dysfunction
A large majority of patients presenting to the outpatient department showed hemoglobin levels indicative of anemia (n = 370; 76.4%). When analyzed against the degree of renal failure, a highly significant relationship was observed between reduced hemoglobin levels and increased severity of renal dysfunction (P <0.001). Similarly, both hematocrit and platelet levels were significantly reduced with increasing degree of renal failure (P <0.001 and P = 0.049). Using the clinical definition of anemia of a hemoglobin level of less than 13 g/dL for men and less than 11.5 g/dL for women, the distribution of anemia was analyzed across the categories of renal dysfunction. While 35.4% of patients with normal kidney function displayed anemia, this rose to 75.3% of patients with mild kidney dysfunction, 91.8% of those with moderate kidney dysfunction and 92.3% of those with severe kidney dysfunction (P <0.001).
Studies have found that patients with end-stage renal disease often display abnormal serum enzyme levels, including alkaline phos-phatase, and abnormal levels of metabolic waste products such as uric acid. We therefore analyzed the relationship between renal dysfunction and serum alkaline phosphatase and uric acid levels. Highly significant increases in alkaline phosphatase (P < 0.001) and uric acid (P < 0.001) levels were observed with increasing renal dysfunction.
Relationship between anemia and thyroid dysfunction
To understand whether anemia may also be related to thyroid dysfunction, we compared the mean serum thyroid hormone levels in patients with and without anemia. Anemic patients displayed significantly reduced free T3 (P = 0.004; [Table 4] and significantly elevated PTH (P = 0.008) levels. There was no difference in the serum levels of TSH or free T4 in patients with or without anemia.
| Discussion|| |
Given the critical role of the kidney in maintaining optimal whole-body homeostasis, kidney dysfunction may be anticipated to impact negatively on other organ systems. However, published reports in the literature to date are conflicting with respect to this and there is a paucity of data regarding the relationship between renal failure and co-morbidities in Saudi Arabia. This retrospective cohort study set out to examine the relationship between renal failure and thyroid, cardiac and pulmonary dysfunction.
Our results found that severity of renal dysfunction was associated with a significant reduction in serum free T3 levels and an increase in both free T4 and PTH. TSH levels were not significantly altered across the four renal function groups, although there was a trend toward higher TSH levels outside of the normal reference range in patients with mild, moderate and severe renal dysfunction. There have been varying reports in the literature with respect to thyroid hormone levels in patients with renal disease. While T3 levels have consistently been found to be low, in line with our results, findings for T4 and TSH have varied significantly. T4 levels have been reported in different studies as lowered, normal or raised, while TSH has been found to be normal even in the presence of lowered T3 or to be raised. ,,, The latter suggests a defective response of the thyroid to TSH, resulting in reduced hormone secretion, while the former may be due to an abnormality in the hypophyseal mechanism of TSH release. Notably, however, it has been suggested that such abnormal hormone levels may not necessarily be harmful and that changes in thyroid function during severe illness may actually have a protective effect by preventing excessive tissue catabolism.  Treating such thyroid abnormalities, therefore, may not be the correct option for such patients, and may cause more harm to the patient than good. Osteodystrophy is a major complication of uremia and is often attributed to secondary hyperparathyroidism. The significant increase in PTH levels with increasing severity of renal disease in our study population supports this concept, although given the raised PTH levels the consistent calcium levels may at first appear surprising. However, studies have suggested that as renal function declines, a small increase in serum phosphate levels results in mild hypocalcemia and stimulation of the parathyroid gland. This leads to normalized serum calcium at the expense of high circulating PTH.  In addition to this, because we have not included any treatment data within our analysis, we cannot rule out the possibility that patients may be receiving treatment to normalize their serum calcium levels, particularly given the recent evidence of a strong link between abnormal calcium levels and increased mortality in patients with end-stage renal disease. ,, Vitamin D3 resistance also plays a major role in renal osteodystrophy, and is thought to be a result of reduced conversion of 1-hydroxyvitamin D3 to 1,25-hydroxyvita-min D3. Although a significant reduction in vitamin D3 levels was not observed in our population, there was a trend toward vitamin D3 deficiency in patients with severe renal dysfunction.
Previous studies have demonstrated cardiovascular disease to be one of the major contributors to premature mortality in patients with renal failure, , suggesting that evidence of cardiovascular disease may be related to severity of renal failure. We examined diastolic and systolic function and left ventricular hypertrophy in our patient population and the relationship with severity of renal disease according to serum creatinine level. In line with previous studies, we observed trends suggesting an increased prevalence of cardiac disease in patients with severe renal disease. ,,,, Although our data were not significant, this may reflect the smaller numbers of patients in the normal and severe renal function groups, and suggests that cardiovascular comorbidities may be associated with later stage, severe renal disease. Further studies with a larger control population may provide significant data with respect to this.
The link between severe renal failure and cardiovascular disease is further supported by our findings of a highly significant association between uremia and anemia. These findings are supported by previous work suggesting that anemia contributes to the pathogenesis of left ventricular hypertrophy in renal patients. Studies have found increased cardiac index and cardiac work in anemic patients with renal failure. , These studies and ours support a hypothesis that anemia occurs early in the renal disease spectrum and that, with increased severity of renal disease, the anemic pheno-type is a contributing factor to the development of cardiac abnormalities, most notably hypertrophy of the left ventricle, in order for the heart to meet tissue oxygen requirements while normalizing systolic wall stress. ,
Serum lipid abnormalities have also been attributed as a major risk factor for cardiovascular disease. Increased LDL-C and reduced HDL-C is known to promote atherosclerosis and therefore increase cardiovascular risk. However, although increased atherosclerosis has been demonstrated in patients with end-stage renal disease,  there have been conflicting results as to alterations in serum lipid levels in response to renal failure. In our study, we found a significant increase in LDL-C levels associated with increased severity of renal dysfunction, in line with a recent study by Tsumura et al, which reported similar findings. 
We also examined changes in alkaline phos-phatase and uric acid levels in our cohort. We observed a highly significant correlation between alkaline phosphatase levels and severity of renal disease, reinforcing findings from earlier studies. , Although alkaline phosphatase is generally produced by the biliary tree, it may also originate from the kidney, explaining why elevated levels of alkaline phosphatase have been frequently reported in patients with chronic renal disease. , Uric acid levels were also significantly increased in patients with renal disease compared with normal subjects in our study population. These findings are consistent with previous studies that have suggested that high serum uric acid levels are commonly associated with renal disease. Notably, recent studies have suggested that rather than renal dysfunction being the causative factor in increasing serum uric acid levels, the relationship may be reversed.  These studies have demonstrated that high serum uric acid levels induce endothelial dysfunction, increase oxidative stress and activate pro-inflammatory and proliferative cascades, all of which may contribute to the initiation, development and progression of renal disease. ,, Strategies to reduce serum uric acid levels may therefore represent promising treatments for preventing both the development and the progression of renal disease. 
There are a number of limitations of this study. Because of the retrospective nature of the study, we were unable to draw any causal relationships between chronic renal failure and thyroid dysfunction, and prospective studies with long-term follow-up are needed to examine the effects on outcome. The study population included a very high proportion of patients with renal disease and future studies may seek to recruit a larger control group to enable a more balanced analysis. As in any retrospective analysis, we were only able to use data contained in medical notes, and, for a number of patients within the sample population, the data were not entirely complete. Future studies may also seek to stratify renal disease according to the estimated glomerular filtration rate (eGFR), as this is a more precise reflection of renal function than creatinine.
In conclusion, our study demonstrates that chronic renal failure is associated with a number of co-morbidities, most notably thyroid dysfunction and anemia. Our results corroborate previous studies demonstrating the complexity of managing patients with chronic renal disease. Further studies are critical to understand how these co-morbidities translate to prognosis for such patients. Although at first it appears contradictory not to treat apparent thyroid dysfunction, in the context of renal failure, such treatment may not be optimal to improve the prognosis of the patient. We hope to explore such anomalies in future studies, with the aim to develop treatment guidelines for managing complex renal disease cases.
Conflict of Interest: None.
Financial Disclosures: None.
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Dr. Maimoona Mushtaq Ahmed
Department of Medicine, King Abdul Aziz University Hospital, Jeddah
[Table 1], [Table 2], [Table 3], [Table 4]