|Year : 2014 | Volume
| Issue : 2 | Page : 145-149
Association of serum uric acid level with estimated glomerular filtration rate in diabetic patients
Nithyananda K Chowta, Mukta N Chowta
Department of Medicine and Pharmacology, Kasturba Medical College, Manipal University, Mangalore, Karnataka, India
|Date of Web Publication||11-Nov-2014|
Mukta N Chowta
Department of Pharmacology, Kasturba Medical College, Manipal University, Mangalore, Karnataka
Source of Support: None, Conflict of Interest: None
Background and Objective: Uric acid may be a novel and important player in the pathogenesis of microvascular complications in diabetes mellitus. The objective of this study was to investigate the association between eGFR and uric acid in patients with type 2 diabetes mellitus. Materials and Methods: A cross-sectional study was done in type 2 diabetic patients of both genders above the age of 18 years. Demographic characteristics collected include age, gender, body weight, height, and duration of diabetes. Laboratory investigations data collected included serum creatinine, blood urea nitrogen, serum uric acid, urine albumin, urine creatinine, urine albumin creatinine ratio, HbA1c, and blood glucose. GFR was calculated using the Modification of Diet in Renal Disease formula (4 variable formula). Results: A total of 63 patients were included in the study. Among them, 35 (55.6%) were males and 28 were females (44.4%). Mean age of the patients was 61.63 ± 10.37 years. Out of 63 patients, 52 had normal uric acid level and 11 patients had elevated uric acid level. eGFR was 81.32 ± 17.53 ml/min in patients with normal uric acid level, whereas it was 61.63 ± 26.18 ml/min in patients with elevated uric acid level. The difference is statistically significant (P = 0.03). Urine albumin creatinine ratio was 12.2 ± 40.92 μg/mg in patients with normal uric acid level and was 47.04 ± 76.58 μg/mg in patients with elevated uric acid level, the difference being statistically significant (P = 0.035). There was a significant negative correlation between uric acid and eGFR (r = -31, P = 0.014), whereas statistically significant correlation was not seen between uric acid level and urine albumin creatinine ratio. Uric acid level was 0.312 ± 0.072 mmol/L in normoalbuminuric patients (55 patients), whereas it was 0.343 ± 0.092 mmol/L in patients with microalbuminuria (8 patients). Conclusion: Serum uric acid is independently and negatively associated with GFR in patients with type 2 diabetes mellitus and thus supporting the concept that uric acid may be involved in the pathogenesis of diabetic nephropathy.
Keywords: Diabetes mellitus, GFR, uric acid
|How to cite this article:|
Chowta NK, Chowta MN. Association of serum uric acid level with estimated glomerular filtration rate in diabetic patients
. Arch Med Health Sci 2014;2:145-9
|How to cite this URL:|
Chowta NK, Chowta MN. Association of serum uric acid level with estimated glomerular filtration rate in diabetic patients
. Arch Med Health Sci [serial online] 2014 [cited 2019 Oct 19];2:145-9. Available from: http://www.amhsjournal.org/text.asp?2014/2/2/145/144318
| Introduction|| |
Diabetes mellitus is the leading cause of end-stage renal disease (ESRD) in the Western world, and the number of patients diagnosed each year with ESRD due to diabetes mellitus is rising.  Uric acid is detrimental to the kidneys in animal models. , Experimental and clinical studies have suggested that uric acid may contribute to the development of hypertension and kidney disease. It has been reported that hyperuricemia (HUA) is an independent risk factor for the progression of renal dysfunction.  Serum uric acid level was previously shown to be higher in patients with diabetes mellitus than in the population without glucose intolerance. 
HUA has been reported to be associated with the onset of diabetes mellitus or metabolic syndrome.  The pathogenesis of diabetic nephropathy is complex and still not fully elucidated. Role of uric acid in human diabetic nephropathy has not been extensively studied. Uric acid has been associated with renal disease, even though hyperuricemia may be a marker of or by itself be responsible for microvascular disease in diabetes. 
In animal models, elevated level of uric acid can lead to arteriolopathy of preglomerular vessels, impaired autoregulation, glomerular hypertension, as well as endothelial dysfunction. Kidney damage in hyperuricemic rats is not dependent on blood pressure, and instead involves the renin-angiotensin system. , In patients with diabetes, serum uric acid early in the course of diabetes is significantly, and independent of confounders, associated with later development of persistent macroalbuminuria. Therefore, uric acid may be a novel and important player in the pathogenesis of microvascular complications in diabetes. , A dose-response relationship between serum uric acid and early decline in renal function has recently been demonstrated in patients with type-1 diabetes.  Iseki et al. showed that an elevated serum uric acid level correlated with the development of renal insufficiency in individuals with normal kidney function. Paradoxically, it has been suggested that uric acid have antioxidant activity in experimental studies.  There are also evidences showing that hyperuricemia seems to induce high blood pressure, renal afferent arteriopathy, a rise in glomerular hydrostatic pressure, and renal scarring.  In addition, epidemiological studies have shown an association between a high level of serum uric acid and increased vascular events and mortality in patients with hypertension.  However, the influence of serum uric acid level on the renal functions has been insufficiently investigated in patients with diabetes mellitus, especially with Indian context. Therefore, we aimed to investigate the association between eGFR and uric acid in patients with type 2 diabetes mellitus.
| Materials and Methods|| |
A cross-sectional study was undertaken in a tertiary care hospital. Type 2 diabetic patients who were screened for their eligibility to participate in clinical trials involving patients of diabetes mellitus were included in the study. Patients were screened for their eligibility in clinical trials after their written informed consent. The study was approved by institutional ethics committee. Patient population included both males and females above the age of 18 years. Demographic characteristics collected include age, gender, body weight, height, and duration of diabetes.
Medical examinations were performed according to a standardized procedure. Participants were asked about concomitant diseases as well as medications taken by them. Body mass index (BMI) was calculated as the ratio of weight (kg)/height (m 2 ). Laboratory investigations data collected include serum creatinine, blood urea nitrogen, serum uric acid, urine albumin, urine creatinine, urine albumin creatinine ratio, HbA1c, and blood glucose. GFR was calculated using the Modification of Diet in Renal Disease formula (4 variable formula). 
All continuous variables are presented as means (±SD), and the categorical variables are summarized as percentages in each group. All continuous variables are analyzed by student 't' test between different categories. Pearson correlation coefficients were determined for uric acid vs. eGFR, urine albumin creatinine ratio, age, BMI, HbA1c, and plasma glucose in men and women. All analyses were conducted using SPSS statistical software (version 15.0). All statistical tests were 2-sided, and significance was determined at a P value < 0.05.
| Results|| |
A total of 63 patients were included in the study. Among them, 35 (55.6%) were males and the remaining 28 were females (44.4%). Mean age of the patients was 61.63 ± 10.37 years (Range: 37-81 years). Comparison of demographic characteristics among patient with or without hyperuricemia (HUA) was shown in [Table 1].
|Table 1: Comparison of demographic characteristics of the patients (n=63)|
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Among these patients, 52 (29 males, 23 females i.e. 55.8% vs. 44.2%) had normal uric acid level and 11 patients (6 males, 5 females i.e. 54.55 vs. 44.5%) had elevated uric acid level. (The normal range of uric acid was 0.2-0.45 mmol/l in men and 0.15-0.35 mmol/l in women). Among patients with hyperuricemia, 6 had hypertension (54.5%) and 22 (42.3%) of patients without hyperuricemia were hypertensives. Fourteen patients (26.9%) without HUA and 2 (18.2%) with HUA had peripheral neuropathy. Seven patients without HUA and 4 patients with HUA had ischemic heart disease. There were no significant differences in the distribution of co-morbidities among two groups. eGFR was 81.32 ± 17.53 ml/min in patients with normal uric acid level, whereas it was 61.63 ± 26.18 ml/min in patients with elevated uric acid level. The difference is statistically significant (P = 0.03). Urine albumin creatinine ratio was 12.2 ± 40.92 μg/mg in patients with normal uric acid level and was 47.04 ± 76.58 μg/mg in patients with elevated uric acid level, the difference being statistically significant (P = 0.035) [Table 2].
|Table 2: Comparison of eGFR and UACR among patients with or without hyperuricemia|
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There was a significant negative correlation between uric acid and eGFR (r = -31, P = 0.014), whereas correlation analysis failed to show any significant association between uric acid level and urine albumin creatinine ratio (r = 0.002, P = 0.99). There was also significant positive correlation of serum uric acid level with body mass index (r = 0.25, P = 0.45). Pearson correlation analysis did not show any significant association of uric acid with duration of diabetes and age of the patients. But, a negative correlation of uric acid with HbA1c and fasting blood glucose was seen (r = -249; P = 0.05, r = -0.415; P = 0.003, respectively, [Table 3])
Out of the 63 patients, 8 had microalbuminuria and the remaining were normoalbuminuric. eGFR was 80.99 ± 18.6 ml/minute in normoalbuminuric patients, whereas it was only 56.55 ± 21.35 ml/minute in patients with microalbuminuria, the difference being statistically highly significant (P = 0.001). Uric acid level was 0.312 ± 0.072 mmol/L in normoalbuminuric patients, whereas it was 0.343 ± 0.092 mmol/L in patients with microalbuminuria, but the difference is not statistically significant [Table 4].
|Table 4: Comparison of eGFR and uric acid level among patients with or without microalbuminuria|
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The proportion of patients who had renal failure (GFR < 60 ml/minute) in our study is 19% (12 patients out of 63 had renal failure). Among 11 patients with hyperuricemia, 6 had renal failure (54.5%) and in patients without hyperuricemia, 6 out of 52 had renal failure (11.5%). This difference is statistically very significant.
| Discussion|| |
The present study aimed at evaluating the association of estimated glomerular filtration rate (eGFR) with serum uric acid level. Our study has clearly shown the significant difference in the eGFR among patients with normal or elevated serum uric acid level. Similarly, there were studies in the western literature documenting hyperuricemia as an independent risk factor for the progression of renal dysfunction. 
Decrease in GFR is an indicator of early stage renal impairment.  Hence, we planned to evaluate its association with serum uric acid level. Our study has demonstrated a significant negative correlation with eGFR. The increase in serum uric acid level was associated with decrease in eGFR, suggesting the role of uric acid in the development of renal impairment. Uric acid is produced in the body by the degradation of dietary and endogenously-synthesized purine compounds. Uric acid undergoes both re-absorption and excretion in the proximal convoluted tubules of nephron. A low renal blood flow stimulates uric acid reabsorption. Although it is possible that a high level of uric acid could be a result of low GFR, several studies have provided evidences that uric acid might actually play a role in the development or progression of renal disease. ,,,, The mechanism involved in uric acid-induced nephrotoxicity has been evaluated in animal studies. , Several studies reported that uric acid levels are not independent predictors of the progression of CKD. , However, Iseki et al. reported that a high level of serum uric acid was more predictive for the development of renal dysfunction than proteinuria. Chonchol et al. reported that high uric acid levels are strongly associated with the risk of kidney disease progression and a decrease in estimated GFR based on a prospective community-based cardiovascular health study of 4,610 participants. Jung DH et al. reported that uric acid is independently and negatively associated with GFR in both men and women with normal serum levels of uric acid, suggesting that a high level of uric acid is a valuable predictor of a GFR decrease.  Hyperuricemia develops frequently in subjects with insulin resistance, because insulin stimulates sodium and uric acid re-absorption in the proximal tubule. 
Hovind P et al. reported that circulating uric acid in the higher end of the normal range to be an independent predictor for development of overt diabetic nephropathy, thus supporting the concept that uric acid may be involved in the pathogenesis of diabetic microvascular complications. Ito H et al. showed in study that HUA is associated with diabetic micro- and macroangiopathies. 
In the present study, serum uric acid was inversely correlated with HbA1C and blood glucose. Similar to our findings, Wen et al. described that it was negatively correlated with the blood glucose level in a population of 484,568 subjects in Taiwan.  Li et al. and Ito H et al. also reported inverse correlations of the blood glucose and HbA1c levels with the serum uric acid concentration in patients with type 2 diabetes mellitus. , These results seem to be conflicting, as it is clear from the earlier studies that hyperuricemia is a risk factor for diabetes mellitus and/or metabolic syndrome. , The discrepancies in the studies are considered to be caused by the effects of insulin on the renal proximal tubules. Hyperinsulinemia reduces the urinary excretion of uric acid by activating the transporter of uric acid (URAT), which is expressed in the proximal tubules of the kidneys.
This study has several important limitations. First, we used eGFR to assess renal function instead of directly measuring GFR. However, several organizations recommend the use of equations that estimate GFR to evaluate renal function in epidemiologic studies.  We did not examine the influence of anti-hypertensive drugs as confounding variables. Diuretics such as thiazides increase serum uric acid by stimulating uric acid re-absorption in the proximal tubule. The number of subjects in this study was relatively small. Hence, the findings of this study should be validated in larger sample size. Also, as this is a cross-sectional study, it is difficult to assess the role of uric acid in the development of renal impairment. Future studies should be directed to examine the potential therapeutic effects of treatment with allopurinol in diabetic patients with chronic kidney disease.
In conclusion, our study as initial observation has shown negative association of serum uric acid with GFR in patients with type 2 diabetes mellitus. But, the sample size in the present study is too small to draw strong conclusion to prove this association, warranting further studies to support the concept of the involvement of uric acid in the pathogenesis of diabetic nephropathy.
| References|| |
|1.||United States Renal Data System [Internet], 2011. Available from: http://www.usrds.org/2011/pdf/v2_ch01_11.pdf [Last accessed on 2012 Jun]. |
|2.||Nakagawa T, Mazzali M, Kang DH, Kanellis J, Watanabe S, Sanchez-Lozada LG, et al. Hyperuricemia causes glomerular hypertrophy in the rat. Am J Nephrol 2003;23:2-7. |
|3.||Mazzali M, Hughes J, Kim YG, Jefferson JA, Kang DH, Gordon KL, et al. Elevated uric acid increases blood pressure in the rat by a novel crystal-independent mechanism. Hypertension 2001;38:1101-6. |
|4.||Madero M, Sarnak MJ, Wang X, Greene T, Beck GJ, Kusek JW, et al. Uric acid and long-term outcomes in CKD. Am J Kidney Dis 2009;53:796-803. |
|5.||Ito H, Abe M, Mifune M, Oshikiri K, Antoku S, Takeuchi Y, et al. Hyperuricemia Is independently associated with coronary heart disease and renal dysfunction in patients with type 2 diabetes mellitus. PLoS One 2011;6:e27817. |
|6.||Yuan HJ, Yang XG, Shi XY, Tian R, Zhao ZG. Association of serum uric acid with different levels of glucose. Chin Med J (Engl) 2011;124:1443-8. |
|7.||Hovind P, Rossing P, Johnson RJ, Parving HH. Serum uric acid as a new player in the development of diabetic nephropathy. J Ren Nutr 2011;21:124-7. |
|8.||Iseki K, Ikemiya Y, Inoue T, Iseki C, Kinjo K, Takishita S. Significance of hyperuricemia as a risk factor for developing ESRD in a screened cohort. Am J Kidney Dis 2004;44:642-50. |
|9.||Jung DH, Lee YJ, Lee HR, Lee JH, Shim JY. Association of renal manifestations with serum uric acid in Korean adults with normal uric acid levels. J Korean Med Sci 2010;25:1766-70. |
|10.||Siu YP, Leung KT, Tong MK, Kwan TH. Use of allopurinol in slowing the progression of renal disease through its ability to lower serum uric acid level. Am J Kidney Dis 2006;47:51-9. |
|11.||Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate method to estimate glomerular filtration rate from serum creatinine: A new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med 1999;130:461-70. |
|12.||Cirillo M, Del Giudice L, Bilancio G, Franzese MD, Chiricone D, De Santo NG. Early detection of chronic kidney disease: Epidemiological data on renal dysfunction. G Ital Nefrol 2008;25:690-3. |
|13.||Mene P, Punzo G. Uric acid: Bystander or culprit in hypertension and progressive renal disease? J Hypertens 2008;26:2085-92. |
|14.||Sturm G, Kollerits B, Neyer U, Ritz E, Kronenberg F. MMKD Study Group. Uric acid as a risk factor for progression of non-diabetic chronic kidney disease? The Mild to Moderate Kidney Disease (MMKD) Study. Exp Gerontol 2008;43:347-52. |
|15.||Obermayr RP, Temml C, Gutjahr G, Knechtelsdorfer M, Oberbauer R, Klauser-Braun R. Elevated uric acid increases the risk for kidney disease. J Am Soc Nephrol 2008;19:2407-13. |
|16.||Chonchol M, Shlipak MG, Katz R, Sarnak MJ, Newman AB, Siscovick DS, et al. Relationship of uric acid with progression of kidney disease. Am J Kidney Dis 2007;50:239-47. |
|17.||Hovind P, Rossing P, Tarnow L, Johnson RJ, Parving HH. Serum uric acid as a predictor for development of diabetic nephropathy in type 1 diabetes: An inception cohort study. Diabetes 2009;58:1668-71. |
|18.||Wen CP, David Cheng TY, Chan HT, Tsai MK, Chung WS, Tsai SP, et al. Is high serum uric acid a risk marker or a target for treatment? Examination of its independent effect in a large cohort with low cardiovascular risk. Am J Kidney Dis 2010;56:273-88. |
|19.||Li Q, Yang Z, Lu B, Wen J, Ye Z, Chen L, et al. Serum uric acid level and its association with metabolic syndrome and carotid atherosclerosis in patients with type 2 diabetes. Cardiovasc Diabetol 2011;10:72. |
|20.||Wiik BP, Larstorp AC, Høieggen A, Kjeldsen SE, Olsen MH, Ibsen H, et al. Serum uric acid is associated with new-onset diabetes in hypertensive patients with left ventricular hypertrophy: The LIFE Study. Am J Hypertens 2010;23:845-51. |
|21.||Viazzi F, Leoncini G, Vercelli M, Deferrari G, Pontremoli R. Serum uric acid levels predict new-onset type 2 diabetes in hospitalized patients with primary hypertension: The MAGIC study. Diabetes Care 2011;34:126-8. |
[Table 1], [Table 2], [Table 3], [Table 4]