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Serum uric acid and its association with hypertension, early nephropathy and chronic kidney disease in type 2 diabetic patients

Abstract

Introduction:

Early detection diabetic nephropathy (DN) is important. Whether serum uric acid (SUA) has a role in the development of DN is not known.

Objective:

To study the relationship between SUA and hypertension, early nephropathy and progression of chronic kidney disease (CKD) in type 2 diabetes mellitus (T2DM).

Methods:

The total number of the study was 986 participants, according to presence and duration of diabetes were classified into three groups. Group I; including 250 healthy participants. Group II; including 352 with onset of diabetes < 5 years. Group III; including 384, with the onset of diabetes > 5 years. All participants were submitted to complete clinical examination, anthropometric measurements, laboratory investigations, including glycosylated hemoglobin (HbA1C), as well triglycerides to high-density lipoprotein ratios (TG/HDL-C), SUA, urinary albumin/creatinine ratio (ACR) and estimated glomerular filtration rate (eGFR).

Results:

SUA, BP, HbA1c, TG/HDL-C ratio, and ACR levels were significantly higher in group III than group I, II and in II than I. eGFR significantly lower in group III than group I, II and in II than I (p < 0.001). Age, BMI, BP, HbA1c, TG/HDL-C, ACR, were positively correlated with SUA, while GFR negatively correlated. SUA at level of > 6.1 mg/dl, > 6.2 mg/dl and > 6.5 mg/dl had a greater sensitivity and specificity for identifying hypertension, early nephropathy and decline eGFR respectively.

Conclusion:

Even high normal SUA level, was associated with the risk of hypertension, early nephropathy and decline of eGFR. Moreover SUA level may identify the onset of hypertension, early nephropathy and progression of CKD in T2DM.

Keywords:
diabetes mellitus, type 2; diabetic nephropathies; hypertension; uric acid

Resumo

Introdução:

A detecção precoce da nefropatia diabética (ND) é importante. O ácido úrico sérico (AUS) tem um papel ainda desconhecido no desenvolvimento de ND.

Objetivo:

Estudar a relação entre AUS e hipertensão, nefropatia precoce e progressão da doença renal crônica (DRC) no diabetes mellitus tipo 2 (DM2).

Métodos:

O estudo contou com 986 participantes, de acordo com a presença e a duração do diabetes, os pacientes foram classificados em três grupos. O Grupo I incluiu 250 participantes saudáveis. O Grupo II incluiu 352 pacientes com início de diabetes < 5 anos. O Grupo III incluiu 384 pacientes com o aparecimento de diabetes > 5 anos. Todos os participantes foram submetidos a exame clínico completo, medidas antropométricas, exames laboratoriais - incluindo hemoglobina glicosilada (HbA1C), bem como a razão entre triglicérides e lipoproteína de alta densidade (TG/HDL-C), AUS, razão creatinina/albumina (RCA) urinária, e taxa estimada de filtração glomerular (eTFG).

Resultados:

A razão AUS, PA, HbA1c, TG/HDL-C e RCA foi significativamente maior no grupo III do que no grupo I, II e em II do que I. A eTFG foi significativamente menor no grupo III do que nos grupos I, II e no II do que no I (p < 0,001). Idade, IMC, PA, HbA1c, razão TG/HDL-C, RCA, foram positivamente correlacionados com AUS, enquanto que a TFG esteve negativamente correlacionada. O AUS a níveis > 6,1 mg/dl, > 6,2 mg/dl e > 6,5 mg/dl apresentou maior sensibilidade e especificidade para identificar hipertensão, nefropatia precoce e declínio da eTFG, respectivamente.

Conclusão:

Mesmo elevados níveis de AUS, foi associado ao risco de hipertensão, nefropatia precoce e declínio da eTFG. Além disso, o nível de AUS pode identificar o início da hipertensão, nefropatia precoce e progressão da DRC em DM2.

Palavras-chave:
ácido úrico; diabetes mellitus tipo 2; hipertensão; nefropatias diabéticas

Introduction

The prevalence of type 2 diabetes mellitus (T2DM) has significantly increased worldwide, which has resulted in an increased burden on individuals and health care systems.11 Eggers PW. Incidence of end-stage renal disease in the USA and other countries stabilized? Curr Opin Nephrol Hypertens 2011;20:241-5. Diabetic nephropathy (DN) is a common complication of diabetes and its earliest clinical sign is a slight elevation of urinary albumin excretion microalbuminuria (MA). Such leakage was believed to progress inexorably to gross proteinuria, which destroyed nephrons and led to end stage renal disease (ESRD).22 Ritz E, Orth SR. Nephropathy in patients with type 2 diabetes mellitus. N Engl J Med 1999;341:1127-33. PMID: 10511612 DOI:http://dx.doi.org/10.1056/NEJM199910073411506
http://dx.doi.org/10.1056/NEJM1999100734...

Chronic kidney disease (CKD) is a worldwide public health issue, with increasing prevalence, poor outcomes, and high treatment costs.33 Eckardt KU, Coresh J, Devuyst O, Johnson RJ, Köttgen A, Levey AS, et al. Evolving importance of kidney disease: from subspecialty to global health burden. Lancet 2013;382:158-69. PMID: 23727165 DOI: http://dx.doi.org/10.1016/S0140-6736(13)60439-0
http://dx.doi.org/10.1016/S0140-6736(13)...
Early detection of CKD is crucial to prevent its progression, and thereby, to potentially improve its outcome.44 Kidney Disease: Improving Global Outcomes CKD Work Group. KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of CKD. Kidney Int Suppl 2013;3:1-150.

Uric acid (UA) is the end product of purine metabolism in humans, and approximately 70% of UA are eliminated by the kidney.55 Cirillo P, Sato W, Reungjui S, Heinig M, Gersch M, Sautin Y, et al. Uric acid, the metabolic syndrome, and renal disease. J Am Soc Nephrol 2006;17:S165-8. DOI: http://dx.doi.org/10.1681/ASN.2006080909
http://dx.doi.org/10.1681/ASN.2006080909...
Several prospective studies have documented that the elevated serum uric acid (SUA) level is associated with the development of T2DM itself,66 Kodama S, Saito K, Yachi Y, Asumi M, Sugawara A, Totsuka K, et al. Association between serum uric acid and development of type 2 diabetes. Diabetes Care 2009;32:1737-42. DOI: http://dx.doi.org/10.2337/dc09-0288
http://dx.doi.org/10.2337/dc09-0288...
hypertension,77 Krishnan E, Kwoh CK, Schumacher HR, Kuller L. Hyperuricemia and incidence of hypertension among men without metabolic syndrome. Hypertension 2007;49:298-303. PMID: 17190877 DOI: http://dx.doi.org/10.1161/01.HYP.0000254480.64564.b6
http://dx.doi.org/10.1161/01.HYP.0000254...
cardiovascular disease88 Zoppini G, Targher G, Negri C, Stoico V, Perrone F, Muggeo M, et al. Elevated serum uric acid concentrations independently predict cardiovascular mortality in type 2 diabetic patients. Diabetes Care 2009;32:1716-20. DOI: http://dx.doi.org/10.2337/dc09-0625
http://dx.doi.org/10.2337/dc09-0625...
and the risk factors of metabolic syndrome (MS).99 Ciarla S, Struglia M, Giorgini P, Striuli R, Necozione S, Properzi G, et al. Serum uric acid levels and metabolic syndrome. Arch Physiol Biochem 2014;120:119-22. PMID: 24914748 DOI: http://dx.doi.org/10.3109/13813455.2014.924145
http://dx.doi.org/10.3109/13813455.2014....
UA has several reported effects by which it may cause DN. Including endothelial dysfunction,1010 Zharikov S, Krotova K, Hu H, Baylis C, Johnson RJ, Block ER, et al. Uric acid decreases NO production and increases arginase activity in cultured pulmonary artery endothelial cells. Am J Physiol Cell Physiol 2008;295:C1183-90. PMID: 18784379 DOI: http://dx.doi.org/10.1152/ajpcell.00075.2008
http://dx.doi.org/10.1152/ajpcell.00075....
increased activity of the renin-angiotensin aldosterone system (RAAS),1111 Mazzali M, Kanellis J, Han L, Feng L, Xia YY, Chen Q, et al. Hyperuricemia induces a primary renal arteriolopathy in rats by a blood pressure-independent mechanism. Am J Physiol Renal Physiol 2002;282:F991-7. PMID: 11997315 DOI: http://dx.doi.org/10.1152/ajprenal.00283.2001
http://dx.doi.org/10.1152/ajprenal.00283...
and induction of inflammatory cascades,1212 Mazzali M, Kanellis J, Han L, Feng L, Xia YY, Chen Q, et al. Hyperuricemia induces a primary renal arteriolopathy in rats by a blood pressure-independent mechanism. Am J Physiol Renal Physiol 2002;282:F991-7. PMID: 11997315 DOI: http://dx.doi.org/10.1152/ajprenal.00283.2001
http://dx.doi.org/10.1152/ajprenal.00283...
in addition to profibrotic cytokine activation,1313 Talaat KM, el-Sheikh AR. The effect of mild hyperuricemia on urinary transforming growth factor beta and the progression of chronic kidney disease. Am J Nephrol 2007;27:435-40. DOI: http://dx.doi.org/10.1159/000105142
http://dx.doi.org/10.1159/000105142...
all of which have been demonstrated to contribute to the progression of microvascular disease and thereby renal injury in DN.

Despite the strides that had made in understanding the factors that contribute to the evolution and the progression of diabetic kidney disease. The pathophysiology of diabetic nephropathy is complex and still not fully elucidated.1414 Parving HH, Mauer M, Ritz E. Diabetic nephropathy. In: Brenner BM, ed. Brenner and Rector's The Kidney. Philadelphia: WB Saunders; 2004. p. 1777-818. Beside MA may not be as sensitive and specific a predictor of the DN as previously suggested.1515 Tabaei BP, Al-Kassab AS, Ilag LL, Zawacki CM, Herman WH. Does Microalbuminuria Predict Diabetic Nephropathy? Diabetes Care 2001;24:1560-6. So we conducted this study to investigate the relationship between SUA and hypertension, early nephropathy and progression of CKD in patients with T2DM.

Patients and methods

Study design and population

A case-control study was carried out among patients with T2DM attending the Zagazig University hospital in between January 2015 and February 2016. The study was approved by the local Institutional Ethics Committee and conformed to the Helsinki Declaration. The aim of the study was explained, and informed consent was obtained.

Demographic information was collected; the enrolled number of the study was 986 participants, among them 484 males and 502 females, with mean age of 49.8 ± 10.6 years.

The inclusion criteria included the following: patients with T2DM attending at the Zagazig University hospital outpatient clinic for treatment and their current age ≥ 18 years. Patients were excluded from the study if they suffered from other chronic systemic inflammatory or autoimmune disease or malignancy, type 1 diabetes patients, undetermined onset of diabetes, patients with other causes of CKD were excluded, patients receiving medications for hyperuricemia or drugs known to influence both uric acid levels or urinary albumin excretion were also excluded. However hypertensive patients were not excluded if there was no evidence of a causal role of hypertension in proteinuria.

According to the presence and duration of diabetes the study populations were categorized into three groups. Group I; control group was selected of healthy 250 healthy subjects with comparable age, sex and BMI to other participants. Group II; including 352 type 2 diabetic patients, with onset of diabetes less than 5 years. Group III; including 384 type 2 diabetic patients, with onset of diabetes more than 5 years. Among diabetic patients 486 on oral hypoglycemic drugs, and the remaining 250 on insulin therapy.

Physical examination and measurements

All participants in this study were subjected to complete clinical examination and anthropometric measurements. Height (height was measured using calibrated height meters while subjects stood erect and barefooted, with feet, placing together, and looking forward). Weight (the weight scale was calibrated daily). Waist circumference (WC) the circumference below the costal margin at the level of the umbilicus). Body mass index (BMI) = BW/H2 kg/m), patients with BMI ≥ 30 considered obese.1616 World Health Organization. Obesity and overweight. Geneva: World Health Organization; 2016 [Internet][cited 2016 Sep 27]. Available from: http://www.who.int/mediacentre/factsheets/fs311/en
http://www.who.int/mediacentre/factsheet...
Fundus examination was performed to confirm diabetic retinopathy in participants with overt proteinuria to confirm the diagnosis of DN. Blood pressure was measured with a mercury sphygmomanometer on the right arm with the patient in a sitting position after a rest of 5 min. Hypertension was defined as a systolic blood pressure ≥ 130 mmHg and/or a diastolic blood pressure ≥ 85 mmHg and/or the current use of antihypertensive medication.

Laboratory measurements

Venous blood was drawn in the morning after an overnight fast. All participants were subjected to routine investigations, including SCr, HbA1C, lipid profile, including HDL-C, low-density lipoprotein (LDL), total cholesterol (TC), and TG beside TG/HDL-C ratio. Finally SUA was measured by uricase/peroxidase enzymatic method. Hyperuricemia was defined as SUA level 7.0 mg/dl.1717 Roubenoff R. Gout and hyperuricemia. Rheum Dis Clin North Am 1990;16:539-50. Metabolic syndrome (MS) was defined by the presence of at least three of the following: HDL-C < 40 mg/dl for men or 50 mg/dl for women, fasting blood sugar (FBS) > 100 mg/dl, fasting TG level over 150 mg/dl, BP ≥ 130/85 mmHg, WC ≥ 102 cm for men or ≥ 88 cm for women.1818 Grundy SM, Cleeman JI, Daniels SR, Donato KA, Eckel RH, Franklin BA, et al.; American Heart Association; National Heart, Lung, and Blood Institute. Diagnosis and management of the metabolic syndrome: An American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement. Circulation 2005;112:2735-52. PMID: 16157765 DOI: http://dx.doi.org/10.1161/CIRCULATIONAHA.105.169404
http://dx.doi.org/10.1161/CIRCULATIONAHA...

All participants were instructed how to obtain a fresh, clean first morning urine specimen to exclude orthostatic proteinuria. Urine samples examined for urinary ACR. Early nephropathy defined urine ACR ≥ 30 mg/g, and overt nephropathy was defined as the data urinary ACR ≥ 300 mg/g. Albuminuria was measured by immunoturbidimetry. All positive cases re-examined after three months to confirm diagnosis.

GFR is estimated by CKD-EPI equation formula, as follows: CKD-EPI formula = 141 × min(Scr/κ,1)α × max(Scr/κ, 1)-1.209 × 0.993Age × 1.018 [if female] × 1.159 [if black].1919 Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF 3rd, Feldman HI, et al.; CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration). A new equation to estimate glomerular filtration rate. Ann Intern Med 2009;150:604-12. PMID: 19414839 DOI: http://dx.doi.org/10.7326/0003-4819-150-9-200905050-00006
http://dx.doi.org/10.7326/0003-4819-150-...
CKD was defined according to KDIGO guidelines for the evaluation and management of CKD by glomerular filtration rate (G1-5) G1 Normal or high ≥ 90 but with active urinary sediment, G2 mildly decreased 60-89, G3a mildly to moderately decreased 45 - 59, G3b moderately to severely decreased 30 - 44, G4 severely decreased 15 - 29, and G5 Kidney failure < 15, as well albuminuria category (A1-3) A1 normal to mildly increased < 30 mg/g < 3 mg/mmol, A2 moderately increased 30 - 300 mg/g 3-30 mg/mmol, and A3 severely increased > 300 mg/g > 30 mg/mmol.44 Kidney Disease: Improving Global Outcomes CKD Work Group. KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of CKD. Kidney Int Suppl 2013;3:1-150.

Statistical analyses

Results were expressed as mean ± standard deviation (SD), analysis of variance by ANOVA and post hoc analysis with LSD tests were applied for comparing differences among groups. Data of SCr and ACR were expressed as median because of skewed distribution and analyzed by KruskalWallis test. Qualitative data were expressed in the form of numbers and percentages and comparison between data was performed by using the Chi-square test. The correlation between variables was calculated using the Pearson's and the Spearman correlation tests. Predictive values were assessed by the area under curve/the receiver operator characteristic curve (AUC/ROC). The AUC/ROC was used to determine the discriminatory ability of risk factor in detecting CKD. The criterion for statistical significance was set at p < 0.05. All calculations were carried out using a standard statistical package (SPSS version 19, Inc., Chicago, USA).

Results

Demographic data and characteristic of study

The existent studied number was 986 participants, their mean age 47.9 ± 11.8, male gender represented by 484 (49%) and female gender represented by 502 (51%) of the total study. The age, gender, smoking and BMI did not differ between the 3 studied groups. SUA significantly higher in diabetic patients than the healthy control group, meanwhile SUA levels were significantly higher in diabetic patients over 5 years duration than lesser duration of diabetes. Similarly systolic, diastolic, mean arterial BP, duration of diabetes, HbA1C, TG, TC, LDL, TG/HDL-C ratio, SCr and ACR levels were significantly higher in group III than group I, II, likewise higher in group II than group I. Lastly eGFR significantly lower in group III than group I, II, likewise lower in group II than group I (Table 1).

Table 1
Demographic and laboratory characteristics of the study

Prevalence and significance of SUA

In the cohort of type 2 diabetic patients we found, the overall prevalence of hyperuricemia was 32% and the mean value of SUA was significantly higher among hypertensive, obese, poor glycemic control, high TG/HDL-C ratios patients as well as patients with ACR ≥ 300 mg/g, followed by ACR ≥ 30 mg/g. Meanwhile, there was non-significant difference of SUA level regarding genders and line of treatment (Table 2).

Table 2
Comparative difference of sua levels

Correlates of SUA with study parameters

Although age, gender, duration of diabetes, BMI, WC, mean BP, HbA1c, TC, HDL-C, LDL, TG, TG/HDL-C, SCr, ACR and GFR were assessed in for association with SUA. Only age (r = 0.30; p = 0.05), duration of diabetes (r = 0.47; p = 0.001), BMI (r = 0.42; p = 0.001), WC (r = 0.44; p = 0.001), mean BP (r = 0.35; p = 0.01), HbA1c (r = 0.4; p = 0.001), TC (r = 0.31; p = 0.05), HDL-C (r = 0.36; p = 0.01), LDL (r = 0.33; p = 0.05), TG (r = 0.45; p = 0.001), TG/HDL-C (r = 0.59; p = 0.001), SCr (r = 0.6; p = 0.001), ACR (r = 0.51; p = 0.001), were positively correlated with SUA, while HDL (r = 0.-0.36; p = 0.01) and eGFR (r = -0.65; p = 0.001), were negatively correlated with SUA. Hence SUA was significantly associated with all components of MS (Table 3).

Table 3
Correlates of sua with other study parameters

Sensitivity and specificity of UA

In the cohort of type 2 diabetic patients we found, SUA at level of > 6.1, > 6.2 and > 6.5 had a greater sensitivity 86.8%, 81.25%, 65.4% and specificity 82.8%, 85.94%, 77.1% for identifying hypertension, early nephropathy and diminished GFR respectively (Table 4).

Table 4
Validity of sua in prediction of, hypertension, early nephropathy and impaired GFR

Demographic, clinical and laboratory features of the patients with SUA above and below 6.2 mg/dL.

The mean age, duration of diabetes, BP, BMI, HBA1C, TG/H.D.L-C ratio and SCr were significantly higher in patients with elevated SUA > 6.2 mg/dl. Similarly the prevalence of hypertension, ACR ≥ 30 mg/g and ACR ≥ 300 mg/g were significantly higher among patients with elevated SUA > 6.2 mg/dl. Moreover, patients with elevated SUA > 6.2 mg/dl had lesser eGFR (Table 5).

Table 5
Demographic, clinical and laboratory features of the patients with sua above and below 6.2 mg/dl

Discussion

Early detection of DN has a pivotal role in the prevention of ESRD.2020 Zelmanovitz T, Gerchmann F, Balthazar AP, Thomazelli FC, Matos JD, Canani LH. Diabetic nephropathy. Diabetol Metab Syndr 2009;1:10. DOI:http://dx.doi.org/10.1186/1758-5996-1-10
http://dx.doi.org/10.1186/1758-5996-1-10...
Conflicting data exist about the role of SUA in patients with T2DM; the present study was addressed to evaluate the relation between SUA and hypertension, albumin excretion rate and CKD in a cohort of T2DM patients.

Hyperuricemia is usually defined as an SUA level of 7.0 mg/dl and of ≥ 6 mg/dl in women.1717 Roubenoff R. Gout and hyperuricemia. Rheum Dis Clin North Am 1990;16:539-50. In the current study, we demonstrated that that solely 32% of diabetic patients were hyperuricemic, but in contrast to healthy control subjects SUA levels were higher in T2DM patients with onset of diabetes less than 5 years and continue to rise with disease progression and clinical presentation of DN. Moreover, we also observed a positive correlation between SUA and HbA1C. Our findings were consistent with other reports that link not only a positive association between elevated SUA levels and diabetes2121 Kramer CK, Von Mühlen D, Jassal SK, Barrett Connor E. Serum uric acid levels improve prediction of incident type 2 diabetes in individuals with impaired fasting glucose: the Rancho Bernardo Study. Diabetes Care 2009;32:1272-3. DOI: http://dx.doi.org/10.2337/dc09-0275
http://dx.doi.org/10.2337/dc09-0275...
but also with DN.2222 Bonakdaran S, Hami M, Shakeri MT. Hyperuricemia and albuminuria in patients with type 2 diabetes mellitus. Iran J Kidney Dis 2011;5:21-4.

Contrary to our results other studies found higher SUA levels were inversely associated with diabetes mellitus.2323 Bandaru P, Shankar A. Association between Serum Uric Acid Levels and Diabetes Mellitus. Int J Endocrinol 2011;2011:604715. PMID: 22114591 DOI:http://dx.doi.org/10.1155/2011/604715
http://dx.doi.org/10.1155/2011/604715...
The excuse of such contradictory results is hyperinsulinemia/insulin resistance, which is the cardinal feature of T2DM.2424 Modan M, Halkin H, Karasik A, Lusky A. Elevated serum uric acid-a facet of hyperinsulinemia. Diabetologia 1987;30:713-8. DOI:http://dx.doi.org/10.1007/BF00296994
http://dx.doi.org/10.1007/BF00296994...
It has been proposed that elevated plasma insulin concentrations may decrease urinary uric acid clearance in insulin-resistant individuals.2525 Quiñones-Galvan A, Ferranini E. Renal effects of insulin in man. J Nephrol 1997;10:188-91. Contrary, hypouricemia may be the consequence of glomerular hyperfiltration, typically defined by a GFR of between 125 mL/min and 140 mL/min/1.73 m2, consequently increasing renal clearance of the urate,2626 Shichiri M, Iwamoto H, Marumo F. Diabetic hypouricemia as an indicator of clinical nephropathy. Am J Nephrol 1990;10:115-22. DOI:http://dx.doi.org/10.1159/000168065
http://dx.doi.org/10.1159/000168065...
while the mean GFR of our patients study much lesser.

Unexpectedly, we failed to find a correlation between SUA levels and sex; however, the possible reason that may explain these conflicting results, is the mean age of women was significantly higher and most of them older than 50 years, moreover most of them were menopausal, as menopausal women have higher SUA levels than premenopausal women.2727 Hak AE, Choi HK. Menopause, postmenopausal hormone use and serum uric acid levels in US women-the Third National Health and Nutrition Examination Survey. Arthritis Res Ther 2008;10:R116. doi: 10.1186/ar2519 DOI: http://dx.doi.org/10.1186/ar2519
http://dx.doi.org/10.1186/ar2519...
Estrogen is known to promote excretion of uric acid, so reduce the prevalence of hyperuricemia in premenopausal women.2828 Sumino H, Ichikawa S, Kanda T, Nakamura T, Sakamaki T. Reduction of serum uric acid by hormone replacement therapy in postmenopausal women with hyperuricaemia. Lancet. 1999;354:650. DOI: http://dx.doi.org/10.1016/S0140-6736(99)92381-4
http://dx.doi.org/10.1016/S0140-6736(99)...

In the Current study, we found, a higher level of SUA among hypertensive patients, SUA levels were associated with the risk of hypertension, and furthermore SUA at level 6.1 mg.dl identify the onset of hypertension in T2DM. Our findings were consistent with other studies which reported that higher UA concentrations were independently associated with increased odds of developing hypertension.2929 Forman JP, Choi H, Curhan GC. Uric acid and insulin sensitivity and risk of incident hypertension. Arch Intern Med 2009;169:155-62. PMID: 19171812 DOI: http://dx.doi.org/10.1001/archinternmed.2008.521
http://dx.doi.org/10.1001/archinternmed....
Potential mechanisms behind the link between hyperuricemia and the development of hypertension have included nitric oxide and RAAS pathways. UA could lead to endothelial cell dysfunction via nitric oxide synthetase and stimulate vascular smooth muscle cell proliferation.1010 Zharikov S, Krotova K, Hu H, Baylis C, Johnson RJ, Block ER, et al. Uric acid decreases NO production and increases arginase activity in cultured pulmonary artery endothelial cells. Am J Physiol Cell Physiol 2008;295:C1183-90. PMID: 18784379 DOI: http://dx.doi.org/10.1152/ajpcell.00075.2008
http://dx.doi.org/10.1152/ajpcell.00075....
Furthermore, UA may also directly stimulate the RAAS.1111 Mazzali M, Kanellis J, Han L, Feng L, Xia YY, Chen Q, et al. Hyperuricemia induces a primary renal arteriolopathy in rats by a blood pressure-independent mechanism. Am J Physiol Renal Physiol 2002;282:F991-7. PMID: 11997315 DOI: http://dx.doi.org/10.1152/ajprenal.00283.2001
http://dx.doi.org/10.1152/ajprenal.00283...

Hyperuricemia has gained attention as it has been reported that it plays an important role in the development of MS. It has been suggested that the plasma TG/HDL-C ratio can serve as a simple and easily accessible marker for the diagnosis of MS and insulin resistance.3030 Bagby SP. Obesity-Initiated Metabolic Syndrome and the Kidney: A Recipe for Chronic Kidney Disease? J Am Soc Nephrol 2004;15:2775-91. In the current study, we found SUA negatively correlated with HDL-C and positively correlated with other components of MS as, BMI, WC, BP, HbA1C, TG, TG/HDL-C. Moreover diabetic patients with a higher SUA level > 6.2 mg/dl have a higher BMI, BP, TG/HDL-C. So, increased SUA concentration may be an additional risk factor for MS. The underlying mechanisms may explain the association between UA and MS includes deleterious effects of UA on endothelial function [10], oxidative metabolism,3131 Sautin YY, Nakagawa T, Zharikov S, Johnson RJ. Adverse effects of the classic antioxidant uric acid in adipocytes: NADPH oxidase-mediated oxidative/nitrosative stress. Am J Physiol Cell Physiol 2007;293:C584-96. DOI: http://dx.doi.org/10.1152/ajpcell.00600.2006
http://dx.doi.org/10.1152/ajpcell.00600....
and the systemic inflammatory state.3232 Baldwin W, McRae S, Marek G, Wymer D, Pannu V, Baylis C, et al. Hyperuricemia as a mediator of the proinflammatory endocrine imbalance in the adipose tissue in a murine model of the metabolic syndrome. Diabetes 2011;60:1258-69. DOI: http://dx.doi.org/10.2337/db10-0916
http://dx.doi.org/10.2337/db10-0916...
Our findings were consistent with other reports that the link between UA and MS.3333 Chen D, Zhang H, Gao Y, Lu Z, Yao Z, Jiang Y, et al. Cross-sectional and longitudinal associations between serum uric acid and metabolic syndrome: Results from Fangchenggang Area Male Health and Examination Survey in China. Clin Chim Acta 2015;446:226-30. PMID: 25913163 DOI:http://dx.doi.org/10.1016/j.cca.2015.04.019
http://dx.doi.org/10.1016/j.cca.2015.04....

UA is produced by xanthine oxidoreductase. Oxidoreductase activity also contributes to macrophage foam cell formation and inflammation and macrophage activation is thought to be involved in the pathogenesis of DN.3434 Kushiyama A, Okubo H, Sakoda H, Kikuchi T, Fujishiro M, Sato H, et al. Xanthine oxidoreductase is involved in macrophage foam cell formation and atherosclerosis development. Arterioscler Thromb Vasc Biol 2012;32:291-8. DOI: http://dx.doi.org/10.1161/ATVBAHA.111.234559
http://dx.doi.org/10.1161/ATVBAHA.111.23...
MA is a marker of endothelial dysfunction and associated with an increased risk of cardiovascular morbidity in patients with diabetes.3535 Redon J, Pascual JM. Development of microalbuminuria in essential hypertension. Curr Hypertens Rep 2006;8:171-7. DOI: http://dx.doi.org/10.1007/s11906-006-0015-x
http://dx.doi.org/10.1007/s11906-006-001...
In the present study, we have evaluated the relationships between UA concentration and degree of urinary albumin excretion. We demonstrated not only a higher level of SUA in patients with ACR ≥ 30 mg/g, but also a positive correlation with ACR ≥ 30 mg/g, and at a cutoff level of > 6.2 mg/dl identify the onset of early nephropathy in type 2 diabetic patients. Moreover SUA level continues to raise with progression of overt diabetic nephropathy patients with ACR ≥ 300 mg/g, and still positively correlated with ACR ≥ 300 mg/g. Generally, these results appear compatible with other studies which found, SUA concentration was associated with microalbuminuria and increased progression to overt nephropathy in patients with T2DM3636 Fukui M, Tanaka M, Shiraishi E, Harusato I, Hosoda H, Asano M, et al. Serum uric acid is associated with microalbuminuria and subclinical atherosclerosis in men with type 2 diabetes mellitus. Metabolism 2008;57:625-9. PMID: 18442624 DOI:http://dx.doi.org/10.1016/j.metabol.2007.12.005
http://dx.doi.org/10.1016/j.metabol.2007...
as well SUA levels, even within the normal range > 6.3 mg/dl can predict the onset of overt nephropathy.3737 Tanaka K, Hara S, Hattori M, Sakai K, Onishi Y, Yoshida Y, et al. Role of elevated serum uric acid levels at the onset of overt nephropathy in the risk for renal function decline in patients with type 2 diabetes. J Diabetes Invest 2015;6:98-104. DOI: http://dx.doi.org/10.1111/jdi.12243
http://dx.doi.org/10.1111/jdi.12243...

Overt nephropathy resulted in an increased risk for declining renal function in T2DM. The role of UA in patients with T2DM is still not well studied, particularly in association with declining renal function. In the present study, we demonstrated that higher levels of SUA were associated with declines of eGFR and identify the onset of rapid progression of CKD, furthermore at a cutoff level of > 6.5 mg/dl may link to progression of CKD in T2DM patients.Our results were consistent with previous findings, which registered that hyperuricemia seemed to be an independent risk factor for the development of incident CKD rather associated with overt nephropathy3737 Tanaka K, Hara S, Hattori M, Sakai K, Onishi Y, Yoshida Y, et al. Role of elevated serum uric acid levels at the onset of overt nephropathy in the risk for renal function decline in patients with type 2 diabetes. J Diabetes Invest 2015;6:98-104. DOI: http://dx.doi.org/10.1111/jdi.12243
http://dx.doi.org/10.1111/jdi.12243...
and even in normalbuminuria patients with T2DM.3838 De Cosmo S, Viazzi F, Pacilli A, Giorda C, Ceriello A, Gentile S, et al.; AMD-Annals Study Group. Serum Uric Acid and Risk of CKD in Type 2 Diabetes. Clin J Am Soc Nephrol 2015;10:1921-9. DOI: http://dx.doi.org/10.2215/CJN.03140315
http://dx.doi.org/10.2215/CJN.03140315...

Collectively in the current study we, achieved that T2DM patients with UA ≤ 6.2 mg/dl were, younger, recently diabetic, better glycemic control, normotensive, lesser BMI, comparatively ideal TG/HDL-C, lower prevalence of early and overt nephropathy and preserved GFR. The current data give an important, highlighting to maintain SUA ≤ 6.2 mg/dl.

Conclusion

Even the high normal SUA level, was associated with the risk of hypertension, MS, early nephropathy and decline of eGFR. Moreover SUA level may identify and link with the onset of hypertension, early nephropathy, a procession of nephropathy and progression of CKD in T2DM. Measuring SUA levels routinely may help to identify high risk patients, as well as great attention to maintain SUA ≤ 6.2 mg/dl. Further studies are needed to examine the impact of lowering SUA levels on diabetic complications.

Acknowledgments

The authors wish to thank the staff of the Clinical pathology and the Nepherology division of Zagazig University Hospital.

References

  • 1
    Eggers PW. Incidence of end-stage renal disease in the USA and other countries stabilized? Curr Opin Nephrol Hypertens 2011;20:241-5.
  • 2
    Ritz E, Orth SR. Nephropathy in patients with type 2 diabetes mellitus. N Engl J Med 1999;341:1127-33. PMID: 10511612 DOI:http://dx.doi.org/10.1056/NEJM199910073411506
    » http://dx.doi.org/10.1056/NEJM199910073411506
  • 3
    Eckardt KU, Coresh J, Devuyst O, Johnson RJ, Köttgen A, Levey AS, et al. Evolving importance of kidney disease: from subspecialty to global health burden. Lancet 2013;382:158-69. PMID: 23727165 DOI: http://dx.doi.org/10.1016/S0140-6736(13)60439-0
    » http://dx.doi.org/10.1016/S0140-6736(13)60439-0
  • 4
    Kidney Disease: Improving Global Outcomes CKD Work Group. KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of CKD. Kidney Int Suppl 2013;3:1-150.
  • 5
    Cirillo P, Sato W, Reungjui S, Heinig M, Gersch M, Sautin Y, et al. Uric acid, the metabolic syndrome, and renal disease. J Am Soc Nephrol 2006;17:S165-8. DOI: http://dx.doi.org/10.1681/ASN.2006080909
    » http://dx.doi.org/10.1681/ASN.2006080909
  • 6
    Kodama S, Saito K, Yachi Y, Asumi M, Sugawara A, Totsuka K, et al. Association between serum uric acid and development of type 2 diabetes. Diabetes Care 2009;32:1737-42. DOI: http://dx.doi.org/10.2337/dc09-0288
    » http://dx.doi.org/10.2337/dc09-0288
  • 7
    Krishnan E, Kwoh CK, Schumacher HR, Kuller L. Hyperuricemia and incidence of hypertension among men without metabolic syndrome. Hypertension 2007;49:298-303. PMID: 17190877 DOI: http://dx.doi.org/10.1161/01.HYP.0000254480.64564.b6
    » http://dx.doi.org/10.1161/01.HYP.0000254480.64564.b6
  • 8
    Zoppini G, Targher G, Negri C, Stoico V, Perrone F, Muggeo M, et al. Elevated serum uric acid concentrations independently predict cardiovascular mortality in type 2 diabetic patients. Diabetes Care 2009;32:1716-20. DOI: http://dx.doi.org/10.2337/dc09-0625
    » http://dx.doi.org/10.2337/dc09-0625
  • 9
    Ciarla S, Struglia M, Giorgini P, Striuli R, Necozione S, Properzi G, et al. Serum uric acid levels and metabolic syndrome. Arch Physiol Biochem 2014;120:119-22. PMID: 24914748 DOI: http://dx.doi.org/10.3109/13813455.2014.924145
    » http://dx.doi.org/10.3109/13813455.2014.924145
  • 10
    Zharikov S, Krotova K, Hu H, Baylis C, Johnson RJ, Block ER, et al. Uric acid decreases NO production and increases arginase activity in cultured pulmonary artery endothelial cells. Am J Physiol Cell Physiol 2008;295:C1183-90. PMID: 18784379 DOI: http://dx.doi.org/10.1152/ajpcell.00075.2008
    » http://dx.doi.org/10.1152/ajpcell.00075.2008
  • 11
    Mazzali M, Kanellis J, Han L, Feng L, Xia YY, Chen Q, et al. Hyperuricemia induces a primary renal arteriolopathy in rats by a blood pressure-independent mechanism. Am J Physiol Renal Physiol 2002;282:F991-7. PMID: 11997315 DOI: http://dx.doi.org/10.1152/ajprenal.00283.2001
    » http://dx.doi.org/10.1152/ajprenal.00283.2001
  • 12
    Mazzali M, Kanellis J, Han L, Feng L, Xia YY, Chen Q, et al. Hyperuricemia induces a primary renal arteriolopathy in rats by a blood pressure-independent mechanism. Am J Physiol Renal Physiol 2002;282:F991-7. PMID: 11997315 DOI: http://dx.doi.org/10.1152/ajprenal.00283.2001
    » http://dx.doi.org/10.1152/ajprenal.00283.2001
  • 13
    Talaat KM, el-Sheikh AR. The effect of mild hyperuricemia on urinary transforming growth factor beta and the progression of chronic kidney disease. Am J Nephrol 2007;27:435-40. DOI: http://dx.doi.org/10.1159/000105142
    » http://dx.doi.org/10.1159/000105142
  • 14
    Parving HH, Mauer M, Ritz E. Diabetic nephropathy. In: Brenner BM, ed. Brenner and Rector's The Kidney. Philadelphia: WB Saunders; 2004. p. 1777-818.
  • 15
    Tabaei BP, Al-Kassab AS, Ilag LL, Zawacki CM, Herman WH. Does Microalbuminuria Predict Diabetic Nephropathy? Diabetes Care 2001;24:1560-6.
  • 16
    World Health Organization. Obesity and overweight. Geneva: World Health Organization; 2016 [Internet][cited 2016 Sep 27]. Available from: http://www.who.int/mediacentre/factsheets/fs311/en
    » http://www.who.int/mediacentre/factsheets/fs311/en
  • 17
    Roubenoff R. Gout and hyperuricemia. Rheum Dis Clin North Am 1990;16:539-50.
  • 18
    Grundy SM, Cleeman JI, Daniels SR, Donato KA, Eckel RH, Franklin BA, et al.; American Heart Association; National Heart, Lung, and Blood Institute. Diagnosis and management of the metabolic syndrome: An American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement. Circulation 2005;112:2735-52. PMID: 16157765 DOI: http://dx.doi.org/10.1161/CIRCULATIONAHA.105.169404
    » http://dx.doi.org/10.1161/CIRCULATIONAHA.105.169404
  • 19
    Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF 3rd, Feldman HI, et al.; CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration). A new equation to estimate glomerular filtration rate. Ann Intern Med 2009;150:604-12. PMID: 19414839 DOI: http://dx.doi.org/10.7326/0003-4819-150-9-200905050-00006
    » http://dx.doi.org/10.7326/0003-4819-150-9-200905050-00006
  • 20
    Zelmanovitz T, Gerchmann F, Balthazar AP, Thomazelli FC, Matos JD, Canani LH. Diabetic nephropathy. Diabetol Metab Syndr 2009;1:10. DOI:http://dx.doi.org/10.1186/1758-5996-1-10
    » http://dx.doi.org/10.1186/1758-5996-1-10
  • 21
    Kramer CK, Von Mühlen D, Jassal SK, Barrett Connor E. Serum uric acid levels improve prediction of incident type 2 diabetes in individuals with impaired fasting glucose: the Rancho Bernardo Study. Diabetes Care 2009;32:1272-3. DOI: http://dx.doi.org/10.2337/dc09-0275
    » http://dx.doi.org/10.2337/dc09-0275
  • 22
    Bonakdaran S, Hami M, Shakeri MT. Hyperuricemia and albuminuria in patients with type 2 diabetes mellitus. Iran J Kidney Dis 2011;5:21-4.
  • 23
    Bandaru P, Shankar A. Association between Serum Uric Acid Levels and Diabetes Mellitus. Int J Endocrinol 2011;2011:604715. PMID: 22114591 DOI:http://dx.doi.org/10.1155/2011/604715
    » http://dx.doi.org/10.1155/2011/604715
  • 24
    Modan M, Halkin H, Karasik A, Lusky A. Elevated serum uric acid-a facet of hyperinsulinemia. Diabetologia 1987;30:713-8. DOI:http://dx.doi.org/10.1007/BF00296994
    » http://dx.doi.org/10.1007/BF00296994
  • 25
    Quiñones-Galvan A, Ferranini E. Renal effects of insulin in man. J Nephrol 1997;10:188-91.
  • 26
    Shichiri M, Iwamoto H, Marumo F. Diabetic hypouricemia as an indicator of clinical nephropathy. Am J Nephrol 1990;10:115-22. DOI:http://dx.doi.org/10.1159/000168065
    » http://dx.doi.org/10.1159/000168065
  • 27
    Hak AE, Choi HK. Menopause, postmenopausal hormone use and serum uric acid levels in US women-the Third National Health and Nutrition Examination Survey. Arthritis Res Ther 2008;10:R116. doi: 10.1186/ar2519 DOI: http://dx.doi.org/10.1186/ar2519
    » http://dx.doi.org/10.1186/ar2519
  • 28
    Sumino H, Ichikawa S, Kanda T, Nakamura T, Sakamaki T. Reduction of serum uric acid by hormone replacement therapy in postmenopausal women with hyperuricaemia. Lancet. 1999;354:650. DOI: http://dx.doi.org/10.1016/S0140-6736(99)92381-4
    » http://dx.doi.org/10.1016/S0140-6736(99)92381-4
  • 29
    Forman JP, Choi H, Curhan GC. Uric acid and insulin sensitivity and risk of incident hypertension. Arch Intern Med 2009;169:155-62. PMID: 19171812 DOI: http://dx.doi.org/10.1001/archinternmed.2008.521
    » http://dx.doi.org/10.1001/archinternmed.2008.521
  • 30
    Bagby SP. Obesity-Initiated Metabolic Syndrome and the Kidney: A Recipe for Chronic Kidney Disease? J Am Soc Nephrol 2004;15:2775-91.
  • 31
    Sautin YY, Nakagawa T, Zharikov S, Johnson RJ. Adverse effects of the classic antioxidant uric acid in adipocytes: NADPH oxidase-mediated oxidative/nitrosative stress. Am J Physiol Cell Physiol 2007;293:C584-96. DOI: http://dx.doi.org/10.1152/ajpcell.00600.2006
    » http://dx.doi.org/10.1152/ajpcell.00600.2006
  • 32
    Baldwin W, McRae S, Marek G, Wymer D, Pannu V, Baylis C, et al. Hyperuricemia as a mediator of the proinflammatory endocrine imbalance in the adipose tissue in a murine model of the metabolic syndrome. Diabetes 2011;60:1258-69. DOI: http://dx.doi.org/10.2337/db10-0916
    » http://dx.doi.org/10.2337/db10-0916
  • 33
    Chen D, Zhang H, Gao Y, Lu Z, Yao Z, Jiang Y, et al. Cross-sectional and longitudinal associations between serum uric acid and metabolic syndrome: Results from Fangchenggang Area Male Health and Examination Survey in China. Clin Chim Acta 2015;446:226-30. PMID: 25913163 DOI:http://dx.doi.org/10.1016/j.cca.2015.04.019
    » http://dx.doi.org/10.1016/j.cca.2015.04.019
  • 34
    Kushiyama A, Okubo H, Sakoda H, Kikuchi T, Fujishiro M, Sato H, et al. Xanthine oxidoreductase is involved in macrophage foam cell formation and atherosclerosis development. Arterioscler Thromb Vasc Biol 2012;32:291-8. DOI: http://dx.doi.org/10.1161/ATVBAHA.111.234559
    » http://dx.doi.org/10.1161/ATVBAHA.111.234559
  • 35
    Redon J, Pascual JM. Development of microalbuminuria in essential hypertension. Curr Hypertens Rep 2006;8:171-7. DOI: http://dx.doi.org/10.1007/s11906-006-0015-x
    » http://dx.doi.org/10.1007/s11906-006-0015-x
  • 36
    Fukui M, Tanaka M, Shiraishi E, Harusato I, Hosoda H, Asano M, et al. Serum uric acid is associated with microalbuminuria and subclinical atherosclerosis in men with type 2 diabetes mellitus. Metabolism 2008;57:625-9. PMID: 18442624 DOI:http://dx.doi.org/10.1016/j.metabol.2007.12.005
    » http://dx.doi.org/10.1016/j.metabol.2007.12.005
  • 37
    Tanaka K, Hara S, Hattori M, Sakai K, Onishi Y, Yoshida Y, et al. Role of elevated serum uric acid levels at the onset of overt nephropathy in the risk for renal function decline in patients with type 2 diabetes. J Diabetes Invest 2015;6:98-104. DOI: http://dx.doi.org/10.1111/jdi.12243
    » http://dx.doi.org/10.1111/jdi.12243
  • 38
    De Cosmo S, Viazzi F, Pacilli A, Giorda C, Ceriello A, Gentile S, et al.; AMD-Annals Study Group. Serum Uric Acid and Risk of CKD in Type 2 Diabetes. Clin J Am Soc Nephrol 2015;10:1921-9. DOI: http://dx.doi.org/10.2215/CJN.03140315
    » http://dx.doi.org/10.2215/CJN.03140315

Publication Dates

  • Publication in this collection
    Oct-Dec 2016

History

  • Received
    11 Apr 2016
  • Accepted
    09 Aug 2016
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