Int Urol Nephrol (2007) 39:1227–1233 DOI 10.1007/s11255-007-9253-3
ORIGINAL ARTICLE
Effect of treatment of hyperuricemia with allopurinol on blood pressure, creatinine clearence, and proteinuria in patients with normal renal functions Mehmet Kanbay Æ Adem Ozkara Æ Yusuf Selcoki Æ Bunyamin Isik Æ Faruk Turgut Æ Nuket Bavbek Æ Ebru Uz Æ Ali Akcay Æ Ramazan Yigitoglu Æ Adrian Covic
Received: 26 April 2007 / Accepted: 19 June 2007 / Published online: 15 August 2007 Ó Springer Science+Business Media B.V. 2007
Abstract Background Hyperuricemia has been associated with the development of hypertension, cardiovascular, and renal disease. However, there is no data about the effect of lowering uric acid level on hypertension, renal function, and proteinuria in patients with glomerular filtration rate (GFR) >60 ml/min. We therefore conducted a prospective study to investigate the benefits of allopurinol treatment in hyperuricemic patients with normal renal function.
M. Kanbay (&) 35. Sokak, 81/5, Bahcelievler, Ankara 06490, Turkey e-mail:
[email protected] M. Kanbay F. Turgut N. Bavbek E. Uz A. Akcay Department of Internal Medicine, Section of Nephrology, Fatih University School of Medicine, Ankara, Turkey A. Ozkara B. Isik Department of Family Medicine, Fatih University School of Medicine, Ankara, Turkey Y. Selcoki Department of Cardiology, Fatih University School of Medicine, Ankara, Turkey R. Yigitoglu Department of Biochemistry, Fatih University School of Medicine, Ankara, Turkey A. Covic Department of Nephrology Clinic and Dialysis and Transplantation Center, ‘‘C. I. PARHON’’ University Hospital, Iasi, Romania
Materials and methods Forty-eight hyperuricemic and 21 normouricemic patients were included in the study. Hyperuricemic patients received 300 mg/day allopurinol for three months. All patients’ serum creatinine level, 24-h urine protein level, glomerular filtration rate, and blood pressure levels were measured at baseline and after three months of treatment. Results A total of 59 patients completed the threemonth follow-up period of observation. In the allopurinol group, serum uric acid levels, GFR, systolic and diastolic blood pressure, and C-reactive protein (CRP) levels significantly improved (P < 0.05). However, urine protein excretion remained unchanged (P > 0.05). No correlation was observed between changes in GFR and changes in CRP, or blood pressure in the allopurinol group. No significant changes were observed in the control group (P > 0.05). Conclusion We bring indirect evidence that hyperuricemia increases blood pressure, and decreases GFR. Hence, management of hyperuricemia may prevent the progression of renal disease, even in patients with normal renal function, suggesting that early treatment with allopurinol should be an important part of the management of chronic kidney disease (CKD) patients. Long-term follow-up studies are warranted to identify the benefits of uric acid management on renal function and hypertension. Keywords Uric acid Allopurinol Blood pressure Renal function Proteinuria
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Introduction Recent studies have found that hyperuricemia is associated with increased mortality and development of hypertension, cardiovascular, and chronic renal diseases [1–3]. Serum uric acid level may reflect a decrease in renal blood flow and early hypertensive nephrosclerosis. Additionally, hyperuricemia is not only a marker of renal disease but may also play a pathogenic role in the progression of disease [4–6]. Furthermore, hyperuricemia is commonly encountered in patients with metabolic syndrome (7, 8)— where, again, it is not just a harmless component of the metabolic syndrome constellation, but is strongly associated with insulin resistance, hypertension, dyslipidemia, endothelial dysfunction, and renal impairment [9–13]. Hence, lowering of uric acid might be an important therapeutic option/strategy. Animal studies, have shown that treatment of hyperuricemia significantly improves blood pressure, decreases proteinuria, and prevents glomerulosclerosis, tubulointerstitial fibrosis, and vasculopathy [6]. However, there is no data about the effect of lowering serum uric level in patients with normal renal function. The present study aims to investigate the effect of lowering the serum uric acid level on GFR, proteinuria and blood pressure, in patients with normal renal function.
Materials and methods Study population Thirty-six hypertensive and 12 normotensive patients attending the outpatient nephrology and cardiology clinics of our hospital meeting the following inclusion criteria were enrolled: (1) glomerular filtration rate (GFR) >60 ml/min (MDRD4 formulae—see below); and (2) hyperuricemia—defined as a serum uric acid level greater than 7.0 mg/dl. Patients with a history of gouty arthritis, renal stones, proteinuria (>500 mg/day), uncontrolled hypertension, diabetes mellitus, heart failure, clinical evidence of atherosclerosis (stroke, coronary, and peripheral artery disease), infection, alcohol abuse, cancer, a known history of allopurinol hypersensitivity, or those already on allopurinol were not included to the study.
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None of the comorbidities.
patients
had
any
additional
Control group Twenty-one healthy subjects with normal serum uric acid levels (8 women, 13 men) were used as an ageand sex-matched reference group. Clinical information including height, weight, medical history, current medications, laboratory data, and smoking history was recorded. Body weight was measured with the subjects in light clothing without shoes. Body mass index (BMI) was calculated as weight (kg)/height squared (m2).
Allopurinol administration Patients were treated with 300 allopurinol mg/day. All adverse events considered to be related to the use of allopurinol were recorded. Any adverse events, including Stevens-Johnson syndrome and an increase in transaminase level prompted discontinuation of the allopurinol therapy.
Blood pressure measurements Subjects were followed up for three months. Systolic and diastolic blood pressure were measured before and three months after starting allopurinol using a random-0 sphygmomanometer. Following a standardized protocol, the second and third of three measurements were averaged to estimate systolic and diastolic blood pressure. Hypertension was defined as systolic blood pressure 140 mmHg, diastolic blood pressure 90 mmHg, or use of antihypertensive medications. During the follow-up the antihypertensive therapy, as well as the concurrent medications (lipid-lowering drugs and other drugs that may possibly affect uric acid metabolism), were kept constant.
Determination of urine protein level and renal function At baseline and 12 weeks after starting uric-acidlowering therapy, 24-h urine collection and venous
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blood specimens were drawn to measure, creatinine, uric acid, albumin, C-reactive protein (CRP), hemoglobin, alanine aminotransferase, urine protein, and creatinine (to calculate spot morning urine protein creatinine ratio). Venous blood samples were obtained in the morning after 8 h of fasting. To avoid interference with the assessment of renal function, patients were requested to stop any nonsteroidal anti-inflammatory drugs or cimetidine at least one week before the procedure. Serum uric acid was measured by means of autoanalyzer (Integra 800, Roche, Germany). The GFR was calculated using the modification of diet in renal disease four-variable equation [14]. The study was approved by the Fatih University School of Medicine ethics committee and was conducted in accordance with the ethical principles described by the Declaration of Helsinki.
Statistical analysis All statistical analyses were performed using the SPSS program, version 12.0 (SPSS Inc., Chicago, IL, USA) for Windows XP. Unless otherwise stated, values are expressed as ± standard deviation (SD). Comparison of various parameters between baseline and different intervals were performed by means of paired Student’s t-tests. Statistical significance was defined as a two-tailed P values of less than 0.05.
Results A total of 59 patients (41/48 from the initial allopurinol group and 18/21 from the control group) completed the three-month treatment and follow-up period of observation. Seven patients in the allopurinol group and three in the control group dropped out of the study because of poor compliance (five patients), and poor blood pressure control (>160/ 100 mmHg, four patients). In addition, one patient in the allopurinol group was withdrawn because of the development of an urticarial skin rash after starting allopurinol. Baseline characteristics, laboratory parameters, and medications for the allopurinol and control groups are presented in Table 1. No significant differences were observed between the allopurinol
1229 Table 1 Baseline demographic characteristics Allopurinol group Control group Number of patients
48
Age (years)
66.4 ± 11.3
Male/Female Hypertension (mmHg)
34/14 34
21 64.5 ± 12.5 13/8 13
Systolic
135.4 ± 4.6
133.2 ± 6.9
Diastolic
80.2 ± 6.2
82.7 ± 5.6
Medications ACE inhibitors
15
7
ARB
12
5
Ca+-channel
9
4
Beta blockers
6
3
22
8
Thiazides Statins Smoking
8
4
16
10
Body mass index (kg/m2)
26.4 ± 2.6
27.3 ± 3.4
Total cholesterol (mg/dl)
196.7 ± 26.7
194.2 ± 38.4
LDL-cholesterol (mg/dl)
123.1 ± 31.4
121.3 ± 24.2
HDL-cholesterol Triglyceride (mg/dl) Glucose (mg/dl)
41.7 ± 12.9
39.2 ± 8.5
143.5 ± 48.6 109 ± 8.6
132.6 ± 54.2 107 ± 12.5
Abbreviations: ACE inhibitors, angiotensin converting enzyme inhibitors; ARB, angiotensin receptor blockers; Ca+-channel, calcium channel blockers; LDL, low-density lipoprotein; HDL, high-density lipoprotein
and the control group in baseline demographic parameters, except serum uric acid, and GFR (P = NS). Baseline GFR was lower (P = 0.018) and serum uric acid was higher (P = 0.00) in the allopurinol group. As expected, after 12 weeks of allopurinol therapy, uric acid levels improved significantly (P < 0.001), whereas in the control group no significant change was recorded (P > 0.05, Table 2). Patients treated with allopurinol also had a significantly greater decrease in systolic and diastolic blood pressure compared to the control group. At the same time, there were no significant differences between the two groups regarding the number and types of antihypertensives or lipid lowering medications. Finally, although baseline serum CRP levels were similar in both groups, CRP significantly decreased only in the allopurinol group (P = 0.007), whereas in the control group no significant changes were observed (Table 2).
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Table 2 Laboratory parameters and blood pressure measurements of the treatment and control groups Allopurinol group Baseline
Control group After 3 months
Baseline
After 3 months
Uric acid (mg/dl)
8.0 ± 0.76
5.5 ± 1.2*
5.8 ± 0.2
5.8 ± 0.0
Creatinine (mg/dl)
1.24 ± 0.36
1.14 ± 0.32*
1.1 ± 0.0
1.09 ± 0.4
Glomerular filtration rate (ml/min)
79.2 ± 31.9
92.9 ± 36.8*
89.4 ± 3.0
91.0 ± 6.1
2.8 ± 1.4
2.5 ± 1.3*
2.6 ± 1.6
2.4 ± 1.5
Urine protein (mg/day)
134.5 ± 132.0
131.5 ± 108.1
111.0 ± 17.5
114.6 ± 12.9
Systolic blood pressure (mmHg)
135.4 ± 4.6
131.5 ± 4.1*
133.2 ± 6.9
132.6 ± 7.9
Diastolic blood pressure (mmHg)
80.2 ± 6.2
78.3 ± 3.1*
82.1 ± 5.6
80.8 ± 6.4
C-reactive protein (mg/l)
Glomerular filtration rate
*P < 0.05
95
93 89
90
91
85 80
79
75 70
Allopurinol
Control
Fig. 1 Glomerular filtration rate at baseline and after 12 weeks in the control and allopurinol groups
By the end of the study, GFR significantly increased in the allopurinol group (P = 0.008), whereas in the control group no significant changes were observed (P > 0.05, Table 2 and Fig. 1). No correlation was observed between changes in GFR and changes in CRP, or blood pressure in the allopurinol group. In both groups proteinuria was unchanged at the end of study (P > 0.05). We also divided the hyperuricemic patients into two groups, according to GFR: group 1 with an eGFR >90 ml/min (13 patients) and group 2 with 90 ml/ min > eGFR > 60 ml/min (28 patients) to better investigate any impact of abnormalities in the renal function. Systolic and diastolic blood pressure were similarly decreased in both group after allopurinol treatment (P > 0.05). However, GFR increased high in group 2 when compared to group 1 (P = 0.02).
Discussion The salient findings of this study are that: (i) lowering the serum uric level improves the glomerular
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filtration rate in patients with GFR > 60 ml/min, (ii) the serum uric acid level does not have a direct effect on urine protein level, and (iii) lowering the serum uric acid level decreases the CRP level in patients with normal renal functions. Hyperuricemia has been related to high blood pressure. In previous studies, it was reported that 50– 70% of hyperuricemic patients had hypertension; conversely, 25% of all hypertensive patients had elevated uric acid levels [15, 16]. Hyperuricemia can induce high blood pressure through the activation of the renin-angiotensin system, either directly, by decreasing neuronal nitric oxide synthesis in the juxtaglomerular apparatus, or indirectly, through reduced renal perfusion consecutive to afferent arteriolar vascular smooth cell proliferation or through the induction of cyclooxygenase-2 in the macula densa and arterioles [17–19]. In patients with malignant hypertension Lip et al. described that those with high urate levels had higher baseline diastolic blood pressures and greater renal impairment. Most importantly, at follow-up, patients with hyperuricemia showed a greater deterioration in renal function and higher blood pressures, but no significant difference in survival [20]. Hyperuricemia is also common in patients with renal disease. In a recent study of 6,400 subjects with normal renal function, a serum uric acid of >8.0 mg/ dl, when compared with a serum uric acid level of 60 ml/min. To the best of our knowledge, these are the first data in the literature that have revealed the benefits of allopurinol therapy on GFR, inflammation, and blood pressure, in hyperuricemic patients with normal renal function. Lowering uric acid with allopurinol had no benefit in decreasing the amount of urinary protein in patients with normal excretory renal function, in accord with previous data from Siu et al. obtained in CKD patients followed for a longer period of time (12 months follow-up) [34]. Our data and timeframe are compatible with more-rapid correction of an inflammatory-mediated endothelial impairment [35]. Butler et al. showed that allopurinol improves endothelial dysfunction (to near-normal levels) in patients with type 2 diabetes and mild hypertension, but not in matched control subjects [36]. In summary, we bring indirect evidence that hyperuricemia increases systolic-diastolic blood pressure, and decreases glomerular filtration rate. Hence, management of hyperuricemia may prevent progression of renal disease even in patients with normal renal functions, suggesting that early treatment with allopurinol should be an important part of the management of chronic kidney disease patients. To our knowledge, this is the first study that has showed such benefits for treating hyperuricemia. Randomized controlled trials with long-term follow-up are warranted to identify the benefits of uric acid management on renal function and hypertension/vasculopathy.
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