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Saudi Journal of Kidney Diseases and Transplantation
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Table of Contents   
ORIGINAL ARTICLE  
Year : 2014  |  Volume : 25  |  Issue : 2  |  Page : 316-320
Allopurinol reduces cardiovascular risks and improves renal function in pre-dialysis chronic kidney disease patients with hyperuricemia


1 Department of Nephrology, Baskent University, Ankara, Turkey
2 Department of Internal Medicine, Baskent University, Ankara, Turkey
3 Department of Nephrology, Baskent University, Istanbul, Turkey

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Date of Web Publication11-Mar-2014
 

   Abstract 

To determine the effect of hyperuricemia and allopurinol therapy on renal functions in chronic kidney disease (CKD) stage 3-4, we studied 96 patients in stage 3-4 CKD (57% male, age 65.3 ± 12.4 years). The mean estimated glomerular filtration rate (GFR) was 44.62 ± 14.38 iriL/ min/1.73 m 2 . The study patients were divided into non-allopurinol users (n = 47) and those using allopurinol (n = 49) in the last 12 months. Serum uric acid (UA) and C-reactive protein levels decreased after allopurinol therapy (P = 0.00 and P = 0.04, respectively), but no change was observed in the control group during the study period. In the allopurinol group, the mean GFR increased 3.3 ±1.2 mL/min/1.73 m 2 /year, while it decreased 1.3 ± 0.6 mL/min/1.73 m 2 in the control group during the follow-up period (P = 0.04); the patients in the allopurinol group exhibited lower levels of serum potassium, serum low-density lipoprotein (LDL) and renal resistance index (RRI) (P-values were <0.05). The patients with stable renal functions or GFR change <10% (n = 25) at the end of 12 months had significantly lower LDL and RRI values and more allopurinol users than the group with deceasing GFR (74% vs. 48%, P <0.05). In the regression analysis, UA and RRI were found as independent variables (r 2 = 0.68, P <0.01; r 2 = 0.25, P <0.01) that affected loss of renal function. We conclude that our study suggests a role for allopurinol, an effective agent in lowering serum UA levels, as a reliable therapeutic option in controlling renal progression in pre-dialysis CKD patients.

How to cite this article:
Sezer S, Karakan S, Atesagaoglu B, Acar F N. Allopurinol reduces cardiovascular risks and improves renal function in pre-dialysis chronic kidney disease patients with hyperuricemia. Saudi J Kidney Dis Transpl 2014;25:316-20

How to cite this URL:
Sezer S, Karakan S, Atesagaoglu B, Acar F N. Allopurinol reduces cardiovascular risks and improves renal function in pre-dialysis chronic kidney disease patients with hyperuricemia. Saudi J Kidney Dis Transpl [serial online] 2014 [cited 2019 Sep 21];25:316-20. Available from: http://www.sjkdt.org/text.asp?2014/25/2/316/128520

   Introduction Top


An elevated serum uric acid (UA) level is consistently associated with increased cardiovascular risks and renal disease. [1] In patients with chronic kidney disease (CKD), there is decreased UA urinary excretion [2] and hyperuricemia is common in subjects with end-stage renal disease (ESRD in up to 50% of the patients. [2],[3],[4] Chronic hyperuricemia stimulates the renin-angiotensin system and inhibits the release of endothelial nitric oxide that contribute to renal vasoconstriction and increase blood pressure, and may have a pathogenic role in the interstitial inflammation and progression of the kidney disease. [5],[6]

Although studies reported an association between the elevated serum UA and kidney disease, the actual mechanism is not clearly understood. Using animal models, Nakagawa et al and Khosla et al suggest that decreasing UA levels using allopurinol, a xanthine oxidase inhibitor, could reverse or inhibit cardiovascular risk factors, namely hypertension, serum lipid levels and triglyceride levels in rats. [7],[8] There are few data on patients with CKD that confirm these findings.

We aimed in this study to determine the effect of allopurinol therapy on hyperuricemia and the kidney disease progression in patients with CKD stage 3-4. The secondary objective was to analyze the effect of allopurinol treatment on the cardiovascular risk factors.


   Materials and Methods Top


This cross-sectional study includes cohorts of 96 stage 3-4 CKD patients (57% male; age 65.3 ± 12.4 years). The inclusion criteria were age over 18 years, presence of renal disease, defined as having an estimated glomerular filtration rate (GFR) (eGFR) lower than 60 mL/min, stable clinical condition in terms of neither hospitalizations nor cardiovascular events within the three months before screening. We excluded patients with a history of allopurinol intolerance, an ongoing allopurinol treatment, active infections or inflammatory diseases, a chronic liver disease and an ongoing immunosuppressive therapy. Demographic and clinical characteristics and laboratory measurements of the study population at baseline are shown in [Table 1]. The etiology of the CKD included diabetic nephropathy in 18 (18%) patients, chronic glomerulonephritis in 16 (16%) patients, autosomal polycystic kidney disease in 13 (13%) patients, interstitial nephritis in 11 (11%) patients and other or unknown etiologies in 38 (38%) patients. The study protocol was approved by the local scientific ethics committee and informed consent was obtained from all patients.
Table 1: Baseline features in the control and the allopurinol groups.

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The following data were recorded for each patient: Age, gender, drugs on admission, relevant medical history and results of routine laboratory tests. In biochemical analysis, a fasting blood sample was collected from each patient and analyzed for serum levels of all laboratory parameters at baseline and 12 months of follow-up. Anthropometric measurements (height, weight, circumferences of waist, hip and calculated body mass indices) were recorded.

Creatinine clearance rate and protein excretion were measured by 24-h urine samples. CKD was defined as a sustained decrease in eGFR, which was estimated by using the MDRD study formula in all the patients and applied the National Kidney Foundation's GFR calculator. [9]

Ultrasonographic examination and Doppler examinations were all performed and the renal resistive index (RRI) was measured at the start and at the end of the 12 months of follow-up by the same operator (Sonoline Elegra Cx 5-2 multi-Darray transducer; Siemens Medical Solutions Washington; USA).


   Statistical Analysis Top


Statistical analysis was conducted by using the SPSS computer program (version 13.0; SPSS Inc., Chicago, IL, USA). Values of P <0.05 were considered to be statistically significant. Descriptive statistics are presented as means and frequencies with standard deviations. To test for differences between the patients with allopurinol use and GFR stages, independent samples t-test were used for continuous variables, while chi-square tests were used for categorical variables. Multiple regression analysis was employed to estimate the relationship between baseline and study period variables and GFR change.


   Results Top


We studied 96 stage 3-4 CKD patients (42 patients, 44% stage 3). The mean eGFR (mL/min/ 1.73 m 2 , ±SD) measurements at baseline and at 12 months were 43.4 ± 16.5 mL/min/1.73 m 2 and 45.8 ± 12.4 mL/min/1.73 m 2 , respectively. Forty-seven patients were randomized to the control group and 49 patients to the allopurinol group. The mean allopurinol dose was 1.5 ± 0.8 mg/kg/daily (range 0.7-3.9 mg/kg/daily). The baseline characteristics and laboratory parameters are listed in [Table 1].

After 12 months of allopurinol treatment, the serum UA levels were significantly decreased in the patients treated with allopurinol, from 7.8 ± 2.1 mg/dL to 6.0 ± 1.2 mg/dL (P = 0.00), whereas the serum UA levels for the patients in the control group remained unchanged throughout the study period (7.3 ±1.6 mg/dL at baseline and 7.5 ± 1.7 mg/dL at 12 months; P = 0.12). The CRP median levels decreased significantly after 12 months of allopurinol treatment (from 4.4 mg/L to 3.0 mg/L, P = 0.04), whereas the levels in the control group remained unchanged in the follow-up period (from 4.3 to 2.2 mg/L). In the allopurinol group, the GFR increased 3.3 ± 1.2 mL/min/1.73 m 2 / year, while it decreased 1.3 ± 0.6 mL/min/1.73 m 2 in the control group during the follow-up period (P = 0.04). The patients in the allopurinol group exhibited lower levels of serum potassium, serum low-density lipoprotein (LDL) and RRI at the end of the follow-up period (P <0.05) [Table 2].
Table 2: The effects of allopurinol on the laboratory parameters after 12 months of therapy.

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The patients were stratified into three groups according to the loss in GFR: Group 1 with loss of GFR 20% (n = 28), group 2 with loss of GFR 10-20% (n = 43) and group 3 with GFR change <10% (n = 25) at the end of the 12 months of follow-up. LDL and RRI values were significantly lower in group 3; most of patients were allopurinol users in group 3 than in group 1 (74% vs. 48%, P <0.05). In the regression analysis, the UA and the RRI were found to be independent variables (r 2 = 0.68, P <0.01; r 2 = 0.25, P <0.01) that affected the loss of renal function.

No hematologic alterations or serious adverse events in relation to allopurinol treatment appeared in the follow-up study.


   Discussion Top


In this study, we found that allopurinol treatment decreased cardiovascular risk factors and slowed the progression of renal disease. The results of this study are, therefore, distinct from the previous studies of ESRD patients in Taiwan and Sweden. [2],[3] A number of factors regulate the UA in the CKD patient. Dietary intake of purines and fructose is a primary source of UA; therefore, its levels could vary with the nutritional status. Because the kidney eliminates much of the generated UA, a decrease in the eGFR is associated with an increase in blood UA levels (although there is a compensatory increase in the gut elimination). UA is also an anti-oxidant and, upon reaction with oxidants, it will undergo degradation to allantoin and other products. [10] In the CKD patients, this degradation pathway is increased five-fold or more. [3] Finally, a variety of demographic factors and co-morbid conditions are associated with abnormal serum UA levels in the ESRD populations. [1],[2],[3]

In our study, allopurinol was able to slow the progression of renal disease after a mean time of 12 months. Elevated UA levels were associated with a greater incidence of ESRD. Hyperuricemia induces renal afferent arteriolopathy and increases glomerular hydrostatic pressure and renal scarring. Kang et al found that hyperuricemic rats showed greater proteinuria and greater serum creatinine levels than those treated with allopurinol to decrease the serum UA levels. [11] Allopurinol, by decreasing the serum UA levels, may serve as an agent to decrease glomerular hydrostatic pressure indirectly and thus help alleviate the renal damage. In our study, there was a significant inverse correlation between the UA serum levels and the mean eGFR in all the patients and within each experimental group. The beneficial effect of allopurinol slowing down the progression of renal disease could be related to the decrease of the UA levels. Recent studies suggest that lowering the levels of UA may slow the progression of renal disease, especially in patients with hyperuricemia. Kanbay et al reported that the treatment of asymptomatic hyperuricemia improved renal function. [12] Likewise, Siu et al reported that the treatment of asymptomatic hyperuricemia delayed disease progression. [13] The results of our study are similar to these studies.

Moreover, we found in our study that the allopurinol treatment was related with low CRP, potassium and LDL levels. A correlation of the CRP, a marker of subclinical inflammation related to atherosclerosis, and the UA serum levels has been described. [14] A significant independent association was found between the UA levels and the inflammatory markers such as the white blood cell count, the CRP, the interleukins and the TNF-alfa levels. There is also evidence that hyperuricemia per se impairs endothelial function-dependent vasodilatation by the reduction in nitric oxide synthase in animal experiments. [15] There are no previous data regarding the effect of the allopurinol treatment on the inflammatory markers in moderate CKD. In our study, we found that allopurinol decreased the hs-CRP levels after 12 months of treatment compared with the control group.

The relation of the UA to the cardiovascular diseases in the general population is controversial, with studies showing conflicting results. The National Health and Nutrition Examination Survey (NHANES I) study demonstrated a positive correlation. [16] An analysis of the Framingham data showed no relation between the UA and the cardiovascular diseases after adjustment for the diuretic use. [17] It should be noted that the findings of the effects of allopurinol on the LDL serum levels corresponds well with the studies in the patients without ESRD. [18],[19] We found a distinct correlation with the LDL serum levels and the allopurinol use in CKD patients. Larger prospective studies are required to understand this complex interrelation in the general population.

Although in our study no serious adverse effects appeared, the allopurinol therapy can produce serious reactions such as Stevens-Johnson syndrome.

Finally, our study patients were advised about the dietary composition of their food, although the potential role of diet has not been evaluated. This is the main limitation of our study. The authors indicate no relationships that could be perceived as a conflict of interest. We conclude that our study found that allopurinol treatment decreases inflammation and slows the progression of renal disease in patients with moderate CKD. In addition, allopurinol reduces cardiovascular risk factors by decreasing the CRP and the LDL levels. These results have to be confirmed in larger prospective trials and are the basis for a hypothesis that still needs to be tested.

 
   References Top

1.Johnson RJ, Kang DH, Feig D, et al. Is there a pathogenetic role for uric acid in hypertension, cardiovascular and renal disease? Hypertension 2003;41:1183-90.  Back to cited text no. 1
    
2.Hsu SP, Pai MF, Peng YS, Chiang CK, Ho TI, Hung KY. Serum uric acid levels show a 'J shaped' association with all-cause mortality in haemodialysis patients. Nephrol Dial Transplant 2004;19:457-62.  Back to cited text no. 2
    
3.Suliman ME, Johnson RJ, Garcia-Lopez E, et al. J shaped mortality relationship for uric acid in CKD. Am J Kidney Dis 2006;48:761-71.  Back to cited text no. 3
    
4.Edwards NL. The role of hyperuricemia and gout in kidney and cardiovascular disease. Clev Clin J Med 2008;75 Suppl 5:S13-6.  Back to cited text no. 4
    
5.Feig DI, Kang D, Johnson R. Uric acid and cardiovascular risk. N Engl J Med 2008;358: 1811-21.  Back to cited text no. 5
    
6.Johnson RJ, Kang DH, Feig D, et al. Is there a pathogenetic role for uric acid in hypertension and cardiovascular and renal disease? Hypertension 2003;41:1183-90.  Back to cited text no. 6
    
7.Nakagawa T, Hu H, Zharikov S, et al. A causal role for uric acid in fructose-induced metabolic syndrome. Am J Physiol Renal Physiol 2006; 290:F625-31.  Back to cited text no. 7
    
8.Khosla UM, Zharikov S, Finch JL, et al. Hyperuricemia induces endothelial dysfunction. Kidney Int 2005;67:1739-42.  Back to cited text no. 8
    
9.National Kidney Foundation K/DOQI. Clinical Practice Guidelines for Chronic Kidney Disease: Evaluation, Classification and Stratification. Am J Kidney Dis 2002;39 Suppl l:Sl-266.  Back to cited text no. 9
    
10.Sorenson LB. Role of the intestinal tract in the elimination of uric acid. Arthritis Rheum 1965; 8:694-706.  Back to cited text no. 10
    
11.Kang DH, Nakagawa T, Feng L, et al. A role for uric acid in the progression of renal disease. J Am Soc Nephrol 2002;13:2888-97.  Back to cited text no. 11
    
12.Kanbay M, Ozkara A, Selcoki Y, et al. Effect of treatment of hiperuricemia with allopurinl on blood pressure, Creatinine clearance, and proteinuria in patients with normal renal function. Int Urol Nephrol 2007;39:1227-33.  Back to cited text no. 12
    
13.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.  Back to cited text no. 13
    
14.Ruggiero C, Cherubini A, Ble A, et al. Uric acid and inflammatory markers. Eur J Heart 2006; 27:1174-81.  Back to cited text no. 14
    
15.Khosla UM, Zharikov S, Finch JL, et al. Hyperuricemia induces endothelial dysfunction and vasoconstriction. Kidney Int 2005;67:1739-42.  Back to cited text no. 15
    
16.Fang J, Aderman M. Serum uric acid and cardiovascular mortality: The NHANES I epidemiologic follow-up study, 1971-1972. JAMA 2000;283:2404-10.  Back to cited text no. 16
    
17.Culleton BJ, Larson MG, Kannel WB, Levy D. Serum uric acid and risk for cardiovascular disease and death: The Framingham Heart Study. Ann Intern Med 1999;131:7-13.  Back to cited text no. 17
    
18.Bluestone R, Lewis B, Mervart I. Hyperlipo-proteinaemia in gout. Ann Rheum Dis 1971; 30:134-7.  Back to cited text no. 18
[PUBMED]    
19.Darlington LG, Scott JT. Study of the effect of hypouricaemic therapy on serum lipid levels in gout patients. Adv Exp Med Biol 1986; 195:341-4.  Back to cited text no. 19
[PUBMED]    

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Correspondence Address:
Sebnem Karakan
Department of Nephrology, Baskent University, Ankara
Turkey
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DOI: 10.4103/1319-2442.128520

PMID: 24625997

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