A Randomised Prospective Study Analysing the Effects of Lowering Serum Uric Acid in Chronic Kidney Disease (CKD) Progression and Cardiovascular Outcomes

Patient’s Population

This was a prospective randomised study conducted at tertiary teaching care hospital during the period from January 2013 to April 2014. Patients with presence of renal disease, defined as having an estimated GFR (eGFR) lower than 60 ml/min, stable clinical condition in terms of no hospitalizations or cardiovascular events within the 3 months before screening; and serum UA >5.6 mg/dl in females and >7 mg/dl in males were included in the study.

The exclusion criteria included the patients who did not provide consent, age <18 years, those who had current treatment or previous hypersensitivity/intolerance to allopurinol, 2 or more episodes of gout in past 6 months, active infections or serum UA level >13 mg/dl in men and >10 mg/dl in women, history of UA calculi. Patients with pregnancy or breast feeding, end stage renal disease or on concurrent treatment with immunosuppressive drugs were also excluded from study. The study protocol was approved by Institutional Ethics Committee. Informed consent form was obtained from participants before enrolling into the study.

Randomization and Intervention

Patients were randomly assigned into two groups. One group received allopurinol 100-300 mg/day (adjusted according to eGFR) in addition to standard management of CKD, while the other group continued with the standard management. Randomization was conducted by simple randomization method and allocation concealment was implemented by envelope technique.

Outcome Analysis and Follow-up

Initial assessment of cardiovascular risk factors in patients was done at beginning of the study. Hypertension was defined as systolic blood pressure (SBP) > 140 mm Hg or diastolic BP (DBP) > 90 mm Hg on repeated measurements or the use of antihypertensive drugs. The arterial blood pressure was measured three times after a 15-min resting period and mean values were calculated for SBP and DBP for all participants. eGFR was estimated by Modification of the Diet in Renal Disease (MDRD)-4 equation and was carefully recorded during follow-up assessment.

Cardiovascular event was considered if the patient had a myocardial infarction, coronary revascularization, or angina pectoris. All symptomatic patients with New York Heart Association (NYHA) class II to IV dyspnoea were subjected to chest x-ray examination and echocardiogram to assess left ventricular function. Congestive heart failure (CHF) was defined as ejection fraction <45% [10]. Occurrence of any congestive heart failure, cerebrovascular accidents or peripheral vascular disease during the period of follow-up were also taken into account and included in cardiovascular events.

Clinical, biochemical, and inflammatory parameters were measured at baseline, 3, 6, and 12 months of treatment. During each follow-up session, SBP and DBP were recorded, and daily urinary protein excretion, haemoglobin level, white blood cell count, platelet count, serum Cr level, alanine aminotransferase level, fasting total cholesterol level, low-density lipoprotein cholesterol Parameters Allopurinol Group (n=100) Control Group (n=50) P value Age (years) 42.67 (13.902) 43.84 (12.831) 0.619 Sex, Male: Female 1.439 1.173 0.341 Hemoglobin (g/dL) 11.42 (0.89) 11.48 (0.49) 0.664 Serum creatinine (mg/dl) 2.28 (0.83) 2.15 (0.70) 0.339 eGFR (ml/min per 1.73 m2) 34.47 (12.50) 35.10 (12.12) 0.768 Serum uric acid (mg/dL) 8.09 (0.87) 7.91 (0.70) 0.195 Serum hs-CRP (mg/L) 6.89 (1.72) 6.63 (1.05) 0.335 ESR (mm/hr) 24.46 (7.65) 22.16 (5.37) 0.059 level, high-density lipoprotein cholesterol level, triglyceride level, serum UA level, and high sensitivity C- reactive protein level were checked.

Statistical Analysis

Data was analysed by SPSS Statistics 19 of windows 7. Standard statistical tools were used to analyse the data. The data was double entered and checked for any discrepancies. Values were expressed as mean ± SD, mean ± SEM, or median to study samples in two categories separately. Students T-test or Chi-square test was used to study the correlation of treatment with allopurinol on the progression of CKD. Analysis of variance test was used when parameters of more than two groups were compared. Pearson's correlation coefficient was calculated to analyse correlation between two parameters. Cox proportional hazard models were used to evaluate the risk of cardiovascular events, adjusted for several groups of covariates. The P value less than 0.05 was considered to be statistically significant.

Biochemical Parameters Analysis within the Groups

After 12 months of allopurinol treatment, serum UA levels were significantly decreased in subjects treated with allopurinol, from 8.095 ± 0.877 mg/dl to 6.977 ± .569mg/dl (P<0.0001), whereas serum UA levels increased in subjects with the control group over a period of 12 months from 7.910 ± 0.701 mg/dl to 8.196 ± 0.741 mg/dl (P<0.0001).

Comparison between the Groups

There was a decrease of 1.11 ± 0.70 mg/dl in mean UA level in the allopurinol group, whereas there was an increase of 0.286 ± 0.29 mg/dl in the control group at the end of the 12 months. There was a significant difference between changes in UA levels from baseline when two groups were compared (P<0.0001 at 3, 6 and 12 months). Mean value of serum creatinine increased from 2.28 ± 0.83 mg/dl to 2.38 ± 0.90 mg/dl at 12 months in allopurinol group and from 2.15 ± 0.70 mg/dl to 2.34 ± 0.76 mg/dl in the control group (P<0.0001 for change of creatinine at 12 months between the groups). There was no significant difference in mean values of hemoglobin, total cholesterol, LDL cholesterol and serum albumin in either group throughout the study.

Progression of Renal Disease Analysis within the Groups

There was a fall in eGFR (MDRD-4) observed in both the groups by the end of the study. In the allopurinol group eGFR decreased from 34.47 ± 12.50 ml/min. per 1.73 m2 at baseline to 32.90 ± 12.51 ml/min. per 1.73 m2at 12 months (P<0.0001 in comparison to baseline values), whereas in the control group, it decreased from 35.10 ± 12.12 ml/min. per 1.73 m2 at baseline to 31.55 ± 10.86 ml/min. per 1.73 m2 at 12 months (P<0.0001 in comparison to baseline values). In the allopurinol group, the change in eGFR from baseline was insignificant at 3 months but it came out to be significant at the end of the study.

Comparison between the Groups

The change in mean eGFR during follow-up at 3, 6 and 12 months as compared to the baseline and a comparison of this change between the 2 groups was analysed. In the control group, eGFR decreased 3.55 ± 2.50 ml/min per 1.73m2, and in allopurinol group, eGFR decreased 1.57 ± 2.85 per 1.73 m2 after 12 months (P<0.0001 between the groups).

Correlation between Change in eGFR (CKD Progression) and UA

A decrease in eGFR was observed at the end of 12 months in both the groups, but the decrease in eGFR was significantly more in the control group as compared to the allopurinol group (P<0.0001) as shown in figure 1. 1. Another important observation was that serum UA decreased significantly in allopurinol group, whereas it increased in the control group (P<0.0001).

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The correlation between change in eGFR and change in serum UA was evaluated in patients with control group. An inverse correlation was observed between changes in eGFR and changes in serum UA in patients who didn’t receive allopurinol intervention. This was consistent at 3, 6 and 12 months of follow-up.

Cardiovascular Events and Deaths

In the allopurinol group 18 (18%) patients had cardiovascular co-morbidity. Eight patients had ischemic coronary events, four patients had congestive heart failure and six patients had cerebro-vascular accidents. In the control arm four patients had cardiovascular events, ischemic heart disease (n=3) and cerebro-vascular accidents (n=1). No deaths were recorded in either group during the follow-up period. Two patients required dialysis at the end of the study, one from the allopurinol group and other from the control group. After 12 months of follow-up period, 19 patients suffered from cardiovascular event including 11 from allopurinol group and 8 from control group. Among these 19 patients, 15 were diabetic and 12 were hypertensive. The

cardiovascular events were ischemic coronary events (n=6), congestive heart failures (n=10), cerebrovascular accidents (n=3). All received appropriate therapy based on good clinical practices.

Kaplan-Meier survival showed that patients in the allopurinol group had lower cardiovascular risk than patients in the control group but this difference didn’t reach the statistical significance (Figure 2).

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Cox- Regression Analysis for Cardiovascular Events

Regression cox analysis adjusted for age, eGFR change, DM, previous CAD, and UA levels showed that high hs-CRP levels increased the risk of cardiovascular events while there was no significant impact of allopurinol treatment on cardiovascular events (Table 3).

Allopurinol Treatment and Hypertension

Hyperuricemia has been related to high blood pressure. This is thought to be mediated through activation of the renin-angiotensin system, either directly, by decreasing neuronal nitric oxide synthase in the juxtaglomerular apparatus, or indirectly, through decreasing renal perfusion by stimulating the afferent arteriolar vascular smooth cell proliferation or through the induction of cyclo-oxygenase-2 in the macula densa and arterioles.2,6 To our knowledge there is only one study which demonstrated the antihypertensive effect of allopurinol in adolescent patients with initial hypertension [11]. In the present study, although we showed that BP decreased in the allopurinol group (140.56 ± 15.51/85.10 ± 6.67 mmHg at baseline and 134.98 ± 9.83/83.04 ± 5.37 mmHg at the end of the study), it was not significantly different from the control group (P=0.910, 0.533). The proportion of patients maintaining blood pressure on 3 or more antihypertensives (as compared to baseline) was higher in the control group but it was not statistically significant.

These results were similar to the study of 113 patients by Goicoechea, et al. which evaluated the effect of allopurinol on hypertension and other cardiovascular risk factors in CKD patients. There may be two main reasons for this observation. At the time of study participation most of the patients had history of long-term hypertension and all the patients had confirmed renal diseases with impaired renal function. This may have caused damage to the arteries and kidneys, and the hypertension could have been the result of multiple factors. Hence, allopurinol treatment alone couldn’t affect BP control to a significant extent. Secondly, the concomitant use of antihypertensives and dietary advice to all patients in the study population intended to maintain normal blood pressure might have led to similar BP control in both the group.

Allopurinol Treatment and Progression of CKD

There are several observational studies demonstrating the possible correlation between serum UA levels and the progression of CKD; however, the results were conflicting. In view of these conflicting results, the most appropriate method to evaluate the involvement of UA in the pathogenesis of CKD progression is to determine whether lowering UA levels slows the rate of renal disease progression. In this direction, Siu, et al. studied the effect of the lowering of serum UA levels on progression of CKD in an open-label RCT of allopurinol therapy (100-300 mg/d) for 12 months in 54 patients [12]. They concluded allopurinol therapy significantly decreases serum UA levels in hyperuricemic patients with mild to moderate chronic kidney disease. Allopurinol was well tolerated and may contribute in maintaining renal function during 12 months of therapy. Similarly, Goicoechea, et al. randomized 113 patients with CKD to allopurinol 100 mg daily (n=57) or no study medication (n=56). After 24 months, eGFR decreased by 3.3 ml/min/1.73m2 in the control group and increased by 1.3 ml/min/1.73 m2 in the allopurinol group (P=0.018).

In our study, we demonstrated that allopurinol is able to slow the progression of renal disease after a follow-up of 12 months. In the control group, eGFR decreased 3.55 ml/min/1.73m2, and in allopurinol group, eGFR decreased 1.57 ml/min/1.73m2 after 12 months (P<0.0001 between the groups). The baseline characteristics like age, sex ratio, primary kidney disease, degree of hypertension, serum UA levels, hs-CRP levels, albuminuria and use of antihypertensives were similar in both groups.

We observed a decrease in eGFR in both the groups, however, in Goicoechea, et al. study, eGFR increased in the allopurinol group by the end of the study. Though in this study, the decrease in eGFR was significantly less in the allopurinol group as compared to the control group. Serum UA levels decreased significantly in the allopurinol group whereas it increased in the control group. By the end of the study, a significant inverse correlation was found between serum UA levels and eGFR in the control group. Hence, the beneficial effect of allopurinol slowing down the progression of renal disease could be related to the decrease of UA levels.

Allopurinol Treatment and Cardiovascular Risk

The role of UA as an independent cardiovascular risk factor is controversial. Sub analysis of the Atherosclerosis Risk in Communities (ARIC) has demonstrated that hyperuricemia is associated with insulin resistance and mortality in the non-CKD population [13]. In another report when the use of diuretics was adjusted, no correlation was found between UA and cardiovascular disease [14]. A few small, short-term, single-Centre studies have indicated that xanthine oxidase inhibitors may exert favourable effects on cardiovascular risk factors and surrogate outcome measures. In this study, we did not find any significant beneficial effect of allopurinol treatment on cardiovascular outcomes in CKD patients. In cox regression analysis adjusted for age, gender, serum UA and GFR change; only hs-CRP had a significant effect on cardiovascular outcomes (HR = 1.703, P=0.001).

No serious adverse effects related to allopurinol were reported. Majority of the studies evaluated the effect of allopurinol on CKD progression, showing the efficient and safe use of allopurinol in patients with CKD with dose adjusted eGFR. However, serious reactions like Stevens- Johnson syndrome have also been reported with allopurinol. Hence, it should be used with precaution in patients with history of drug allergies.

There were some limitations to the present study. It was not designed in a double-blinded fashion; the patients were followed for a relatively shorter period of time and the potential role of dietary factors in the results was not evaluated.