An update on allopurinol and kidney failure ; new trend for an old drug

1Clinical Research and Development Center at Shahid Modarres Hospital, Department of Nephrology, Shahid Beheshti University of Medical Sciences, Tehran, Iran 2Department of Nephrology, Rouhani Hospital of Medical Sciences, Babol, Iran 3Department of Health & Community Medicine, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran 4Department of Community Medicine, School of Medicine, Alborz University of Medical Sciences, Karaj, Iran 5Department of Epidemiology and Biostatistics, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran


Introduction
Uric acid is the end-product of the purine catabolic pathway.The enzyme xanthine oxidoreductase (XOR) is involved in formation of uric acid from hypoxanthine and xanthine.The XOR exists in two distinct functional forms including xanthine dehydrogenase and xanthine oxidase (XO) (1).Allopurinol or 1,5-dihydro-4Hpyrazolo [3,4-d]pyrimidin-4-one, is a purine inhibitor of the enzyme XO.This substance as an important drug for hyperuricemia can inhibit the synthesis of uric acid.Since 50 years ago, it has been administered in the treatment of gout (2).In 1946, allopurinol was developed by Elion and colleagues, at the Burroughs-Wellcome Company (3).Allopurinol is quickly oxidized by XO to hypoxanthine and xanthine, respectively.Moreover, allopurinol at low concentrations is competitive inhibitor of the XO and at higher concentrations is a noncompetitive inhibitor of this enzyme.Allopurinol after oral administration is rapidly absorbed and has a short half-life in plasma (about 2-3 hours) (4).XO is a significant biological source of free radical generation and allopurinol, as an antioxidant, has direct and indirect antioxidant activity on these free radicals.Furthermore, it can scavenge free radicals such as hydroxyl radical and superoxide anion and numerous studies have shown these effects of allopurinol (5).Oxidative tissue damage after the ischemic diseases such as renal IRI (ischemia/reperfusion injury) is related to the XO and using allopurinol can reduce the renal ischemiainduced oxidative tissue damage (6).Besides the role of XO in hyperuricemia in the past two decades, renal ischemic and various types of tissue injuries, inflammatory diseases and chronic and acute renal failure has been studied extensively.Allopurinol revealed beneficial effects in the treatment of some renal disorders both in experimental and clinical trials (4).The goal of this paper is to give comprehensive information about positive and negative therapeutic effects of allopurinol as an antioxidant agent in some diseases including hyperuricemia, renal IRI, nephrotoxicity and contrast-induced nephropathy (CIN).

Materials and Methods
For this review, we used a variety of sources including PubMed, Embase, Scopus and directory of open access journals (DOAJ).The search was performed by using combinations of the following key words and or their equivalents; allopurinol, free radicals, hyperuricemia, renal ischemia, nephrotoxicity, contrast-induced nephropathy, hydroxyl radical, ischemia/reperfusion injury, antioxidant, uric acid and xanthine oxidase.Manuscripts published in English as full-text articles and or as abstracts were included in the study.

Allopurinol and hyperuricemia
About two-thirds of uric acid is eliminated by the kidneys and one-third is excreted via the gastrointestinal tract (7).Hyperuricemia is a term describing abnormal high level of uric acid in the blood (˃6.0 mg/dL in female and >7.0 mg/dL in male individuals).Increase in level of serum uric acid is associated with various biological effects such as increased oxidative stress, platelet aggregation, high level of inflammatory markers and endothelial dysfunction (8).Hyperuricemia caused oxidative stress in patients with gout and treatment with 100 mg every 8 hours of allopurinol reduced oxidative stress and serum uric acid after 1 and 3 months.In these patients after treatment, the level of serum malondialdehyde, as a marker of lipid peroxidation, was significantly decreased and erythrocyte superoxide dismutase and erythrocyte catalase levels were significantly increased (5).Additionally, hyperuricemia is related to declining glomerular filtration rate (GFR) and progression of chronic kidney disease (CKD) and acute kidney injury (AKI) in different disease states (9).Hyperuricemia and GFR decline was shown in 40% to 60% of patients with CKD stages I to III and 70% of patients with CKD stages IV or V (7).Hyperuricemia could disturb endothelial function by increasing C-reactive protein, leukocytes, TNF-α and interleukins as inflammatory markers.Treatment with allopurinol (100 mg/d) decreased uric acid level in CKD patients and this effect caused a significant decrease in serum C-reactive protein level, and an increase in GFR.It also caused progression of renal disorder in a prospective, randomized trial (10).A study on 30 patients with stage 2-4 CKD and serum uric acid level over 5.5 mg/dL reported that oral treatment of those patients with allopurinol (300 mg/d) for 3 months, significantly decreased the level of serum uric acid from 7.9 ± 1.6 mg/dL to 6.4 ± 1.7 mg/dL (P = 0.001) (9).In a prospective randomized controlled trial, 54 hyperuricemic patients with mild to moderate CKD received allopurinol (100 to 300 mg/d) for 12 months and at the end of follow-up the levels of serum uric acid were significantly decreased (11).Hyperuricemia accelerates diabetic kidney injury induced by streptozotocin.Treatment with allopurinol (10 mg/kg) regulated kidney urate transport-related proteins, reducing hyperuricemia and lipid metabolismrelated genes to alleviate kidney lipid accumulation in streptozotocin-treated rats (12).In a randomized parallel-controlled trial, the effect of long-term treatment (3 years) with allopurinol on 176 patients with type 2 diabetes and asymptomatic hyperuricemia was investigated.This article compared the changes in the levels of serum creatinine, GFR and urinary albumin excretion rate and incidence of hypertension and new-onset diabetic nephropathy in patients before and after 3 years of treatment with allopurinol between two groups.Allopurinol was effective in reducing the urinary albumin excretion rate, serum creatinine and serum uric acid.Additionally, it increased levels of GFR and declined the incidence of new-onset diabetic nephropathy and hypertension (13).Furthermore, administration of allopurinol for 3 months lowered uric acid and improved systemic inflammation and insulin resistance in asymptomatic hyperuricemia patients (14).

Allopurinol and renal IRI
Renal IRI is an important causative factor for AKI and oxygen-free radicals are thought to play a key role in the pathogenesis of renal IRI.Excessive production of reactive oxygen species (ROS) elevates renal IRI through affecting the function of cellular DNA, lipids and proteins (3,15).XO, mitochondrial respiration chain and NADPH oxidase are involved in generation of ROS during IRI.Numerous studies showed the effect of various doses of allopurinol in kidney IRI and most of them reported that allopurinol was effective in attenuating renal damage induced by ischemia/reperfusion. Positive effects have been reported in ranging 3, 40, 50, 100 and 150 mg/kg of allopurinol and the most commonly used dose was 50 mg/kg (3).Summaries of allopurinol's effects against renal IRI are shown in Table 1.In a recently published study, 30 rats were divided into five groups including 1) sham group, 2) renal IR control group, 3) allopurinol group, 4) apocynin group and 5) allopurinol and apocynin group.Rats were pretreated with allopurinol (50 mg/kg, i.p.) and apocynin (20 mg/kg, i.p.) alone as well as together.Treatment with allopurinol alone or in co-administration prevented IR-induced Treatment with allopurinol alone or in co-administration with apocynin prevented IR-induced renal damage through lowering serum blood urea nitrogen, creatinine and malondialdehyde levels and increasing superoxide dismutase levels.

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renal damage via lowering serum blood urea nitrogen, creatinine and malondialdehyde levels and increasing superoxide dismutase level (33).Degradation products of lipid peroxidation can prevent enzymes such as Na+/K+ ATPase, which is essential for maintaining cell viability and it is exceedingly sensitive to lipid peroxidation.The function of allopurinol is connected to protection of Na+/K+ ATPase activity and so it has protective ability against oxidative injury in kidneys (3).According to this ability, the collection of adenosine and its degradation by-products adenine nucleotides, xanthine and hypoxanthine inhibited by allopurinol and therefore, ATPase pump could operate adequately.Moreover, allopurinol by blocking the activation of NODlike receptor 3 (NLRP3) inflammasome, which mediate inflammation in the development of renal injury in this process, could decrease lipid accumulation in kidneys and reducing kidney damage.The activation of Na+/ K+ ATPase was low in ischemic and re-perfused kidney and treatment with allopurinol (50 mg/kg) increased the activity of this enzyme (3,22).Clamping of the renal hilum in rat significantly increased 8-isoprostane level as the real-time biomarker for renal ischemia.Keel et al demonstrated that the largest increase in 8-isoprostane level was occurred after 60 minutes of clamp time in rats and pretreatment with allopurinol (100 mg/kg) significantly decreased isoprostane level to baseline level (32).

Allopurinol and nephrotoxicity
Nephrotoxicity by drugs is one of the most significant kidney problems and especially occurs when the body is exposed to more than one nephrotoxic drug (34,35).Cisplatin, as an antineoplastic drug with dose-dependent renal toxicity, is administered for the treatment of solid tumors.Kidneys accumulate cisplatin more than other organs of body and contribute to cisplatin-induced nephrotoxicity.It is well recognized that reactive oxygen species like singlet oxygen, hydroxyl radical and superoxide anion radical play a key role in the nephrotoxicity of some drugs such as cisplatin.The combination of allopurinol and ebselen reduced cisplatin-induced nephrotoxicity by reducing ROS generation and inhibiting XO (34).However, Erdinç et al investigated the effect of allopurinol (50 mg/kg/d) for 5 days on nephrotoxicity induced by a single dose of 5 mg/kg cisplatin in male albino rats.However, allopurinol was not able to inhibit cisplatininduced lipid peroxidation in the kidney and severely augmented this nephrotoxicity (35).Similarly, Namikawa et al reported the same results about negative effects of allopurinol in this nephrotoxicity (36).
Gentamicin is an aminoglycoside antibiotic that can act against gram-negative infections, however, it has limited therapeutic utility due to nephrotoxicity (37).Gentamicin accumulates in renal proximal convoluted tubules, causing loss of its brush border integrity.It seems that allopurinol as OH -scavenger, can ameliorate the the formation of free radicals including hydroxyl and superoxide radicals that are involved in gentamicin induced acute renal tubular necrosis.Two studies reported that allopurinol was unable to protect gentamicin-induced renal toxicity in rats (37,38).Smyth et al revealed that, after oral treatment of rats with allopurinol (40 mg/kg) twice daily for 4 days, the alterations in serum gentamicin, serum creatinine, body weight, blood pressure, urinary N-acetyl-beta-D-glucosaminidase excretion and urinary output were equivalent in gentamicin with allopurinol and gentamicin only treatment groups (38).

Allopurinol and contrast-induced renal toxicity
CIN is one of the most significant popular causes of hospital-acquired AKI and is defined as the impairment of renal function and increase in serum creatinine of 0. In the allopurinol group, they showed that median serum creatinine concentration decreased significantly 4 days after radio contrast administration.On the other hand, allopurinol along with hydration reduced the prevalence of CIN in individuals with impaired kidney function (39).In another report in 2014, the patients received either of 3 drugs including saline hydration (1 mL/kg/h), allopurinol (300 mg/d) and N-acetylcysteine (600 mg bid) 12 hours before and after administration of contrast agent.
Results of this article demonstrated that prophylactic oral administration of allopurinol along with hydration had protective effect against CIN in patients undergoing coronary procedures, even better than N-acetylcysteine and saline hydration alone (40).

Conclusion
The role of XO in hyperuricemia, renal ischemic and various types of tissue injuries, chronic and acute renal failure has been studied extensively.Findings of this review showed that treatment with allopurinol as a purine inhibitor of XO enzyme could decrease oxidative stress and uric acid levels and might help to restore the endothelial function and slow down the progression of renal disorder to end stage renal disease.The results of many studies indicated that allopurinol was effective to attenuate hyperuricemia, renal damage induced by ischemia/reperfusion and CIN, although, some studies also reported the negative effects of allopurinol on nephrotoxicity induced by drugs including cisplatin and gentamicin.Further experimental and clinical investigations are necessary to estimate the positive effects of allopurinol on renal disorders especially nephrotoxicity.

Table 1 .
Allopurinol's effects against renal IRI (39,40) or 25% from baseline within 48-72 hours of intravenous contrast administration.CIN is detected in up to 50% of patients with pre-existing renal impairment and diabetic nephropathy and less than 2% of patients with normal renal function(39,40).