Therapy Of Hyperuricemia Research Articles

Study of epidemiological aspects of hyperuricemia in Poland.

The results of the latest epidemiological studies show that the problem of hyperuricemia affects many millions of people. The main purpose of the study was to assess the knowledge of physicians with regard to the epidemiology and treatment of hyperuricemia in Poland. CAPI (computer assisted personal interview) interviews were conducted using short questionnaires among primary health care physicians, cardiologists and diabetologists. The entire questionnaire included 11 questions. Questions were asked to physicians at 5 different periods in time. The number of physicians surveyed, depended on the time period, and ranged from 8663 to 9980. Only every 1 in 7 physicians (14%) considered that hyperuricemia in patients with cardiovascular risk factors begins when the uric acid level is 5 mg/dL, thus in line with the expert recommendations. 72% of respondents asked to indicate the uric acid levels they consider to be indicative of hyperuricemia in patients in the cardiovascular risk group, gave values ranging from 6 to 7 mg/dL, namely the values justified in cases of a patient without such a risk, i.e. in the general population. 86% of doctors surveyed gave values different from that recommended by experts. The findings of the questionnaire in this survey suggests that doctors often underestimate the problem of hyperuricemia in patients with a high risk of cardiovascular disease. An important step towards more effective therapy of hyperuricemia in routine clinical practice is to raise the awareness of hyperuricemia and its comorbidities both among doctors and patients and encourage monitoring and treatment.

Inhibiting PNP for the therapy of hyperuricemia in Lesch-Nyhan disease: Preliminary in vitro studies with analogues of immucillin-G.

Lesch-Nyhan disease (LND) is a rare X-linked genetic disorder, with complete hypoxanthine-guanine phosphoribosyltransferase (HGPRT) deficiency, uric acid (UA), hypoxanthine and xanthine accumulation, and a devastating neurologic syndrome. UA excess, causing renal failure, is commonly decreased by xanthine oxidoreductase (XOR) inhibitors, such as allopurinol, yielding a xanthine and hypoxanthine increase. Xanthine accumulation may result in renal stones, while hypoxanthine excess seems involved in the neurological disorder. Inhibition of purine nucleoside phosphorylase (PNP) represents a different strategy for lowering urate. PNP catalyzes the cleavage of purine ribo- and d-ribo-nucleosides into ribose/deoxyribose phosphate and free bases, starting catabolism to uric acid. Clinical trials demonstrated that PNP inhibitors, initially developed as anticancer drugs, lowered UA in some gouty patients, in association or not with allopurinol. The present study tested the reliability of an analogue of immucillin-G (C1a), a PNP inhibitor, as a therapy for urate, hypoxanthine, and xanthine excess in LND patients by blocking hypoxanthine production upstream. The therapeutic aim is to limit the administration of XOR inhibitors to LND patients by supplying the PNP inhibitor in low doses, avoiding d-nucleoside toxicity. We report studies conducted in primary cultures of skin fibroblasts from controls and LND patients grown in the presence of the PNP inhibitor. Cell viability, oxypurine release in culture medium, and endocellular nucleotide pattern have been monitored in different growth conditions (inhibitor concentration, time, added inosine). Our results demonstrate effective PNP inhibition by low inhibitor concentration, with reduced hypoxanthine release, and no appreciable toxicity in control or patient cells, suggesting a new therapeutic strategy for LND hyperuricemia.

Inhibiting PNP for the therapy of hyperuricemia in Lesch-Nyhan disease: preliminary in vitro studies with analogues of immucillin-G

Inhibiting PNP for the therapy of hyperuricemia in Lesch-Nyhan disease: preliminary in vitro studies with analogues of immucillin-G

Preparation, characterization and systemic application of self-assembled hydroxyethyl starch nanoparticles-loaded flavonoid Morin for hyperuricemia therapy.

BackgroundMorin, one of the most widely distributed flavonoids in plants, has been identified as a potent antihyperuricemic agent. Its poor water solubility and fast in vivo clearance, however, have limited its application in the treatment of hyperuricemia. In this study, a novel amphiphilic polymer (hydroxyethyl starch-deoxycholic acid [HES-DOCA]) was synthesized to overcome these limitations.MethodsHES-DOCA conjugates with various substitution degrees were prepared by chemical grafting DOCA to HES through ester formation. The structures of the conjugates were confirmed by infrared spectroscopy and 1H-NMR. Physicochemical characterizations of HES-DOCA nanoparticles-loaded Morin (Morin/HES-DOCA-NPs) were studied using dynamic light scattering and transmission electron microscopy (TEM). In vitro release studies were performed to evaluate the release properties of Morin from the NPs. Subsequently, in vivo pharmacokinetic parameters of Morin/HES-DOCA-NPs were investigated in Wistar rats through intravenous administration (2 mg/kg, equivalent to Morin). Antihyperuricemic efficacy of the NPs was evaluated in a rat hyperuricemic model.ResultsThe optimized HES-based amphiphilic polymer contained approximately 10 DOCA groups per 100 anhydroglucose units of HES, which can spontaneously self-assemble to form spherical NPs as demonstrated by TEM images. Morin/HES-DOCA-NPs were monodispersed (polydispersity index = 0.05) with a mean diameter of 197 nm and exhibited a zeta potential of −14 mV. The use of DOCA as the polymer’s hydrophobic segment enabled high drug loading efficiency (15.6%). After systemic administration, Morin/HES-DOCA-NPs exhibited significantly longer half-life and higher systemic exposure (elimination half-life and area under the plasma concentration–time curve) compared with free drug Morin. In a rat hyperuricemic model, treatment with Morin/HES-DOCA-NPs demonstrated superior therapeutic efficacy over Morin in decreasing serum uric acid level, increasing the uricosuric action, as well as attenuating hyperuricemia-associated inflammation in kidney of rats.ConclusionCollectively, these findings suggest that the novel HES-based NP formulation of Morin may have great potential for clinical treatment of hyperuricemia.

Green Tea Extract (Camellia sinensis L.) Effects on Uric Acid Levels on Hyperuricemia Rats (Rattus norvegicus)

Uric acid is the end product of purine degradation. When uric acid levels exceed normal limits, it will build up and cause hyperuricemia. Allopurinol is one of the most effective and common medicine for hyperuricemia, but it brings serious side effects, therefore it is needed alternative therapy for hyperuricemia. One plant that may be expected to low uric acid levels is green tea ( Camellia sinensis L.), that contains many antioxidants polyphenols, especially flavonoids. Flavonoid has strong antioxidant properties, act as free radical and metal scavengers, and also xanthine oxidase (XOD) inhibitors. This study investigates the potential of green tea using various doses of 150 mg/kg, 300 mg/kg, and 600 mg/kg of body weight in 24 white male rats ( Rattus norvegicus ) Wistar strain that has been received high purine diet in 60 consecutive days. This study used DHBSA methods to measure uric acid levels in blood serum and urine that excreted 8 hours before surgery. Green tea extract that contains polyphenol can inhibit XOD activities, therefore, it leads to decrease uric acid level in blood and increase the excretion through urine by modulating urate gene transporter. A therapy with 600 mg/kg body weight of GTE is the most effective dose to decrease uric acid levels in serum and to increase excretion of exceeding uric acid significantly (p < 0.01), from One Way ANOVA and Tukey analysis.

An evidence-based review on urate-lowering treatments: implications for optimal treatment of chronic hyperuricemia.

Several studies suggest that chronic hyperuricemia, the main precursor of gout, is involved in the pathogenesis of different systemic disorders that affect cardiovascular and renal systems, such as hypertension, obesity, hypercholesterolemia, atherosclerosis, metabolic syndrome, chronic heart failure, and chronic kidney disease. Recent epidemiological evidence has shown an increasing trend in the prevalence of hyperuricemia and gout in the Western world: a number of population-based studies estimate a prevalence of up to 21% for hyperuricemia and 1%–4% for gout. As such, early detection and careful management of this pathological condition is required, starting from lifestyle changes (mainly based on a diet low in red meat, sugars, and alcoholic beverages, with increased intake of vegetables, water, and vitamin C sources), adding specific drugs to lead serum uric acid (SUA) levels under the target value of 7 mg/dL. In particular, nonselective and selective XO inhibitors (allopurinol, oxypurinol, febuxostat) reduce SUA levels and the overproduction of reactive oxygen species, mainly related to XO overactivity that often causes inflammatory damage to the vascular endothelium. The effect of lowering SUA levels via XO inhibition includes an attenuation of oxidative stress and related endothelial dysfunction that largely contribute to the pathophysiology of metabolic syndrome and cardiovascular diseases. Therefore, the inhibition of XO overactivation seems to be an excellent therapeutic option to limit the harmful effects of excess UA and reactive oxygen species. In conclusion, rapid diagnosis and correct therapy for hyperuricemia may also improve the prevention and/or treatment of serious and multifactorial diseases. The available evidence supports the importance of promoting new experimental clinical trials to confirm the emerging antioxidant role of XO inhibitors, which could effectively contribute to cardiovascular and chronic kidney disease prevention.

Effect of a traditional Chinese medicine prescription Quzhuotongbi decoction on hyperuricemia model rats studied by using serum metabolomics based on gas chromatography-mass spectrometry.

Morbidity of hyperuricemia has constantly increased in population in decades, and hyperuricemia has proved to be an important risk factor for gout, cardiovascular diseases and others. Many urate-lowering drugs have unfavorable side effects and drug interactions. Quzhuotongbi decoction (QZTBD) is an empirical traditional Chinese medicine prescription for clinical therapy of hyperuricemia without serious adverse effects. In the study, we investigated the effects of QZTBD on urate and other metabolites in the sera of hyperuricemia model rats. Hyperuricemia model was established by orally administering yeast extract paste, and allopurinol served as a positive control drug. Serum metabolomics was performed by using a gas chromatography-mass spectrometry (GC-MS) method. Student's t-test and the principal component analysis (PCA) were employed to find the metabolic perturbations in hyperuricemia model rats. The levels of urate, lactate, pyruvate and ornithine were significantly increased, and xanthine, glyconic acids (ribonate, galactonate), amino acids (aspartate, proline, glutamine, serine, pyroglutamate, glutamate) and glucose were down-regulated greatly in the model rats. It demonstrated that nucleotide metabolism, amino acid metabolism and glycolytic pathway were disturbed by yeast administration. An orthogonal signal correction-partial least-squares discriminant analysis (OSC-PLS DA) was performed to assess the effects of yeast administering and drug treatment. 11 significantly distinctive metabolites among four groups were defined according to the variable importance for project values (VIP>1) and univariate ANOVA (p value<0.05). As compared to the model rats, the serum uric acid levels were lowered markedly under the treatment of allopurinol or QZTBD. Aspartate and glutamine involved in purine metabolism, were raised to normal level as well. The different influences on xanthine, glutamate pyroglutamate and galactonate suggested there were different mechanisms of two drugs in urate-lowering therapy. Our finding proved that QZTBD can efficiently lower the level of serum uric acid in a different way from allopurinol, which suggested that QZTBD based on the theory of TCM could be an effective therapeutic option for hyperuricemia.

Molecular docking analysis of xanthine oxidase inhibition by constituents of cichory

Human xanthine oxidase is considered to be a target for therapy of hyperuricemia. Cichorium intybus is a Chinese plant medicine which widely used in Xinjiang against various diseases. In order to screen the inhibitors of xanthine oxidase from C. intybus and to explore main pharmacological actions of cichory a compound collection of C. intybus was built via consulting related references about chemical research on cichory. The three-dimensional crystal structure of xanthine oxidase (PDB code: 1N5X) from Protein Data Bank was downloaded.. Autodock 4.2 was employed to screen the inhibitors of xanthine oxidase from cichory 70 compounds were found to possess quite low binding free energy comparing with TEI (febuxostat). C. intybus contains constituents possessing potential inhibitive activity against xanthine oxidase. It can explain the main pharmacological actions of cichory which can significantly lower the level of serum uric acid.

Mechanistic insights into xanthine oxidoreductase from development studies of candidate drugs to treat hyperuricemia and gout.

Xanthine oxidoreductase (XOR), which is widely distributed from humans to bacteria, has a key role in purine catabolism, catalyzing two steps of sequential hydroxylation from hypoxanthine to xanthine and from xanthine to urate at its molybdenum cofactor (Moco). Human XOR is considered to be a target of drugs not only for therapy of hyperuricemia and gout, but also potentially for a wide variety of other diseases. In this review, we focus on studies of XOR inhibitors and their implications for understanding the chemical nature and reaction mechanism of the Moco active site of XOR. We also discuss further experimental or clinical studies that would be helpful to clarify remaining issues.

EXPERIENCE OF ADMINISTRATION OF CANAKINUMAB, AN INTERLEUKIN 1β INHIBITOR, IN A PATIENT WITH CHRONIC TOPHACACEOUS GOUT

Система комплексной поддержки и сопровождения научного журнала Elpub позволяет запустить двуязычный сайт журнала со встроенной системой электронной редакции в соответствии с лучшими издательскими практиками, а так же предусматривает техническую и методическую поддержку со стороны специалистов НЭИКОН.

3,4-Dihydroxy-5-nitrobenzaldehyde (DHNB) is a potent inhibitor of xanthine oxidase: A potential therapeutic agent for treatment of hyperuricemia and gout

Hyperuricemia, excess of uric acid in the blood, is a clinical problem that causes gout and is also considered a risk factor for cardiovascular disease. The enzyme xanthine oxidase (XO) produces uric acid during the purine metabolism; therefore, discovering novel XO inhibitors is an important strategy to develop an effective therapy for hyperuricemia and gout. We found that 3,4-dihydroxy-5-nitrobenzaldehyde (DHNB), a derivative of the natural substance protocatechuic aldehyde, potently inhibited XO activity with an IC50 value of 3μM. DHNB inhibited XO activity in a time-dependent manner, which was similar to that of allopurinol, a clinical XO inhibitory drug. DHNB displayed potent mixed-type inhibition of the activity of XO, and showed an additive effect with allopurinol at the low concentration. Structure–activity relationship studies of DHNB indicated that the aldehyde moiety, the catechol moiety, and nitration at C-5 were required for XO inhibition. DHNB interacted with the molybdenum center of XO and was slowly converted to its carboxylic acid at a rate of 10−10mol/L/s. In addition, DHNB directly scavenged free radical DPPH and ROS, including ONOO− and HOCl. DHNB effectively reduced serum uric acid levels in allantoxanamide-induced hyperuricemic mice. Furthermore, mice orally given a large dose (500mg/kg) of DHNB did not show any side effects, while 42% of allopurinol (500mg/kg)-treated mice died and their offspring lost their fur. Thus, DHNB could be an outstanding candidate for a novel XO inhibitory drug that has potent activity and low toxicity, as well as antioxidant activity and a distinct chemical structure from allopurinol.

Variation of Urate Transport in the Nephrons in Subtypes of Hyperuricemia

Background: Hyperuricemia cases (HU) can be classified into four subgroups by combining the two main causes of hyperuricemia, i.e. urate underexcretion and overproduction. These subgroups are as follows: underexcretion-type cases (UE); overproduction-type cases (OP); combined-type cases, and normal-type cases. Since urinary urate excretion (Uua) and urate clearance differ significantly between UE and OP, urate transport in the nephrons and the intratubular urate contents might also differ. Such differences might help clarify the pathophysiology of urate underexcretion in subgroups of hyperuricemia, and thus reveal its underlying mechanisms. Methods: Urate transport coefficients in each subtype of HU were determined employing the previously reported benzbromarone-loading urate clearance tests. The subtype cases of HU were plotted on a graph of urate transport coefficients versus Uua as coordinates. The characteristic features in the distribution of subtype cases on graphs were analyzed in relation to Uua. Results: The mean (±standard error) tubular secretion rate (TSR) in the UE (48.7 ± 1.7 ml/min) was significantly lower and the postsecretory urate reabsorption rate (R₂) in the UE (0.904 ± 0.004) was significantly higher than those in the normal controls (78.0 ± 2.1 ml/min and 0.877 ± 0.003) or the OP (61.1 ± 3.2 ml/min and 0.861 ± 0.009). Decrements of TSR and increments of R₂ in the UE were largest in the subtypes of the HU, in terms of case numbers and the deviation rate of the group. Conversely, decrements of TSR and increments of R₂ were smallest in the OP. A significant correlation was identified between TSR and Uua (r = 0.345, p < 0.0001), and a significant negative correlation was also found between R₂ and Uua (r = -0.393, p < 0.0001). Conclusion: In the UE, hyperuricemia is induced mainly by urate underexcretion, which results from the combination of two main causes in urate transporters of the nephron: significantly lower TSR and significantly higher R₂. Neither of these was observed in OP. Differences in urate transporters in subtypes of the HU might be important not only for understanding the pathophysiology and mechanisms of urate underexcretion and hyperuricemia, but also for providing a strategic therapy for hyperuricemia.

SP0168 Win lecture-GOUT and crystal diseases

Gout is the articular manifestation of a systemic metabolic disorder – hyperuricemia. The causes of hyperuricemia and its epidemiology have been intensely investigated these last 10 years, and there is...

Integrating Cellular Metabolism into a Multiscale Whole-Body Model

Cellular metabolism continuously processes an enormous range of external compounds into endogenous metabolites and is as such a key element in human physiology. The multifaceted physiological role of the metabolic network fulfilling the catalytic conversions can only be fully understood from a whole-body perspective where the causal interplay of the metabolic states of individual cells, the surrounding tissue and the whole organism are simultaneously considered. We here present an approach relying on dynamic flux balance analysis that allows the integration of metabolic networks at the cellular scale into standardized physiologically-based pharmacokinetic models at the whole-body level. To evaluate our approach we integrated a genome-scale network reconstruction of a human hepatocyte into the liver tissue of a physiologically-based pharmacokinetic model of a human adult. The resulting multiscale model was used to investigate hyperuricemia therapy, ammonia detoxification and paracetamol-induced toxication at a systems level. The specific models simultaneously integrate multiple layers of biological organization and offer mechanistic insights into pathology and medication. The approach presented may in future support a mechanistic understanding in diagnostics and drug development.

Uric acid, allopurinol therapy, and mortality in patients with acute heart failure—results of the Acute HEart FAilure Database registry

Study ObjectiveThe aim of this study was to explore the prognostic role of serum uric acid (UA) measurement in the hospital and long-term mortality assessment in subjects with acute heart failure (AHF) from the Acute HEart FAilure Database registry (AHEAD). The AHEAD registry comprised 4153 patients with AHF syndromes hospitalized at the AHEAD participating centers. Patients and MethodsThe study included 1255 patients who were admitted to the AHEAD participating centers with acute decompensated chronic heart failure, de novo heart failure, or cardiogenic shock between September 2006 and October 2009 and who had information about serum UA concentration available at the time of hospital admission. The hospital and long-term mortality was followed using the centralized database of the Ministry of Health, Czech Republic.The mean age of the cohort was 73.4 years, the female population represented 43%, the median hospital stay was 8 days, and the mean hospital mortality was 7.6%. ResultsThe median UA concentration of the patients with AHF was 432 μmol/L (7.26 mg/dL), the median estimated glomerular filtration rate (eGFR) was 49.0 mL/min, and N-terminal pro–brain natriuretic peptide level was 5510 pg/mL. Among other laboratory variables, UA concentration greater than 515 μmol/L (8.67 mg/dL) was associated with increased hospital mortality (P < .001), as well as eGFR less than 30 mL/min (P < .001), Na 135 mmol/L or less, and positive troponin. Uric acid concentration greater than 500 μmol/L (8.41 mg/dL) was associated with increased long-term mortality (P < .001), followed by eGFR less than 30 mL/min (P < .001), Na 135 mmol/L or less, and hemoglobin level lower than 130 g/L (P < .001). The 1-year survival rate of patients discharged from hospital (n = 1159) was 75.6%, and the 2-year rate was 66.8%. Survival of patients treated with allopurinol for hyperuricemia was significantly lower compared with untreated subjects (70.1 vs 77.2 for 1-year survival and 60.3 vs 68.5 for 2-year survival). ConclusionIn patients with AHF, increased UA levels and documented allopurinol therapy for hyperuricemia were associated with increased hospital and long-term mortality. Allopurinol therapy is not a cause but the identifier of the subjects at risk.

Management of Pediatric Tumor Lysis Syndrome

Tumor lysis syndrome (TLS) is a serious complication of malignancies and can result in renal failure or death. In tumors with a high proliferative rate with a relatively large mass and a high sensitivity to cytotoxic agents, the initiation of therapy often results in the rapid release of intracellular anions, cations and the metabolic products of proteins and nucleic acids into the bloodstream. The increased concentrations of uric acid, phosphates, potassium and urea can overwhelm the body's homeostatic mechanisms to process and excrete these materials and result in the clinical spectrum associated with TLS. Typical clinical sequelae include gastrointestinal disturbances, neuromuscular effects, cardiovascular complications, acute renal failure and death. Tumor lysis syndrome can also compromise the efficacy or administration of curative therapies. Available evidence suggests that the incidence of clinical TLS is approximately 3-7% for acute leukemias and 4-11% for lymphomas. Pediatric cancers are the leading cause of death by disease in children. The most common pediatric cancers include the leukemias, lymphomas, central nervous system tumors and neuroblastoma. Thus, TLS is a major concern to practitioners caring for pediatric oncology patients. Given the complexity of TLS prevention and treatment, a multidisciplinary approach involving the collaboration of medical oncologists/ hematologists and nephrologists has the greatest potential of ensuring optimal patient outcomes. Rehydration is fundamental in the management of TLS in addition to the current standard therapy for hyperuricemia which include rasburicase and allopurinol. The early recognition and treatment of metabolic abnormalities often prevents the severe and life-threatening complications associated with tumor lysis syndrome.

Allopurinol to Febuxostat: How far have we come?

For decades allopurinol has been used as a xanthine oxidase inhibitor for treatment of hyperuricemia and gout. Although effective in many patients, some experience sensitivity to the drug. In some cases, this sensitivity may lead to allopurinol hypersensitivity disorder, which if untreated can be fatal. Recently the Food and Drug Administration has approved the use of febuxostat as an alternative therapy for hyperuricemia and gout. Febuxostat is a new xanthine oxidase inhibitor, but is not purine based and therefore decreases adverse reactions due to patient sensitivity. This review is a comprehensive look at the background of hyperuricemia and gout treatment with allopurinol compared to recent clinical studies with febuxostat. Each clinical study is evaluated and summarized, identifying the advances in treatment that have been made as well as the concerns that still exist with either treatment.

Interaction of a novel urate efflux transporter URATv1 (SLC2A9) with uricosuric agents.

Hyperuricemia is a significant factor in a variety of diseases, including gout and cardiovascular diseases. And renal excretion largely determines plasma urate concentration. Previously we identified a major urate reabsorptive transporter, URAT1 (SLC22A12), on the apical side of the renal proximal tubular cells. Recently, we identified that URATv1 (SLC2A9) functions as an efflux transporter of urate from the tubular cell. URATv1‐expressed Xenopus oocytes transported urate favoring negative to positive potential direction. Considering its basolateral localization, SLC2A9 is likely to mediate the second step of urate reabsorption. To further characterize the transport properties of URATv1, we performed the urate transport studies in the URATv1 expressed oocytes. URATv1‐mediated urate transport was not trans‐stimulated by intracellularly‐injected glucose, fructose, monocarboxylates such as lactate, nicotinate or pyrazinoate (PZA) for urate. In addition, urate efflux via URATv1 was not enhanced by extracellular glucose or fructose. Urate transport via URATv1 was affected by uricosuric agents probenecid, benzbromarone, phenylbutazone and losartan, but not by monocarboxylates such as lactate, nicotinate, orotate, PZA, or β‐hydroxybutyrate. In summary, different substrate selectivity between URATv1 and URAT1 suggests that targeting URATv1 may lead to a novel therapy for hyperuricemia.

A critical reappraisal of allopurinol dosing, safety, and efficacy for hyperuricemia in gout

Allopurinol, the first-line drug for serum urate-lowering therapy in gout, is approved by the US Food and Drug Administration for a dose up to 800 mg/d and is available as a low-cost generic drug. However, the vast majority of allopurinol prescriptions are for doses < or = 300 mg/d, which often fails to adequately treat hyperuricemia in gout. This situation has been promoted by longstanding, non-evidence-based guidelines for allopurinol use calibrated to renal function (and oxypurinol levels) and designed, without proof of efficacy, to avoid allopurinol hypersensitivity syndrome. Severe allopurinol hypersensitivity reactions are not necessarily dose-dependent and do not always correlate with serum oxypurinol levels. Limiting allopurinol dosing to < or = 300 mg/d suboptimally controls hyperuricemia and fails to adequately prevent hypersensitivity reactions. However, the long-term safety of elevating allopurinol dosages in chronic kidney disease requires further study. The emergence of novel urate-lowering therapeutic options, such as febuxostat and uricase, makes timely this review of current allopurinol dosing guidelines, safety, and efficacy in gout hyperuricemia therapy, including patients with chronic kidney disease.

Allopurinol-induced aplastic anemia in a patient with chronic kidney disease

Aplastic anemia is a rare complication of allopurinol use. We report an unusual case of aplastic anemia associated with allopurinol therapy for hyperuricemia in a patient with chronic kidney disease. A 37-year-old female patient diagnosed with Stage III chronic kidney disease was admitted with pancytopenia. She had a history of taking allopurinol for 5 months. Her bone marrow showed extremely decreased cellularity (< 20%) and there was no malignant cell infiltration. She was free of infections, including parvovirus B19, cytomegalovirus and Epstein-Barr virus. These results suggested a diagnosis of aplastic anemia. Allopurinol was discontinued immediately and treatment with blood transfusions and prednisolone was begun. After 6 months, the bone marrow cellularity improved to approximately 70%. Recently, it was suggested that decreased activity of multidrug resistance P-glycoprotein may play a role in acquired aplastic anemia. So we measured the inhibitory effect of allopurinol and oxypurinol on P-glycoprotein activity. But neither allopurinol nor oxypurinol inhibited P-glycoprotein activity.