uric acid is the poorly soluble circulating end product of the purine nucleotide metabolism in human beings . a decrease in the glomerular filtration rate ( gfr ) contributes to hyperuricemia ( hua ) , which is frequently observed in patients with chronic kidney disease ( ckd ) ( 1 - 4 ) . most mammals are endowed with an additional enzyme , urate oxidase , which converts uric acid to allantoin for excretion , whereas humans have evolutionarily acquired distinct gene mutations that render this latter enzyme inactive , resulting in the inability to produce allantoin ( 5 ) . therefore , the physiologic catabolism of endogenous and dietary purine nucleotides ends with uric acid in humans . however , the presence of ischemic stress and/or excess production of reactive oxygen species can independently advance uric acid oxidation to allantoin and other breakdown products ( 6 ) . kidneys are responsible for the excretion of two - thirds of the daily uric acid , with the remaining one - third being excreted through the gastrointestinal tract . more than 90% of all cases of hua are the result of the impaired renal excretion of uric acid ( 7 ) . it has been demonstrated that the prevalence of hua rises in parallel with the gfr decline , which is present in 40% to 60% of patients with ckd stages i to iii and 70% of patients with ckd stage iv or stage v ( 8 , 9 ) . in patients receiving dialysis , the prevalence of hua also rises in parallel with dialysis vintage ( 10 ) . hua is defined as a serum uric acid level > 7.0 mg / dl in males and  6.0 mg / dl in females ( 11 ) . the kidney disease outcomes quality initiative ( kdoqi ) definition and classification were accepted , with clarifications . ckd is defined as kidney damage or a gfr  60 ml / min/1.73 m for 3 months or more , irrespective of the cause . kidney damage in many kidney diseases can be ascertained by the presence of albuminuria , defined as an albumin - to - creatinine ratio  30 mg / g in 2 of 3 spot urine specimens . the gfr can be estimated from calibrated serum creatinine and estimating equation such as the modification of diet in renal disease ( mdrd ) study equation or the cockcroft - gault formula . kidney disease severity is classified into 5 categories according to the level of the gfr ( table 1 ) . abbreviations : gfr , glomerular filtration rate ; kdoqi , kidney disease outcomes quality initiative , kdigo , kidney disease : improving global outcomes . ckd has become a global public health problem because of its high prevalence and the accompanying increase in the risk of end - stage renal disease , cardiovascular disease , and premature death ( 12 ) . uric acid crystals have the capacity to adhere to the surface of renal epithelial cells ( 13 ) and induce an acute inflammatory response in such cell lines ( 14 ) . in addition to an increased risk of kidney stone formation , such effects have been shown to reduce the gfr ( 15 ) . uric acid in the blood is saturated at 6.4 - 6.8 mg / dl at ambient conditions and the upper limit of solubility placed at 7 mg / dl . urate is freely filtered , reabsorbed , and secreted at the glomerulus , and again reabsorbed in the proximal tubule . a urate or anion exchanger ( urat1 ) has been identified in the brush - border membrane of the kidneys and is inhibited by an angiotensin ii receptor blocker . a human organic anion transporter ( hoat1 ) has been found to be inhibited by both uricosuric drugs and antiuricosuric drugs , while another urate transporter ( uat ) has been found to facilitate urate efflux out of the cells . these transporters may facilitate the reabsorption , secretion , and reabsorption pattern of the renal handling of urate . hua may occur because of decreased excretion , increased production , or a combination of both mechanisms . urate handling by the kidneys involves filtration , reabsorption , and secretion at the glomerulus , and finally , postsecretory reabsorption . altered uric acid excretion can result from decreased glomerular filtration , decreased tubular secretion , or enhanced tubular reabsorption . while decreased urate filtration may not cause primary hua glycogenoses types iii , iv , and vii can result in hua from the excessive degradation of skeletal muscle atp . combined mechanisms can also cause hua . the most common cause under this group is alcohol consumption ( 16 ) , which results in the accelerated hepatic breakdown of atp and the generation of organic acids that compete with urate for tubular secretion . enzymatic defects such as glycogenoses type i and aldolase - b deficiency are other causes of hua that result from a combination of overproduction and underexcretion . urate is filtered readily by the glomerulus and subsequently reabsorbed by the proximal tubular cells of the kidney , and the normal fractional excretion of uric acid is approximately 10% ( 17 ) . human kidneys reabsorb urate , which may contribute to the higher serum uric acid levels in humans compared with other species . in addition , uricase mutation prevents further uric acid degradation in human beings ( 18 ) . the human urate transporter , i.e. urat1 ( encoded by the slc22a12 gene ) , facilitates uric acid reabsorption in the proximal convoluted tubule ( 19 ) . a recent study showed that glut9 ( encoded by slc2a9 ) , which is a member of the glucose transporter family , could be a major regulator of uric acid homeostasis ( 20 ) . uric acid homeostasis and the main factors that lead to increased serum uric acid levels in ckd are schematically depicted in figure 1 . uric acid has been shown to activate the cytoplasmic phospholipase a2 and inflammatory transcription factor nuclear factor-b ( nf-b ) , leading to the inhibition of proximal tubular cellular proliferation in vitro ( 21 ) . increasing serum uric acid levels include systemic cytokine production , i.e. tumor necrosis factor  ( 22 ) , and the local expression of chemokines , i.e. monocyte chemotactic protein 1 in the kidney ( 23 , 24 ) and cyclooxygenase 2 ( cox-2 ) in blood vessels ( 24 ) . the withdrawal of uric acid lowering therapy was found to increase urinary transforming growth factor-1 in a group of hua patients with ckd ( 25 ) . the putative mechanisms by which increased serum uric acid levels may contribute to ckd onset and progression are shown in figure 2 . increasing uric acid levels could induce oxidative stress and endothelial dysfunction , resulting in the development of both systemic and glomerular hypertension in association with elevated renal vascular resistance and reduced renal blood flow ( 26 , 27 ) . obesity and the metabolic syndrome are the most common risk factors for ckd and are strongly associated with hua probably as a consequence of insulin resistance and the effects of insulin to reduce urinary urate excretion ( 28 ) . hypertension is also commonly associated with renal vasoconstriction , which also leads to uric acid retention ( 29 ) . low - level intoxication with lead and cadmium can also raise serum uric acid levels by blocking the renal excretion of uric acid . wang et al . ( 30 ) performed a meta - analysis based on 11 papers with a total of 753 participants and reported that uric acid lowering is associated with a significant reduction in the serum creatinine concentration and an increase in the estimated gfr . in one study , hua rose to 58% among the patients receiving antihypertensive therapy , particularly in those receiving diuretics ( 31 ) . high plasma uric acid levels are common in patients with arterial hypertension ( 29 , 32 ) . blood pressure elevation was found to be associated with the development of an initial salt - insensitive hypertension that was reversible with the restoration of normal urate levels ( 33 ) . serum uric acid influences many of the proposed mechanisms of acute kidney injury such as renal vasoconstriction . impaired autoregulation has proinflammatory and antiangiogenic properties ( 34 ) and plays a key role in both innate and adaptive immune responses ( 35 ) . vascular and endothelial functions are known to have a major role in driving ckd ( 36 , 37 ) . endothelial function assessed by the flow - mediated vasodilation of the brachial artery or acetylcholine - induced coronary blood flow is reported to be inversely correlated with serum uric acid levels ( 38 - 40 ) . uric acid in the blood is saturated at 6.4 - 6.8 mg / dl at ambient conditions and the upper limit of solubility placed at 7 mg / dl . urate is freely filtered , reabsorbed , and secreted at the glomerulus , and again reabsorbed in the proximal tubule . a urate or anion exchanger ( urat1 ) has been identified in the brush - border membrane of the kidneys and is inhibited by an angiotensin ii receptor blocker . a human organic anion transporter ( hoat1 ) has been found to be inhibited by both uricosuric drugs and antiuricosuric drugs , while another urate transporter ( uat ) has been found to facilitate urate efflux out of the cells . these transporters may facilitate the reabsorption , secretion , and reabsorption pattern of the renal handling of urate . hua may occur because of decreased excretion , increased production , or a combination of both mechanisms . urate handling by the kidneys involves filtration , reabsorption , and secretion at the glomerulus , and finally , postsecretory reabsorption . altered uric acid excretion can result from decreased glomerular filtration , decreased tubular secretion , or enhanced tubular reabsorption . while decreased urate filtration may not cause primary hua glycogenoses types iii , iv , and vii can result in hua from the excessive degradation of skeletal muscle atp . combined mechanisms can also cause hua . the most common cause under this group is alcohol consumption ( 16 ) , which results in the accelerated hepatic breakdown of atp and the generation of organic acids that compete with urate for tubular secretion . enzymatic defects such as glycogenoses type i and aldolase - b deficiency are other causes of hua that result from a combination of overproduction and underexcretion . urate is filtered readily by the glomerulus and subsequently reabsorbed by the proximal tubular cells of the kidney , and the normal fractional excretion of uric acid is approximately 10% ( 17 ) . human kidneys reabsorb urate , which may contribute to the higher serum uric acid levels in humans compared with other species . in addition , uricase mutation prevents further uric acid degradation in human beings ( 18 ) . the human urate transporter , i.e. urat1 ( encoded by the slc22a12 gene ) , facilitates uric acid reabsorption in the proximal convoluted tubule ( 19 ) . a recent study showed that glut9 ( encoded by slc2a9 ) , which is a member of the glucose transporter family , could be a major regulator of uric acid homeostasis ( 20 ) . uric acid homeostasis and the main factors that lead to increased serum uric acid levels in ckd are schematically depicted in figure 1 . uric acid has been shown to activate the cytoplasmic phospholipase a2 and inflammatory transcription factor nuclear factor-b ( nf-b ) , leading to the inhibition of proximal tubular cellular proliferation in vitro ( 21 ) . increasing serum uric acid levels include systemic cytokine production , i.e. tumor necrosis factor  ( 22 ) , and the local expression of chemokines , i.e. monocyte chemotactic protein 1 in the kidney ( 23 , 24 ) and cyclooxygenase 2 ( cox-2 ) in blood vessels ( 24 ) . the withdrawal of uric acid lowering therapy was found to increase urinary transforming growth factor-1 in a group of hua patients with ckd ( 25 ) . the putative mechanisms by which increased serum uric acid levels may contribute to ckd onset and progression are shown in figure 2 . increasing uric acid levels could induce oxidative stress and endothelial dysfunction , resulting in the development of both systemic and glomerular hypertension in association with elevated renal vascular resistance and reduced renal blood flow ( 26 , 27 ) . obesity and the metabolic syndrome are the most common risk factors for ckd and are strongly associated with hua probably as a consequence of insulin resistance and the effects of insulin to reduce urinary urate excretion ( 28 ) . hypertension is also commonly associated with renal vasoconstriction , which also leads to uric acid retention ( 29 ) . low - level intoxication with lead and cadmium can also raise serum uric acid levels by blocking the renal excretion of uric acid . wang et al . ( 30 ) performed a meta - analysis based on 11 papers with a total of 753 participants and reported that uric acid lowering is associated with a significant reduction in the serum creatinine concentration and an increase in the estimated gfr . in one study , hua rose to 58% among the patients receiving antihypertensive therapy , particularly in those receiving diuretics ( 31 ) . high plasma uric acid levels are common in patients with arterial hypertension ( 29 , 32 ) . blood pressure elevation was found to be associated with the development of an initial salt - insensitive hypertension that was reversible with the restoration of normal urate levels ( 33 ) . serum uric acid influences many of the proposed mechanisms of acute kidney injury such as renal vasoconstriction . impaired autoregulation has proinflammatory and antiangiogenic properties ( 34 ) and plays a key role in both innate and adaptive immune responses ( 35 ) . vascular and endothelial functions are known to have a major role in driving ckd ( 36 , 37 ) . endothelial function assessed by the flow - mediated vasodilation of the brachial artery or acetylcholine - induced coronary blood flow is reported to be inversely correlated with serum uric acid levels ( 38 - 40 ) . uric acid in the blood is saturated at 6.4 - 6.8 mg / dl at ambient conditions and the upper limit of solubility placed at 7 mg / dl . urate is freely filtered , reabsorbed , and secreted at the glomerulus , and again reabsorbed in the proximal tubule . a urate or anion exchanger ( urat1 ) has been identified in the brush - border membrane of the kidneys and is inhibited by an angiotensin ii receptor blocker . a human organic anion transporter ( hoat1 ) has been found to be inhibited by both uricosuric drugs and antiuricosuric drugs , while another urate transporter ( uat ) has been found to facilitate urate efflux out of the cells . these transporters may facilitate the reabsorption , secretion , and reabsorption pattern of the renal handling of urate . hua may occur because of decreased excretion , increased production , or a combination of both mechanisms . urate handling by the kidneys involves filtration , reabsorption , and secretion at the glomerulus , and finally , postsecretory reabsorption . altered uric acid excretion can result from decreased glomerular filtration , decreased tubular secretion , or enhanced tubular reabsorption . while decreased urate filtration may not cause primary hua glycogenoses types iii , iv , and vii can result in hua from the excessive degradation of skeletal muscle atp . combined mechanisms can also cause hua . the most common cause under this group is alcohol consumption ( 16 ) , which results in the accelerated hepatic breakdown of atp and the generation of organic acids that compete with urate for tubular secretion . enzymatic defects such as glycogenoses type i and aldolase - b deficiency are other causes of hua that result from a combination of overproduction and underexcretion . urate is filtered readily by the glomerulus and subsequently reabsorbed by the proximal tubular cells of the kidney , and the normal fractional excretion of uric acid is approximately 10% ( 17 ) . human kidneys reabsorb urate , which may contribute to the higher serum uric acid levels in humans compared with other species . in addition , uricase mutation prevents further uric acid degradation in human beings ( 18 ) . the human urate transporter , i.e. urat1 ( encoded by the slc22a12 gene ) , facilitates uric acid reabsorption in the proximal convoluted tubule ( 19 ) . a recent study showed that glut9 ( encoded by slc2a9 ) , which is a member of the glucose transporter family , could be a major regulator of uric acid homeostasis ( 20 ) . uric acid homeostasis and the main factors that lead to increased serum uric acid levels in ckd are schematically depicted in figure 1 . uric acid has been shown to activate the cytoplasmic phospholipase a2 and inflammatory transcription factor nuclear factor-b ( nf-b ) , leading to the inhibition of proximal tubular cellular proliferation in vitro ( 21 ) . increasing serum uric acid levels include systemic cytokine production , i.e. tumor necrosis factor  ( 22 ) , and the local expression of chemokines , i.e. monocyte chemotactic protein 1 in the kidney ( 23 , 24 ) and cyclooxygenase 2 ( cox-2 ) in blood vessels ( 24 ) . the withdrawal of uric acid lowering therapy was found to increase urinary transforming growth factor-1 in a group of hua patients with ckd ( 25 ) . the putative mechanisms by which increased serum uric acid levels may contribute to ckd onset and progression are shown in figure 2 . increasing uric acid levels could induce oxidative stress and endothelial dysfunction , resulting in the development of both systemic and glomerular hypertension in association with elevated renal vascular resistance and reduced renal blood flow ( 26 , 27 ) . obesity and the metabolic syndrome are the most common risk factors for ckd and are strongly associated with hua probably as a consequence of insulin resistance and the effects of insulin to reduce urinary urate excretion ( 28 ) . hypertension is also commonly associated with renal vasoconstriction , which also leads to uric acid retention ( 29 ) . low - level intoxication with lead and cadmium can also raise serum uric acid levels by blocking the renal excretion of uric acid . wang et al . ( 30 ) performed a meta - analysis based on 11 papers with a total of 753 participants and reported that uric acid lowering is associated with a significant reduction in the serum creatinine concentration and an increase in the estimated gfr . in one study , hua rose to 58% among the patients receiving antihypertensive therapy , particularly in those receiving diuretics ( 31 ) . high plasma uric acid levels are common in patients with arterial hypertension ( 29 , 32 ) . blood pressure elevation was found to be associated with the development of an initial salt - insensitive hypertension that was reversible with the restoration of normal urate levels ( 33 ) . serum uric acid influences many of the proposed mechanisms of acute kidney injury such as renal vasoconstriction . impaired autoregulation has proinflammatory and antiangiogenic properties ( 34 ) and plays a key role in both innate and adaptive immune responses ( 35 ) . vascular and endothelial functions are known to have a major role in driving ckd ( 36 , 37 ) . moreover endothelial function assessed by the flow - mediated vasodilation of the brachial artery or acetylcholine - induced coronary blood flow is reported to be inversely correlated with serum uric acid levels ( 38 - 40 ) . the symptoms of hua that cause gout include a painful joint , usually the toes . the joint will become red and swollen and the pain can be intense . gout can also affect the ankles , knees , hands , and wrists . during the physical examination , the doctor will examine the painful joints and ask about the pain and swelling to determine whether the hua is from gout . blood test is also done to determine the amount of uric acid in the blood . a simple blood test will show increased levels of uric acid , which can cause kidney stones in addition to gout . for those who have kidney disease , the level of uric acid in the blood can indicate a worsening condition . chemotherapy and radiation therapy for cancer can also cause the level of uric acid to increase . joint fluid is drawn for the crystals of hua . in this test , the doctor withdraws fluid from the affected joint and examines it under a microscope . swollen and painful joints may be caused by crystals , which form when the body can not dispose of uric acid . the uric acid that remains will form crystals , which can be seen under the microscope . the crystals are pointy and cause a great deal of pain when surrounding the joint . the crystals , named urate crystals , are also responsible for certain types of kidney stones . cyclosporine is a widely used drug for immunosuppression post transplantation and to a lesser degree in patients with other autoimmune diseases . it has been strongly associated with the development of hua and gout ( 41 ) . however , the mechanism for cyclosporine s strong association with hua is unclear and may include an inhibitory effect on urate secretion ( 42 ) . tacrolimus also commonly is used in transplantation immunosuppressive regimens and has been reported to increase serum urate levels in a manner similar to cyclosporine ( 43 ) . however , data from the us renal data system in combination with medicare claims data suggest that it may induce less clinical gout in kidney transplantation recipients ( hazard ratio for cyclosporine versus tacrolimus : 1.24 ; 95% confidence interval : 1.06 to 1.45 ) ( 44 ) . other drugs and toxins associated with hua and gout include lead , pyrazinamide , ethambutol , and niacin ( 45 ) . xanthine oxidase inhibitors such as allopurinol or febuxostat are the preferred agents to decrease uric acid levels due to their effectiveness in both overproducers and undersecretors of uric acid . allopurinol is metabolized by xanthine oxidase to oxypurinol and both substrates act to inhibit xanthine oxidase ( 46 ) . patients with ckd may be at an increased risk of toxicity with allopurinol because oxypurinol is cleared by the kidney ( 47 ) . it is widely recommended to start with low dosages of allopurinol in patients with ckd and slowly titrate it to an effective dose . febuxostat has been shown to be safe and effective for decreasing serum uric acid levels ( 48 ) and is deemed an alternative to allopurinol in hua patients unable to tolerate the latter . other agents that can be used to decrease uric acid levels include uricosuric agents such as probenecid and benzbromarone . in a small randomized trial by siu et al . ( 49 ) , 54 hua patients with mild to moderate ckd were assigned to allopurinol ( 100 - 300 mg / d with the goal of normalizing serum uric acid levels ) versus no therapy and followed up for 12 months . at the end of follow - up , a significantly larger number of participants in the control group achieved the combined end point of a serum creatinine level increase  40% , dialysis , or death . ( 50 ) included 113 hua patients with ckd randomly assigned to the allopurinol group ( 100 mg / d ) and the control group . at the end of the 2-year follow - up , the estimated gfr decreased in the control group and the gfr increased in the allopurinol group . some recent studies have suggested that treating hua may prevent or delay the onset of ckd . a randomized double - blinded study by feig et al . ( 51 ) showed that treating hua in adolescents with newly diagnosed hypertension was effective at lowering the blood pressure . similar to the studies mentioned , allopurinol was used to decrease serum uric acid levels and resulted in significant improvements in the systolic and diastolic blood pressures compared with a placebo . ( 52 ) conducted a small case - controlled study on 59 hua individuals with an estimated gfr  60 ml / min/1.73 m treated with 300 mg of allopurinol daily for a 3-month period and reported improvements in the systolic and diastolic blood pressures as well as a significant increase in the estimated gfr . allopurinol did not significantly alter kidney disease progression or proteinuria , but the blood pressure was significantly improved in these patients after 6 months of treatment . allopurinol therapy can be associated with fatal stevens - johnson syndrome , while screening for hla - b68 may allow the elimination of subjects at highest risk for this condition ( 54 ) . the new xanthine oxidase inhibitor , i.e. febuxostat , does not appear to be associated with stevens - johnson - syndrome to date , and its dosage does not need to be modified in ckd . it may also be more effective at lowering the uric acid level in the setting of ckd ( 55 ) . the symptoms of hua that cause gout include a painful joint , usually the toes . the joint will become red and swollen and the pain can be intense . gout can also affect the ankles , knees , hands , and wrists . during the physical examination , the doctor will examine the painful joints and ask about the pain and swelling to determine whether the hua is from gout . blood test is also done to determine the amount of uric acid in the blood . a simple blood test will show increased levels of uric acid , which can cause kidney stones in addition to gout . for those who have kidney disease , the level of uric acid in the blood can indicate a worsening condition . chemotherapy and radiation therapy for cancer can also cause the level of uric acid to increase . joint fluid is drawn for the crystals of hua . in this test , the doctor withdraws fluid from the affected joint and examines it under a microscope . swollen and painful joints may be caused by crystals , which form when the body can not dispose of uric acid . the uric acid that remains will form crystals , which can be seen under the microscope . the crystals are pointy and cause a great deal of pain when surrounding the joint . the crystals , named urate crystals , are also responsible for certain types of kidney stones . cyclosporine is a widely used drug for immunosuppression post transplantation and to a lesser degree in patients with other autoimmune diseases . it has been strongly associated with the development of hua and gout ( 41 ) . however , the mechanism for cyclosporine s strong association with hua is unclear and may include an inhibitory effect on urate secretion ( 42 ) . tacrolimus also commonly is used in transplantation immunosuppressive regimens and has been reported to increase serum urate levels in a manner similar to cyclosporine ( 43 ) . however , data from the us renal data system in combination with medicare claims data suggest that it may induce less clinical gout in kidney transplantation recipients ( hazard ratio for cyclosporine versus tacrolimus : 1.24 ; 95% confidence interval : 1.06 to 1.45 ) ( 44 ) . other drugs and toxins associated with hua and gout include lead , pyrazinamide , ethambutol , and niacin ( 45 ) . xanthine oxidase inhibitors such as allopurinol or febuxostat are the preferred agents to decrease uric acid levels due to their effectiveness in both overproducers and undersecretors of uric acid . allopurinol is metabolized by xanthine oxidase to oxypurinol and both substrates act to inhibit xanthine oxidase ( 46 ) . patients with ckd may be at an increased risk of toxicity with allopurinol because oxypurinol is cleared by the kidney ( 47 ) . it is widely recommended to start with low dosages of allopurinol in patients with ckd and slowly titrate it to an effective dose . febuxostat has been shown to be safe and effective for decreasing serum uric acid levels ( 48 ) and is deemed an alternative to allopurinol in hua patients unable to tolerate the latter . other agents that can be used to decrease uric acid levels include uricosuric agents such as probenecid and benzbromarone . in a small randomized trial by siu et al . ( 49 ) , 54 hua patients with mild to moderate ckd were assigned to allopurinol ( 100 - 300 mg / d with the goal of normalizing serum uric acid levels ) versus no therapy and followed up for 12 months . at the end of follow - up , a significantly larger number of participants in the control group achieved the combined end point of a serum creatinine level increase  40% , dialysis , or death . ( 50 ) included 113 hua patients with ckd randomly assigned to the allopurinol group ( 100 mg / d ) and the control group . at the end of the 2-year follow - up , the estimated gfr decreased in the control group and the gfr increased in the allopurinol group . some recent studies have suggested that treating hua may prevent or delay the onset of ckd . a randomized double - blinded study by feig et al . ( 51 ) showed that treating hua in adolescents with newly diagnosed hypertension was effective at lowering the blood pressure . similar to the studies mentioned , allopurinol was used to decrease serum uric acid levels and resulted in significant improvements in the systolic and diastolic blood pressures compared with a placebo . ( 52 ) conducted a small case - controlled study on 59 hua individuals with an estimated gfr  60 ml / min/1.73 m treated with 300 mg of allopurinol daily for a 3-month period and reported improvements in the systolic and diastolic blood pressures as well as a significant increase in the estimated gfr . allopurinol did not significantly alter kidney disease progression or proteinuria , but the blood pressure was significantly improved in these patients after 6 months of treatment . allopurinol therapy can be associated with fatal stevens - johnson syndrome , while screening for hla - b68 may allow the elimination of subjects at highest risk for this condition ( 54 ) . the new xanthine oxidase inhibitor , i.e. febuxostat , does not appear to be associated with stevens - johnson - syndrome to date , and its dosage does not need to be modified in ckd . it may also be more effective at lowering the uric acid level in the setting of ckd ( 55 ) . the symptoms of hua that cause gout include a painful joint , usually the toes . the joint will become red and swollen and the pain can be intense . gout can also affect the ankles , knees , hands , and wrists . during the physical examination , the doctor will examine the painful joints and ask about the pain and swelling to determine whether the hua is from gout . blood test is also done to determine the amount of uric acid in the blood . a simple blood test will show increased levels of uric acid , which can cause kidney stones in addition to gout . for those who have kidney disease , the level of uric acid in the blood can indicate a worsening condition . chemotherapy and radiation therapy for cancer can also cause the level of uric acid to increase . joint fluid is drawn for the crystals of hua . in this test , the doctor withdraws fluid from the affected joint and examines it under a microscope . swollen and painful joints may be caused by crystals , which form when the body can not dispose of uric acid . the uric acid that remains will form crystals , which can be seen under the microscope . the crystals are pointy and cause a great deal of pain when surrounding the joint . the crystals , named urate crystals , are also responsible for certain types of kidney stones . cyclosporine is a widely used drug for immunosuppression post transplantation and to a lesser degree in patients with other autoimmune diseases . it has been strongly associated with the development of hua and gout ( 41 ) . however , the mechanism for cyclosporine s strong association with hua is unclear and may include an inhibitory effect on urate secretion ( 42 ) . tacrolimus also commonly is used in transplantation immunosuppressive regimens and has been reported to increase serum urate levels in a manner similar to cyclosporine ( 43 ) . however , data from the us renal data system in combination with medicare claims data suggest that it may induce less clinical gout in kidney transplantation recipients ( hazard ratio for cyclosporine versus tacrolimus : 1.24 ; 95% confidence interval : 1.06 to 1.45 ) ( 44 ) . other drugs and toxins associated with hua and gout include lead , pyrazinamide , ethambutol , and niacin ( 45 ) . xanthine oxidase inhibitors such as allopurinol or febuxostat are the preferred agents to decrease uric acid levels due to their effectiveness in both overproducers and undersecretors of uric acid . allopurinol is metabolized by xanthine oxidase to oxypurinol and both substrates act to inhibit xanthine oxidase ( 46 ) . patients with ckd may be at an increased risk of toxicity with allopurinol because oxypurinol is cleared by the kidney ( 47 ) . it is widely recommended to start with low dosages of allopurinol in patients with ckd and slowly titrate it to an effective dose . febuxostat has been shown to be safe and effective for decreasing serum uric acid levels ( 48 ) and is deemed an alternative to allopurinol in hua patients unable to tolerate the latter . other agents that can be used to decrease uric acid levels include uricosuric agents such as probenecid and benzbromarone . in a small randomized trial by siu et al . ( 49 ) , 54 hua patients with mild to moderate ckd were assigned to allopurinol ( 100 - 300 mg / d with the goal of normalizing serum uric acid levels ) versus no therapy and followed up for 12 months . at the end of follow - up , a significantly larger number of participants in the control group achieved the combined end point of a serum creatinine level increase  40% , dialysis , or death . ( 50 ) included 113 hua patients with ckd randomly assigned to the allopurinol group ( 100 mg / d ) and the control group . at the end of the 2-year follow - up , the estimated gfr decreased in the control group and the gfr increased in the allopurinol group . some recent studies have suggested that treating hua may prevent or delay the onset of ckd . a randomized double - blinded study by feig et al . ( 51 ) showed that treating hua in adolescents with newly diagnosed hypertension was effective at lowering the blood pressure . similar to the studies mentioned , allopurinol was used to decrease serum uric acid levels and resulted in significant improvements in the systolic and diastolic blood pressures compared with a placebo . ( 52 ) conducted a small case - controlled study on 59 hua individuals with an estimated gfr  60 ml / min/1.73 m treated with 300 mg of allopurinol daily for a 3-month period and reported improvements in the systolic and diastolic blood pressures as well as a significant increase in the estimated gfr . allopurinol did not significantly alter kidney disease progression or proteinuria , but the blood pressure was significantly improved in these patients after 6 months of treatment . allopurinol therapy can be associated with fatal stevens - johnson syndrome , while screening for hla - b68 may allow the elimination of subjects at highest risk for this condition ( 54 ) . the new xanthine oxidase inhibitor , i.e. febuxostat , does not appear to be associated with stevens - johnson - syndrome to date , and its dosage does not need to be modified in ckd . it may also be more effective at lowering the uric acid level in the setting of ckd ( 55 ) . many evidence - based studies have suggested that uric acid itself may harm patients with ckd by increasing inflammation and ckd progression , but the issue is still shrouded in controversy . the prevalence of ckd continues to increase , and it is likely that the management of hua and gout will continue to be a challenge in these patients . special attention should be given to specific contraindications to certain drugs and the possibility of infectious arthritis , especially relevant in such complex patients as those with ckd or transplantation recipients . allopurinol often is the treatment of choice for patients with chronic gout given its effectiveness , even in the setting of a decreased gfr . however , caution should be exercised in this setting , with low starting doses and conservative dose escalations tailored to the serum urate concentration .
context : in human beings , uric acid is the poorly soluble circulating end product of the purine nucleotide metabolism . 
 a reduction in the glomerular filtration rate ( gfr ) contributes to hyperuricemia , which is frequently observed in patients with chronic kidney disease ( ckd).evidence acquisition : hyperuricemia is defined as a serum uric acid level > 7.0 mg / dl in males and > 6.0 mg / dl in females , while ckd is defined as kidney damage or a gfr < 60 ml / min/1.73 m2 for 3 months or more , irrespective of the cause . 
 hyperuricemia is common in ckd and may occur because of decreased excretion , increased production , or a combination of both mechanisms.results:the causes for hyperuricemia in overproducers may be either exogenous or endogenous . 
 ckd has become a global public health problem because of its high prevalence and the accompanying increase in the risk of end - stage renal disease , cardiovascular disease , and premature death . 
 the most common risk factors for ckd are obesity and the metabolic syndrome , which is strongly associated with hyperuricemia probably as a consequence of insulin resistance and the effects of insulin to reduce the urinary urate excretion . for recurring bouts of hyperuricemia or gout 
 , patients should have a blood test and joint fluid test to determine whether the medication taken is effective . 
 interventional studies are a useful clinical research tool in clarifying the role of hyperuricemia in ckd.conclusions:although many evidence - based studies have suggested that uric acid itself may harm patients with ckd by increasing inflammation and ckd progression , the issue is still a matter of controversy . 
 special attention should be paid to specific contraindications to certain drugs and the possibility of infectious arthritis .