Xiaoyu Zi
Xi Zhang
Chuan Hao2*- 1Department of Rheumatology, The Second Hospital of Shanxi Medical University, Taiyuan, China
- 2Department of Urology, The Second Hospital of Shanxi Medical University, Taiyuan, China
Hyperuricemia (HUA) is a common complication after renal transplantation. Currently, there is no uniform consensus on factors which increase the risk for and treatment of HUA in renal transplant recipients. The purpose of this review is to summarize current and proposed risk factors and strategies to manage HUA after renal transplantation in order to assist renal function protection and prolong graft survival time.
Introduction
Hyperuricemia (HUA) is a common complication after renal transplantation (1), and the upper limit of the HUA incidence in renal transplant recipients reported over 80% with the wide applications of cyclosporine (1). HUA is defined as a serum uric acid (UA) level greater than 7.0 mg/dl in men and 6.0 mg/dl in women (2). UA reportedly causes oxidative damage in various tissues (3). HUA induces kidney damage traditionally thought to occur from inflammation brought on by sodium urate crystals deposition in renal tissue (4, 5). There are a number of risk factors associated with post transplant HUA including, older age, male gender, calcineurin inhibitors, diuretics, hypercalcemia, lower estimated glomerular filtration rate (eGFR), long-term pre transplantation dialysis and the presence of pre transplant hyperuricemia (1, 6–9). Elevated serum UA levels can decline long-term eGFR and worsen kidney graft function (10). More specifically, HUA was found to be associated with an increase in graft loss, short term graft survival and a higher risk of cardiovascular disease and mortality (11), resulting in poor quality of life and a dramatic increase in the economic burden of renal transplant recipients.
This review aims to deliver a comprehensive and accurate understanding of the risk factors for HUA after renal transplantation, as well as provide new insights into individualized prevention strategies and therapy protocols for HUA in renal transplant recipients.
Production and excretion of uric acid
Production of uric acid
UA is an end product of the digestion of exogenous purines derived largely from animal proteins in the liver, intestines, and vascular wall (12). In addition, UA is also the byproduct of the degradation of endogenous purines of damaged, dying, and dead cells that have nucleic acids, adenine, and guanine (12, 13). Adenine and guanine are converted to inosine and guanosine through deamination and dephosphorylation, respectively. The enzyme purine nucleoside phosphorylase subsequently converts inosine and guanosine to hypoxanthine and guanine, which are both converted to xanthine by xanthine oxidase (XO) through oxidation of hypoxanthine and deamination of guanine by guanine deaminase (14). XO further oxidizes xanthine to UA (15).
Excretion of uric acid
The kidney excretes approximately 70% of UA produced daily, and the remaining 30% is excreted via the intestine by bacteria cleaving UA into waste substances that are ultimately eliminated in feces (12, 16). Renal urate excretion mainly involves three processes: filtration, reabsorption and secretion (17). As reported, the proximal tubule is the main site of UA reabsorption and secretion, and approximately 90% of UA is reabsorbed into blood, which is primarily accomplished at the proximal tubular level by transporters that exchange intracellular anions for UA (18). Various transporters play a significant role in renal reabsorption of UA (13, 19). The urate transporter 1 (URAT1) protein is the product of the SLC22A12 gene, which is mainly located on the apical (luminal) side of the proximal tubule; while glucose transporter 9 (GLUT9) encoded by SLC2A9, which has roles similar to those of URAT1, is present on the basolateral side of proximal tubule cells (13, 15, 19). These two transporters are the main targets of present uricosuric drugs (19). Apart from these, organic anion transporter 4 (OAT4) and OAT10, respectively encoded by the SLC22A11 and SLC22A13 genes, are both expressed on the apical membrane of the proximal tubule and have similar roles as URAT1 (13).
The kidney also expresses secretory transporters to excrete UA. OAT1, which is encoded by the SLC22A6 gene and OAT3, encoded by SLC22A8, are both present on the basolateral membrane of renal proximal tubules, and they are principally involved in luminal secretion of UA (14), transporting urate from the interstitial fluid into proximal tubule cells (13). Since the balance of production and elimination of UA determines the level of UA in the body, an increased UA production and/or impaired renal UA excretion, causes the development of HUA (12).
Risk factors for HUA after renal transplantation
The risk factors for HUA after renal transplantation can be broadly classified into demographic characteristics, metabolism-related factors, drug use and other factors.
Demographic characteristics
Factors such as age, sex seem to affect UA in kidney transplant recipients. A study reported that reduced renal function appears likely to be responsible for the increase in UA in aged people (20). Kevin et al. conducted a retrospective cohort study of 59,077 renal transplant patients, and found that an older recipient age significantly contributed to increased risks of new-onset gout after renal transplantation (21). A retrospective cohort study of 302 renal transplant recipients showed that hyperuricemic patients were predominately older age (22). Therefore, older age is a risk factor for HUA after renal transplantation, but the detailed mechanisms remain unknown.
Many studies have shown that the development of HUA after renal transplantation is associated with the male sex (8, 22). Malheiro et al. found that hyperuricemic patients were overwhelmingly male of 302 renal transplant patients (22). This gender bias could be explained by the fact that estrogenic compounds enhance renal urate excretion in women, possibly reducing the active renal urate transporters resulting in less tubular UA reabsorption (7, 23).
Metabolism-related factors
HUA is associated with metabolism-related factors, such as obesity, diabetes mellitus, hypertriglyceridaemia and hypertension. Metabolic risk factors could negatively affect the graft function and cause graft loss (24). Previous studies showed that an increase in Body Mass Index was directly related to a higher risk for HUA, and obesity could contribute to elevated UA levels by decreasing urinary UA excretion (22, 25, 26). A study of 302 renal transplant patients showed that increasing Body Mass Index is a risk factor for HUA after renal transplantation (22). The most probable reason for this link is that obesity is characterized by insulin resistance, which activates the sympathetic nervous system and renin–angiotensin system and then produces lactic acid, which competitively inhibits UA secretion and ultimately causes higher serum UA (26).
As extensively reported, diabetic nephropathy causes renal structural changes (including glomerular hypertrophy, glomerular basement membrane thickening, partial glomerulosclerosis and extensive glomerulosclerosis) and dysfunction of renal tubular excretion (26, 27). HUA in renal transplant recipients with diabetes is possibly caused by the reduced eGFR and the increased reabsorption of renal tubules (26, 27). So diabetes mellitus may increase the risk of HUA after renal transplantation.” after the references number (26, 27).
The activity of glyceraldehyde 3 phosphate dehydrogenase which is reduced by hyperglycemia and hyperlipidemia can also enhance UA synthesis (26). At present, there is not much evidence available to fully elucidate whether hypertriglyceridaemia is a risk factor for HUA after kidney transplantation. Some studies have shown that UA progressively increases with increasing serum triglyceride levels (6, 28). The exact mechanisms, however, remain unknown. It is generally known that adenosine-triphosphate is needed for fatty acid synthesis and triglyceride anabolism, and depletion of adenosine-triphosphate can lead to the accumulation of adenosine monophosphate and overproduction of UA (28). Thus, hypertriglyceridaemia is a probable risk factor for HUA after kidney transplantation.
Many studies have reported that hypertension is associated with HUA in renal transplant recipients (8, 25, 29). Hypertension-caused renal ischemia could enhance reabsorption of UA by the renal proximal tubule (30). Experimental studies have reported that HUA induces hypertension and kidney injury via renal vasoconstriction mainly induced by endothelial dysfunction and the activation of the renin-angiotensin system (29). However, further studies are still needed to confirm a bidirectional link between HUA and hypertension.
Drug use
Currently, calcineurin inhibitors (CNIs) are the standard immunosuppressive therapy after renal transplantation (31). Previous studies have observed that CNIs, including tacrolimus and cyclosporin A (CsA), are risk factors for HUA after renal transplantation (1, 22, 32). Calcineurin is a significant target of immunosuppressive therapy with the main aim of inhibiting T-cell proliferative responses to donor alloantigens (33). CsA and tacrolimus are widely used in clinical transplantation (33), and their primary mechanism of pharmacological function mainly includes inhibiting phosphorylation of nuclear factor of activated T- cell which consequently reduces T-cell activation and proliferation mediated by Interleukin-2 and inhibits T cell-mediated rejection (34, 35). CNIs are nephrotoxic agents, and HUA is a common complication of CNI therapy (36, 37). Cyclosporine-induced HUA has been associated with the reduction of urinary clearance of UA due to increased proximal tubular reabsorption, decreased tubular secretion, and decreased GFR (22, 38, 39). Tacrolimus has also been found to be associated with HUA (38, 40), but at a less frequency compared to CsA (32). For tacrolimus, the effect on UA levels is not as well established and is only known to decrease the excretion and glomerular filtration of UA caused by vasoconstriction (41, 42).
Apart from that, renal transplant recipients are prone to hypertension and edema, so diuretics and other antihypertensive drugs are commonly used in their management (38). A large case-control study of 74,768 patients from the United Kingdom reported that beta blockers and diuretics were related to a higher risk of HUA (43). Since, there is not much evidence to prove that the use of beta blockers is a risk factor for HUA after renal transplantation, a detailed mechanism needs further investigation. Multiple studies have reported that diuretics were directly related to a higher risk for HUA after renal transplantation (7, 8, 32). Among these, thiazide diuretics and loop diuretics can interact with renal OAT; they enter the proximal tubular cells from the blood by OAT1 and OAT3, which could probably compete with UA, causing the reduced secretion of UA (30, 44, 45). Moreover, diuretics also decrease UA excretion, possibly by causing blood volume depletion with a consequent increase in proximal tubular reabsorption of UA (38).
Hypercalcemia
A retrospective study revealed that of 356 renal transplant recipients, 55 (15.45%) had HUA and their serum calcium concentrations were significantly associated with increased UA levels (46). Therefore, hypercalcemia highly increases the risk of HUA after kidney transplantation. It was reported that hypercalcemia can induce kidney injury, and the pathophysiologic mechanisms may be vasoconstrictive processes, intra-tubular calcifications, interstitial nephritis and hypovolemia (47). Additional studies are needed to explore the effects of serum calcium concentrations in HUA after renal transplant recipients.
Lower eGFR
Although, the incidence of rejection has already decreased with the development and administration of immunosuppressants, chronic cellular or humoral rejection unavoidably occurs (48). Renal ischemia reperfusion injury is also a common and unavoidable event after renal transplantation (49). The factors mentioned could cause renal graft injury, which probably causes reduced eGFR. A study showed significantly increased odds of HUA linked to a decline in eGFR values in renal allograft recipients (22). Numakura et al. found that decreased eGFR (<60.0 mL/min /1.73 m2) was a risk factor for HUA at 1 year after renal transplantation (8). Since UA is excreted mainly by the kidney, a rise in serum UA occurs as the GFR falls (7, 8). Conversely, HUA induces arteriolopathy of preglomerular vessels and impairs the autoregulatory response of afferent arterioles, which causes glomerular hypertension and reduced GFR (8), ultimately leading to loss of graft function. Thus, HUA is both a result of and a cause of reduction of eGFR in renal transplant recipients.
Long-term pre transplantation dialysis
Maintenance hemodialysis is the commonly used kidney replacement methods in end-stage kidney disease (50). Studies have shown that short-term hemodialysis significantly reduces UA levels by approximately 60% without additional ULT in patients with end-stage kidney disease (50, 51). However, some studies have shown that long-term pre transplantation dialysis (>36 months) is associated with HUA after renal transplantation (8, 32). One reliable interpretation is that hyperparathyroidism, a common complication in dialysis patients, causes HUA by increased urate absorption (52). Another possible explanation is that hypoxia and oxidative stress contribute to an increase in hypoxanthine, which can be converted to UA by xanthineoxidase. Hemodialysis patients are undoubtedly exposed to potential hypoxia and oxidative stress during the hemodialysis process (53). Thus, long-term pre transplantation dialysis is a risk factor for HUA after kidney transplantation.
The presence of pre transplant HUA
As we have already mentioned, although short-term hemodialysis significantly reduces UA levels, long-term pre transplantation dialysis may cause HUA. Previous studies have demonstrated that a preexisting history of HUA is related to HUA after kidney transplantation (1, 32, 46). The mechanisms of HUA-induced inflammation, oxidative stress, endothelial dysfunction, and renal fibrosis (54) may be associated with HUA post transplantation.
As mentioned above, numerous risk factors act separately or synergistically to induce HUA after renal transplantation. Serum UA concentration elevated to pathological levels may lead to renal damage (55), which may affect renal graft function. Thus, HUA may contribute to the reduced renal allograft function and eventually cause graft loss. In the following section, we will discuss the progress in HUA management after renal transplantation.
Management of HUA after renal transplantation
At-risk populations
Keeping in view all the factors discussed so far, it can be concluded that recipients are at a high risk of HUA after renal transplantation. Improving treatment adherence for metabolism-related factors, selecting rational CNIs and standardizing the utilization of drugs that inhibit UA excretion are particularly important for reducing the risk of HUA in recipients. When the condition allows, drugs that increase UA levels should be discontinued, such as loop and thiazide diuretics, beta-blockers (56). Moreover, HUA can be caused using CNIs, especially CsA (57). Thus, individualized immunosuppressive protocols that focus on cellular rejection as well as humoral rejection during renal transplantation promise a better balance between necessary control of alloreactivity (58) and reduced incidence of HUA. Additionally, new therapeutic strategies targeting renal ischemia reperfusion injury to extend graft survival include machine perfusion, exogenous administration of mesenchymal stem cells, and ex vivo preservation using preservation solutions saturated with alternative gases (49). This may reduce renal injury during renal transplantation and maintain normal UA excretion.
Lifestyle intervention
HUA may be caused by UA overproduction as a result of a high purine diet, fructose ingestion, alcohol consumption, and genetic causes such as hypoxanthine-guanine phosphor-ribosyl-transferase deficiency and phosphor-ribosyl-pyrophosphate synthetase hyperactivity (59). A critical review reported that the metabolism of fructose can cause elevated UA levels due to decreased UA excretion and increased hepatic adenosine-triphosphate degradation to adenosine monophosphate, a UA precursor (16, 59). A 2018 meta-analysis showed that several kinds of food: soft drinks, wine, liquor, beer and meat (lamb, pork, beef) contributed to raised UA levels (60). Thus, lifestyle intervention may play a pivotal role in the prevention of HUA after renal transplantation. Lifestyle interventions including exercise, weight reduction, low consumption of purine-rich meat, limiting the intake of alcoholic beverages, and avoiding high fructose intake (including sweetened soft drinks and energy drinks), are recommended for all HUA patients (61). Remarkably, gradual weight loss is more beneficial than a drastic reduction, as abrupt weight loss contributes to ketosis, which increases UA reabsorption via URAT1, resulting in increased serum UA (62). In addition, profuse sweating exercise causes a reduction in urinary UA excretion and results in increased serum UA after exercise; therefore, drinking enough fluids to prevent dehydration and maintain sufficient urine output is recommended (63). Moreover, alkalization of urine via manipulation of food materials can promote the removal of UA (64). Dairy products, such as vegetables, fruits (less sugary ones), legumes, nuts and whole grains are beneficial for the comorbidities of HUA and may also help prevent HUA by reducing insulin resistance (65).
Treatment for HUA after renal transplantation
It has been reported that lowering UA can prevent renal functional loss and vascular injury (66). UA-lowering treatments (ULTs) can be classified as direct-acting and indirect-acting agents. For direct-acting agents, there are two major classes of ULT agents widely used in clinical practice: one suppressing UA synthesis and another promoting UA excretion (67). Most guidelines do not recommend treating asymptomatic HUA, but drug therapy is officially allowed in asymptomatic HUA according to the Japanese guidelines on management of HUA, particularly when serum UA level reaches 8.0 mg/dL or more in cases with comorbidities such as hypertension, renal impairment (68).
Uricostatic drugs
Allopurinol is an XO inhibitor and its major metabolite, oxypurinol, is predominantly eliminated by the kidney; thus it is required to adjust the dose in renal impairment. Patients with renal impairment may also have a higher risk of life-threatening allopurinol hypersensitivity syndrome (69). For patients with creatinine clearances above 60 ml/min, the allopurinol should decrease serum UA to below 6.0 mg/dl in individualized dosage (70). It should be noted that administering allopurinol in renal transplant recipients receiving azathioprine has the danger of fatal pancytopenia. Azathioprine is a commonly used immunosuppressive agent for the prevention of graft rejection in renal transplant patients (71). Azathioprine is a prodrug, and its active form is 6-mercaptopurine. 6-mercaptopurine has three metabolic pathways in the body: by thiopurine methyltransferase into 6-methylmercaptopurine, by XO into 6-thiouracil, and by hypoxanthine guanine phosphoribosyltransferase into 6-thioguanine (72). Severe anemia is a recognized but uncommon manifestation of azathioprinerelated myelosuppression (73). It was reported that an interaction between azathioprine and allopurinol inhibiting the XO pathway of azathioprine metabolism, was the main reason for severe anemia (74). Therefore, when using allopurinol with azathioprine, a lower dose is suggested, with weekly complete blood counts in the first month to monitor for toxic adverse effects, simultaneously (72, 75).
Febuxostat, which is a novel nonpurine-selective XO inhibitor, is metabolized primarily by glucuronide formation and oxidation in the liver (76), and strongly inhibits both the oxidized and reduced forms of XO at low concentrations; therefore, there is no need to adjust its dose in mild to moderate renal impairment (77). Although febuxostat should be administered with caution in patients with severe renal dysfunction (GFR < 30 ml/min), its metabolic characteristics are more advantageous than allopurinol (78).
Uricosuric drugs
Benzbromarone, a URAT-1 inhibitor, generally shows high efficacy and safety even for patients with chronic kidney diseases (79). The drug was not licensed in the United States and numerous European Union nations due to its severe idiosyncratic hepatotoxic side effects (80); however, in some HUA patients with impaired renal function, benzbromarone is significantly effective in lowering UA levels (81). However, liver toxicity due to benzbromarone is still a concern (82).
Probenecid, inhibiting OAT and URAT1, exhibits less potent hypouricaemic effects than benzbromarone (80). Notably, probenecid cannot be used in patients with urolithiasis and a GFR < 50 ml/min when adverse events and drug interactions frequently occur (83). Thus, probenecid is not recommended for patients with severe renal impairment (eGFR < 30 ml/min/1.73 m2) (82).
Arhalofenate, a novel anti-inflammatory uricosuric agent, mainly decreases UA by inhibiting URAT1, OAT4 and OAT10, and reduces the release of interleukin-1β stimulated by monosodium urate crystals through the peroxisome proliferator-activated receptor gamma pathway (84, 85). The dual mode of action of arhalofenate exhibits a substantial advantage over other ULTs (86). Arhalofenate was reported to be more potent than probenecid in uricosuric activity (85), and could be a potentially attractive novel agent for HUA therapy for renal transplant recipients.
Tranilast, also an anti-inflammatory drug, exerts uricosuric properties by interacting with URAT1, GLUT9, OAT4, and OAT1 (87). Preclinical trials of tranilast in healthy volunteers showed that not only did it have a urate-lowering effect but also reduced urate crystal-associated inflammation (88), making it an ideal therapeutic agent for HUA after renal transplantation. Nevertheless, the adverse effects of tranilast, such as liver injury, eosinophilic cystitis, eosinophilic polymyositis and immune thrombocytopenia, have been reported (83). Therefore, a better knowledge of the kidney tolerance of these new uricosuric drugs is urgently needed to determine their risk: benefit ratio (82).
Indirect UA-lowering treatment
HUA is usually accompanied by various comorbidities, including cardiovascular disease, metabolic syndrome and other conditions (89, 90). When making treatment regimens for these comorbidities, drugs that increase renal UA excretion are recommended, such as calcium channel inhibitors or losartan for hypertension, glitazones and biguanides for diabetes (sodium-glucose cotransporter 2 inhibitors, SGLT-2), and fenofibrate or atorvastatin for dyslipidemia (56, 90–92).
Losartan has a hypouricaemic effect among antihypertensive medications (93). Hyon et al. showed that losartan and calcium channel blockers may be protective against the risk of HUA among people with hypertension due to their uricosuric properties (92, 94).
SGLT-2 inhibitors are a new class of antidiabetic drugs that increases urinary glucose excretion by reducing renal glucose reabsorption in the proximal convoluted tubule (95). Several clinical trials of patients with and without type 2 diabetes have shown that SGLT-2 inhibitors have consistently favorable cardiovascular and kidney effects (96). The SGLT-2 inhibitors (dapagliflozin, empagliflozin, canagliflozin, etc.) reportedly had a UA-lowering effect by increasing the glucose concentration in renal tubules and excreting UA at the S1 segment of the proximal tubule, both of which enhanced the excretion of UA (66, 97). Moreover, SGLT-2 inhibitors have added benefits, such as blood pressure control, weight loss, and possible lipid lowering effects, to meet uncertain clinical needs (98). However, SGLT-2 inhibitors have not been approved for renal transplant recipients, and may have great application prospects in renal transplant recipients with type 2 diabetes and HUA to reduce the risk of cardiovascular death (67).
Fenofibrate, a peroxisome proliferator-activated receptor alpha agonist, has lipid-modifying effects on high triglyceride and reduces the microvascular complications of diabetes (99). Fenofibrate was recommended as part of a comprehensive strategy to lower UA concentrations, as it decreases UA by promoting UA clearance (91). Thus, the renal transplant recipients with HUA with different comorbidities should use corresponding indirect UA-lowering drugs to enhance the effect of UA lowering therapy.
Conclusions
Renal transplant recipients are particularly vulnerable to HUA since there are several risk factors that contribute to deteriorating renal function. HUA severely impairs renal function and ultimately results in graft loss. Thus, the management of risk factors for HUA and lifestyle interventions in renal transplant recipients are critical to prevent renal damage caused by HUA and are extremely important for prolonging the survival time of grafts. Future studies need to focus on the mechanisms of HUA-induced renal injury in renal transplant recipients, which will further guide effective treatments for HUA after renal transplantation.
Author contributions
XZ and XYZ designed the study and wrote the original draft. CH and ZXW reviewed and edited the manuscript .All authors contributed to the article and approved the submitted version.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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References
1. Mazali FC, Mazzali M. Uric acid and transplantation. Semin Nephrol. (2011) 31:466–71. doi: 10.1016/j.semnephrol.2011.08.012
2. Li Y, Liu M, Zhang X, Lu Y, Meng J. Switching from allopurinol to febuxostat: efficacy and safety in the treatment of hyperuricemia in renal transplant recipients. Renal Failure. (2019) 41:595-9. doi: 10.1080/0886022x.2019.1632717
3. Chen J, Ge J, Zha M, Miao JJ, Sun ZL, Yu JY. Effects of uric acid-lowering treatment on glycemia: a systematic review and meta-analysis. Front Endocrinol (Lausanne). (2020) 11:577. doi: 10.3389/fendo.2020.00577
4. Park JH, Jo YI, Lee JH. Renal effects of uric acid: hyperuricemia and hypouricemia. Korean J Intern Med. (2020) 35:1291-304. doi: 10.3904/kjim.2020.410
5. Wen S, Wang D, Yu H, Liu M, Chen Q, Bao R, et al. The time-feature of uric acid excretion in hyperuricemia mice induced by potassium oxonate and adenine. Int J Mol Sci. (2020) 21:5178. doi: doi: 10.3390/ijms21155178
6. Li N, Zhang S, Li W, Wang L, Liu H, Li W, et al. Prevalence of hyperuricemia and its related risk factors among preschool children from China. Sci Rep. (2017) 7:9448. doi: 10.1038/s41598-017-10120-8
7. Folkmane I, Tzivian L, Folkmane E, Valdmane E, Kuzema V, Petersons A. Predictors of hyperuricemia after kidney transplantation: association with graft function. Medicina (Kaunas). (2020) 56:95. doi: 10.3390/medicina56030095
8. Numakura K, Satoh S, Tsuchiya N, Saito M, Maita S, Obara T, et al. Hyperuricemia at 1 year after renal transplantation, its prevalence, associated factors, and graft survival. Transplantation. (2012) 94:145–51. doi: 10.1097/TP.0b013e318254391b
9. Liu F, Du GL, Song N, Ma YT, Li XM, Gao XM, et al. Hyperuricemia and its association with adiposity and dyslipidemia in Northwest China: results from cardiovascular risk survey in Xinjiang (CRS 2008-2012). Lipids Health Dis. (2020) 19:58. doi: 10.1186/s12944-020-01211-z
10. Kim DG, Choi HY, Kim HY, Lee EJ, Huh KH, Kim MS, et al. Association between post-transplant serum uric acid levels and kidney transplantation outcomes. PLoS ONE. (2018) 13:e0209156. doi: 10.1371/journal.pone.0209156
11. Isakov O, Patibandla BK, Shwartz D, Mor E, Christopher KB, Hod T. Can uric acid blood levels in renal transplant recipients predict allograft outcome? Ren Fail. (2021) 43:1240–9. doi: 10.1080/0886022X.2021.1969246
12. Yanai H, Adachi H, Hakoshima M, Katsuyama H. Molecular biological and clinical understanding of the pathophysiology and treatments of hyperuricemia and its association with metabolic syndrome, cardiovascular diseases and chronic kidney disease. Int J Mol Sci. (2021) 22:9221. doi: 10.3390/ijms22179221
13. Hyndman D, Liu S, Miner JN. Urate handling in the human body. Curr Rheumatol Rep. (2016) 18:34. doi: 10.1007/s11926-016-0587-7
14. El Ridi R, Tallima H. Physiological functions and pathogenic potential of uric acid: a review. J Adv Res. (2017) 8:487–93. doi: 10.1016/j.jare.2017.03.003
15. Maiuolo J, Oppedisano F, Gratteri S, Muscoli C, Mollace V. Regulation of uric acid metabolism and excretion. Int J Cardiol. (2016) 213:8–14. doi: 10.1016/j.ijcard.2015.08.109
16. Caliceti C, Calabria D, Roda A, Cicero AFG. Fructose intake, Serum uric acid, and cardiometabolic disorders: a critical review. Nutrients. (2017) 9:395. doi: 10.3390/nu9040395
17. Roch-Ramel F, Guisan B. Renal transport of urate in humans. News Physiol Sci. (1999) 14:80–4. doi: 10.1152/physiologyonline.1999.14.2.80
18. Chaudhary K, Malhotra K, Sowers J, Aroor A. Uric acid - key ingredient in the recipe for cardiorenal metabolic syndrome. Cardiorenal Med. (2013) 3:208–20. doi: 10.1159/000355405
19. Zhang Y, Tan X, Lin Z, Li F, Yang C, Zheng H, et al. Fucoidan from laminaria japonica inhibits expression of GLUT9 and URAT1 via PI3K/akt, JNK and NF-kappaB pathways in uric acid-exposed HK-2 cells. Mar Drugs. (2021) 19:238. doi: 10.3390/md19050238
20. Wang Y, Zhang W, Qian T, Sun H, Xu Q, Hou X, et al. Reduced renal function may explain the higher prevalence of hyperuricemia in older people. Sci Rep. (2021) 11:1302. doi: 10.1038/s41598-020-80250-z
21. Abbott KC, Kimmel PL, Dharnidharka V, Oglesby RJ, Agodoa LY, Caillard S. New-onset gout after kidney transplantation: incidence, risk factors and implications. Transplantation. (2005) 80:1383–91. doi: 10.1097/01.tp.0000188722.84775.af
22. Malheiro J, Almeida M, Fonseca I, Martins LS, Pedroso S, Dias L, et al. Hyperuricemia in adult renal allograft recipients: prevalence and predictors. Transplant Proc. (2012) 44:2369–72. doi: 10.1016/j.transproceed.2012.07.033
23. Huang XB, Zhang WQ, Tang WW, Liu Y, Ning Y, Huang C, et al. Prevalence and associated factors of hyperuricemia among urban adults aged 35-79 years in southwestern China: a community-based cross-sectional study. Sci Rep. (2020) 10:15683. doi: 10.1038/s41598-020-72780-3
24. Tainio J, Qvist E, Holtta T, Pakarinen M, Jahnukainen T, Jalanko H. Metabolic risk factors and long-term graft function after paediatric renal transplantation. Transpl Int. (2014) 27:583-92. doi: 10.1111/tri.12300
25. Chen LY, Zhu WH, Chen ZW, Dai HL, Ren JJ, Chen JH, et al. Relationship between hyperuricemia and metabolic syndrome. J Zhejiang Univ Sci B. (2007) 8:593–8. doi: 10.1631/jzus.2007.B0593
26. Gao Z, Zuo M, Han F, Yuan X, Sun M, Li X, et al. Renal impairment markers in type 2 diabetes patients with different types of hyperuricemia. J Diabetes Investig. (2019) 10:118–23. doi: 10.1111/jdi.12850
27. Zhang Y, Yang J, Zheng M, Wang Y, Ren H, Xu Y, et al. Clinical characteristics and predictive factors of subclinical diabetic nephropathy. Exp Clin Endocrinol Diabetes. (2015) 123:132–8. doi: 10.1055/s-0034-1396810
28. Qi J, Dai X, Zhou B, Su Y, Xie Z, Liu D. Association between lipid profiles and Serum urate: a cross-sectional study in Southwestern China. Int J Endocrinol. (2021) 2021:2741131. doi: 10.1155/2021/2741131
29. Johnson RJ, Segal MS, Srinivas T, Ejaz A, Mu W, Roncal C, et al. Essential hypertension, progressive renal disease, and uric acid: a pathogenetic link? J Am Soc Nephrol. (2005) 16:1909–19. doi: 10.1681/ASN.2005010063
30. Cui L, Meng L, Wang G, Yuan X, Li Z, Mu R, et al. Prevalence and risk factors of hyperuricemia: results of the kailuan cohort study. Mod Rheumatol. (2017) 27:1066–71. doi: 10.1080/14397595.2017.1300117
31. Neuwirt H, Leitner-Lechner I, Kerschbaum J, Ertl M, Poggsteiner F, Polt N, et al. Efficacy and safety of belatacept treatment in renal allograft recipients at high cardiovascular risk-A single center experience. J Clin Med. (2019) 8:1164. doi: 10.3390/jcm8081164
32. Bellomo G. Asymptomatic hyperuricemia following renal transplantation. World J Nephrol. (2015) 4:324–9. doi: 10.5527/wjn.v4.i3.324
33. Armstrong-James D, de Boer L, Bercusson A, Shah A. From phagocytosis to metaforosis: calcineurin's Deadly role in innate processing of fungi. PLoS Pathog. (2018) 14:e1006627. doi: 10.1371/journal.ppat.1006627
34. Fruman DA, Klee CB, Bierer BE, Burakoff SJ. Calcineurin phosphatase activity in T lymphocytes is inhibited by FK 506 and cyclosporin A. Proc Natl Acad Sci USA. (1992) 89:3686–90. doi: 10.1073/pnas.89.9.3686
35. Winslow MM, Gallo EM, Neilson JR, Crabtree GR. The calcineurin phosphatase complex modulates immunogenic B cell responses. Immunity. (2006) 24:141–52. doi: 10.1016/j.immuni.2005.12.013
36. Pascual M, Curtis J, Delmonico FL, Farrell ML, Williams WW Jr., Kalil R, et al. A prospective, randomized clinical trial of cyclosporine reduction in stable patients greater than 12 months after renal transplantation. Transplantation. (2003) 75:1501–5. doi: 10.1097/01.TP.0000061606.64917.BE
37. Lin HY, Rocher LL, McQuillan MA, Schmaltz S, Palella TD, Fox IH. Cyclosporine-induced hyperuricemia and gout. N Engl J Med. (1989) 321:287–92. doi: 10.1056/NEJM198908033210504
38. Clive DM. Renal transplant-associated hyperuricemia and gout. J Am Soc Nephrol. (2000) 11:974–9. doi: 10.1681/ASN.V115974
39. Longenecker JC, Waheed S, Bandak G, Murakami CA, McMahon BA, Gelber AC, et al. Hyperuricemia after orthotopic liver transplantation: divergent associations with progression of renal disease, incident end-stage renal disease, and mortality. BMC Nephrol. (2017) 18:103. doi: 10.1186/s12882-017-0518-5
40. Kalantar E, Khalili N, Hossieni MS, Rostami Z, Einollahi B. Hyperuricemia after renal transplantation. Transplant Proc. (2011) 43:584–5. doi: 10.1016/j.transproceed.2011.01.062
41. Afridi SM, Reddy S, Raja A, Jain AG. Gout due to tacrolimus in a liver transplant recipient. Cureus. (2019) 11:e4247. doi: 10.7759/cureus.4247
42. Olyaei AJ, de Mattos AM, Bennett WM. Nephrotoxicity of immunosuppressive drugs: new insight and preventive strategies. Curr Opin Crit Care. (2001) 7:384–9. doi: 10.1097/00075198-200112000-00003
43. Juraschek SP, Appel LJ, Miller ER. Metoprolol increases uric acid and risk of gout in african Americans with chronic kidney disease attributed to hypertension. Am J Hypertens. (2017) 30:871–5. doi: 10.1093/ajh/hpx113
44. Jutabha P, Anzai N, Wempe MF, Wakui S, Endou H, Sakurai H. Apical voltage-driven urate efflux transporter NPT4 in renal proximal tubule. Nucleosides Nucleotides Nucleic Acids. (2011) 30:1302–11. doi: 10.1080/15257770.2011.616564
45. Barone S, Xu J, Zahedi K, Brooks M, Soleimani M. Probenecid pre-treatment downregulates the kidney Cl−/HCO3− exchanger (pendrin) and potentiates hydrochlorothiazide-induced diuresis. Front Physiol. (2018) 9:849. doi: 10.3389/fphys.2018.00849
46. Kim KM, Kim SS, Han DJ, Yang WS, Park JS, Park SK. Hyperuricemia in kidney transplant recipients with intact graft function. Transplant Proc. (2010) 42:3562–7. doi: 10.1016/j.transproceed.2010.07.104
47. Lin Q, Li Y, Dai X, Tang H, Chen R, Xu Q, et al. Hypercalcemia, hyperuricemia, and kidney dysfunction in a 35-month-old boy: answers. Pediatr Nephrol. (2021) 36:73–6. doi: 10.1007/s00467-020-04603-6
48. Pontrelli P, Grandaliano G, Van Kooten C. Editorial: kidney transplantation and innate immunity. Front Immunol. (2020) 11:603982. doi: 10.3389/fimmu.2020.603982
49. Zhao H, Alam A, Soo AP, George AJT, Ma D. Ischemia-reperfusion injury reduces long term renal graft survival: mechanism and beyond. EBioMedicine. (2018) 28:31–42. doi: 10.1016/j.ebiom.2018.01.025
50. Doualla M, Nkeck JR, Halle MP, Kamdem F, Agouak AI, Essouma M, et al. Assessment of the efficacy of hemodialysis on uric acid clearance in a sub-Saharan African population at the end stage kidney disease. BMC Nephrol. (2020) 21:378. doi: 10.1186/s12882-020-02037-8
51. Alkilany RA-O, Einstadter D, Antonelli M. Urate-lowering therapy for patients with gout on hemodialysis. Int J Rheum Dis. (2022) 25:769–74. doi: 10.1111/1756-185X.14334
52. Black DM, Greenspan SL, Ensrud KE, Palermo L, McGowan JA, Lang TF, et al. The effects of parathyroid hormone and alendronate alone or in combination in postmenopausal osteoporosis. N Engl J Med. (2003) 349:1207–15. doi: 10.1056/NEJMoa031975
53. Choi JY, Yoon YJ, Choi HJ, Park SH, Kim CD, Kim IS, et al. Dialysis modality-dependent changes in serum metabolites: accumulation of inosine and hypoxanthine in patients on haemodialysis. Nephrol Dial Transplant. (2011) 26:1304–13. doi: 10.1093/ndt/gfq554
54. Su HY, Yang C, Liang D, Liu HF. Research advances in the mechanisms of hyperuricemia-induced renal injury. Biomed Res Int. (2020) 2020:5817348. doi: 10.1155/2020/5817348
55. Wang M, Lin X, Yang X, Yang Y. Research progress on related mechanisms of uric acid activating NLRP3 inflammasome in chronic kidney disease. Ren Fail. (2022) 44:615–24. doi: 10.1080/0886022X.2022.2036620
56. Chales G. How should we manage asymptomatic hyperuricemia? Joint Bone Spine. (2019) 86:437–43. doi: 10.1016/j.jbspin.2018.10.004
57. Kielstein JT, Pontremoli R, Burnier M. Management of hyperuricemia in patients with chronic kidney disease: a focus on renal protection. Curr Hypertens Rep. (2020) 22:102. doi: 10.1007/s11906-020-01116-3
58. Hofer A, Jonigk D, Hartleben B, Verboom M, Hallensleben M, Manns MP, et al. Non-invasive screening for subclinical liver graft injury in adults via donor-specific anti-HLA antibodies. Sci Rep. (2020) 10:14242. doi: 10.1038/s41598-020-70938-7
59. Merriman TR, Dalbeth N. The genetic basis of hyperuricaemia and gout. Joint Bone Spine. (2011) 78:35–40. doi: 10.1016/j.jbspin.2010.02.027
60. Major TJ, Topless RK, Dalbeth N, Merriman TR. Evaluation of the diet wide contribution to serum urate levels: meta-analysis of population based cohorts. Br Med J. (2018) 363:k3951. doi: 10.1136/bmj.k3951
61. Ramirez-Sandoval JC, Madero M. Treatment of hyperuricemia in chronic kidney disease. Contrib Nephrol. (2018) 192:135–46. doi: 10.1159/000484288
62. Kakutani-Hatayama M, Kadoya M, Okazaki H, Kurajoh M, Shoji T, Koyama H, et al. Nonpharmacological management of gout and hyperuricemia: hints for better lifestyle. Am J Lifestyle Med. (2017) 11:321–9. doi: 10.1177/1559827615601973
63. Huang LL, Huang CT, Chen ML, Mao IF. Effects of profuse sweating induced by exercise on urinary uric acid excretion in a hot environment. Chin J Physiol. (2010) 53:254–61. doi: 10.4077/cjp.2010.amk060
64. Kanbara A, Hakoda M, Seyama I. Urine alkalization facilitates uric acid excretion. Nutr J. (2010) 9:45. doi: 10.1186/1475-2891-9-45
65. Choi HK. A prescription for lifestyle change in patients with hyperuricemia and gout. Curr Opin Rheumatol. (2010) 22:165–72. doi: 10.1097/BOR.0b013e328335ef38
66. Lytvyn Y, Skrtic M, Yang GK, Yip PM, Perkins BA, Cherney DZ. Glycosuria-mediated urinary uric acid excretion in patients with uncomplicated type 1 diabetes mellitus. Am J Physiol Renal Physiol. (2015) 308:F77–83. doi: 10.1152/ajprenal.00555.2014
67. Yu W, Cheng JD. Uric acid and cardiovascular disease: an update from molecular mechanism to clinical perspective. Front Pharmacol. (2020) 11:582680. doi: 10.3389/fphar.2020.582680
68. Yamanaka H. Japanese guideline for the management of hyperuricemia and gout: second edition. Nucleosides, Nucleotides and Nucleic Acids. (2011) 30:1018-29. doi: doi: 10.1080/15257770.2011.596496
69. Hu AM, Brown JN. Comparative effect of allopurinol and febuxostat on long-term renal outcomes in patients with hyperuricemia and chronic kidney disease: a systematic review. Clin Rheumatol. (2020) 39:3287–94. doi: 10.1007/s10067-020-05079-3
70. Chung Y, Stocker SL, Graham GG, Day RO. Optimizing therapy with allopurinol: factors limiting hypouricemic efficacy. Am J Med Sci. (2008) 335:219–26. doi: 10.1097/MAJ.0b013e31815acb10
71. Broen JCA, van Laar JM. Mycophenolate mofetil, azathioprine and tacrolimus: mechanisms in rheumatology. Nat Rev Rheumatol. (2020) 16:167–78. doi: 10.1038/s41584-020-0374-8
72. Madrazo L, Jones E, Hsia CC. Azathioprine-induced severe anemia potentiated by the concurrent use of allopurinol. Can Med Assoc J. (2021) 193:E94–E7. doi: 10.1503/cmaj.201022
73. Agrawal A, Parrott NR, Riad HN, Augustine T. Azathioprine-induced pure red cell aplasia: case report and review. Transplant Proc. (2004) 36:2689–91. doi: 10.1016/j.transproceed.2004.09.047
74. MacKay D. Emergency department visits related to dietary supplements. N Engl J Med. (2016) 374:694–5. doi: 10.1056/NEJMc1514454
75. Hoentjen F, Seinen ML, Hanauer SB, de Boer NK, Rubin DT, Bouma G, et al. Safety and effectiveness of long-term allopurinol-thiopurine maintenance treatment in inflammatory bowel disease. Inflamm Bowel Dis. (2013) 19:363–9. doi: 10.1002/ibd.23021
76. Becker MA, Schumacher HR Jr, Wortmann RL, MacDonald PA, Eustace D, Palo WA, et al. Febuxostat compared with allopurinol in patients with hyperuricemia and gout. N Engl J Med. (2005) 53:2450–61. doi: 10.1056/NEJMoa050373
77. Hosoya T, Ohno I. A repeated oral administration study of febuxostat (TMX-67), a non-purine-selective inhibitor of xanthine oxidase, in patients with impaired renal function in Japan: pharmacokinetic and pharmacodynamic study. J Clin Rheumatol. (2011) 17:S27–34. doi: 10.1097/RHU.0b013e31821d36f2
78. Yamaguchi A, Harada M, Yamada Y, Hashimoto K, Kamijo Y. Identification of chronic kidney disease patient characteristics influencing the renoprotective effects of febuxostat therapy: a retrospective follow-up study. BMC Nephrol. (2017) 18:162. doi: 10.1186/s12882-017-0572-z
79. Kang EH, Park EH, Shin A, Song JS, Kim SC. Cardiovascular risk associated with allopurinol vs. Benzbromarone in patients with gout. Eur Heart J. (2021) 42:4578–88. doi: 10.1093/eurheartj/ehab619
80. Taniguchi T, Ashizawa N, Matsumoto K, Saito R, Motoki K, Sakai M, et al. Pharmacological evaluation of dotinurad, a selective urate reabsorption inhibitor. J Pharmacol Exp Ther. (2019) 371:162–70. doi: 10.1124/jpet.119.259341
81. Sun P, Zhu JJ, Wang T, Huang Q, Zhou YR, Yu BW, et al. Benzbromarone aggravates hepatic steatosis in obese individuals. Biochim Biophys Acta Mol Basis Dis. (2018) 1864:2067–77. doi: 10.1016/j.bbadis.2018.03.009
82. Bardin T, Richette P. Novel uricosurics. Rheumatology (Oxford). (2018) 57:i42–i6. doi: 10.1093/rheumatology/kex433
83. Brucato A, Cianci F, Carnovale C. Management of hyperuricemia in asymptomatic patients: a critical appraisal. Eur J Intern Med. (2020) 74:8–17. doi: 10.1016/j.ejim.2020.01.001
84. Poiley J, Steinberg AS, Choi YJ, Davis CS, Martin RL, McWherter CA, et al. A randomized, double-blind, active- and placebo-controlled efficacy and safety study of arhalofenate for reducing flare in patients with gout. Arthritis Rheumatol. (2016) 68:2027–34. doi: 10.1002/art.39684
85. Neogi T, Choi HK. Editorial: pursuit of a dual-benefit antigout drug: a first Look at arhalofenate. Arthritis Rheumatol. (2016) 68:1793–6. doi: 10.1002/art.39687
86. Barranco C. Crystal arthritis: arhalofenate safely prevents gout flare. Nat Rev Rheumatol. (2016) 12:252. doi: 10.1038/nrrheum.2016.53
87. Mandal AK, Mercado A, Foster A, Zandi-Nejad K, Mount DB. Uricosuric targets of tranilast. Pharmacol Res Perspect. (2017) 5:e00291. doi: 10.1002/prp2.291
88. Shahid H, Singh JA. Investigational drugs for hyperuricemia. Expert Opin Investig Drugs. (2015) 24:1013–30. doi: 10.1517/13543784.2015.1051617
89. Dehlin M, Jacobsson L, Roddy E. Global epidemiology of gout: prevalence, incidence, treatment patterns and risk factors. Nat Rev Rheumatol. (2020) 16:380–90. doi: 10.1038/s41584-020-0441-1
90. Richette P, Perez-Ruiz F, Doherty M, Jansen TL, Nuki G, Pascual E, et al. Improving cardiovascular and renal outcomes in gout: what should we target? Nat Rev Rheumatol. (2014) 10:654–61. doi: 10.1038/nrrheum.2014.124
91. Waldman B, Ansquer J-C, Sullivan DR, Jenkins AJ, McGill N, Buizen L, et al. Effect of fenofibrate on uric acid and gout in type 2 diabetes: a post-hoc analysis of the randomised, controlled FIELD study. Lancet Diab Endocrinol. (2018) 6:310–8. doi: 10.1016/s2213-8587(18)30029-9
92. Choi HK, Soriano LC, Zhang Y, Rodriguez LA. Antihypertensive drugs and risk of incident gout among patients with hypertension: population based case-control study. Br Med J. (2012) 344:d8190. doi: 10.1136/bmj.d8190
93. Soltani Z, Rasheed K, Kapusta DR, Reisin E. Potential role of uric acid in metabolic syndrome, hypertension, kidney injury, and cardiovascular diseases: is it time for reappraisal? Curr Hypertens Rep. (2013) 15:175–81. doi: 10.1007/s11906-013-0344-5
94. Ruilope LM. Antihypertensives in people with gout or asymptomatic hyperuricaemia. Br Med J. (2012) 344:d7961. doi: 10.1136/bmj.d7961
95. Vasilakou D, Karagiannis T, Athanasiadou E, Mainou M, Liakos A, Bekiari E, et al. Sodium-glucose cotransporter 2 inhibitors for type 2 diabetes: a systematic review and meta-analysis. Ann Intern Med. (2013) 159:262–74. doi: 10.7326/0003-4819-159-4-201308200-00007
96. Salah HM, Al'Aref SJ, Khan MS, Al-Hawwas M, Vallurupalli S, Mehta JL, et al. Effects of sodium-glucose cotransporter 1 and 2 inhibitors on cardiovascular and kidney outcomes in type 2 diabetes: a meta-analysis update. Am Heart J. (2021) 233:86–91. doi: 10.1016/j.ahj.2020.12.007
97. Zhao Y, Xu L, Tian D, Xia P, Zheng H, Wang L, et al. Effects of sodium-glucose co-transporter 2 (SGLT2) inhibitors on serum uric acid level: a meta-analysis of randomized controlled trials. Diabetes Obes Metab. (2018) 20:458–62. doi: 10.1111/dom.13101
98. Xin Y, Guo Y, Li Y, Ma Y, Li L, Jiang H. Effects of sodium glucose cotransporter-2 inhibitors on serum uric acid in type 2 diabetes mellitus: a systematic review with an indirect comparison meta-analysis. Saudi J Biol Sci. (2019) 26:421–6. doi: 10.1016/j.sjbs.2018.11.013
Keywords: risk factors, uric acid, hyperuricemia, renal transplantation, drug induced
Citation: Zi X, Zhang X, Hao C and Wang Z (2023) Risk factors and management of hyperuricemia after renal transplantation. Front. Surg. 9:956213. doi: 10.3389/fsurg.2022.956213
Received: 30 May 2022; Accepted: 21 November 2022;
Published: 6 January 2023.
Edited by:
Todd Pesavento, The Ohio State University, United StatesReviewed by:
COSTAS FOURTOUNAS, University of Patras, Greece© 2023 Zi, Zhang, Hao and Wang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Chuan Hao haochuan2003@sina.com Zhenxing Wang wangzhenxingsdey@163.com
†These authors have contributed equally to this work and share first authorship
Specialty Section: This article was submitted to Genitourinary Surgery, a section of the journal Frontiers in Surgery