The Basis Of Uric Acid And Vascular Endothelial Injury And Clinical Research

Background. Uric acid is the product of purine metabolism; however, a relatively higher level of serum uric acid in human is observed than that in other mammals since genetic mutations. The prevalence of hyperuricemia and gout increased markedly around the world. Hyperuricemia often comes with cardiovascular diseases, what’s more Hyperuricemia is highly prevalent in chroic kidney disease. Although the importance of high serum uric acid as a marker of increased cardiovascular risk has been recogised for more than50years. No biologically plausible causal link has been identified. The pathophysiological link between the elevated uric acid and those diseases may be endothelial dysfunction and inflammation. The role of uric acid in this pathophysiological process is controversial.Objective.1) To analyse the clinical characteristic of gout patients by setting up a gout out-patient database;2) To study the endothelial function of gout patients and its variation after urate-lowering treatment;3) To observe the changes in endothelial function and renin-angiotensin system (RAS) in hyperuricemic animal model and gout patients.Methods.1) Data was collected by questionnaire regarding demographic feature, case history, character of arthritic calculus, lifestyle, precipitate factors, kidney store and other comorbidities in gout patients in PUMCH gout out-patient clinic of the general medicine department. A total of358gout patients were included in this study from Jan2008to Feb2012. Physical examinations and laboratory tests were performed and database was set up for further reference and analysis.2) The baseline data of33gout patients in PUMCH gout out-patient clinic and31patient of hyperuricemia for health examination were recorded, including demographic information, case history, comorbidities and current medications. We also performed physical examinations and tests, TNF-α and sICAM-1were tested by ELISA. Then after a28-week urate-lowering treatment, TNF-α and sICAM-1tests were repeated.3) Long term hyperuricemic animal model was developed by2%oxonic acid (OA) forage and100umol/L uric acid water plus OA lavage. eNOS, ICAM, ACE and Ang-II expression in blood vessel endothelium of hyperuricemic rats and gout patients were measured by immunohistochemistry to find evidences of vessel injury and RAS activation.Results.1) Among the358gout patients, there were350male (97.8%) and8females (2.2%), aged46+13, with an average course of disease of99months. Pattern is usually polyarticular, affecting78.4%of patients. Serum uric acid (sUA) level was586±123μmol/L. Arthritic calculus were found in77patients (21.5%), and Logistic regression showed the incidence of arthritic calculus was associated with sUA levels and longitude of disease history.256cases (71.5%) had comorbidities which was higher in patients with older-age (P<0.001). When divided into two groups, the younger group had a shorter course of disease than that of the older group (P<0.01), but had a higher sUA (P<0.05). Rank-sum test showed no statistical significance in the numbers of arthrosis between the two groups. There was a higher rate of comorbidities in the older group (P<0.01).2) Gout patient group had a higher level of diastolic blood pressure than the hyperuricemic group. sUA level, TNF-a and sICAM are higher in the former group with statistical significance. Age, BMI, systolic blood pressure, HDL-C, LDL-C, TC, TG, GFR, Cr and Glu were not statistically significant. Logistic regression showed independent relevance between gout and sICAM. A dosage of Antigut300mg per day and Febuxostat40mg and80mg per day could reduce sUA levels in gout patients, but the rapeutic effect of80mg was worse than the others which would have be influenced by disease course and sUA levels. Febuxostat should be given from a relatively lower dosage in Chinese population. After the exception of patients who experienced gout attack during the followups, there observed a reduction in TNF-a and sICAM.3) In hyperuricemic rats, ICAM expression was up regulated in kidney. There was decrease in ICAM level after antigut treatment but with no statistical significance. Ang-II expression were increased in both hyperuricemic rats and gout patients. Conclusions.1) Gout patients are more diversified and complicated in clinical features, who experience longer course of disease and more incidence of arthritic calculus. They are often polyarticular affected, atypical-joint affected cases are not rare, with more comorbidities and kidney injuries. Along with the increased incidence of gout attacks come the transformation of clinical characteristics of this disease. Earlier and more aggressive control of reversible risk factors such as obesity, excessive alcohol consumption, high purine diet and use of drugs may benefit more patients by reducing the possibility of refractory gout, joint mutilation and gout nephropathy, improving the quality of life and prognosis. In the recent years, the incidence of gout has been increasing in younger population, which calls for our special intention. Physicians should take notice of the symptoms of joints and companying clinical features, so as to be aware of controllable factors to provide effective management.2) Compared with asymptomatic hyperuricemic patients, gout patients have higher levels of TNF-α and sICAM, with only sUA level independently relevant to sICAM. Urate-lowering treatment may improve endothelial function and inflammation.3) There are indications of impairment on endothelial function of rat kidney and localized RAS activation. Uric acid can significantly stimulate the endothelial RAS activity in gout patients, one possible mechanism is the non-ACE passway.