| Background Chronic kidney disease (CKD), hypertension, diabetes and cardiovascular disease (KHDC) were the most important chronic noninfectious diseases not only in the developed countries but also in developing countries. Many of the patients developed into end stage renal disease (ESRD) which needs dialysis or kidney transplantation, and become the unbearable medical burden of the governments and individuals. In the west countries, hypertension and diabetes have become the main causes of ESRD. Under the deteriorating circumstance, the International Society of Nephrology (ISN) proposed the KHDC program for early detecting and managing these diseases, particularly in developing countries. The presented studies were parts of the KHDC program in Guilin, and serum uric acid (SUA) level which was not in the original program was added into the KHDC program as we thought it should be a much important and necessary item of our studies. Our hypothesis was that hyperuricemia (HUA) should be not only a marker of kidney dysfunction, but also a pathogenic factor of CKD, hypertension and cardiovascular diseases, as previous studies have found that HUA might result in oxidative stress, inflammatory reaction, arteriosclerosis and renal damage, and was associated with CKD, hypertension and metabolic diseases, and that HUA might play a key role in the development of these diseases. As the changed lifestyle of ordinary people during the years, the prevalence of hyperuricemia has been increasing, and the pathogenic role of HUA in CKD, metabolic syndrome, cardiovascular and cerebrovascular diseases become more and more interested in the academic circles. Our studies were supported by ISN GO R&P project and the fund of Guangxi province, China. The aim was to obtain the epidemic data of HUA and related diseases, such as CKD, hypertension, diabetes and cardiovascular diseases in the community residents, renal transplant recipients and ESRD patients on hemodialysis, and to explore the relationship of the diseases, and to provide scientific evidence to strengthen the prevention and treatment of HUA and related diseases.Objective1. To investigate the prevalence of HUA and associated risk factors in the community residents;2. To study the relationship between HUA and CKD, hypertension, diabetes, cardiovascular disease and metabolic syndrome, and analyze the latent pathogenic role of HUA in the development of these mentioned diseases;3. To investigate the prevalence of HUA in the renal transplant recipients and associated risk factors;4. To investigate the prevalence of HUA in ESRD patients on hemodialysis and the clearance rate of SUA through dialysis;5. To explore the best measures reducing the prevalence of hyperuricemia in either kidney transplant recipients or ordinary people;6. A database was founded and prepared for further prospective follow-up.Methods1. Community-based epidemic studyBy means of community-based cross-section epidemiological investigation, a total of 7733 community residents, aged 18-75 years, were included in the KHDC screening program. There were 7047 residents with effective data,3130 of them were male with a mean age of 43.79±14.81 years, and 3917 of them were female with a mean age of 44.86±14.12 years. Fasting venous blood and urina sanguinis samples were collected to evaluate blood glucose (FBG), blood lipid, uric acid and serum creatinine (SCr), serum uric acid, insulin, hypersensitive C-reaction protein (hsCRP), urine routine, urine creatinine and urine microalbumin. All the samples were tested by fixed technician in one laboratory center. Urine albumin/creatinine ratio (ACR), eGFR and HOMA-IR were calculated. eGFR is estimated GFR calculated by the abbreviated MDRD equation:eGFR=186×(SCr/88.4)-1.154×(Age)-0.203×(0.742 if female), and HOMA-IR= fasting blood glucose (mmol/L)×fasting insulin (mU/L)/22.5. Renal function, blood glucose and blood lipid were tested with automatic biochemical analyzer (Olympus AU 400), and the reagents were bought from Shanghai Kehua Biotech Co. urine microalbumin and hsCRP were tested with Fixed-Time Nephelometric Assay (Nephstar protein analysis system), and the reagents were bought from Guosai Biotech Co. Insulin was tested with chemiluminescence (ABBOTT AXSYM SYSMEX), and the reagents were bought from Abbott Laboratories Co. The questionnaire including age, sex, eating habit, status of education and works, family medical history, history of past and present illness such as kidney diseases, hypertension, diabetes and cardiovascular diseases, etc., was filled in under the guidance of the trained investigators. Physical examinations including blood pressure (BP), height, weight, waist circumference and hip circumference, were performed by medical staffs trained for the project. The data was input the appointed EpiData by special investigator.2. HUA in renal transplant recipientsIn the retrospective study,216 cases of renal transplant recipients (RTRs),146 males (67.6%) with a mean age of (40.98±11.09) years and 70 females (32.4%) with a mean age of (40.01±11.62) years, received renal allografts in our transplant center from January 2003 to December 2005 and had recovered normal allograft function. The patients with a primary disease of either diabetes or hyperuricemia were excluded. The immunosuppressive protocol was Cyclosporin + Mizoribine + Prednisone. In order to evaluate the influence of SUA increased before or after renal transplantation on long term graft function, all 216 recipients were divided into four groups:group A with normal pre- and post-transplant SUA levels, group B with pre-transplant HUA but normal post-transplant SUA levels, group C with normal pre-transplant SUA levels but post-transplant HUA, and group D with both pre- and post-transplant HUA. In order to compare the influences of post-transplant SUA levels increased to different degrees on long term graft function, all the recipients were divided into three groups. The furrow-up duration was three years and the influence of pre- or post-transplantation hyperuricemia on the long term allograft function was investigated.3. HUA in ESRD patients on hemodialysisIn the clinical observation,200 ESRD patients (128 males and 72 females) with a mean age of 43.87±13.39 years, consecutively entered into maintenance hemodialysis in our blood purification center and received investigation of pre- and post-dialysis blood levels of uric acid, creatinine and cystatin C, for studying the prevalence of HUA and the state of uric acid clearance by hemodialysis and influencing factors. The patients were divided into three groups according to their age and divided into four groups according their status of dialysis:dialysis dosage of 12 hours per week, dialysis dosage of 8-10 hours per week, dialysis dosage less than 8 hours per week, and just at the beginning of dialysis. The patients were treated with single use dialyzer with 1.5m2 of membrane surface area. Another 27 new start dialysis patients taking large dose of diuretic to elevate urine volume were also studied for investigating the influence of diuretics on the serum level of uric acid.4. Diagnostic criteriaThe diagnostic criteria of CKD was according to KDIGO guideline (revised edition 2004); the diagnostic criteria of hypertension was according to The Guidelines for Prevention and Treatment of Hypertension in China (revised edition 2005); the diagnostic criteria of diabetes was according to the diagnostic criteria of The American Diabetes Association (ADA) (2003) and the patients with diabetes were divided into three groups:normal fasting blood glucose, impaired fasting glucose and diabetes according the level of fasting blood glucose and treatment history of diabetes; the diagnostic criteria of metabolic syndrome was according to the criteria of International Diabetic Federation (IDF) (2005); the diagnostic criteria of dyslipidemia was according to the Guidelines on Prevention and Treatment of Blood Lipid Abnormality in Chinese Adults (revised edition 2007). Hyperuricemia was diagnosed when serum uric acid (SUA) was more than 420μmol/L in males and 360μmol/L in females and patients with HUA were divided into groups according the serum level of uric acid.5. Statistic analysisStatistic analysis was performed with SPSS software, version 13.0. One-Way ANOVA was used for groups'measurement data and chi square test was used for the comparison of numeration data. Non-parameter test (Kruskal-Wallis) was used for the comparison of ranked data. Partial Correlation test was used for study the relationship of data in different groups. Binary logistic regression test was used in risk factor analysis. P value of<0.05 was considered statistically significant.Results1. Community-based epidemic studyThe main basic data of participators:44.4% of them were males and 55.6% of them were females; 23.6% of them were smoker; 35.6% of them drink alcohol more than once a month. The prevalence of CKD was 12.6% in all residents (15.0% in the males and 10.8% in the females, P<0.01). The prevalence of hypertension was 22.0% in all residents (24.9% in the males and 19.6% in the females, P<0.01). The prevalence of diabetes was 6.6% in all residents (7.0% in the males and 6.3% in the females, P>0.05). The prevalence of metabolic syndrome was 19.1%. The prevalence of dyslipidemia was 52.7%. The prevalence of insulin resistance was 5.0%.The prevalence of HUA was 24.1% in the community residents, and was 32.8% in the males which was significantly higher than that in the females (16.8%), P<0.01. The risk of HUA in the males was 2.43 times of that in the female. The mean level of serum uric acid in the community residents was 340.1μmol/L (95%CI: 337.1～343.1μmol/L). In the residents under 30 years old, the prevalences of HUA were 31.4% and 11.3% in the male and the females respectively, P<0.01. In the residents aged 30 to 59 years, the prevalences of HUA were 33.3% and 15.0% in the male and the females respectively, P<0.01. In the residents above 60 years old, the prevalences of HUA were 32.2% and 33.2% in the male and the females respectively, P>0.05.The factors influencing the level of serum uric acid:In the community residents, serum level of uric acid was positively correlated to body weight (or BMI), waist circumference and age of females after adjusted with serum creatinine, P<0.01. The highest prevalences of HUA were 33.6% and 41% in the residents without any education and without work respectively, and their mean SUA level were 400.22±99.87μmol/L and 418.92±107.61μmol/L respectively in the males and were 330.76±78.56μmol/L and 312.2±76.30μmol/L respectively in the females. Alcohol consumption and smoking also influenced the SUA level. The mean SUA level in the residents who often drink alcohol and the former smoker was 410.99±111.75μmol/L and 408.50±111.89μmol/L respectively, and they had the highest prevalence of HUA, 48.5% and 41.0% respectively. The prevalence of HUA in the residents drinking once a month or not was 21%.HUA in the related comorbidities:In the residents with CKD and hypertension, the prevalence of HUA was 26.4% and 35.3% respectively, and the mean level of SUA was 354.71±103.59μmol/L and 356.08±93.89μmol/L respectively. The prevalence of CKD in the residents with and without HUA was 30.4% and 18.9% respectively, P<0.01. The risk for CKD in residents with HUA was 1.87 times of that in residents without HUA,1.94 times of that in the males and 1.67 times of that in the females. In the residents with HUA, risk for CKD in the males was 1.50 times of that in the females. Compared with residents without HUA, the prevalence of hypertension was 1.8 times in all of the HUA residents,3.3 times in those HUA residents under 30 years,2.1 times in those HUA residents aged 30 to 60 years. While in those above 60 years there was no significant difference between HUA residents and non-HUA residents. The prevalence of hypertension was high in the residents with uric acid levels in the 3rd and 4th quartile, reaching 35.0% and 50.7% respectively. It is shown in logistic analysis that HUA was an independence risk factor of hypertension. The prevalence of either MS or the compositions in the residents with HUA was significantly higher than those without HUA, P<0.01, and OR was about 1.6～2.6. The prevalence of HUA was not significantly different between the residents with and without diabetes (25.6% and 24.2% respectively). In the analysis of the relationship between SUA and blood lipid, it is shown that the severity of hyperuricemia was associated with the severity of dyslipidemia, the elevation of serum insulin and hs-CRP when comparing between groups. The decrease of eGFR was associated with the degree of dyslipidemia in some extent, but did not associate with the elevation of serum insulin and hs-CRP levels. It is indicated by correlation analysis that SUA level was positively correlative with the levels of TG, serum insulin and hs-CRP, r=0.211, 0.042 and 0.046 respectively, P<0.05.2. HUA in renal transplant recipientsHyperuricemia existed in 39.8% of the patients (30.8% of the male RTRs and 58.6% of the females RTRs) before transplantation, while existed in 38.0% of the RTRs (26.7% of the male RTRs and 61.4% of the females RTRs) at the first month post-transplantation when they had normal SCr level. In female RTRs, the prevalence of post-transplant hyperuricemia was significantly higher than male RTRs, P<0.05; and was no significant difference when compared with the prevalence pre-transplantation. The average post-transplantation SUA level in the male RTRs were higher than females, P<0.01. The average post-transplantation SUA level in the male and female RTRs (405.80±94.10μmol/L and 377.84±89.21μmol/L respectively) was significantly higher than the level of pre-transplantation (329.10±167.67μmol/L and 361.40±146.58μmol/L respectively), all of P<0.01. At the end of three years follow-up, the eGFR level in RTRs with pre-transplantation hyperuricemia was not significantly different from that in RTRs with normal pre-transplantation SUS level, while the eGFR level in RTRs with post-transplantation hyperuricemia was significantly lower than that in RTRs with normal post-transplantation SUA level. The mean eGFR level in the patients with normal level of post-transplantation SUA, slightly post-transplantation hyperuricemia and serious post-transplantation hyperuricemia were 46.71±21.13ml/min,30.36±11.51 ml/min and 16.46±6.25 ml/min respectively, P<0.01.3. HUA in ESRD patients on hemodialysis In the patients on hemodialysis, the mean level of blood uric acid before dialysis was 501.27±157.95μmol/L in all patients,527.16±169.74μmol/L in males and 455.24±122.61μmol/L in females respectively, p<0.01. The prevalence of hyperuricemia before dialysis was 72.0% in all patients,72.7% in males and 70.8% in females respectively, P>0.05. After dialysis, the mean SUA level in the males (231.54±95.25μmol/L) was still higher than that in the females (187.29±73.03μmol/L), P<0.01. The prevalence of hyperuricemia after dialysis either in males or females was lower (only 7.0% and 2.2% respectively), and there was no significant difference between the males and females, P>0.05. Both the pre-and post-dialysis mean levels of SUA and the prevalence of hyperuricemia in sufficient dialysis patients were lower than non-sufficient dialysis patients, P<0.01. In the patients taking a large dosage of diuretics, the urine volume increased, blood pressure and ultrafiltration volume per session decreased, and the mean level of SUA was 379.4±117.6μmol/L which was not significantly different from that in patients taking no diuretics (403.4±122.4μmol/L). In a single dialysis session, the clearance rate of SUA,56.11±14.66%, was significantly higher than the clearance rates of creatinine and cystatin C,49.79±11.32%,49.82±13.68% and 27.89±14.71%, respectively, P<0.001.Conclusions1. It is indicated in our data that the prevalence of hyperuricemia is increasing in the residents of the inland city of China, and the different of prevalences between genders are in the residents of middle and young age. The prevalence of HUA is associated with education, work, smoking and alcohol consumption. It is suggested that the best prevention measure might be to loss weight, control obesity, avoid smoking and restrict alcohol consumption. It is shown in the study that hyperuricemia was closely associated with hypertension, CKD and dyslipidemia, and that the increasing of hyperuricemia also related to IR. Therefore it is suggested that hyperuricemia may be the risk factor of metabolic syndrome. It is indicated in our data that the prevalence of hypertension was high in the residents with hyperuricemia, especially in the younger people, and that hyperuricemia was of mainly influence on systolic blood pressure. It is also indicated that the prevalence of CKD was also increased in the residents with hyperuricemia, even in those only with slightly elevated SUA level. While it is shown in our data that the association between hyperuricemia and diabetes was not significant.2. It is indicated in our data that HUA was still common in post-transplantation recipients, especially in female RTRs, even in the RTRs with normal graft function. It is suggested that post-transplantation hyperuricemia, but not pre-transplantation hyperuricemia, could act as a factor inducing chronic renal allograft dysfunction.3. It is indicated in our data that the blood level of uric acid and the prevalence of hyperuricemia in the patients on maintenance hemodialysis were very high, and there was a good clearance rate of uric acid for hemodialysis. It is shown that dialysis adequacy influenced the post-dialysis level of blood uric acid and the prevalence of hyperuricemia, and the post-dialysis blood level of uric acid and the prevalence of hyperuricemia were lower than general population. It is also shown that diuretics administered by patients on maintenance hemodialysis did not influence the blood level of uric acid.
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