高尿酸血症與蛋白尿相關性的探討

Hyperuricemia and Proteinuria : A Population-based Prospective Study

蔡詩力(Shih-Li Tsai)

指導教授 ： 李龍騰

共同指導教授 ： 陳秀熙(Hsiu-Hsi Chen)

國立臺灣大學/公共衛生學院/預防醫學研究所/碩士(2005年)

https://doi.org/10.6342/NTU.2005.02101

摘要

背景
高尿酸血症有許多後遺症，如腎臟病、代謝症候群、高血壓、第二型糖尿病及心血管疾病等。其中，高血壓、第二型糖尿病與心血管疾病更是導致末期腎臟病的主因。由於蛋白尿是末期腎臟病早期的徵候，因此，釐清高尿酸血症與蛋白尿之間的關係，對於預防末期腎臟病而言，是相當重要的。不過，目前的文獻對於高尿酸血症與蛋白尿之間是否有因果關係，仍有爭議。本研究利用前瞻性的追蹤世代研究來推估蛋白尿的盛行率以及發生率，並釐清高尿酸血症與蛋白尿之間的因果關係。

方法
本世代追蹤研究乃針對基隆市民於民國九十年至九十三年間，計59,840位自願參與合家歡複合式篩檢的民眾，進行問卷調查、身體測量、血液生化數值檢查及尿液測試。其中，若首次即有蛋白尿的個案即逕行轉介，不再追蹤；而新發生蛋白尿的個案則會繼續追蹤後續狀況直到九十三年底。本研究中，蛋白尿為應變項，我們利用盛行率與發生率的比值來推估發生蛋白尿與嚴重蛋白尿(尿液試紙三價以上)所需的時間。並以時變性的帕松迴歸模式來推估各種變項對結果的影響。

結果
本研究所得之蛋白尿盛行率男性為11.8%，女性為12.3%，並且隨年齡增長而升高。再以盛行率與發生率的比值來推估發生蛋白尿所需的時間為3.9年(男3.5年、女4.4年)；再推估發生嚴重蛋白尿所需的時間為3.4年(男3.0年、女3.3年)。嚴重蛋白尿的一年、兩年、三年的累積發生率為0.4%、1.4%、3.0%；中度蛋白尿則是0.4%、1.4%、3.0%；輕度蛋白尿則是2.1%, 9.4%, 與15.6%。
本研究同時發現：在多變項分析中，若是血中尿酸值高過9 mg/dL時，與正常尿酸值者相比較：由正常尿液測試到發生輕度蛋白尿的相對危險性為1.43倍(95%信賴區間為1.03-1.98)；由正常、輕度或中度蛋白尿進展到嚴重蛋白尿的相對危險性為2.41倍(95%信賴區間為1.46-4.00)；由中度蛋白尿進展到嚴重蛋白尿的相對危險性為4.58倍(95%信賴區間為2.47-8.47)；由輕度或中度蛋白尿進展到嚴重蛋白尿的相對危險性為4.02倍(95%信賴區間為2.32-6.95)。另由回復的角度來看，由輕度蛋白尿回復至正常的尿液測試的相對危險性為0.87倍(95%信賴區間為0.79- 0.96)，呈現有意義的負相關。中等程度的高尿酸血症(男性：7-9 mg/dL, 女性：6-9 mg/dL)，與正常尿酸值者相比較：由中度蛋白尿進展到嚴重蛋白尿的相對危險性為2.78倍(95%信賴區間為1.69-4.56)；由輕度或中度蛋白尿進展到嚴重蛋白尿的相對危險性為2.42倍(95%信賴區間為1. 59-3.67)。與正常範圍的尿酸值比較，不論是尿酸值高過9 mg/dL，或是中等程度的高尿酸血症(男性：7-9 mg/dL, 女性：6-9 mg/dL)，都使得蛋白尿較不易回復正常。
若以腎小球過濾速率估算值來看高尿酸血症的影響時，在多變項分析中，與正常尿酸值者相比較，血中尿酸值高過9 mg/dL與中等程度的高尿酸血症(男性：7-9 mg/dL, 女性：6-9 mg/dL)，各別有1.55倍(95%信賴區間為1.18-2.04)與1.32倍(95%信賴區間為1.14-2.51)的相對危險性會發生腎小球過濾速率估算值異常。另由回復的角度來看，與正常尿酸值者相比較，尿酸值高過9 mg/dL與中等程度的高尿酸血症(男性：7-9 mg/dL, 女性：6-9 mg/dL)，腎小球過濾速率估算值異常回復至正常的相對危險性分別為0.63倍(95%信賴區間為0.53- 0.76)與0.79倍(95%信賴區間為0.71- 0.88)，呈現有意義的負相關。若是以血清肌酸酐值的異常來觀察時，也有類似的發現。
當我們以時間應變模式來探討時，多變項分析可以發現類似的結果：尿酸值愈高者愈容易由正常發生重度蛋白尿，也愈不易回復正常；但在中度變重度或輕度變重度蛋白尿者，尿酸血症則是不顯著影響的變項。但是，一旦進展到了重度蛋白尿，回復與否便和血清尿酸值無關了。另以時間應變模式來看血清肌酸酐值以及腎小球過濾速率估算值與高尿酸血症之間的相關時，高尿酸血症是與腎功能減退的有意義的因子，同時也使得減損的腎功能較不易回復。

結論
本研究藉由蛋白尿的測量、血清肌酸酐值以及腎小球過濾速率估算值的探討，證實了血清尿酸值與腎功能不全的因果關係。這樣的研究結果告訴我們，控制血中尿酸值對預防腎功能減退與腎臟傷害是重要且必要的。

關鍵字

高尿酸血症 ； 蛋白尿

並列摘要

Background
The sequale of hyperuricemia involve renal disease, metabolic syndrome (MS), hypertension, Type II diabetes, and cardiovascular disease, while the latter three were well documented as the major causes of end stage renal disease (ESRD). Owing to this, the linkage between hyperuricemia and early sign of ESRD like proteinuria is of paramount importance to prevent ESRD. However, the causal relationship between hyperuricemia and proteinuria still remains controversial. This thesis aimed to use a longitudinal cohort to (1) estimate prevalence and incidence rate or cumulative incidence of proteinuria; and to (2) elucidate the causal relationship between hyperuricemia and proteinuria, serum creatinine or glomerular filtration rate after adjusting other significant correlates.

Materials and Methods
A total of 59,840 participants in the prospective cohort attending the Keelung Community-based Integrated Screening (KCIS) program were included. Subjects with proteinuria, abnormal serum creatinine or abnormal glomerular filtration rate at the entry of the KCIS program were excluded. Newly diagnosed proteinuria were ascertained in successive years of screening regime until the end of 2004 and treated as dependent variables. The longitudinal data on anthropometry measures, blood pressure measures, biochemical markers, dipstick spot urine analyses, and lifestyle factors were also collected at each visit. The concept of P/I ratio was applied to approximate the mean duration of proteinuria/severe proteinuria. Time-dependent Poisson regression models were conducted to estimate the effect of covariates (time-varying) on developing of event of interests.

Results
The prevalence rates of proteinuria was 11.8% and 12.3% for male and female (p<.0001), respectively. Both increased with advancing age. By the application of the concept of P/I ratio, the average duration of staying in proteinuria was 3.9 years (P: 12.1%; I: 3.1%) (3.5 years for male and 4.4 years for female). The corresponding figures for severe proteinuria were 3.4 years (P: 3.1%; I: 0.8% ) (3.0 years for male and 3.3 years for female). One-year, two-year, and three-year cumulative rates were 0.4%, 1.4%, and 3.0% for severe proteinuria. The corresponding figures 0.9%, 3.5%, and 7.6% for moderate proteinuria and 2.1%, 9.4%, and 15.6% for mild proteinuria.
High level of serum uric acid (SUA>9) was associated with progression from normal to mild proteinuria (RR=1.43, 95% CI: 1.03-1.98), from normal, mild, and moderate to severe proteinuria (RR=2.41, 95% CI: 1.46-4.00), from moderate to severe proteinuria (RR=4.58, 95% CI: 2.47-8.47), and from mild and moderate to severe proteinuria (RR=4.02, 2.32-6.95). It was also associated with the regression from mild to normal proteinuria (RR=0.87, 95% CI: 0.79-0.96) compared to those with normal SUA after controlling for other significant clinical correlates. Moderate level of SUA (7-9 for male, and 6-9 for female) was a risk factor of progression from moderate to severe proteinuria (RR=2.78, 95% CI: 1.69-4.56), and from mild and moderate to severe proteinuria (RR=2.42, 1.59-3.67). The moderate level of SUA also played a role of a hindering factor from regression (RR=0.90, 95% CI: 0.81-0.99).
When considering the disease progress of abnormal GFR, high level of serum uric acid (RR=1.55, 95% CI: 1.18-2.04) and moderate level (RR=1.32, 95% CI: 1.14-1.51) were significant risk factors compared to those with normal SUA after controlling for other significant clinical correlates. Both were significant preventive factors for regression with relative risks of 0.63 (95% CI: 0.53-0.76) and 0.79 (95% CI: 0.71-0.88) for high and moderate levels of SUA, respectively. The similar results were observed when considering the abnormal level of S-Cr.
Regarding the time-dependent models, serum uric acid was still positively associated with progression of proteinuria and inversely associated with regression of proteinuria. After controlling for other significant risk factors, similar findings were noted for the progression to severe proteinuria. For progression from mild to severe proteinuria or from moderate to severe, SUA was not important. Again, once the progression to severe proteinuria, the change of SUA was not associated with the regression of severe proteinuria. By using GFR and S-Cr, the results of time-dependent Poisson regression model revealed SUA was positively associated with decreased kidney function and increasingly associated with regression.

Conclusion
The causal relationship between serum uric acid and kidney dysfunction measured by proteinuria, elevated serum creatinine and decreased estimated GFR was substantiated in this study. These findings imply lifestyle modification of serum uric acid for the prevention of kidney dysfunction or decreased kidney function is imperative.

並列關鍵字

Hyperuricemia ； Proteinuria

參考文獻

1997. Randomised placebo-controlled trial of effect of ramipril on decline in glomerular filtration rate and risk of terminal renal failure in proteinuric, non-diabetic nephropathy. The GISEN Group (Gruppo Italiano di Studi Epidemiologici in Nefrologia). Lancet 349, 1857-1863.

2002. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am. J. Kidney Dis. 39, S1-266.

Davidson,M.B. & Smiley,J.F. 1999. Relationship between dipstick positive proteinuria and albumin:creatinine ratios. J. Diabetes Complications 13, 52-55.

Domrongkitchaiporn,S., Sritara,P., Kitiyakara,C., Stitchantrakul,W., Krittaphol,V., Lolekha,P., Cheepudomwit,S. & Yipintsoi,T. 2005. Risk factors for development of decreased kidney function in a southeast Asian population: a 12-year cohort study. J. Am. Soc. Nephrol. 16, 791-799.

Ginsberg,J.M., Chang,B.S., Matarese,R.A. & Garella,S. 1983. Use of single voided urine samples to estimate quantitative proteinuria. N. Engl. J. Med. 309, 1543-1546.