正常成人每天尿蛋白排泄量平均为 80 mg/d，小于 150 mg/d 视为正常。白蛋白大约占健康人群每天尿蛋白排泄的 15%，其他血浆蛋白（例如免疫球蛋白、β2 微球蛋白）和 Tamm-Horsfall 蛋白占 85%。蛋白尿中蛋白含量各异，可为一过性或持续存在。[1]Viswanathan G, Upadhyay A. Assessment of proteinuria. Adv Chronic Kidney Dis. 2011 Jul;18(4):243-8.
http://www.ncbi.nlm.nih.gov/pubmed/21782130?tool=bestpractice.com
[2]Montañés Bermúdez R, Gràcia García S, Pérez Surribas D, et al. Consensus document. Recommendations on assessing proteinuria during the diagnosis and follow-up of chronic kidney disease. Nefrologia. 2011;31(3):331-45.
http://www.ncbi.nlm.nih.gov/pubmed/21780317?tool=bestpractice.com
尿蛋白量排泄异常持续≥3 个月，伴有或不伴有肾小球滤过率 (GFR) 下降，是慢性肾脏病的诊断依据。[3]Kidney Disease: Improving Global Outcomes. KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease. Jan 2013 [internet publication].
https://kdigo.org/guidelines/ckd-evaluation-and-management/
[4]Levey AS, de Jong PE, Coresh J, et al. The definition, classification, and prognosis of chronic kidney disease: a KDIGO Controversies Conference report. Kidney Int. 2011 Jul;80(1):17-28.
http://www.ncbi.nlm.nih.gov/pubmed/21150873?tool=bestpractice.com
尿白蛋白测量是筛查慢性肾脏病的重要部分。在一般人群和慢性肾脏病患者中，蛋白尿是心血管疾病、终末期肾病和死亡的一个独立危险因素。[5]Chronic Kidney Disease Prognosis Consortium; Matsushita K, van der Velde M, Astor BC, et al. Association of estimated glomerular filtration rate and albuminuria with all-cause and cardiovascular mortality in general population cohorts: a collaborative meta-analysis. Lancet. 2010 Jun 12;375(9731):2073-81.
http://www.ncbi.nlm.nih.gov/pubmed/20483451?tool=bestpractice.com
[6]Astor BC, Matsushita K, Gansevoort RT, et al. Lower estimated glomerular filtration rate and higher albuminuria are associated with mortality and end-stage renal disease. A collaborative meta-analysis of kidney disease population cohorts. Kidney Int. 2011 Jun;79(12):1331-40.
http://www.ncbi.nlm.nih.gov/pubmed/21289598?tool=bestpractice.com
[7]van der Velde M, Matsushita K, Coresh J, et al. Lower estimated glomerular filtration rate and higher albuminuria are associated with all-cause and cardiovascular mortality. A collaborative meta-analysis of high-risk population cohorts. Kidney Int. 2011 Jun;79(12):1341-52.
http://www.ncbi.nlm.nih.gov/pubmed/21307840?tool=bestpractice.com
[8]Gansevoort RT, Matsushita K, van der Velde M, et al. Lower estimated GFR and higher albuminuria are associated with adverse kidney outcomes. A collaborative meta-analysis of general and high-risk population cohorts. Kidney Int. 2011 Jul;80(1):93-104.
http://www.ncbi.nlm.nih.gov/pubmed/21289597?tool=bestpractice.com
[9]British Medical Journal. Low eGFR and high albuminuria predict end stage kidney disease and death at all ages. BMJ. 2012 Nov 7;345:e7478.
http://www.ncbi.nlm.nih.gov/pubmed/23135200?tool=bestpractice.com
危重症患者中蛋白尿与更高死亡率相关；[10]Han SS, Ahn SY, Ryu J, et al. Proteinuria and hematuria are associated with acute kidney injury and mortality in critically ill patients: a retrospective observational study. BMC Nephrol. 2014 Jun 18;15:93.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4072664/
http://www.ncbi.nlm.nih.gov/pubmed/24942179?tool=bestpractice.com
[11]Lin LY, Jenq CC, Liu CS, et al. Proteinuria can predict short-term prognosis in critically ill cirrhotic patients. J Clin Gastroenterol. 2014 Apr;48(4):377-82.
http://www.ncbi.nlm.nih.gov/pubmed/24440941?tool=bestpractice.com
肾脏移植后蛋白尿的严重程度对移植物和患者存活率具有预测价值。[12]Borrego J, Mazuecos A, Gentil MA, et al. Proteinuria as a predictive factor in the evolution of kidney transplantation. Transplant Proc. 2013;45(10):3627-9.
http://www.ncbi.nlm.nih.gov/pubmed/24314978?tool=bestpractice.com
药物治疗后蛋白尿的减少可用作针对慢性肾病和许多急性肾小球疾病管理的一项替代标志，且与肾脏结局的改善有关。[13]Lewis EJ, Hunsicker LG, Bain RP, et al. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. N Engl J Med. 1993 Nov 11;329(20):1456-62.
http://www.nejm.org/doi/full/10.1056/NEJM199311113292004#t=article
http://www.ncbi.nlm.nih.gov/pubmed/8413456?tool=bestpractice.com
[14]The GISEN Group. 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. Lancet. 1997 Jun 28;349(9069):1857-63.
http://www.ncbi.nlm.nih.gov/pubmed/9217756?tool=bestpractice.com
[15]Brenner BM, Cooper ME, de Zeeuw D, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med. 2001 Sep 20;345(12):861-9.
http://www.nejm.org/doi/full/10.1056/NEJMoa011161#t=article
http://www.ncbi.nlm.nih.gov/pubmed/11565518?tool=bestpractice.com
[16]Lewis EJ, Hunsicker LG, Clarke WR, et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med. 2001 Sep 20;345(12):851-60.
http://www.nejm.org/doi/full/10.1056/NEJMoa011303#t=article
http://www.ncbi.nlm.nih.gov/pubmed/11565517?tool=bestpractice.com
[17]Parving HH, Lehnert H, Bröchner-Mortensen J, et al; Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria Study Group. The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med. 2001 Sep 20;345(12):870-8.
http://www.nejm.org/doi/full/10.1056/NEJMoa011489#t=article
http://www.ncbi.nlm.nih.gov/pubmed/11565519?tool=bestpractice.com
[18]Wright JT Jr, Bakris G, Greene T, et al. Effect of blood pressure lowering and antihypertensive drug class on progression of hypertensive kidney disease: results from the AASK trial. JAMA. 2002 Nov 20;288(19):2421-31.
http://jama.ama-assn.org/cgi/content/full/288/19/2421
http://www.ncbi.nlm.nih.gov/pubmed/12435255?tool=bestpractice.com
[19]Inker LA, Levey AS, Pandya K, et al. Early change in proteinuria as a surrogate end point for kidney disease progression: an individual patient meta-analysis. Am J Kidney Dis. 2014 Jul;64(1):74-85.
http://www.ncbi.nlm.nih.gov/pubmed/24787763?tool=bestpractice.com
蛋白尿定义
可测量尿蛋白总量或尿白蛋白。尿白蛋白测量值在与慢性肾脏病进展和心血管事件风险的相关性方面得到了更好的验证。
白蛋白尿
白蛋白尿分级如下：[3]Kidney Disease: Improving Global Outcomes. KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease. Jan 2013 [internet publication].
https://kdigo.org/guidelines/ckd-evaluation-and-management/
A1（正常至轻度白蛋白尿）
A2（中度白蛋白尿）
A3（重度白蛋白尿）
肾病性蛋白尿
肾小球性蛋白尿
肾小管性蛋白尿
溢出性蛋白尿
尿液分析试纸是一种有用的蛋白尿半定量筛查工具。1+ 代表尿蛋白 30 mg/dL，2+ 代表 100 mg/dL，3+ 代表 300 mg/dL。过度稀释尿液可能得出假阴性结果。过度浓缩尿液、碱性尿液、脓液、阴道分泌物或精液都可能导致假阳性结果。[20]Carroll MF, Temte JL. Proteinuria in adults: a diagnostic approach. Am Fam Physician. 2000 Sep 15;62(6):1333-40.
https://www.aafp.org/afp/2000/0915/p1333.html
http://www.ncbi.nlm.nih.gov/pubmed/11011862?tool=bestpractice.com
将尿蛋白测量标准化为尿液中的肌酐量有助于避免稀释或浓缩尿液样本引入的误差。
流行病学
蛋白尿常见，且其发生率随着肾脏病的进展而增加。有证据表明，与白种人相比，黑种人出现尿白蛋白中度升高和重度升高的频率均更高。[21]Afkarian M, Zelnick LR, Hall YN, et al. Clinical manifestations of kidney disease among US adults with diabetes, 1988-2014. JAMA. 2016 Aug 9;316(6):602-10.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5444809/
http://www.ncbi.nlm.nih.gov/pubmed/27532915?tool=bestpractice.com
随着 GFR 从＞90 mL/(min·1.73 m²) 下降到 15-59 mL/(min·1.73 m²)，尿白蛋白中度升高（ACR＜300 mg/g）的患病率从 6.0% 升至 23.2%，尿白蛋白重度升高（ACR＞300 mg/g）的患病率从 0.6% 升至 8.6%。[22]Astor BC, Hallan SI, Miller ER 3rd, et al. Glomerular filtration rate, albuminuria, and risk of cardiovascular and all-cause mortality in the US population. Am J Epidemiol. 2008 May 15;167(10):1226-34.
http://aje.oxfordjournals.org/cgi/content/full/167/10/1226
http://www.ncbi.nlm.nih.gov/pubmed/18385206?tool=bestpractice.com
还有证据表明中度白蛋白尿发生率可随体重指数（body mass index, BMI）的增加而上升。英国谢菲尔德大学的一项人口筛查项目发现白蛋白尿发生率从 BMI<25 人群中的 3.1% 增加到 BMI>30 人群中的 27.2%。[23]Kawar B, Bello AK, El Nahas AM. High prevalence of microalbuminuria in the overweight and obese population: data from a UK population screening programme. Nephron Clin Pract. 2009;112(3):c205-12.
http://www.ncbi.nlm.nih.gov/pubmed/19451722?tool=bestpractice.com
检测：半定量检测
半定量尿液试纸条可报告处在微量白蛋白尿范围的白蛋白/肌酐比值和总蛋白/肌酐比值。
将尿蛋白检测以尿液肌酐含量进行标准化，有助于避免稀释或浓缩尿液样本造成的误差。
检测总蛋白含量使得还能够发现肾小管性和溢出性蛋白尿。据报告，这些半定量试纸的灵敏度是 80% 至 97%，特异度为 33% 至 80%。[24]Comper WD, Osicka TM. Detection of urinary albumin. Adv Chronic Kidney Dis. 2005 Apr;12(2):170-6.
http://www.ncbi.nlm.nih.gov/pubmed/15822052?tool=bestpractice.com
检测：定量检测
采用尿白蛋白浓度或尿白蛋白/肌酐比值的白蛋白定量检测，对识别白蛋白尿具有敏感性和特异性。[25]McTaggart MP, Newall RG, Hirst JA, et al. Diagnostic accuracy of point-of-care tests for detecting albuminuria: a systematic review and meta-analysis. Ann Intern Med. 2014 Apr 15;160(8):550-7.
http://www.ncbi.nlm.nih.gov/pubmed/24733196?tool=bestpractice.com
[26]Wu HY, Peng YS, Chiang CK, et al. Diagnostic performance of random urine samples using albumin concentration vs ratio of albumin to creatinine for microalbuminuria screening in patients with diabetes mellitus: a systematic review and meta-analysis. JAMA Intern Med. 2014 Jul;174(7):1108-15.
http://www.ncbi.nlm.nih.gov/pubmed/24798807?tool=bestpractice.com
检测尿白蛋白浓度而不检测尿肌酐浓度的花费更少，对于糖尿病患者，作为一种筛查方法，与白蛋白肌酐比值具有类似的敏感性和特异性。[26]Wu HY, Peng YS, Chiang CK, et al. Diagnostic performance of random urine samples using albumin concentration vs ratio of albumin to creatinine for microalbuminuria screening in patients with diabetes mellitus: a systematic review and meta-analysis. JAMA Intern Med. 2014 Jul;174(7):1108-15.
http://www.ncbi.nlm.nih.gov/pubmed/24798807?tool=bestpractice.com
以往曾使用 24 小时尿液收集法，但这种方法易出现收集量过多或过少的偏差。此外，收集 24 小时尿液对患者而言比较麻烦。报告以 24 小时尿液肌酐进行标准化的 24 小时尿蛋白（g 蛋白/g 肌酐）有助于校正收集过程中产生的偏差。
女性尿肌酐正常范围为 15-20 mg/kg，男性为 20-25 mg/kg
或者尿肌酐排泄量的估值（g）=（140-年龄）×体重（kg）/5000。对于女性，计算结果需乘以 0.85。[27]Ginsberg JM, Chang BS, Matarese RA, et al. Use of single voided urine samples to estimate quantitative proteinuria. N Engl J Med. 1983 Dec 22;309(25):1543-6.
http://www.ncbi.nlm.nih.gov/pubmed/6656849?tool=bestpractice.com
更常见的情况是，使用随机尿的尿蛋白/肌酐比值或尿白蛋白/肌酐比值来分别估计 24 小时尿蛋白排泄量和 24 小时尿白蛋白排泄量。[28]Valdés E, Sepúlveda-Martínez Á, Tong A, et al. Assessment of protein:creatinine ratio versus 24-hour urine protein in the diagnosis of preeclampsia. Gynecol Obstet Invest. 2016;81(1):78-83.
http://www.ncbi.nlm.nih.gov/pubmed/26045043?tool=bestpractice.com
在检测低水平蛋白尿时，白蛋白肌酐比值比蛋白肌酐比值更为敏感。[29]National Institute for Health and Care Excellence. Chronic kidney disease in adults: assessment and management. Jan 2015 [internet publication].
https://www.nice.org.uk/guidance/cg182/
晨尿标本可以更准确的评估 24 小时尿蛋白排泌量，无法采集晨尿时，可采用随机尿标本。[3]Kidney Disease: Improving Global Outcomes. KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease. Jan 2013 [internet publication].
https://kdigo.org/guidelines/ckd-evaluation-and-management/
[27]Ginsberg JM, Chang BS, Matarese RA, et al. Use of single voided urine samples to estimate quantitative proteinuria. N Engl J Med. 1983 Dec 22;309(25):1543-6.
http://www.ncbi.nlm.nih.gov/pubmed/6656849?tool=bestpractice.com
[30]Johnson DW, Jones GR, Mathew TH, et al. Chronic kidney disease and measurement of albuminuria or proteinuria: a position statement. Med J Aust. 2012 Aug 20;197(4):224-5.
https://www.mja.com.au/journal/2012/197/4/chronic-kidney-disease-and-measurement-albuminuria-or-proteinuria-position
http://www.ncbi.nlm.nih.gov/pubmed/22900872?tool=bestpractice.com
由于昼夜变化，如果是用于长期随访患者，最好每天在同一时间采集随机尿样。此外，随机尿样与 24 小时蛋白排泄量的相关性的稳健度不及与肾病范围蛋白尿的相关性。尿蛋白＞300 mg 的孕妇的随机尿样尿蛋白肌酐比值更加缺乏准确性。[31]Papanna R, Mann LK, Kouides RW, et al. Protein/creatinine ratio in preeclampsia: a systematic review. Obstet Gynecol. 2008 Jul;112(1):135-44.
http://www.ncbi.nlm.nih.gov/pubmed/18591319?tool=bestpractice.com
[32]Côté AM, Brown MA, Lam E, et al. Diagnostic accuracy of urinary spot protein:creatinine ratio for proteinuria in hypertensive pregnant women: systematic review. BMJ. 2008 May 3;336(7651):1003-6.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2364863
http://www.ncbi.nlm.nih.gov/pubmed/18403498?tool=bestpractice.com
每 1.73 m² 体表面积的肌酐排泄量大致是 1 g。因此，一个体型适中的人如果尿蛋白肌酐比值为 1 g 尿蛋白/g 肌酐，近似于 24 小时排泄了 1 g 尿蛋白。认识到这一点很重要：一个身体强壮的人，在 24 小时中排泄2 g 肌酐，那么如果其尿蛋白肌酐比值为 2.5 g 尿蛋白/g 肌酐，实际上说明蛋白排泄量为 5 g/d，这已在肾病范畴。同样，一名老年且身体虚弱的女性可能每天排泄＜1 g 肌酐，在这种情况下，随机尿样的尿蛋白肌酐比值将高估其蛋白尿状况。
白蛋白尿对慢性肾病预后的影响
白蛋白尿是慢性肾病进展的一项独立危险因素。[33]McFarlane P, Cherney D, Gilbert RE, et al. Diabetes Canada 2018 clinical practice guidelines for the prevention and management of diabetes in Canada: chronic kidney disease in diabetes. Can J Diabetes 2018;42(Suppl 1):S201-S209.
http://guidelines.diabetes.ca/cpg/chapter29
与轻度 GFR 下降伴正常白蛋白尿相比，正常 GFR 伴大量蛋白尿时，出现慢性肾病进展的风险更高。 
[Figure caption and citation for the preceding image starts]: 依据 GFR 和蛋白尿分类的 CKD 预后：CKD，慢性肾病；GFR，肾小球滤过率；KDIGO，改善全球肾病预后组织获得麦克米伦出版公司重印许可：Kidney International Supplements (vol 3, issue 1, January 2013), copyright 2013 [Citation ends].
对于晚期 CKD 患者，蛋白尿是终末期肾病的最强预测指标。[34]Raman M, Green D, Middleton RJ, et al. Older people with chronic kidney disease: definition, and influence of biomarkers and medications upon cardiovascular and renal outcomes. J Ren Care. 2016 Sep;42(3):150-61.
http://www.ncbi.nlm.nih.gov/pubmed/27364740?tool=bestpractice.com
[35]Grams ME, Li L, Greene TH, et al. Estimating time to ESRD using kidney failure risk equations: results from the African American Study of Kidney Disease and Hypertension (AASK). Am J Kidney Dis. 2015 Mar;65(3):394-402.
http://www.ncbi.nlm.nih.gov/pubmed/25441435?tool=bestpractice.com
