Abstract
Background: There is debate as to whether using the urinary albumin- or protein-to-creatinine ratio (ACR or PCR) should be the primary test for proteinuria. Whilst albuminuria (increased ACR) in the absence of proteinuria (increased PCR) may be expected in some patients, the converse (i.e., proteinuria in the absence of albuminuria) is more unusual and its cause and significance are unclear. We investigated the nature of such apparent non-albuminuric proteinuria in a primary care population of patients.
Methods: ACR and PCR were measured in 569 urine samples from patients who either had chronic kidney disease or were at increased risk of the condition. Samples with apparent proteinuria (PCR ≥23 mg/mmol/≥200 mg/g) but no albuminuria (ACR <3.4 mg/mmol/<30 mg/g) were classified as ‘discrepant’ (37% of proteinuric samples, 6% of all samples); 27 of these samples were available for further analyses. The further analyses included electrophoresis, repeat measurement, immunoassays for markers of tubular proteinuria and use of alternative albumin and total protein methods.
Results: Electrophoresis did not identify significant proteinuria in the discrepant samples. The only evidence of tubular proteinuria following measurement of three urinary markers of the condition was a mildly increased α1-microglobulin-to-creatinine ratio in 10 of the 27 discrepant samples analysed, four of which also had a raised β-trace protein-to-creatinine ratio. Use of an alternative urinary total protein method resulted in significantly lower PCRs and 17 of the 27 samples were no longer classified as proteinuric.
Conclusions: We were unable to confirm the cause of a raised PCR without albuminuria in these patients and suspect that in most cases it is artefactual.
We thank Mrs Catherine Spurgeon (Siemens Medical Solutions Diagnostics) for organising the provision of reagents for the study. We are also grateful to Mr Philip Blake (Willesborough Health Centre, Ashford, Kent, UK), Mrs Sheila Quinney (North Street Surgery, Ashford, Kent, UK) and Miss Paula Jones (Whitstable Health Centre, Whitstable, Kent, UK) for helping to coordinate the study. Additionally, we are thankful to the clinicians and practice nurses who recruited patients, as well as the biomedical scientists at the William Harvey Hospital (Ashford, Kent, UK) for performing the initial laboratory analyses.
Conflict of interest statement
Authors’ conflict of interest disclosure: The authors stated that there are no conflicts of interest regarding the publication of this article. Research funding played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.
Research funding: Siemens Medical Solutions Diagnostics provided funding of reagents required for the study as part of an unrestricted educational grant awarded to Dr Edmund Lamb.
Employment or leadership: None declared.
Honorarium: None declared.
References
1. Kidney Disease: Improving Global Outcomes (KDIGO) CKD work group. KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int 2013;3(Suppl):1–150.Search in Google Scholar
2. Lamb EJ, Levey AS, Stevens PE. The Kidney Disease Improving Global Outcomes (KDIGO) guideline update for chronic kidney disease: evolution not revolution. Clin Chem 2013;59:462–5.10.1373/clinchem.2012.184259http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=000317337600003&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=b7bc2757938ac7a7a821505f8243d9f3Search in Google Scholar PubMed
3. National Institute for Health and Care Excellence. Chronic kidney disease: early identification and management of chronic kidney disease in adults in primary and secondary care. NICE clinical guideline 73, 2008. Available from: http://www.nice.org.uk. Accessed 24 April, 2013.Search in Google Scholar
4. Scottish Intercollegiate Guidelines Network. Diagnosis and management of chronic kidney disease. Guideline 103, 2008. Available from: http://www.sign.ac.uk. Accessed 24 April, 2013.Search in Google Scholar
5. Astor BC, Matsushita K, Gansevoort RT, van der Velde M, Woodward M, Levey AS, 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;79:1331–40.10.1038/ki.2010.550Search in Google Scholar
6. Van der Velde M, Matsushita K, Coresh J, Astor BC, Woodward M, Levey A, 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;79:1341–52.http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=000291093300010&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=b7bc2757938ac7a7a821505f8243d9f310.1038/ki.2010.536Search in Google Scholar
7. Gansevoort RT, Matsushita K, van der Velde M, Astor BC, Woodward M, Levey AS, et al. Lower estimated glomerular filtration rate and higher albuminuria are associated with adverse kidney outcomes. A collaborative meta-analysis of general and high-risk population cohorts. Kidney Int 2011;80:93–104.10.1038/ki.2010.531Search in Google Scholar
8. Mahmoodi BK, Matsushita K, Woodward M, Blankestijn PJ, Cirillo M, Ohkubo T, et al. Associations of kidney disease measures with mortality and end-stage renal disease in individuals with and without hypertension: a meta-analysis. Lancet 2012;380:1649–61.10.1016/S0140-6736(12)61272-0http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=000310951400027&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=b7bc2757938ac7a7a821505f8243d9f3Search in Google Scholar PubMed
9. Fox CS, Matsushita K, Woodward M, Bilo HJ, Chalmers J, Heerspink HJ, et al. Associations of kidney disease measures with mortality and end-stage renal disease in individuals with and without diabetes: a meta-analysis. Lancet 2012;380: 1662–73.10.1016/S0140-6736(12)61350-6http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=000310951400028&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=b7bc2757938ac7a7a821505f8243d9f3Search in Google Scholar PubMed
10. Hallan SI, Matsushita K, Sang Y, Mahmoodi BK, Black C, Ishani A, et al. Age and association of kidney measures with mortality and end-stage renal disease. J Am Med Assoc 2012;308:2349–60.10.1001/jama.2012.16817Search in Google Scholar PubMed PubMed Central
11. Lamb EJ, MacKenzie F, Stevens PE. How should proteinuria be detected and measured? Ann Clin Biochem 2009;46:205–17.10.1258/acb.2009.009007http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=000266289800004&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=b7bc2757938ac7a7a821505f8243d9f3Search in Google Scholar PubMed
12. de Jong PE, Bakker SJ, Gansevoort RT. What to measure-albuminuria or total proteinuria? Am J Kidney Dis 2011;57:1–2.10.1053/j.ajkd.2010.11.005http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=000285621600003&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=b7bc2757938ac7a7a821505f8243d9f3Search in Google Scholar PubMed
13. Methven S, MacGregor M. Empiricism or rationalism: how should we measure proteinuria? Ann Clin Biochem 2013; DOI: 10.1177/0004563212473283.10.1177/0004563212473283Search in Google Scholar PubMed
14. Lamb EJ, McTaggart MP, Stevens P. Why albumin to creatinine ratio should replace protein to creatinine ratio: it is not just about nephrologists. Ann Clin Biochem 2013; DOI: 10.1177/0004563212473284.10.1177/0004563212473284Search in Google Scholar PubMed
15. Atkins RC, Briganti EM, Zimmet PZ, Chadban SJ. Association between albuminuria and proteinuria in the general population: the AusDiab study. Nephrol Dial Transplant 2003;18:2170–4.10.1093/ndt/gfg314Search in Google Scholar PubMed
16. McTaggart MP, Price CP, Pinnock RG, Stevens PE, Newall RG, Lamb EJ. The diagnostic accuracy of a urine albumin-creatinine ratio point-of-care test for detection of albuminuria in primary care. Am J Kidney Dis 2012;60:787–94.10.1053/j.ajkd.2012.05.009http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=000310508100030&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=b7bc2757938ac7a7a821505f8243d9f3Search in Google Scholar PubMed
17. Flachaire E, Damour O, Bienvenu J, Aouiti T, Later R. Assessment of the benzethonium chloride method for routine determination of protein in cerebrospinal fluid and urine. Clin Chem 1983;29:343–5.10.1093/clinchem/29.2.343Search in Google Scholar PubMed
18. Payn MM, Webb MC, Lawrence D, Lamb EJ. Alpha1-microglobulin is stable in human urine ex vivo. Clin Chem 2002;48:1136–8.10.1093/clinchem/48.7.1136Search in Google Scholar
19. D’Amico G, Bazzi C. Pathophysiology of proteinuria. Kidney Int 2003;63:809–25.10.1046/j.1523-1755.2003.00840.xSearch in Google Scholar PubMed
20. Penders J, Delanghe JR. Alpha 1-microglobulin: clinical laboratory aspects and applications. Clin Chim Acta 2004;16:107–18.10.1016/j.cccn.2004.03.037Search in Google Scholar PubMed
21. Vynckier LL, Flore KM, Delanghe SE, Delanghe JR. Urinary beta-trace protein as a new renal tubular marker. Clin Chem 2009;55:1241–3.10.1373/clinchem.2008.119727Search in Google Scholar PubMed
22. Conti M, Moutereau S, Zater M, Lallali K, Durrbach A, Manivet P. Urinary cystatin C as a specific marker of tubular dysfunction. Clin Chem Lab Med 2006;44:288–91.10.1515/CCLM.2006.050Search in Google Scholar PubMed
23. Jury DR, Mikkelsen DJ, Dunn PJ. Prozone effect and the immunoturbidimetric measurement of albumin in urine. Clin Chem 1990;36:1518–9.10.1093/clinchem/36.8.1518Search in Google Scholar PubMed
24. Pullen NJ, Hitch T. Development of an automatic laboratory computer flagging system to identify urine albumin samples potentially affected by antigen excess (‘hooking’). Ann Clin Biochem 2012;49:289–91.10.1258/acb.2011.011210http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=000304784800012&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=b7bc2757938ac7a7a821505f8243d9f3Search in Google Scholar
25. Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med 1999;130:461–70.10.7326/0003-4819-130-6-199903160-00002Search in Google Scholar
26. National Kidney Foundation. Clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis 2002;39(2 Suppl 1):S1–266.Search in Google Scholar
27. Saydah SH, Pavkov ME, Zhang C, Lacher DA, Eberhardt MS, Burrows NR, et al. Albuminuria prevalence in first morning void compared with previous random urine from adults in the national health and nutrition examination survey, 2009–2010. Clin Chem 2013;59:675–83.http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=000317338200016&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=b7bc2757938ac7a7a821505f8243d9f310.1373/clinchem.2012.195644Search in Google Scholar
28. Levey AS, Eckardt KU, Tsukamoto Y, Levin A, Coresh J, Rossert J, et al. Definition and classification of chronic kidney disease: a position statement from Kidney Disease: Improving Global Outcomes (KDIGO). Kidney Int 2005;67:2089–100.10.1111/j.1523-1755.2005.00365.xhttp://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=000248394300007&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=b7bc2757938ac7a7a821505f8243d9f3Search in Google Scholar PubMed
29. Roberts WL, McMillin GA, Burtis CA, Bruns DE. Reference information for the clinical laboratory. In: Tietz Textbook of Clinical Chemistry and Molecular Diagnostics, 5th ed. St Louis, Missouri: Elsevier Saunders, 2012:1231–88.Search in Google Scholar
30. Osicka TM, Comper WD. Characterization of immunochemically nonreactive urinary albumin. Clin Chem 2004;50:2286–91.10.1373/clinchem.2004.039743Search in Google Scholar PubMed
31. Sviridov D, Drake SK, Hortin GL. Reactivity of urinary albumin (microalbumin) assays with fragmented or modified albumin. Clin Chem 2008;54:61–8.http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=000252295600012&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=b7bc2757938ac7a7a821505f8243d9f310.1373/clinchem.2007.092825Search in Google Scholar PubMed
32. Dube J, Girouard J, Leclerc P, Douville P. Problems with the estimation of urine protein by automated assays. Clin Biochem 2005;38:479–85.10.1016/j.clinbiochem.2004.12.010Search in Google Scholar PubMed
33. Jung K, Pergande M, Schreiber G, Thierfelder W. Reference intervals for alpha 1-microglobulin in urine. Clin Chim Acta 1992;206:245–7.10.1016/0009-8981(92)90095-8Search in Google Scholar PubMed
34. Jung K, Pergande M. Sex- and age-dependent reference values of alpha-1-microglobulin in urine. Nephron 1992;62:474–5.10.1159/000187106Search in Google Scholar PubMed
35. Hong CY, Hughes K, Chia KS, Ng V, Ling SL. Urinary α1-microglobulin as a marker of nephropathy in type 2 diabetic Asian subjects in Singapore. Diabetes Care 2003;26:338–42.10.2337/diacare.26.2.338Search in Google Scholar PubMed
36. Schrader J, Lüders S, Kulschewski A, Hammersen F, Züchner C, Venneklaas U, et al. Microalbuminuria and tubular proteinuria as risk predictors of cardiovascular morbidity and mortality in essential hypertension: final results of a prospective long-term study (MARPLE Study). J Hypertens 2006;24:541–8.10.1097/01.hjh.0000209991.48928.c4Search in Google Scholar PubMed
37. Galanti LM, Jamart J, Dell’omo J, Donckier J. Comparison of urinary excretion of albumin, alpha 1-microglobulin and retinol-binding protein in diabetic patients. Diabetes Metab 1996;22:324–30.Search in Google Scholar PubMed
38. Chambers RE, Bullock DG, Whicher JT. External quality assessment of total urinary protein estimation in the United Kingdom. Ann Clin Biochem 1991;28:467–73.10.1177/000456329102800508Search in Google Scholar PubMed
39. Marshall T, Williams KM. Total protein determination in urine: elimination of a differential response between the coomassie blue and pyrogallol red protein dye-binding assays. Clin Chem 2000;46:392–8.10.1093/clinchem/46.3.392Search in Google Scholar PubMed
40. National Institute for Health and Care Excellence. Type 1 diabetes: diagnosis and management of type 1 diabetes in children, young people and adults. NICE clinical Guideline 15, 2004. Updated March 2010). Available from: http://www.nice.org.uk. Accessed 24 April, 2013.Search in Google Scholar
41. National Institute for Health and Care Excellence. Type 2 diabetes. NICE clinical guideline 66, 2009. Available from: http://www.nice.org.uk. Accessed 24 April, 2013.Search in Google Scholar
42. Scottish Intercollegiate Guidelines Network. Management of diabetes. NICE clinical guideline 116, 2010 (revised May 2011). Available from: http://www.sign.ac.uk. Accessed 24 April, 2013.Search in Google Scholar
43. Gross JL, de Azevedo MJ, Silveiro SP, Canani LH, Caramori ML, Zelmanovitz T. Diabetic nephropathy: diagnosis, prevention, and treatment. Diabetes Care 2005;28:164–76.10.2337/diacare.28.1.164Search in Google Scholar PubMed
44. Ninomiya T, Perkovic V, de Galan BE, Canani LH, Caramori ML, Zelmanovitz T. Albuminuria and kidney function independently predict cardiovascular and renal outcomes in diabetes. J Am Soc Nephrol 2009;20:1813–21.10.1681/ASN.2008121270http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=000268903200025&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=b7bc2757938ac7a7a821505f8243d9f3Search in Google Scholar PubMed PubMed Central
45. Viazzi F, Leoncini G, Conti N, Tomolillo C, Giachero G, Vercelli M, et al. Combined effect of albuminuria and estimated glomerular filtration rate on cardiovascular events and all-cause mortality in uncomplicated hypertensive patients. J Hypertens 2010;28:848–55.10.1097/HJH.0b013e328336ed09http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=000275729300032&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=b7bc2757938ac7a7a821505f8243d9f3Search in Google Scholar PubMed
46. Shihabi ZK, Konen JC, O’Connor ML. Albuminuria vs urinary total protein for detecting chronic renal disorders. Clin Chem 1991;37:621–4.10.1093/clinchem/37.5.621Search in Google Scholar PubMed
47. Dawnay A, Wilson AG, Lamb E, Kirby JD, Cattell WR. Microalbuminuria in systemic sclerosis. Ann Rheum Dis 1992;51:384–8.10.1136/ard.51.3.384Search in Google Scholar PubMed PubMed Central
48. Methven S, MacGregor MS, Traynor JP, O’Reilly DS, Deighan CJ. Assessing proteinuria in chronic kidney disease: protein-creatinine ratio versus albumin-creatinine ratio. Nephrol Dial Transplant 2010;25:2991–6.10.1093/ndt/gfq140Search in Google Scholar PubMed
49. Methven S, Traynor JP, Hair MD, St J O’Reilly D, Deighan CJ, MacGregor MS. Stratifying risk in chronic kidney disease: an observational study of UK guidelines for measuring total proteinuria and albuminuria. QJM 2011;104:663–70.10.1093/qjmed/hcr026http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=000293072400004&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=b7bc2757938ac7a7a821505f8243d9f3Search in Google Scholar PubMed
50. Methven S, MacGregor MS, Traynor JP, Hair M, O’Reilly DS, Deighan CJ. Comparison of urinary albumin and urinary total protein as predictors of patient outcomes in CKD. Am J Kidney Dis 2011;57:21–8.10.1053/j.ajkd.2010.08.009http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=000285621600007&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=b7bc2757938ac7a7a821505f8243d9f3Search in Google Scholar PubMed
©2013 by Walter de Gruyter Berlin Boston
