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Letters to the Editor |
1 Clinical Pathology Division, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil
2 FEEVALE University Centre, Novo Hamburgo, Brazil
3 Endocrinology Division, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil
aAddress correspondence to this author at: Serviço de Patologia Clínica, Hospital de Clínicas de Porto Alegre, Rua Ramiro Barcellos, 2350, 2° andar, Porto Alegre, RS, 90035-903, Brazil, Fax +55-51-33325188, e-mail jcamargo{at}hcpa.ufrgs.br
To the Editor:
Diagnosis of diabetic nephropathy (DN) is based on measurements of urinary albumin (UALB) by a sensitive analytical method with sufficient analytical precision (CV <15%) to detect changes in UALB concentration(1)(2)(3). We evaluated the comparative diagnostic accuracies of 4 UALB assays for DN.
We used urine samples from 98 diabetic outpatients. UALB was measured by 4 immunoturbidimetric (IT) assays: the Urine Pack Immuno method (Bayer) as implemented on a Roche Cobas Mira Plus (method A), Malb Aptec Diagnostic (BioSys) (method B), Albumin Tina-quant (Roche) (method C), and Microalbumin (Randox) (method D). Methods B, C, and D were implemented on a Hitachi 917 analyzer (Roche). Method A was considered as the reference standard (comparison method) because it had been used in our laboratory since 1996 and validated in previous studies(2)(4)(5). Total urinary protein was measured before UALB, and the U/CSF Protein assay (Roche) on the Hitachi 917 analyzer (Roche) was used to estimate the contribution (%) of albumin to total protein for each sample(5). Based on this estimate, we prediluted samples to allow UALB measurement within the linearity interval for each assay. Urine samples were classified as normo-, micro-, or macroalbuminuric on the basis of the UALB measured using method A(1)(4). Intra- and interassay (n = 20) CVs were calculated for each IT method in pooled material at UALB concentrations of 30 and 100 mg/L. The agreement between methods was evaluated by Bland-Altman plots and 
coefficients.
Of 98 urine samples analyzed (58 random and 40 24-h urine), 27 urine samples were classified by method A as normoalbuminuric, 49 as microalbuminuric, and 22 as macroalbuminuric. The intra- and interassay CVs were <6% for all IT methods at both tested UALB concentrations. The analytical sensitivities ranged from 3 to 5 mg/L, and the upper limits of linearity from 160 to 400 mg/L. Method C had the highest linearity. All methods had an excellent correlation (r) with the comparison method A: 0.991, 0.996, and 0.988; P < 0.05, for methods B, C, and D, respectively. UALB results among the 4 methods were not found to be different (ANOVA; P > 0.812), and no significant differences were seen in pairwise comparisons of UALB values (n = 98) obtained with each method and those obtained with the comparison method A [median (range) 54.4 (5.0–1392.0) mg/L], method B [59.3 (2.3–1151.0) mg/L], method C [56.0 (3.0–1109.0) mg/L], and method D [48.2 (4.0–950.0) mg/L], P > 0.05. The observed mean differences (range) in UALB (mg/L) were: method A vs B, 8.17(–1.23 to 17.58); A vs C, 13.34 (3.99–22.69); and A vs D, 35.1 (19.69–50.48). These differences are shown in Bland-Altman plots (Fig. 1
).
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The diagnostic agreements with the comparison method across the DN stages (values within the reference interval, or values outside the reference interval indicating microalbuminuria or macroalbuminuria), were 91.8%, 94.9%, and 91.8% for methods B, C, and D, respectively, classified as excellent by Kappa statistics ( = 0.887, 0.929, and 0.887 for methods B, C, and D, respectively). Of the 98 urine samples, disagreement with UALB results obtained by method A occurred in 8 samples (8.2%) analyzed by method B, 5 samples (5.1%) analyzed by method C, and 8 samples (8.2%) analyzed by method D. The UALB values of these 21 samples were near the diagnostic cutoff values for the different stages of DN(4).
Use of different IT methods for UALB measurement in this study did not notably alter the classification of DN. Considering all methods, on average only 6.6% of samples were misclassified. Twelve of 21 samples misclassified were in the normoalbuminuria range by the reference method. In only 2 cases were patient samples labeled as DN by method A misclassified as normoalbuminuric by another method. These 2 samples were from microalbuminuric patients (UALB = 18.9 mg/L and 30.8 mg/24 h) and were erroneously classified as normoalbuminuric (UALB = 16.5 mg/L and 25.5 mg/24 h). The misclassification of 5 macroalbuminuric patient samples as microalbuminuric by method D was not clinically relevant, because the diagnosis of DN was maintained and the clinical management of micro- and macroalbuminuric patients is similar. The UALB values in these patients were near the lower cutoff limit for macroalbuminuria. Because UALB biological variation can be as much as 30%, it is recommended that the final diagnosis of DN be confirmed in a second urine sample(1)(2)(3). By reducing the effects of analytical variation, analysis of a second urine sample should be helpful in evaluating UALB values close to the adopted cutoffs for the diagnosis of micro- and macroalbuminuria. The immunoassay methods for UALB evaluated in this study appear to give results that can be applied interchangeably without clinically relevant misclassification of different stages of DN.
Acknowledgments
Grant/Funding Support: This work was supported by a Grant from Programa de Apoio a Núcleos de Excelência do Ministério de Ciência e Tecnologia (Pronex).
Financial Disclosures: None declared.
Acknowledgment: We thank the Clinical Chemistry Unit at Clinical Pathology Division, HCPA, for providing urine samples and UALB results.
References
The following articles in journals at HighWire Press have cited this article:
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  J. C. Seegmiller, D. Sviridov, T. S. Larson, T. M. Borland, G. L. Hortin, and J. C. Lieske Comparison of Urinary Albumin Quantification by Immunoturbidimetry, Competitive Immunoassay, and Protein-Cleavage Liquid Chromatography-Tandem Mass Spectrometry Clin. Chem., November 1, 2009; 55(11): 1991 - 1994. [Abstract] [Full Text] [PDF]
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 C. K. Kramer, J. Camargo, E. D. Ricardo, F. K. Almeida, L. H. Canani, J. L. Gross, and M. J. Azevedo Does bacteriuria interfere with albuminuria measurements of patients with diabetes? Nephrol. Dial. Transplant., April 1, 2009; 24(4): 1193 - 1196. [Abstract] [Full Text] [PDF]
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