American Association for Clinical Chemistry
Better health through laboratory medicine
April 2009 Clinical Laboratory News: Diagnostic Profiles

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April 2009: Volume 35, Number 4

Proteomic Analysis Discriminates Between Two Causes of Chronic Allograft Dysfunction

A groundbreaking proof-of-concept study combining proteomic analysis of urine and bioinformatics tools discriminated between and correctly identified 100% of samples with pure interstitial fibrosis and tubular atrophy (IF/TA) and chronic active antibody-mediated rejection (CAAR), respectively. If confirmed in larger studies, the findings could have significance for identifying and developing early treatments for chronic allograft dysfunction (CAD), the cause of more than 50% of kidney transplant failures (J Am Soc Nephrol 2009;20: 428–435).

Elevated serum creatinine levels eventually signal proteinuria and arterial hypertension associated with CAD, but the disorder is difficult to diagnose in the early stages. Detection usually requires invasive graft biopsies for histological evaluation. The researchers posited that use of chromatography by solid-phase extraction coupled to mass spectrometry would differentiate urinary polypeptide patterns in patients who had either IF/TA or CAAR versus two control groups, including healthy individuals and clinically stable renal transplant recipients. The study involved 50 patients, including 14 with previously diagnosed IF/TA, 18 with CAAR, 10 healthy control subjects, and 8 patients who were clinically stable following kidney transplant.

The researchers used MALDI-TOF MS to detect patterns and peaks of signals from the urine samples. They found that subjects with IF/TA and CAAR had peak clusters in three regions distinct from those of healthy subjects whose analysis only showed a single peak. An unsupervised hierarchical clustering of proteins showed good segregation of samples into groups corresponding to the four groups of patients. Subsequent differential expression analysis and significance analysis identified statistically significant differences between the IF/TA and CAAR groups, with 366 values that changed. Discrimination analysis of these 366 protein ions resulted in correct identification of 100% of the IF/TA and CAAR groups, respectively.

RaCVD Risk Prediction of NMR Lipoprotein Profiles Not Superior to Standard Lipid Tests

A large-scale prospective study found that NMR lipoprotein profiles were comparable to, but not superior than standard lipid tests or immunoassay-measured apolipoproteins. The study supports recommendations of current guidelines to use a standard lipid panel, particularly the total/HDL-C ratio, to assess CVD risk, and addresses a recent statement by a panel of lipid experts that CVD risk may be related more closely to atherogenic lipoprotein particle number than to LDL cholesterol (Circulation 2009; 119:931-939).

The study involved 27,673 participants in the Women’s Health Study, a randomized controlled trial of low-dose aspirin and vitamin E in the primary prevention of CVD and cancer in women. Baseline NMR measurements were taken and the participants were followed for a mean of 11 years for CVD events. After adjustment for nonlipid risk factors, NMR-measured lipoproteins were significantly associated with incident CVD, but with a magnitude of risk comparable to standard lipids and immunoassay-measured apolipoproteins. No reclassification improvement was found by adding LDLnmr particle concentration or apolipoprotein B100 to a model that already included the total/HDL cholesterol ratio and nonlipid risk factors. The findings do not support routine measurement of NMR lipoproteins or immunoassay apolipoproteins when a standard lipid panel is available, according to the researchers.