Increased sensitivity in detecting renal impairments by quantitative measurement of marker protein excretion compared to detection of pathological particles in urine sediment analysis.

BACKGROUND: Positive test strip results, pathological particles in urine and the presence of proteinuria are common findings in nephropathies. A comparison between these methods and renal biopsies became available with the introduction of quantitative measurement of marker proteins (albumin, transferrin, IgG, alpha(1)-microglobulin, retinol binding protein, alpha(2)-macroglobulin, Bence Jones proteins) and standardised urine sediment analysis by flow cytometry or microscopy. METHODS: A total of 400 urine samples were examined using marker protein patterns, test strips and quantitative sediment analyses. RESULTS: Results from standardised urine sediment analyses were compared with the excretion of renal marker proteins. Increased erythrocyte and leukocyte counts in urine were observed in only 29% and 39% of the samples for which pathological protein excretion was found. The sensitivity in detecting pathological particles in urine sediment, such as casts and/or dysmorphic erythrocytes, was only 19%. Renal biopsies from 65 patients who were classified as pathological were compared with proteinuria and sediment analyses. Increased excretion of marker proteins was found in all cases, whereas only 41% of the cellular urine sediments showed pathological results. CONCLUSIONS: Quantitative measurement of marker proteins from both the glomerular and tubular sides should be used upfront as screening parameters for the early detection of renal disorders.

Immunohistochemical analysis reveals high frequency of PMS2 defects in colorectal cancer.

BACKGROUND & AIMS: Germline mutations in the DNA mismatch repair (MMR) genes MSH2, MSH6, or MLH1 predispose to colorectal cancer (CRC) with an autosomal dominant inheritance pattern. The protein encoded by PMS2 is also essential for MMR; however, alterations in this gene have been documented only in extremely rare cases. We addressed this unexpected finding by analyzing a large series of CRCs. METHODS: Expression of MSH2, MSH6, MLH1, and PMS2 was studied by immunohistochemistry in 1048 unselected, consecutive CRCs. Where absence of MMR proteins was detected, microsatellite instability and cytosine methylation of the respective gene promoter were analyzed. The DNA of patients presenting with PMS2-deficient cancers was examined for germline and somatic alterations in the PMS2 gene. RESULTS: An aberrant pattern of MMR protein expression was detected in 13.2% of CRCs. Loss of expression of MSH2, MSH6, or MLH1 was found in 1.4%, 0.5%, and 9.8%, respectively. PMS2 deficiency accompanied by microsatellite instability was found in 16 cases (1.5%) with a weak family history of cancer. The PMS2 promoter was not hypermethylated in these cases. Despite interference of the PMS2 pseudogenes, we identified several heterozygous germline mutations in the PMS2 gene. CONCLUSIONS: PMS2 defects account for a small but significant proportion of CRCs and for a substantial fraction of tumors with microsatellite instability. However, the penetrance of heterozygous germline mutations in PMS2 is considerably lower than that of mutations in other MMR genes. The possible underlying causes of this unorthodox inheritance pattern are discussed.