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

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September 2009: Volume 35, Number 9

Urine IgM Excretion Has Predictive Value in Type 1 Diabetes

A long-term follow-up study has found increased urine IgM excretion to be associated with higher cardiovascular-related mortality and a higher rate of progression to end-stage renal disease (ESRD) in type 1 diabetics, independent of the level of albuminuria (BMC Medicine 2009, doi:10.1186/1741-7015-7-339). The findings suggest there may be a new approach to managing renal complications in type 1 diabetics. Albuminuria is routinely used to assess kidney function in diabetics, but use of IgM excretion might indentify patients more specifically at risk for serious cardiovascular complications, according to the authors.

The observational study involved 139 patients with type 1 diabetes followed in an ambulatory care setting for a median of 18 years. Urine albumin and urine IgM levels were measured at the time of recruitment and in subsequent evaluations. Univariate Cox-regression analysis showed that urinary IgM excretion was one of seven predictors of cardiovascular-related mortality, with a hazard ratio of 4.6 (p <0.001), and one of 5 predictors of ESRD, with a hazard ratio of 5.7 (p <0.002). Stepwise multivariate Cox-regression analysis showed that urine IgM excretion predicted cardiovascular mortality and renal failure independent of albuminuria levels.

Patients with high urine IgM excretion levels were at higher risk for cardiovascular-related mortality whether they had macro-, micro-, or normoalbuminuria. Likewise, subjects with either macro- or microalbuminuria and high IgM excretion were at higher risk for renal failure than those with low IgM excretion.

Previous research has indicated that albuminuria could be due to minor or major glomerular damage. The researchers speculated that the atherosclerotic vascular disease in diabetics may trigger ischemia and more severe structural changes in the glomeruli, which allow for large compounds like IgM to pass through the glomerular filtration barrier via large shunts. This possibly explains the correlation between urine IgM excretion and cardiovascular events that they observed.

Researchers Call for Revised Normal Serum Uric Acid Values in Acute Gout

The authors of a recent study recommend that labs lower the normal value of serum uric acid to <6.8 mg/dL from <8 mg/dL, the commonly reported and accepted normal level (J Rheumatol 2009; 36:1287–9). The purpose of the study was to evaluate the distribution of serum uric acid and frequency of normal serum uric acid levels during acute gout in the largest studies of acute gout to date. According to the authors, non-rheumatologists often are unaware that serum uric acid can be normal during acute gout, and even rheumatologists may consider it unusual, leading to rejection of a gout diagnosis because serum uric acid levels are normal.

The identical, controlled, double-blinded gout trials involved 339 patients with clinically diagnosed acute gout who were randomized to receive either etoricoxib 120 mg once per day or indomethacin 50 mg three times per day. Since efficacy was similar for the two medications, the two groups were combined for analysis. One of a series of sub-groups analyzed subjects’ use of allopurinol, a xanthine oxidase inhibitor used to treat hyperuricemia.

At baseline, mean serum uric acid was 7.1 mg/dL in subjects taking allopurinol versus 8.5 mg/dL in those not taking the drug, a difference that persisted on day 8 of randomization. Overall, 32% of patients had serum uric acid levels ≤8 mg/dL, while 14% had levels ≤6 mg/dL. Patients receiving chronic allopurinol therapy were more likely to have lower serum uric acid levels at onset of acute gout, with 29% having levels ≤6 mg/dL and 49% having levels ≤8 mg/dL at onset. The authors did not have data on the length of therapy or any dose adjustments of allopurinol prior to randomization, but they speculate that development of gout in the presence of allopurinol may occur early in treatment or be associated with starting or stopping treatment.

Although serum uric acid levels <8 mg/dL generally are considered normal, serum uric acid levels >6.8 mg/dL “are above saturation level and may allow deposition of gouty crystals,” according to the authors. The researchers hypothesize that gout in patients with serum uric acid levels <6.8 mg/dL may occur due to the persistence of tophi and an increased body uric acid pool. The authors called for further studies to better understand the correlation between serum uric acid and body uric acid pool as well as the relationship to timing of changes during acute gout.

uNGAL Found to be Modest Predictor of Acute Kidney Injury

A study by Vanderbilt University researchers indicates that urine neutrophil gelatinase-associated lipocalin (uNGAL) is independently associated with and moderately discriminate for acute kidney injury (AKI) in ICU patients (J Am Soc Nephrol 2009;20:1823–1832). Previous research also found a modest correlation and suggested that uNGAL held particular promise in patients with temporally defined mechanisms of injury, such as cardiac bypass and post-renal transplant. uNGAL is one of at least five biomarkers that have been examined in an effort to identify and/or predict AKI. The incidence of AKI has been increasing, and the condition is an independent predictor of morbidity and mortality.

The researchers used data from the Validation of biomarkers in Acute Lung Injury Diagnosis (VALID) study. AKI was detected in 86 of 451 subjects within 48 hours of enrollment, with AKI defined as a minimum 50% or 0.3 mg/dL increase in serum creatinine. Median uNGAL in these subjects was 190 ng/mg, versus 57 ng/mg in subjects without AKI (p <0.001). Areas under the ROC of uNGAL in predicting AKI occurrence within 24 and 48 hours were 0.71 and 0.64, respectively.

One of the study's limitations was the absence of baseline renal function data in 52% of subjects. To address this, researchers performed sensitivity analysis and multiple imputation methodology to estimate baseline GFR in subjects with missing data.

The study also examined the role of uNGAL in predicting clinical outcomes such as acute dialysis and death within 28 days of enrollment. Median uNGAL levels for patients who died was significantly higher than in those who survived (223 ng/mg versus 56 ng/mg; p <0.001), and in those who subsequently received acute dialysis versus those who did not (548 ng/mg versus 61 ng/mg).

Given uNGAL’s modest predictive performance and the complexity of AKI, the researchers observed that “it is unlikely that a single biomarker such as uNGAL can alone explain all the observed causes of serum creatinine elevations in an ICU population.” The authors called for further evaluation of uNGAL as part of a panel of biomarkers, and in a large cohort of patients.