American Association for Clinical Chemistry
Better health through laboratory medicine
November 2011 Clinical Laboratory News: Diagnostic Profiles

Diagnostic Profiles

FGF-23 Early Predictor of Poor Outcomes in Chronic Kidney Disease

Fibroblast growth factor-23 (FGF-23) is strongly and independently associated with all-cause mortality, cardiovascular events, and start of chronic dialysis among patients with advanced kidney disease who had not previously started dialysis, according to new research (J Am Soc Nephrol 2011;22:1913–22). The findings point to the potential utility of FGF-23 as a marker to guide therapies in patients with chronic kidney disease (CKD) who have normal serum phosphorus levels.

The analysis involved 1,099 participants from the Homocysteine in Kidney and End Stage Renal Disease study, 98% of whom were male with a mean age of 69 years and mean estimated Modified Diet Renal Disease-glomerular filtration rate of 18 ± 6 ml/min/1.73 m2. The researchers were interested in exploring any association of FGF-23 with risk in CKD because FGF-23 levels increase early in the course of CKD, long before serum phosphorus concentrations rise. Because small increases in serum phosphorus levels have been independently associated with all-cause mortality and cardiovascular events, and FGF-23 is a regulator of serum phosphorus, the investigators hypothesized that elevated FGF-23 levels might be an early marker of disordered phosphorus metabolism in CKD patients.

During a median follow-up of 2.9 years, 41% of patients died from any cause, 20% had a cardiovascular event, and 56% started chronic dialysis. Compared with the lowest quartile of FGF-23, each successive quartile was associated with progressively higher risk for death, rising from a 1.24 hazard ratio in the second quartile to 2.17 in the fourth quartile. In addition, patients in the two highest quartiles of FGF-23 were at significantly elevated risk for cardiovascular events and start of chronic dialysis versus those in the lowest quartiles.

The researchers called for further studies to understand the mechanisms behind the association between rising FGF-23 levels and worse outcomes in CKD.

Elevated Transferrin Saturation Associated with Risk of Diabetes

Danish researchers have found that elevated transferrin saturation confers a two- to three-fold increased risk of developing any form of diabetes (Diabetes Care 2011;34:2256–58). The results underscore the importance of investigating iron overload in the differential diagnosis of secondary causes of diabetes and support arguments in favor of screening for iron overload in the general population, according to the authors.

The study involved three large populations, including 9,121 participants in the Copenhagen City Heart Study (CCHS), 24,195 subjects from the Copenhagen General Population Study (CGPS), and 6,129 individuals who were part of a consecutively recruited population-based case-control study. The investigators measured transferrin levels using turbidimetry and iron levels by colorimetry. Transferrin saturation >50% was considered suggestive of increased saturation, and it varied among the different study populations: 2.8–236% in CCHS; 0.9–130% in CGPS; and 0.1–97% in the population-based case-control study.

Hazard ratios for any form of diabetes in individuals with transferrin saturation ≥50% in comparison to those with transferrin saturation ≤50% also varied by study population, ranging from 1.8 in CCHS and 1.5 in CGPS to 3.3 in the population-based case-control study. In a meta-analysis of the combined populations, the odds ratio for any form of diabetes was 2.1 in those with transferrin saturation ≥50% versus in individuals with transferrin saturation ≤50%. Odds ratios for type 1 and type 2 diabetes in the combined analysis were 2.6 and 1.7, respectively, in those with transferrin saturation ≥50% versus ≤50%.

NGAL Tops BNP for Heart Failure Risk Prediction

A recently published study found that plasma neutrophil gelatinase-associated lipocalin (NGAL) level at the time of discharge is a powerful predictor of 30-day outcomes in patients with acute heart failure (AHF) (Eur J Heart Fail 2011;13:846–851). The authors concluded that NGAL is a stronger predictor than B-type natriuretic peptide (BNP), which is considered the standard for risk prediction. They also found NGAL “substantially superior” to conventional measures of renal function like serum creatinine and estimated glomerular filtration rate (eGFR), making it both a risk predictor for renal injury and a strong marker for cardiac events in HF.

Renal dysfunction is common in AHF, but creatinine—a marker of renal function, not injury—rises comparatively slowly after an insult to the kidney, making it less appealing than a marker like NGAL that rises quickly after kidney injury. The authors hypothesized that combining NGAL and BNP results could improve risk stratification of HF patients.

The study involved 186 adult patients who presented to the emergency department with symptoms of new or decompensated HF. Overall, 16% reached an endpoint of all-cause mortality or HF readmission within 30 days. Patients with events had significantly higher levels of NGAL than those without, and the area under the receiver operating characteristic curve was 0.72 for NGAL versus 0.65 for BNP, 0.57 for serum creatinine and 0.55 for eGFR. In multivariate analyses, NGAL predicted events and BNP approached significance, while neither serum creatinine nor eGFR were significant. Patients with both elevated NGAL and BNP were at significant risk, with a hazard ratio of 16.85.

Hyponatremia Linked to Worsened Outcomes in Stable Heart Failure

Hyponatremia is a significant independent predictor of hospitalization and death in patients with chronic heart failure (HF) followed in outpatient HF clinics (Euro J Heart Fail 2011;13:968–973). The findings call for further research to determine whether interventions aimed specifically at treating hyponatremia in HF can reduce morbidity and mortality in outpatients with HF.

Hyponatremia is common in patients hospitalized with HF, and has been reported to be a strong predictor of poor outcomes in this population. However, the incidence and prognostic importance of hyponatremia in stable outpatients with HF has not been studied extensively. This prompted the authors’ investigation.

The study involved 2,863 consecutive patients referred for HF management at 18 HF clinics. Overall, 83% of patients had normal plasma sodium levels >136 mmol/L, with a mean of 139.6 ±2.4 mmol/L. The 17% of patients with hyponatremia—defined as plasma sodium level <136 mmol/L—had a mean of 132.4 ±3.2 mmol/L. Hyponatremic patients were more likely to have a higher mean heart rate and lower systolic blood pressure as well as severe symptoms corresponding to New York Heart Association class III–IV HF. Patients with hyponatremia also were more likely to have been hospitalized within the 90 days prior to referral to the HF clinic and to have been prescribed loop diuretics.

Total mortality and rates of hospitalization or death were significantly higher in hyponatremic patients versus those with normal plasma sodium levels. In a multivariate model adjusted for confounders, patients with hyponatremia were at increased risk for hospitalization or death, with a 1.2 hazard ratio. Hyponatremia also was an independent predictor of all-cause mortality, with a hazard ratio of 1.5.