CLN Article

Diagnostic Profiles

Filtration Markers May Have Prognostic Value Independent of GFR

After adjustments for glomerular filtration rate (GFR), levels of creatinine, cystatin C, and ß trace protein each remained directly associated with kidney failure but differed in their associations with mortality, according to a newly published study (J Am Soc Nephrol 2011 doi: 10.1681/ASN.2011070663). The findings add to the body of knowledge about how these markers contribute prognostic information beyond that reflected in GFR.

The investigators analyzed data from the Modification of Diet in Renal Disease study, which included baseline levels for the markers from 816 participants with a median follow-up of 16.6 years. They measured GFR by urinary clearance of 125I iothalamate and examined the association between the reciprocals of the biomarkers and 125I iothalamate GFR. After adjustment for GFR in a Cox proportional hazards model and other statistical analyses, the authors found higher creatinine levels to be associated with increased risk for kidney failure but lower risk for all cause mortality. Higher levels of cystatin C and ß trace protein were associated with higher risk for both kidney failure and all-cause mortality.

Based on their findings, the researchers called for future studies to report both associations with measured GFR and filtration markers in multivariable models assessing outcomes of chronic kidney disease and mortality.

Proteins Linked to Poor Outcomes in Idiopathic Pulmonary Fibrosis

University of Pittsburgh researchers have identified and independently validated that five proteins are associated with poor outcomes in patients with idiopathic pulmonary fibrosis (IPF) (Am J Respir Crit Care Med doi:10.1164/rccm.201101-00580C). Using a combination of protein markers and patient characteristics, they also derived a risk score that accurately distinguishes high- and low-mortality risk in IPF. This panel of proteins, along with three others the researchers previously identified, represents a "key step forward" in improving classification and management of IPF patients, according to the authors.

The investigators conducted the study because IPF has a variable course, and while clinical and physiological parameters have proven useful in monitoring disease, they have limited utility in predicting disease progression or IPF-related mortality. In addition, currently available medical therapies have little affect on IPF, so the authors hoped their findings might lay the groundwork for future drug studies.

The study involved 241 IPF patients, 140 in a derivation cohort and 101 in a validation cohort. The investigators analyzed a total of 95 proteins, 92 using a multiplex bead-based immunoassay and three using an enzyme-linked immunosorbent assay. In all, 75 were detectable in plasma and five—MMP7, ICAM1, IL8, VCAM1, and S100A12—were found to be significantly associated with mortality and disease progression. The researchers similarly found in a validation cohort a significant association between these five markers and poor outcomes. In the latter, all five were predictive of significantly reduced survival when lung transplant was included as an event, but only two—ICAM1 and IL8—when transplant was excluded, and only ICMA1 predicted progression free survival.

The researchers also developed a personal clinical and molecular mortality index using both clinical parameters and protein concentrations in the derivation cohort, which was highly predictive of mortality in the validation cohort.

Three-Metabolite Signature Predictive of Progression to Alzheimer's disease

Finnish researchers have identified a three-metabolite signature that is predictive of progression from mild cognitive impairment (MCI) to Alzheimer's disease (AD) (Transl Psychiatry 2011 doi:10.1038/tp.2011.55). The findings could facilitate early diagnosis of AD and help identify new therapeutics for AD.

The PredictAD study involved 143 patients with diagnosed MCI, whose molecular signature was compared with both healthy controls and patients with AD. The researchers also identified patients with progressive (P-MCI) versus stable MCI. They used two different platforms to perform a broad metabolomics analysis at baseline and at follow-up. One involved ultra performance liquid chromatography-mass spectrometry (MS) to assess a global lipid signature, and the other used two-dimensional gas chromatography coupled to time-of-flight MS to assess small molecules such as amino acids, free fatty acids, ketoacids, and other organic acids. In all, 139 molecular lipids and 544 small polar metabolites were measured.

At baseline, AD patients had lower levels of ether phospholipids, phosphatidylcholines, sphingomyelins, and sterols. The researchers identified a three-metabolite signature associated with P-MCI and development of AD, including a lipid cluster containing predominantly phosphatidylcholines, a previously undescribed carboxylic acid, and 2,4-dihydroxybutanoic acid. The latter, which was the major contributor to the AD progression model, is a major component of cerebrospinal fluid (CSF), and also is found in plasma at concentrations nearly two orders of magnitude lower than in CSF. The findings primarily point to hypoxia, oxidative stress, and membrane lipid remodeling in progression to AD. The authors called for validation of their findings in other studies.

Lower Post-Operative Hemoglobin Levels not Associated with Poorer Outcomes

A consortium of researchers representing 47 clinical sites found that in comparison to a restrictive strategy, a liberal transfusion strategy aimed at maintaining hemoglobin ≥10 g/dL did not reduce rates of death, inability to walk independently on 60-day follow-up, or in-hospital morbidity in elderly patients at high cardiovascular risk (N Engl J Med 2011;365:2453–62). The findings suggest that in post-operative patients who do not have symptoms of anemia or hemoglobin levels <8 g/dL, it would be reasonable to withhold transfusion, even if they are elderly and have underlying cardiovascular disease (CVD) or risk factors.

The researchers conducted the study because even though post-operative and elderly patients frequently receive transfusions, the indications for this practice have not been studied thoroughly and remain controversial. The investigators sought to test the hypothesis that a higher threshold for blood transfusion would improve functional recovery and reduce morbidity and mortality, as compared to a more restrictive strategy.

The study involved 2,016 patients who were at least age 50 and had a history of or risk factors for CVD, and whose hemoglobin level was <10 g/dL after hip-fracture surgery. Patients were randomly assigned to either a liberal transfusion strategy, with a hemoglobin threshold of 10 g/dL, or a restrictive strategy requiring symptoms of anemia or hemoglobin level <8 g/dL for transfusion. Patients in the restrictive strategy group received 65% fewer units of blood than those in the liberal strategy group, and more than half of them did not receive any blood transfusion. Yet all primary and secondary outcomes between the two groups were not significantly different.

Tripled Clopidogrel Dosage in CYP2C19*2 Heterozygotes Lowers Platelet Reactivity

In patients with stable cardiovascular disease, tripling the maintenance dose of clopidogrel to 225 mg/day in CYP2C19*2 heterozygotes resulted in levels of platelet reactivity similar to that achieved with the standard 75-mg dose in noncarriers (JAMA 2011;306:2221–28). However, in CYP2C19*2 homozygotes, doses as high as 300 mg daily did not achieve comparable degrees of platelet inhibition. These findings help define how patients with different CYP2C19 genotypes respond to different dosages of clopidogrel and may help guide further clinical studies.

Numerous studies have shown that in comparison to noncarriers, heterozygotes and homozygotes for loss-of-function CYP2C19 alleles taking the standard 75-mg maintenance dose of clopidogrel have lower levels of the drug's active metabolite, reduced platelet inhibition, and higher rates of adverse cardiovascular events. However, data are needed to guide optimal treatment in patients with loss-of-function CYP2C19 alleles. This prompted the researchers to conduct a multicenter, randomized, double-blind trial under the hypothesis that increasing the maintenance dose of clopidogrel in CYP2C19*2 allele carriers would reduce platelet reactivity.

CYP2C19*2 heterozygotes taking 75 mg/day had significantly higher on-treatment platelet reactivity than did noncarriers, but doses up to 300 mg daily significantly reduced platelet reactivity, as measured by two different methods. In all, 52% of CYP2C19*2 heterozygotes were clopidogrel nonresponders at a 75 mg dosage, but only 10% were at either 225 or 300 mg dosages. A daily dose of 225 mg reduced platelet reactivity in CYP2C19*2 heterozygotes to levels seen in noncarriers taking a 75 mg dose. Similar reductions in platelet reactivity were not seen in CYP2C19*2 homozygotes.

Fasting Serum Glucose Linked To Risk of Colorectal Cancer in Postmenopausal Women

In postmenopausal women, elevated fasting serum glucose, but not insulin or homeostasis model assessment-insulin resistance index (HOMA-IR), was associated with approximately a two-fold increased risk of colorectal cancer (Br J Cancer doi:10.1038/bjc.2011.512). The findings suggest that insulin resistance may confer an increased risk of colorectal cancer, although the biological mechanism has yet to be fully described.

Obesity, diabetes, and physical inactivity have consistently been associated with increased risk for colorectal cancer, but studies examining the association between the latter and circulating insulin and/or glucose levels have yielded conflicting results. This prompted a consortium of researchers to conduct a longitudinal study of a subsample of Women's Health Initiative clinical trial participants. The study involved 4,902 non-diabetics for whom there were baseline fasting serum insulin and glucose values. Fasting serum insulin and glucose tests also were performed during the median follow-up of 11.9 years.

In all, 81 cases of colorectal cancer developed during follow-up. These patients on average tended to be older, less physically active, and were more likely to be non-Hispanic whites. The researchers found baseline glucose levels to be positively associated with colorectal cancer and colon cancer risk. In both age- and multivariable-adjusted analyses, baseline insulin and HOMA-IR levels were not associated with colorectal cancer risk. However, in both analyses, baseline glucose levels were associated with risk: in the multivariable-adjusted analysis, the hazard ratio from highest to lowest tertile of glucose was 1.74. In just the subjects who developed colorectal cancer, the hazard ratio for highest tertile of glucose versus the lowest was 2.25, but insulin and HOMA-IR were not associated with risk.