Consensus Document Cautions on Limitations of eGFR, Albuminuria in Monitoring Diabetic Kidney Disease
A consensus conference of the American Diabetes Association (ADA), American Society of Nephrology, and the National Kidney Foundation (NKF) recently issued a report on diabetic kidney disease (DKD), one of the most frequent complications of diabetes and the leading cause of end-stage renal disease (Diabetes Care 2014;37:2864–83). The document summarizes the current state of DKD-related care and is intended to guide patient care and research.
The authors emphasized the importance of using estimated glomerular filtration rate (eGFR) to assess kidney function but noted that many clinicians and patients are unaware of how imprecise this estimate can be. eGFR has “at best, a 90% chance of being within 30% of the measured GFR,” they wrote. Currently used eGFR equations also are “significantly less precise” at higher GFRs, a particular concern in early DKD when elevated GFR—also known as hyperfiltration—may exist.
Although hyperfiltration has been implicated in the development and progression of nephropathy, studies of this relationship have produced inconsistent results.
The report also underscored the importance and clinical utility of measuring albuminuria as a marker for kidney disease and cardiovascular disease risk. However, measurements for albuminuria have not been standardized and have significant imprecision, according to the authors. “The most common assays were compared with a recently developed isotope dilution mass spectrometry assay and varied by approximately 40% across albumin concentrations from 13 mg/L to 1,084 mg/L,” they wrote. Compounding this imprecision, labs do not have a standardized way of reporting albuminuria and clinicians do not always understand how to interpret the results.
Still other issues with measuring and interpreting albuminuria include considerable intra-individual daily variation and “vagaries of study outcomes.” “A coefficient of variation of 40% has traditionally been reported for those with type 1 diabetes and an [albumin to creatinine ratio] of 30–300 mg/G creatinine,” according to the authors. Studies looking at albuminuria results have not taken a standardized approach, so some have used only a single urine sample, collected at various times of the day or at long periods between samples. The authors emphasize that ADA, NKF, and National Kidney Disease Education Program (NKDEP) recommendations all call for measuring albuminuria more than once, with two or three samples elevated during a 3-to-6 month period required to confirm the diagnosis of albuminuria.
The report notes that the NKDEP Laboratory Working Group and the National Institute of Standards and Technology already have standardized creatinine measurements and are collaborating with the International Federation of Clinical Chemistry and Laboratory Medicine to standardize urine albumin measurements and reporting. Despite these efforts “residual imprecision” in both biomarkers “makes it likely” that other biomarkers will be used in future, more precise predictive tools.
The authors cautioned clinicians about basing prognosis on a single biomarker measurement, yet they note that the American College of Physicians has challenged the concept of serial albuminuria monitoring in patients taking renin-angiotensin-aldosterone system antagonists. The report also suggests that it might be preferable to report urine albumin as a continuous variable.
Finally, the authors cite eight issues ripe for future clinical research including reporting cutoffs to define normal albuminuria, sex-specific cutoffs to identify patients at increased risk for cardiovascular disease, and whether albuminuria should be the primary endpoint in clinical trials to establish an evidence base for ongoing monitoring.
Serial ANCA Measurement Predicts Relapse in ANCA-Associated Vasculitis
Dutch researchers recently found that serial increases in anti-neutrophil cytoplasmic antibody (ANCA) were associated with relapses in ANCA-associated vasculitis, particularly in patients with renal involvement (J Am Soc Nephrol 2014; doi:10.1681/ASN.2013111233). Although ANCAs play an important role in ANCA-associated vasculitis, measuring ANCA levels during follow-up to predict relapse is controversial.
The investigators followed 166 patients with ANCA-associated vasculitis for an average of 49 months and 18 ANCA measurements. In all, 74 patients relapsed. At the time of a major relapse, all 26 such patients were ANCA-positive, and in 24, the relapse was preceded by an ANCA rise.
Rises in ANCA were most strongly correlated with relapses among patients who had renal involvement, defined as showing on biopsy pauci-immune necrotizing glomerulonephritis. In these patients, longitudinal increases in ANCA were correlated with an 11.09 hazard ratio for relapse. Rises in ANCA overtime did not have as strong a correlation for relapse in patients without renal involvement, yielding a 2.79 hazard ratio.
The authors suggested that serial monitoring of ANCA levels could help better manage patients with ANCA-associated vasculitis. “By measuring ANCA levels in patients with kidney involvement, doctors can predict which patients are going to relapse. It is expected that by using ANCAs as a guideline, severe relapses necessitating dialysis can be prevented,” said senior author, Jan Willem Cohen Tervaert, MD, PhD, in a prepared statement.
PSA Screening Still Not in Line With Current Recommendations
In recent years, medical associations and other healthcare groups have revised their guidelines on prostate-specific antigen (PSA)-based screening for prostate cancer, recommending more restrictive use of PSA than in prior guidelines. However, the effects of these changes, such as not routinely screening elderly men, have been “minimal at best,” according to new research (JAMA Intern Med 2014; doi:10.1001/jamainternmed.2014. 4117).
The authors analyzed data from the 2012 Behavioral Risk Factor Surveillance System to gauge current nation-wide patterns of PSA screening. Of 114,544 men 50 years and older, 37.1% reported having undergone PSA screening within the past year. Factors associated with the highest rates of screening included: having access to regular healthcare; income greater than $75,000; college education; health insurance; and being age 70 to 74. After adjustment for covariates, the highest self-reported rate of screening was among men in Hawaii (59.4%) versus the lowest in New Hampshire (24.5%).
Contrary to current guidelines advising against the practice, 45.7% of men ages 75 to 79 reported undergoing PSA screening within the preceding year. The researchers also noted wide state-by-state variances in screening rates. “It is alarming that the prevalence of PSA screening can double from one state to the next,” they wrote.
Guideline Endorses EGFR and ALK Mutation Testing in All Patients With Lung Adenocarcinoma
The American Society of Clinical Oncologists (ASCO) recently endorsed a previously published guideline on molecular testing for selecting patients with lung cancer for therapies targeting epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) (J Clin Oncol 2014; doi:10.1200/JCO.2014.57.3055). The guideline, originally developed by the College of American Pathologists (CAP), International Association for the Study of Lung Cancer (IASLC), and Association of Molecular Pathologists (AMP), was first published in 2013 (Arch Pathol Lab Med 2013;137:828–60).
In endorsing the CAP/IASLC/AMP guideline, ASCO noted that the document represents an important advance towards standardizing EGFR and ALK testing practices. Up to 20% of patients with lung adenocarcinoma will test positive for either EGFR or ALK mutations.
The guideline recommends testing for EGFR and ALK in all patients with lung adenocarcinoma or mixed lung cancers with adenocarcinoma component. Labs should validate their EGFR testing method to ensure that EGFR testing detects mutations in samples with as few as 50% tumor cells. However, the guideline encourages sensitivity to detect mutations in samples containing >10% tumor cells. Labs should turn around EGFR and ALK mutation test results within 5 to 10 working days. Immunohisto-chemistry for total EGFR, EGFR copy number, and ALK real-time polymerase chain reaction testing are not helpful as predictive assays for treatment selection.