The story of growth differentiation factor 15: another piece of the puzzle.

The research interest in risk markers in general, and biochemical risk markers in particular, has exploded in the last 2 decades. A Medline search on “cardiovascular risk markers” yields only 21 hits for the publication year 1990. By contrast, for 2010 the figure has risen almost 100-fold to 2032 hits. Despite the high number of new biomarkers examined, only a few have gained widespread use in routine clinical practice. In the cardiovascular area cardiac troponin T (cTnT), cTnI, B-type natriuretic peptide (BNP), and N-terminal proBNP are examples of biomarkers that have been put into widespread use on the basis of their excellent diagnostic properties rather than their similarly excellent prognostic properties. Why then is there such great interest in biomarkers studies for risk prediction? And what criteria must a biomarker fulfill to be accepted clinically? These 2 questions come to the forefront when considering the elegant study by Jennifer Ho and coworkers on biomarkers of cardiovascular stress and incident chronic kidney disease (CKD) presented in this issue of Clinical Chemistry (1 ). In the Framingham cohort, the authors evaluated 2 new markers, growth differentiation factor 15 (GDF-15) and soluble ST2, and 1 established marker, cTnT, for the prediction of the development of CKD. Convincing associations were shown between GDF-15 concentrations and the development of CKD and rapid decline of renal function. However, no similar statistically significant associations were demonstrated with the 2 other biomarkers. There was a gradual increase in risk with increasing quartiles of GDF-15; following multivariable adjustment, individuals with GDF-15 concentrations in the highest quartile, compared to those with concentrations in the lowest, had 5.65-fold (95% CI, 2.97–10.75) higher odds of incident CKD and 2.51-fold (95% CI, 1.54 – 4.09) higher odds of a rapid decline in renal function during 9.5 years of follow-up. Thus, another piece is added to the intriguing puzzle of GDF-15. GDF-15 is a member of the transforming growth factor superfamily; it is also known as macrophage inhibitory cytokine-1, placental transforming growth factor, gene placental bone morphogenic protein, prostate-derived factor, NSAID (nonsteroidal antiinflammatory drug)-activated gene 1, and placental transforming growth factor. The expression of GDF-15 in virtually all tissues suggests its importance in general and basic cellular functions. Although the exact biological functions of GDF-15 are still poorly understood, it has been shown to be involved in regulating inflammatory and apoptotic pathways and its expression is upregulated in many different pathological conditions, including inflammation, cancer, cardiovascular disease, pulmonary disease, and renal disease. GDF-15 exhibits differing and even opposing functions under various circumstances. For instance, GDF-15 may show proapoptosis, antiapoptosis, proangiogenesis, antiangiogenesis, proproliferative, antiinflammatory, and immunosuppressive properties (2, 3 ). Therefore, GDF-15 exhibits a complex pattern of beneficial and harmful functions. Whether increased serum concentrations can cause direct damage or may represent a protective response to biologic stress is still an open question, and the answer might well depend on the circumstances. GDF-15 has been shown to be a strong and independent predictor of mortality and disease progression in patients with established disease, such as acute coronary syndromes, angina pectoris, heart failure, stroke, chronic kidney disease, and different types of cancer (3– 6 ). In addition, in community dwellers, higher concentrations of GDF-15 have been associated with increased cardiovascular as well as noncardiovascular mortality, and development and progression of a broad range of diseases, such as coronary artery disease, heart failure, diabetes, cancer, and even cognitive impairment (7–10 ). The study of Ho et al. now adds CKD to that list (1 ). A study on twins indicated that although genetic and environmental factors contributed nearly equally to variations in GDF-15 concentrations, differences in the environmental factors, rather than in the genetic background, were the major determinants of the differ1 Department of Medical Sciences, Cardiology, and Uppsala Clinical Research Center, University of Uppsala, Sweden. * Address correspondence to the author at: Uppsala Clinical Research Center, University Hospital, SE-751 85 Uppsala, Sweden. Fax 46-18515570; e-mail [email protected]. Received August 21, 2013; accepted August 23, 2013. Previously published online at DOI: 10.1373/clinchem.2013.212811 2 Nonstandard abbreviations: cTnT, BNP, B-type natriuretic peptide; CKD, chronic kidney disease; GDF-15, growth differentiation factor 15. Clinical Chemistry 59:11 1550–1552 (2013) Editorials