Growth-Differentiation Factor 15 Predicts Worsening of Albuminuria in Patients With Type 2 Diabetes

Abstract

OBJECTIVEDevelopment of micro- or macroalbuminuria is associated with increased risk of cardiorenal complications, particularly in diabetes. For prevention of transition to micro- or macroalbuminuria, more accurate prediction markers on top of classical risk markers are needed. We studied a promising new marker, growth-differentiation factor (GDF)-15, to predict transition to increasing stage of albuminuria in type 2 diabetes mellitus (T2DM). In addition, we looked at the GDF-15 potential in nondiabetic subjects with hypertension (HT).RESEARCH DESIGN AND METHODSCase and control subjects were selected from the PREVEND cohort, a large (n = 8,592), prospective general population study on the natural course of albuminuria, with >10 years of follow-up and repeated albuminuria measurements. We found 24 T2DM and 50 HT case subjects transitioning from normo- to macroalbuminuria and 9 T2DM and 25 HT case subjects transitioning from micro- to macroalbuminuria (average follow-up 2.8 years). Control subjects with stable albuminuria were pair matched for age, sex, albuminuria status, and diabetes duration. GDF-15 was measured in samples prior to albuminuria transition.RESULTSPrior to transition, GDF-15 was significantly higher in case subjects with T2DM than in control subjects (median [IQR] 1,288 pg/mL [885–1,546] vs. 948 pg/mL [660–1,016], P < 0.001). The odds ratio for transition in albuminuria increased significantly per SD of GDF-15 (2.9 [95% CI 1.1–7.5], P = 0.03). GDF-15 also improved prediction of albuminuria transition, with significant increases in C statistic (from 0.87 to 0.92, P = 0.03) and integrated discrimination improvement (0.148, P = 0.001). In HT, GDF-15 was also independently associated with transition in albuminuria stage (2.0 [1.1–3.5], P = 0.02) and improved prediction significantly.CONCLUSIONSWe identified GDF-15 as a clinically valuable marker for predicting transition in albuminuria stage in T2DM beyond conventional risk markers. These findings were confirmed in nondiabetic HT subjects.

Diabetic nephropathy in type 1 diabetes: a review of early natural history, pathogenesis, and diagnosis

“…Glomerular and renal tubular interstitial injuries play the main role in the pathogenesis of diabetic nephropathy, and to diagnose this pathologic entity, several glomerular and tubular damage markers have been recently identified. Increased levels of these markers are supposed to indicate proximal tubular damage in the case of kidney injury molecule 1, neutrophil gelatinase–associated lipocalin, N ‐acetyl‐β‐ d ‐glucosaminidase, cystatin C, chitinase‐3–like protein 1, plasma growth differentiation factor 15 . These tubular damage markers have been extensively investigated in predicting the occurrence of acute kidney injury after various nephrotoxic insults, such as ischemia during cardiac surgery or sepsis .…”

“…Increased levels of these markers are supposed to indicate proximal tubular damage in the case of kidney injury molecule 1, neutrophil gelatinase-associated lipocalin, 71 N-acetyl-β-D-glucosaminidase, cystatin C, chitinase-3-like protein 1, 72 plasma growth differentiation factor 15. 73 These tubular damage markers have been extensively investigated in predicting the occurrence of acute kidney injury after various nephrotoxic insults, such as ischemia during cardiac surgery or sepsis. 49,[74][75][76] The most studied biomarkers associated with DN are listed in Table 1.…”

Growth differentiation factor 15 impairs aortic contractile and relaxing function through altered caveolar signaling of the endothelium

“…Although measurements of GDF15 levels are technically not feasible in murine blood samples, several human studies (6,9,12,21) have shown increased GDF15 plasma levels in patients with T2DM. Therefore, to confirm the upregulation of GDF15 in the mouse model of T2DM, we measured GDF15 expression in white adipose tissue of db/ϩ and db/db mice by real-time PCR.…”

“…T2DM in mice. As GDF15 levels are rather low in healthy mice, we also explored the effects of genetic deletion of GDF15 on vascular function in a model of T2DM, a condition associated with increased GDF15 levels (12). Five female db/ϩ mice (B6.Cg-Dock7mϩ/ϩ Lepr db/J, 7 wk of age), heterozygous for a leptin receptor mutation, were purchased from The Jackson Laboratories (Charles River, L'Arbresle, France).…”

Multiplexed VeraCode bead-based serological immunoassay for colorectal cancer

“…In the future, , it is expected that the CRC biomarker panel would not only expand, but would be refined through elimination of biomarkers as further studies are performed using the VeraCode™ immunoassay methods presented here. For example, GDF15 is a stress-induced cytokine and in addition to CRC has been shown to be a biomarker for a variety of conditions such as heart disease (reviewed in (Wollert and Kempf, 2012)) and worsening albuminuria in patients with type 2 diabetes (Hellemons et al, 2012). …”