Cachexia and protein-energy wasting are potent predictors of higher mortality risk in dialysis-dependent chronic kidney disease (CKD) patients. The novel cachexia marker, GDF15, is a protein associated with inflammation, cardiovascular disease, and decreased survival in patients with underlying malignancy. However, the impact of GDF15 on the survival of CKD patients is unknown. Among 203 prevalent hemodialysis patients enrolled in the prospective MADRAD study over the period of 10/2011-8/2014, we examined the association of GDF15 levels with all-cause mortality risk. Associations between GDF15 categorized into tertiles with mortality were estimated using unadjusted and case-mix adjusted Cox models. Compared with the lowest GDF15 tertile, the highest GDF15 tertile was associated with higher mortality risk in unadjusted and case-mix adjusted models: HR (95%CI) 3.19 (1.35-7.55) and 2.45 (1.00-6.00), respectively, p-for-trend 0.03 (Figure 1A). Higher circulating GDF15 levels in hemodialysis patients are associated with higher all-cause mortality. Future studies are needed to determine whether modulation of GDF15 levels and subsequent correction of cachexia improves survival in this population.

Background/aims

Cardiovascular disease and protein-energy wasting are among the strongest predictors of the high mortality of dialysis patients. In the general population, the novel cardiovascular and wasting biomarker, growth differentiation factor 15 (GDF15), is associated with decreased survival. However, little is known about GDF15 in dialysis patients.

Methods

Among prevalent hemodialysis patients participating in a prospective study (October 2011 to August 2015), we examined the association of baseline GDF15 levels with all-cause mortality using unadjusted and case mix-adjusted death hazard ratios (HRs) that controlled for age, sex, race, ethnicity, diabetes, and dialysis vintage.

Results

The mean age ± SD of the 203 patients included in the study was 53.2 ± 14.5 years, and the cohort included 41% females, 34% African-Americans, and 48% Hispanics. GDF15 levels (mean ± SD 5.94 ± 3.90 ng/mL; range 1.58-39.8 ng/mL) were higher among older patients and were inversely associated with serum creatinine concentrations as a surrogate for muscle mass. Each 1.0 ng/mL increase in GDF15 was associated with an approximately 17-18% higher mortality risk in the unadjusted and case mix models (p < 0.05). Increments of about 1 SD (a 4.0 ng/mL increase in GDF15) were associated with a nearly 2-fold higher death risk. The highest GDF15 tertile was associated with higher mortality risk (reference: lowest tertile): the HRs (95% CI) were 3.19 (1.35-7.55) and 2.45 (1.00-6.00) in the unadjusted and the case mix-adjusted model, respectively. These incremental death trends were confirmed in cubic spline models.

Conclusion

Higher circulating GDF15 levels are associated with higher mortality risk in hemodialysis patients. Future studies are needed to determine whether GDF15 may represent a novel therapeutic target for cardiovascular disease, wasting, and death in this population.