Transthyretin Predicts Cardiovascular Outcome in Hemodialysis Patients With Type 2 Diabetes

OBJECTIVE

BMI and albumin are commonly accepted parameters to recognize wasting in dialysis patients and are powerful predictors of morbidity and mortality. However, both parameters reveal limitations and may not cover the entire range of patients with wasting. The visceral protein transthyretin (TTR) may be helpful in overcoming the diagnostic and prognostic gap. Therefore, the aim of this study was to assess the association of TTR with morbidity and mortality in hemodialysis patients.

RESEARCH DESIGN AND METHODS

The TTR concentration was determined in plasma samples of 1,177 hemodialysis patients with type 2 diabetes. Cox regression analyses were used to determine hazard ratios (HRs) for the risk of cardiovascular end points (CVEs) and mortality according to quartiles of TTR concentration for the total study cohort and the subgroups BMI ≥23 kg/m², albumin concentration ≥3.8 g/dL, and a combination of both.

RESULTS

A low TTR concentration was associated with an increased risk for CVE for the total study cohort (HR 1.65 [95% CI 1.27–2.14]), patients with BMI ≥23 kg/m² (1.70 [1.22–2.37]), albumin ≥3.8 g/dL (1.68 [1.17–2.42]), and the combination of both (1.69 [1.13–2.53]). Additionally, a low TTR concentration predicted mortality for the total study cohort (1.79 [1.43–2.24]) and patients with BMI ≥23 kg/m² (1.46 [1.09–1.95]).

CONCLUSIONS

The current study demonstrated that TTR is a useful predictor for cardiovascular outcome and mortality in diabetic hemodialysis patients. TTR was particularly useful in patients who were not identified to be at risk by BMI or albumin status.Transthyretin (TTR), formerly referred to as prealbumin, is known as a sensitive indicator of inflammation and malnutrition (1,2) and has also been described as a marker of body composition (3,4). With regard to hemodialysis patients, TTR is a well-accepted marker of protein-energy wasting (PEW), which is highly prevalent in patients with end-stage renal disease (5,6). PEW represents a syndrome characterized by depletion of body energy and protein stores, inflammation, and development of comorbidities (7) and is highly associated with the risk of death as well as fatal and nonfatal cardiovascular disease (CVD) in hemodialysis patients (8,9). An expert panel suggested a combination of several parameters for the diagnosis of PEW (7); among these, the most frequently and routinely applied are BMI and serum albumin concentration. Both parameters are known to be inversely associated with mortality and morbidity in hemodialysis patients (10–12).However, BMI and serum albumin concentration have several limitations in diagnosing PEW and subsequently the risk for all-cause mortality and CVD. Among other things, it has been criticized that BMI is not able to discriminate between fat and lean body mass, and a high body mass might be misinterpreted as an appropriate nutritional status. Consequently, patients may be misclassified and wasting may not be recognized. On the other hand, the detrimental effects of being overweight and obesity may also not be recognized or underestimated (13–15). Furthermore, the importance of serum albumin concentration is probably limited since it is more sensitive to inflammation than to nutrition (16), and thus nutrition-related complications are insufficiently considered (13). Additionally, serum albumin is sensitive to hydration status (17,18), and in diabetic patients, the capillary permeability of serum albumin is increased, which might adulterate the serum levels (19).In this context, the analysis of TTR might be useful in overcoming the resulting diagnostic and prognostic gap since TTR is known to be very sensitive to changes in visceral protein stores, correlated with muscle mass, and not affected by hydration status (3,20). Therefore, we hypothesized that TTR may likewise be a potent predictor of mortality and morbidity in hemodialysis patients beyond BMI and serum albumin concentration. Furthermore, since diabetes is a major risk factor for chronic kidney disease, aggravates PEW, and unequivocally increases the risk for cardiovascular events and mortality (6,21,22), the current study was particularly focused on hemodialysis patients with type 2 diabetes using data from the German Diabetes and Dialysis (4D) study.