Association of ESA hypo-responsiveness and haemoglobin variability with mortality in haemodialysis patients

Abstract

Background: Anaemia is a common complication in dialysis patients. In most cases, it is treated with erythropoietin-stimulating agents (ESA). It is not entirely clear whether the variability of haemoglobin caused by changing ESA response is associated with increased mortality. Therefore, we conducted a retrospective cohort study to evaluate ESA responsiveness and haemoglobin variability in association with mortality.

Methods: We used the Austrian dialysis and transplant registry, and identified 932 patients who were on maintenance haemodialysis in the years 2005-08 with recorded weekly ESA doses and haemoglobin concentrations. ESA response was defined as a positive regression slope over the observation period. Cox regression analysis with spline functions and purposeful variable selection algorithms were used.

Results: Adjusted Cox regression analysis showed an increased mortality risk in subjects with wide ranges of haemoglobin variability (from <10 to >12 g/dL) (HR = 2.38, 95% CI 1.20-4.71, P = 0.013). Furthermore, patients that never reached haemoglobin levels >10 g/dL despite ESA therapy exhibited the highest risk of mortality (HR = 6.37, 95% CI 2.15-18.82, P < 0.001). ESA hypo-responsiveness was associated with increased risk of mortality in the low as well as high haemoglobin ranges [HR = 2.06, 95% CI 1.49-2.86 at haemoglobin of 9.5 g/dL and HR = 1.64, 95% CI 0.68-3.92 at 13.5 g/dL both vs. 11 g/dL (reference)]. ESA dose equivalents >16,000 units per week were associated with increased mortality in ESA responders (HR = 1.30, 95% CI 1.02-1.64). However, in hypo-responders, mortality is not associated with ESA dose (HR = 1.02, 95% CI 0.87-1.20) [both at weekly ESA dose of 20,000 units vs. 16,000 (reference)].

Conclusions: These findings suggest that the risk of mortality of haemodialysis patients requiring ESA therapy is lowest if the haemoglobin concentration is stably maintained in the range between 10 and 12 g/dL with weekly ESA dose equivalents <16,000 units.

Fig. 1

Forest plot of hazard ratios of mortality. The variability group MM was used as reference and is indicated by the dashed line. ADS, ‘age, dialysis and sex’. The imputed model (D) is adjusted for ADS, ESA response, diabetes and BMI.

Fig. 2

Hazard ratio for haemoglobin levels in ESA response group with (A) slopes ≤0 (hypo-responders) and (B) slopes >0 (responders—restricted cubic spline with four knots). Coloured bands indicate the 95% confidence intervals. The following variables were included in the model: haemoglobin, ESA dose, age, sex and vintage of dialysis.

Fig. 3

Hazard ratio for ESA dose in ESA response group with (A) slopes ≤0 and (B) slopes >0 (restricted cubic spline with four knots). Coloured bands depict the 95% confidence intervals. The following variables were included in the model: haemoglobin, ESA dose, age, sex and vintage of dialysis.