Extracellular fluid volume and EPO dose in haemodialysis

Sir,

Erythropoietin (EPO) requirements vary in haemodialysis patients. The most commonly recognized causes of EPO resistance are iron deficiency and chronic inflammation. We have previously noted a correlation between serum albumin and extracellular fluid volume (Vecf) in HD patients [1]. If serum albumin is lower in subjects with an increased Vecf, then haemoglobin may be too. However, unlike albumin, the haemoglobin concentration can be manipulated by the administration of drugs, particularly EPO and iron. We use a computerized anaemia management algorithm to manage the haemodialysis population. EPO and iron doses are determined by: (i) the actual haemoglobin, i.e. the threshold (below which EPO dose increases) and ceiling (above which the EPO dose decreases); (ii) the relative change in haemoglobin, i.e. the size of change in the EPO dose; (iii) the ferritin, i.e. the ceiling for iron administration; and (iv) the percentage iron saturation (TSAT), i.e. the prescribed iron dose.

This algorithm gives a stable haemoglobin and ferritin outcome. Within this framework, we have looked for factors that influence the achieved haemoglobin and the dose of EPO required to obtain it. In particular, we have explored the influence of inflammatory markers and of Vecf.

This was an observational cohort study using data that are collected routinely in our haemodialysis population. We measure pre-dialysis Vecf and total body water (Vtbw) as part of our hypertension management programme. Vecf and Vtbw are measured by multiple frequency bioelectric impedance (Hydra, Xitron technologies) as previously described [2]. Vecf was normalized as a ratio of Vtbw (Vecf/Vtbw). Haemoglobin, serum ferritin, albumin, and C-reactive protein (CRP) were measured by standard assays in a fully accredited hospital laboratory. Correlations were sought between haemoglobin, CRP, serum ferritin, albumin, EPO dose/kg body weight and Vecf/Vtbw.

Bio-impedance data were available in 61 non-selected patients. The median (25th and 75th centile) haemoglobin, CRP, serum ferritin, serum albumin, EPO dose/kg and Vecf/Vtbw were 11.6 g/dl (10.7–12.8), 10 mg/l (5–26.3), 473 µg/l (348–582), 38 g/l (34.8–40), 124 U/kg/week (47–208) and 0.51 (0.48–0.52), respectively. A correlation matrix is shown in Table 1. The achieved haemoglobin was negatively correlated with CRP (r = -0.311, P = 0.01) and EPO dose/kg (r = -0.344, P = 0.006) and positively correlated with serum albumin (r = 0.344, P = 0.006). EPO dose/kg was positively correlated with Vecf/Vtbw (r = 0.249, P = 0.049; Figure 1) and negatively correlated with serum albumin (r = -0.312, P = 0.013).


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Table 1. Correlation between haemoglobin (Hb), serum ferritin, serum albumin, CRP, EPO dose/kg body weight per week and extracellular fluid volume as a ratio of total body water (Vecf/Vtbw)

 


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Fig. 1. Graph demonstrating an increasing EPO dose with increasing extracellular fluid volume.

 
Under the influence of a treatment algorithm that maintains a stable haemoglobin outcome and iron status, inflammation is the major determinant of achieved haemoglobin. This is indicated by a negative correlation with CRP (an acute phase protein) and a positive correlation with serum albumin (a negative acute phase protein). The quantity of EPO required to achieve this haemoglobin outcome was positively correlated with the Vecf as a ratio of total body water. This suggests that under the influence of a treatment algorithm, volume expansion will result in a greater EPO requirement.

This observation cannot be fully explained by the present study. The relationship may be straightforward; the intravascular volume is expanded and haemoglobin concentration is diluted. Alternatively, a high CRP may indicate an inflammatory process that both impairs haemoglobin production and increases vascular permeability, resulting in an increased Vecf.

The findings could have important implications in clinical practice. First, increased EPO doses may not be needed in volume-expanded patients, as one might accept a lower pre-dialysis haemoglobin. It might be possible in the future to incorporate Vecf into the anaemia management algorithm. Secondly, one way of achieving an improved haemoglobin outcome might be to increase the ultrafiltration volume and thus decrease the dry weight of the patient population. Whether this could lead to a sustained improvement in haemoglobin outcome has not been tested. Thirdly, achieving a pre-dialysis haemoglobin concentration in the normal range in a volume-expanded subject will mean that the post-dialysis haemoglobin will be greater than normal, with potential detrimental consequences. This might be particularly relevant in avoiding post-dialysis polycythaemia where clinicians are attempting to comply with the European Best Practice Guidelines [3] for anaemia (pre-dialysis Hb >11 g/dl), which requires a population mean haemoglobin of 12.7 g/dl with an SD of ~1.7 g/dl [4].

In conclusion, an expanded Vecf may increase the amount of EPO prescribed in order to obtain recommended pre-dialysis haemoglobin values. Perhaps routine assessment of Vecf, or ideally but less practically plasma volume, should become part of an anaemia management protocol.

Conflict of interest statement. D.R. and C.H.J. have received sponsorship to attend national and international meetings from the manufacturers of all EPO brands. D.R. has acted as medical adviser to the manufacturers of all EPO brands.

Colin H. Jones, Lucy Martin, Lynn Ridley and Donald Richardson

Renal Unit York Hospital York UK Email: colinjones{at}doctors.org.uk

References

  1. Jones CH, Akbani H, Croft DC, Worth DP. The relationship between serum albumin and hydration status in hemodialysis patients. J Renal Nutr 2002; 12: 209–212[CrossRef][ISI][Medline]
  2. Jones CH, Newstead CG, Will EJ, Smye SW, Davison AM. Assessment of nutritional status in CAPD patients: serum albumin is not a useful measure. Nephrol Dial Transplant 1997; 12: 1406–1413[Abstract]
  3. Jacobs C, Horl WH, Macdougall IC et al. European best practice guidelines 5: target haemoglobin. Nephrol Dial Transplant 2000; 15 [Suppl 4]: 15–19[Medline]
  4. Will EJ, Cameron JS. European guidelines for renal anaemia-predicting 85% compliance. Nephrol Dial Transplant 2000; 15: 439–440[Free Full Text]