Erythropoietin resistance due to dialysate chloramine: the two-way traffic of solutes in haemodialysis

Donald Richardson1, Cherry Bartlett1, Eddie Goutcher1, Colin H. Jones2, Alex M. Davison1 and Eric J. Will1

1 Department of Renal Medicine, St James's University Hospital, Leeds and 2 Department of Renal Medicine, York District General Hospital, York, UK

Correspondence and offprint requests to: Dr Donald Richardson, Renal Research Registrar, Department of Renal Medicine, St James's University Hospital, Beckett Street, Leeds LS9 7TF, UK.

Keywords: anaemia; chloramine; erythropoietin resistance; haemodialysis; haemolysis; renal failure

Introduction

Renal anaemia is primarily a consequence of erythropoietin deficiency and is amenable to treatment with exogenous erythropoietin. Erythropoietin is expensive and can consume a large proportion of the budget for end-stage renal replacement therapy so that any cause of erythropoietin resistance has important resource implications. The usual cause of erythropoietin resistance is inadequate available iron for erythropoiesis in the bone marrow although the definitive list is long [1]. We developed a clinical management system in an attempt to improve the cost-benefit ratio for erythropoietin and intravenous iron therapy in our haemodialysis population. We encountered a potent and insidious cause of anaemia in a subset of our haemodialysis population from a recognized cause not usually included in such a list. Investigations were prompted by continuous audit of the management of renal anaemia, which indicated that patients in one of our satellite units suffered declining haemoglobin concentrations despite adequate iron therapy and steadily increasing doses of erythropoietin.

Cohort study

A computer aided algorithm to optimize erythropoietin and intravenous iron therapy was in use for all our haemodialysis patients (n=236: main unit (137), four satellite units (99)). Following introduction of the algorithm, haemoglobin values increased from a median of 10.0 g/dl (inter-quartile range (IQR) 8.8–11.4) to 11.7 g/dl (10.3–12.7) (P<0.001 Wilcoxon signed rank test) over 14 months of study. This outcome was achieved by the systematic adjustment of intravenous iron and erythropoietin therapy. The median erythropoietin dose increased from 82 IU/kg/week (IQR 44–120) to 105 IU/kg/week (48–173) (P=0.001 Wilcoxon signed rank test) at the end of the study. At month 10 it was noticed that the erythropoietin requirements for patients in satellite unit 2 (204 IU/kg/week (145–269) (n=18)) was greater than that of patients in the other four units (128 IU/kg/week (IQR 70–201)) (P=0.04 U-Mann Whitney test) and yet the haemoglobin remained lower (10.4 g/dl (9.2–11.3) vs 11.6 g/dl (10.4–12.7) (P<0.01 U-Mann Whitney test)). In month 11, there was a further significant decrease in the median haemoglobin in satellite unit 2 to 9.0 g/dl (8.3–10.6) (cf. the other units: 11.8 g/dl, IQR 10.5–12.9) (P<0.01 U-Mann Whitney test) in spite of appropriate standard intervention as determined by the management system. This prompted detailed investigation, particularly of the mains water supply, which revealed an unexpectedly high mains water chlorine content (0.7 mg/l, desirable limit <0.1 mg/l) (Figure 1Go) and evidence of haemolysis (i.e. high ferritin: median 607 ng/ml (IQR 369–777) vs 226 (149–326) (P<0.01 U-Mann Whitney test), low mean haptoglobin: 0.63 g/l (0.3–1.4) vs normal range: 0.64–2.56).



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Fig. 1. Total [chlorine] in mains water supply during months 1-14.

 
An activated charcoal filter was installed to pre-treat the water and this decreased the chlorine concentration to <0.02 mg/l at the outlet to the dialysis machines. There was subsequently an increase in haemoglobin (12.8 g/dl (10.7–14.4)) (Figure 2Go) and a reduction in erythropoietin requirement over the next 3 months (median 165 IU/kg/week (50–276)) with continued management through the algorithm.



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Fig. 2. Percentage of patients with Hb>10.0 g/dl at satellite unit 2.

 
Discussion

Water quality and haemodialysis
Water contaminants can cause infectious or toxic complications during the haemodialysis process. Water quality first became an issue for patients on haemodialysis with the recognition of the `hard water' syndrome. Hypercalcaemia and hypermagnesaemia resulted as a consequence of high concentrations of these solutes in untreated water used to prepare dialysis fluid [2]. In addition to acute toxic episodes from inadequate water treatment, chronic exposure to low concentrations of toxic substances can produce complications as demonstrated by the development of aluminium-related anaemia, osteopathy and dementia [3]. Mains water contains many other potential contaminating substances, including sodium, calcium, magnesium, lead, sulphates, and some that can induce anaemia, such as aluminium, copper, nitrates, fluorine, arsenic, zinc, chlorinated compounds, free chlorine and chloramines. Some contaminants are present in the water at source, others are added as part of a treatment process for the production of safe drinking water, for public health reasons (fluorine), or leached from the distribution system. The maximum allowable concentrations for drinking water have been developed on the basis of a daily oral intake of approximately 2 l. During haemodialysis, blood comes into contact with approximately 120 l per dialysis session (4 h, 500 ml/min dialysate flow).

Chlorine as a toxic additive to water
Chlorinated compounds are used widely for disinfecting water for human consumption. Compounds such as liquid chlorine, chlorine oxide, sodium and calcium hypochlorites are oxidizing agents. Chloramines are the result of the combination of `free' chlorine and ammonium. The chlorine is used to disinfect the water in amounts proportional to bacterial counts and the ammonium is added to reduce the odour and taste of the chlorine. The two react immediately to produce three possible chloramines, mono-, di- and tri-chloramines (NH2Cl, NHCl2 and NCl3). Chloramines cause denaturing of haemoglobin and also inhibit the hexose monophosphate pathway that normally produces nicotinamide adenine dinucleotide phosphate (NADPH). Intracellularly the hexose monophosphate pathway produces reduced NADPH via glucose-6-phosphate dehydrogenase (G6PD) and 6-phosphogluconate dehydrogenase. As a reducing agent NADPH protects against oxidative damage to proteins. Incubation of red cells with dialysis fluid containing chloramines increases methaemoglobin, produces Heinz body formation and increases red cell lysis.

Haemolysis secondary to oxidative damage to this pathway was demonstrated in 1972 [4]. An oxidizing agent was demonstrated in the dialysis fluid. In 1973 this oxidizing agent was revealed as the chlorinated compound, chloramine [5].

Low chloramine water content on one day does not guarantee low levels on another, as the amount of chlorine added at source varies from day to day. Reverse osmosis, the method of choice for the preparation of dialysis water in most dialysis units does not remove chloramines. Deionizers are only partially effective, as the extraction rate is low and quite inadequate if the water chloramine content is high.

Ascorbic acid and chloramine activity
In 1977 ascorbic acid (a potent reducing agent) given intravenously or added to the dialysate water was demonstrated to protect against oxidative haemolysis secondary to chloramines at lower levels of contamination [6]. Ascorbic acid reduces chloramine to ammonium and hydrochloric acid and increased haemoglobin levels. Yet, higher chloramine concentrations in the mains water supply (likely in dry periods with lower water levels and higher bacterial counts) were associated with further episodes of haemolysis, despite continuing ascorbic acid therapy.

Recent reports have shown benefit from intravenous ascorbic acid post-dialysis in some erythropoietin resistant patient groups with high serum ferritins [7]. Ascorbic acid therapy may protect against oxidative damage to red cells whatever its origin. Up to 20% of dialysis patients have been reported as showing reduced hexose monophosphate activity [8]. These patients may be particularly susceptible to oxidative damage. Further investigation is necessary to determine whether the benefits of ascorbic acid in the setting of high ferritin and erythropoietin resistance is due to prevention of insidious haemolysis (possibly chloramine associated) or, say, through the utilization of previously inaccessible stored iron.

The present observation confirms and amplifies an observation which has recently been reported in this Journal [10].

Conclusion

Serial monitoring of `sub-populations' can provide a valuable insight into factors affecting outcome in many settings. Our standardized therapy of renal anaemia using a computer algorithm allowed early detection of this cause of `erythropoietin resistance'. It also demonstrated its convincing reversal using an activated charcoal filter in the satellite unit. It is useful to remember that dialysis membranes allow bi-directional solute transport and the transfer of water borne toxins. Water purity must be carefully maintained in the preparation of dialysis fluid as stressed in a recent article in this journal [9]. The authors did not, however, discuss chloramines or their removal. It appears that the preparation of pure water will need to include the use of activated charcoal filters in addition to the standard components (a reverse osmosis unit, de-ionizer and a safety UV disinfection step) in any unit where the mains water is `treated' by the use of chlorinated compounds. It is uncertain, currently, how widespread an issue this may be. The purchase of an activated charcoal filter and servicing costs are likely to be recovered from the erythropoietin budget very quickly, if chloramine-associated `erythropoietin resistance' is present.

Notes

Editor's note

Please see also the Editorial Comment by Pérez-García and Rodríguez-Benítez (pp. 2579–2582 in this issue).

References

  1. Macdougall IC. Poor response to erythropoietin: practical guidelines on investigation and management. Nephrol Dial Transplant 1995; 10: 607–614[ISI][Medline]
  2. Freeman RM, Lawton RL, Chamberlain MA. Hard water syndrome. New Eng J Med 1967; 276: 113–118
  3. Davison AM, Oli H, Giles GR, Lewins AM. Water supply aluminium concentration, dementia and effect of reverse osmosis water treatment. Lancet 1982; 2: 785–786[Medline]
  4. Yawata Y, Kjellstrand CM, Buselmeier TJ, Howe J, Jacob HS. Haemolysis in dialysis patients: Tap water-induced red blood cell metabolic deficiency. Trans Amer Soc Artif Int Organs 1972; 18: 301
  5. Eaton JW, Koplin CF, Swofford HS, Kjellstrand CM, Jacob HS. Chlorinated urban water: a cause for dialysis induced hemolytic anemia. Science 1973; 181: 98: 463–464[ISI][Medline]
  6. Botella J, Traver JA, Sanz-Guajardo, Torres MT, Sanjuan I, Zabala P. Chloramines, an aggravating factor in the anaemia of patients on regular dialysis treatment. Dial Transplant Nephrol Proc 1977; 14: 192–199
  7. Tarng DC, Huang TP. A parallel, comparative study of intravenous iron versus intravenous ascorbic acid for erythropoietin-hyporesponsive anaemia in haemodialysis patients with iron overload. Nephrol Dial Transplant 1998; 13: 2867–2872[Abstract]
  8. Yawata Y, Howe R, Jacob HS. Abnormal red cell metabolism causing haemolysis in uremia. A defect potentiated by tap water haemodialysis. Ann Intern Med 1973; 79: 632[ISI][Medline]
  9. Vorbeck-Meister I, Sommer R, Vorbeck F, Horl WH. Quality of water used for haemodialysis: bacteriological and chemical parameters. Nephrol Dial Transplant 1999; 14: 666–675[Abstract]
  10. Fluck S, McKane W, Cairns T et al. Chloramine induced haemolysis presenting as erythropoietin resistance. Nephrol Dial Transplant 1999; 14: 1687–1691.[Abstract]




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