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Published on 1 November 2007

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Conformity to treatment objectives with erythropoiesis-stimulating factors in pre-dialysis CRF

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Genma Silva*
PharmD

Hospital Pharmacist Resident

Nuria Rudi*

Anisi Moron*

Esther Ponz†

Victor de Pedro*

Joan Altimiras*

*Department of Pharmacy

†Department of Nephrology

Corporacio Sanitària Parc Taulí
Sabadell
Barcelona
Spain

E: gsilva@tauli.cat

Normocytic and normochromic anaemias are present in most patients with impaired renal function. The leading cause of anaemia in patients with chronic renal failure (CRF) is insufficient erythropoietin (EPO) production as a result of impaired kidney function; consequently, they are treated with EPO, a glycoprotein hormone produced by recombinant DNA technology which is identical to human erythropoietin in terms of protein sequence, biological activity and immunological reactivity. Its mechanism of action is based on stimulating red-cell production (erythropoiesis).[1–3]

For the treatment of anaemia in patients with CRF, the current guidelines of the European Dialysis and Transplantation Association (EDTA) recommend a target haematocrit range of 33–36% and a target haemoglobin range of 11–14 g/dl.[4–5] To achieve and maintain these objectives, most patients on EPO therapy must have adequate iron stores. However, many patients present absolute and/or functional ferropenia; hence, routine exogenous iron is essential in obtaining optimal treatment outcomes with EPO.[6–10] The Transferrin Saturation Index (TSAT) indicates the amount of iron available for erythropoiesis and is a good marker of functional iron deficit, and serum ferritin is the best single test for reflecting iron metabolism; however, because it is an acute-phase reactant it loses value in the presence of inflammatory and infiltrative processes.[11]

If the chronic anaemia is not treated properly during the initial stages of kidney disease, the risk of cardiac complications is significantly higher, increasing mortality during the first year of dialysis and markedly diminishing quality of life. Most CRF patients have multiple cardiovascular risk factors – the leading cause of death in this patient population.[12–18]

We must also consider that elevated haemoglobin levels increase the risk of arteriovenous thrombi and poorer control of hypertension, and can increase morbimortality.[4,5,19–23]

It is therefore interesting to comprehend the ­reality about EPO prescription and its surveillance in our environment in order to adopt the corresponding corrective measures, if pertinent.

The objective was to analyse EPO prescription adjustment in pre-dialysis CRF patients according to EDTA recommendations.

Materials and methods
A cross-sectional, retrospective, descriptive study was conducted in a level II general teaching hospital in February-March 2006. Fifty-five patients with pre-dialysis CRF in active treatment with EPO ß were included and recorded on the database of available ambulatory patients in the pharmacy department. According to the EDTA, treatment with EPO ß seeks to achieve haemoglobin (Hb) levels of 11–14 g/dl, in the absence of cardiovascular risk factors that require Hb levels to be maintained at 11–12 g/dl. The recommended level of ferritin (FE) must be greater than 100 ng/ml, and transferrin saturation (TSAT) must be greater than 20%.[5] The following patient information was recorded: demographic data, CRF aetiology, diagnosis of diabetes mellitus (DM), weight, EPO dose, ­creatine (Cr), glomerular filtration rate (GFR) by means of the Cockroft-Gault formula, Hb, FE, TSAT. The existence of CRF and DM was regarded as confirmation of cardiovascular disease.

EPO prescription conformity was assessed at two timepoints: when it was first prescribed, and at the cross-sectional study cutoff point. The first conformity assessment was evaluated in terms of Hb levels and iron stores. At the time of the cross-­sectional analysis, Hb levels, iron deposits, EPO dose, GFR, and the attitude adopted when Hb values fell outside the recommended limits were assessed.

Kidney function was measured by calculating the variations in glomerular filtration rate on time elapsed from the start of treatment until the cross-sectional cutoff point.

Results
Fifty-five patients in active treatment with EPO ß were evaluated. The demographic characteristics of the sample, as well as CRF aetiology, are presented in Table 1. Of the subjects, 60% were diabetic and were considered to have cardio­vascular disease.

[[HPE35_43_1]]

At the time of the first prescription for EPO, the mean values were as follows: Hb 9.9 g/dl ± 0.7, FE 323.5 ng/ml ± 355.19, TSAT 21.8% ± 9.4, Cr 3 mg/dl ± 1.19, GFR 4.56 ml/min ± 15.44.

In 58% of the patients the initial prescription did not conform to EDTA recommendations on one or more parameters:

  • Two patients presented Hb levels that exceeded 11 g/dl.
  • Seven patients displayed FE levels of 100 ng/ml or less.
  • Twenty-five patients exhibited TSAT values of 20% or less.

At the time of the cross-sectional evaluation, the mean values were as follows: Hb 11.9 g/dl ± 1.5, FE 310.29 ng/ml ± 298.43, TSAT 17.4% ± 6.4, Cr 3.37 mg/dl ± 1.6, GFR 23 ml/min ± 13.3. Mean follow-up time was 17.3 months.

More than 85% (85.45%) of the patients did not meet EDTA guideline recommendations for one or more parameters at cutoff:

  • Hb levels: seven patients had Hb values of less than 11 g/dl and had been on treatment for more than three months; one patient presented a Hb value greater than 14 g/dl; 19 patients with cardiovascular disease had Hb levels greater than 12 g/dl.
  • Nine presented FE levels of 100 ng/ml or less.
  • Thirty-six patients had TSAT values of 20% or less.

The prescription conformity to EDTA guidelines is summarised in Table 2.

[[HPE35_43_2]]

Percentages of patients according to degree of kidney failure and course of illness are presented in Table 3. CRF severity has been quantified according to NKF/DOQI clinical practice guidelines.

[[HPE_35_45_1x]]

The degree of renal function impairment was moderate and the 50th percentile of GFR decrease was 1.33 ml/min in one year.

At the cross-sectional cutoff point, 27 patients had Hb values not to target; the attitude adopted was not consistent with EDTA guideline recommendations in 96.29% of the patients in terms of suspending treatment and/or dose titration. Patients presenting Hb <11 g/dl with treatment duration of less than three months were not evaluated. Patients with diabetes were considered cardiovascular patients; consequently, Hb levels should have been at 11–12 g/dl; figures that fell outside this range were considered inadequate, as they represented a serious health risk. The dose of EPO was not titrated down in any of the 19 diabetic patients with Hb levels >12 g/dl or in the subject who presented Hb >14 g/dl.

Discussion
These results reveal a high degree of divergence in EPO prescription with respect to EDTA recommendations. The number one problem at the beginning of treatment with EPO is that ferropenia, both absolute and functional, do not comply with EDTA guidelines. At the time of the cross-sectional evaluation, insufficient iron levels are also seen. The guidelines recommend maintaining ferritin levels at 200–500 ng/ml to improve Hb levels, given that if these stores fail to reach minimum levels, erythropoiesis will not be effective.[5]

During the maintenance phase, EPO doses were not adjusted in six patients of the seven who presented Hb <11 g/dl; this may be justified on the basis that none of these subjects had adequate functional or absolute iron levels, and increasing the dose would not be effective in the absence of proper iron levels.[5–6]

The high percentage of failure to conform to EDTA guidelines insofar as dose titration during the maintenance phase is concerned is due in part to the fact that at the time the study was carried out, diabetic patients were considered to have a cardiovascular disease and, as a result, Hb levels should have been at 11–12 g/dl; however, until the time the study was carried out, the clinicians did not take the objective stated in the guidelines into account.[5,24] There has been controversy surrounding appropriate Hb levels. For a time, attempts were made to demonstrate that even levels of Hb >12 g/dl were a better treatment target, although this theory has been disproved.[4,5,19–21]

In the cross-sectional study, only 50.91% of the patients met Hb targets. This is a target that is not easily reached, since the optimal margin is a very narrow one and levels often readily fall out of limits of recommendations. High Hb levels in patients with kidney disease have been seen to increase the risk of morbimortality associated with cardiovascular events.[5]

The decrease in GFR during the study is irrelevant during treatment with EPO. Nevertheless, we have not studied GFR evolution in patients with CRF during the period prior to therapy with these drugs. It is known that treatment with EPO does not aggravate GFR and some studies have even concluded that it conserves it.[25–26]

This study has at least the following limitations:

  • A comprehensive review of the clinical histories has not been carried out, since patients with intercurrent pathologies might account for Hb levels <11 g/dl due to other causes.
  • Hydration status was not examined and could have interfered with Hb levels.
  • During the time elapsed between the first prescription and the cross-sectional cutoff point, the monitoring of several points was not assessed.
  • Most clinical guidelines set Hb targets based on patients who are on haemodialysis, whereas our patients are in the pre-dialysis stage.

Finally, these data suggest that closer surveillance and coordinated monitoring between the nephrology department and the pharmacy department dispensing the EPO would improve the percentage of patients meeting Hb targets that conform to EDTA guidelines.

Conclusions
There are divergences between guideline recommendations and reality regarding the targets. The haemoglobin targets should be met, given the fact that when Hb levels fall outside those targets, morbi­mortality as well as costs are increased.

These results also suggest that closer monitoring would improve treatment effectiveness in these patients. The establishment of a database and joint action between the departments of nephrology and pharmacy could make this objective feasible.

The authors have no conflicts of interest that are directly relevant to the content of this article.

References
1. Valderrábano F. Nephrol Dial Transplant 2002;17 suppl 1:13-18.

2. Macdougall IC. Nephrol Dial Transplant 2001;16 Suppl 5:50-55.

3. Roche. Neorecormon® 3000UI drug information. Basel: Roche Laboratories; 2005.

4. Working Party for European Best Practices. Nephrol Dial Transplant 1999;14;Suppl 5:1-50

5. European Renal Association/European Dialysis and Transplant Association. Nephrol Dial Transplant 2004;19(Suppl 2):ii6-ii15.

6. Post JB, et al. Int Urol Nephrol 2006;38(3-4):719-23.

7. Fernández-Rodríguez AM, et al. Am J Kidney Dis 1999;34:508-13.

8. Drueke TB, et al. Clin Nephrol 1997;48:1-8.

9. NKF-DOQI Work Group. Am J Kidney Dis 2001;60:2406.

10. NKF-DOQI Work Group. Am J Kidney Dis 2006;47(Suppl 3):S1.

11. Navajas A. Alteraciones del metabolismo del hierro. Paper presented at 17th Jornadas de Pediatría en Atención Primaria, Vitoria-Gasteiz, Spain, 11 November 2005.

12. Jurkovitz CT, et al. J Am Soc Nephrol 2003;14:2919-25.

13. Abramson JL, et al. Kidney Int 2003; 64:610-15.

14. McClellan WM, et al. J Am Soc Nephrol 2002;13:1928-36.

15. Fink J, et al. Am J Kidney Dis 2001;37:348-55.

16. Ma JZ, et al. J Am Soc Nephrol 1999;10:610-19.

17. Xia H, et al. J Am Soc Nephrol 1999;10:1309-6.

18. Collins AJ, et al. Semin Nephrol 2000;20:345-9.

19. Singh AK, N Engl J Med 2006;355(20):2085-98.

20. Volkova N, Arab L. Am J Kidney Dis 2006;47(1):24-36.

21. Phrommintikul A, et al. Lancet 2007;369(9559):381-8.

22. European Renal Association/European Dialysis and Transplant Association. Nephrol Dial Transplant 1999;14(suppl 5):31-32.

23. European Renal Association/European Dialysis and Transplant Association. Nephrol Dial Transplant 1999;14(suppl 5):30.

24. Jacobs C, et al. Nephrol Dial Transplant 2000;15 (Suppl 4):15-19.

25. Islam S, et al. Bangladesh Med Res Counc Bull 2005;31(2):83-7.

26. Jungers P, et al. Nephrol Dial Transplant 2001;16(2):307-12.



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