December 1991, Volume 41, Issue 12

Original Article

EXPERIENCE OF ERYTHROPOIETIN IN ANEMIA OF END STAGE RENAL DISEASE

Rizwan Hussain  ( The Kidney Centre, Jinnah Postgraduate Medical Centre, Karachi. )
S. Ali Jaffar Naqvi  ( The Kidney Centre, Jinnah Postgraduate Medical Centre, Karachi. )

ABSTRACT

Recombinant human erythropoietin 50 units/kg intravenous twice a week was given to 9 anemic patients and end stage renal disease (ESRD) who were undergoing dialysis at the Kidney Centre. Of the total, 8 required no transfusion since the initiation of therapy and their haematocrit increased to approximately 29% or more with the improvement in general condition, sense of well being and exercise tolerance. One patient showed an increase in serum creatinine and two iron deficiency during therapy. In all cases blood pressure remained adequately controlled. No organ dysfunction or any other complication was observed (JPMA 41:310,1991).

INTRODUCTION

Anemia is a major and predictable complication of chronic renal failure. When ESRD evolves, anemia is usually severe and often impairs rehabilitation despite adequate dialysis therapy1. The mechanisms underlying anemia are complex but mainly involve reduction of erythropoietin production and variable shortening of red cells survival1-3. Iron deficiency, hyperspleenism and aluminium induced microcytosis may aggravate the anemia of ESRD1. Retained inhibitors and toxic metabo­lites in ESRD2, impaired marrow function, osteitis fibrosa associated with hyperparathyroidism and folic acid deficiency all contribute to the development of anemia. Most of the patients are treated with blood transfusions but the response is temporary1. Iron supplementation is required to prevent or correct iron deficiency3,4. This study was conducted to evaluate the response of patient with anemia of ESRD to erythropoietin replacement therapy.

PATIENTS AND METHODS

Nine patients of ESRD diagnosed on ultrasound and creatinine clearance studies (less than 10 mi/mm) referred from different hospitals and registered for maintenance haemodialysis at the Kidney Centre were included in the study. Informed consent was taken from all cases. Most patients were transfusion dependent. Of nine, 7 were hypertensive (adequately controlled) and 2 were nor­motensive. None had any history of seizures, sensitivity to mammalian derived product, albumin sensitivity or any associated systemic infection. Financial status of all cases justified the long term use of erythropoietin therapy. Serum iron, total iron binding capacity (TIBC), serum ferritin and transferrin saturation were evaluated before therapy and then every month (serum ferritin 100 ng/ml and transferrin saturation at least 20% prior to initiation of therapy). Haematocrit was assessed in the beginning and then weekly for at least 2-6 weeks. Total leukocyte and platelet count, urea, creatinine, electrolytes, inor­ganic phosphorus and potassium were monitored monthly. No cause other than uremia accounted for anemia. Erythropoietin was given in a dose of 50 units/kg body weight intravenously two times a week at the end of dialysis.

RESULTS

Nine patients (6 males, 3 females) were included in the study. Their ages ranged from 42 to 73 years with a mean weight of 54 kgs. Cause of ESRD was chronic nephritis in 4, chronic pyelonephritis in 2 and hyperten­sion, polycystic kidney and diabetes mellitus in one each case. Blood group was B-positive in 5 and 0-positive in 4 cases. Duration on dialysis was between three months to one year. In 6 patients blood transfusion requirement was very often before the erythropoietin therapy. Since the initiation of therapy, 8 of 9 required no blood transfusion and only 1 required blood transfusion at very initial stages. In 7 hypertensives, blood pressure ade­quately controlled with anti- hypertensive therapy, no episode of rise in blood pressure was observed in 2 normotensives. At the initiation of therapy mean haemoglobin was 6.6 gm% and PCV 2 1.08%. Transferrin saturation was more than 20% and serum ferritin more than 100 ng/ml in 8, but less than 20% in 1. Total leukocyte and platelet count was within normal limits. Erythropoietin was started in all with a dose of 50 units/kg body weight (the minimum recommended dosage). Eight cases received twice weekly and 1 three times a week. Results of therapy on haemoglobin levels is shown in Figure.

No change in total leukocyte and platelet count was observed during therapy, urea, creatinine, electrolytes studies remained uneffected in 8 cases while a rise in serum creatinine was observed in 1 case. Oral haematinics were advised according to the individual’s requirement. On an average 325 mg of ferrous sulphate and 3 mg of folic acid per day was given in divided doses. Patients were assessed clinically during therapy. General condition improved in all these patients.

Ap­petite improved in all but 1. Improvement in the sense of well being and exercise tolerance was observed in all. The reported complications of erythropoietin therapy such as hypertensive crises, myocar4ial infarction, were brovascular accident, transient ischaemic attacks, dialyzer clotting and blockage of vascular access was not observed in any patient. Neurological complications like seizures were also not observed.

DISCUSSION

Recombinant human erythropoietin have shown that it can fully correct anemia in patients undergoing haemodialysis. Renal origin of erythropoietin was demonstrated by Jacobson et a!. They potentiated the search for humoral erythropoietic factor (erythropoie tin). This hormone serves as one limb in the oxygen mediated feedback loop that controls the production of red cells and is produced in response to renal hypoxia. Recombinant human erythropoietin is a 165 amino acid glycoprotein manufactured by recombinant DNA tech­nology. It has same biological effects as endogenous erythropoietin and is produced by mammalian cells into which recombinant erythropoietm gene has been intro­duced. Ninety percent of erythropoietin is produced by the kidney from pen- tubular capillary endothelial cells of renal cortex and outer medulla, less than ten percent is produced by the liver6. Half life of erythropoietin varies from 4-13 hours, detectable levels of EPO is maintained for atleast 24 hours. It is formulated as a sterile colourless, preservative free fluid for intravenous or sub. cutaneous administration. Each vial contains 2,000, 4,000, 10,000 units whose cost varies between Rs. 1,200 to over 3,000, therefore, the long time for which it has to be continued makes EPO beyond the reach of most of the patients. The age, duration of dialysis, blood group and weight of the patient had no effect on the response to erythropoietin. We started with the minimal recom­mended dosage of 50 units/kg body weight. The target re sponse (Hb 9-10 gm%, PCV 28-30%) was achieved in less than three months in 8 patients and in I response is still awaited. This patient was re-evaluated but no cause other than uremia for anemia was found, so the dosage and the frequency of erythropoietin has been increased. The normotensives did not show any variation in blood pressure during therapy and in hypertensives no change in medication was required. Reduction in transferrin saturation, serum ferritin and plasma iron concentration were recorded in 2 patients during erythropoietin treatment, probably due to rapid increase in synthesis of haemoglobin. Iron supplementation is, therefore, re­quired to prevent iron and ferritin depletion which might alter the response to erythropoietin7,8. Seven transfusion dependent cases did not require any more transfusion after the initiation of therapy. This represents a major improvement as patients undergoing dialysis have no longer the risk of iron overload, exposure to infection or development of cytotoxic antibodies. The correction of anemia as expected was accompanied with substantial improvement in patients rehabilitation and the quality of life and this was maintained throughout the period of study. In only 1, rise in serum creatinine was observed during the therapy, but it was not significant enough to require any change in the frequency of dialysis. In the same patient the initial improvement in the appetite later decreased probably due to hypophosphatemia (serum phosphorus was 1.5-2.0 mg). In2roduction of dairy products in his diet improved not only his serum phosphorus level (3.0 mg) but also the appetite. During the 8 months period of this study, none of the reported complications to erythropoietin therapy were observed in any of the patients. The human erythropoietin therapy can therefore be safely recommended as the treatment of choice in the anemia of patients with ESRD who can afford the drug.

REFERENCES

1. Eschbach, J.W.. Egrie, J.C., C., Downing, MR., Browne, J.K. and Adamson, J.W. Correction of the anemia of endstage renal disease with recombinant human erythropoietin. Results of a combined phase land II clinical trial. N. Engl. J. Med., 1987; 316:73.
2. Eschbach,J.W. andAdamson, J.W. Recombinant human erythropoietin implication for nephrology. Am. 3. Kidney Dis., 1988; 3:203.
3. Mohini, R. Clinical efficacy of recombinant human erythropoietin in haemodialysis patients. Semin. Nephrol., 1989; 9:16.
4. Eschbach, J.W. and Adamson,J.W. Guideline forrecombinant human erythropoietin therapy. Am. 3. Kidney Dis., 1989; 2:2.
5. Hoynck Van Papendrecht, M.A.W., Marquet, R.L and Jeckel, J. Erythropoietin during acute anemia. Adis Int., 1990; 1:39.
6. Paganini. E.P. Overview of anemia associated with chronic renal disease. Primary and secondary mechanisms. Semin. Nephrol., 1989; 9:3.
7. Casati, S., Passerini, P., Campise, M.R., Graziani, 0., Casena, B., Perisic, M. and Ponticelli, C. Benefits and risks of pro tracted treatment with human recombinant erythropoietin in pa tients having haemodialysis. Br. Med.J., 1987; 295:1017.
8. Watson. A.J. Adverse effects of therapy for correction of anemia in haemodialysis patients. Semin. Nepbrol.. 1989; 9:30.

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