CUBAN MEDICAL LITERATURE

Broad Use of Cuban Recombinant Human
Erythropoietin (ior-EPOCIM) in Dialysis Patients at the Institute of Nephrology

JF Pérez-Oliva, MD(1);
AM Lagarde, MD(2);
R Herrera Valdés, MD, PhD(1);
AI Martínez, MD(1);
ME Raola, MD(1);
Ch Magrans, MD, PhD(1)

ABSTRACT:

The results obtained using Cuban human recombinant alpha erythropoietin, ior-EPOCIM, at the Institute of Nephrology, Havana, are presented. From June 1999 to June 2001, 143 hemodialysis patients with renal anemia were treated during a minimum of four months with initial subcutaneous 30 U/Kg dosage. Results: 88% of the patients met criteria for satisfactory response, hematocrit rising from 22.1% to 33.1%. The average weekly dosage of EPOCIM, individually adjusted to maintain a target hematocrit of no less than 33%, ranged from 87 to 105 U/Kg. The number of transfused patients was reduced from 94.4% before treatment to less than 24.5% at the end of the study. The only complication detected was transient arterial pressure increase, not associated with other complications and not requiring interruption of r-HuEPO use. In short, ior-EPOCIM showed results similar to other international commercial r-HuEPO for improving and correcting renal anemia. As a result of this research, progressive national extension of the product was begun, free of charge to all patients in hemodialysis.

Keywords: RENAL ANEMIA, ERYTHROPOIETIN, HEMODIALYSIS

INTRODUCTION

The progressive damage caused by chronic renal failure (CRF) leads to insufficient production of erythropoietin (EPO), in turn resulting in anemia. EPO is a glycoprotein secreted in the kidney in response to hypoxia, and is the main regulator of erythrocyte production. This regulation occurs by stimulation of red bone marrow cells through membrane receptors on the erythroid colony forming cells, which proliferate and differentiate, thus increasing hemoglobin levels.[1] For this reason, anemia is common in these patients, although multiple other factors may contribute to it, such as the shortening of the erythrocyte half life, lack of iron, folates and/or vitamin B12, hemoglobinopathies, etc.

During the hemodialysis stage, other mechanisms may worsen it: repeated blood loss, absolute and functional iron shortage, malnutrition, hemolysis, aluminum toxicity, bone marrow fibrosis, infections, and a chronic inflammatory state caused by the continuous exposure of blood to extra-corporeal circuits.[2,3] Physiopathologically, chronic tissue hypoxia is the most important uremic toxin, demonstrated by the different systemic changes it causes, directly affecting morbidity and mortality rates and rehabilitation of these patients.[4]

Severe anemia was controlled by blood transfusions with all its associated risks: biological, because of the potential transmission of infectious agents; allergic and immune, producing incompatibility and sensitization to histocompatibility antigens, thereby reducing opportunities for successful kidney transplant; and clinical, due to volume overload, risk of hyperpotassemia, iron overload, etc.[5] Human recombinant EPO (r-HuEPO) emerged as a solution for kidney anemia in 1986. Its cardiovascular and non-cardiovascular efficacy and benefits, and the improvement of patients’ general well-being, allow us to state that its advent marks the beginning of a new era because of the change in quality of life for dialysis and transplant patients.[6,7]

Only a few companies have patented this drug, raising the already high price of substitution therapy with similar clinical efficacy.[8] The production of erythropoietin in Cuba by CIMAB using recombinant DNA techniques and its registry based on a clinical trial carried out by our center and CIMEQ (the Spanish acronym for its name: Medical-Surgical Research Center),[9] enabled use of this hormone for all hemodialysis patients at the Institute.

The objective of this study was to analyze improvement or correction of anemia in our patients, using ior-EPOCIM.

MATERIAL AND METHODS

An open, clinical prospective study was carried out with nationally produced human alpha r-HuEPO (ior-EPOCIM) in 143 adult patients with ESRD. All were being treated by hemodialysis with < 28% hematocrit levels, had not used erythropoietin previously, and had completed four months of treatment starting in June 1999. The 143 patients studied until June 2001 averaged 42.8 years old and had received hemodialysis treatment for an average of 61.2 months. They all received erythropoietin treatment subcutaneously at an initial dosage of 30 U/kg/dose three times a week. The dosage was increased according to response, or reduced if the hematocrit was > 36%. Iron Dextran was administered endovenously during the first 10 weeks at 100 mg/week and at 50 mg/week thereafter, as a maintenance dosage.

Samples for analysis were collected mid-week, on an empty stomach, by puncture of the arteriovenous fistula. Hematocrit determinations were carried out at the hematological complex COBAS-ARGOS 5 DIFF, Roche, France. Hematocrit increase in % with respect to the individual basal level was taken into account to establish efficacy. Increased hematocrit e” 6% over the basal level without blood transfusion, was considered a satisfactory response. Linear regression was calculated for hematocrit variations with respect to treatment duration variance analysis, with a significance level of 0.05.

Table 1: Response to Cuban r-HuEPO (ior-EPOCIM) Treatment

Source : Department of Hemodialysis, Institute of Nephrology.2002
Note: Hematocrit prior to ior-EPOCIM treatment: 22.4 V%. *p< 0.05 **p< 0.001

RESULTS

A satisfactory response was observed in 126 patients after four months of treatment (88%).

Statistically significant increase in hematocrit rose from 22.4% before treatment with ior-EPOCIM, to 33.1% using individually adjusted dosages.

Hematocrit values over 30% were observed in 69% of patients. Only 11 patients (7.69%), showed hematocrit values higher than 28%, but all had increased more than 3% over the basal hematocrit.

The number of transfused patients fell from 94% before the treatment to 24.5% after four months, which was characteristic for this dosage-adjustment phase and conditioned by individual response to r-HuEPO and the appearance of complications typical of ESRD.

The only adverse effect found was the appearance or worsening of high blood pressure (HBP) in 53% of total cases, reaching a maximum of 63% of patients by the second month of treatment in 63% of the patients, and dropping to 34% by the fourth month.

HBP was not associated with serious secondary complications, nor was it necessary to interrupt use of ior-EPOCIM.

DISCUSSION

Reports indicate that up to 80% of patients at the beginning of hemodialysis have anemia.[10] In our work, we found that practically all our patients had anemia, which indicated a delayed inclusion in dialysis.

The target hematocrit with r-HuEPO treatment has changed over time. Initially the 1998 DOQI guidelines placed it between 30-33%, later increased to 33-36%. This value is similar to the target of the European Best Practice Guidelines, which point out that less than 50% of patients do not reach that goal.[11] We aimed at having our patients reach a hematocrit of no less than 30%, result attained by 69.22%. Hematocrits higher than 33% were found in 47.55% of patients.

It has been demonstrated that to achieve the planned hematocrit level in the initial phase of dosage adjustment, the time required for anemia correction fluctuates between one and four months. The various increases in hematocrit levels during the period under study, and with the EPOCIM dosages used, are in accordance with those described in other clinical trials.[12,13]

It has been reported that 23% to 77% of patients do not reach the proposed hematocrit level until after three months of treatment. Only 10% of patients require dosages higher than 300 U/Kg/week subcutaneously to attain this.[11] Average dosages in Europe vary from 93 to 161 IU/Kg/week.[14] The dosage required in this study to reach the proposed hematocrit values were within this range.

There is the opinion that the target hematocrit is easier to attain with peritoneal dialysis than with hemodialysis,[15] and that higher r-HuEPO dosages are necessary in the latter procedure. All our patients received ior-EPOCIM subcutaneously at an average maximum dosage of 107.4 U/Kg/week.

Figure 1: Hematocrit Response and Percent to Patients Transfused During oir-EPOCIM Use

Source : Department of Hemodialysis, Institute of Nephrology.2002

The main adverse event directly related to r-HuEPO is high blood pressure, which must be controlled prior to beginning treatment and closely monitored thereafter. An increased dosage of antihypertensive agents may be required, or HBP may reappear in a controlled patient. Such an increase is usually temporary, but must be monitored to avoid typical complications of severe HBP.

Clinical factors that predict risk of HBP development are: its presence in the predialytic stage; degree of anemia; rate of hematocrit increase; maximum hematocrit reached;

r-HuEPO dosage; and endovenous application.[16] Several mechanisms explain HBP in these patients: hematocrit increase leading to a rise in blood viscosity and elimination of hypoxic vasodilatation; activation of the sympathetic system of renin-angiotensin; lack of balance in the synthesis of vasoactive substances in detriment to vasodilating ones; inactivation of the nitric oxide system; direct vascular action caused by intracellular calcium increase in the smooth vascular muscle; vascular receptor stimulation; and rise in vascular reactivity to endotelin I and angiotensin II.[17]

Table 2: Percent of Patients with Changed Hematocrit by 4th Month of Treatment

Source : Department of Hemodialysis, Institute of Nephrology. 2002

When analyzing this phenomenon, it becomes clear that it is ESRD that determines HBP appearance, since use of r-HuEPO in chemotherapy and anticancer drug-induced anemia in newborns, AIDS and multiple myeloma patients, is not associated with a rise in blood pressure, despite endovenous administration and use of dosages up to five times higher.[18]

In our patients, HPB was carefully managed, evaluating whether hematocrit values were related to it and adjusting the pharmacological treatment accordingly. Changes were made in dialysis indication (adjustment of dry weight, change of dialysis machines, and increase in the length of hemodialysis). In our experience, HBP events were transitory and could be corrected, and they were not associated with severe secondary complications, or the need to interrupt ior-EPOCIM treatment.

In any case, a risk-benefit analysis shows cardiovascular advantages and benefits are much greater than the temporary appearance of HBP.[19,20]

In conclusion, this experience with ior-EPOCIM confirms the efficacy of Cuban r-HuEPO and its safety, predicting that its prompt extension to all patients in the country will be just as successful.

Table 3: High Blood Pressure Behavior with Cuban r-HuEPO (ior-EPOCIM) Treatment

Source : Department of Hemodialysis, Institute of Nephrology.2002

(To date, April 2005, all patients undergoing dialysis and transplant patients with graft malfunctions, are receiving ior-EPOCIM free of charge. The Authors).

REFERENCES

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15. Lui, SF; Law, CB; Ting, SM; Li, P, Lai, KN. Once weekly versus twice weekly subcutaneous administration of recombinant human erythropoietin in patients on continuous ambulatory peritoneal dialysis. Clin Nephrol 1991, 36: 246-51.
16. Pascual Santos, J. Efectos cardiovasculares de la Eritropoyetina. In: Valderräbano F. Eritropoyetina humana recombinante . Barcelona: Masson, 1998.
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20. Mc Mahon, LP, Johns, JA, Mckenzie, A; Austin, M; Fowler, R; Dawborn, JKL. Haemodynamic changes and physical performance at comparative levels of haemoglobin after long-term treatment with recombinant erythropoietin. Nephrol Dial Transplant 1999, 7:1199-1206.

This paper was originally presented at the Second International Mexico-Cuba Symposium on Nephrology, May 2002.

THE AUTHORS

1. JF Pérez-Oliva, MD; R Herrera Valdés, MD, PhD; I Martínez, MD; ME Raola, MD; Ch Magrans, MD, PhD nephrologists at the Institute of Nephrology, Havana, Cuba.
2. AM Lagarde, MD, hematologist at the Institute of Nephrology, Havana, Cuba. This last line should be in century, smaller.