| Abstract|| |
Anemia is a well recognized complication of chronic renal failure (CRF). Although the use of erythropoietin (EPO) in the treatment of anemia in patients on dialysis is well established, its use in pre-dialysis patients is less well recognized. The preferred route of administration of EPO in pre-dialysis patients is subcutaneous and it is indicated in any patient with CRF who is symptomatic of anemia. Studies have shown that EPO is effective in correcting anemia in these patients with a considerable improvement in qualityof-life scores. There have been no deleterious effects on blood pressure or rate of decline of renal function. However, these two indices should be monitored closely. Common causes of treatment failure include iron deficiency, blood loss and occult sepsis. The available evidence indicates that EPO therapy is safe and effective in the treatment of anemia in predialysis patients.
Keywords: Anemia, Chronic renal failure, Pre-dialysis, Erythropoietin.
|How to cite this article:|
Paul T T, Ramprasad K S, Shaheen FA. Use of Erythropoietin in the Correction of Anemia in Pre-dialysis Patients. Saudi J Kidney Dis Transpl 1995;6:298-303
|How to cite this URL:|
Paul T T, Ramprasad K S, Shaheen FA. Use of Erythropoietin in the Correction of Anemia in Pre-dialysis Patients. Saudi J Kidney Dis Transpl [serial online] 1995 [cited 2020 Feb 29];6:298-303. Available from: http://www.sjkdt.org/text.asp?1995/6/3/298/40666
| Introduction|| |
Anemia is a well known complication of chronic renal failure (CRF) , . Erythropoietin (EPO), a glycoprotein, is the main humoral regulator of erythropoiesis. It stimulates the proliferation and differentiation of erythroid precursor cells. It was in 1906 that Carnot and Deflandre  discovered a humoral factor that stimulates erythropoiesis. Since then, many advances have been made and we now know the molecular structure , , the sequence of its mRNA ,, and the organs containing mRNA for EPO , . It is now believed that EPO is synthesized by the fetal liver and the adult kidney  . The physiological impact of fetal EPO production remains poorly understood till now. Since the major source of EPO, is the kidneys, secretion of this hormone gets reduced when renal damage occurs. This results in anemia, the severity of which generally depends on the degree of renal failure , . The prevalence of anemia in patients with CRF as well as in patients on hemodialysis (HD) is not exactly known. Some studies performed before the advent of replacement therapy With EPO, have shown that among the patients on HD nearly 40% had hemoglobin concentrations below 8 g/dl  .The deficiency of EPO alone cannot fully account for the anemia in patients with CRF. Serum concentrations of EPO have been reported to be higher than the normal range in patients with CRF. However, the levels are well below what one would expect in normal individuals with a comparable degree of anemia  . In patients with CRF, although the hemoglobin level does rise in response to hypoxic stress  , the reserve capacity for EPO production is limited  . In addition, the marrow is relatively hyporesponsive to EPO as evidenced by reduced reticulocyte count, a decreased erythroid-granuloid ratio in the bone marrow, etc. ,, . Some authors have reported the existence of uremic inhibitors of erythropoiesis, though the evidence has not been convincing  . In addition to these, there are other factors which operate in uremic patients which might aggravate anemia such as, reduced erythrocyte survival time and blood loss from the gastrointestinal tract and from frequent laboratory samplings.
Although the severity of anemia in predialysis patients is not to the degree seen in patients on HD, it is nevertheless a cause of considerable morbidity. Patients with CRF are usually symptomatic with complaints of weakness, easy fatigability, loss of appetite, insomnia, depression, cold intolerance, angina pectoris and effort dyspnea. These symptoms were earlier attributed to 'uremia' in these patients. However, the consensus now is that these symptoms are mainly caused by anemia  .
Several studies have demonstrated the efficacy of EPO in correcting uremic anemia in patients on dialysis, both HD and CAPD  . However, its beneficial effect in the pre-dialysis population is less well recognized. Since some earlier studies had suggested that the serum of uremic patients contains inhibitors of EPO and erythropoiesis, which are dialyzable, it was considered that pre-dialysis patients may not respond to EPO therapy. However, studies did show that these patients respond well to erythopoietin therapy  . The following is a summary of the current status of use of EPO in the predialysis patients.
| Available Forms of Recombinant Human Erythropoietin|| |
There are two types of recombinant human erythropoietin, of nearly equal efficacy  available namely, erythropoietin-alpha (EPREX, Cilag UK), and erythropoietinbeta (Recormon, Boehringer Mannheim UK).
This drug can be administered either by the intravenous (i.v.) or by the subcutaneous (s.c.) routes. However in pre-dialysis patients, use of the i.v. route may not be very practical. Also, it has been shown that the dose requirement of EPO by the s.c. route is smaller  and unlike the i.v. route, the drug can be administered once weekly with the same efficacy as thrice weekly dose schedule  . Also, the patients can be taught self administration. For these reasons, s.c. route is ideally suited for administration in predialysis patients.
The recommended initial dose of EPO-alfa is 50 U/Kg/ given thrice weekly, i.v. or s.c. For EPO-beta the recommended i.v. dose is 40 U/Kg three times weekly and the s.c. dose 20 U/Kg. However, it has been suggested that adhering to a rigid U/Kg dose is not necessary since this results in wastage of the left over drug  . Instead, it is advised to prescribe whole-vial doses aiming for a weekly dose of 100 U/Kg. If no response, defined as an increase in hemoglobin concentration of 1 g/dl, is seen after a month of treatment, the dose should be increased by a quarter or a third. If no positive response is obtained with a total dose of 300 U/Kg/ week, causes of unresponsiveness should be sought and detailed investigations undertaken.
| Who are the Candidates for EPO Treatment?|| |
A hemoglobin concentration below the normal range is, in itself, not an indication for initiating EPO treatment. The current practice is to offer EPO treatment to patients with CRF who are symptomatic with anemia, patients who subconsciously limit their activities because of anemia, and/or patients requiring repeated blood transfusions in order to maintain a reasonable hematocrit level. However, it is difficult at times to ascertain who symptomatic patients are, since some of them adopt a sedentary life style and learn to avoid their symptoms. A trial of blood transfusion has been suggested as a test to ascertain whether anemia is an unrecognized problem. If the patient's symptoms improve after a two-unit blood transfusion, it is likely that EPO treatment would be beneficial  . Also, in patients with symptomatic anemia, other factors that may cause or aggravate the underlying renal anemia, should be looked for and corrected. The foremost of them is the iron status of the patient  . The parameters suggestive of adequate iron stores include a ferritin concentration of > 100 µg/L and/or a transferring saturation of 20% or above. Deficiencies of vitamin B12and folate are rare in CRF patients, and as such there is no need to monitor them routinely. Excessive blood loss through any source should be excluded diligently. The presence of any infection should be looked for and corrected before initiating EPO treatment.
Treatment with EPO is aimed at achieving a hematocrit of 35% as values greater than this may result in  . It is also advisable to achieve a gradual rise of the hematocrit. The dose of EPO has to be titrated so as to avoid rapid rise of hematocrit and to avoid overshoot, this parameter should be monitored monthly until it gets stabilized.
| Effects of EPO|| |
Hematocrit and Blood Volume
The efficacy of EPO in improving the anemia in pre-dialysis patients has been shown in many studies wherein a weekly increment in hematocrit levels of 1.4% to 1.8% has been demonstrated depending on the dosage of EPO used ,,,,,, . Both increased erythrocyte production and prolonged red blood cell survival have been shown to be associated with the improvement in hematocrit during EPO therapy  . This results in an increase in red cell mass, but with a reciprocal change in plasma volume thereby keeping the total blood volume constant  .
Quality of Life and Physical Performance
Good improvement in quality-of-life scores has been shown with EPO therapy in predialysis patients as well as patients on maintenance HD. Fatigue disappears and sense of well-being increases  . In a multi-center study, Abels has shown that the patients receiving EPO had increased energy level and work capacity scores to the tune of 61%  .
Many studies have reported subjective improvement in the well being of dialysis patients after correction of anemia , . In a study performed at the Jeddah Kidney Center (JKC), Jeddah, Saudi Arabia it was reported that weakness, easy fatigability, and loss of appetite showed marked improvement in 83.3% of the patients after instituting treatment with EPO  . A weight gain of 2 to 4 Kg was demonstrated in more than 50% of the study patients. The EPO treated patients had considerably lesser complaints such as fatigability, loss of appetite and intolerance to cold while all the patients of the control group continued to have these complaints. One patient who had angina pectoris before starting EPO treatment showed complete remission of chest pain as well as reversion of the ischemic changes on electrocardiogram after correction of anemia with EPO  .
However, direct correlation between improvement in exercise capacity on objective testing and, improvement in hematocrit has not been demonstrated  indicating that poor physical performance in CRF can be due to factors other than anemia such as peripheral neuropathy and cardiovascular disease. One negative aspect of this improved well being could be that the patients may report late to the hospitals resulting in a delay in the initiation of HD with its associated hazards.
A rise in blood pressure has been frequently reported to be associated with EPO treatment , . Two factors are considered primarily to be responsible for this. They are: (i) increased blood viscosity and (ii) increased peripheral resistance due to reduction in hypoxia induced vasodilatation. Abels reported the occurrence of hypertension in 22% of his EPO treated cases and 19% of the controls. The percenttage of the affected cases was related to the dosage of EPO used; 14% in the 50 U/Kg group, 18% in the 100 U/Kg group, and 36% in the 150 U/Kg group  . In the JKC study, during the 48 weeks observation period after instituting EPO therapy, out of the eight hypertensive patients, anti-hypertensive therapy had to be increased only in one  .
Thus, it appears that hypertension is not a serious adverse effect of EPO treatment in pre-dialysis patients. However, it is advisable to start with a lower dose of EPO and allow the hematocrit to increase slowly, at the rate of approximately 1% per week, to minimize the increase in blood pressure. Also, it is a good idea not to start EPO administration unless hypertension is adequately controlled and patients on EPO should be asked to monitor their blood pressure regularly and report any sudden changes.
Residual Renal Function
One of the major concerns regarding the use of EPO in pre-dialysis patients is the possibility that the increase in the hematocrit level might result in a more rapid deterioration of residual renal function. With lower hematocrit values, an increased renal plasma flow results in a relatively increased glomerular filtration rate (GFR). Both afferent and the efferent arteriolar resistance are reduced, resulting in a reduction of the glomerular transcapillary pressure. These changes are reversed when there is an increase in hematocrit levels, thus resulting in a lowered GFR. However, this picture is rarely seen in day to day practice. Treatment with EPO has not been reported to stop or accelerate the progression of renal failure  . In the JKC study also, the progression of renal failure in the EPO group was found to be similar to the control group  . In a report by Lim, et al assessment of the rate of decline of renal function by plotting the reciprocal of serum creatinine against time did not show any significant difference between the preand post-EPO periods  .
Based on the available evidence it appears that EPO treatment does not accelerate the decline of renal function in pre-dialysis CRF patients.
| Treatment Failure and its Investigations|| |
The most common cause of failure to respond to EPO is unrecognized iron deficiency  . Iron requirement increases greatly when there is an increase production of erythrocytes. Thus, iron stores which may be 'normal' at the start of treatment, get depleted rapidly. Iron deficiency may not be truely reflected by the serum ferritin concentration alone and transferrin saturation is a better indicator  . In some patients, the stored iron cannot be mobilized fast enough to cope up with the demand and a state of functional iron deficiency develops. This is indicated by a fall in the transferrin saturation to below 20% with a concomitant appearance of hypochromic and microcytic erythrocytes in the blood  . Blood loss is another important cause of failure to respond to EPO. Investigations like fecal occult blood, endoscopy and barium studies may be required. Detailed menstrual history is mandatory in female patients. An increase in the reticulocyte count without a concomitant rise of the hematocrit is a clue to blood loss. Another cause of treatment failure is presence of occult infection. The C-reactive protein value might offer a clue and search for occult sepsis in sites such as bone, sites of previous surgery, prostheses, vascular access and the urinary tract should be undertaken. Aluminum intoxication is yet another cause of poor response to EPO treatment and is associated with the presence of hypochromic microcytic anemia with normal iron stores  . Other miscellaneous rare causes of treatment failure include deficiencies of iron, vitamin B12 and/or folic acid as well as some inflammatory disorders.
| Conclusion|| |
Based on current available evidence, it appears that EPO treatment is safe and effective for use in pre-dialysis patients. Increasing the hematocrit levels to between 30% and 35% does not result in accelerated decline in renal function. Currently, EPO is not widely used in pre-dialysis patients, partly because of its cost. However, the benefits of this treatment are many. Blood transfusion, with the associated hazard of transmission of blood-borne infections such as hepatitis B, hepatitis C, HIV etc. can be avoided. Reduced incidence of iron overload and improved survival rates following renal transplantation due to a lower incidence of acquiring cytotoxic antibodies are the other benefits of restricting the number of transfusions. Correction of anemia would prevent the necessity of changing life-style due to lack of energy associated with anemia of renal failure. These factors more than outweigh the cost involved in treatment with EPO.
| Acknowledgment|| |
We would like to thank Mr. Pedly F. Atienza and Mr. S. Mohammedali of SCOT for their valuable secretarial assistance in preparing the manuscript.
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Faissal A.M Shaheen
Consultant Nephrologist and Director, Saudi Center for Organ Transplantation, P.O. Box 27049, Riyadh 11417