| 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 Jun 4];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.
| References|| |
|1.||Bright R. Cases and observations, illustrative of renal diseases accompanied with the secretion of albuminous urine. Guys Hosp Rep 1836;l:338-79. |
|2.||Eschbach JW, Adamson JW. Anemia of end-stage renal disease (ESRD). Kidney Int 1985;28:l-5. |
|3.||Carnot P, Deflandre C. Sur l'activite hemopoietique des differents organes au cours de la regeneration d sang. C.r. hebd Seanc Acad Sci Paris 1906;143:432-5. |
|4.||Miyake T, Kung CK, Goldwasser E. Purification of human erythropoietin. J Biol Chem 1977;252:5558-64. [PUBMED] [FULLTEXT]|
|5.||McDonald JD, Lin FK, Goldwasser E. Cloning, sequencing, and evolutionary analysis of the mouse erythropoietin gene. Mol Cell Biol 1986;6:842-8. [PUBMED] [FULLTEXT]|
|6.||Jacobs K, Shoemaker C, Rudersdorf R, et al. Isolation and characterization of genomic and cDNA clones of human erythropoietin. Nature, Lond. 1985;313:806-10. |
|7.||Lin FK, Suggs S, Lin CH, et al. Cloning and expression of the human erythropoietin gene. Proc Natl Acad Sci USA 1985;82:7580-4. [PUBMED] [FULLTEXT]|
|8.||Bondurant MC, Koury MJ. Anemia induces accumulation of erythropoietin mRNA in the kidney and liver. Mol Cell Biol 1986;6:2731-3. [PUBMED] [FULLTEXT]|
|9.||Beru N, McDonald J, Lacombe C, Goldwasser E. Expression of the erythropoietin gene. Mol Cell Biol 1986;6:2571-5. [PUBMED] [FULLTEXT]|
|10.||Zanjani ED, Peterson EN, Gordon AS, Wasserman LR. Erythropoietin production in the fetus : role of the kidney and maternal anemia. J LabClin Med 1974;83:281-7. |
|11.||Jascobson LO, Goldwasser E, Fried W, Plzak LF. The role of the kidney in erythropoiesis. Nature, Lond. 1957;179:633-4. |
|12.||Jelkmann W. Renal erythropoietin: properties and production. Rev Physiol Biochem Pharmacol 1986;104:139-215. |
|13.||Winearls CG. Treatment of the anaemia of chronic renal failure with r-HuEPO. in: Erythropoiesis. New dimensions in the treatment of anaemia. Chester, Adis International Limited, 1993;4:3-9. |
|14.||Caro J, Brown S, Miller O, Murray T, Erslev AJ. Erythropoietin levels in uremicnephric and anephric patients. J Lab Clin Med 1979;93:449-58. [PUBMED] |
|15.||Chandra M, Clemons GK, McVicar MI. Relation of serum erythropoietin levels to renal excretory function: evidence for lowered set point for erythropoietin production in chronic renal failure. J Pediatr 1988;113:1015-21. [PUBMED] |
|16.||Tan CC, Eckardt KU, Ratcliffe PJ. Organ distribution of erythropoietin messenger RNA in normal and uremic rats. Kidney Int 1991;40:69-76. [PUBMED] |
|17.||Cotes PM, Pippard MJ, Reid CD, Winearls CG, Oliver DO, Royston JP. Characterization of the anaemia of chronic renal failure and the mode of its correction by a preparation of human erythropoietin (rHuEPO). An investigation of the pharmacokinetics of intravenous erythropoietin and its effects on erythrokinetics. Q J Med 1989;70:l 13-37. |
|18.||Eschbach JW, Haley NR, Egrie JC, Adamson JW. A comparison of the responses to recombinant human erythropoietin in normal and uremic subjects. Kidney Int 1992;42:407-16. [PUBMED] |
|19.||Delwiche F, Segal GM, Eschbach JW, Adamson JW. Hematopoietic inhibitors in chronic renal failure: lack of in vitro specificity. Kidney Int 1986;29:641-8. [PUBMED] |
|20.||DiPalma JR. Uraemia, isn't it mostly anaemia? Contemp Dial Nephrol 1987;8:24-8. |
|21.||Eschbach JW, Egrie JC, Downing MR, Browne JK, Adamson JW. Correction of the anemia of end-stage renal disease with recombinant human erythropoietin. Results of a combined phase I and II clinical trial. N Engl J Med 1987;316:73-8. |
|22.||Winearls CG, Oliver DO, Pippard MJ, Reid C, Downing MR, Cotes PM. Effect of human erythropoietin derived from recombinant DNA on the anaemia of patients maintained by chronic haemodialysis. Lancet 1986;2:1175-8. [PUBMED] |
|23.||Macdougall IC, Roberts DE, Neubert P, Dharmasena AD, Coles GA, Williams JD. Pharmacokinetics of recombinant human erythropoietin in patients on continuous ambulatory peritoneal dialysis. Lancet 1989;l:425-7. |
|24.||Shaheen FAM, Al-Aqeil N, Badawi L, et al. Erythropoietin in hemodialysis patients: intravenous or subcutaneous. Saudi Kid Dis Transplant Bull 1993;4(l):13-7. |
|25.||Stone WJ, Graber SE, Krantz SB, et al. Treatment of the anemia of predialysis patients with recombinant human erythropoietin: a randomized, placebocontrolled trial. Am J Med Sci 1988;296(3):171-9. |
|26.||Lim VS, DeGowin RL, Zavala D, et al. Recombinant human erythropoieti treatment in predialysis patients. A doubleblind placebo-controlled trial. Ann Intern Med 1989;110(2)108-14. |
|27.||Shaheen FAM, El-Aqeil NA, Badawi L, et al. Correction of anemia by erythropoietin in predialysis patients. Saudi Kid Dis Transplant Bull 1993;4(3):215-9. |
|28.||Granolleras C, Branger B, Beau MC, Deschodt G, Alsabadani B, Shaldon S. Experience with daily self-administered subcutaneous erythropoietin. Contrib Nephrol 1989;76:143-7. |
|29.||Bommer J, Weinreich T, Ritz E, Zeier M, Bommer G. Efficacy of subcutaneous or intravenous recombinant human erythropoietin therapy in dialysis patients (Abstracts). Nephrol Dial Transplant 1989;4:471. |
|30.||Geerlings W, Tufveson G, Brunner FP, et al. Combined report on regular dialysis and transplantation in Europe, XXI, 1990. Nephrol Dial Transplant 1991;6(Suppl 4):5-29. [PUBMED] |
|31.||Rutkowski B, Debska Slizien A, Biedunkiewicz B, Bullo B. Importance of iron status monitoring during erythropoietin treatment in uremic predialysis patients. Ann Univ Mariae Curie Sklodowska Med 1994;48(Suppl 3):17-21. |
|32.||Dimitrskov D, Kunchev E. Application of recombinant human erythropoietin in patients with polycystic kidney disease and chronic renal failure. Folia Med Plovdiv 1992;34(l):41-4. |
|33.||Wiecek A, Kokot F, Marcinkowski W, Rudka R,Klimek D. Treatment of anemia with erythropoietin (rHuEPO) in patients with chronic kidney failure who are not yet in need of dialysis therapy. Pol Arch Med Wewn 1992;88(5):310-23. |
|34.||Furukawa A, Numata A, Imagawa A, et al. Study of recombinant human erythropoietin treatment on the anemia of predialysis patients. Nippon Jinzo Gakkai Shi 1992;34(6):693-700. |
|35.||Effectiveness and safety of recombinant human erythropoietin in predialysis patients. Austrian Multicenter Study Group of r-HuEPO in predialysis patients. Nephron 1992;61(4):399-403. |
|36.||Briggs WA, Gimenez LF. Clinical application of recombinant erythropoietin in predialysis renal failure. Hematol Oncol Clin North Am 1994;8(5):927-32. |
|37.||Schwartz AB, Kahn SB, Kelch B, Kim KE, Pequignot E. RBC improved survival due to recombinant human erythropoietin explains effectiveness of less frequent, low dose subcutaneous therapy. Clin Nephrol 1992:38(5):283-9. |
|38.||Lim VS. Recombinant human erythropoietin in predialysis patients. Am J Kidney Dis 1991;18(4 Suppl l):34-7. |
|39.||Abels R. Rate of progression of chronic renal failure in predialysis patients treated with erythropoietin. Semin Nephrol 1990;10(2Suppl l):20-5. |
|40.||Mayer G, Thum J, Cada EM, Stummvoll HK, Graf H. Working capacity is increased following recombinant human erythropoietin treatment. Kidney Int 1988;34:525-8. [PUBMED] |
|41.||Stone WJ, Graber SE, Krantz SB, et al. Treatment of the anemia of predialysis patients with recombinant human erythropoietin: a randomized, placebocontrolled trial. Am J Med Sci 1988;296(3):171-9. |
|42.||Lim VS, Fangman J, Flanigan MJ, DeGowin RL, Abels RT. Effect of recombinant human erythropoietin on renal function in humans. Kidney Int 1990;37:131-6. [PUBMED] |
|43.||Van Wyck DB, Stivelman JC, Ruiz J, Kirlin LF, Katz MA, Ogden DA. Iron status in patients receiving erythropoietin for dialysis-associated anemia. Kidney Int 1989;35:712-6. [PUBMED] |
|44.||Macdougall IC, Cavill I, Hulme B, et al. Detection of functional iron deficiency during erythropoietin treatment: a new approach. Br Med J 1992;304:225-6. |
|45.||Rosenlof K, Fyhrquist F, Tenhunen R. Erythropoietin, aluminium, and anaemia in patients on haemodialysis. Lancet 1990;335:247-9. |
Faissal A.M Shaheen
Consultant Nephrologist and Director, Saudi Center for Organ Transplantation, P.O. Box 27049, Riyadh 11417