Correspondence
Intensity of Hemodialysis and Response to Erythropoietin
N Engl J Med 1996; 334:1669-1671June 20, 1996
- Article
To the Editor:
Ifudu et al. (Feb. 15 issue)1 state that decreasing blood urea nitrogen levels in patients receiving hemodialysis by a strategy of intensive dialysis improves the response to intravenous recombinant human erythropoietin. We congratulate the authors on this excellent piece of work. However, the observation that efficient dialysis improves physiologic and erythropoietin-stimulated erythropoiesis is not new. Charra et al. reported that lengthy dialysis (18 to 24 hours per week) was associated with a higher hematocrit and a higher survival rate than conventional dialysis (<12 hours per week).2
In their study, Ifudu et al. switched from a low-permeability, nonbiocompatible dialysis membrane (MCA 160) to a high-permeability, biocompatible membrane (F80). This in itself could have had a beneficial effect on erythropoiesis. It is recognized that only 30 to 40 percent of erythropoiesis depends on erythropoietin; the other 60 to 70 percent depends on growth factors (growth hormone, insulin-like growth factor I, insulin-like growth factor II, and colony-stimulating factor), cytokines (interleukin-1, interleukin-2, interleukin-3, interleukin-6, and tumor necrosis factor) and other, undefined factors.3 Plasma levels of interleukin-1, interleukin-6, and tumor necrosis factor α are higher in patients undergoing dialysis with cellulose membranes than in those using biocompatible membranes (such as polyacrylonitrile and AN69).4,5 The use of the F80 membrane may reduce inflammation, improve iron utilization, and stimulate protein synthesis. Perhaps this explains the increase in serum albumin, which was independent of erythropoietin treatment, in the patients studied by Ifudu et al.
We found that eight weeks after changing a cellulose dialysis membrane (cuprophane) for a more biocompatible, synthetic cellulose membrane (Hemophane, GFS), the mean hematocrit rose from 30 percent to 37 percent (unpublished data), even though the doses of erythropoietin and the dialysis schedule were kept the same.
5 ReferencesPablo Ureña, M.D.
Maurice Petrover, M.D.
Clinique de l'Orangerie, 93300 Aubervilliers, France1
Ifudu O ,Feldman J ,Friedman EA . The intensity of hemodialysis and the response to erythropoietin in patients with end-stage renal disease. N Engl J Med 1996;334:420-425
Full Text | Web of Science | Medline2
Charra B ,Calemard E ,Ruffet M , et al. Survival as an index of adequacy of dialysis. Kidney Int 1992;41:1286-1291
CrossRef | Web of Science | Medline3
Jones AL ,Millar JL . Growth factors in haemopoiesis. Baillieres Clin Haematol 1989;2:83-111
CrossRef | Medline4
Herbelin A ,Nguyen AT ,Zingraff J ,Urena P ,Descamps-Latscha B . Influence of uremia and hemodialysis on circulating interleukin-1 and tumor necrosis factor α. Kidney Int 1990;37:116-125
CrossRef | Web of Science | Medline5
Herbelin A ,Urena P ,Nguyen AT ,Zingraff J ,Descamps-Latscha B . Elevated circulating levels of interleukin-6 in patients with chronic renal failure. Kidney Int 1991;39:954-960
CrossRef | Web of Science | Medline
To the Editor:
In the study by Ifudu et al. of the relation between the intensity of hemodialysis and the hemoglobin response, both the intensity of dialysis, as measured by the reduction in urea, and the type of dialyzer were changed at the same time. The dialyzer used in the lower-intensity group was made of cellulose acetate and had a limited ability to remove molecules larger than 2000 daltons. In the second period of the study a high-flux polysulfone dialyzer was used, which removes molecules of up to 20,000 to 30,000 daltons. Increased intensity of dialysis may have improved the erythropoietic response, but the removal of large-molecular-weight toxins could also explain the favorable results.
Nathan W. Levin, M.D.
Beth Israel Medical Center, New York, NY 10003Frank Gotch, M.D.
Davies Medical Center, San Francisco, CA 94114To the Editor:
The report by Ifudu et al. left unanswered the question of whether the changes in the hematocrit and the serum albumin concentration were due to the enhanced ultrafiltration that occurs with the increased dialysis treatments. It was also not clear whether the reported hematocrit values were measured before or after the treatment. It is possible that the increased serum albumin and hematocrit values resulted from a decrease in the extracellular volume. We have reported that the response to erythropoietin is probably enhanced in selected patients undergoing peritoneal dialysis when dialytic therapy is increased.1 We agree with the authors' conclusions and the comments in the accompanying editorial by Klahr,2 but the authors should report how they controlled their study for the potential effects of a changing extracellular volume on the hematocrit and the serum albumin concentration.
2 ReferencesDeepak Malhotra, M.D., Ph.D.
Antonios H. Tzamaloukas, M.D.
Veterans Affairs Medical Center, Albuquerque, NM 871081
Tzamaloukas AH ,Murata GH ,Sena P . When do plasma levels of azotemic indices indicate inadequacy of peritoneal dialysis? Nephron 1994;67:495-496
CrossRef | Medline2
Klahr S . Anemia, dialysis, and dollars. N Engl J Med 1996;334:461-463
Full Text | Web of Science | Medline
To the Editor:
Ifudu et al. seem not to have adequately ruled out the possibility of iron deficiency in their patients. Over half the patients enrolled in the study had values for transferrin saturation of 20 percent or less. Even in renal failure, when the usual serum markers of iron deficiency may be difficult to interpret, such low values are usually considered markers of iron deficiency.1 Although all the patients were receiving oral iron supplements, the dose is not stated and it may not have been enough to treat iron deficiency. Furthermore, parenteral iron therapy is often needed to replenish iron stores in patients with end-stage renal disease.
Occult gastrointestinal blood loss, an easily treatable cause of iron deficiency, is usually indicated by the presence of at least one positive fecal occult-blood test in three separate samples. The authors do not state the frequency of stool testing in their patients. Together with the low sensitivity of some methods of detecting gastrointestinal blood loss,2 this makes the negative results of fecal occult-blood testing in this study difficult to interpret.
Many patients with end-stage renal disease have clinically important disease of the upper gastrointestinal tract; for example, treatment with an H2-receptor antagonist almost halved the requirement for transfusion in patients on hemodialysis who had gastritis.3 We have studied 46 patients (mean age, 60 years; 40 of the patients were on dialysis) with end-stage renal disease (mean serum creatinine concentration, 790 μmol per liter) and a mean hematocrit of 29.1 percent (range, 26.4 to 30.4 percent). Seventeen patients (37 percent) had abnormal results of upper gastrointestinal endoscopy; the most common finding was gastritis, in 12 patients (26 percent). Three patients (6.5 percent) had evidence of active or healed peptic ulcers, and two had esophagitis. Colonoscopy or a barium-enema examination was performed in 15 patients (33 percent), and no cause of anemia was identified. The upper gastrointestinal findings are similar to those reported by other investigators,3,4 who also found that the incidence of upper gastrointestinal disease decreased with the longer duration of dialysis.4
We suggest that the increase in the intensity of dialysis in the study by Ifudu et al. may have partially or completely resolved the upper gastrointestinal disease, leading to reduced loss of blood and hence an increased hematocrit.
4 ReferencesAnne B. Ballinger, M.R.C.P.
Peter D. Fairclough, M.D.
Michael L. Clark, M.D.
Michael J.G. Farthing, M.D.
St. Bartholomew's and the Royal London School of Medicine and Dentistry, London EC1M 6BQ, United Kingdom1
Macdougall IC . Poor response to erythropoietin. BMJ 1995;310:1424-1425
CrossRef | Web of Science | Medline2
Allison JE ,Tekawa IS ,Ransom LJ ,Adrain AL . A comparison of fecal occult-blood tests for colorectal-cancer screening. N Engl J Med 1996;334:155-159
Full Text | Web of Science | Medline3
Robert D ,Voirol M ,Guelpa G ,Pfister E . Erosive gastritis: an aggravating cause of anaemia in patients treated for chronic renal insufficiency. J Suisse Med 1987;117:1221-12234
Chachati A ,Godon JP . Effect of haemodialysis on upper gastrointestinal tract pathology in patients with chronic renal failure. Nephrol Dial Transplant 1987;1:233-237
Medline
To the Editor:
The report by Ifudu et al. is an important study, demonstrating clearly what many nephrologists have thought to be true on the basis of clinical observation.
Another clinical observation1 is the resistance to erythropoietin in patients who are receiving hemodialysis during treatment with angiotensin-converting–enzyme (ACE) inhibitors. An increased frequency of anemia has also been seen in patients who receive such inhibitors after transplantation.2 I wonder whether the patients described by Ifudu et al. were balanced with respect to treatment with ACE inhibitors.
A hitherto unrecognized link between ACE inhibition and anemia may be the reduced hydrolysis of N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) by ACE. Ac-SDKP is a regulatory factor of hematopoiesis that prevents the recruitment of pluripotent hematopoietic stem cells and normal early progenitors into the S phase of the cellular cycle by maintaining the G0 phase.3 Captopril has been shown to increase the serum concentrations of Ac-SDKP by inhibiting its hydrolysis.4 An increased intensity of hemodialysis may increase the clearance of Ac-SDKP, thereby reducing levels of this inhibitor of erythropoiesis.
4 ReferencesP. Kotanko, M.D.
Krankenhaus Barmherzige Brüder, A-8020 Graz, Austria1
Vlahakos DV ,Balodimos C ,Papachristopoulos V ,Vassilakos P ,Hinari E ,Vlachojannis JG . Renin-angiotensin system stimulates erythropoietin secretion in chronic hemodialysis patients. Clin Nephrol 1995;43:53-59
Web of Science | Medline2
Sizeland PC ,Bailey RR ,Lynn KL ,Robson RA . Anemia and angiotensin-converting enzyme inhibition in renal transplant recipients. J Cardiovasc Pharmacol 1990;16:Suppl 7:S117-S119
Web of Science | Medline3
Bonnet D ,Lemoine FM ,Pontvert-Delucq S ,Baillou C ,Najman A ,Guigon M . Direct and reversible inhibitory effects of the tetrapeptide acetyl-N-Ser-Asp-Lys-Pro (Seraspenide) on the growth of human CD34+ subpopulations in response to growth factors. Blood 1993;82:3307-3314
Web of Science | Medline4
Azizi M ,Rousseau A ,Ezan E , et al. Acute angiotensin-converting enzyme inhibition increases the plasma level of the natural stem cell regulator N-acetyl-seryl-aspartyl-lysyl-proline. J Clin Invest 1996;97:839-844
CrossRef | Web of Science | Medline
Author/Editor Response
The authors reply:
To the Editor: We thank our colleagues for their comments. Ballinger et al. ask whether the increased hematocrit we found in patients receiving hemodialysis treatments for an increased duration resulted from improvement in (undetected) gastrointestinal disease. We did not note peptic ulcers or bowel disorders in any patient; gastrointestinal blood loss was of minor importance (only 8 of 135 patients had positive fecal occult-blood tests). So-called iron deficiency in many patients on hemodialysis may indicate impaired use of iron; most patients on hemodialysis require 6 to 10 g of parenteral iron yearly to maintain normal iron indexes,1 even though annual iron loss is about 2 g.2 In a study of patients with chronic renal failure and anemia, the cohort with a mean creatinine clearance of less than 20 ml per minute did not have an increased hematocrit after five months of parenteral iron therapy.3 In patients on dialysis who have normal iron levels, such therapy may mask resistance to erythropoietin induced by insufficient dialysis, and the iron therapy carries the risk of hemosiderosis, which was a consequence of repeated blood transfusion in the pre-erythropoietin era.
Kotanko comments on the remarkable effect of ACE inhibitors in inducing resistance to erythropoietin. No patient in our study (receiving either conventional or intensified dialysis) was treated with ACE inhibitors. Ureña and Pétrover presume, as do Levin and Gotch, that purportedly biocompatible hemodialysis membranes affect the hematocrit. Although vigorously championed, this intriguing hypothesis is unsubstantiated. Patients described by Charra et al.,4 treated according to the original “long-duration” Scribner regimen, had nearly normal hematocrits when “bioincompatible” cuprophane membranes were used. Furthermore, a clear relation between the duration of hemodialysis treatments and the hematocrit was demonstrated in the National Cooperative Dialysis Study, in which bioincompatible membranes were used.5 Over 15 years ago, investigators from our program reported that patients receiving successful hemodialysis at home regularly had hematocrits of 35 percent or above while using bioincompatible membranes exclusively.6
Enhanced removal of large solutes by biocompatible high-flux membranes may have contributed to the increased hematocrit in the group receiving intensified dialysis. We caution that the criteria defining the type of dialyzer, the duration of dialysis, and indeed the entire dialysis prescription are by no means established. The finding of a constant serum albumin concentration throughout the six weeks of our study is evidence against the hemoconcentration postulated by Malhotra and Tzamaloukas.
6 ReferencesOnyekachi Ifudu, M.B., B.S.
Joseph Feldman, Dr.P.H.
Eli A. Friedman, M.D.
State University of New York Health Science Center, Brooklyn, NY 112031
Barth RH ,Aboul-Magd A ,Goldwasser P . Response to iron dextran therapy is not precluded by high serum ferritin (Ferr). J Am Soc Nephrol 1995;6:519-519 abstract.
Web of Science2
Eschbach JW ,Cook JD ,Scribner BH ,Finch CA . Iron balance in hemodialysis patients. Ann Intern Med 1977;87:710-713
Web of Science | Medline3
Silverberg DS ,Iaina A ,Peer G , et al. Intravenous iron supplementation for the treatment of the anemia of moderate to severe chronic renal failure patients not receiving dialysis. Am J Kidney Dis 1996;27:234-238
CrossRef | Web of Science | Medline4
Charra B ,Calemard E ,Ruffet M , et al. Survival as an index of adequacy of dialysis. Kidney Int 1992;41:1286-1291
CrossRef | Web of Science | Medline5
Santiago GC ,Rao TK ,Laird NM . Effect of dialysis therapy on the hematopoietic system: the National Cooperative Dialysis Study. Kidney Int Suppl 1983;13:S95-S100
Medline6
Charles G ,Lundin AP III ,Delano BG ,Brown C ,Friedman EA . Absence of anemia in maintenance hemodialysis. Int J Artif Organs 1981;4:277-279
Web of Science | Medline
- Citing Articles (1)
Citing Articles
1
Karel Opatrny, Tomas Reischig, Jorg Vienken, Jaromir Eiselt, Ladislav Vit, Sylvie Opatrna, Frantisek Sefrna, Jaroslav Racek, Gail S. Brown. (2002) Does Treatment Modality Have an Impact on Anemia in Patients with Chronic Renal Failure? Effect of Low- and High-Flux Biocompatible Dialysis. Artificial Organs 26:2, 181-188
CrossRef
