Role of type of vascular access in erythropoietin and intravenous iron requirements in haemodialysis

Marian Goicoechea1, Carlos Caramelo2,, Patrocinio Rodriguez1, Eduardo Verde3, Enrique Gruss1, Marta Albalate1, Alberto Ortiz2, Santos Casado2 and Fernando Valderrábano3

1 Fundación Renal Iñigo Alvarez de Toledo, 2 Fundación Jiménez Díaz and 3 Hospital General Universitario Gregorio Marañon, Instituto Reina Sofía de Investigación Nefrológica, Madrid, Spain



   Abstract
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Background. Recent data have suggested the existence of a relationship between the use of synthetic vascular accesses and increased erythropoietin (Epo) requirements. The present study aimed to evaluate the possible role of the type of vascular access in both Epo and intravenous (i.v.) iron requirements.

Methods. One-hundred-and-seven individuals without recognized causes of Epo resistance, 62 of them undergoing chronic haemodialysis through native arteriovenous fistulae (AVF) and 45 through PTFE grafts, were retrospectively studied (one-year follow-up). Sixty-nine patients, i.e. all but three with a PTFE graft and 27 with native AVF, were taking anti-platelet agents. Doses of i.v. iron and Epo and laboratory parameters were recorded.

Results. Erythropoietin and i.v. iron requirements were higher in the patients dialysed through PTFE grafts compared with those with native AVF (Epo: 103.8±58.4 vs 81.0±44.5 U/kg/week, P=0.025; i.v. iron: 178.9±111 vs 125.9±96 mg/month, P=0.01). On a yearly basis, the difference in Epo dose represented a total of 94582±16789 U Epo/patient/year. Moreover, the patients with PTFE grafts received more red blood cell transfusions than patients with native AVF (P=0.021). No differences between laboratory, dialysis kinetics, demographic or comorbidity parameters were found. The type of vascular access was the best predictor of the requirement of >=150 U/kg/week Epo (P=0.03). Even though the patients who received anti-platelet therapy required more i.v. iron (167.5±103.6 vs 114.5±101.4 mg/month, P=0.008) but not more Epo (P=NS), the possibility of an accessory role of anti-platelet agents in the increased Epo requirements with PTFE grafts cannot be ruled out.

Conclusions. The use of a PTFE graft and anti-platelet drugs represents a previously undescribed association related to higher Epo and i.v. iron requirements. The association described herein adds new arguments to the debate concerning the choice of vascular access in chronic haemodialysis patients.

Keywords: anaemia; native fistulae; polytetrafluoroethylene (PTFE) graft



   Introduction
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Erythropoietin (Epo) has become a critical part of the treatment of patients with end-stage renal disease ESRD [1]. Erythropoietin treatment provides consistent improvement in a variety of clinical outcomes that bear on the morbidity and mortality of dialysis patients [2,3]. However, optimal use of Epo is a particularly cost-sensitive issue. For this reason, the diagnosis of conditions producing Epo hyporesponsiveness is a most relevant subject. In the first studies on Epo treatment in dialysis patients, less than 5% of subjects had total or partial resistance to Epo therapy [4,5]. At the present time, many possible causes of an inadequate response to Epo have been identified, including absolute or functional iron deficiency [6], blood losses, severe secondary hyperparathyroidism [7], aluminium excess [8], infectious and inflammatory states, and neoplastic diseases [9,10]. In addition, in recent years, a number of potentially modifiable factors influencing the response to Epo, including higher delivered dose of dialysis and biocompatibility of membranes, have been described [1114]. However, a large variation in the amount of Epo administered to the different patients still exists. The reasons for these differences are largely unknown [15], and the existence of non-identified factors, which would influence the response to Epo treatment, should be assumed.

In a recent study, aimed to specifically assess the role of anti-platelet agents in iron needs in dialysis patients, we obtained substantial preliminary evidence in favour of a possibly significant association, namely, between the type of vascular access and Epo needs [16]. Accordingly, the present study was focused on analysing whether there is a significant relationship between the type of vascular access, i.e. native arteriovenous fistulae (AVF) vs synthetic grafts, and Epo and intravenous (i.v.) iron requirements.



   Subjects and methods
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Subjects
All the patients studied were on conventional haemodialysis for a minimum of 4 months in two university hospitals or in two external facilities associated with the same hospitals. Restrictive exclusion criteria were applied to eliminate the patients with any of the recognized putative causes of Epo resistance. In brief, patients with the following conditions were excluded from the study: severe hyperparathyroidism (iPTH >700 pg/ml) (32 subjects), possible aluminium excess (baseline serum aluminium higher than 40 µg/l in the absence of oral aluminium-containing phosphate binders) (nine subjects), absolute iron deficiency (serum ferritin <100 µg/l or transferrin saturation <15%) (nine subjects), dialysis-unrelated coagulopathy (three subjects), liver disease (three subjects), severe malnutrition (two subjects), use of a catheter as vascular access (16 subjects), active bleeding from different sources (12 subjects), active or recent neoplasia (16 subjects), Kt/V <1 (27 subjects), anticoagulation with acenocumarol (11 subjects) and long-term hospitalization during the follow-up period or active chronic inflammatory or infectious processes (13 subjects). Further exclusions involved the individuals (n=14) participating in a study requiring the maintenance of haematocrit values higher than 36% and any patient who had insufficient data collection, did not complete the follow-up or changed the type of vascular access during the observational period (56 subjects).

One-hundred-and-seven patients with ESRD (mean age: 62.3±15 years) who were undergoing regular haemodialysis therapy for a mean time of 44.3±52 months were included in the final evaluation. They were studied from 1 January 1999 to 31 December 1999. The aetiology of chronic renal disease was diabetic nephropathy (n=21), glomerulonephritis (n=20), interstitial nephropathy (n=17), ischaemic nephropathy (n=16), polycystic renal disease (n=6), congenital nephropathy (n=3) and unknown nephropathy (n=24). The patients were dialysed for 180 to 270 min (X±SD: 205±24.2), three times a week, with the following types of membranes: cellulose acetate (35 patients), haemophane (28 patients), cellulose triacetate (one patient), SMC (four patients), polymethylmethacrylate (10 patients), polysulphone (19 patients) and AN69 (10 patients). The dialyser surface areas were between 1.8 and 2.6 m2. Dialysers were not reused and bicarbonate dialysate (39 mmol/l) was employed in all the cases. Blood flow was between 300 and 400 ml/min and dialysate flow was between 500 and 700 ml/min. Sixty-two subjects had an autologous AVF and 45 had a polytetrafluoroethylene (PTFE) (Gore-Tex®) graft. The localization of the vascular access was in 45 patients radio-cephalic, in 28 brachio-cephalic, in five brachio-basilic and in 29 brachio-axillar.

Erythropoietin was administered by the subcutaneous route in all patients and the dose was adjusted to the target of maintaining haematocrit and haemoglobin values higher than 33% and 11 g/dl, respectively. Sixty-nine patients were on anti-platelet agents (24 aspirin alone, 37 ticlopidine alone, 2 dipyridamole and 6 dipyridamole plus aspirin). The doses of these agents were: aspirin between 125 and 200 mg/day, ticlopidine 250 mg every day or every other day, and dipyridamole 300 mg/day. All but three patients with graft prosthesis and 27 out of 62 patients with AVF were on anti-platelet therapy. In the patients with a prosthetic graft, the anti-platelet agents were administrated for prevention of graft thrombosis. In addition, in this group 8 subjects had cardiopathy, 3 vascular cerebral accidents and 1 peripheral vascular disease. The reasons for administrating anti-platelet therapy in the group of patients with autologous AVF were: cardiopathy with arrhythmia in 10 patients, thrombotic vascular cerebral accidents in 3, peripheral vascular disease in 2, and prevention of thrombosis in a troublesome vascular access in the remaining 12 patients. As an additional, a posteriori study, based on the results obtained in the 107 patients, the levels of blood C-reactive protein (CRP) were analysed in 46 patients having similar characteristics to those included in the main study. The objective of this measurement was to ascertain whether there are differences in CRP between patients with autologous AVF vs PTFE grafts. Similar exclusion criteria to those applied in the first 107 individuals were used. Thirty (22 with autologous AVF and 8 with PTFE) out of 46 individuals belonged to the original group.

Eighty-nine patients received treatment with i.v. iron (Ferrlecit®, Rhone-Poulenc-Rorer, Germany, 62.5 mg iron as ferric gluconate). As previously described, the doses of i.v. iron were targeted to maintain values of serum ferritin >150 µg/l and transferrin saturation >15–20% [16]. Sixteen patients did not receive iron supplements and two patients took oral iron (ferrous sulphate) supplementation (80 mg tablet, Tardyferon®, Robapharm, Barcelona, Spain or 105 mg tablet, Fero-gradumet®, Abbot, Madrid, Spain) (one or two tablets/day). Fifteen out of 18 patients who did not receive parenteral iron had an autologous AVF and 3 patients had a PTFE graft.

Parameters studied
Haematocrit (Hct), haemoglobin (Hb), mean corpuscular volume (MCV), serum albumin, alanine aminotransferase (ALAT), aspartate aminotransferase (ASAT), {gamma}-glutamyltransferase (GGT) and lactate dehydrogenase (LDH) were measured bimonthly by standard techniques. Serum iron, ferritin and transferrin and transferrin saturation were measured bimonthly by radioimmunoassay (Allegro Nichols Institute, San Juan Capistrano, CA, USA). iPTH was measured by radioimmunoassay (Allegro Nichols Institute) and serum aluminium was measured by atomic absorption spectrometry in a graphite furnace, all as described previously [17], both a minimum of twice yearly. C-reactive protein was measured by a nephelometric method (normal range: 0–1 mg/dl). Kt/V and protein catabolism rate (nPCR) were measured as described [18] by the Daugirdas (second generation) method, three times a year using samples extracted prior to and 5 min after the end of a midweek dialysis session. Kt/V was calculated with the formula: ln(R-(0.008xt))+(4-3.5xR)xUF/W) where R is the post-/pre-urea ratio, t haemodialysis session time, UF ultrafiltrate volume and W post-dialysis weight. Erythropoietin and iron doses and transfusions (number per year) were recorded. The mean values of these parameters throughout the follow-up were used for calculations. In addition, the number of hospital admissions per year was recorded. The presence of diabetes mellitus, severe pre-existing cardiovascular disease, i.e. congestive heart failure, history of stroke or cerebrovascular disease or previous myocardial infarction, severe atherosclerosis manifested as peripheral vascular disease, and chronic liver disease were recorded to evaluate comorbid pathology.

Statistical analysis
The Kolmogorov–Smirnov test was applied for analysing the normality of the distribution of the parameters. The unpaired Student's t-test was used to compare mean values between groups. The parameters that did not fit into a normal (Gaussian) distribution were compared using the Mann–Whitney U test. Pearson's and Spearman's coefficients were used to correlate parameters as appropriate. Chi-square and Fisher's tests were used to compare qualitative variables. Logistic regression was used for multivariate analysis. All the statistics were done by means of the statistical package SPSS 7.5 for Windows 95 (SPSS Systat Inc., Chicago, Illinois, USA). The values are expressed as mean±SD. A P value of <0.05 was considered significant.



   Results
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
The study revealed significant differences (P=0.025) in terms of Epo requirements between patients who were dialysed through PTFE grafts compared with those dialysed through autologous AVF (PTFE: 103.8±58.4 vs AVF: 81±44.5 U/kg/week) (Figure 1Go). Calculated on the theoretical basis of total yearly Epo doses, the difference in Epo requirements represented a total of 94582±16789 Epo U/patient/year more in the patients with a PTFE graft compared with the patients with autologous AVF (P=0.025). In addition, the subjects with a PTFE graft required a higher amount of i.v. iron supplements than did the subjects with AVF (2146.8±1332 vs 1510.8±1152 mg/year, P=0.01) (Figure 1Go). The significance of these results did not change if the patients who had not received parenteral iron supplements were excluded from the analysis (data not shown).



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Fig. 1. Erythropoietin (left graphic) and parenteral iron (right graphic) requirements in patients with autologous AVF vs patients with synthetic PTFE grafts.

 
No differences between groups were found in Hct, Hb, MCV, serum iron, plasma ferritin, serum transferrin and transferrin saturation, serum aluminium and PTH (Table 1Go). Also, no differences were found in Kt/V, nPCR, and the following dialytic parameters: mean time on haemodialysis, area of dialysers and haemodialysis session time in both groups of patients (P=NS in all cases). The patients being dialysed through a PTFE graft were not older and did not present more diabetes mellitus, cardiovascular disease and hepatitis C positivity (P=NS, Chi-square test). In fact, when the diabetic patients were analysed separately, the Epo doses were higher in the group of patients with PTFE graft vs the subjects with autologous AVF (102±56 vs 60.1±43, P<0.05), therefore, maintaining the same tendency as the total PTFE group. The percentages of synthetic membranes used were similar in both groups of patients (33.8% in patients with autologous AVF and 40% in patients with prosthetic grafts) and additional evaluation indicated that the Epo requirements were not statistically related with the type of haemodialysis membrane.


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Table 1. Comparison of laboratory parameters between patients with autologous AVF and PTFE grafts

 
To obtain further evidence on the actual relevance of the data, a supplementary analysis has been done with the data of the patients grouped according to the existence of high Epo requirements. The cut-off point (150 U/kg/week) was chosen after analysing our data population and represents the mean plus one standard deviation of Epo doses. Analysis using this cut-off showed that the group of patients who required >=150 U/kg/week Epo included only two patients with autologous AVF but 8 with PTFE graft; on the contrary, 60 patients with autologous AVF and 37 subjects with PTFE grafts required <150 U/kg/week Epo dosage (P=0.011, Chi-square test). Furthermore, in the multivariate analysis by logistic regression, the type of vascular access was the best predictor of requirement of higher Epo doses (>=150 U/kg/week) (P=0.04). The variables considered were gender, serum albumin, anti-platelet therapy, and type of vascular access (Table 2Go).


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Table 2. Factors related to the risk of requiring higher Epo dose (>=150 U/kg/week)

 
Nine subjects required red blood cell (RBC) transfusions during the study. The patients dialysed through a prosthetic graft received more transfusions than the patients dialysed through autologous AVF (2/62 vs 7/45, P=0.021). No correlation was found between the transfusions and the therapy with anti-platelet drugs or the type of dialysis membrane.

The hypothesis could be raised that the observed differences in Epo requirements between patients with prosthetic vs autologous vascular access were related to the fact that a majority of the former was taking anti-platelet drugs. This issue was addressed by analysing the data with the patients grouped according to the use or not of anti-platelet drugs. This analysis yielded evidence against a main role of anti-platelet drugs in Epo requirements, showing no differences in Epo requirements between patients taking or not anti-platelet therapy (Table 3Go). However, higher i.v. iron requirements in relation to the use of anti-platelet therapy were observed (P=0.008, Figure 2Go). In spite of the higher i.v. iron supplementation, serum ferritin and transferrin saturation were significantly lower in the group of patients on anti-platelet therapy (Table 3Go). As a collateral finding, the patients who took anti-platelet treatment were older than patients who did not receive therapy (P=0.001) (Table 3Go). The type of anti-platelet therapy, i.e. ticlopidine (37 patients) or aspirin (24 patients), did not influence the Epo and i.v. iron requirements (P>0.05).


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Table 3. Comparison of parameters between patients on anti-platelet therapy and patients who did not receive anti-platelet therapy

 


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Fig. 2. Increased parenteral iron requirements in patients taking anti-platelet agents.

 
To further ascertain the possible causes of the differences detected, the data were evaluated by an analysis that included only the patients with autologous AVF distributed according to their use or not of anti-platelet therapy. In this analysis, no significant differences were found in i.v. iron requirements; however, the patients who received anti-platelet therapy had lower values of plasma ferritin and transferrin saturation (P=0.022 and P=0.001, respectively) (Table 4Go). No differences were found between the groups in plasma aluminium, iPTH, KT/V and nPCR, with values that did not differ from those shown in Table 1Go (all P=NS). The values of blood CRP were 0.34±0.58 mg/dl in AVF (n=36) vs 0.38±0.51 mg/dl in PTFE grafts (n=10) (P=NS).


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Table 4. Comparison of parameters between patients who were dialysed through autologous AVF and received anti-platelet therapy with patients who were dialysed through autologous AVF but did not receive anti-platelet therapy

 
Fifteen patients were admitted to hospital during the follow-up period (13 patients once and two twice a year). The causes of admission were: myocardial ischaemia (n=5), surgical procedures (n=4), infectious processes (n=2), vascular access thrombosis (n=2), seizures (n=1), and renal colic (n=1). No correlation was found between the admissions at the hospital and the type of vascular access, age, Epo doses, Hct or Hb values.



   Discussion
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
In a recent study aimed to analyse the determinants of iron requirements in haemodialysis patients, we collaterally detected that the patients being dialysed through a PTFE graft had Epo requirements about 35% higher than patients with autologous AVF [16]. The number of patients examined in this first study was not large enough to obtain definitive conclusions. The potential relevance of this intriguing finding lead to the design of the present investigation, focused on elucidating whether the type of vascular access is a critical factor in Epo requirements. In the present study, the use of restrictive exclusion criteria was stressed, to avoid other causes of Epo resistance which may constitute a source of confusion. Our data support the existence of a clear-cut relationship between the type of vascular access and the requirement of higher Epo doses, more RBC transfusions and more i.v. iron supplements. Even though our data will undoubtedly need further analysis on a larger scale, we are directly signalling to a previously undescribed phenomenological association with important practical consequences.

At a first glance, our findings have at least two possible causal interpretations. In the first place, the patients with PTFE grafts may have had higher blood losses and, therefore, higher Epo and iron needs. This possibility is based on the common practical knowledge that post-puncture bleeding is more frequent in synthetic grafts, confirmed by our own measurements, which have demonstrated that PTFE grafts have a markedly slower homeostasis of the puncture sites than autologous AVF (9.1±3.6 vs 5.5±3.05 min of post-dialysis bleeding, respectively) [16]. Our data also showed that the increased post-dialytic bleeding time of PTFE was not mainly due to the use of anti-platelet therapy, since the patients with PTFE graft bleed for a significantly longer time than autologous AVF exposed to similar doses of anti-platelet agents (9.1±3.6 vs 5.4±2.2 min of post-dialysis bleeding) [16]. Another possible explanation for the differences in Epo requirements would be that the patients with a PTFE graft may have a higher degree of either chronic inflammation or intermittent infections associated with the prosthetic graft [19]. This circumstance would putatively have caused increased Epo requirements, perhaps through the increase of inflammatory cytokines [20,21]. However, if that were the case, data of functional iron deficiency [22], as well as Epo resistance, would have been found. As aforementioned, patients with Epo resistance were excluded from the study at the outset. In addition, our data show that blood CRP did not differ between patients with AVF or prosthetic access, a finding which favours the suggestion that PTFE does not increase Epo requirements through inflammatory mechanisms. However, since CRP values were available from only 46 patients, no definitive conclusions are warranted.

The present study amplifies our previous findings showing that increased i.v. iron is required in patients treated with anti-platelet drugs [16]. In this regard, the patients who were receiving anti-platelet therapy needed higher i.v. iron supplements to maintain iron reserves than the patients without anti-platelet drugs. The fact that in our study all but three patients with PTFE grafts were receiving anti-platelet therapy, precluded the performance of a comparative analysis of the effects of these drugs in PTFE bleeding. Taken together, our data do not sustain directly, but do not rule out completely, a role of anti-platelet agents in the increased Epo needs in patients with PTFE graft. On the other hand, the data shown in Table 4Go are clear in demonstrating that anti-platelet drugs do not influence Epo needs in patients with autologous AVF. One possible interpretation is that anti-platelet drugs may increase a natural predisposition to bleeding in PTFE grafts, therefore, contributing to blood losses. The administration of parenteral iron matches the iron losses, as shown in Table 3Go. Accordingly, this maintenance of serum iron is sufficient to avoid an increase in Epo dose in autologous AVF, but the more important bleeding may imply an excessive burden to the haemopoietic mechanism in patients with PTFE grafts. This, therefore, may create the conditions for the increase in Epo needs. The similarity in the data of iron kinetics between the two groups does not necessarily indicate that these patients actually have equivalent moment-to-moment access to iron stores; therefore, the PTFE patients could probably have subclinical iron deficiency.

The use of PTFE grafts is more frequent in North America compared to European countries [23]. This fact could explain, in part, differences in the Epo doses used in North American dialysis patients. The recent National Kidney Foundation Dialysis Outcomes Quality Initiative (NFK-DOQI) (Optimizing vascular access: guideline 3) definitely indicates the preference for AVF as the first vascular access in patients requiring chronic haemodialysis [24]. Our data revealing the need for increased Epo and i.v. iron supplements in patients with PTFE grafts add new arguments for not recommending the use of synthetic vascular accesses. Even though additional studies are required to further ascertain the mechanisms involved in the relationship between synthetic grafts and Epo requirements, the present results detect a source of potentially high impact on dialysis practice and dialysis economy and should be taken into account in the strategies of choice of the vascular access.



   Notes
 
Correspondence and offprint requests to: Carlos Caramelo, MD, Laboratorio de Nefrología, Fundación Jiménez Díaz, Universidad Autónoma, Av. Reyes Católicos n° 2, E-28040 Madrid, Spain. Email: ccaramelo{at}fjd.es Back



   References
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 

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Received for publication: 8. 2.01
Revision received 28. 6.01.