Impact of Water Treatment on Anemia in Hemodialysis Patients

Introduction

Prevalent hemodialysis patients undergoing hemodialysis (HD) three times/week, 4 h per session are exposed to a high water volume of 360–576 liters per week depending on their dialysate blood flow (500–800 mL/min). The quality of dialysis water is responsible for inflammation, which is a potent trigger of atherosclerosis and a pathogenic factor in anemia, increasing the mortality and morbidity in these patients. Therefore, this mandates the achievement of the highest level of purity of water coming into close contact with a patient’s blood.[1,2]

Currently, the available dialysis fluid delivery systems include the single-patient dialysis fluid delivery system (SPDDS) (individual dialysis fluid delivery system) and the central concentrates delivery systems (CCDS), in addition to the central dialysis fluid delivery system (CDDS). In SPDDS, dialysis fluid supply equipment is contained in the patient monitor. Nowadays, it is used widely and is considered a dialysis treatment global standard. Apart from the advantage of the relatively free location, SPDDS allows for the dialysis fluid composition individualization to meet unique patient needs.[3]

CDDS is especially useful in multi-patient treatment with in-center regular hemodialysis. It is a cost-effective, labor-saving, safe, and time-tested system with experience of almost 40 years. Microbial concerns have been cleared by a refined system design, tight RO membrane, placement of multiple endotoxin retentive filters (ETRF), and disinfecting the entire system on a daily basis.[4]

Endotoxemia is reported commonly in the dialysis population and has been linked to systemic inflammation. Endotoxins are much implicated in the pathogenesis of sepsis syndrome and are potent mediators of inflammation. Reported levels of endotoxemia in the dialysis population range from 0.209 to 2.31 endotoxin units/mL (EU/mL). Supposing an average 70-kg patient with approximately 3 L of circulating plasma volume, it is expected that as little as 0.12 EU/mL would be sufficient to trigger pyrogenic symptoms.[5]

The bacteriological qualities of the dialysis fluid water in CDDS were proven to be extremely high, having a strong impact on the patient outcome. The acceptable level of ET of dialysis fluid should be <0.1 EU/ml. The excellent water quality in CDDS might be one of the important factors of patient survival in chronic dialysis.[6]

Renal anemia, one of the most common complications in chronic kidney disease (CKD) that has deleterious effects on the patients’ quality of life, increases the risk of cardiovascular events and is associated directly and indirectly with various infections.[7]

The pathogenesis of anemia in CKD is usually multifactorial. The main features include the deficiency in erythropoietin (Epo) production and disordered iron balance. In addition to circulating uremia-associated inhibitors of Epo action, shortened survival of the red blood cell (RBC), iron losses, bleeding, and chronic inflammatory state can further aggravate the anemia.[8]

With such a proposed benefit of CDDS on dialysis water endotoxin levels and the deleterious effects of endotoxemia and its implication in the pathogenesis of anemia in this group of patients, we aimed to compare the effect of using CDDS and SDDS on anemia in prevalent hemodialysis patients.

Patients and Methodology

This is a prospective cohort study conducted in the hemodialysis units at Ain Shams University hospitals & Mansheiyat El-Bakry General Hospital, Cairo, Egypt between May and July 2019.

In total, 100 prevalent hemodialysis patients participated in this study. Adult patients with transferrin saturation of more than 20% were included. Patients with chronic infections and patients with other causes of anemia (malignancies, gastrointestinal bleeding) were excluded.

Results

No significant difference was noted between patients in both groups as regard age and sex. In the CDDS group, patients were maintained on dialysis for 3.4 ± 1.1 years, whereas SPDDS patients were dialyzing for 3.2 ± 0.9 years [Table 1].

Endotoxin level in the dialysis fluid of the CDDS group was significantly lower compared to the SPDDS group (0.05 vs. 0.11 EU/ml, P = 0.001).

Use of UPD yielded from CDDS dialysate improved the inflammatory status of this group of patients as reflected by a significant drop in the CRP level over 3-month follow-up (P < 0.001 for 1^st, 2^nd, and 3^rd months) compared to the baseline in the study group, unlike the SPDDS group where CRP level exhibited no significant change through the 3-month follow-up period compared to baseline (P = 0.55, 0.197, and 0.54 for 1^st, 2^nd, 3^rd months, respectively), with a significant difference between both groups (P < 0.001for 1^st, 2^nd, and 3^rd months). [Figure 1]

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Figure 1

Comparison of CRP level in both groups during the study period

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The CDDS group also showed a significant sustained improvement in hemoglobin level (P = 0.008 for 1^st month, <0.001 for 2^nd and 3^rd months) and ERI (P = 0.002 for 1^st month, <0.001 for 2^nd and 3^rd months) over the 3-month follow-up compared to baseline, together with a decrease in their ESA requirements as reflected by decreased erythropoietin stimulating agents’ doses at 3 months (5217± 2539.80 Vs 10272.73 ± 2781.70 for CDDS & SPDDS respectively, P-value: 0.001) compared to baseline [Table 1], needed to maintain the same hemoglobin level.

Conversely, in the SPDDS group, there was a significant increase in ERI through the 3-month follow-up period (P = 0.039, 0.025, and 0.047 for 1^st, 2^nd, and 3^rd months) associated with failure of improvement in Hb level all through the study period (P = 0.70, 0.14, and 0.149 for 1^st, 2^nd, and 3^rd months) compared to baseline, with a significant difference between both groups (P = <0.001 for 1^st, 2^nd, and 3^rd months for both hemoglobin and ERI) [Figures 2 and 3].

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Figure 2

Comparison of hemoglobin level in both groups during the study period

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Figure 3

Comparison of ERI level in both groups during the study period

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Moreover, no significant correlation was detected between CRP as a representative of the inflammatory state and neither hemoglobin level nor ERI at baseline (P = 0.46 and 0.29, respectively) and after 3 months of follow-up (P= 0.32 and 0.51, respectively) in the CDDS group of patients [Table 2], unlike SPDDS group, there was a negative correlation between CRP and hemoglobin level (P = 0.019) after 2 months, together with a positive correlation between CRP and ERI (P = 0.018) after 2 months, further confirming that the worsened inflammatory state in these patients is associated with the poor response to EPO and low hemoglobin level [Table 3].

Furthermore, there was a significant decrease in ferritin level in the CDDS group at 3 months compared to baseline (1119.61 ± 852.40 versus 851.88 ± 599.50 respectively, P-value: 0.056), which might further indicate the aforementioned improvement in the inflammatory status in this group, together with a slight (although statistically insignificant) improvement in the T-SAT was also noticed in the CDDS group at 3 months follow up (36.99 ± 16.41, P-value: 0.066). The use of CDDS did not affect the URR in our study, baseline data are listed in table 1.

Discussion

The microbiological quality of the water in the dialysate used in hemodialysis treatment has been suggested as a major contributor to the inflammatory status in this group of patients with the background idea that microbiologic contaminants in the dialysate and level of endotoxin might induce inflammation and resistance to ESA in dialysis patients.[10,11]

In the current study, endotoxin level in the dialysis fluid of the CDDS group was found to be significantly lower compared to the dialysis fluid of the SPDDS group, which was associated with significantly lower levels of CRP level at 3-month follow-up compared to baseline (P < 0.001) in the same group, unlike the SPDDS group, with a statistically significant difference between both groups [Figure 1].

Similarly, Praditpornsilpa et al. showed that chronic inflammation in patients undergoing high-flux HD is minimized in the case of lower endotoxin contamination. They stated that chronic inflammation in HD is strongly associated with water quality and can be assessed by measuring the concentrations of endotoxin in the dialysate.[11]

These results are also coping with the meta-analysis of Susantitaphong et al.,[12] who examined ultrapure dialysate (UPD) versus standard dialysate effects on markers of inflammation, and anemia parameters by the analysis of 23 study arms or cohorts (n = 2221) where UPD resulted in a significant decline in CRP (P < 0.001).

Our study showed that improved inflammatory status of this group of patients was associated with a significant, sustained improvement in their hemoglobin level [Figure 2], ERI, and a decrease in their ESA requirements over the 3 months of follow-up that was also absent in the SPDDS group [Figure 3 and Table 2].

The results of Maoujoud et al. also showed that the use of UPD by applying endotoxin filter on conventional dialysate circuit is associated with better control of anemia in a follow-up of chronic HD patients; moreover, the ERI was significantly lower after conversion to UPD (P = 0.01) at 1 year.[10]

Again, the aforementioned meta-analysis by Susantitaphong et al.[12] stated that UPD resulted in a significant increase in hemoglobin level (P = 0.022) with a decrease in the weekly erythropoietin dose (P < 0.001).

These results are in concordance with the results by Hung et al.,[13] which yielded a positive correlation between high sensitivity CRP, IL-6, and TNF-serum levels with the required epoetin dose and epoetin responsiveness index. The results of this analysis support a strong relationship between high CRP levels and epoetin hypo-responsiveness in HD patients.

Our findings are also in agreement with the data reported by Ledebo, who had evaluated the effect of UPD on anemia management and reported signs of improved erythropoietin response, manifested either by decreased EPO requirements to maintain a certain Hb or by an increase in Hb levels in response to the same EPO dose.[14]

Our prospective study showed no effect of improved dialysate purity on the efficacy of the hemodialysis sessions as reflected by the urea reduction ratio (URR). Similarly, Molina et al.[15] stated that dialysis with ultrapure dialysis fluid (by placing a hydrophilic nylon filter (capable of trapping particles bigger than 0.22 microns) post-osmosis and a polysulfone filter before the dialyzer (Diasafe, Fresenius Medical Care^®)) showed no significant differences as compared to baseline for Kt/V at any of the cut-off points.

However, our results conflict with Molina et al. where they showed an insignificant change in serum ferritin level, unlike our results, where there was a significant decrease in serum ferritin level at 3-month follow-up.[15]

Conclusion

UPD produced by the CDDS was positively reflected in minimizing the inflammatory status of this group of patients, together with a significant sustained improvement in their hemoglobin level, ERI, and a decrease in their ESA requirements, compared to the SPDDS.