Biochemical and Clinical Benefits of HDF
HDF provides an enhanced clearance of β2-microglobulin and osteocalcin compared to HD (30–40% higher with HDF than with high-flux HD) (1). Several large cohort studies indicate that extended use of convective therapies has a beneficial impact on the development of β2-microglobulin amyloidosis (2,3), reducing the incidence of carpal tunnel syndrome and other related manifestations. This beneficial effect probably results from the regular use of ultrapure fluids and less bioincompatible materials that could help to prevent inflammation, combined with convective transport mechanisms that enhance β2-microglobulin removal (4-13).
A prospective study, based on direct dialysis quantification methodology, found that phosphate removal was enhanced by 15–20% with post-dilution HDF compared to high-flux HD (14).
Studies indicate higher clearances of a number of other solutes with HDF, including complement factor D (a pro-inflammatory mediator) (15), leptin (16kDa, involved in loss of appetite) (16), FGF23 (30kDa, implicated in metabolic bone disorders and vascular calcification) (17,18), PTH (19), various cytokines (13,20,21), and circulating advanced glycation end products (AGEs) and AGE precursors (22).
Several prospective studies, including RISCAVID, have shown that levels of CRP (C-reactive protein) and other sensitive biomarkers of inflammation (e.g., IL-6) and/or proinflammatory cells are reduced with HDF (23). A recent meta-analysis suggested that a low inflammatory profile, associated with long-term use of HDF, relies most probably on regular exposure to ultrapure dialysis fluid and is less likely due to removal of pro-inflammatory mediators (24).
Erythropoiesis-stimulating agent (ESA) dose could be reduced in several clinical studies with HDF, the benefit being attributed to the combined effects of the higher removal of middle-sized retention solutes (erythropoietic inhibitor substances), the use of higher quality water, and reduced inflammation (25). However, the extent to which HDF might reduce ESA resistance compared to HD remains uncertain, with no effect found in a preplanned secondary analysis of a prospective randomized trial (26) or in a recent meta-analysis (27). Nevertheless, a significant decrease was observed in patients treated with erythropoetin in a large observational study (28).
A significant reduction in the number of intradialytic hypotension episodes was observed with HDF compared to conventional HD; this was also seen in high cardiovascular risk patients (29). Hemodynamic stability benefit of HDF is usually ascribed to the negative thermal balance (i.e., hypothermic dialysis) due to infusion of relatively cool substitution fluid, rather than a high sodium concentration in the substitution fluid and/or removal of vasodilation mediators (30, 31, 32).
Nutritional status preservation is a crucial parameter for dialysis adequacy. Despite potential increased losses of amino acids and/or nutrients due to its higher efficiency, HDF tends to better preserve body composition and nutritional status compared to HD, even in malnourished patients (33, 34). In a prospective one-year follow-up study, HDF-treated patients had better preservation of muscle mass, increased protein intake and reduced inflammatory state compared to high-flux HD, supporting the hypothesis that appropriate HDF dosing favors physical activity, benefits nutritional status, and prevents protein-energy wasting in HD patients (35).
Optimal bone mineral disease management, an important component to prevent progression of bone disease and vascular calcification, may be facilitated by HDF (36). HDF was shown to have beneficial effects on mineral and bone biomarkers in a cross-sectional study (19). In the CONTRAST study, pre-dialysis serum phosphate levels were reduced by 6% at steady state, and the percentage of patients reaching target pre-treatment serum phosphorus levels increased from 64% to 74% (37). Potential pathways for this could involve increased removal rate of FGF23 (+20%), improved response to calcidiol (+30%), but there are conflicting results on the levels of sclerostin and of alkaline phosphatase (18, 38-41). However, it is important to note that divalent ion prescription (calcium, magnesium), treatment time and phosphate binder type (calcium- or non-calcium-based) are still major confounders in interpretation of bone mineral biomarker changes (42-44).
Health-Related Quality of Life (HRQOL) studies have provided conflicting results (45). Several crossover studies support a beneficial role of HDF in enhancing quality of life. However, most parallel-group randomized clinical trials on this subject demonstrate no or limited improvement in HRQOL associated with HDF. The available data on HRQOL in patients under HDF is limited and of low quality. The inconsistency of these results is probably related to different methods used to assess quality of life, heterogeneity of population studies, and variations in convective dose delivered.
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