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Saudi Journal of Kidney Diseases and Transplantation
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Table of Contents   
REVIEW ARTICLE  
Year : 2012  |  Volume : 23  |  Issue : 6  |  Page : 1145-1161
Modalities of hemodialysis: Quality improvement


Department of Nephrology, Kanoo Kidney Center, Dammam Medical Complex, Dammam, Saudi Arabia

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Date of Web Publication17-Nov-2012
 

   Abstract 

Hemodialysis (HD) treatment had, over many years, improved the survival rate of patients with end-stage renal disease. However, standard or conventional HD prescription is far from being optimal in replacing the function of normal kidneys. Its unphysiologic clearance pattern and inability to remove all types and sizes of uremic toxins results in inter- and intra-dialysis complications and an unacceptably high rate of cardiovascular morbidity and mortality. Efficiency of HD can be improved by increasing blood and dialysate flow rates, dialyzer size and surface area and duration and frequency of dialysis sessions. Home HD, where short daily or long slow nocturnal HD sessions can conveniently be performed, provides an excellent option for quality of life improvement and reduction in morbidity and mortality. Recent innovations in the specifications of HD machines and improvement in dialysis membranes characteristics and water treatment technology paved the way for achieving quality HD. These advancements have resulted in efficient implementation of adsorption, diffusion and/or convection principles using adsorption HD, hemofiltration, hemodiafiltration (HDF) and online HDF modalities in order to achieve optimum HD. Implementation of these innovations resulted in better quality care achievements in clinical practice and reduction in morbidity and mortality rates among HD patients.

How to cite this article:
Karkar A. Modalities of hemodialysis: Quality improvement. Saudi J Kidney Dis Transpl 2012;23:1145-61

How to cite this URL:
Karkar A. Modalities of hemodialysis: Quality improvement. Saudi J Kidney Dis Transpl [serial online] 2012 [cited 2019 Jul 23];23:1145-61. Available from: http://www.sjkdt.org/text.asp?2012/23/6/1145/103553

   Introduction Top


The aim of hemodialysis (HD) technique has, and will always be, to simulate or reproduce the physiologic process of glomerular ultrafil tration. Conventional HD, which is performed over 4-h duration and conducted three times per week, does not fulfill this criterion. [1] The major deficiencies of this technique include limited solute clearance and volume control, which have been associated with poor quality of life [2] and unacceptably high rates of morbidity and mortality. [3],[4],[5],[6],[7]

Over the past four decades, it has been proposed that the accumulation of various "uremic toxins", and in particular middle-size and protein-bound molecules, contribute to this increased mortality. These toxins include urea, phosphorus, parathyroid hormone (PTH), β2-microglobulin, homocysteine, leptin and a variety of esoteric molecules such as advanced glycation end products, asymmetric dimethylarginine and advanced oxidation protein products. [8],[9],[10] Furthermore, persistence of increased interdialytic weight gain and limited ability of conventional HD to maintain adequate homeostasis, without frequent episodes of hypotension and increased risk for cardiovascular and all-cause mortality, [11] resulted in failure of many HD patients to achieve adequate volume control and remain permanently volume overloaded. [12] This has been associated with increased prevalence of hypertension, left ventricular hypertrophy and increased cardiovascular mortality as a major cause of death among patients treated with conventional HD. [12],[13]

Observational studies [14],[15],[16],[17],[18],[19] and randomized controlled trials [20],[21] of improving the efficiency of HD, by increasing frequency and duration of HD treatment, demonstrated better clearance efficiency of uremic toxins and volume control and improved quality of life. However, the recent innovations in HD technologies paved the way for better quality HD. These include higher specifications of HD machines, creation and improvement in dialysis membranes with different transport (clearance) capabilities of middle, large and even protein-bound molecules by using all the available membrane separation phenomena: diffusion, convection and adsorption and quality improvement in the technology of water treatment plants with almost nil presence of bacteria growth and endotoxin concentration.

Based on different observational studies and randomized clinical trials and new innovations, the aim of this review is to illustrate the possible and available options of the different HD techniques, their influence on improving the adequacy of HD and the patient's quality of life and reduction of the morbidity and mortality rates.


   Conventional Hemodialysis Top


Conventional HD remains the main modality of renal replacement therapy for patients with end-stage renal disease (ESRD) worldwide. [1],[6],[22],[23],[24] The technique of HD is based on the physiologic principle of "diffusion," which means clearance or removal of a high concentration of uremic toxins (in the blood) to the lower concentration solution (dialysate) through a semi-permeable membrane (the dialyzer or filter). [25] Conventional HD is usually conducted over a 4-h duration three times per week for stable patients with ESRD. The dialyzer or filter used is usually of the low-flux type, and the filtered molecules are water-soluble, small-size (molecular weight <500 Dalton) compounds [Table 1]. Conventional HD treatment had, over many years, improved the survival rate of patients with ESRD [6] [Figure 1]a and b. However, this basic modality of dialysis is far from replacing the function of the normal kidneys. In fact, conventional HD prescription provides only about 10% of the clearance power of the natural kidneys. [26] Although it is capable of removing excess water and small size uremic toxins, yet, conventional HD is not capable of removing middle and large size (>500 Dalton) and protein-bound toxic molecules. [9] These middle- and large-size molecules include β2-microglobulin (β2 -M), which is strongly associated with carpal tunnel syndrome and dialysis-related amyloidosis, [27] and pro-inflammatory cytokines and severe vasoactive molecules such as p-cresol and uridine adenosine tetraphosphate [Table 1]. The accumulation and retention of all types and sizes of uremic compounds (and excess water), which have concentration-dependent toxicity, results in increased morbidity and mortality. Furthermore, the unphysiologic pattern of the conventional intermittent HD with rapid change in fluid volume and electrolytes and uremic solutes serum levels can cause permanent disequilibrium of the internal milieu and inter- and intra-dialysis complications. [28]
Figure 1: a and b: The undeniable clinical progress in hemodialysis reflected by the significant drop in mortality rates in incident ESRD patients from 1980 to 2010. U.S. Renal Data System, the data supplied by the United States Renal Data System (USRDS): 2010 Annual Data Report: Atlas of End-Stage Renal Disease in the United States, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 2010.

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Table 1: Examples of types and sizes of different uremic toxic molecules.[9],[10]

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Furthermore, conventional HD has been associated with frequent intradialysis complications (hypotension, sickness and cramps) and post-dialysis complaints of headache, fatigue and inability to concentrate and function, which may significantly impair the quality of life, resulting in poor compliance, inconsistency in achieving HD prescription and inadequacy of HD sessions. Inadequate HD is mainly due to poor compliance and non-adherence to HD regimens (e.g., fluid restriction, regular attendance of dialysis sessions and adherence to 4-h sessions) and the clearance limitations of the conventional HD technique. It has been demonstrated that skipping at least one dialysis session is associated with a 25-30% increase in the risk of death. [23] Moreover, even patients attending regular HD sessions are at increased risk of death, heart attacks and hospital admissions (for myocardial infarction, congestive heart failure, dysrhythmia and stroke) on the day after the two-day interval between HD treatments each week than at other times. [29] Inadequate HD delivery also has cost implications as a consequence of increased frequency of hospitalization, days stay at hospital and inpatient expenditures. [30] Patients managed with conventional HD are potentially exposed to hemodynamic instability, excessive intradialytic weight gain, anemia, mineral and bone metabolism disorder, inadequate nutrition, infection and sexual and psychosocial problems. The increased risks of cardiovascular complications, which are the main cause of death in HD patients, continue to be much higher than in the general population. It has been reported that only 32-33% of patients on conventional HD survive to the fifth year of treatment. [31] In fact, the mortality rate in conventional HD ranges between 14% and 26% in Europe [3],[4] and 24% in the USA. [1],[6] Actually, conventional HD does support life but has failed to restore patients to full functional normality and longevity. Quality management of dialysis patients is best achieved by implementation of "pre-dialysis care" [32] and care improvement at the "post-dialysis" stage. [33] Post-dialysis care should ensure strict control of infection [34],[35] and predominance of arterio-venous fistula (avoidance of indwelling catheters for vascular access). [36] Furthermore, dialysis care should include (1) adequate control of body fluids (achievement of euvolemic status), where strict volume control has been shown to reduce both morbidity and mortality and dialysis adequacy outcomes, [12],[37] (2) mitigation of left ventricular hypertrophy and fibrosis and (3) efficient removal of all types and different sizes of retained uremic toxic solutes that would result in inflammation and exacerbation of cardiovascular damage. [36] Actually, improvement in the quality of HD care should achieve optimum HD rather than adequate HD.


   High-Efficiency Hemodialysis Top


The adequacy of HD is usually assessed and measured by Kt/V. [38] This represents the product of clearance per time (K) multiplied by the duration (t) and adjusted for body size by dividing this clearance by the distribution volume (V). Kt/V reflects the clearance of urea as a surrogate marker for the clearance of small, but not middle or large-sized, uremic toxins. The single-pool Kt/V overestimates the delivered dose of dialysis because it fails to account for blood urea rebound after dialysis. A more accurate measure of the dialysis dose, the equilibrated Kt/V, corrects for urea rebound and is usually 0.15-0.20 lower than the single-pool Kt/V. Ideally, single-pool Kt/V should not be below 1.4, as lower values have been associated with increased morbidity and costs, [30] and reduction in survival rate. [39],[40],[41] The efficacy of high-efficiency HD, where low-flux dialyzers are usually used, is limited by its inability to clear from circulation the middle or large-size or protein-bound toxic molecules. Increasing the dose of dialysis or using high-flux dialyzer membrane should help in ensuring optimal values of Kt/V. However, the HD study (HEMO Study), which was a randomized clinical trial, did not demonstrate improvement of survival or morbidity by increasing the dose of dialysis or using a high-flux dialyzer membrane. [42] Efficiency of HD can be increased by avoiding intradialytic hypotension episodes and frequent interruption of the 4-h HD session. This can be achieved, in part, by controlling intradialytic weight gain (<4%) by restriction of fluid and sodium intake, lowering dialysate sodium concentration [43] and avoiding rapid ultrafiltration (not to exceed 10 mL/kg/h), where exceeding this limit has been associated with increased risk for cardiovascular and all-cause mortality. [11],[13] The efficiency of HD can also be improved by increasing the blood [44],[45],[46] and dialysate [47],[48] flow rates and the dialyzer size and surface area. [49],[50] However, recent improvements in dialyzer technology, such as hollow fiber undulations, spacer yarns and changes in fiber packing density, [51] have led to improvement in dialysate flow distribution through the dialysate compartment (with improved urea clearance) and reduced the need of increasing dialysate flow rate from 600 to 800 mL/min, an achievement with important economic impact allowing a significant reduction (25%) in water consumption. [52] Finally, a significant improvement in efficiency of HD can be achieved by increasing the duration and frequency of dialysis sessions. [53]

Duration of hemodialysis session

Different studies have confirmed that dialysis duration of less than 4 h was associated with increased mortality rate by up to 42%. [5],[7],[13] By contrast, increasing the duration of dialysis, independent of blood or dialysate flow rates, to 8 h has been associated with significant improvement in clearance of urea, creatinine, phosphorus, uric acid and even β2 -M, but not much of protein-bound toxic molecules. [13],[54],[55]

Frequency of hemodialysis sessions

Another approach to improve the efficiency of HD is by increasing the frequency of HD sessions. This can be achieved by avoiding the two days weekend gap and implementation of in-center every other day dialysis. [29],[56] A recent study of analyzing records of 32,000 patients receiving dialysis three times a week from 2005 through 2008 found a 22% greater risk of death on the day after a long break compared with other days. In particular, stroke and heart-related hospitalizations more than doubled on the days after the long break. [29] The efficiency of HD can also be improved by short daily dialysis, [14],[18],[20],[54],[57] long slow nocturnal dialysis [16],[17] or home daily or nocturnal HD, [19],[50] instead of three HD sessions per week [Table 2].
Table 2: Benefits of frequent (daily/nocturnal) hemodialysis.[14],[15],[16],[17],[18],[19],[20],[21],[29],[50],[54],[55],[56],[57],[58],[59],[60],[61],[62],[63],[64]

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Home HD, and in particular nocturnal type, is probably the most convenient and efficient modality of HD. It can be performed on a daily basis or at night at most suitable times, where the patient dialyzes for about twice the time (approximately 8 h per session) of the conventional in-center HD. This ensures a better chance that the patients will not be under-dialyzed; therefore, more toxins and fluids may be removed. Because this process occurs more slowly, there is less of a chance of cramping and hypotension episodes during dialysis. [19] Unlike conventional HD, patients on nocturnal HD do not report the "washed out" feeling after longer dialysis (no need to take a nap after treatment). Different studies have repeatedly confirmed the strong positive impact of nocturnal or more frequent dialysis on ultrafiltration rate (much better control of fluid excess), clearance of uremic toxins and adequacy of dialysis. [20] The better ultrafiltration rate has been associated with better control of blood pressure, [17],[20],[21] where the majority of dialysis patients discontinued antihypertensive medications after six to 12 months of daily/nocturnal dialysis. [14],[58] Increasing dialysis frequency, and in particular nocturnal HD, has also been linked to significant improvement in renal anemia [15],[59] and reduction in erythropoietin dosage and iron supplements, [58] significant reduction in left ventricular mass index, [17],[20],[60] improvement in mineral metabolism and significant reduction in phosphorus binders, [17],[20],[21],[57] improvement in nutritional status, [14],[61] enhanced quality of life [17],[20],[62] and increased cumulative survival rate. [18] Moreover, patients on nocturnal HD have a similar survival rate as that in deceased kidney transplant recipients. [63]

Despite its great benefits [Table 1] the implementation of daily/nocturnal HD has not gained much attraction among patients, treating physicians and decision makers. Kjellstrand et al [18] contributed the slow and difficult introduction of daily dialysis to multiple factors including logistic problems, conservatism by physicians and nurses, patient worries and concerns of governments and administrators about expenses, which are expected to be a major obstacle. However, the clinical and quality of life improvement brought by daily/nocturnal HD has been associated with dose reduction of different pharmaceutical medications (antihypertensive medications, phosphorus binders and erythropoetin dosage and iron supplements), extended use of dialyzers and tubing and decreased waste production and transportation upon implementation of home HD, and significant reduction in frequency of hospitalization and morbidity (and mortality) rates, all of which may result in reduction in management costs and total annual expenses. [16],[62] A recent economic assessment model for in-center conventional home and more frequent home HD revealed that home-based conventional and more frequent HD are similar in cost to incenter HD in the first year, but can be less costly than in-center HD from the second year onward. [64] The higher cost for more frequent home HD in the first year is mainly due to higher consumable usage due to dialysis frequency. Frequent home HD (and conventional home HD), however, have been associated with much lower hospitalization costs than for in-center HD treated patients in the first and subsequent years.


   High-Flux Hemodialysis Top


Conventional and high-efficiency HD techniques, using low-flux dialyzers, are incapable of removing large-sized uremic toxins and/or protein-bound toxic molecules of >500 Dalton [Table 1]. This would result in their accumulation in circulation, where they can exert concentration-dependent toxicity, particularly on the endothelium, in the cardiovascular system. Examples of these molecules include uridine adenosine tetraphosphate and endothelin, [10] which exert vasoconstrictive effect, and Indoxyl sulfate and p-cresylsulfate - p-cresol, which has a pro-inflammatory effect and causes endothelial dysfunction together with the pro-inflammatory cytokines, and has been associated with increased cardiovascular mortality. [65] Other retained molecules, which are known to cause harmful effects, include β2 -M, immunoglobulin light chains, parathyroid hormone, advanced glycation end products [66] and advanced oxidation products. [10],[67],[68]

The recent innovations in the technology of dialysis membranes have resulted in improvement of their biocompatibility as well as in their hydraulic and permselective properties. [69] The creation of larger pore size semipermeable membranes in compact cartridges (high-flux dialyzers), with variable sizes of these pores, enhanced their ability to remove small solutes and "middle molecules." [70] High-flux dialyzers allow the passage and removal of retained solutes of higher molecular weight than do low-flux membranes. Dialyzers are considered as high-flux type if their ultrafiltration coefficient (KUF) exceeds 15 mL/h/mmHg and their ability to clear β2 -M exceeds 20 mL/min (low-flux dialyzer clears KUF <15 mL/h/mmHg and β2 -M <10 mL/min). [49] However, the fluids (dialysate and water) used with these high-flux dialyzers should be sterile, non-pyrogenic and endotoxin free in order to avoid reverse filtration of endotoxins and blood contamination. [71]

β2 -M, which is considered a surrogate marker of middle molecules, is strongly associated with carpal tunnel syndrome and dialysis-related amyloidosis. [72] Different studies have documented the efficiency of high-flux dialyzers in removing β2 -M from the circulation of patients on dialysis, which has been associated with clinical and radiological improvement of carpal tunnel syndrome and dialysis-related amyloidosis. [27] In addition, high-flux HD has been shown to be superior to peritoneal dialysis in clearing β2 -M and the protein-bound middle molecule p-cresol. [73] Furthermore, observational studies have documented the improvement of survival rates of patients on high-flux-dialyzers when compared with those on low-flux dialyzers. [27],[74],[75],[76],[77] These findings have been confirmed by two large randomized clinical trials: The HEMO study and the Membrane Permeability Outcome study (MPO Study). In the entire cohort of the HEMO Study, the high-flux arm had no significant effect on the all-cause mortality rate or any of the four arms of the secondary outcomes. However, the high-flux HD provided significantly less cardiac and cerebrovascular mortality rates after 3.7 years HD than low-flux HD. [42],[78],[79] The MPO study, which was conducted in Europe, showed higher survival rate in the high-flux HD patients with low serum albumin (≤4 g/dL) and diabetic patients. [80] Following these two major studies, the European Best Practice Guidelines have recommended the use of high-flux dialyzers in patients at high risk (serum albumin <4 g/dL) and even in low-risk patients. [81] Ever since, high-flux dialysis have surpassed low-flux use worldwide. [82]


   Adsorption Hemodialysis Top


Despite the efficiency of removing middle-size uremic toxin molecules by high-flux HD, this technique is still incapable of removing larger-size and, more importantly, the protein-bound uremic toxins. Protein-bound uremic toxins are, in fact, small in size but become larger molecular weight compounds (50,000- 200,000 Dalton) once they are bound to different types of proteins depending on their binding affinity. Protein-bound uremic toxins have been potentially involved in important uremia co-morbidities such as itching and altered immune response caused by the retained and deposited free molecules (κ-type and λ-type) of the immunoglobulin light chain in internal organs. [83],[84],[85],[86]

Removing protein-bound uremic toxins from the blood by means of diffusion and convection is virtually impracticable. The technology of dialysis membranes has yielded thicker type of membranes (more than conventional 1 micron thickness) that have a great affinity to stick larger sized molecules to their surfaces, hence, known as adsorptive membranes. [87] Synthetic membrane micro porous zeolite silica lite (MFI) has been shown to be quite effective in adsorbing high levels of the protein-bound solute p-cresol, [88] which is not eliminated efficiently by conventional HD. Furthermore, the synthetic thick polymethylmethacrylate (PMMA) membranes (30 micron thickness), which have good solute permeability and a high degree of biocompatibility, do have high adsorptive capacity reaching up to 160,000 Dalton [89]

Recent studies have shown a variety of efficient clinical implications for adsorption HD. The use of PMMA membranes has been shown to ameliorate the severity and frequency of pruritis [86] in HD patients due to adsorption of a 160,000 Dalton molecular weight molecule with stimulatory effect on mast cells. [90] PMMA membranes also efficiently adsorb ί 2 -M (representative of middle molecules), where they have been shown to improve carpal tunnel syndrome or total joint pain score in HD patients. [87] In addition, patients dialyzed with PMMA membrane have lower need for erythropoietin due to the elimination of an inhibitor of erythropoesis retrieved in the dialysate. [91] Furthermore, the free molecules (κ-type and λ-type) of the immunoglobulin light chain (Bence Jones protein), which accumulate at high levels in the blood of HD patients, [92] may lead to various protein deposits in the internal organs and act as inhibitors of leukocyte and immune function in dialysis patients. These molecules, which usually exist as dimers (56,000 Dalton) and are not removed by high-flux HD, are significantly removed by HD with PMMA membrane [93] in patients with primary amyloidosis [94] and in patients on HD, resulting in reduction in pain and frequency of analgesic treatment. [95] In addition, PMMA (BK-F) membranes have been shown to be quite effective in removing soluble CD40 from the circulation of patients on HD. Soluble CD40, which mostly coexists as dimeric and even higher oligomerized forms of 50,000 and 150,000 Dalton, respectively, [96] acts as a natural antagonist of the CD40/CD40L contact [83],[96],[97] and has been associated with a lack of response to hepatitis B vaccination. The efficient removal of these molecules by PMMA membranes has been associated with improved response to hepatitis B immunization. [85]

Finally, adsorption techniques have been used successfully, in conjunction with plasma filtration and hemofiltration (HF), in efficiently clearing pro-inflammatory mediators in experimental animals [98] and in humans with acute kidney injury and sepsis. [99] This is known as "coupled plasma filtration adsorption" (CPFA) technique, where the treatment consists of the separation of plasma from the whole blood, using a plasma filter with high cutoff membrane of 800,000 Dalton, coupled with adsorption of the inflammatory mediators and cytokines from plasma, using a cartridge that contains hydrophobic resins, followed by HF using a hemofilter.


   Hemofiltration, Hemodiafiltration and Online Hemodiafiltration Top


Attempts to increase the intensity or "dose" of HD with higher blood and dialysate flow rates, larger and adsorptive membranes and longer and more frequent dialysis sessions, have improved the adequacy of HD but failed to bring about the desired improvement in outcome. [20],[21],[42],[78],[79] Recent innovations in the HD techniques have resulted in advancements in specifications of HD machines, HD medical devices, sterile ultrapure solutions and high-quality water treatment plants. [100] These advancements have largely contributed to the ability to reconsider the implementation of the other physiologic principle of "convection." [101],[102] This means that larger size uremic toxins can be dragged and removed from blood by filtering a large volume of fluid pushed under high hydrostatic pressure through a larger pore size membrane (high cut-off membrane/high-flux dialyzer). This technique is known as "hemofiltration". Fluid balance is maintained by infusion of replacement solutions, which can be administered before the filter (pre-dilution) or after the filter (post-dilution). "Post-dilution" mode is the preferred method due to its superior efficacy in clearing small or low molecular weight solutes and, to a lower extent, some protein-bound molecules. [103] These solutions are infused directly into blood in order to replace the large volume of filtered fluids (convection volume). The replacement solutions, which are also referred to as substitution fluid, are mixed with the blood and should, therefore, be sterile, non-pyrogenic and endotoxin free buffered solutions with a composition similar to plasma water. Combination of the two physiologic principles of diffusion (HD) and convection (HF) in the management of patients with ESRD is known as "hemodiafiltration" (HDF); [25] a technique that was described and implemented in 1974 [101] and a treatment modality that simulates, to a large extent, the natural function of a normal kidney.

The implementation of HF or HDF as a renal replacement therapy in patients with ESRD requires the supply of large quantities of replacement solutions. These solutions are usually industrially prepared in autoclaved, expensive plastic bags, which have been used in earlier studies, in order to fulfill the requirement of sterile, non-pyrogenic and endotoxin-free buffered solutions. [104] However, the need of large quantities of these bags makes the implementation of this technique rather costly and impractical. The recent advancement and improvement in the performance of water treatment plants that are capable of producing ultrapure water (almost nil bacterial growth and endotoxin free) have greatly contributed to the success of this technique. [4],[105] Such quality of water, which is available continuously and in unlimited amounts at the dialysis machine during each treatment, has been used directly from the water treatment plant to form the dialysate and the replacing solutions for the HDF, [104] and hence this technique is known as online HDF. [106]

Online HDF offers the most physiologic clearance profile for a broad range of small, medium-sized and large toxic molecules [Table 1]. Like conventional HD, online HDF session is usually performed three times per week as an outpatient treatment that usually lasts for 4 h. Prescription of effective online HDF should ensure higher blood and dialysate flow rates, ultrafiltration not less than 20% depending on the mode of HDF (it differs between post- and pre-dilution HDF) and substitution/replacement fluids 5-25 L/session. Earlier studies defined replacement fluids of 5-14.9 L/session as low-efficiency HDF and replacement fluids of 15- 24.9 L/session or more as high-efficiency HDF. [4],[55] However, the data from recent randomized controlled studies: CONTRAST [107],[108] and Turkish [109] studies, suggested a convection volume higher than 15 L in the post-dilution mode [103] in order to achieve successful HDF. In clinical practice, HDF (low- and high-efficiency) has been shown to be more effective than HD (low-flux and high-flux) in achieving significantly higher values of Kt/V (averages of 1.37 and 1.44 versus 1.35 and 1.33, respectively). [4]

Hyperphosphatemia, which is associated with vascular calcification and considered as an independent predictor of mortality in dialysis patients, [110] has been well controlled with efficient removal of phosphorus by online HDF, [56],[107],[111] with marked reduction in the use of phosphate binders. [56] Furthermore, the reduction ratio of β2 -M per session has been shown to be 20-30% higher with online HDF than with high-flux HD (72.7 versus 49.7%). [112] Likewise, online high-efficiency HDF achieves higher serum-free light chain removal than high-flux HD in multiple myeloma patients. [113] In addition, HDF is highly efficient in clearing other larger solutes such as myoglobin (16,000 Dalton), retinol-binding protein (25,000 Dalton) and the protein-bound p-cresol than high-flux HD. [109],[114] It has also been shown that online HDF efficiently reduces the circulating levels of advanced glycation-end products. [66],[115] The efficient removal of different types and sizes of uremic toxins by online HDF [116] has been associated with reduction of skin pigmentation, [117] promotion of catch-up growth in children on chronic dialysis [118] and nutritional status improvement. [119] More recently, Maduell et al [56] have demonstrated a remarkable improvement in nutritional status with adequate social and occupational rehabilitation in patients treated with online HDF.

Online HDF empowered with biocompatible high-cut-off membranes, ultrapure water and efficiency of removal of pro-inflammatory stimuli, including oxidative stress molecules, advanced glycation end-products, homocysteine, [120] p-cresol and pro-inflammatory cytokines, ensures abolishing virtually the possibility of stimulation of an inflammatory process in dialysis patients. [104] This effect of online HDF, at least in part, has been shown to improve the patients' responsiveness to erythropoetin and reduce the requirement of erythropoietin-stimulating agents. [121]

Online HDF had attracted much attention in the recent years as a promising optimal modality of HD. [122] In addition to its efficient improvement in dialysis adequacy and clearing small and large-size uremic toxins, [123] HDF significantly reduces inter-dialysis symptoms including less fatigue and cramps together with effective correction of intradialytic hemodynamic instability and blood pressure control, [124],[125] especially for the elderly, the heart-compromised or the prone-to-hypotension patients. A recent study by Maduell et al, [56] where high-volume (high efficiency) online HDF combined with more frequent (every-other-day nocturnal 7-8 h ) dialysis sessions, showed marked improvement in hypertension control with a substantial reduction in drug requirements and regression of left ventricular hypertrophy, an independent cardiovascular risk factor for mortality in dialysis patients. [126],[127]

Finally, observational studies have shown the benefit of online HDF in decreasing the mortality rate in patients on dialysis. [128],[129] Canaud et al [4] reported a 35% lower mortality risk with high-efficiency HDF compared with low-flux HD. Jirka et al [129] also observed a 35.3% reduction rate in mortality risk in online HDF-treated patients after adjustment for age, comorbidities and time on dialysis. More recently, in a randomized clinical trial, it was noted that in the sub-group of HDF patients treated with a substitution volume over 17.4 L/session (n = 195), cardiovascular and overall survival were better than both the HDF subgroup with substitution volume ≤17.4 L/session (n = 196) (P = 0.03) and the HD group (P = 0.002). Primary outcome was similar in these three groups (85.2%, 83.8% and 81.2%, respectively, P = 0.26). In adjusted Cox-regression analysis, HDF with substitution volume over 17.4 L was associated with a 46% risk reduction for overall mortality [RR = 0.54 (95% CI 0.31-0.93), P = 0.02] and a 71% risk reduction for cardiovascular mortality [RR = 0.29 (95% CI 0.12-0.65), P = 0.003] compared with HD. [108]

The performance, success and benefits of online HDF [Figure 2], however, depend on the availability of special requirements. These include (1) experienced nephrologists and nursing staff, (2) high-quality water treatment plant that can provide ultrapure water (bacterial growth <0.1 colony factor unit/mL and endotoxin level <0.03 endotoxin unit/mL) with frequent assessment of water quality, [130],[131],[132] (3) dialysis machine specially designed and approved for online fluid preparation, (4) high-flux dialyzers and (5) good functioning vascular access with adequate blood flow. These essential requirements for ensuring successful online HDF therapy may incur extra costs and may limit its widespread implementation. However, training of medical and nursing staff is achievable, high-flux dialyzers have already been recommended and are in use in conventional HD with lower cost, different quality online HD machines are becoming cheaper and more affordable and investing in quality ultrapure water treatment plant should not be a major barrier toward implementation of this premium modality of HD. In fact, investing in these requirements would improve the quality of life of dialysis patients and reduce the rates of morbidity and mortality. Furthermore, additional savings can be achieved by (1) reduction in the costs associated with hospitalization due to high morbidity rate of conventional HD, [30],[133] (2) less requirements of phosphate binders due to better clearance of phosphorus, [56] (3) better control of hypertension with less use of anti-hypertensive drugs, [56] (4) less doses required of erythropoietin stimulating agents (ESA) and iron supplements due to improved sensitivity to ESA as a result of abolishing or reducing the inflammatory response [104] and (5) improved hemodynamic stability, with no or less frequent hypotension episodes, [56],[125] and consequently, less consumption of normal saline and human serum albumin.
Figure 2: Benefits of online hemodiafiltration.[4],[20],[21],[25],[42],[55],[65],[78],[79],[100],[101],[102],[103],[104],[105],[106],[107],[108],[109],[110],[111],[112],[113],[114],[115],[116],[117],[118],[119],[120],[121],[122],[123],[124],[125],[126],[127],[128],[129],[130],[131],[132],[133]

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In conclusion, conventional or standard HD remains a valuable and basic life-supporting treatment for ESRD patients. Recent innovations in HD techniques have resulted in advancements in specifications of HD machines and HD medical devices, including the high-flux dialyzers and high-quality water treatment plants. High efficiency, high flux and adsorption dialysis are improved HD techniques aiming at improving the adequacy of dialysis. High-flux dialyzer provides significantly less cardiac and cerebrovascular mortality rates, and has been associated with higher survival rate in dialysis patients with low serum albumin or diabetes than low-flux dialyzers, and therefore, should not be limited to high-risk dialysis patients. Home HD, where short daily or long slow nocturnal HD sessions can conveniently be performed, provides an excellent choice for quality of life improvement and reduction in morbidity and mortality. Online HDF is an ideal HD technique with much less morbidity and mortality rates. In fact, online HDF is considered currently as the preferred modality of HD that ensures optimal results. Therefore, these HD modalities, and particularly online HDF, should be considered more seriously, if financial and human resources are available and/or affordable, to replace conventional HD in order to improve the quality of life and reduce morbidity and mortality rates, which are still unacceptably high, among conventional HD patients, besides the costs associated with it.

 
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124.Altieri P, Sorba G, Bolasco P, et al. On-line hemofiltration in chronic renal failure: Advantages and limits. Saudi J Kidney Dis Transpl 2001;12:387-97.  Back to cited text no. 124
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126.Silberberg JS, Barre PE, Prichard SS, Sniderman AD. Impact of left ventricular hypertrophy on survival in end-stage renal disease. Kidney Int 1989;36:286-90.  Back to cited text no. 126
    
127.Foley RN, Parfrey PS, Harnett JD, et al. Clinical and echocardiographic disease in patients starting end-stage renal disease therapy. Kidney Int 1995;47:186-92.  Back to cited text no. 127
    
128.Vilar E, Fry AC, Wellsted D, Tattersall JE, Greenwood RN, Farrington K. Long-term outcomes in online haemodiafiltration and high-flux hemodialysis: A comparative analysis. Clin J Am Soc Nephrol 2009;4:1944-53.  Back to cited text no. 128
    
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Correspondence Address:
Ayman Karkar
Department of Nephrology, Kanoo Kidney Center, Dammam Medical Complex, P. O. Box 11825, Dammam 31463
Saudi Arabia
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DOI: 10.4103/1319-2442.103553

PMID: 23168842

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