**4. Dialysis modality selection**

Although the life expectancy of patients with end-stage renal disease has improved since the introduction of dialysis in the 1960s, it is still far below that of the general population. As an example, the mean life span at age 49 in the United States is 33 years in the general population but only approximately seven years in patients receiving maintenance dialysis (15), in whom the overall five-year survival rate is about 30 to 50 percent in nondiabetics (depending upon the co-morbid diagnoses) and 25 percent in diabetics (15). Despite improvements in technology and patient care, the mortality rate of patients on maintenance dialysis remains alarmingly high, at approximately 15 to 20 percent per year (16).

There are two principal choices for maintenance dialysis: hemodialysis (HD) and peritoneal dialysis (PD). Selecting one of these modalities is influenced by a number of considerations such as availability and convenience, comorbid conditions, socioeconomic and dialysis center factors, the patient's home situation, method of physician reimbursement, and the ability to tolerate volume shifts (17-23). Most studies suggest a better survival rate in PD than in HD patients during the first few years after starting therapy (24). However, after 2 or 3 years, outcome on PD becomes equal to HD, or worse (25-28). This section mainly focuses on different means of receiving hemodialysis.

Registry from 2001 to 2007, the investigators identified a cohort of 25,910 patients 18 years or older who began hemodialysis. Dialysis was defined as beginning early if the eGFR exceeded 10.5 mL/minute/1.73 m2. Mean eGFR at initiation of dialysis increased from 9.3 mL/minute/1.73 m2 in 2001 to 10.2 mL/minute/1.73 m2 in 2007 (*P* < .001). During the same period, the proportion of early dialysis initiations increased from 28% (95% confidence interval [CI], 27% - 30%) to 36% (95% CI, 34% - 37%). Among those starting dialysis early, mean GFR at initiation was 15.5 mL/minute/1.73 m2 vs 7.1 mL/minute/1.73 m2 among those who started dialysis late. For early vs late initiation of dialysis, the unadjusted hazard ratio (HR) for death was 1.48 (95% CI, 1.43 - 1.54). This suggests that early initation is associated with higher mortality. After adjustment for demographic factors, serum albumin, primary cause of endstage renal disease, type of vascular access, comorbid conditions, late referral, and transplant status, the hazard ratio for death decreased to 1.18 (95% CI, 1.13 - 1.23). Difference in mortality per 1000 patient-years between starting dialysis early vs late decreased after 1 year of followup but persisted and began increasing again after 24 months of follow-up, with significant

There may be two additional advantages to early dialysis: control of hypertension and increased dietary intake. Reversal of volume overload with dialysis often leads to a reduction in blood pressure, which is typically volume-dependent in CKD. Perhaps more important, patients on dialysis patients require at least 1 g/kg of protein per day to replace dialysis losses and maintain nitrogen balance. Thus, early institution of dialysis can allow a

The overall conclusion of these trials largely supports current practice that dialysis initiation should be based upon clinical factors rather than the estimated GFR alone. Patients with progressive CKD require close follow up, early nephrology referral, and adequate advance dialysis planning (including the presence of a functioning peritoneal or vascular access and referral for transplantation). Among patients with progressive CKD, clinicians must be vigilant for the presence of symptoms and/or signs of uremia and dialysis should be

Although the life expectancy of patients with end-stage renal disease has improved since the introduction of dialysis in the 1960s, it is still far below that of the general population. As an example, the mean life span at age 49 in the United States is 33 years in the general population but only approximately seven years in patients receiving maintenance dialysis (15), in whom the overall five-year survival rate is about 30 to 50 percent in nondiabetics (depending upon the co-morbid diagnoses) and 25 percent in diabetics (15). Despite improvements in technology and patient care, the mortality rate of patients on maintenance

There are two principal choices for maintenance dialysis: hemodialysis (HD) and peritoneal dialysis (PD). Selecting one of these modalities is influenced by a number of considerations such as availability and convenience, comorbid conditions, socioeconomic and dialysis center factors, the patient's home situation, method of physician reimbursement, and the ability to tolerate volume shifts (17-23). Most studies suggest a better survival rate in PD than in HD patients during the first few years after starting therapy (24). However, after 2 or 3 years, outcome on PD becomes equal to HD, or worse (25-28). This section mainly focuses

dialysis remains alarmingly high, at approximately 15 to 20 percent per year (16).

differences at 6, 12, 30, and 36 months. (14)

more liberal diet in terms of both food and fluid.

initiated in the patient with these symptoms.

on different means of receiving hemodialysis.

**4. Dialysis modality selection** 

The European Best Practice Guidelines for Hemodialysis recommends the standard hemodialysis dose should be delivered as three times per week for 4 hours each session (29). In an attempt to improve outcomes, it was postulated that a higher dialysis dose than commonly provided during conventional dialysis may increase survival among patients undergoing renal replacement therapies (30).

However, this hypothesis was refuted in two large well-designed studies in both hemodialysis and peritoneal dialysis patients:


In light of these negative studies, significant attention has turned to alternative dialysis schedules, such as, short-daily HD (SHD), nocturnal HD (NHD), and long, intermittent hemodialysis (LHD). It is suggested that more frequent dialysis may be associated an improvement in health-related quality of life (HRQoL) and with improved survival (33-34).

The first successful use of short daily, or "quotidian" hemodialysis was first reported by DePalma in 1969 (35). This approach was based upon the premise that improved patient outcomes, compared with conventional three times per week hemodialysis, would occur with a dialysis schedule that consisted of the same number of hours of dialysis per week but delivered over twice as many sessions. More specifically, it involves five to seven treatments per week, each lasting 1.5 to 2.5 hours. The rationale for short daily hemodialysis is based upon a strategy that is proposed to enhance both dialysis efficiency and hemodynamic stability. With short daily dialysis, shortening the dialysis time while increasing the frequency of dialysis allows more time to be spent dialyzing against higher uremic solute concentration gradients. This enhances the efficiency of solute removal (36). More frequent dialysis allows for less interdialytic fluid accumulation. This is likely to improve hemodynamic stability during dialysis with increased potential for normalizing the extracellular fluid volume. This form of therapy has been associated with significant improvement in serum albumin, calcium phosphate, and volume control in small scale studies. However, no mortality data is available.

A recent study, Frequent Hemodialysis Network (FHN) Daily Trial, was a multicenter, randomized trial that included 245 patients assigned to either frequent hemodialysis (six times weekly) or conventional hemodialysis. Two primary composite outcomes were determined at one year, including death or one-year change from baseline in left ventricular (LV) mass as assessed by cardiac resonance imaging, and death or one-year change in physical health as assessed by a RAND health survey. Both composite outcomes showed significant benefit to the frequent-dialysis group compared with the conventional-dialysis group (with hazard ratios of 0.61, 95% CI, 0.46-0.82 for death or change in LV mass; and 0.70, 95% CI, 0.53-0.92, for death or change in physical health) (37). This study also demonstrated benefits in pre-determined secondary outcomes to the frequent dialysis group such as a decrease in LV mass, improved blood pressure control and phosphate balance but not on cognitive performance, depression, serum albumin concentration, or use of erythropoiesis-stimulating agents.

Nocturnal hemodialysis (e.g, long nightly home hemodialysis) was introduced as a potentially more desirable alternative to conventional dialysis, since it provides superior dialysis based upon dose, duration, and frequency (38). This can be accomplished because it is performed during nightly sleep, an otherwise unproductive time (39). The late Robert

Hemodialysis Principles and Controversies 233

 In another study of eight patients undergoing in center daily hemodiafiltration for six months, there were lower serum levels of predialysis BUN and creatinine (which were expected by the change to a daily schedule), as well as lower levels of other solutes including beta-2-microglobulin and homocysteine (51). Additional benefits included improved phosphate control, discontinuation of all antihypertensive agents, and a 30 percent regression in left ventricular mass. Although some of these results can be attributed to the daily treatment schedule, the decrease in the pretreatment levels of beta-2-microglobulin and the improvement in phosphate control are clearly attributable

For greater than 50 years hemodialysis (HD) has been performed in some form or another. Outcomes for dialysis patients expressed in terms of quality of life (QOL), mortality, and hospitalization, is reportedly similar to those seen in patients with solid organ cancer. Despite improvements in long-term outcomes demonstrated with all dialysis modalities, the adjusted annual mortality of dialysis patient remains high at 19% (52-53). There are many factors (dialysis and non-dialysis) that determines outcome. One such influential factor is "adequacy" of dialysis. Adequate dialysis was originally used to describe dialysis dosing measured by small solute removal, but is now deemed as the amount of dialysis required to keep a patient symptoms free, functional, with a life expectancy similar to that of healthy individuals. Since its inception, there have been numerous approaches to quantify the delivered dialysis dose in a reproducible manner, and to link the dialysis dose with clinical

**4.3 Importance of urea and its use as a surrogate marker of uremic toxicity** 

Solute removal during hemodialysis focuses on urea. Urea is produced from the anabolism, catabolism of proteins and is the principal way by which nitrogenous substances are excreted from the body. Urea is a small water soluble molecule (molecular weight 60 daltons) that is slightly toxic. Recent studies have demonstrated that urea removal does not closely parallel that of other small water-soluble compounds, protein-bound solutes, or middle molecules. (54) Despite this information, adequacy of HD dosing is predominantly evaluated by removal of urea. During the development of the uremic syndrome, losses of kidney function are accompanied by deteriorating organ function attributable to the accumulation of uremic retention solutes or uremic toxins. (54) Uremic toxins are diverse and complex, they include inorganic compounds (phosphate water, potassium, water and trace elements), as well as organic compounds that comprises small water-soluble solutes (<500 d), middle molecules (>500 d), and protein-bound solutes. These peptides can be altered by glycosylation, oxidization or carbamylation, and they can provoke inflammation, hypertrophy, oxidative stress, coagulation, constriction, thus uremia is more than the retention and accumulation of urea or water-soluble compounds alone. (54) Mortality has repeatedly been shown to be associated with the clearance of urea. Of commonly measured protein-derived substances, only the serum concentration of ß2-microglobulin correlates

offered a standard Kt/V of approximately 2.0.

**4.2 Adequacy of hemodialysis** 

outcomes.

to both convection and the increased treatment frequency.

improved quality of life, findings consistent with previous reports on short daily HD (49-50). A trend toward a decrease in serum beta-2-microglobulin could be ascribed to the HF alone. The infusion volume used was 40 percent of total body water, which

Uldall started the first quotidian (daily) nocturnal hemodialysis program in 1994 at the Wellesley Hospital in Toronto (40). Since then, its use has been extended to more centers in Canada, the United States, Australia, and several European countries (41-44). This hemodialysis modality is performed five to seven times per week, with each treatment lasting 6 to 8 hours. Although the number of patients studied has been rather limited, but these evidence suggest signficant improvements in caloric intake and serum albumin results.

Long intermittent hemodialysis is given three times a week and a dialysis time of 6 to 8 hours. This procedure is practiced in Tassin, France, and has been associated with improvements in blood pressure control and better overall nutritional status.

Although, no data on randomized controlled trials are available on home hemodialysis, some recent well-conceived cohort studies have indicated that outcome of home (daily) HD is superior to conventional in-centre dialysis, and even equal to cadaveric transplantation, when differences in case mix are taken into account (45).
