**4.2 Adequacy of hemodialysis**

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 outcomes.

### **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

Hemodialysis Principles and Controversies 235

increases when *spKt/V* falls below 1.2, and international guidelines (e.g., KDOQI) recommend a target *spKt/V* of 1.3 for a conventional dialysis schedule of three times per

Online clearance is the term used when the dialysis dose is calculated by measuring conductivity or ionic clearance across the dialysis membrane. Multiple ions can be tracked at the same time to minimize error, and the delivered Kt/V can be predicted in real time before the treatment is over. Although sound in theory, the practical application is limited. UKM is also used to calculate the protein catabolic rate (PCR) and the protein catabolic rate

Urea reduction ratio (URR) is another way of quantifying the delivered dialysis dose. However, it's over simplified since it does not take into account intradialytic urea generation and convective urea removal by ultrafiltration. Because the relative decrease in urea concentration during dialysis is the most significant determinant of Kt/V, direct measurement of URR is an accepted method for assessment of dialysis adequacy. The URR equation is as follows: URR = (BUNpre -BUNpost)/BUNpre where BUNpre is pre-dialysis urea concentration and BUNpost is post-dialysis urea concentration. By convention, the value is multiplied by 100 and expressed as a percentage. A minimum URR of 65% to 70% is recommended for adequate HD. Kt/V and URR are mathematically linked by the following equation: Kt/V= -ln(1-URR), where ln is the natural logarithm. (60) Accordingly, *Kt/V*

normalized to body weight (nPCR), both of which are useful measures of nutrition.

equals 1.0 when URR equals 0.63 or 63% of whole-body urea has been removed. (60)

based on body surface area (BSA), thus, smaller patients can receive more dialysis.

One of the criticisms of UKM is the use of urea as the reference marker for measurement. We know that it's a very small solute. Clearance of a solute is multifactorial; it is dependent on the molecular weight, charge, volume of distribution, and protein binding. Furthermore, clearance of solutes with different molecular weights from urea or bound to proteins would be different. Thus, clearance of urea cannot be extrapolated to other substances such as "uremic toxin" because they act differently. In addition UKM does not take into account residual renal function (RRF), which has a significant impact on patient outcome. (57) Also, it has been shown that V calculated by anthropometric formulas systematically overestimates volume by about 15%. (58) Kt/V underestimate that body water has an independent effect on outcomes, it is now recognized that smaller patients require higher Kt/v compared to larger patients. (61) Also, Kt/V does not confer that time (t) has an independent effect on outcome. The National Cooperative Dialysis (NCDS) was the first multicenter, randomized controlled trial of hemodialysis adequacy in which UKM was used to analyse the effect of BUN and HD time. Longer time was associated with better outcomes, however the statistical relationship between treatment time and patient outcome in was considered not to be significant (*p* value of 0.056). (61-62) Kt/V does not account for QOL, BP and volume control, clinically stability or biochemical factors. We know from the analysis of Hurricane Katrina that patients who missed three HD sessions were associated with odds ratio for hospitalization of 2.15. (61,63) Thus, Kt/V only measure the adequacy of one dialysis session, it does not incorporate missed HD sessions or shorten dialysis time. Some of these limitations are rectifiable. One can increase HD time for intradialytic hypotension, inability to control volume, or if dialysis dosage is inadequate. HD dose can be

week.

**4.5 Limitations of UKM** 

with mortality. Recently, a higher free concentration of the protein-bound solute *p*-cresol has also been reported to be associated with mortality. (55) Current dialysis and dialysis-related treatments do not remove any significant quantity of substances larger than 10 to 15 kd. Future means of removing higher molecular weight toxins or protein-bound substances may include the use of sorbents in addition to traditional diffusive and convective dialysis strategies.

### **4.4 Urea kinetic modeling, URR and KT/V**

The mathematical model known as urea kinetics can be used to calculate the rate of production and removal of urea. Measurement of the dialysis dose has, for the most part, relied on estimation of clearance of the small, water-soluble, and nitrogenous waste product urea, and hence the mathematical model is referred to as urea kinetic modeling (UKM). Formal (UKM) is the most accurate method for assessment of delivered dialysis dose. It assumes that urea is distributed in a single, well-mixed pool. UKM presumes that full equilibration occurs immediately between blood and tissue compartments. However, in vivo there is a delay in redistribution and it takes 30 to 60 minutes for equilibration between blood and tissue compartments post dialysis. UKM also assumes that urea is generated at a constant rate by protein metabolism and is removed at a constant rate by residual renal function, and intermittently by dialysis. Hence, in a person with negligible renal function, the extent of urea removal provides a measure of dialysis adequacy, and the rate of production correlates with dietary protein intake. (56) Thus, it's inappropriate to follows predialysis blood urea nitrogen (BUN) or serum urea only; because low serum urea could be attributed to malnutrition (insufficient protein diet) rather than adequate dialysis urea removal. UKM has formed the basis for retrospective interpretation of the National Cooperative Dialysis Study and for prescription and control of the HEMO and the Frequent Hemodialysis Network studies. (60) Due its mathematical intricacy, UKM requires advanced computer support. UKM is the most rigorous available method for prescribing and evaluating dialysis dose and is widely used in the United States. Current methods for assessment of dialysis dose are based on the predialysis and postdialysis difference in BUN and include the urea reduction ratio (URR), the single-pool *Kt/V* (*spKt/V*), the equilibrated *Kt/V* (*eKt/V*), and the weekly standard *Kt/V* (*std-Kt/V*).

Kt/V is a dimensionless ratio representing fractional urea clearance, where *K* is the dialyzer urea clearance (liters per hour), *t* is the length of HD session (hours), and *V* is the volume of distribution of urea (liters). It is the most widely used parameter to assess dialysis dose. Kt/V is derived from single-pool urea kinetics and is referred to as spKt/V. A value of spKt/V of 1 indicates that the total volume of blood completely cleared of urea during a dialysis session is equivalent to the volume of distribution of urea. Solute disequilibrium occurs when dialysis time is decreased in addition to increasing dialysis and blood flow rates. Solute disequilibrium can be corrected by adjusting the Kt/V for the rebound in urea, which happens mainly in the 30–60 minutes immediately post dialysis. The resultant Kt/V is termed equilibrated Kt/V or eKt/V. Numerous equations have been developed by Daugirdas and others to help derive the eKt/V from spKt/V.(57-59) With a conventional 4 hour HD treatment, eKt/V is usually about 0.2 units lower than spKt/V. The difference is even larger with short, high-efficiency HD or hemodiafiltration, in which urea rebound is higher. Single-pool *Kt/V* or, even better, *eKt/V* should be assessed monthly, and dialysis prescription should be adapted accordingly. In large cross-sectional studies, mortality

with mortality. Recently, a higher free concentration of the protein-bound solute *p*-cresol has also been reported to be associated with mortality. (55) Current dialysis and dialysis-related treatments do not remove any significant quantity of substances larger than 10 to 15 kd. Future means of removing higher molecular weight toxins or protein-bound substances may include the use of sorbents in addition to traditional diffusive and convective dialysis

The mathematical model known as urea kinetics can be used to calculate the rate of production and removal of urea. Measurement of the dialysis dose has, for the most part, relied on estimation of clearance of the small, water-soluble, and nitrogenous waste product urea, and hence the mathematical model is referred to as urea kinetic modeling (UKM). Formal (UKM) is the most accurate method for assessment of delivered dialysis dose. It assumes that urea is distributed in a single, well-mixed pool. UKM presumes that full equilibration occurs immediately between blood and tissue compartments. However, in vivo there is a delay in redistribution and it takes 30 to 60 minutes for equilibration between blood and tissue compartments post dialysis. UKM also assumes that urea is generated at a constant rate by protein metabolism and is removed at a constant rate by residual renal function, and intermittently by dialysis. Hence, in a person with negligible renal function, the extent of urea removal provides a measure of dialysis adequacy, and the rate of production correlates with dietary protein intake. (56) Thus, it's inappropriate to follows predialysis blood urea nitrogen (BUN) or serum urea only; because low serum urea could be attributed to malnutrition (insufficient protein diet) rather than adequate dialysis urea removal. UKM has formed the basis for retrospective interpretation of the National Cooperative Dialysis Study and for prescription and control of the HEMO and the Frequent Hemodialysis Network studies. (60) Due its mathematical intricacy, UKM requires advanced computer support. UKM is the most rigorous available method for prescribing and evaluating dialysis dose and is widely used in the United States. Current methods for assessment of dialysis dose are based on the predialysis and postdialysis difference in BUN and include the urea reduction ratio (URR), the single-pool *Kt/V* (*spKt/V*), the equilibrated

Kt/V is a dimensionless ratio representing fractional urea clearance, where *K* is the dialyzer urea clearance (liters per hour), *t* is the length of HD session (hours), and *V* is the volume of distribution of urea (liters). It is the most widely used parameter to assess dialysis dose. Kt/V is derived from single-pool urea kinetics and is referred to as spKt/V. A value of spKt/V of 1 indicates that the total volume of blood completely cleared of urea during a dialysis session is equivalent to the volume of distribution of urea. Solute disequilibrium occurs when dialysis time is decreased in addition to increasing dialysis and blood flow rates. Solute disequilibrium can be corrected by adjusting the Kt/V for the rebound in urea, which happens mainly in the 30–60 minutes immediately post dialysis. The resultant Kt/V is termed equilibrated Kt/V or eKt/V. Numerous equations have been developed by Daugirdas and others to help derive the eKt/V from spKt/V.(57-59) With a conventional 4 hour HD treatment, eKt/V is usually about 0.2 units lower than spKt/V. The difference is even larger with short, high-efficiency HD or hemodiafiltration, in which urea rebound is higher. Single-pool *Kt/V* or, even better, *eKt/V* should be assessed monthly, and dialysis prescription should be adapted accordingly. In large cross-sectional studies, mortality

strategies.

**4.4 Urea kinetic modeling, URR and KT/V** 

*Kt/V* (*eKt/V*), and the weekly standard *Kt/V* (*std-Kt/V*).

increases when *spKt/V* falls below 1.2, and international guidelines (e.g., KDOQI) recommend a target *spKt/V* of 1.3 for a conventional dialysis schedule of three times per week.

Online clearance is the term used when the dialysis dose is calculated by measuring conductivity or ionic clearance across the dialysis membrane. Multiple ions can be tracked at the same time to minimize error, and the delivered Kt/V can be predicted in real time before the treatment is over. Although sound in theory, the practical application is limited. UKM is also used to calculate the protein catabolic rate (PCR) and the protein catabolic rate normalized to body weight (nPCR), both of which are useful measures of nutrition.

Urea reduction ratio (URR) is another way of quantifying the delivered dialysis dose. However, it's over simplified since it does not take into account intradialytic urea generation and convective urea removal by ultrafiltration. Because the relative decrease in urea concentration during dialysis is the most significant determinant of Kt/V, direct measurement of URR is an accepted method for assessment of dialysis adequacy. The URR equation is as follows: URR = (BUNpre -BUNpost)/BUNpre where BUNpre is pre-dialysis urea concentration and BUNpost is post-dialysis urea concentration. By convention, the value is multiplied by 100 and expressed as a percentage. A minimum URR of 65% to 70% is recommended for adequate HD. Kt/V and URR are mathematically linked by the following equation: Kt/V= -ln(1-URR), where ln is the natural logarithm. (60) Accordingly, *Kt/V* equals 1.0 when URR equals 0.63 or 63% of whole-body urea has been removed. (60)

### **4.5 Limitations of UKM**

One of the criticisms of UKM is the use of urea as the reference marker for measurement. We know that it's a very small solute. Clearance of a solute is multifactorial; it is dependent on the molecular weight, charge, volume of distribution, and protein binding. Furthermore, clearance of solutes with different molecular weights from urea or bound to proteins would be different. Thus, clearance of urea cannot be extrapolated to other substances such as "uremic toxin" because they act differently. In addition UKM does not take into account residual renal function (RRF), which has a significant impact on patient outcome. (57) Also, it has been shown that V calculated by anthropometric formulas systematically overestimates volume by about 15%. (58) Kt/V underestimate that body water has an independent effect on outcomes, it is now recognized that smaller patients require higher Kt/v compared to larger patients. (61) Also, Kt/V does not confer that time (t) has an independent effect on outcome. The National Cooperative Dialysis (NCDS) was the first multicenter, randomized controlled trial of hemodialysis adequacy in which UKM was used to analyse the effect of BUN and HD time. Longer time was associated with better outcomes, however the statistical relationship between treatment time and patient outcome in was considered not to be significant (*p* value of 0.056). (61-62) Kt/V does not account for QOL, BP and volume control, clinically stability or biochemical factors. We know from the analysis of Hurricane Katrina that patients who missed three HD sessions were associated with odds ratio for hospitalization of 2.15. (61,63) Thus, Kt/V only measure the adequacy of one dialysis session, it does not incorporate missed HD sessions or shorten dialysis time. Some of these limitations are rectifiable. One can increase HD time for intradialytic hypotension, inability to control volume, or if dialysis dosage is inadequate. HD dose can be based on body surface area (BSA), thus, smaller patients can receive more dialysis.

Hemodialysis Principles and Controversies 237

dialysers, would be more beneficial and practical to improve adequacy. Muscle exercise before or during dialysis improves *Kt/V* by increasing blood supply to poorly perfused urea rich muscle tissue and thus facilitates urea equilibration. Delivered *Kt/V* should be checked whenever the dialysis prescription has been modified substantially. Online clearance monitoring allows assessment of *Kt/V* during each single session without blood sampling.

In an attempt to address the question of optimal dialysis dose, several clinical trial have proposed that patients with small urea *V,* such as women, do worst compared to larger people. This is secondary to the notion that muscle mass closely correlate to total body water than to body weight. Thus, small urea *V* is a good indicator for low muscle mass. The Hemodialysis Study (HEMO) was performed in which 1846 patients were randomly assigned to a standard or high dose of dialysis and a low- or high-flux dialyzer (based on clearance of beta-2-microglobulin) which revealed a beneficial effect of higher *Kt/V* for women but not for men. (65) This suggests that individuals with low muscle mass may require a higher clearance in relation to *V* and therefore raises the question of whether *V* is the appropriate denominator for dialysis dose. (60) Native renal clearances, in contrast, are commonly related to body surface area (BSA), not to total body water. (60) It has been suggested to relate BSA to dialysis clearances. The ratio of BSA to urea *V* is generally higher in women than in men and decreases with an increment in *V*. Prescribing dialysis dose in relation to BSA (*K* × *t*/BSA) would result in more dialysis for smaller patients of either gender and for women of any size. (57,60) More work need to be done to validate this novel

There are many other factors that play a role in the outcome of dialysis adequacy. Such factor includes but is not restricted to middle molecule removal, hyperphosphatemia, preservation of RRF, vascular access, QOL and treatment time. In general, middle molecule removal is determined by the dialyser permeability, the presence of convection, protein binding, and dialysis duration. Given that daily dialysis results in more frequent solute level equilibration with less rebound, this technique provides higher middle molecule removal than with conventional hemodialysis. The retention of solutes of middle molecular size is proposed to play an important role in the pathogenesis of the uremic state and contribute significantly to the high mortality of dialysis patients. (60) High-flux dialyzers have the propensity to remove larger amounts of middle molecules than low-flux dialyzers due to higher membrane porosity, and this may even be further increased by the use of convective dialysis strategies, such as hemodiafiltration. Serum β2-microglobulin, is a surrogate for other uremic middle molecules, is effectively removed by high-flux than by low-flux dialysis, and predialysis β2-microglobulin levels were found to be related to mortality in patients treated randomly with high-flux or low-flux dialyzers. (70) Patient who has diabetes on HD, or on dialysis for longer than 3.7 years, and those with serum albumin levels below 40 g/l, may benefit most from high-flux dialysis. (69,71) The European Best Practice Guidelines have recommended maximizing the removal of middle molecules in all

Hyperphosphatemia is a major problem in HD and is managed by phosphate removal via dialysis, use of phosphate binder medication to prevent intestinal phosphate absorption

**4.9 Should volume (V) be included in Kt/V to assess target clearance?** 

**4.10 Other dialysis factors related to outcomes** 

idea.

dialysis patients. (60,72)
