Urea Kinetic Modeling for Hemodialysis Prescription in Children

Chronic Hemodialysis in Children

Although renal transplantation is the optimal treatment for end-stage kidney disease in children and adolescents, many pediatric patients nonetheless must spend some time on chronic dialysis. Historically, a much larger proportion of children than adults undergo peritoneal dialysis, but registry data from the U.S. Renal Data System (USRDS) and the North American Pediatric Renal Trials and Collaborative Studies (NAPRTCS) suggest that the proportion of children with end-stage renal disease (ESRD) receiving hemodialysis (HD) has increased. In NAPRTCS cohorts from 1992–2001 and 2002–11, 35% and then 42% of children, respectively, used HD as an initial dialysis modality. With more recent USRDS data from 2019, among incident dialysis patients from infancy up to age 21 years, 65% were receiving HD, and the choice of HD as a preferred modality was similar in prevalent patients of an equivalent age range at 62%. As a result, clinicians caring for children and adolescents on dialysis must be familiar with assessing HD adequacy and cognizant of the value of urea kinetic modeling in formulating HD prescriptions. Moreover, quality measures stipulating HD adequacy standards for children are now endorsed by many health care improvement organizations, and pediatric dialysis adequacy measures have been included in the ESRD Quality Incentive Program administered by the Centers for Medicare & Medicaid Services (CMS) in the United States.

Despite this increased focus on dialysis adequacy in children, limited data on long-term outcomes of dialyzed children continue to exist, especially analyzed in the context of certain standards of adequacy. The 2006 National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NKF KDOQI) guidelines for HD adequacy acknowledged this issue. They specify that because of limited specific pediatric data, many recommendations are based on extrapolation from the much broader experience in adults. In the 2015 update of these guidelines, dialysis adequacy in children was not even mentioned. Unfortunately, many outcome measures looking at dialysis adequacy in adults are focused on narrowly assessing mortality rates or specific organ system morbidity over time and do not consider clinical variables of special import to assessing the adequacy and effectiveness of renal replacement therapy in children, such as somatic growth and development, cognitive and emotional maturation, and school attendance and performance.

As dialysis adequacy guidelines are applied more broadly to children with ESRD for both clinical care and assessment of quality care, it is incumbent on pediatric clinicians to determine whether adult standards really do define a proper dose of dialysis for children and to then assess further the applicability of these current standards to appropriate long-term outcome measures. Along these same lines, as new methods of assessing dialysis adequacy are proposed and considered, their application and usefulness to children on HD should be analyzed with pediatric-specific data as well.

Dialysis Prescription in Children

Because clinicians caring for children with ESRD will be prescribing dialysis to patients whose size and weights may vary 20- or 30-fold, there is much more of an individualized focus on the dialysis prescription in children than in adults. For instance, the HD prescription for an 85-kg adolescent will differ dramatically from the treatment given to a 5-kg baby, which will, in turn, be quite different from the prescription for a 25-kg elementary school student. Because children receiving dialysis are more likely than adults to have broad variations in size and total blood volume (which in turn affect many technical aspects of safe and successful HD provision), the quantity of dialysis that a child receives needs to be more precisely calculated and readjusted. Moreover, as the child grows, the prescription must be reformulated, mindful of ongoing changes in total body water and evolving nutritional requirements.

Similar to adults receiving chronic HD, urea kinetic modeling is used in children, both to serve as an objective measure of HD adequacy and to monitor nutritional adequacy by allowing for the determination of protein catabolic rate (PCR). With this approach, urea clearance is used as a surrogate to reflect removal of low-molecular-weight uremic toxins, and the interdialytic rise in urea levels can be used to estimate protein catabolism. The choice of urea as a marker stems from its relatively even distribution over the total body water, its low molecular mass and ensuing ready dialysis clearance, and its status as the principal constituent of nitrogen waste that accumulates in body water. The extent of clearance of urea from body water has been correlated with morbidity and mortality outcomes.

One of the prime advantages of urea kinetic modeling is that it provides quantitative data that is not only reproducible but can also guide the individualization of dialysis prescriptions. Most notably, urea kinetic modeling elucidates disparities between expected or calculated doses of dialysis and actually delivered dialysis. A major disadvantage of kinetic modeling is the need to coordinate obtaining specific data at stipulated time points. Depending on local resources, these maneuvers may be relatively labor and time intensive and may add cost to the chronic therapy. Although the calculations for kinetic modeling are complicated, numerous web-based programs or electronic applications exist that simplify the compilation of necessary data and facilitate computation of overall adequacy rapidly.

There has also been controversy as to whether the adequacy of dialysis is best measured using a single- or double-pool model of estimated volume. In a single-pool model, the clearance of urea from the blood volume may overestimate the dose of dialysis measured by kinetic modeling because blood measurements are performed before effective re-equilibration of urea from the intracellular space into the intravascular space (urea rebound). This concern is especially true in children with smaller distributions of urea which are dialyzed with filters with the capability of high rates of solute clearance.

On the other hand, the need for patients to remain for a substantial period after the dialysis treatment is completed to draw a re-equilibrated postdialysis blood urea nitrogen (BUN) adds another layer of logistical complexity to utilization of a double-pool model. There are some data suggesting that for the majority of children generally able to achieve relatively high levels of Kt/V, the discordance rate between single-pool and equilibrated values does not impact the ultimate management of adequate dialysis prescriptions.

While the Kt/V of urea is generally used to assess dialysis adequacy, Daugirdas has reviewed a variety of other approaches. He describes a number of drawbacks of spKt/V, including its limitations in patients receiving HD at frequencies other than three times a week and challenges in harmonizing weekly Kt/V values derived in peritoneal dialysis patients with those receiving HD. This intriguing review compares other models based on such parameters as body surface area versus volume of distribution, total weekly time spent on HD, and the role of nonurea solutes such as phosphorus, middle molecules, and other uremic toxins. The use of what is termed a “standard Kt/V” has been endorsed by some guidelines in those situations where dialysis is occurring at some frequency other than three times a week.

It remains incumbent on the clinician prescribing chronic dialysis to be aware that a patient’s particular dialysis regimen and any residual renal function need to be kept in mind when assessing dialysis adequacy and setting targets for adequacy. For instance, children receiving dialysis four or more times a week or children with substantial native residual renal function will need to have these extra sessions and their native kidney function included in both the calculation of dialysis adequacy and setting of dialysis adequacy targets for an individual dialysis session. As noted earlier, although this necessitates the use of more complex calculations than with typical estimation of dialysis adequacy, the ready availability of dialysis adequacy programs and applications that take into account these variables allow for these individualized approaches.