I. NKF-K/DOQI CLINICAL PRACTICE GUIDELINES FOR
`HEMODIALYSIS ADEQUACY:
`UPDATE 2000
`
`NOTE: The citation for these guidelines should read as follows: National Kidney Foundation. K/DOQI
`Clinical Practice Guidelines for Hemodialysis Adequacy, 2000. Am J Kidney Dis 37:S7-S64, 2001
`(suppl 1)
`
`S7
`
`Pharmacosmos A/S v. Luitpold Ex. Pharmaceuticals, Inc., IPR2015-01490
`
`Luitpold Pharmaceuticals, Inc., Ex. 2046, P. 1
`
`

`
`Acronyms and Abbreviations
`
`Term
`Association for the Advancement of Medical Instrumentation
`blood urea nitrogen
`chronic kidney disease
`estimated dry weight
`end-stage renal disease
`glomerular filtration rate
`Health Care Financing Administration
`hemodialysis
`HEMOdialysis Study
`National Cooperative Dialysis Study
`normalized protein catabolic rate
`percent reduction of urea
`quality-adjusted life expectancy
`Renal Physicians Association
`total cell volume
`transmembrane pressure
`ultrafiltration rate
`urea kinetic modeling
`urea reduction ratio
`United States Renal Data System
`
`Abbreviation
`AAMI
`BUN
`CKD
`EDW
`ESRD
`GFR
`HCFA
`HD
`HEMO
`NCDS
`NPCR
`PRU
`QALE
`RPA
`TCV
`TMP
`UFR
`UKM
`URR
`USRDS
`
`S8
`
`Pharmacosmos A/S v. Luitpold Ex. Pharmaceuticals, Inc., IPR2015-01490
`
`Luitpold Pharmaceuticals, Inc., Ex. 2046, P. 2
`
`

`
`Introduction
`
`APPROXIMATELY 284,000 Americans suf-
`
`fered from end-stage renal disease (ESRD)
`in 1996,1 of whom 62% were treated by mainte-
`nance hemodialysis (HD).2 Despite a longer life
`expectancy for the general population of the
`United States in comparison to that of most other
`industrialized nations, several analyses have re-
`ported that the gross and adjusted annual mortal-
`ity of Americans with ESRD greatly exceeds the
`analogous rates observed in other countries.3-8
`Several explanations have been proposed for
`these differences in ESRD patient outcome, in-
`cluding:
`1. The acceptance of patients for maintenance
`dialysis in the United States who are rela-
`tively older and/or have more comorbidity
`than dialysis patients in other countries.9,10
`2. Genetic differences between the prevalent
`patient populations in the United States and
`abroad that confer differing risks for comor-
`bid conditions such as cardiovascular dis-
`ease.11
`3. The prevalent practice in the United States
`of dialyzer reuse (81% of dialysis centers
`in 1996) that may expose hemodialysis
`patients to toxic chemicals, increased risk
`of infection, and/or less effective dialysis
`due to compromised dialyzer function.12-17
`4. The lower tendency in the United States to
`adequately meet the nutritional needs of
`hemodialysis patients.18-21
`5. The incomplete and/or inaccurate reporting
`of relevant patient comorbidity and out-
`comes by non-US ESRD registries.7,22-25
`6. The lower tendency to deliver an adequate
`dose of hemodialysis to patients in the
`United States.14,18,19,26-32
`Regardless of the precise reasons for the appar-
`ent difference in outcome between Americans
`with ESRD and patients from other industrial-
`ized nations, it is indisputable that the delivered
`dose of hemodialysis is a significant predictor of
`patient outcome19,33-42 and that the dose of hemo-
`dialysis provided to many American patients can
`and should be increased.19,27,29-31,43 This asser-
`tion is based on several premises, including:
`1. The dose of hemodialysis can be measured
`precisely, reproducibly, and routinely in the
`clinical setting.19,34,42-50
`
`2. A scientific consensus exists on what con-
`stitutes an adequate dose of hemodialy-
`sis.51,52
`3. Many patients do not receive that dose of
`hemodialysis.19,31,43,53-57
`4. Reasons for deficiencies in the delivered
`dose of dialysis can be identified and re-
`dressed.35,51,53-55,58-61
`The Renal Physicians Association’s (RPA)
`1993 Clinical Practice Guideline on Adequacy
`of Hemodialysis* describes acceptable methods
`for measuring hemodialysis adequacy and de-
`fines a minimum acceptable delivered dose of
`hemodialysis for adults (⬎18 years old) with
`ESRD who have negligible residual kidney func-
`tion and are receiving outpatient hemodialysis
`three times per week. Specifically, the RPA rec-
`ommended that the variable volume, single-pool
`model of urea kinetic modeling (Kt/Vd) should
`be measured monthly to assure the adequacy of
`hemodialysis (HD), such that patients receive the
`full benefit of HD for ESRD. The recommended
`Kt/Vd should be at least 1.2 (urea reduction ratio
`ⱖ65%). When the Kt/Vd falls below this level,
`corrective action should be undertaken.51
`The NKF-K/DOQI HD Adequacy Work Group
`identified several topics pertinent to implement-
`ing and maintaining adequate hemodialysis that
`had received limited attention in the RPA’s Clini-
`cal Practice Guideline on Adequacy of Hemodi-
`alysis. As a result, the NKF-K/DOQI Work Group
`summarized data and developed recommenda-
`tions that supplement the RPA guideline in the
`following areas:
`1. Optimum hemodialysis dose.
`2. Adequacy of hemodialysis for pediatric pa-
`tients.
`3. Blood sampling to measure the hemodialy-
`sis dose.
`4. Reuse of hemodialyzers.
`5. Patient comfort and adherence.
`
`* To obtain a copy of the RPA guideline, see ordering
`information in Appendix A.
`
`© 2001 by the National Kidney Foundation, Inc.
`0272-6386/01/3701-0102$3.00/0
`doi:10.1053/ajkd.2001.20777
`
`AmericanJournalofKidneyDiseases,Vol 37, No 1, Suppl 1 (January), 2001: pp S9-S14
`
`S9
`
`Pharmacosmos A/S v. Luitpold Ex. Pharmaceuticals, Inc., IPR2015-01490
`
`Luitpold Pharmaceuticals, Inc., Ex. 2046, P. 3
`
`

`
`S10
`
`GUIDELINES FOR HEMODIALYSIS ADEQUACY
`
`Optimum Hemodialysis Dose
`The RPA’s Clinical Practice Guideline on Ad-
`equacy of Hemodialysis described a minimum
`delivered dose of hemodialysis for adults with no
`residual kidney function who were receiving
`hemodialysis three times per week. In this re-
`spect, the RPA’s Clinical Practice Guideline on
`Adequacy of Hemodialysis did not describe a
`dose of hemodialysis that maximizes the sur-
`vival, health, and quality of life of ESRD pa-
`tients. In the absence of financial constraints, a
`dose of dialysis that maximizes patient outcomes
`is the optimal dose of hemodialysis and is a more
`appropriate target for prescribed dialysis therapy
`than a minimum adequate dialysis dose. The HD
`Adequacy Work Group examined peer-reviewed
`literature published since the release of the RPA
`guideline in an attempt to define an optimal
`delivered dose of hemodialysis. Because of
`changes in the demographics of the ESRD popu-
`lation, eg, an aging ESRD population, an increas-
`ing prevalence of patients with diabetes melli-
`tus,1 the HD Adequacy Work Group considered
`what constitutes a minimum adequate dose for
`different subpopulations. Selected patient sub-
`sets (blacks and diabetics) were examined to
`determine if the minimum hemodialysis dose for
`them should differ from that for the rest of the
`dialysis population.
`Because of inappropriate timing of acquisition
`of the postdialysis blood urea nitrogen (BUN)
`sample in many patients, some of the apparent
`improvement in hemodialysis adequacy that has
`been reported may be spurious.62-64 Therefore,
`significant opportunities for improvement still
`exist. The HD Adequacy Work Group developed
`an algorithm that details recommended proce-
`dures for identifying and correcting deficiencies
`in the delivered dose of dialysis. The intent of the
`algorithm is to help dialysis care teams:
`1. recognize deficiencies in the delivered dose
`of hemodialysis.
`2. identify the cause(s) of inadequate deliv-
`ered dose of hemodialysis.
`3. correct the cause(s) of inadequate delivered
`dose of hemodialysis.
`
`Adequacy of Hemodialysis for Pediatric
`Patients
`Pediatric patients comprise less than 1% of the
`total hemodialysis patient population, even in
`
`industrialized countries with established pediat-
`ric ESRD treatment capabilities. In the United
`States, the point prevalence of ESRD patients
`less than 20 years of age was 4,777 per million in
`1994-1996. Eighteen percent of ESRD patients
`less than 20 years old received maintenance
`hemodialysis.1,65 There are two predominant rea-
`sons for the small number of pediatric as com-
`pared with adult patients. First, ESRD is not a
`common pediatric disorder. Its incidence in pedi-
`atric patients is just over 15 new patients per
`million per year. In contrast, incidence rates are
`122/million/yr for people 20 to 44 years of age.1,65
`Second, most children spend a relatively short
`time on dialysis, typically only the time awaiting
`kidney transplantation. As a result, even the
`largest pediatric hemodialysis programs are quite
`small by adult program standards and rarely
`exceed 10 to 15 patients per facility.
`There are few reports in the medical literature
`of studies involving pediatric hemodialysis pa-
`tients and no data on outcomes as a function of
`hemodialysis dose in children. Previous efforts
`to develop guidelines for hemodialysis, includ-
`ing the RPA’s Clinical Practice Guideline on
`Adequacy of Hemodialysis, did not address pedi-
`atric patients. The HD Adequacy Work Group
`recognized the paucity of data on adequacy of
`hemodialysis in pediatric patients, and decided
`that it was desirable and possible to extend the
`guideline development process to children. All
`available pediatric hemodialysis literature was
`reviewed; where pediatric data were lacking, the
`Work Group extrapolated from adult patient data.
`Thus, the NKF-K/DOQI Clinical Practice Guide-
`lines for Hemodialysis Adequacy addresses chil-
`dren as well as adults.
`
`Blood Sampling Procedure
`Considerable variability in sampling proce-
`dures exists in dialysis practice in the United
`States. For example, 33% of the hemodialysis
`units represented by members of the Medical
`Review Board of the ESRD Network of New
`England (ESRD Network 1) reported that the
`samples for testing postdialysis BUN were drawn
`immediately before the hemodialysis treatment
`was terminated, 25% obtained samples immedi-
`ately after the end of the dialysis treatment, and
`42% drew the sample 5 minutes after all blood
`was reinfused into the patient.62 Similar proce-
`
`Pharmacosmos A/S v. Luitpold Ex. Pharmaceuticals, Inc., IPR2015-01490
`
`Luitpold Pharmaceuticals, Inc., Ex. 2046, P. 4
`
`

`
`INTRODUCTION
`
`S11
`
`dural inconsistency has been observed in ESRD
`Network 16. Data for all hemodialysis patients in
`Network 16 suggest
`that postdialysis BUN
`samples were drawn immediately upon the
`completion of dialysis at 21% of the dialysis
`facilities, after an interval of 1 to 2 minutes at
`52% of the facilities, 2 to 10 minutes after the
`completion of dialysis at 15% of the facilities,
`and more than 10 minutes after completion of
`dialysis at 13% of facilities.43 During 1993, the
`United States Renal Data System (USRDS) re-
`ported that, in the dialysis facilities surveyed, the
`postdialysis BUN sample was drawn immedi-
`ately at the end of hemodialysis without changes
`in the blood flow at 15% of facilities, immedi-
`ately upon ending hemodialysis with a slowing
`or stopping of the blood pump at 48% of facili-
`ties, 20 to 60 seconds after the end of dialysis at
`9% of facilities, 1 to 2 minutes after the end of
`dialysis at 12% of facilities, 3 to 15 minutes after
`the end of dialysis at 15% of facilities, and more
`than 15 minutes after the completion of dialysis
`at 1% of facilities.66 Because of inappropriate
`timing of the acquisition of postdialysis blood
`samples, the actual delivered dose of hemodialy-
`sis may be overestimated.47,58,67,68 A 1995 survey
`of 195 dialysis units in the United States found
`that 5% and 42% of the centers used predialysis
`and postdialysis blood drawing procedures, re-
`spectively, that were judged to be erroneous.64
`Erroneous blood drawing techniques and need-
`less procedural variability compromise the abil-
`ity to compare the dose of hemodialysis deliv-
`ered by different dialysis units, even when the
`same formulae for calculating Kt/V are used.
`More precise specification of appropriate proce-
`dural technique will increase the accuracy and
`comparability of measured hemodialysis doses.
`To address this problem, the HD Adequacy Work
`Group developed supplemental procedural guide-
`lines for predialysis and postdialysis BUN sam-
`pling.
`
`Reuse of Dialyzers
`Predominantly for economic reasons, reuse of
`hemodialyzers is a prevalent practice in the
`United States.16,17,69-71 In 1993, approximately
`79% of adult hemodialysis patients used repro-
`cessed dialyzers. Data describing the prevalence
`of dialyzer reuse among pediatric hemodialysis
`patients are not available. Because the essential
`
`function of a hemodialyzer is to permit the mass
`transfer of solutes from the patient’s blood into
`the dialysate and vice versa, the solute transport
`capacity or clearance of a hemodialyzer is a
`critical variable in writing and delivering an
`adequate hemodialysis prescription. Reuse of a
`hemodialyzer can change its solute transport
`capacity.72,73 For this reason, clinicians need an
`accurate assessment of the solute clearance of
`the hemodialyzer. In the absence of direct mea-
`sures of change in solute clearance with reuse,
`change in the total cell volume (TCV), also
`described as the fiber bundle volume, has been
`the conventional surrogate used to monitor
`changes in solute transport characteristics for
`hollow fiber dialyzers.74,75 Several
`factors
`prompted the HD Adequacy Work Group to
`evaluate the use of TCV as a measure of clear-
`ance, including:
`● The TCV is an indirect measure of solute
`clearance.
`● Reprocessing techniques have evolved.
`The HD Adequacy Work Group examined the
`peer-reviewed literature and the Association for
`the Advancement of Medical Instrumentation
`Standards and Recommended Practices for Re-
`use of Hemodialyzers.76
`
`Patient Comfort and Adherence
`The HD Adequacy Work Group recognizes
`that a major barrier to providing adequate hemo-
`dialysis is patient nonadherence with the hemodi-
`alysis prescription. Patients may confound the
`health care teams’ attempts to provide an other-
`wise adequate treatment by missing hemodialy-
`sis sessions, arriving late for treatments, tempo-
`rarily interrupting the treatment, or discontinuing
`the hemodialysis session prematurely.32,53,77,78 The
`RPA’s Clinical Practice Guideline on Adequacy
`of Hemodialysis focused on the processes of
`patient care necessary to provide an adequate
`dose of hemodialysis, but did not offer clinical
`strategies and interventions to enhance patient
`acceptance of the hemodialysis prescription. The
`HD Adequacy Work Group examined the peer-
`reviewed literature to identify strategies that mini-
`mize patient discomfort during and immediately
`after hemodialysis treatments. Complications,
`such as hypotension and cramps, that would
`compromise patient acceptance of hemodialysis,
`were a major focus.
`
`Pharmacosmos A/S v. Luitpold Ex. Pharmaceuticals, Inc., IPR2015-01490
`
`Luitpold Pharmaceuticals, Inc., Ex. 2046, P. 5
`
`

`
`S12
`
`GUIDELINES FOR HEMODIALYSIS ADEQUACY
`
`In 1997, the NKF-DOQI HD Adequacy Work
`Group published the initial version of their evi-
`dence-based clinical practice guideline for hemo-
`dialysis adequacy.52 In brief, the guidelines rec-
`ommended:
`1. Preferential use of a single pool, variable
`volume model for calculating urea distribu-
`tion and removal during hemodialysis at
`least once per month;
`2. Quantification of urea removal during a
`single dialysis session using formal urea
`kinetic modeling for adults and children;
`3. Prescription of a Kt/V of ⱖ1.3, so that the
`minimum delivered Kt/V would be ⱖ1.2;
`4. Routine baseline measurement of a hemo-
`dialyzer’s TCV prior to the first use and
`prior to each subsequent use;
`5. Discarding of a hemodialyzer if its TCV is
`less than 80% of the original value; and
`6. Vigorous effort to ensure patient comfort
`during hemodialysis by using strategies to
`minimize cramps and hypotension.
`In the years since the RPA and NKF-DOQI
`recommended how the delivered dose of hemodi-
`alysis should be measured and clarified the mini-
`mum acceptable dose of hemodialysis, a signifi-
`cant improvement in reported dialysis dose has
`been reported in the United States.29-31 In 1993, a
`population-based cohort study of 13,500 adult
`ESRD patients noted that only 36% of the pa-
`tients received a urea reduction ratio (URR) of
`ⱖ65%.19 U.S. News and World Reports de-
`scribed this state of care as “deadly dialysis.”79
`These findings were confirmed and extended by
`the ESRD Core Indicators Project, a nationwide
`quality improvement project, and conducted by
`the Health Care Financing Administration
`(HCFA) using the ESRD Networks. A random
`national sample of adult, ESRD patients from
`October to December 1993 showed that only
`43% of the patients had a URR ⱖ65%; the mean
`URR was 62.7%.31 The greatest deficiency in
`URR was observed for blacks, who had a 60%
`greater likelihood of receiving an inadequate
`dialysis dose compared with whites.80 From 1993
`to 1997, the mean URR increased from 62.7% to
`68.0%.31 Improvement of a similar magnitude
`was observed in another national data set; the
`median URR increased from 58.9% ⫾ 9.8% to
`69.5% ⫾ 8.75% from 1990 to 1997, respec-
`
`tively.29 The percentage of patients receiving a
`benchmark URR ⱖ65% increased from 43% in
`1993 to 72% in 1997. The most dramatic im-
`provement
`in dialysis dose was achieved by
`blacks, for whom a 92% increase in the number
`receiving a URR ⱖ65% was achieved.31,80 In
`contrast, there was a 59% increase in the number
`of whites receiving a URR ⱖ65%. As a result,
`the racial disparity in dialysis dose has narrowed.
`The odds ratio of achieving an inadequate dialy-
`sis dose for blacks compared with whites has
`declined from 1.6 in 1993 to 1.2 in 1997. Several
`data sets have demonstrated that the dose of
`dialysis varies inversely by weight, total body
`water, body surface area, and body mass in-
`dex.55,57,81 In that all these anthropometric param-
`eters are greater on average in blacks with ESRD
`than whites, and fixed dialysis doses are pre-
`scribed, it may not be inappropriate that the
`average dialysis dose is lower in blacks than in
`whites. Patient and/or nephrologist behaviors also
`seem to be contributing factors.55 Thus, the incre-
`ment in dialysis dose for blacks is all the more
`significant, since it occurred in the setting of
`unfavorable anthropometric attributes and treat-
`ment compliance for improvement. Blacks with
`ESRD have greater urea distribution volumes
`than whites and are more likely to terminate
`hemodialysis prematurely. If dialysis care teams
`are offered advice regarding “best” clinical prac-
`tices, as provided by the RPA and NKF-DOQI’s
`clinical practice guidelines, quality of care can
`be improved. Translation of some of the NKF-
`DOQI clinical practice guidelines into national
`clinical performance measures (CPM) may be
`helpful.82 The national HD adequacy CPM initia-
`tive will provide some insights into the potential
`impact of NKF-DOQI guidelines on hemodialy-
`sis adequacy.
`Despite these improvements in patient care,
`many opportunities for significant improvement
`remain. Firstly, more than 20% of the ESRD
`patients in the 1996 Core Indicators Project re-
`ceived a Kt/V less than 1.2.31 Secondly, proce-
`dural problems persist with the sampling method
`used for obtaining the predialysis and postdialy-
`sis blood samples to measure the BUN concentra-
`tion. Using spline techniques to determine the
`dialysis dose at which optimal mortality benefit
`is conferred, a recent analysis suggests that inap-
`
`Pharmacosmos A/S v. Luitpold Ex. Pharmaceuticals, Inc., IPR2015-01490
`
`Luitpold Pharmaceuticals, Inc., Ex. 2046, P. 6
`
`

`
`INTRODUCTION
`
`S13
`
`propriate timing/technique for acquisition of the
`postdialysis BUN samples is so prevalent that
`the potential mortality benefit associated with the
`apparent increase in dialysis dose may be mini-
`mal.63
`Because many ESRD patients still do not
`receive an adequate dose of hemodialysis, and
`the literature suppporting the NKF-DOQI HD
`Adequacy Guidelines has expanded, the HD Ad-
`equacy Work Group has reevaluated the topics
`addressed in the previous clinical practice guide-
`lines. The NKF-K/DOQI HD Adequacy Work
`Group focused its efforts on a review of the
`existing Clinical Practice Guideline on Hemodi-
`alysis Adequacy and a discussion of operational
`and clinical issues that may affect the practical
`acceptance and/or implementation of the RPA
`and DOQI hemodialysis adequacy guidelines.
`Three specific Work Group objectives were de-
`fined:
`1. Review the NKF-DOQI Clinical Practice
`Guideline on Adequacy of Hemodialysis.
`Based upon this review, develop updates
`and supplements as needed.
`2. Identify barriers to the acceptance and
`implementation of the NKF-DOQI guide-
`lines for hemodialysis adequacy.
`3. Develop strategies for enhancing the imple-
`mentation of the NKF-DOQI clinical prac-
`tice guidelines for hemodialysis adequacy.
`
`TOPICS NOT COVERED BY THESE
`GUIDELINES
`Flux of Large Molecular Weight Solutes
`
`The HD Adequacy Work Group recognizes
`that the clearance of a marker solute, such as
`urea,45,83 is only one of the many parameters that
`define or are relevant to the global concept of
`hemodialysis adequacy. Another parameter is
`membrane flux of larger molecular weight sol-
`utes. For example, the use of hemodialysis mem-
`branes that have relatively higher clearances for
`larger molecular weight solutes, such as vitamin
`B12 and ␤2-microglobulin (molecular weight of
`1,355 and 12,500 daltons, respectively), may
`reduce the likelihood of developing dialysis-
`associated amyloidosis,84-89 decrease the severity
`of lipid abnormalities in ESRD patients,90 and
`improve survival.87-89,91 However, because of the
`clinical impact of persistent deficiencies in the
`
`delivered dose of hemodialysis based on urea
`clearance, a limited literature on the association
`between patient outcomes and membrane flux,
`and limited time and resources, the HD Ad-
`equacy Work Group focused on the clearance of
`the more conventional marker solute—urea. The
`Work Group did not address membrane flux. The
`ongoing National Institutes of Health HEMO
`Study, a prospective, randomized intervention
`trial, will evaluate the effect of membrane flux
`on morbidity and mortality in hemodialysis pa-
`tients.49,92
`
`Membrane Biocompatibility
`Independent of the delivered dose of hemodi-
`alysis as measured by urea clearance, hemodia-
`lyzers composed of selected membrane materials
`may interact with the effector limb of adaptive
`immunity.93,94 Described as membrane biocom-
`patibility, interactions between soluble and cellu-
`lar components of the blood and selected dialysis
`membrane materials result in perturbations in the
`complement cascade95-99 and granulocyte num-
`ber and function.100-102 As a consequence of these
`membrane-associated immunologic abnormali-
`ties, ESRD patients may be at increased risk of
`malnutrition,
`infection, hospitalization, and
`death.93,94,103-107 Because of the extensive scope
`of this topic, resource limitations, and the focus
`of the Work Group on small molecular weight
`solute clearance, membrane biocompatibility was
`excluded from the literature review.
`
`Appropriate Timing for Initiation of
`Hemodialysis
`Delaying the initiation of dialysis until frank
`uremia develops is clearly deleterious to the
`patient’s physical and psychological well-be-
`ing.108 For patients with less severe degrees of
`advanced kidney failure (glomerular filtration
`rate [GFR], 10 to 20 mL/min), the benefit of
`relatively early dialysis is less clear, however.
`The HD Adequacy Work Group recognizes that
`patients who are initiated on hemodialysis rela-
`tively early will have greater residual kidney
`function that will enhance small and large solute
`clearance over that provided by dialysis alone.
`However, the Work Group did not undertake a
`full literature review in an attempt to define an
`optimal time or clinical setting for the initiation
`of maintenance hemodialysis because:
`
`Pharmacosmos A/S v. Luitpold Ex. Pharmaceuticals, Inc., IPR2015-01490
`
`Luitpold Pharmaceuticals, Inc., Ex. 2046, P. 7
`
`

`
`S14
`
`GUIDELINES FOR HEMODIALYSIS ADEQUACY
`
`1. The preponderance of outcome studies of
`the impact of hemodialysis dose has ex-
`cluded patients with residual kidney func-
`tion or assumed that none was present.
`2. Few outcome analyses have been reported
`that examine the relationship between re-
`sidual kidney function and mortality/mor-
`bidity on maintenance hemodialysis.
`3. Residual kidney function declines with in-
`creasing vintage on hemodialysis, making
`it an unstable influence on the delivered
`dose of dialysis.
`4. The Work Group elected to focus resources
`on the fundamental issue of the impact of
`small molecular solute clearance on patient
`outcomes once hemodialysis is initiated.
`For dialysis care teams who seek direction on
`appropriate timing for initiation of dialysis, the
`NKF-K/DOQI Clinical Practice Guidelines for
`Peritoneal Dialysis Adequacy provide guid-
`ance.109
`
`Hemodialysis Dose and Nutrition
`
`Another topic not reviewed by the HD Ad-
`equacy Work Group is the relationship between
`hemodialysis dose and nutrition. Some investiga-
`tors have suggested that the dose of hemodialysis
`and/or the composition of the hemodialyzer mem-
`brane affect a patient’s dietary protein intake, as
`measured by the normalized protein catabolic
`rate.110,111 This and other issues related to nutri-
`tion in kidney disease patients are addressed in
`the NKF-K/DOQI Nutrition Guidelines.112
`
`Quality of Life and Rehabilitation
`
`Although the HD Adequacy Work Group rec-
`ognizes the importance of the patients’ percep-
`tion of their quality of life as an outcome measure-
`ment,113,114 this topic was not reviewed. The
`connection between rehabilitation and adequacy
`of hemodialysis is likewise important. Adequacy
`of dialysis is crucial for success in any of these
`areas. However, the Work Group elected to focus
`resources on the fundamental issue of the impact
`of small molecular weight solute clearance on
`the principal patient outcome of mortality.
`
`PATIENTS TO WHOM THE NKF-K/DOQI
`HEMODIALYSIS ADEQUACY CLINICAL
`PRACTICE GUIDELINES APPLY
`These guidelines apply to all adult and pediat-
`ric hemodialysis patients with ESRD and negli-
`gible kidney function (GFR ⬍5 mL/min) who
`receive outpatient hemodialysis three times per
`week. These guidelines are not applicable to
`patients who undergo hemodialysis less than or
`greater than three times per week, hospitalized
`patients receiving hemodialysis, patients with a
`residual GFR ⱖ5 mL/min, or patients with a
`reasonable presumption of recovery of kidney
`function. The guidelines also may not be appli-
`cable to hemodialysis patients outside of the
`United States and the American Trust Territories
`(Puerto Rico, Guam, American Samoa, and Sai-
`pan) because of substantial international differ-
`ences in patient mix, processes of patient care,
`and reimbursement mechanisms for the care of
`ESRD patients.
`
`EVIDENCE-BASED VERSUS
`OPINION-BASED CLINICAL PRACTICE
`GUIDELINES
`These guidelines are based on evidence in the
`published literature and, where evidence is not
`available, on consensus opinion of the HD Ad-
`equacy Work Group based on the available litera-
`ture. For each guideline, there is a notation of
`whether the guideline is based on evidence or
`opinion. It is the intent of the HD Adequacy
`Work Group that the material provided herein be
`used solely as recommendations for patient care
`and not as standards. However, it is the duty of
`the dialysis patient care team to consider imple-
`menting these recommendations on an indi-
`vidual patient basis and, where they are not or
`cannot be applied, to strive to optimize patient
`care by offering reasonable and safe alternative
`processes of care. Furthermore, the Work Group
`acknowledges its awareness of the financial rami-
`fications of these guideline statements for the
`providers of hemodialysis care. Successful imple-
`mentation of the Clinical Practice Guidelines for
`Hemodialysis Adequacy will also depend on pay-
`ers providing adequate reimbursement for high
`quality patient care, including the appropriate
`use of laboratory-based performance measures
`and requisite dialysis supplies and equipment.
`
`Pharmacosmos A/S v. Luitpold Ex. Pharmaceuticals, Inc., IPR2015-01490
`
`Luitpold Pharmaceuticals, Inc., Ex. 2046, P. 8
`
`

`
`I. Measurement of Hemodialysis Adequacy
`
`GUIDELINE 1
`Regular Measurement of the Delivered Dose of
`Hemodialysis (Evidence)
`
`The dialysis care team should routinely mea-
`sure and monitor the delivered dose of hemodi-
`alysis.
`Rationale Numerous outcome studies have
`demonstrated a correlation between the deliv-
`ered dose of hemodialysis and patient mortality
`and morbidity.19,33,34,36,38-42,57 The evidence dem-
`onstrates that mortality among ESRD patients is
`lower when sufficient hemodialysis treatments
`are provided. Because there is poor correlation
`between the dialysis care team’s clinical assess-
`ment of hemodialysis adequacy and patients’
`clinical outcomes, unnecessary risk is placed on
`the patient unless rigorous methods of evaluation
`are used. Clinical signs and symptoms alone are
`not reliable indicators of hemodialysis ad-
`equacy.115,116 To ensure that ESRD patients treated
`with chronic hemodialysis receive a sufficient
`amount of dialysis, the delivered dose should be
`measured and monitored routinely. Guideline 6:
`Frequency of Measurement of Hemodialysis Ad-
`equacy offers guidance to the dialysis care team
`about the appropriate frequency for measuring
`and monitoring the dose of hemodialysis for
`adult and pediatric patients.
`
`GUIDELINE 2
`Method of Measurement of Delivered Dose of
`Hemodialysis (Evidence)
`
`The delivered dose of hemodialysis in adult
`and pediatric patients should be measured using
`formal urea kinetic modeling, employing the
`single-pool, variable volume model.
`Rationale
`The HD Adequacy Work Group considered
`several issues regarding the definition of accept-
`able and preferred measures of the delivered
`dose of hemodialysis. These included:
`1. The comparative accuracy of alternative
`methods;
`2. The completeness of information provided
`by alternative methods (eg, does the method
`support calculation of normalized protein
`catabolic rate [NPCR], which provides an
`estimate of the dietary protein intake in
`
`steady-state; will the method account for
`the impact of residual kidney function on
`the delivered dose of hemodialysis and
`NPCR);
`3. The availability of dialysis unit staff to
`properly collect blood samples and record
`information from the dialysis session, such
`as the type of dialyzer used, intradialytic
`weight loss, blood and dialysate flows, true
`dialysis time, etc; and
`4. The time to record, enter, and process this
`information.
`Urea is the substance that is most often moni-
`tored in clinical practice as a surrogate for mea-
`surement of the clearance of small solutes in
`general. Reasons for this are that urea is a small,
`readily dialyzed solute that is the bulk catabolite
`of dietary protein,47,83 constitutes 90% of waste
`nitrogen accumulated in body water between
`hemodialysis treatments,47,83 is easily measured
`in blood, and that the fractional clearance of urea
`in body water correlates with patient outcomes,
`such as mortality19,33,35,36,38,39,42,48,57 and morbid-
`ity.34,36,39 Conventional methods of quantifying
`the prescribed or delivered hemodialysis dose
`begin by estimating the difference in predialysis
`and postdialysis urea concentration by sampling
`a patients blood before and after a single dialysis
`session.
`The dialysate collection method is an alterna-
`tive approach for quantifying the delivered hemo-
`dialysis dose. In this approach, the total dialysate
`that passes through the dialyzer during a hemodi-
`alysis treatment is collected. The total mass of
`urea removed is then calculated as the product of
`the urea concentration and the volume of spent
`dialysate. This method has been considered by
`some investigators to be the gold standard for
`urea kinetic analysis.45,117-119 Advocates of this
`method emphasize the advantage of minimizing
`exposure of patients and staff to blood-borne
`pathogens. However, the HD Adequacy Work
`Group recognized that dialysate measurement
`techniques are not routinely available, are imprac-
`tical to implement in most hemodialysis units,
`have not been examined in relation to patient
`outcomes, and may be associated with the exag-
`geration of systematic collection errors.58,120-123
`For example, a 7% error in dialysate collection
`
`AmericanJournalofKidneyDiseases,Vol 37, No 1, Suppl 1 (January), 2001: pp S15-S26
`
`S15
`
`Pharmacosmos A/S v. Luitpold Ex. Pharmaceuticals, Inc., IPR2015-01490
`
`Luitpold Pharmaceuticals, Inc., Ex. 2046, P. 9
`
`

`
`S16
`
`GUIDELINES FOR HEMODIALYSIS ADEQUACY
`
`can result in a 20% error in the equilibrated Kt/V.
`Although, the HD Adequacy Work Group also
`recognizes that dialysate side urea kinetics are
`best characterized as an equilibrated model, the
`Work Group thought it was best to focus on
`single-pool models of urea removal. Therefore,
`the Work Group focused on blood-based measure-
`ments of urea removal.
`To normalize for differences in the size and
`habitus of patients, a dose of hemod