KDOQI Update 2000



Introduction - Continuous Quality Improvement: DOQI Becomes KDOQI and Is Updated

Hemodialysis Adequacy

Peritoneal Dialysis Adequacy

Vascular Access

Treatment of Anemia of Chronic Kidney Disease

Introduction - Continuous Quality Improvement: DOQI Becomes KDOQI and Is Updated

Garabed Eknoyan, MD, Nathan W. Levin, MD, Joseph W. Eschbach, MD, Thomas A. Golper, MD, William F. Owen, Jr, MD, Steven Schwab, MD and Earl P. Steinberg, MD, MPP

From the Baylor College of Medicine, Houston, TX; the Renal Research Institute, New York, NY; Beth Israel Hospital Center, Boston, MA; Minor & James Medical Center, Seattle, WA; Vanderbilt University, Nashville, TN; Duke University Medical Center, Durham, NC; Covance Health Economics and Outcomes Services Inc; and The Johns Hopkins University, Baltimore, MD.

ABOUT 300,000 individuals in the United States receive some form of dialysis, which provides life-saving renal replacement therapy for end-stage renal disease (ESRD). While significant improvement has been made in dialysis technology, many more opportunities remain for further improvement. Publication of the National Kidney Foundation’s Dialysis Outcomes Quality Initiative (NKF-DOQI) Clinical Practice Guidelines in 1997 represented the first comprehensive effort to give evidence-based guidance to clinical care teams, thereby decreasing practice pattern variation in over 3,100 dialysis facilities in the United States. In addition, the guidelines were the first comprehensive effort to develop concrete plans that could have a measurable impact on improving quality of life for dialysis patients.

The DOQI guidelines, supported by an educational grant from Amgen, have been widely adopted in the United States and abroad and have been a stimulus for several national organizations to develop their own guidelines. The DOQI guidelines have been translated into at least 10 languages, been the focus of numerous quality improvement activities, and served as the basis for ESRD clinical performance measures being developed by the Health Care Financing Administration (HCFA).

By definition, any set of guidelines begins to be outdated the moment a time limit is set on the literature search they will encompass. They age exponentially once they are published, as new data in the field become available. It was agreed from the outset of DOQI that the guidelines would be maintained as an evolving and live document, with periodic reviews of the literature and revision of the guidelines. Consequently, the four original Work Groups—adequacy of hemodialysis, adequacy of peritoneal dialysis, management of vascular access, and management of anemia—were reactivated in 1999 to review the literature published since 1996, the end point of the time period that formed the basis of the original guidelines. Rather than conduct an exhaustive search of the articles published since 1996, a "top-down" approach was adopted, whereby the experts on the Work Groups scanned the literature and selected pertinent articles. These articles were subjected to external review, and the Work Groups selected a final list to undergo structured review. The methods cited by Steinberg et al1 and used to evaluate the quality of evidence underlying the original guidelines prior to publication were applied to the new round of selected articles to determine what revisions were required for the update. The review process was designed to address the following three end products in decreasing order of priority: changes in guidelines, changes in rationales, and addition of new evidence that is supportive of existing rationales. Articles identified by the Work Group chairs as being relevant to any of the three types of target changes in the Guidelines were subjected to the established NKF-DOQI structured review process to evaluate both the content and methodology of each article.

The original Work Groups appointed to examine the four areas that are the focus of the Guidelines reviewed more than 11,000 articles in development of the initial DOQI Guidelines (Ref 1997 public). Over 3,000 of these publications were subjected to preliminary review, and over half this number underwent formal, structured review. In contrast, the update process focused on a total of 85 articles published since 1996 and considered to be potentially relevant by the Work Groups. Of these, 57 were subjected to structured review according to the published DOQI methods. The other 28 articles, which included review articles and articles on basic science, did not lend themselves to such reviews.

As was the case with the initial Guidelines (Ref 1997 public), the current guideline updates were subjected to a three-stage review process. They were presented first to the NKF-DOQI Steering Committee and revised in response to the comments received. In the second stage, the KDOQI Advisory Board, along with other experts in the field, provided comments. After considering these, the Work Groups produced a third draft of the guidelines. In the final stage, this draft was made available for public review and comment by all interested parties, including ESRD Networks, professional and patient associations, dialysis providers, government agencies, product manufacturers, managed care groups, and individuals. The comments received were reviewed and, where appropriate, incorporated in the final version of the updated guidelines.

While extensive effort has gone into the guideline development process, and careful attention has been paid to detail and scientific rigor, it is absolutely essential to emphasize that these documents are guidelines, not standards or mandates. Each recommendation in the guidelines is accompanied by a rationale, enabling caregivers of patients with chronic kidney disease to make informed decisions about the proper care plan for each individual patient. Variations in practice are expected and can be appropriate. Please refer to the disclaimer statement that accompanies these guidelines for further details regarding their intended use.

While the guideline update process was underway, it was decided that, with the beginning of the new millennium, the DOQI clinical practice guideline initiative should enter a new phase that would enlarge its scope to encompass the spectrum of chronic kidney disease well before the need for dialysis arises, when early intervention and prevention measures can delay or prevent the need for dialysis, and improve the outcomes of patients who develop end-stage disease. This expanded scope increases the opportunity to improve the outcomes of care for millions of individuals with kidney disease rather than only the hundreds of thousands who have end-stage disease. To reflect this expansion, the reference to "Dialysis" in DOQI was changed to "Disease" and the new initiative has been renamed the Kidney Disease Outcomes Quality Initiative (KDOQI).

The methodologic process and implementation strategies that have proven so effective for NKF-DOQI have been adapted and expanded to reflect the new mission of KDOQI and its broadened multidisciplinary focus. Relevant material to be included in future KDOQI guidelines will be translated into implementation tools appropriate not just for nephrology, but also for other specialties likely to encounter those at risk for chronic kidney disease early in the course of illness, including cardiology, hypertension, diabetes, family practice, pediatrics, and internal medicine.

It is the tremendous contribution of the entire renal community that made the NKF-DOQI possible. But it is the members of the Work Groups, especially the Work Group Chairs—Dr Joseph Eschbach, Dr Thomas Golper, Dr William Owen, and Dr Steve Schwab—who, through their innumerable hours of dedication and invaluable expertise, synthesized and produced the guidelines. Their enthusiasm, leadership, and tireless efforts to achieve a quality product made the NKF-DOQI Clinical Practice Guidelines what they are today—a beacon to provide guidance, direction, and vision on a diversity of issues with a single-focused goal: make lives better by improving patient outcomes.

What follows is an executive summary of the changes made in the update process and published as a supplement to the January 2001 American Journal of Kidney Diseases.


Address reprint requests to Kerry Willis, PhD, National Kidney Foundation, 30 East 33rd St, New York, NY 10016. E-mail: KerryW@kidney.org


  1. Steinberg E, Eknoyan G, Levin N, Eschbach J, Golper T, Owen W, Schwab S: Methods used to evaluate the quality of evidence underlying the National Kidney Foundation-Dialysis Outcomes Quality Initiative Clinical Practice Guidelines: Description, findings, and implications. Am J Kidney Dis 36:1-11, 2000


Hemodialysis Adequacy

William F. Owen, Jr, MD

From the Baylor College of Medicine, Houston, TX; the Renal Research Institute, New York, NY; Beth Israel Hospital Center, Boston, MA; Minor & James Medical Center, Seattle, WA; Vanderbilt University, Nashville, TN; Duke University Medical Center, Durham, NC; Covance Health Economics and Outcomes Services Inc; and The Johns Hopkins University, Baltimore, MD.

IN THE YEARS SINCE the 1993 Clinical Practice Guidelines (CPG) of the Renal Physician’s Association (RPA) and the 1997 NKF-DOQI guidelines recommended how the delivered dose of hemodialysis (HD) should be measured, and articulated an evidence-based minimum acceptable dose of HD, significant improvements in the reported dialysis dose have been observed in the United States.1-3 From 1993 to 1997, the mean urea reduction ratio (U) increased from 62.7% to 68.0%.3 Improvement of a similar magnitude was observed in another national data set in which the median U increased from 58.9% 9.8% to 69.5% 8.75% from 1990 to 1997, respectively.1 The most dramatic improvement in dialysis dose was achieved by blacks, for whom a 92% increase in the number receiving a U>65% was achieved.3 In contrast, there was only a 59% increase in the number of whites receiving a U>65%. As a result, the racial disparity in dialysis dose has narrowed.4,5 Several data sets have demonstrated that the HD dose varies inversely by weight, total body water (TBW), body surface area, and body mass index, implying that inadequate use of urea kinetic modeling may be a factor contributing to inadequate dosing.4-8 Despite this improvement, the continued observation of large percentages of patients who are not receiving adequate HD doses suggests that continued improvement is still needed. The formal translation of some of the NKF-DOQI clinical practice guidelines into national clinical performance measures (CPM) may be helpful.3 Moreover, the national HD adequacy CPM will provide quantitative insights into the potential impact of NKF-DOQI Clinical Practice Guidelines on HD adequacy.


Despite improvement in ESRD patient care, opportunities for further improvement persist. First, over 20% of the ESRD patients in the 1998 Core Indicators Project received a Kt/V <1.2.3 Second, the Uremains the preponderant measure of HD dose in the US.3 Third, procedural problems persist with the sampling method used for obtaining the predialysis and postdialysis blood samples to measure the blood urea nitrogen concentration (BUN).3 Because many ESRD patients still do not receive an adequate dose of hemodialysis and the literature supporting the HD adequacy guidelines has expanded, the HD Adequacy Work Group reevaluated the topics addressed in the previous guidelines. The Work Group focused its efforts on a review of the existing clinical practice guidelines and a discussion of operational and clinical issues that may affect the acceptance and/or implementation of these guidelines. Three specific Work Group objectives were defined: (1) review the literature that has become available since 1997 and, based upon this review, develop updates and supplements as needed; (2) identify barriers to acceptance and implementation of the CPG; and (3) develop strategies to enhance implementation of the guidelines.

The updated HD adequacy guidelines continue not to include all topics relevant to the global concept of HD adequacy. Topics not covered include the flux of large molecular weight solutes,9-14 membrane biocompatibility,14-29 appropriate timing for the initiation of HD,30,31 interplay between HD dose and nutrition,32-34 and the affect of HD dose and patients’ quality of life and rehabilitation.35,36 Some of these topics are discussed in other K/DQOI guidelines (ie, nutrition in the Clinical Practice Guidelines for Nutrition in Patients with Chronic Renal Failure; timing of the initiation of dialysis in the Clinical Practice Guidelines on Peritoneal Dialysis Adequacy). The HD Work Group’s focus remained on the fundamental issue of the impact of small molecular weight solute clearance on patient mortality. As in the original, the updated Clinical Practice Guidelines on Hemodialysis Adequacy apply to adult and pediatric hemodialysis patients who have ESRD, experience negligible kidney function (glomerular filtration rate [GFR] <5 mL/min), and receive outpatient HD three times per week.


Comparison to the Original CPG

Based on a structured identification and review of the literature since 1996, no evidence was found that resulted in the inclusion of new guideline statements. Similarly, there was no new literature that necessitated the deletion of any of the original guideline statements. Only one CPG statement was modified (Guideline 16: Strategies to Minimize Hypotensive Symptoms). On the other hand, a substantial amount of new evidence in support of the rationale for the existing CPG statements has appeared in the literature and is summarized below in the context of the individual CPG statements.

GUIDELINE 1: Regular Measurement of the Delivered Dose of Hemodialysis (Evidence)

The dialysis care team should routinely measure and monitor the delivered dose of hemodialysis.

Since 1997, two additional large retrospective studies were published demonstrating the relationship between the dose of HD and patient mortality.37,38

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 (UKM), employing the single-pool, variable volume model.

The evidence model supporting this statement used the following criteria: (1) comparative accuracy of alternative methods of measuring HD dose; (2) completeness of information provided by alternative methods (eg, does the method support calculation of normalized protein catabolic rate [NPCR], which is equivalent to the dietary protein intake in steady-state; capacity to account for the impact of residual kidney function on the delivered dose of hemodialysis and NPCR); (3) availability of dialysis unit staff to collect blood samples properly and record information from the HD session, such as the type of dialysis membrane used, intradialytic weight loss, blood and dialysate flows, true dialysis time; and (4) time to record, enter, and process this information. Recognizing that a minority of providers is unable or unwilling to perform UKM, one alternative method for calculating Kt/V (Kt/V natural logarithm [Ln] formula)39 and one other measurement of the delivered dose of hemodialysis (urea reduction ratio [U])40 were recommended for routine use in adults.

Since 1997, a small analysis validated the second generation Kt/V Ln formula for children.39,41 Moreover, the measured HD dose was equivalent whether using formal UKM or the Kt/V Ln formula for children,41 but the HD Adequacy Work Group continues to favor the use of UKM to derive the Kt/V for pediatric ESRD patients. HD doses measured by Uhave not been validated for pediatric patients, so use of Uinstead of Kt/V may be problematic for this patient subset. Children have smaller anthropometric attributes and relatively higher TBW, so they are at increased risk for significant amounts of urea rebound.

Again, the dialysate collection method was recognized as an alternative approach for quantifying the delivered HD dose. However, the HD Adequacy Work Group’s decision not to support use of this technique was strengthened by recent literature demonstrating the possibility of exaggeration of systematic collection errors.42,43 For example, a 7% error in dialysate collection can result in a 20% error in the equilibrated Kt/V (Kt/Vequil). The Solute (or Urea) Removal Index, defined as the percentage of total body urea nitrogen that is removed by a dialysis treatment or direct device measurement of urea removal during an HD session, could not be evaluated by the HD Adequacy Work Group because of the lack of experience with their accuracy and utility.42,43 As was the case during the original Work Group deliberations, consensus again could not be reached about the use of the duration of HD as an independent surrogate of HD dose. Some Work Group members felt that, independent of the HD delivered dose calculated using a single-pool or equilibrated variable volume model of urea kinetics, the duration of HD should not be permitted to fall to less than 2.5 hours. Despite new literature describing the relationship between blood pressure and mortality in ESRD patients,44-46 and the putative benefits of dialyzer flux,12-16 consensus remained elusive.

Dialysis time and rate of clearance (K/V) was considered extensively in the context of double-pool effects of urea removal, which can substantially reduce the accuracy of single-pool urea kinetic calculations. Some patients, whose HD dose is measured by the single pool model alone, are at risk for unappreciated underdelivery of HD. Although not yet achieving the status of a clinical practice guideline (CPG) recommendation, the HD Adequacy Work Group strongly encourages the use of Kt/Vequil measurements, especially in patients with a large K/V.47 Use of Kt/Vequil is considerably easier now that the Daugirdas rate formula has been validated48 by the prospective randomized controlled NIH’s HEMOdialysis Study.49 In a prospective analysis that compared Kt/Vequil calculated using a 30-minute postdialysis sample and Kt/Vequil calculated using the Daugirdas rate formula, an r value of 0.85 was observed. The Work Group still did not find literature that demonstrates a mortality benefit of Kt/Vequil over single-pool models of urea clearance, and so did not express a preference for Kt/Vequil. However, at the completion of the HEMO Study, definitive evidence will be provided of the best measure of dialysis dose and its association with mortality and morbidity.

GUIDELINE 3: Uniformity of Method of Measurement (Opinion)

All patients receiving hemodialysis in the same dialysis facility should have the delivered dose of hemodialysis measured using the same method.

Minor changes were made to the rationale.

GUIDELINE 4: Minimum Delivered Dose of Hemodialysis (Adults—Evidence, Children—Opinion)

The dialysis care team should deliver a Kt/V of at least 1.2 (single-pool, variable volume) for both adult and pediatric hemodialysis patients. For those using the U, the delivered dose should be equivalent to a Kt/V of 1.2 (ie, an average U of 65%). Ucan vary substantially as a function of fluid removal, however.

This clinical practice guideline statement was strengthened by a new analysis by Gotch et al37 in which several retrospective studies of the relationship between HD dose and mortality were converted to Kt/Vequil measurements. In the larger studies that used data from the US Renal Data System (USRDS) and Fresenius Medical Care, the mortality-HD dose relationship behaved as a 1 knot spline, ie, no further improvement in survival was observed at Kt/Vequil >1.05. On average, the Kt/Vequil is 0.2 units less than the single-pool Kt/V.48,50 These analyses thus suggest that a minimum Kt/V value of 1.20 is appropriate. Moreover, the paper offered an additional explanation for why some smaller studies observed a putative benefit associated with higher HD doses. If the improvement in survival for ESRD patients occurs as a step function above some minimum Kt/V, increasing the dialysis dose for the population of patients will result in a decrease in mortality for the group. With a normal distribution, increasing the group mean minimizes the number of patients at risk, so the false impression of continued benefit from higher dialysis doses is portrayed.

In the revised HD Adequacy guidelines, the recommended minimum delivered dose in selected patient populations was not modified. The Work Group scrutinized a retrospective analysis of mortality by race and gender that suggested a relative insensitivity of mortality to HD delivered dose in blacks.38 This counterintuitive finding seems to be a consequence of the arithmetic construction of Kt/V, in which V behaves as a biologic-based, independent outcome predictor reflecting the patient’s nutritional health.38,51,52

GUIDELINE 5: Prescribed Dose of Hemodialysis (Opinion)

To prevent the delivered dose of hemodialysis from falling below the recommended minimum dose, the prescribed dose of hemodialysis should be Kt/V 1.3. In terms of U, a Kt/V of 1.3 corresponds to an average Uof 70%, but the Ucorresponding to a Kt/V of 1.3 can vary substantially as a function of ultrafiltration.

Several new publications have continued to identify the disparity between prescribed and delivered HD doses,6,7,53,59 and the fact that many of these deficiencies can be detected and corrected if a structured approach, such as is offered in the KDOQI HD Adequacy Clinical Practice Guidelines, is employed. However, underprescription of HD remains a difficult challenge to overcome.6,7,54 A recent survey of hemodialysis practices demonstrated that a low dialysis prescription was one of the strongest predictors of inadequate HD dose.7 Recognizing that some dialysis care teams prefer to monitor HD dosing using Kt/Vequil, the Work Group recommends that the minimum prescribed Kt/Vequil be 1.05. In the updated KDOQI HD Adequacy clinical practice guidelines, a new table is provided to quantify the relationship between dialysis treatment time, single-pool Kt/V, and Kt/Vequil.

GUIDELINE 6: Frequency of Measurement of Hemodialysis Adequacy (Opinion)

The delivered dose of hemodialysis should be measured at least once a month in all adult and pediatric hemodialysis patients. The frequency of measurement of the delivered dose of hemodialysis should be increased when: (1) patients are noncompliant with their hemodialysis prescriptions (missed treatments, late for treatments, early sign-off from hemodialysis treatments, etc), (2) frequent problems are noted in delivery of the prescribed dose of hemodialysis (such as variably poor blood flows, or treatment interruptions because of hypotension or angina pectoris), (3) wide variability in urea kinetic modeling results is observed in the absence of prescription changes, and (4) the hemodialysis prescription is modified.

Minor changes were made to the rationale.

GUIDELINE 7: Blood Urea Nitrogen (BUN) Sampling (Evidence)

Predialysis and postdialysis blood samples for measurement of BUN levels must be drawn at the same hemodialysis session. The same machine should be used for estimation of both samples. (Evidence)

Strong quantitative support for this guideline statement was offered by an analysis of individual variability in measures of HD adequacy that standardized for blood sampling technique (4.0% and 2.4% coefficient of variation for Kt/V and U, respectively).55 Most of the variation was attributable to variation in the laboratory’s BUN measurement.

GUIDELINE 8: Acceptable Method for BUN Sampling (Evidence)

Blood samples for BUN measurement must be drawn in a particular manner. Predialysis BUN samples should be drawn immediately prior to dialysis, using a technique that avoids dilution of the blood sample with saline or heparin. Postdialysis BUN samples should be drawn using the Slow Flow/Stop Pump Technique that prevents sample dilution with recirculated blood and minimizes the confounding effects of urea rebound.

Minor changes were made to the rationale.

GUIDELINE 9: Standardization of BUN Sampling Procedure (Opinion)

Hemodialysis facilities should adopt a single BUN sampling method. If several different methods are used, the sampling method should be routinely recorded. The sampling method used for a given patient should remain consistent. The predialysis and postdialysis BUN samples for a given patient should be processed in the same batch analysis at the laboratory.

Minor changes were made to the rationale.

GUIDELINE 10: Use of the Association for the Advancement of Medical Instrumentation (AAMI) Standards and Recommended Practices for Hemodialyzer Reprocessing (Opinion)

When hemodialyzers are reused, they should be reprocessed following the Association for the Advancement of Medical Instrumentation (AAMI) Standards and Recommended Practices for reuse of hemodialyzers, with the exception of the AAMI guideline regarding baseline measurement of the total cell volume.

The HD Adequacy Work Group was impressed that, among dialysis units that reprocess dialyzers, the median of the average number of reuses has increased from 9 in 1986 to 14 in 1994.56 The median of the maximum number of reported reuses has increased from 23 to 30 over the same interval. The expanded literature on the impact of dialyzer reuse on the mortality of dialysis patients was examined57 in response to previous reports of a 10% increase in death risk for patients who used hemodialyzers reprocessed in selected hemodialysis settings with the use of certain germicides.58 It is noteworthy that the finding of increased risk of death has not been observed consistently,57 even with uniform data set extraction and risk modeling. The Work Group was concerned that this variability might be a consequence of unappreciated, thence unadjusted for differences in HD dose. The HEMO study, however, shows virtually no effect of reuse on urea clearance as contrasted to 2M clearance.59 This concern was increased by the finding that hemodialyzer reprocessing can substantially affect solute clearance, and hence the delivered dialysis dose, if measured using blood side urea clearance.59-62 In a study examining polysulfone high-flux hemodialyzers reprocessed with formaldehyde and bleach, urea clearance decreased at least 20% by 10 reuses, even though conventional AAMI dialyzer practices were followed.59

GUIDELINE 11: Baseline Measurement of Total Cell Volume (Evidence)

If a hollow fiber dialyzer is to be reused, the total cell volume (TCV) of that hemodialyzer should be measured prior to its first use. Batch testing and/or use of an average TCV for a group of hemodialyzers is not an acceptable practice.

Minor changes were made to the rationale.

GUIDELINE 12: Monitoring Total Cell Volume (Evidence)

During each reprocessing, the total cell volume (TCV) of reused dialyzers should be checked.

A new report supports the HD Adequacy Work Group’s appeal for the development of new techniques that can provide a better indication of anticipated dialyzer performance than that provided by TCV. Using a novel dilution technique for in vivo determination of fiber bundle volume (FBV), a substantial disparity was observed; volumetric TCV overestimated FBV.62

GUIDELINE 13: Minimum Required Total Cell Volume (Opinion)

Dialyzers having a total cell volume (TCV) < 80% of original measured value should not be reused.

Minor changes were made to the rationale.

GUIDELINE 14: Inadequate Delivery of Hemodialysis (Opinion)

If the delivered Kt/V falls below 1.2 or the Udeclines to <65% on a single determination, at least one of the following actions should be performed: (1) investigate potential errors in the delivery of the prescribed hemodialysis dose, (2) increase empirically the prescribed dose of hemodialysis, and/or (3) suspend use of the reprocessed hollow fiber hemodialyzer. The impact of these corrective interventions should be followed by performing more frequent measurements of Kt/V or U.

Minor changes were made to the rationale.

GUIDELINE 15: Optimizing Patient Comfort and Adherence (Opinion)

Without compromising the delivered dose of hemodialysis, efforts should be undertaken to modify the hemodialysis prescription to prevent the occurrence of intradialytic symptoms that adversely affect patient comfort and adherence.

A substantial amount of in literature documenting the frequency of HD noncompliance (missing, arriving late, and/or interrupting HD treatments) and illustrating its deleterious effects has appeared since 1997. These studies validated the Work Group’s concerns about patient discomfort contributing to noncompliance.7,63,64

GUIDELINE 16: Strategies to Minimize Hypotensive Symptoms (Evidence)

Without compromising the delivered dose of hemodialysis, efforts should be undertaken to minimize intradialytic symptoms that compromise the delivery of adequate hemodialysis, such as hypotension and cramps. These efforts may include one or more of the following: avoid excessive ultrafiltration, slow the ultrafiltration rate, perform isolated ultrafiltration, increase the dialysate sodium concentration, switch from acetate to bicarbonate-buffered dialysate, reduce the dialysate temperature, administer midodrine predialysis, correct anemia to the range recommended by the KDOQI Anemia Guidelines, and/or administer supplemental oxygen.

Evidence of the safety and efficacy of reducing the dialysate temperature from 37C to 34C to 35C has been extended,65 so the rationale for this CPG statement has been expanded. Since the original DOQI HD Adequacy guidelines, midodrine, an oral selective β1-adrenergic agonist, has been evaluated for treatment of symptomatic intradialytic hypotension. Midodrine has been demonstrated to minimize intradialytic hypotensive symptoms and events, to raise the lowest intradialytic blood pressure, and to decrease interventions for hypotension.66-69 When administered within 30 minutes of the initiation of hemodialysis, midodrine raises blood pressure by increasing peripheral vascular resistance (arteriolar vasoconstriction) and enhancing venous return and cardiac output (venular constriction).70 The drug is well tolerated and associated with few side effects. The hemodynamic benefits of hypothermic dialysis alone, or in combination with midodrine, were comparable across interventions.69

APPENDIX C: Anthropometric Determination of the Urea Distribution Volume

The Mellits-Cheek formulae are now included to calculate TBW for pediatric ESRD patients.71


  1. Owen WF: Status of hemodialysis adequacy in the United States. Does it account for improved patient survival? Am J Kidney Dis 32:S39-S43, 1998 (suppl 4)
  2. Port FK, Orzol SM, Held PJ, Wolfe RA: Trends in treatment and survival for hemodialysis patients in the United States. Am J Kidney Dis 32:S34-S38, 1998 (suppl 4)
  3. Health Care Financing Administration: 1999 Annual Report, End Stage Renal Disease Core Indicators Project. Department of Health and Human Services, Health Care Financing Administration, Office of Clinical Standards and Quality, Baltimore, MD, December, 1999
  4. Frankenfield D, McClellan WM, Helgerson SD, Lowrie EG, Rocco M, Owen WF: Relationship between urea reduction ratio, demographic characteristics, and body weight for patients in 1996 National ESRD Core Indicators Project. Am J Kidney Dis 33:584-591, 1999
  5. Owen WF, Chertow G, Lazarus JM, Lowrie EG: The dose of hemodialysis: Mortality responses by race and gender. JAMA 280:1764-8, 1998
  6. Ifudu O, Mayers JD, Matthew JJ, Fowler AM, Homel P, Friedman EA: Standardized hemodialysis prescriptions promote inadequate treatment in patients with large body mass. Ann Intern Med 128:451-454, 1998
  7. Sehgal A, Snow RJ, Sinder ME, Amini SB, DeOreo PB, Silver MR., Cebul RD: Barriers to adequate delivery of hemodialysis. Am J Kidney Dis 31:593-601, 1998
  8. Coyne DW, Delmez J, Spence G, Windus DW: Impaired delivery of hemodialysis prescriptions: An analysis of causes and an appropach to evaluation. J Am Soc Nephrol 8:1315-1318, 1997
  9. van Ypersele de Strihou, Jadoul M, Malghem J: Effect of dialysis membrane and a patient’s age on signs of dialysis-related amyloidosis. The Working party on Dialysis Amyloidosis. Kidney Int 39:1012-1019, 1991
  10. Koch KM: Dialysis-related amyloidosis (clinical conference). Kidney Int 41:1416-1429, 1992
  11. Hakim RM: Influence of high-flux biocompatible membrane on carpal tunnel syndrome and mortality. Am J Kidney Dis 32:338-343, 1998
  12. Koda Y, Nishi S, Miyazaki S, Haginoshita S, Sakurabayashi T, Suzuki M, Sakai S, Yuasa Y, Hirasawa Y, Nishi T: Switch from conventional to high-flux membrane reduces the risk of carpal tunnel syndrome and mortality of hemodialysis patients. Kidney Int 52:1096-1101, 1997
  13. Locatelli F, Marcelli D, Conte M, Limido A, Malberti F, Spotti D, Registro Lombardo Dialisi E Trapianto: Effect of dialysis membranes and middle molecule removal on chronic hemodialysis patient survival. Kidney Int 55:286-293, 1999
  14. Seres DS, Strain GW, Hashim SA, et al: Improvement of plasma lipoprotein profiles during high-flux dialysis. J Am Soc Nephrol 3:1409-1415, 1993
  15. Hakim RM, Held PJ, Stannard DC, Wolfe RA, Port FK, Daugirdas JT, Agodoa L: Effect of dialysis membranes on mortality of chronic hemodialysis patients. Kidney Int 50:566-570, 1996
  16. Levin NW, Zasuwa G: Relationship between dialyser type and signs and symptoms. Nephrol Dial Transplant 8:S30-S39, 1993 (suppl 2)<
  17. Hakim RM, Breillatt J, Lazarus JM, Port FK: Complement activation and hypersensitivity reactions to dialysis membranes. N Engl J Med 311:878-882, 1984<
  18. Schoels M, Jahn B, Hug F, et al: Stimulation of mononuclear cells by contact with cuprophan membranes: further increase of beta 2-microglobulin synthesis by activated late complement components. Am J Kidney Dis 21:394-399, 1993
  19. Lazarus JM, Owen WF: Role of bioincompatability in dialysis morbidity and mortality. Am J Kidney Dis 24:1019-1032, 1994 [Abstract]
  20. Hakim R: Clinical implications of hemodialysis membrane: Effect of chronic complement activation. Kidney Int 44:484-494, 1993
  21. Hakim R, Fearon DT, Lazarus JM: Biocompatibility of dialysis membranes: Effects of chronic complement activation. Kidney Int 26:194-200, 1984
  22. Himmelfarb J, Gerard NP, Hakim RM: Intradialytic modulation of granulocyte C5a receptors. J Am Soc Nephrol 2:920-926, 1997 [Abstract]
  23. Craddock PR, Fehr J, Dalmasso AP, et al: Hemodialysis leukopenia. Pulmonary vascular leukostasis resulting from complement activation by dialyzer cellophane membranes. J Clin Invest 59:879-888, 1977
  24. Himmelfarb J, Lazarus J, Hakim R: Reactive oxygen species production by monocytes and polymorphonuclear leukocytes during dialysis. Am J Kidney Dis 17:271-276, 1991 [Abstract]
  25. Vanholder R, Ringoir S: Infectious morbidity and defects of phagocytic function in end-stage renal disease; a review (editorial). J Am Soc Nephrol 3:1541-1554, 1993 [Abstract]
  26. Vanholder R, Dell’Aquila R, Jacobs V, et al: Depressed phagocytosis in hemodialyzed patients: In vivo and in vitro mechanisms. Nephron 63:409-453, 1993
  27. Vanholder R, Van Loo A, Dhondt AM, Ringoir S: The role of dialysis membranes in infection. Nephrol Dial Transplant 11:101-103, 1996
  28. Parker TF, Wingard RL, Husni L, et al: Effect of membrane biocompatibility on nutritional parameters in chronic hemodialysis patients. Kidney Int 49:551-556, 1996
  29. Himmelfarb J, Hakim RM: Biocompatibility and risk of infection in haemodialysis patients. Nephrol Dial Transplant 9:S138-S144, 1994 (suppl)<
  30. Hakim RM, Lazarus JM: Initiation of dialysis. J Am Soc Nephrol 6:1319-1328, 1995
  31. National Kidney Foundation: NKF-DOQI Clinical Practice Guidelines for Peritoneal Dialysis Adequacy. Am J Kidney Dis 30:S69-S133, 1997 (suppl 2)
  32. Lindsay RM, Spanner E: A hypothesis: The protein catabolic rate is dependent upon the type and amount of treatment in dialyzed uremic patients. Am J Kidney Dis 13:S382-S389, 1989 (suppl)
  33. Lindsay RM, Spanner E, Heidenheim P, et al: Which comes first, Kt/V or PCR—Chicken or egg? Kidney Int 41:S267-S273, 1993 (suppl)<
  34. National Kidney Foundation: NKF-DOQI clinical practice guidelines for nutrition in chronic renal failure. Am J Kidney Dis 35:S1-S140, 2000 (suppl)
  35. DeOreo P: Hemodialysis patient assessed functional health status predicts continued survival, hospitalization, and dialysis-attendance compliance. Am J Kidney Dis 30:204-212, 1997
  36. Kimmel PL, Peterson RA, Weihs KL, Simmens SJ, Alleyne S, Cruz I, Veis JH: Psychosocial factors, behavioral compliance and survival in urban hemodialysis patients. Kidney Int 54:245-254, 1998
  37. Gotch F, Levin NW, Port FK, Wolfe RA, Uehlinger E: Clinical outcome relative to the dose of dialysis is not what you think: The fallacy of the mean. Am J Kidney Dis 30:1-15, 1997
  38. Owen WF, Chertow G, Lazarus JM, Lowrie EG: The dose of hemodialysis: Mortality responses by race and gender. JAMA 280:1-6, 1998
  39. Daugirdas JT: Second generation logarithmic estimates of single-pool variable volume Kt/V: An analysis of error. J Am Soc Nephrol 4:1205-1213, 1993
  40. Owen WF, Lew NL, Liu Y, Lowrie EG, Lazarus JM: The urea reduction ratio and serum albumin concentration as predictors of mortality in patients undergoing hemodialysis. N Engl J Med 329:1001-1006, 1993
  41. Goldstein SL, Sorof JM, Brewer E: Natural logarithmic estimates of Kt/V in the pediatric hemodialysis population. Am J Kidney Dis 33:518-522, 1999
  42. Depner TA, Greene T, Gotch FA, Daugirdas JT, Keshaviah PR, Star RA, Hemodialysis Study Group: Imprecision of the hemodialysis dose when measured directly from urea removal. Kidney Int 55:635-647, 1999
  43. Cheng YL, Shek CC, Wong FKM, Choi KS, Chau KF, Ing T, Li CS: Determination of the solute removal index for urea by using a partial spent dialysate collection method. Am J Kidney Dis 31:986-990, 1998
  44. Fishbane S, Natke E, Maesaka JK: Role of volume overload in dialysis-refractory hypertension. Am J Kidney Dis 28:257-261, 1996
  45. Rahman M, Dixit A, Donley V, Gupta S, Hanslik T, Lacson E, Ogundipe A, Weigel K, Smith MC: Factors associated with inadequate blood pressure control in hypertensive hemodialysis patients. Am J Kidney Dis 33:498-506, 1999
  46. Sorof JM, Brewer ED, Portman RJ: Ambulatory blood pressure monitoring and interdialytic weight gain in children receiving chronic hemodialysis. Am J Kidney Dis 33:667-674, 1999
  47. Kloppenburg WD, Stegeman CA, Hooyschuur M, Van der Ven J, De Jong PE, Huisman RM: Assessing dialysis adequacy and dietary intake in the individual patient. Kidney Int 55:1961-1969, 1999
  48. HEMO Study Group, Daugirdas JT, Depner TA, Gotch F, Greene T, Keshaviah P, Levin NW, Schulman G: Comparison of methods to predict equilibrated Kt/V in the HEMO Pilot Study. Kidney Int 52:1395-1405, 1997
  49. Eknoyan G, Levey AS, Beck GJ, Agodoa LY, Daugirdas JT, Kusek JW, Levin NW: The Hemodialysis (HEMO) Study: Rationale for selection of interventions. Semin Dial 9:24-33, 1996
  50. Spiegel DM, Baker PL, Babcock S, Contiguglia R, Klein M. Hemodialysis urea rebound: The effect of increasing dialysis efficiency. Am J Kidney Dis 25:26-29, 1995
  51. Chertow GM, Owen WF, Lazarus JM, Lew SM, Lowrie EG: The interplay of uremia and malnutrition: An hypothesis for the reverse J-shaped curve between Uand mortality. Kidney Int 56:1872-1878, 1999
  52. Lowrie EG, Chertow G, Lazarus JM Owen WF: The mortality effect of the clearance x time product. Kidney Int 56:729-737, 1999
  53. Coyne DW, Delmez J, Spence G, Windus DW: Impaired delivery of hemodialysis prescriptions: An analysis of causes and an approach to evaluation. J Am Soc Nephrol 8:1315-1318, 1997
  54. Frankenfield D, McClellan WM, Helgerson SD, Lowrie EG, Rocco M, Owen WF: Relationship between urea reduction ratio, demographic characteristics, and body weight for patients in 1996 National ESRD Core Indicators Project. Am J Kidney Dis 33:584-591, 1999
  55. Kloppenburg WD, Stegeman CA, Hooyschuur M, Van der Ven J, De Jong PE, Huisman RM: Assessing dialysis adequacy and dietary intake in the individual patient. Kidney Int 55:1961-1969, 1999
  56. Tokars J, Alter MJ, Favero MS, Moyer LA, Miller E, Bland LA: National surveillance of dialysis associated disease in the United States, 1994. ASAIO J 42:119-129, 1996
  57. Collins AJ, Ma JZ, Constantini EG, Everson SE: Dialysis unit and patient characteristics associated with reuse practices and mortality: 1989-1993. J Am Soc Nephrol 9:2108-2117, 1998
  58. Feldman HI, Kinosian M, Bilker WB, Simmons C, Holmes JH, Pauly MV, Escarce JJ: Effect of dialyzer reuse on survival of patients treated with hemodialysis. JAMA 276:620-625, 1996
  59. Murthy BVR, Sundaram S, Jaber BL, Perrella C, Meyer KB, Pereira BJG: Effect of formaldehyde/bleach reprocessing on in vivo performances of high efficiency cellulose and high flux polysulfone dialyzers. J Am Soc Nephrol 9:464-472, 1998
  60. Cheung AK, Agodoa LY, Daugirdas JT, Depner TA, Gotch FA, Greene T, Levin NW, Leypoldt JK, Hemodialysis Study Group: Effects of hemodialyzer reuse on clearances of urea and 2-microglobulin. J Am Soc Nephrol 10:117-127, 1999
  61. Garred LJ, Canuad B, Flavier J-L, Poux C, Polito-Bouloux C, Mion C: Effect of reuse on dialyzer efficacy. Artif Organs 14:80-84, 1990
  62. Krivitski M, Kislukhin VV, MacGibbon DR, Kuznetsova OA, Reasons AM, Depner TA: In vivo measurement of hemodialyzer fiber bundle volume: Theory and validation. Kidney Int 1751-1758, 1998
  63. Bleyer AJ, Hylander B, Sudo S, Nomoto Y, de la Torre E, Chen RA, Burkart JM: An international study of patient compliance with hemodialysis. JAMA 281:1211-1213, 1999
  64. Leggat JE, Orzol SM, Hulbert-Shearon TE, Golper TA, Jones CA, Held PJ, Port FK: Noncompliance in hemodialysis patients: Predictors and survival analysis. Am J Kidney Dis 32:139-145, 1998
  65. Kaufman A, Morris AT, Lavarias VA, Wang Y, Leung JF, Glabman MB, Yusuf SA, Levoci AL, Polaschegg HD, Levin NW: Effects of controlled blood cooling on hemodynamic stability and urea kinetics during high efficiency hemodialysis. J Am Soc Nephrol 44:606-612, 1997<
  66. Fynn JJ, Mitchell MC, Caruso FS, McElligott MA: Midodrine treatment for patients with hemodialysis hypotension. Clin Nephrol 45:261-7, 1996
  67. Cruz DN, Mahnensmith RL, Perazella MA: Intradialytic hypotension: Is midodrine beneficial in symptomatic hemodialysis patients? Am J Kidney Dis 101-107, 1996
  68. Cruz DN, Mahnensmith RL, Brickel HM, Perazella MA: Midodrine is effective and safe therapy for intradialytic hypotension over 8 months of follow-up. Clin Nephrol 101-107, 1998
  69. Cruz DN, Mahnensmith RL, Brickel HM, Perazella MA: Midodrine and cool dialysate are effective therapies for symptomatic intradialytic hypotension. Am J Kidney Dis 33:920-926, 1999
  70. Janvokic J, Gilden JL, Hiner BC, Kaufman H, Brown DC, Coghlan CH, Rubin M, Fouad-Tarazi FM: Neurogenic orthostatic hypotension: A double-blind, placebo-controlled study with midodrine. Am J Med 95:38-48, 1993
  71. Jabs K, Warady BA: The impact of the Dialysis Outcomes Quality Initiative guidelines on the care of the pediatric end-stage renal disease patient. Adv Renal Replace Ther 6:97-106, 1999


Peritoneal Dialysis Adequacy

Thomas Golper, MD

From the Baylor College of Medicine, Houston, TX; the Renal Research Institute, New York, NY; Beth Israel Hospital Center, Boston, MA; Minor & James Medical Center, Seattle, WA; Vanderbilt University, Nashville, TN; Duke University Medical Center, Durham, NC; Covance Health Economics and Outcomes Services Inc; and The Johns Hopkins University, Baltimore, MD.

IN 1999 THE PERITONEAL Dialysis (PD) Adequacy Work Group was reconstituted to include several original members and four new members. The original members who continued were Tom Golper (chair), John Burkart (vice-chair), David Churchill, Cathy Firanek, Karl Nolph, Frank Gotch, Tony Tzamaloukas, and Brad Warady. New members were Peter Blake, Dinesh Chatoth, Alan Kliger, and Steve Korbet. The Workgroup made two major changes to the clinical practice guidelines published in 1997. In addition to these major changes, there were several newly derived formulae that were included, as well as clarifications and occasional corrections of other statements in the text and rationales. No new guidelines were added. What follows is a brief overview that highlights the changes, additions, clarifications, and corrections that have been made in the update.


Nutritional Indications for the Initiation of Renal Replacement Therapy
Joel Kopple and Brad Maroni, representing the Nutrition Work Group, and John Burkart and Tom Golper from the PD Adequacy Work Group formed a subgroup to reconcile differences between the recently issued Nutritional Guidelines and the original 1997 PD Clinical Practice Guideline 2: Nutritional Indications for Dialysis. The key discrepancies were related to the efficacy and role of prescribed low-protein diets in slowing the progression of kidney disease, the role of spontaneous low-protein intake due to uremia as a potential cause of malnutrition, and the ability of dialysis to reverse the malnutrition associated with progressive uremia. The subgroup rapidly reconciled the differences and both Work Groups then agreed to use the same clinical practice guideline. The lengthy version of the clinical practice guideline, including the relevant references, now appears in the Clinical Practice Guidelines for Nutrition in Chronic Renal Failure as Guideline 27. The same text, but without the references, appears as Guideline 2 of the updated guidelines related to PD Adequacy. While the new guideline reconciles the differences between the low-protein diet proponents and those less inclined to use that approach, it also articulates specific criteria to follow and states clearly the interventions recommended to correct various problems. The new CPG is opinion based and reads as follows: "In patients with chronic kidney failure (ie, GFR <20 mL/min) who are not undergoing maintenance dialysis, if protein-energy malnutrition develops or persists despite vigorous attempts to optimize protein and energy intake and there is no apparent cause for malnutrition, initiation of maintenance dialysis or a renal transplant is recommended. (Opinion)"

Within the rationale, there is a particularly important statement regarding institution of protein restriction; namely that it "is mandatory to document a negative inquiry for clinical signs or symptoms of uremia... ." The rationale describes the potential role for low protein diets and emphasizes the importance of adequate energy intake in this setting. Furthermore, the rationale goes on to state that the initiation of renal replacement therapy (RRT) should be considered if any of the following nutritional indicators shows evidence of deterioration despite vigorous attempts to optimize protein and energy intake: (1) more than 10% reduction in usual body weight in nonobese individuals or to less than 90% of standard body weight (NHANES II) within 6 months, (2) greater than 10% decline in serum albumin (and below the lower end of the normal range), or (3) a deterioration in SGA by one category.

Dialysis Dose Targets and Transport Status
For continuous ambulatory peritoneal dialysis (CAPD), the total delivered creatinine clearance dose target for low (L) and low average (LA) transporters was lowered from 60 to 50 L/wk/1.73 m.2 The Kt/Vurea target for L and LA transporters remains at 2.0 per week. The creatinine and urea clearance targets for high (H) and high average (HA) transport types are unchanged.

The rationale for lowering the creatinine target in L and LA transporters is that, even after controlling for delivered dose, L and LA transporters have better outcomes than do H and HA transporters.1 In the absence of adequate residual kidney function (RKF), L and LA transporters may not be able to achieve a CCr of 60 L/wk/1.73 m2 on any reasonable prescription. However, because urea clearance is affected less than CCr by peritoneal transport status, L and LA transporters can achieve a weekly Kt/V of 2.0. Therefore, it seems reasonable to lower the CCr target in L and LA transporters without jeopardizing outcomes. These patients must be observed closely for evidence of inadequate PD. The Canadian Society of Nephrology chose these targets because of new data that became available after the NKF-DOQI publication of 1997.2 Thus, there was a broad consensus to make this change.


The debate over whether peritoneal and residual kidney clearances are equivalent is not resolved. The clinical practice guideline update elaborates on the debate. The rationale for the preservation of residual kidney function is emphasized more strongly.

Throughout the guidelines update new data regarding the pediatric population have been added, which for the most part, corroborate the previous guidelines. In a few minor cases, some previous recommendations that were made for children were withdrawn or qualified. The Nutrition guidelines include a major pediatric section that allowed for this to occur smoothly.

The equations derived in the Modification of Diet in Renal Disease (MDRD) study to estimate GFR were added as methods to estimate GFR in the setting of decreased kidney function. Specifically, the equations that use a combination of demographic, serum, and urine variables are now suggested for estimation of GFR.3

Comments on the normalization of PD dosing measures using total body water and body surface area were expanded and updated.

Bergstrom et al derived new formulae to determine the normalized protein equivalent of nitrogen appearance, which were added to those included in the original guidelines.4 These formulae allow for inclusion or exclusion urinary and peritoneal protein losses.


The Dubois formula for body surface area was corrected to be in square meters rather than in square centimeters. Corrections also were made in the formulae for estimation of the total body water and body surface area of amputee patients in Appendix E.


Are the automated peritoneal dialysis (APD) therapies intermittent enough to require higher targets than continuous therapies? This remains a dilemma and, in the absence of data to the contrary, the previous recommendations were not changed. The argument is not over true intermittent therapies, such as nocturnal intermittent PD, but rather over when continuous cycling PD should be performed with one or two diurnal exchanges. These are asymmetric (over 24 hours) with regard to clearance, but is the asymmetry enough to require different dosing recommendations? This issue may have to be updated in the near future in light of the many studies underway to address it.


  1. Churchill DN, Thorpe KE, Nolph KD, Keshaviah PR, Oreopoulos DG, Page D (CANUSA Study Group): Increased peritoneal membrane transport is associated with decreased patient and technique survival for continuous peritoneal dialysis patients. J Am Soc Neph 9:1285-1292, 1998
  2. Clinical Practice Guidelines of the Canadian Society of Nephrology for Treatment of Patients with Chronic Renal Failure. Chapter 5: Guidelines for adequacy and nutrition in peritoneal dialysis. J Am Soc Nephrol 10:S289-S321, 1999 (suppl 13)
  3. Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D (MDRD Study Group): A more accurate method to estimate glomerular filtration rate from serum creatinine: A new prediction equation. Ann Int Med 130:461-470, 1999
  4. Bergstrom J, Heimburger O, Lindholm B: Calculation of the protein equivalent of total nitrogen appearance from urea appearance. Which formulas should be used? Perit Dial Int 18:467-473, 1998.


Vascular Access

Steve Schwab, MD

From the Baylor College of Medicine, Houston, TX; the Renal Research Institute, New York, NY; Beth Israel Hospital Center, Boston, MA; Minor & James Medical Center, Seattle, WA; Vanderbilt University, Nashville, TN; Duke University Medical Center, Durham, NC; Covance Health Economics and Outcomes Services Inc; and The Johns Hopkins University, Baltimore, MD.

THE VASCULAR Access Work Group reviewed all scientific literature published in English from the initial publication of the NKF-DOQI guidelines in 1997 through 1999. Based on review of this literature, a limited number of significant changes were made to the guidelines. In Guideline 3, it was the opinion of the Work Group that the weight of the evidence now supports addition of a statement that a transposed brachiobasilic vein fistula is preferable to a PTFE graft provided surgical expertise to establish a new AV fistula is available and venous anatomy is adequate. One published manuscript shows the significantly better patency with a transposed brachiobasilic vein fistula compared to a PTFE graft,1 as do two manuscripts that are currently in press.

In addition, in Guideline 10, it was felt that there is now sufficient evidence to recommend intra-access flow monitoring as the preferred technique for monitoring AV access. The primary reason for this recommendation is the superiority of intra-access flow measurements in detecting venous outflow stenosis and in predicting stenosis in native AV fistula. Static venous pressures were considered to be the next most reliable technique, with dynamic venous dialysis pressures still considered to be a satisfactory, but not preferred technique. A table for the interpretation of monthly intra-access flow measurements, as well as a method for monitoring static venous pressure changes,2-5 have been added to the Guideline.

New evidence supports the use of antibiotic ointment at the catheter exit site in both cuffed and noncuffed catheters as a mechanism for minimizing exit site infection and catheter-related bacteremia.6 Some manufacturers, however, have indicated that ointments that contain glycol constituents should not be used on their polyurethane catheters. A specific recommendation from C. R. Bard, Inc (Pittsburgh, PA), is identified in the guidelines.

The Work Group identified an emerging body of evidence that suggests that lytic therapy applied to dialysis catheters, either by slow continuous infusion or by infusion throughout dialysis, has been shown to have significant benefit in the treatment of fibrin sheaths. Preliminary trials using these techniques were indeed promising. However, the withdrawal of Urokinase (Abbott, Abbott Park, IL) from the North American market limited additional studies that may have met the evidentiary basis to have this actually included as a guideline recommendation.7

Novel subcutaneous dialysis access ports are also mentioned in the rationale of Guideline 5. Clinical trials regarding their utility are currently underway and may result in the updating of their preferential use.


  1. Matseura J, Rosenthal D, Clark M, et al: Transposed basillic vein versus PTFE for brachial axillary arteriovenous fistulae. Am J Surg 176:219-211, 1998
  2. Bosman P, Boerboom FT, Smits H, et al: Pressure or flow recordings for surveillance of hemodialysis grafts. Kidney Int 52:1084-1088, 1998
  3. May RE, Himmelfarb J, Ynicesu M, et al: Predicitive measures of vascular access thrombosis: A prospective study. Kidney Int 52:1656-1662, 1997
  4. Neyra R, May R, Ikizler TA, et al: Time-dependent changes in intra-access blood flow is predicitive of subsequent vascular access thrombosis. Kidney Int 54:1714-1719, 1998
  5. Besarab A, Frinak S, Sherman R, et al: Simplified measurement of intra-access pressure. J Am Soc Nephrol 9:284-289, 1998
  6. Sesso R, Barbosa D, Leme I, et al: Staphylococcus aureus prophylaxis in hemodialysis patients using central venous catheters: Effect of mupirocin ointment. J Am Soc Nephrol 9:1085-1092, 1998
  7. Twardowski Z: High dose intradialytic urokinase to restore the patency of permanent central vein hemodialysis catheters. Am J Kidney Dis 31:841-847, 1998


Treatment of Anemia of Chronic Kidney Disease

Joseph W. Eschbach, MD

From the Baylor College of Medicine, Houston, TX; the Renal Research Institute, New York, NY; Beth Israel Hospital Center, Boston, MA; Minor & James Medical Center, Seattle, WA; Vanderbilt University, Nashville, TN; Duke University Medical Center, Durham, NC; Covance Health Economics and Outcomes Services Inc; and The Johns Hopkins University, Baltimore, MD.

DURING THE 3 YEARS since the original 1997 guidelines regarding evidenced-based treatment of the anemia of chronic kidney disease (CKD) were published, over 130 articles have been published on various aspects of anemia as it relates to either erythropoietin (Epoetin) or CKD. The original Anemia Work Group was reconvened to evaluate these articles (one member elected not to continue with the group) and concluded that 37 articles presented new data that supported the original guidelines, or necessitated changes in a guideline, or should result in modification of the original rationale for a Guideline. Changes we have made in the guidelines are discussed below.

Anemia causes many physiological abnormalities, which were well described in the original Introduction. New data confirm that intellectual performance decreases in pediatric patients with CKD who are anemic.1

Perhaps the most significant new recommendation is that anemia should be quantified using hemoglobin rather than hematocrit measurements. The rationale for this change is detailed in Guideline 1. Hematocrit, as measured by an autoanalyzer, is a product of the mean corpuscular volume (MCV) and the total erythrocyte count. Storage of an anticoagulated blood sample at room temperature for more than 8 hours (or for >24 hours when refrigerated), results in erythrocyte swelling and, therefore, in an erroneously high hematocrit. In contrast, the hemoglobin level remains constant under the same conditions. Since many dialysis centers ship blood samples to distant laboratories, under poorly controlled environmental conditions, the risk of erythrocyte swelling is significant. Also, hyperglycemia increases the MCV, resulting in a falsely elevated hematocrit. Automated analyzers also vary a great deal in estimating the number and size of erythrocytes in a blood sample, such variability does not occur for measurement of hemoglobin. For these reasons, hemoglobin is the measurement of choice for all patients.

The target hemoglobin/hematocrit (Guideline 4) of 11 to 12 g/dL/33% to 36% has been reaffirmed by new data showing that patient survival is better when these values are >11 g/dL or >32% to 33%, respectively. An Italian study2 showed that survival was better in those maintained at hematocrit values >32% compared with <32%. In the United States, a hematocrit of 33% to 36% was associated with a 10% reduction in the risk of death when compared with patients maintained in a hematocrit range of 30% to 33%.3 In another study, 1,200 anemic hemodialysis patients with underlying heart disease were randomized to be maintained at either a normal or low hematocrit group.4 The study was terminated early because there was a detectable, albeit still nonstatistically significant, increased incidence of nonfatal myocardial infarctions or death in those that were randomized to the normal hematocrit group. However, the 200 patients who attained and maintained a normal hematocrit (42% 3%) for at least 6 months had approximately a 15% mortality/year compared with a 40% mortality in patients maintained at a hematocrit of approximately 30%. This study also showed that in those cardiac patients who were randomized to be maintained at a hematocrit of 30% 3%, survival improved in those who achieved higher hematocrit levels.

Additional studies that have been reported also confirm the value of maintaining hemoglobin values >11 and hematocrit >33%. Hospitalization rates were lower when the hematocrit was 33% to 36% compared with lower values5 and various physiological parameters: physical performance,6 cognitive function,7 and brain oxygen supply8 were better at a normal hemoglobin level than at lower levels. In striving to maintain the Hgb/Hct within this target range, the Hgb/Hct will likely, at times, rise above this range. The reasons why some patients will temporarily exceed an Hbg/Hct of 12g/dL/36% is that the response to Epoetin varies among patients, the interplay between IV iron supplementation and Epoetin dosing may be unpredictable, and it is mathematically impossible for the bell-shaped distribution for all patients to be limited to between 11 and 12 g/dL of hemoglobin or 33% and 36% hematocrit. As of June 1999, HCFA will continue to provide reimbursement for the cost of Epoetin alfa even if the Hct temporarily rises above their target range, as long as the rolling 3-month average Hct is <37.5%. Medical justification is needed for maintaining the Hct above 36%.

Guideline 7: Monitoring Iron Status, and Guideline 8: Administration of Supplemental Iron, have been modified to account for the availability of a new intravenous iron preparation, sodium ferric gluconate complex in sucrose (iron gluconate), and to eliminate the recommendation to wait 2 to 3 weeks after the last weekly dose of intravenous iron for an accurate measurement of serum ferritin and serum iron. If the weekly dose is 125 mg or less, these tests are accurate after 7 days following iron administration. However, for doses of 500 to 1,000 mg of IV iron, it is best to wait at least 2 weeks to obtain accurate iron measurements. Iron gluconate, in contrast to iron dextran, comes in a preparation containing 62.5 mg/5 mL. Weekly dosing can be done with any fraction of this amount, just as occurs with iron dextran (12.5, 25, 50, or 100 mg dosing). In contrast to the situation for iron dextran, there are no data from experience in the United States that a single infusion of 500 to 1,000 mg of iron gluconate is safe. On the other hand, intravenous administration of iron gluconate has not been reported to cause fatal anaphylaxis, as can occur with iron dextran.

Previously, there was concern that rapid intravenous administration of iron gluconate would result in "oversaturation" of transferring, resulting in hypotension from circulating free iron. It is now known that this may be a laboratory artifact depending on how serum iron is measured. When the laboratory method uses a buffer with ascorbic acid and guanidine, more iron is released from recently administered IV iron compounds, thus artificially raising the serum iron level and leading to the apparent "oversaturation" of transferrin, thus overestimating availability of "free iron." A better method utilizes an acetate buffer with hydroxylamine hydrochloride, which measures iron bound to transferrin (true bioavailable serum iron).9

Two new studies examine the relationship between serum ferritin levels (iron overload) and the incidence of infection in dialysis patients. The author of a French study10 noted previously (prior to Epoetin) that an elevated serum ferritin level was one of three factors associated with an increased incidence of infection (the presence of a central dialysis catheter and history of previous infections being more important), but in a follow-up study11 in patients treated with Epoetin, the same author noted that anemia (Hgb 9 g/dL), but not an elevated serum ferritin, was associated with an increased incidence of bacteremia. Another study12 noted that in vitro neutrophil function was abnormal in a small group (n = 8) of hemodialysis patients who were receiving 30 mg of intravenous iron weekly and had a serum ferritin level >650 ng/mL (911 69 [SEM]). The patients also had transferrin saturation values <20% (16.5 1.2), however. By definition, these patients were not iron overloaded (because of their low transferrin saturation values), but the significance of this study awaits further resolution.

Guideline 9: Administration of a Test Dose of IV Iron, has been rewritten to include iron gluconate.

Guideline 11: Route of Administration of Epoetin, states that the preferred route of Epoetin administration is subcutaneous (SC) in hemodialysis patients. The largest study to date, based on male United States veterans, noted a 30% decrease in the average amount of Epoetin needed to maintain a hematocrit of 30% to 33% when Epoetin was administered SC compared with IV administration. However, 23% of the 208 patients required more Epoetin when switched from IV to SC administration.13 On the other hand, a European study failed to show any greater efficiency of one route compared to the other.14 In aggregate, the bulk of the published data still suggest that SC administration results in a more efficient use of Epoetin.

Guideline 20: Causes for Inadequate Response to Epoetin. Two studies note that an elevated C-reactive protein level (often associated with inflammation and/or infection) is a predictor of resistance to Epoetin.15,16 Previously, there was not enough data to list the use of angiotensin-converting enzyme (ACE) inhibitors as a potential cause of inadequate response to Epoetin. Two new studies continue to provide conflicting data: one study noted that patients taking enalapril for blood pressure control required approximately 75% more Epoetin to maintain the same hemoglobin than did patients treated with nifedipine or control patients not requiring antihypertensive drugs.17 On the other hand, another study failed to document any resistance to Epoetin when ACE inhibitors were used in hemodialysis patients.18 Therefore, if patients on ACE inhibitors are noted to be requiring a greater than average amount of Epoetin, a change to another antihypertensive drug is now worth considering.

Guideline 24: Possible Adverse Effects Related to Epoetin Therapy: Hypertension. The etiology of this adverse effect continues to be investigated. Two in vitro studies demonstrate conflicting results: in one study, Epoetin inhibited interleukin-1–induced apoptosis of vascular smooth muscle cells (which might induce hypertension since nitric oxide production is inhibited),19 whereas another study noted that longer-term exposure of human endothelial cells in culture with Epoetin had a vasodilatory effect.20 These in vitro studies are contrasted to recent in vivo studies suggesting that a single intravenous infusion (100 U/Kg) of Epoetin will increase mean arterial pressure (MAP), but that this effect does not occur if the dose of Epoetin is given subcutaneously.21 The increase in MAP has been reported to be associated with an increase in the ratio of plasma endothelin to proendothelin and/or an elevated cytosolic ionic calcium and nitric oxide resistance. Regardless of the mechanism, it does not seem to be related to the hemoglobin level, since two investigators noted that the incidence of hypertension did not increase when the hemoglobin was increased to normal levels.4,22 The cause of the Epoetin-associated clinical hypertension continues to remain unresolved.

Guidelines 26 and 27 have been combined into a single guideline regarding Possible Adverse Effects Related to Epoetin Therapy: Increased Clotting Tendency. One new study notes that Epoetin therapy does not increase the risk of progressive stenosis in native fistulae,23 whereas another study noted that the incidence of access thrombosis increased in both native fistulae and synthetic arteriovenous grafts in patients randomized to achieve a normal hematocrit.4 However, there was no correlation between the hematocrit level achieved, the dose of Epoetin and the occurrence of access thrombosis. Nevertheless, there still is the perception, by some, that Epoetin therapy increases the incidence of vascular clotting. In an attempt to allay concerns associated with this perception, we refer to the results of an autopsy study of Austrian hemodialysis patients treated with Epoetin that failed to note any increased incidence of preterminal pulmonary thromboembolism.24


  1. Burke JR: Low-dose subcutaneous recombinant erythropoietin in children with chronic renal failure. Pediatr Nephrol 9:558-561, 1995
  2. Locatelli F, Conte F, Marcelli D: The impact of haematocrit levels and erythropoietin treatment on overall and cardiovascular mortality and morbidity—The experience of the Lombardy Dialysis Registry [news]. Nephrol Dial Transplant 13:1642-1644, 1998
  3. Ma JZ, Ebben J, Xia H, Collins AJ: Hematocrit level and associated mortality in hemodialysis patients. J Am Soc Nephrol 10:610-619, 1999
  4. Besarab A, Bolton WK, Browne JK, et al: The effects of normal as compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and Epoetin. N Engl J Med 339:584-590, 1998
  5. Xia H, Ebben J, Ma JZ, Collins AJ: Hematocrit levels and hospitalization risks in hemodialysis patients. J Am Soc Nephrol 10:1309-1316, 1999
  6. McMahon LP, McKenna MJ, Sangkabutra T, Mason K, Sostaric S, Skinner SL, Burge C, Murphy B, Crankshaw D: Physical performance and associated electrolyte changes after haemoglobin normalization: A comparative study in haemodialysis patients. Nephrol Dial Transplant 14:1182-1187, 1999
  7. Picket JL, Theberge DC, Brown WS, Schweitzer SU, Nissenson AR: Normalizing hematocrit in dialysis patients improves brain function. Am J Kidney Dis 33:1122-1130,1999
  8. Metry G, Wikstrom B, Valind S, Sandhagen B, Linde T, Beshara S, Langstrom B, Danielson BG: Effect of normalization of hematocrit on brain circulation and metabolism in hemodialysis patients. J Am Soc Nephrol 10:854-863, 1999
  9. Seligman PA, Schleicher RB: Comparison of methods used to measure serum iron in the presence of iron gluconate or iron dextran. Clin Chem 45:898-901, 1999
  10. Hoen B, Kessler M, Hestin D, Fondu P: Risk factors for bacterial infections in chronic haemodialysis adult patients: A multicenter prospective survey. Nephrol Dial Transplant 10:377-381, 1995
  11. Hoen B, Paul-Dauphin A, Hestin D, et al: EPIBACDIAL: A multicenter prospective study of risk factors for bacteremia in chronic hemodialysis patients. J Am Soc Nephrol 1999
  12. Patruta SI, Edlinger R, Sunder-Plassmann G, et al: Neutrophil impairment associated with iron therapy in hemodialysis patients with functional iron deficiency. J Am Soc Nephrol 9:655-663, 1998
  13. Kaufman JS, Reda DJ, Fye CL, et al: Subcutaneous versus intravenous administration of erythropoietin in hemodialysis patients. N Engl J Med 339:578-583, 1998
  14. de Schoenmakere G, Lameire N, Dhondt A, et al: The haematopoietic effect of recombinant human erythropoietin in haemodialysis is independent of the mode of administration. Nephrol Dial Transplant 13:1770-1775, 1998
  15. Barany P, Divino Filho JC, Bergstrom J: High C-reactive protein is a strong predictor of resistance to erythropoietin in hemodialysis patients. Am J Kidney Dis 29:565-568, 1997
  16. Gunnell J, Yeun JY, Depner TA, et al: Acute-phase response predicts erythropoietin resistance in hemodialysis and peritoneal dialysis patients. Am J Kidney Dis 33:63-72, 1999
  17. Albitar S, Genin R, Fen-Chong M, et al: High dose enalapril impairs the response to erythropoietin treatment in haemodialysis patients. Nephrol Dial Transplant 13:1206-1210, 1998
  18. Abu-Alfa AK, Cruz D, Perazella MA, Mahnensmith RL, Simon D, Bia MJ: ACE inhibitors do not induce recombinant erythropoietin resistance in hemodialysis patients. Am J Kidney Dis 35:1076-1082, 2000
  19. Angnostou A, Liu Z, Steiner M, Chin K, Lee ES, Kessimian N, Noguchi CT: Erythropoietin receptor mRNA expression in human endothelial cells. Proc Natl Acad Sci USA 91:3974-3978, 1999
  20. Banerjee D, Rodriguez M, Nag M, Adamson JW: Exposure of endothelial cells to recombinant human erythropoietin induces nitric oxide synthase activity. Kidney Int 57:1895-1904, 2000
  21. Kang D, Yoon K, Han D: Acute effects of recombinant human erythropoietin on plasma levels of proendothelin-1 and endothelin-1 in haemodialysis patients. Nephrol Dial Transplant 13:2877-2883, 1998
  22. Berns JS, Rudnick MR, Cohen RM, et al: Effects of normal hematocrit on ambulatory blood pressure in epoetin-treated hemodialysis patients with cardiac Disease. Kidney Int 56:253-260, 1999
  23. de Marchis, Cecchin E, Falleti E, et al: Long-term effects of erythropoietin therapy on fistula stenosis and plasma concentrations of PDGF and MCP-1 in hemodialysis patients. J Am Soc Nephrol 8:1147-1156, 1997
  24. Wiesholzer M, Kitzwogerer M, Harm F, Barbieri G, Hauser A-C, Pribasnig A, Bankl H, Balcke P: Prevalence of preterminal pulmonary thromboembolism among patients on maintenance hemodialysis treatment before and after introduction of recombinant erythropoietin. Am J Kidney Dis 33:702-708, 1999




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