Hemodialysis Prescription for Incident Patients: Twice Seems Nice, But Is It Incremental?
2016; Elsevier BV; Volume: 68; Issue: 2 Linguagem: Inglês
10.1053/j.ajkd.2016.04.005
ISSN1523-6838
AutoresStephanie M. Toth‐Manikowski, Tariq Shafi,
Tópico(s)Chronic Kidney Disease and Diabetes
ResumoRelated Article, p. 256 Related Article, p. 256 During the next decade, about one million people in the United States are expected to start dialysis therapy.1Saran R. Li Y. Robinson B. et al.US Renal Data System 2015 Annual Data Report: epidemiology of kidney disease in the United States.Am J Kidney Dis. 2016; 67: S1-S434PubMed Google Scholar The majority of these people will be treated with a fixed-dose (single-pool Kt/Vurea [spKt/Vurea] ≥ 1.2) thrice-weekly hemodialysis regimen irrespective of whether they are just starting dialysis therapy (incident) or have been receiving dialysis for some time (prevalent) and without consideration for residual kidney function (RKF). Although the regulatory agencies might consider this hemodialysis regimen as “standard of care” and “adequate,” it is by no means perfect.2Foley R.N. Gilbertson D.T. Murray T. Collins A.J. Long interdialytic interval and mortality among patients receiving hemodialysis.N Engl J Med. 2011; 365: 1099-1107Crossref PubMed Scopus (326) Google Scholar, 3Fotheringham J. Fogarty D.G. El Nahas M. Campbell M.J. Farrington K. The mortality and hospitalization rates associated with the long interdialytic gap in thrice-weekly hemodialysis patients.Kidney Int. 2015; 88: 569-575Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar, 4Meyer T.W. Sirich T.L. Hostetter T.H. Dialysis cannot be dosed.Semin Dial. 2011; 24: 471-479Crossref PubMed Scopus (38) Google Scholar Therefore, questions remain. What is the optimal regimen for incident hemodialysis patients? How did we get to the current fixed-dose thrice-weekly paradigm? How do we move forward? The path to thrice-weekly hemodialysis was gradual, guided by dialysis prescribed to control patient symptoms, peripheral neuropathy in particular.5Tenckhoff H. Peripheral neuropathy complicating chronic dialysis. Proceedings of the Working Conference Chronic Dialysis; Seattle, WA; 1964. Seattle, WA: University of Washington Press; 1965:120-123.Google Scholar In the 1960s, sessions took place once weekly, lasting 20 to 24 hours. Due to recurrent uremic symptoms, frequency was increased to twice weekly for 16 to 23 hours per session, and later to thrice weekly for 8 to 10 hours per session.6Scribner B.H. Cole J.J. Ahmad S. Blagg C.R. Why thrice weekly dialysis?.Hemodial Int. 2004; 8: 188-192Crossref PubMed Scopus (42) Google Scholar In 1973, the Seattle thrice-weekly 8- to 10-hour per session hemodialysis program was the norm when the Medicare End-Stage Renal Disease Program legislation was passed. Subsequently, attempts to individualize hemodialysis prescriptions focused only on prevalent patients dialyzed thrice weekly. The National Cooperative Dialysis Study (NCDS; 1978-1981) led to the eventual development of Kt/Vurea as a patient-specific metric.7Gotch F.A. Sargent J.A. A mechanistic analysis of the National Cooperative Dialysis Study (NCDS).Kidney Int. 1985; 28: 526-534Abstract Full Text PDF PubMed Scopus (1073) Google Scholar, 8Lowrie E.G. Laird N.M. Parker T.F. Sargent J.A. Effect of the hemodialysis prescription of patient morbidity: report from the National Cooperative Dialysis Study.N Engl J Med. 1981; 305: 1176-1181Crossref PubMed Scopus (605) Google Scholar The Hemodialysis (HEMO) Study (1995-2001) failed to demonstrate a survival benefit from a higher spKt/Vurea (1.7) compared to standard dose (1.3) delivered thrice weekly.9Eknoyan G. Beck G.J. Cheung A.K. et al.Effect of dialysis dose and membrane flux in maintenance hemodialysis.N Engl J Med. 2002; 347: 2010-2019Crossref PubMed Scopus (1581) Google Scholar Thus, the thrice-weekly schedule stems from observations during the 1960s and the per-session dialysis dose (spKt/Vurea) from the NCDS and HEMO Study. However, it is important to note that the NCDS and HEMO Study findings are only generalizable to prevalent patients without RKF because incident patients and patients with RKF were explicitly excluded from both trials. The optimal regimen for patients initiating hemodialysis therapy is not known. It is plausible that the routine practice of fixed-dose thrice-weekly hemodialysis in incident patients with substantial RKF may be harmful, contributing to accelerated loss of this residual function.10Daugirdas J.T. Greene T. Rocco M.V. et al.Effect of frequent hemodialysis on residual kidney function.Kidney Int. 2013; 83: 949-958Abstract Full Text Full Text PDF PubMed Scopus (163) Google Scholar, 11Golper T.A. Mehrotra R. The intact nephron hypothesis in reverse: an argument to support incremental dialysis.Nephrol Dial Transplant. 2015; 30: 1602-1604Crossref PubMed Scopus (24) Google Scholar Loss of RKF is linked to decreased survival,12Shafi T. Jaar B.G. Plantinga L.C. et al.Association of residual urine output with mortality, quality of life, and inflammation in incident hemodialysis patients: the Choices for Healthy Outcomes in Caring for End-Stage Renal Disease (CHOICE) Study.Am J Kidney Dis. 2010; 56: 348-358Abstract Full Text Full Text PDF PubMed Scopus (215) Google Scholar, 13van der Wal W.M. Noordzij M. Dekker F.W. et al.Full loss of residual renal function causes higher mortality in dialysis patients; findings from a marginal structural model.Nephrol Dial Transplant. 2011; 26: 2978-2983Crossref PubMed Scopus (107) Google Scholar likely from poorer uremic solute clearance,14Marquez I.O. Tambra S. Luo F.Y. et al.Contribution of residual function to removal of protein-bound solutes in hemodialysis.Clin J Am Soc Nephrol. 2011; 6: 290-296Crossref PubMed Scopus (84) Google Scholar volume and blood pressure control,15Vilar E. Wellsted D. Chandna S.M. Greenwood R.N. Farrington K. Residual renal function improves outcome in incremental haemodialysis despite reduced dialysis dose.Nephrol Dial Transplant. 2009; 24: 2502-2510Crossref PubMed Scopus (115) Google Scholar, 16Menon M.K. Naimark D.M. Bargman J.M. Vas S.I. Oreopoulos D.G. Long-term blood pressure control in a cohort of peritoneal dialysis patients and its association with residual renal function.Nephrol Dial Transplant. 2001; 16: 2207-2213Crossref PubMed Scopus (153) Google Scholar higher erythropoietin requirements,12Shafi T. Jaar B.G. Plantinga L.C. et al.Association of residual urine output with mortality, quality of life, and inflammation in incident hemodialysis patients: the Choices for Healthy Outcomes in Caring for End-Stage Renal Disease (CHOICE) Study.Am J Kidney Dis. 2010; 56: 348-358Abstract Full Text Full Text PDF PubMed Scopus (215) Google Scholar more inflammation,12Shafi T. Jaar B.G. Plantinga L.C. et al.Association of residual urine output with mortality, quality of life, and inflammation in incident hemodialysis patients: the Choices for Healthy Outcomes in Caring for End-Stage Renal Disease (CHOICE) Study.Am J Kidney Dis. 2010; 56: 348-358Abstract Full Text Full Text PDF PubMed Scopus (215) Google Scholar and higher left ventricular mass.17Wang A.Y. Wang M. Woo J. et al.A novel association between residual renal function and left ventricular hypertrophy in peritoneal dialysis patients.Kidney Int. 2002; 62: 639-647Abstract Full Text Full Text PDF PubMed Scopus (169) Google Scholar RKF is routinely incorporated into peritoneal dialysis dose calculations. A similar approach to prescribing hemodialysis for incident patients is to individualize the prescription to the patient’s small-solute (urea) clearance needs, incrementally increasing hemodialysis clearance (dose and/or frequency) as RKF declines.18Wong J. Vilar E. Davenport A. Farrington K. Incremental haemodialysis.Nephrol Dial Transplant. 2015; 30: 1639-1648Crossref PubMed Scopus (63) Google Scholar This incremental dialysis approach is supported by opinion-based US and European guidelines,19National Kidney FoundationKDOQI clinical practice guideline for hemodialysis adequacy: 2015 update.Am J Kidney Dis. 2015; 66: 884-930Abstract Full Text Full Text PDF PubMed Scopus (622) Google Scholar, 20Section II. Haemodialysis adequacy.Nephrol Dial Transplant. 2002; 17: 16-31Google Scholar but its safety and efficacy in incident hemodialysis patients remains undefined. In this issue of AJKD, Obi et al21Obi Y. Streja E. Rhee C.M. et al.Incremental hemodialysis, residual kidney function, and mortality risk in incident dialysis patients: a cohort study.Am J Kidney Dis. 2016; 68: 256-265Abstract Full Text Full Text PDF PubMed Scopus (159) Google Scholar report results of a retrospective cohort study of incident in-center hemodialysis patients comparing twice-weekly hemodialysis prescribed to 351 patients to thrice-weekly hemodialysis prescribed to a matched cohort of 8,068 patients. Of note, only 0.3% (351/103,703) of all incident patients were treated with twice-weekly hemodialysis, limiting the generalizability of the findings. As displayed in Fig 2A of the report, the slope of decline in urinary urea clearance (KRU) for the thrice-weekly group from the first to the second patient-quarter was ∼1 mL/min/1.73 m2, quite a bit steeper than the decline of ∼0.25 mL/min/1.73 m2 for the twice-weekly group. However, there was significant variability, with wide confidence intervals. After year 1, the risk for death with twice-weekly hemodialysis was statistically similar to thrice-weekly hemodialysis (P = 0.3), but with wide confidence intervals ranging from 11% lower to 38% higher risk for death. In subgroup analyses, patients on a twice-weekly regimen with a baseline KRU ≤ 3 mL/min/1.73 m2 (n = 73) had a trend toward a higher risk for death compared with patients with KRU > 3 mL/min/1.73 m2. The authors concluded that twice-weekly hemodialysis may be safe in incident hemodialysis patients with substantial RKF at baseline; thus, they called for a clinical trial to examine the safety and efficacy of twice-weekly hemodialysis. Overall, the study is thoughtfully designed within the confines of an administrative data set. However, the key question is whether twice-weekly hemodialysis, as prescribed in routine care, was truly incremental hemodialysis that is adjusting dialysis clearance to supplement RKF. Or did a fixed-dose twice-weekly regimen simply supplant the fixed-dose thrice-weekly schedule without consideration of RKF, perhaps driven by factors such as patients’ wishes or health? Looking at Table S2 in the report, dialysis frequency, duration, and treatment time in the twice-weekly group remained generally similar from patient-quarters 1 to 4. Results for per-session spKt/Vurea are not reported. Of the 351 patients in the twice-weekly group, repeat urine measurements were available for only 24%, 63%, 30%, and 42% of patients in patient-quarters 2 to 5, respectively. The absence of increasing dialysis frequency or treatment time and infrequent urine monitoring implies that these patients were simply on a fixed-dose twice-weekly regimen and not an individualized incremental hemodialysis schedule. It might also explain why only 30% of the patients with KRU ≤ 3 mL/min/1.73 m2 met the NKF-KDOQI (National Kidney Foundation–Kidney Disease Outcomes Quality Initiative) adequacy goal. Hence, although it is possible to conclude from this study that a fixed-dose twice-weekly regimen can only be safely undertaken in patients with KRU > 3 mL/min/1.73 m2, this conclusion cannot be extended to incremental dialysis, which may be safe in patients with lower RKF levels. Other studies of fixed-dose twice-weekly hemodialysis, generally prescribed in a resource-constrained environment, also suggest better preservation of RKF, as well as less intradialytic hypotension and similar nutritional indexes and survival.22Chauhan R. Mendonca S. Adequacy of twice weekly hemodialysis in end stage renal disease patients at a tertiary care dialysis centre.Indian J Nephrol. 2015; 25: 329-333Crossref PubMed Scopus (18) Google Scholar, 23Zhang M. Wang M. Li H. et al.Association of initial twice-weekly hemodialysis treatment with preservation of residual kidney function in ESRD patients.Am J Nephrol. 2014; 40: 140-150Crossref PubMed Scopus (91) Google Scholar, 24Panaput T. Thinkhamrop B. Domrongkitchaiporn S. et al.Dialysis dose and risk factors for death among ESRD patients treated with twice-weekly hemodialysis: a prospective cohort study.Blood Purif. 2014; 38: 253-262Crossref PubMed Scopus (22) Google Scholar, 25Lei G. Li X. Tu W. Xu C. Duan Z. Wu X. Risk of intradialytic hypotension in patients on thrice-weekly versus twice-weekly hemodialysis.Int J Cardiol. 2014; 174: 821-823Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar, 26Cheng Y. Tu W. Xiao Q. Chen Y. Hu L. Wu X. Risk of cardiovascular disease in patients on thrice-weekly versus twice-weekly hemodialysis.Int J Cardiol. 2014; 174: 780-783Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar, 27Bieber B. Qian J. Anand S. et al.Two-times weekly hemodialysis in China: frequency, associated patient and treatment characteristics and quality of life in the China Dialysis Outcomes and Practice Patterns study.Nephrol Dial Transplant. 2014; 29: 1770-1777Crossref PubMed Scopus (62) Google Scholar, 28Bello B.T. Raji Y.R. Sanusi I. Braimoh R.W. Amira O.C. Mabayoje O.M. Challenges of providing maintenance hemodialysis in a resource poor country: experience from a single teaching hospital in Lagos, Southwest Nigeria.Hemodial Int. 2013; 17: 427-433Crossref PubMed Scopus (15) Google Scholar, 29Lin X. Yan Y. Ni Z. et al.Clinical outcome of twice-weekly hemodialysis patients in Shanghai.Blood Purif. 2012; 33: 66-72Crossref PubMed Scopus (56) Google Scholar, 30Stankuviene A. Ziginskiene E. Kuzminskis V. Bumblyte I.A. Impact of hemodialysis dose and frequency on survival of patients on chronic hemodialysis in Lithuania during 1998-2005.Medicina (Kaunas). 2010; 46: 516-521PubMed Google Scholar, 31Supasyndh O. Satirapoj B. Seenamngoen S. Yongsiri S. Choovichian P. Vanichakarn S. Nutritional status of twice and thrice-weekly hemodialysis patients with weekly Kt/V > 3.6.J Med Assoc Thai. 2009; 92: 624-631PubMed Google Scholar, 32Lin Y.F. Huang J.W. Wu M.S. et al.Comparison of residual renal function in patients undergoing twice-weekly versus three-times-weekly haemodialysis.Nephrology (Carlton). 2009; 14: 59-64Crossref PubMed Scopus (86) Google Scholar, 33Tzamaloukas A.H. Vanderjagt D.J. Agaba E.I. et al.Inadequacy of dialysis, chronic inflammation and malnutrition in Nigerian patients on chronic hemodialysis.Int J Artif Organs. 2006; 29: 1067-1073PubMed Google Scholar Reports of incremental hemodialysis are far fewer, but suggest that this approach may be safe in patients with KRU as low as 1 mL/min15Vilar E. Wellsted D. Chandna S.M. Greenwood R.N. Farrington K. Residual renal function improves outcome in incremental haemodialysis despite reduced dialysis dose.Nephrol Dial Transplant. 2009; 24: 2502-2510Crossref PubMed Scopus (115) Google Scholar and may improve survival in incident dialysis patients.34Fernandez-Lucas M. Teruel-Briones J.L. Gomis-Couto A. Villacorta-Perez J. Quereda-Rodriguez-Navarro C. Maintaining residual renal function in patients on haemodialysis: 5-year experience using a progressively increasing dialysis regimen.Nefrologia. 2012; 32: 767-776PubMed Google Scholar The results of the study by Obi et al are generally consistent with these prior studies. Additionally, less frequent dialysis may reduce access complications and risk for infections, potentially improving quality of life and reducing cost. The 2 approaches, fixed-dose twice weekly and incremental hemodialysis, are not mutually exclusive. Extensive work on urea kinetics over the past few decades, including the development of the dialysis “equivalent renal urea clearance (EKRC)” by Casino and Lopez35Casino F.G. Lopez T. The equivalent renal urea clearance: a new parameter to assess dialysis dose.Nephrol Dial Transplant. 1996; 11: 1574-1581Crossref PubMed Scopus (209) Google Scholar and weekly standard Kt/Vurea proposed by Gotch36Gotch F.A. The current place of urea kinetic modelling with respect to different dialysis modalities.Nephrol Dial Transplant. 1998; 13: 10-14Crossref PubMed Scopus (284) Google Scholar and refined by Daugirdas et al,37Daugirdas J.T. Depner T.A. Greene T. Levin N.W. Chertow G.M. Rocco M.V. Standard Kt/Vurea: a method of calculation that includes effects of fluid removal and residual kidney clearance.Kidney Int. 2010; 77: 637-644Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar provide the framework for combining dialysis and residual urea clearances. Figure 1, adapted from an approach described by Keshaviah et al,38Keshaviah P.R. Emerson P.F. Nolph K.D. Timely initiation of dialysis: a urea kinetic approach.Am J Kidney Dis. 1999; 33: 344-348Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar illustrates this concept for incremental hemodialysis. The mathematical complexity of these approaches has limited their widespread application; however, increasing availability of computers at the point of care may simplify their implementation. A key factor limiting the feasibility of incremental hemodialysis is the requirement for frequent and reliable assessment of RKF by timed urine collections, which are unreliable and burdensome.19National Kidney FoundationKDOQI clinical practice guideline for hemodialysis adequacy: 2015 update.Am J Kidney Dis. 2015; 66: 884-930Abstract Full Text Full Text PDF PubMed Scopus (622) Google Scholar Glomerular filtration rate measurement using plasma clearance of iohexol can be considered for assessing RKF, but it is also cumbersome, is not feasible on a large scale, and may give erroneous results due to nonrenal iohexol clearance.39Shafi T. Levey A.S. Inker L.A. et al.Plasma iohexol clearance for assessing residual kidney function in dialysis patients.Am J Kidney Dis. 2015; 66: 728-730Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar We recently developed and validated equations that estimate KRU in dialysis patients from serum β-trace protein (BTP), β2-microglobulin, or cystatin C concentration without requiring urine collection.40Shafi T. Michels W.M. Levey A.S. et al.Estimating residual kidney function in dialysis patients without urine collection.Kidney Int. 2016; 89: 1099-1110Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar These equations (available at www.kidneymodels.org/rkf/) are valid for patients with self-reported urine volume of at least 1 cup (250 mL) per day. In particular, the BTP equation seems attractive given that BTP remains in a steady state during the interdialytic interval.40Shafi T. Michels W.M. Levey A.S. et al.Estimating residual kidney function in dialysis patients without urine collection.Kidney Int. 2016; 89: 1099-1110Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar Routine estimation of RKF using serum markers may simplify incremental hemodialysis prescription, allowing frequent monitoring of RKF without increasing patient burden. However, we must also consider the limitations of an incremental dialysis approach.41Vanholder R. Van Biesen W. Lameire N. Is starting hemodialysis on a twice-weekly regimen a valid option?.Am J Kidney Dis. 2014; 64: 165-167Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar Refractory volume overload is often an indication for dialysis initiation, but volume status in dialysis patients is difficult to assess and there is no gold standard for volume assessment.42Agarwal R. Volume overload in dialysis: the elephant in the room, no one can see.Am J Nephrol. 2013; 38: 75-77Crossref PubMed Scopus (21) Google Scholar Volume overload may require more frequent or longer dialysis sessions. Additionally, the native kidneys’ removal of low-molecular-weight proteins and protein-bound solutes by tubular clearance and removal of sequestered solutes by virtue of the slow continuous clearance are not matched by dialysis. Therefore, we must be cognizant that although combining urea clearance from dialysis and RKF is mathematically feasible, the nature of solute clearance provided by dialysis and RKF is fundamentally different. We agree with the authors’ call for a clinical trial. We would like to stress that the only way to improve the care of more than a million patients who will start hemodialysis therapy in the next decade is by challenging the existing paradigm and striving for evidence-based changes in clinical practice. The equipoise between the use of incremental hemodialysis or usual-care fixed-dose thrice-weekly hemodialysis for incident patients can only be answered by a clinical trial. Such a trial could have a cluster-randomized pragmatic noninferiority design, using RKF estimation instead of urine collections to enhance the feasibility of implementation and safety of the participants. The potential benefits and economic savings make the reasons to pursue such an endeavor evident. Financial Disclosure: Dr Shafi reports having consulted for Siemens, as well as research funding to Johns Hopkins University from the National Institute of Diabetes and Digestive and Kidney Diseases (K23-DK-083514). Dr Toth-Manikowski declares that she has no relevant financial interests. Peer Review: Evaluated by a Co-Editor and the Editor-in-Chief. Incremental Hemodialysis, Residual Kidney Function, and Mortality Risk in Incident Dialysis Patients: A Cohort StudyAmerican Journal of Kidney DiseasesVol. 68Issue 2PreviewMaintenance hemodialysis is typically prescribed thrice weekly irrespective of a patient’s residual kidney function (RKF). We hypothesized that a less frequent schedule at hemodialysis therapy initiation is associated with greater preservation of RKF without compromising survival among patients with substantial RKF. Full-Text PDF
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