The optimal time to commence dialysis in

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1 PERITONEAL DIALYSIS Early Start Peritoneal Dialysis Carol A. Pollock, Bruce A. Cooper, and David C. Harris The timing of commencement of dialysis is controversial, as it has an impact on the patient s lifestyle, the dialysis capacity of renal services, and costs to both the individual and community. In patients with chronic kidney disease, the commencement of dialysis based on clinical features of uremia and laboratory indices that mandate dialysis therapy may not optimize outcomes. Currently reported studies are subject to potential confounding factors, including lead-time bias, the timing of referral, uniform predialysis care, patient age, comorbidity, and compliance. Despite the lack of supporting evidence, national and international expert panels have generally recommended adopting guidelines that support the initiation of dialysis at levels of kidney function that are higher than observed in current practice. No compelling evidence supports the initial use of one modality of dialysis over another, but initiation of peritoneal dialysis will likely preserve residual kidney function to a greater extent than will initiation of hemodialysis. As preservation of endogenous kidney function is an important goal in patients with end-stage kidney disease, this outcome may contribute to the choice of modality. Objective parameters that will guide the initiation of dialysis to maximize survival, reduce morbidity, and inform as to the economic benefit of implementing such practice will be available when the Initiating Dialysis Early and Late (IDEAL) study reports in by the National Kidney Foundation, Inc. Index Words: Early-start; Peritoneal dialysis The optimal time to commence dialysis in patients with chronic kidney disease is not clear. This uncertainty has been recognized by nephrologists internationally as potentially the most important dialysis-related question to be addressed in the next decade. A number of groups have tried to resolve the issue of when to commence dialysis by use of either cohort or case-control studies. 1-6 These investigations have, in general, supported the concept that starting dialysis with a relatively higher level of kidney function affords a benefit with respect to morbidity, mortality, capacity for employment, and quality of life. However, these studies are subject to potential confounding factors, including lead-time bias, the timing of referral, uniform predialysis care, patient age, comorbidity, and compliance. As a result, no firm conclusion can be reached about the optimal time to start dialysis. Indeed the largest cohort study reported to date concluded that despite the need for an adequately powered randomized trial to address this issue, such a trial would be unlikely ever to occur. 7 We have initiated and fully recruited such a trial (Initiating Dialysis Early and Late [the IDEAL trial]), with results expected in This trial should provide key information to patients, clinicians, and health economists as to the optimal time to commence renal replacement therapy. Current Guidelines Despite the lack of supporting evidence, guidelines have been issued by national bodies and international expert panels recommending the initiation of dialysis at a level of kidney function much higher than is currently practiced. The Kidney Disease Outcomes and Quality Initiatives (KDOQI) of the National Kidney Foundation of the USA 9 has recommended that dialysis be commenced at a glomerular filtration rate (GFR) of approximately 10.5 ml/min/1.73 m 2, a level based on the minimum target level of total (residual renal and dialysis) clearance for peritoneal dialysis, unless all 3 of the following criteria are met: stable or increased edema-free body weight; From the Department of Renal Medicine, Kolling Institute, University of Sydney, Royal North Shore Hospital, St. Leonards, NSW, Australia; and Department of Renal Medicine, Millenium Institute, University of Sydney, Westmead Hospital, Wentworthville, NSW, Australia. Address correspondence to Carol Pollock, MD, University of Sydney, Department of Medicine, Royal North Shore Hospital, St. Leonards, NSW 2065, Australia. carpol@ med.usyd.edu.au 2007 by the National Kidney Foundation, Inc /07/ $32.00/0 doi: /j.ackd Advances in Chronic Kidney Disease, Vol 14, No 3 (July), 2007: pp e27-e34 e27

2 e28 Pollock, Cooper, and Harris no evidence of malnutrition; and absence of clinical signs and symptoms of uremia. The European Best Practice Guidelines recommend that dialysis should be commenced whenever uremia is present or when blood pressure or hydration status cannot be controlled. In the absence of these indications, dialysis should commence at a GFR between 8 to 10 ml/min to avoid the creatinine clearance falling below 8 ml/min/1.73 m 2 or the GFR below 6 ml/min/1.73 m The Canadian Society of Nephrology 11 has recommended that dialysis be commenced when GFR falls below 12 ml/min, with a provision that dialysis can be deferred if no evidence of uremia or malnutrition is present. The Caring for Australians with Renal Impairment (CARI) guidelines, developed under the auspices of the Australian and New Zealand Society of Nephrology and the Australian Kidney Foundation 12 recommend dialysis at a GFR of 10 ml/min or less, with the discretion to start later if malnutrition or symptoms of uremia are absent. Data from the United States 13 and Australia and New Zealand 14 show that dialysis is currently commenced well below these targets. The IDEAL Trial The primary objective of the IDEAL trial is to determine whether the early initiation of dialysis reduces all-cause mortality in patients with end-stage kidney disease. The secondary objectives are to determine if early initiation of dialysis is associated with a reduction in morbidity (infections and cardiovascular disease, including echocardiographic parameters), associated with dialysis complications (access problems, fluid and electrolyte disorders, and the requirement for temporary dialysis access), reduces overall treatment costs, reduces hospitalization days, alters loss of residual kidney function, and improves quality of life and nutritional state. The broader economic impact of early-start versus late-start dialysis is additionally being assessed. The study has enrolled over 800 patients drawn from 32 participating units in Australia and New Zealand. Patients were enrolled into the study if they were aged 18 years or older, had progressive kidney disease, and had a GFR at baseline of 10 to 20 ml/min/1.73 m 2. Once the GFR fell to 15 ml/min/1.73m 2,patients were randomized to early-start or latestart dialysis and observed every 3 months from randomization. Early-start patients were targeted to commence dialysis with a GFR 10 to 14 ml/min/1.73 m 2 and latestart patients when the GFR reached 7 ml/ min/1.73 m 2. Hence, the study is appropriately designed to address the issue of whether elective early-start dialysis improves morbidity and mortality and at what cost. Why Start Dialysis Early? The case for starting dialysis early is based on the incongruous observation that we allow endogenous renal clearances to fall below the minimal clearances that we target once dialysis has commenced. The rationale for commencing dialysis once renal clearance falls below this minimal value is largely derived from secondary analyses of large-scale cohort studies. The CANUSA study demonstrated that 1-year and 2-year survival was greater in patients commencing dialysis with more preserved levels of kidney function. The relative risk of death was 0.95 (95% CI, 0.91 to 0.99) for a 5 L/wk greater GFR at initiation 15 In a retrospective analysis, commencing dialysis early (mean creatinine clearance 13 ml/min versus late 2.1 ml/min) resulted in better mean 12-year survival (77% v 51%), less hospitalization (7 days v 16 days per year), and greater employment (72% v 42%). In a subsequent longitudinal study of 90 patients well matched for comorbidity, degree of kidney dysfunction, and length of follow up in the predialysis period, these differences in survival and morbidity were not easily explained by lead-time bias, age, or kidney disease. 3 A follow-up of a subset of the patients who were subsequently transplanted demonstrated a survival advantage for those who had commenced dialysis early. 4 Additional studies demonstrate that delayed referral to a nephrologist, resulting in late commencement of dialysis, is associated with a worse outcome. 6 However, the converse has also been observed in that incident patients who start dialysis at greater levels of GFR had more comorbid conditions and a 42% greater mortality compared with patients who commenced dialysis with lower levels of GFR. 16 The

3 Early Start Peritoneal Dialysis e29 difference in outcome was not fully explained by the additional comorbidity. Moreover, a 25% increased risk of mortality in commencing dialysis early was observed in older patients, and a 39% increased risk was observed in patients without diabetes mellitus, heart failure, or vascular disease. The effect of lead-time bias in studies demonstrating that patients who commence dialysis earlier and, hence, survive longer on dialysis was adjusted for by Traynor et al, 7 who measured survival from the time of an estimated GFR of 20 ml/min, independent of the timing of dialysis. In multivariate analysis an 11% increase in risk of death was seen for each 1 ml/min higher GFR at the time of initiation of dialysis. In a further study, Beddhu et al 17 also demonstrated a 14% increased mortality risk for each 5 ml/min increase in GFR, calculated by the MDRD equation, 18 at the start of dialysis, but this result was not confirmed when a direct measure of creatinine clearance was used as the estimate of kidney function. In light of the evidence that a decline in kidney function is associated with a spontaneous reduction in protein intake, 19 that those commencing dialysis late have a poor nutritional profile, 20 and that increased mortality is observed in patients commencing renal replacement therapy with a low serum albumin, an early start of renal replacement therapy has been suggested to improve nutrition. 2,21,22 The Netherlands Cooperative Study on the Adequacy of Dialysis (NECOSAD) is a multicenter, prospective cohort study that includes adult patients who commence either hemodialysis or peritoneal dialysis and who are then observed until transplantation or death. The NECOSAD study group has explored the presumed interaction between protein intake and kidney function in a cohort of 114 incidentdialysis patients. Only 10% of the cohort fulfilled the KDOQI recommendations for initiation of dialysis with a Kt/V of greater than 2.0/wk. Despite this circumstance, 69% met the recommended protein-nitrogen appearance target of greater than 0.8 g/kg/d, which demonstrated the mismatch between renal clearance and protein intake in this population. 23 The cost implications of varying the time renal replacement therapy is commenced is at present not clear and will be defined in the economic evaluation of the IDEAL study. Simulated cohort studies suggest that early referral results in cost savings, improved patient survival, and reduced inpatient stays. 24 The cost-effectiveness decreased as rates of kidney-function loss for patients referred early versus late approximated each other, which suggests that an early start of dialysis is likely to have an economic benefit. Trends in Timing of Initiation of Dialysis A trend for the earlier commencement of dialysis has occurred in Europe, the United States, and Canada in the last decade of the twentieth century. 13,25,26 Patients enrolled in the NECOSAD study have trended toward earlier initiation of dialysis over time. Despite this development, no difference in survival or health-related quality of life has been observed. 27 A paucity of data on the timing of dialysis in pediatric patients exists. Relatively recent data derived from the United States Renal Data Systems have shown that children commence dialysis with more preserved kidney function than do adults. Approximately 50% of children who commence dialysis do so with a GFR of greater than 10 ml/min/ 1.73 m 2. In contrast, 7.3% commence dialysis with a GFR less than 5 ml/min/1.73 m 2. Over the period 1995 to 2002, a steady increase occurred in the percentage of children commencing dialysis at higher levels of kidney function. No difference in GFR was observed between patients who initiated hemodialysis compared with peritoneal dialysis. 28 Does a Preferred Mode of Dialysis at Initiation Exist? The mode of dialysis therapy is best decided by a fully informed patient with due consideration given to comorbidities that may influence the choice of therapy and resource availability. Hemodialysis induces a decline in kidney function within the first 3 months of dialysis, 23 and residual kidney function has an important effect on survival. 29,30 Although earlier initiation of dialysis could possibly lead to a more rapid loss of endogenous clearance and accelerate morbidity and mortality,

4 e30 Pollock, Cooper, and Harris this risk appears to be less if peritoneal dialysis (in particular, continuous ambulatory peritoneal dialysis) is used as the initial form of therapy. 31,32 Automated peritoneal dialysis (APD) may be associated with a more precipitous decline in residual kidney function. In a small prospective study of 36 patients, endogenous creatinine clearance declined more rapidly in the first year in patients on APD compared with CAPD. 33 Patients referred for dialysis late in the course of disease have more often been treated with hemodialysis than with peritoneal dialysis. This outcome has been at least in part because of the ease of placing a temporary catheter for vascular access and the ability to use it immediately after placement. However, newer approaches to peritoneal catheter placement by use of fluoroscopy-assisted percutaneous techniques, 34,35 or minilaparotomy plus omentopexy 36 have enabled easier catheter placement with the opportunity to commence dialysis within days rather than weeks. In light of studies that demonstrate an initial survival advantage in patients commencing peritoneal dialysis, 37 an integrated-care approach has been advanced: start dialysis with peritoneal and transfer to hemodialysis if complications arise. 38 Empirical and theoretical arguments have proposed that initiating dialysis in incremental doses may be sufficient to maintain clearances and limit the time commitment inherent in dialysis. Incremental dialysis is practical for patients commencing peritoneal dialysis, by initially utilizing 1 overnight exchange when the GFR is between 10 and 12 ml/min and increasing the exchanges as endogenous kidney function declines. 39 Implementation of incremental dialysis requires careful monitoring of residual kidney function, with potentially frequent changes in dialysis prescription to avoid underdialysis. No trials have compared outcomes in patients initiating dialysis with incremental versus full-dose dialysis. Late Referral Versus Late Dialysis Given the lack of randomized trials, the effect of late referral to a nephrologist versus the elective late commencement of dialysis is difficult to delineate in the literature. Although a randomized trial that compares late or early referral to a nephrologist would be impossible to conduct, cohort studies suggest that late referral and nonelective commencement of dialysis results in a 1.6-fold to 4.9-fold increased morbidity and mortality in both the diabetic and nondiabetic populations The Dialysis Outcomes and Practice Patterns Study (DOPPS) demonstrated that predialysis nephrology care for patients treated with hemodialysis resulted in a 50% lower rate of cardiac death and withdrawal from dialysis during the first 120 days of dialysis therapy when compared with patients who did not receive predialysis nephrology care. No difference in mortality was observed in the subsequent 121 to 365 days. 47 In the peritoneal population, early referral to a nephrologist is associated with improved biochemical parameters, reduced length of stay for first hospitalization, and a higher percentage of elective catheter placements. 48 Although the majority of the excess risk occurs in the first 90 to 120 days after commencement of dialysis, data from the Australian and New Zealand Dialysis Registry demonstrated an increased mortality risk for patients who are referred late that persists beyond the first year of dialytic therapy. 49 Furthermore, patients who are referred late have a reduced likelihood of being placed on the cadaveric transplant waiting list and receiving a transplant. The difference is maximal within the first 3 months of commencing dialysis, but remains significant for up to 2 years of dialysis therapy. 50 Despite the evidence that supports early referral to a nephrology unit, unfortunately, the incidence of late referrals has not diminished over the past 5 years and still accounts for more than 30% of patients who commence dialysis. 51 Approximately 25% of patients who enter end-stage renal failure programs in Australia and New Zealand commence dialysis late, 52 which is similar to European data, but the percentage is potentially higher in North American centers. 41,44,45,53 Despite European data to the contrary, 54 late referrals were surprisingly equally likely to occur in the younger and older population in Australia and New Zealand (ANZDATA), but this observation may be the result of patients coming

5 Early Start Peritoneal Dialysis e31 from socioeconomically disadvantaged areas. 55 The majority of late referrals occur in patients with known kidney disease. In a study that specifically assessed patients with a known history of kidney disease for more than 12 months but with no nephrologic contact for more than 90 days before the start of dialysis, a 37% increased risk of death occurred in the first year of dialysis. 56 Late referral for dialysis is not restricted to the adult population. Pediatric patients who commence dialysis late have poorer metabolic and clinical status compared with patients referred earlier for renal replacement therapy. 57 These studies emphasize the need for education among primary-care physicians and patients. Australian studies have highlighted that patients are more likely to be referred late if they come from a socially disadvantaged background. 55 Studies based in North America have demonstrated that patients who are black, uninsured, and have severe comorbidities are more likely to present for late evaluation. 58 Pediatric studies have demonstrated that women, nonwhite minority populations, and those without medical insurance are likely to start dialysis late 28 Clearly, physicians and patients resist early referral and the reasons underpinning these attitudes need to be more fully explored. Influence of Predialysis Management Referral to a nephrologist has a positive impact on metabolic and hematologic parameters, on a planned start of dialysis, on consideration for preemptive transplantation, and on management of comorbidites (Table 1). 50,58 63 Additionally the opportunity exists to implement strategies to delay the progression of kidney failure and to reduce the overall burden of illness in the population. In the study by Kessler and coworkers, 41 more prolonged predialysis care was positively associated with a higher hemoglobin and albumin and more stable calcium and phosphate control. The lack of an arteriovenous fistula at the start of hemodialysis decreases survival. 64 The value of a mature access and avoidance of a temporary or permanent catheter is reinforced Table 1. Potential Benefits of Early Referral to a Nephrologist Metabolic and Hematologic Parameters Regulation of calcium, phosphate, and parathyroid hormone homeostasis Correction of metabolic acidosis Correction of anemia with appropriate attention to erythropoetic-stimulating agents and iron therapy Nutritional advice Planned Transition to Renal Replacement Therapy Informed choice of dialysis modality Timely placement of access (peritoneal catheter of arteriovenous fistula) Planned commencement of dialytic therapy Assessment of the appropriateness of preemptive transplantation Social supports in place Management of Nonrenal Risks Appropriate blood pressure management Assessment and management of vascular disease and heart failure by DOPPS data 47 that showed commencing dialysis with catheter access increased mortality by 62%, which was only exceeded if dialysis commenced at 75 years of age or older, with congestive heart failure or with HIV/ AIDS. Despite enthusiasm for early nephrology referral, studies suggest that almost 60% of patients seeing nephrologists commence dialysis with a serum albumin less than 35 g/l, 58 and anemia management is less than optimal. 59 Recent data suggest that an experienced nurse practitioner, working to dedicated protocols, is more likely to achieve the desired outcomes than is referral to a service in which multiple nephrology trainees are responsible for patient care. 65 Furthermore, referral to a multidisciplinary clinic is likely to be more effective in achieving outcomes than is referral to a single nephrologists. 66 Implementation of a predialysis clinical pathway in Melbourne, Australia has recently been shown to reduce the percentage of inadequately prepared patients commencing dialysis from 29% to 6% and the corresponding median time from registration to commencement of dialysis from less than 1 month to 14 months. The proportion of patients commencing dialysis with permanent vascular access increased proportionately from 24% to 83%. 67 The observed improvement was the result of a

6 e32 Pollock, Cooper, and Harris multidisciplinary approach, rather than referral to a nephrologist per se. Conclusions The reasons underpinning the timing of initiation and mode of dialysis in patients with end-stage chronic kidney disease are complex. Clearly a proportion of patients will present late, and the opportunity to consider the timing of dialysis is limited. Improved education of patients and physicians to date has had limited impact on the problem of late referrals. A dedicated approach to the smooth transition onto dialysis improves outcomes. Whether this approach includes the early initiation of dialysis will be defined by the results of the IDEAL Study. References 1. McCusker FX, Teehan BP, Thorpe KE, et al: How much peritoneal dialysis is required for the maintenance of a good nutritional state? Canada-USA (CANUSA) Peritoneal Dialysis Study Group. Kidney Int 56:S56-S61,1996 (suppl) 2. Tattersall J, Greenwood R, Farrington K: Urea kinetics and when to commence dialysis. Am J Nephrol 15: , Bonomini V, Feletti C, Scolari MP, et al: Benefits of early initiation of dialysis. Kidney Int 17:S57-S59, 1985 (suppl) 4. Bonomini V, Feletti C, Stefoni S, et al: Early dialysis and renal transplantation. Nephron 44: , Jungers P, Zingraff J. Albouze G, et al: Late referral to maintenance dialysis: Detrimental consequences. Nephrol Dial Transplant 8: , Sesso R, Belasco AG: Late diagnosis of chronic renal failure and mortality on maintenance dialysis. Nephrol Dial Transplant 11: , Traynor JP, Simpson K, Geddes CC, et al: Early initiation of dialysis fails to prolong survival in patients with end-stage renal failure. J Am Soc Nephrol 13: , Cooper BA, Branley P, Bulfone L, et al: The Initiating Dialysis Early and Late (IDEAL) study: Study rational and design. Perit Dial Int 24: , NKF-DOQI: Clinical practice guidelines and clinical practice recommendations for diabetes and chronic kidney disease. Am J Kidney Dis 49:S12-S154, 2007 (suppl 2) 10. The initiation of dialysis. Nephrol Dial Transplant 20:ix3-ix7, 2005 (suppl 9) 11. Churchill DN, Blake PG, Jindal KK, et al: Clinical practice guidelines for initiation of dialysis. Canadian Society of Nephrology. J Am Soc Nephrol 10:S289- S291, 1999 (suppl) 12. Kelly J, Stanley M, Harris D: The CARI Guidelines: Acceptance into Dialysis Guidelines. Nephrology 10: S46-S60, 2005 (suppl 4) 13. Obrador GT, Arora P, Kausz AT, et al: Level of renal function at the initiation of dialysis in the U.S. endstage renal disease population. Kidney Int 56: , Russ GR: ANZDATA Registry Report Australia and New Zealand Dialysis and Transplant Registry; Woodville, South Australia. 15. Churchill DN, Taylor DW, Keshiviah PR; Canada- USA (CANUSA) peritoneal dialysis study group: Adequacy of dialysis and nutrition in continuous peritoneal dialysis: Association with clinical outcomes. J Am Soc Nephrol 7: , Kazmi WH, Gilbertson DT, Obrador GT, et al: Effect of co-morbidity on the increased mortality associated with early initiation of dialysis. Am J Kidney Dis 46: , Beddhu S, Samore M, Roberts M, et al: Impact of timing of initiation of dialysis on mortality. J Am Soc Nephrol. 142: , Levey AS, Bosch JP, Lewis JB, et al: A more accurate method to estimate glomerular filtration rate from serum creatinine: A new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med 130: , Pollock CA, Ibels LS, Zhu FY, et al: Protein intake in renal disease. J Am Soc Nephrol 8: , Cooper BA, Aslani A, Ryan M, et al: Nutritional state correlates with renal function at the start of dialysis. Perit Dial Int 23: , Keshaviah PR, Emmerson PF, Nolph KD: Timely initiation of dialysis: A urea kinetic approach. Am J Kidney Dis 33: , Mehrotra R, Nolph KD: Treatment of advanced renal failure: Low protein diets or timely initiation of dialysis? Kidney Int 28: , Jansen MAM, Korevaar JC, Dekker FW, et al, on behalf of the NECOSAD Study Group: Renal function and nutritional status at the start of chronic dialysis treatment. J Am Soc Nephrol 12: , McLaughlin K, Manns B, Donaldson C, et al: An economic evaluation of early versus late referral of patients with progressive renal insufficiency. Am J Kidney Dis 38: , Termorshuizen F, Korevaar JC, Dekker FW, et al, for the NECOSAD Study Group: Time trends in the initiation and dose of dialysis in end-stage renal disease patients in The Netherlands. Nephrol Dial Transplant 18: , Mehrotra R, Lee J, Elivera H, et al: Trends in initiation of dialysis in an urban dialysis clinic in the United States: A long way from dialysis outcomes quality initiatives. Adv Perit Dial 15: , Korevaar JC, Jansen MA, Dekker FW, et al: Evaluation of DOQI guidelines: Early start of dialysis treatment is not associated with better health-related quality of life. Am J Kidney Dis 39: , Seikaly MG, Salhab N, Browne R: Patterns and time of initiation of dialysis in US children. Pediatr Nephrol 20: , 2005

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Khan SS, Xue JL, Kazmi WH, et al: Does predialysis nephrology care influence patient survival after initiation of dialysis. Kidney Int 67: , Schwenger V, Morath C, Hofmann A, et al: Late referral a major cause of poor outcome in the very elderly dialysis patient. Nephrol Dial Transplant 21: , Cass A, Cunningham J, Snelling P, et al: Urban disadvantage and delayed nephrology referral in Australia. Health Place 9: , Avorn J, Bohn RL, Levy E, et al: Nephrologist care and mortality in patients with chronic renal insufficiency. 162: , Jander A, Nowicki M, Tkaczyk M, et al: Does a late referral to a nephrologist constitute a problem in children starting renal replacement therapy in Poland? A nationwide study. Nephrol Dial Transplant 21: , Obrador GT, Ruthazer R, Arora P, et al: Prevalence of and factors associated with suboptimal care before initiation of dialysis in the United States. 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8 e34 Pollock, Cooper, and Harris 63. Kinchen KS, Sadler J, Fink N, et al: The timing of specialist evaluation in chronic kidney disease and mortality. Ann Int Med 137: , Ortega T, Ortega F, Diaz-Corte C, et al: The timely construction of arteriovenous fistulae: A key to reducing morbidity and mortality and to improving cost management. Nephrol Dial Transplant 20: , Lee W, Campoy S, Smits G, et al: Effectiveness of a chronic kidney disease clinic in achieving K/DOQI guideline targets at initiation of dialysis a single centre experience. Nephrol Dial Transplant 22: , Levin A, Lewis M, Mortiboy P, et al: Multidisciplinary predialysis programs: quantification and limitations of their impact on patient outcomes in two Canadian settings. Am J Kidney Dis 29: , Owen JE, Walker RJ, Edgell L, et al: Implementation of a pre-dialysis clinical pathway for patients with chronic kidney disease. Int J Qual Health Care 18: , 2006