ICURT PROCEEDINGS

Timing of Dialysis Initiation: When to Start? Which Treatment? Paul Leurs, MD, PhD,*,† Anna Machowska, MSc,† and Bengt Lindholm, MD, PhD† During the late 1990s early initiation of dialysis was introduced on a large scale and between 1996 and 2008, the percentage of patients with an estimated glomerular filtration rate (eGFR) above 10 mL/minute starting dialysis rose from 25% to 54% in the United States. However, several subsequent studies showed no survival benefit for patients commencing dialysis earlier. One possible explanation for the negative results could be that eGFR may be a flawed index; s-creatinine is lower in patients with muscle wasting or fluid overload and these vulnerable patients with high comorbidity burden often start ‘‘early’’, i.e., at higher eGFR. Another explanation could be that dialysis is in fact harmful; dialysis initiation with conventional thrice weekly in-center hemodialysis clearly associates with increased initial mortality risk especially when using temporary dialysis catheters. Interestingly, patients starting on peritoneal dialysis (PD) appear to have better initial outcomes. More attention should be given to finding new objective mortality-predictive markers of uremia, reducing the use of temporary hemodialysis catheters, and increasing the use of PD as initial dialysis modality. PD may not only provide better initial dialysis outcomes but may also preserve renal function and vessels for vascular access for the benefit of better long-term outcomes. Ó 2015 by the National Kidney Foundation, Inc. All rights reserved.

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N PATIENTS WITH chronic kidney disease (CKD), the risk of all-cause and cardiovascular mortality increases with decline in renal function, especially when the glomerular filtration rate (GFR) decreases below 60 mL/minute.1 As patients with CKD are more likely to die than progress to renal replacement therapy,2 one may ask whether the high mortality risk in patients with CKD stages 4 to 5 can be reduced by earlier dialysis initiation. On the other hand, if the dialysis procedure is associated with factors leading to increased risk of morbidity and mortality,3 what is the added risk by starting dialysis earlier rather than later and would in fact earlier dialysis initiation instead increase the mortality risk? In this review, we briefly discuss these questions and some of the factors that could influence the decision on when to start dialysis and the choice of dialysis treatment modality.

Early Dialysis Initiation: Not as Good as Previously Thought In the past, and still during the 1980s, resources for dialysis therapy were lacking, and dialysis was in general *

Department of Nephrology, Admiraal de Ruyter Hospital, Goes, The Netherlands. † Renal Medicine and Baxter Novum, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden. Financial Disclosure: Baxter Novum is the result of a grant from Baxter Healthcare Corporation to the Karolinska Institutet. B.L. and A.M. are affiliated with Baxter Healthcare. P.L. does not declare any conflicts of interest. Address correspondence to Bengt Lindholm, MD, PhD, Baxter Novum and Renal Medicine, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, M99 Karolinska University Hospital Huddinge, 141 86 Stockholm, Sweden. E-mail: [email protected] Ó 2015 by the National Kidney Foundation, Inc. All rights reserved. 1051-2276/$36.00 http://dx.doi.org/10.1053/j.jrn.2014.10.015

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initiated only when patients demonstrated clear signs of life-threatening uremic complications. In 1985, Bonomini et al4 from Bologna, Italy, reported that earlier initiation of dialysis could convey survival benefits; patients, who started dialysis early at a mean creatinine clearance rate of 11 mL/ minute, had a higher survival rate than those who started late at a clearance rate of less than 5 mL/minute. Although this report did not appear to influence dialysis initiation practices much, the publication of the Canada–USA study5 in 1996, which reported that survival was greater in patients starting peritoneal dialysis (PD) with a higher residual renal function (RRF) resulted in major changes. Based on the observation in the Canada–USA study that a total (peritoneal plus renal) removal of urea corresponding to Kt/V .2.0 per week associated with improved survival, the US National Kidney Foundation-Dialysis Outcomes Quality Initiative working group on the initiation of dialysis therapy in 1997 proposed that the adequacy target for dialysis patients not yet on dialysis should not fall below this threshold.6 Predialysis patients should have RRF equal to a GFR of 10.5 mL/minute or more (corresponding to weekly Kt/V .2.0); if this cut-off point was not achieved, the patients should be started on dialysis6 This policy led to a major change in the timing of dialysis initiation practices in the United States and—although to a lesser extent—also in other countries. Thus, in the United States, between 1996 and 2008, the percentage of patients starting dialysis with an estimated GFR (eGFR) above 10 mL/minute rose from 25% to 54%, and the percentage of patients initiating dialysis at an eGFR above 15 mL/minute increased from 4% to 17%.7 After these dramatic changes in the timing of dialysis initiation practices, several large observational studies were performed comparing outcomes in patients starting dialysis at

Journal of Renal Nutrition, Vol 25, No 2 (March), 2015: pp 238-241

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various levels of eGFR. These studies included large numbers of patients; in some cases, more than 800,000, in registry-type data sets, including the United States Renal Data System (USRDS), Bureau of National Health Insurance in Taiwan, European Registry, the French Renal Epidemiology and Information Network Registry, and the Canadian Organ Replacement Registry as well as one randomized study, the Initiating Dialysis Early and Late (IDEAL) study.7,8 However, perhaps unexpectedly, these studies showed that an early start of dialysis had no beneficial effect7-10 or even resulted in a worse outcome1113 ; starting dialysis at lower levels of eGFR (5 ‘‘late start’’) thus appeared to be associated with lower mortality. Altogether, these studies indicated that early start of dialysis especially when using in center-hemodialysis (HD) as initial therapy could be harmful and questioned the trend to early dialysis initiation based primarily on eGFR; the clinical status of the patients, besides eGFR levels, should also be taken into account in the decision making process. Furthermore, a meta-analysis concluded that the outcome after dialysis initiation was not only affected by GFR and patient characteristics but also appeared to associate with the type of dialysis modality used; interestingly, although early dialysis initiation using in-center HD associated with worse outcomes, this was not a consistent finding when PD was used as initial therapy.13

Possible Factors That May Explain Lack of Favorable Effect of Early Dialysis Initiation When analyzing factors explaining why starting dialysis early appear to be harmful, first of all, it should be noted that observational studies do not–and cannot—prove that starting dialysis with higher eGFR is indeed causing the observed worse outcomes. One important confounder is that patients are only included in studies if they actually started dialysis; only the fittest patients survive long enough to be included in the late start groups; this is the survivor bias. Furthermore, among patients who survived long enough to take part in these studies, those with symptoms or comorbidities are more likely to be started on dialysis early. In addition, eGFR based on s-creatinine may overestimate true GFR in the latter patients who may have a low s-creatinine concentration because of low muscle mass or fluid overload, or both; these patients who have an increased high mortality risk due to frailty and comorbidities are likely to be started ‘‘earlier’’ at a higher eGFR level. In a study based on the Nederlands Co-operative Study Adequacy of Dialysis treatment cohort, it was reported that although patients with lower eGFR had worse survival than those with higher eGFR at start of dialysis, such a survival difference was not seen when comparing the same patients according to their levels of renal function based on measured GFR; muscle mass was found to associate with eGFR but not with measured GFR.14

Another reason is that eGFR–or any index based on creatinine (or urea)—may be a poor predictor of the concentrations for a broad range of uremic toxins. Thus, because eGFR is poorly associated with concentrations of uremic toxins in patients with different degrees of CKD and correlates differently with each individual solute, eGFR cannot be considered representative for evaluating the accumulation of solutes in the course of CKD.15 Furthermore, although eGFR (or measured GFR) is not a good predictor of the concentrations of uremic solutes or their biological action, other factors may be more important such as tubular secretion of toxins, generation of toxins by the intestinal flora, and the metabolism of toxins.15 Because of the association between nutritional status and eGFR and the other reasons mentioned previously, there is now consensus that renal function estimated by screatinine (eGFR) may be useless or even misleading as a sole guide on when to start dialysis.

Harmful Effects of Dialysis Another reason why early dialysis initiation could associate with worse outcomes could be that the dialysis procedure is harmful. Dialysis, and especially conventional intermittent thrice-weekly HD, leads to an accelerated loss of RRF, a powerful predictor of mortality in CKD patients. The rate of RRF loss should therefore be an important consideration for the timing of the dialysis initiation decision and the choice of initial dialysis modality; several studies have shown that RRF is better preserved in terms of slower rate of decline in GFR and a longer time to loss of RRF in patients treated with PD compared with those treated with conventional thrice weekly HD. Furthermore, dialysis introduces the risk of access-related infections, a powerful predictor of worse outcomes, induces an inflammatory response and—especially when using intermittent dialysis—leads to unphysiological fluctuations in solutes and fluid that increase the risk for sudden cardiac death, the most common cause of death in dialysis patients according to USRDS data. In fact, mortality increases markedly during the first month after initiation of HD suggesting possible harmful effect of the dialysis procedure as such or complications caused by dialysis.12 Potential biological factors contributing to poor outcomes on early dialysis initiation in HD and PD may be more often associated with HD than with PD.9 Furthermore, mortality during the initial years after start of dialysis was found to be similar or better with PD than with in-center HD.16 A propensity-matched mortality comparison of 6,337 incident HD–PD patient pairs showed that survival from the first day on dialysis was 8% higher for PD patients than for HD patients (hazard ratio 0.92; 95% confidence interval 0.86-1.00; P 5 .04).17 Furthermore, the latest USRDS report shows that the first year mortality rate (in year 2010) was much lower in patients initiating dialysis with PD than with HD even when adjusting for age, gender, race, and primary diagnosis;

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Table 1. Timing of Dialysis Initiation: When Should Dialysis Should Be Started? Which Treatment? Planning for dialysis initiation  Early referral to nephrologist is essential for planning initial dialysis modality;  Planning for timely placement of dialysis access; use of dialysis catheters for HD is associated with high mortality risk. When should dialysis be started?  If uremic symptoms and signs are getting worse in patient with GFR ,15 mL/min/1.73 m2;  Dialysis is usually indicated when GFR is 5 to 9 mL/min/1.73 m2, if the patient has uremic symptoms and signs;  But, there is no single criterion. Which treatment? If no contraindications and if it is feasible and patient is able/willing: 1. renal transplantation, 2. home-based dialysis therapy, and, as last choice, 3. in-center hemodialysis; thrice weekly conventional HD is no longer the norm.

furthermore, there has been a dramatic improvement of the first year (and the second year) survival rates in patients starting on PD.18

Current Recommendations on Dialysis Initiation What have been the lessons learned and the impact of the IDEAL study and the many observational studies showing no benefit of early start of dialysis? First of all, it should be noted that the dissemination of the results from these studies have made an impact as according to USRDS, the accelerating trend toward earlier and earlier initiation of dialysis appears to have stopped after 2010.18 Secondly, there is now consensus that no specific level of kidney function defined by an estimation of GFR based on serum creatinine should direct timing of the initiation of dialysis. The European Renal Best Practice advisory board have concluded that eGFR is not useful in determining need for dialysis, that a GFR of 6 mL/minute/1.73 m2 is no longer seen as an absolute lower limit to starting dialysis, and that there may still be time preparing patients for home dialysis therapy although GFR is low.10 Investigators from the United States suggest that dialysis initiation is usually indicated at GFR levels of 5 to 9 mL/minute/1.73 m2 if accompanied by uremia symptoms or fluid management issues (Table 1), but there is no single criterion.19 Third, it should be noted that early versus late dialysis initiation does not equal early versus late referral to nephrology referral in CKD; early nephrology referral is reported to associate with reduced mortality and hospitalization, better uptake of PD, and earlier timely placement of arteriovenous fistula for HD.20

Summary and Future Directions Multiple factors need to be taken into account when determining the optimal moment at which dialysis should be started to optimize the prognosis; timing of dialysis initiation should not be determined solely based on eGFR. eGFR is influenced by muscle mass and overhydration and does not provide a good measure of uremic toxicity. Therefore, there is a need for novel mortality-predictive markers of

uremia including perhaps also protein-bound solutes such as indoxyl sulfate and p-cresyl sulfate21; such novel markers may potentially improve guidance on when to start dialysis in the future. Still, however, clinical assessment of the patients appears to remain the most important decision tool according to a survey among European nephrologists on factors influencing the decision to start renal replacement therapy.22 But, there is a scarcity of studies documenting the exact reason(s) why a particular patient was initiated on dialysis at a particular time; such studies are much needed. We await further such studies on factors involved in the decision making to start dialysis as in the European Quality Study on when dialysis should be initiated.23 Also, the effect of different dialysis modalities appear to be important; using conventional thrice weekly HD therapy as initial dialysis therapy associates with a substantial increase of mortality risk compared with PD. Finally, it should be noted that although early dialysis initiation may not be associated with improved survival, early referral to nephrology care may not only improve outcomes in terms of morbidity and mortality but also leaves enough time for implementation of an appropriate dialysis access and allows patients and their caregivers to choose the most appropriate initial dialysis modality. Conventional thrice weekly in-center HD is clearly not an ideal initial dialysis modality (Table 1). Alternative approaches including more frequent HD and home-based therapies (both PD and home HD) are promising24 and according to the most recent USRDS report these modalities are being increasingly used in the United States.18

References 1. Matsushita K, van der Velde M, Astor BC, et al. Association of estimated glomerular filtration rate and albuminuria with all-cause and cardiovascular mortality in general population cohorts: a collaborative meta-analysis. Lancet. 2010;375:2073-2081. 2. Keith DS, Nichols GA, Gullion CM, et al. Longitudinal follow-up and outcomes among a population with chronic kidney disease in a large managed care organization. Arch Intern Med. 2004;164:659-663. 3. Collins AJ, Foley RN, Gilbertson DT, et al. The state of chronic kidney disease, ESRD, and morbidity and mortality in the first year of dialysis. Clin J Am Soc Nephrol. 2009;4(suppl 1):S5-S11.

INITIATION OF DIALYSIS 4. Bonomini V, Feletti C, Scolari MP, et al. Benefits of early initiation of dialysis. Kidney Int Suppl. 1985;17:S57-S59. 5. 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. 1996;7:198-207. 6. NKF-KDOQI clinical practice guidelines. Am J Kidney Dis. 1997;30(3 suppl 2):S67-S136. 7. Rosansky SJ, Clark WF, Eggers P, et al. Initiation of dialysis at higher GFRs: is the apparent rising tide of early dialysis harmful or helpful? Kidney Int. 2009;76:257-261. 8. Cooper BA, Branley P, Bulfone L, et al. A randomized, controlled trial of early versus late initiation of dialysis. N Engl J Med. 2010;363:609-619. 9. Molnar MZ, Ojo AO, Bunnapradist S, et al. Timing of dialysis initiation in transplant-naive and failed transplant patients. Nat Rev Nephrol. 2012;8:284-292. 10. Tattersall J, Dekker F, Heimb€ urger O, et al. When to start dialysis: updated guidance following publication of the Initiating Dialysis Early and Late (IDEAL) study. Nephrol Dial Transplant. 2011;26:2082-2086. 11. Wright S, Klausner D, Baird B, et al. Timing of dialysis initiation and survival in ESRD. Clin J Am Soc Nephrol. 2010;5:1828-1835. 12. Rosansky SJ, Eggers P, Jackson K, et al. Early start of hemodialysis may be harmful. Arch Intern Med. 2011;171:396-403. 13. Susantitaphong P, Altamimi S, Ashkar M, et al. GFR at initiation of dialysis and mortality in CKD: a meta-analysis. Am J Kidney Dis. 2012;59:829-840. 14. Grootendorst DC, Michels WM, Richardson JD, et al. The MDRD formula does not reflect GFR in ESRD patients. Nephrol Dial Transplant. 2011;26:1932-1937.

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15. Eloot S, Schepers E, Barreto DV, et al. Estimated glomerular filtration rate is a poor predictor of concentration for a broad range of uremic toxins. Clin J Am Soc Nephrol. 2011;6:1266-1273. 16. Mehrotra R, Chiu YW, Kalantar-Zadeh K, Bargman J, Vonesh E. Similar outcomes with hemodialysis and peritoneal dialysis in patients with end-stage renal disease. Arch Intern Med. 2011;171:110-118. 17. Weinhandl ED, Foley RN, Gilbertson DT, Arneson TJ, Snyder JJ, Collins AJ. Propensity-matched mortality comparison of incident hemodialysis and peritoneal dialysis patients. J Am Soc Nephrol. 2010;21:499-506. 18. United States Renal Data System, 2014 Annual Data Report: Epidemiology of Kidney Disease in the United States. National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 2014. www.usrds.org. Accessed December 4, 2014. 19. Rosansky S, Glassock RJ, Clark WF. Early start of dialysis: a critical review. Clin J Am Soc Nephrol. 2011;6:1222-1228. 20. Smart NA, Titus TT. Early versus late nephrology referral in CKD: a systematic review. Am J Med. 2011;124:1073-1080. 21. Niwa T. Targeting protein-bound uremic toxins in chronic kidney disease. Expert Opin Ther Targets. 2013;17:1287-1301. 22. van de Luijtgaarden MW, Noordzij M, Tomson C, et al. Factors influencing the decision to start renal replacement therapy: results of a survey among European nephrologists. Am J Kidney Dis. 2012;60:940-948. 23. Jager KJ, Ocak G, Drechsler C, et al. The EQUAL study: a European study in chronic kidney disease stage 4 patients. Nephrol Dial Transplant. 2012;27(suppl 3):iii27-iii31. 24. Lindholm B, Davies S. End-stage renal disease in 2010: timing of dialysis initiation and choice of dialysis modality. Nat Rev Nephrol. 2011;7: 66-68.

Timing of dialysis initiation: when to start? Which treatment?

During the late 1990s early initiation of dialysis was introduced on a large scale and between 1996 and 2008, the percentage of patients with an estim...
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