Extended hours hemodialysis and survival: extended hours, extended evidence?

Extended hours hemodialysis and survival: extended hours, extended evidence?

commentary Extended hours hemodialysis and survival: extended hours, extended evidence? Ron Wald1,2 and Jeffrey Perl1,2 Extended-hours hemodialysis p...

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Extended hours hemodialysis and survival: extended hours, extended evidence? Ron Wald1,2 and Jeffrey Perl1,2 Extended-hours hemodialysis presents another approach to the intensification of therapy for maintenance hemodialysis recipients. Smaller studies have demonstrated several potential benefits with this modality, but the impact on patient-centered outcomes has been unclear. We review the largest published study to compare survival among patients who received extended-hours hemodialysis with those who received conventional hemodialysis. Kidney International (2016) 90, 1155–1157; http://dx.doi.org/10.1016/j.kint.2016.09.007 Copyright ª 2016, International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

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onventional hemodialysis (CHD), which consists of 3- to 4-hour sessions delivered 3 times per week, is entrenched as the central pillar of maintenance hemodialysis (HD) care in developed countries. In contemporary practice, CHD session duration has traditionally been guided by surpassing a threshold for urea clearance rather than the consideration of the wider benefits afforded by treatment time prolongation.1 The recognition that CHD is an inadequate substitute for endogenous kidney function and the high morbidity and mortality observed in dialysis recipients have stimulated interest in HD intensification. Intensification has entailed increasing the frequency of sessions, the duration of sessions, or both of these parameters. Given the logistic challenges of accommodating prolonged or frequent sessions in the HD unit and the desire of some patients to self-manage their care, intensive HD often involves transfer to a home-based dialysis modality. 1 Division of Nephrology, St. Michael’s Hospital and the University of Toronto, Toronto, Canada; and 2Li Ka Shing Knowledge Institute of St. Michael’s Hospital, Toronto, Canada

Correspondence: Ron Wald, Division of Nephrology, St. Michael’s Hospital, 61 Queen Street East, 9-140, Toronto, Ontario, M5C 2T2, Canada. E-mail: [email protected] Kidney International (2016) 90, 1146–1163

The wide adoption of intensified HD regimens has been stymied by a variety of factors. Reliance on the home setting, where patients must self-manage all aspects of their HD treatment, is a major deterrent for many individuals. As a result, home HD has remained a potential option for an exceedingly small segment of the global end-stage renal disease population. Short, daily in-center HD requires the patient to attend 5 to 6 times per week, which many might find disruptive. Moreover, clinical trials of intensified dialysis modalities have been of relatively short duration, yielded mixed results, and have largely used surrogate endpoints.2–4 It is therefore difficult to convince patients that dialysis intensification in any form has a sustained impact on relevant clinical outcomes. Extended-hours HD, also known as in-center nocturnal HD highlighting administration during the overnight hours, entails thrice weekly HD for 6 to 8 hours per session. The effective doubling of dialysis time as compared with CHD comes with the benefits of more effective solute removal and lower ultrafiltration rates with the advantage of supervision within a facility environment. The overnight sessions facilitate patient employment, education, and engagement in other productive daytime activities. The introduction of

an extended-hours HD program enables an HD facility at maximum capacity to accommodate more patients without the infrastructure costs of additional HD equipment and physical space. Notwithstanding these conceivable advantages, definitive evidence that extended-hours HD improves survival has been lacking. Within a cohort of 136,207 adults who commenced dialysis between 2007 and 2011, Rivara et al.5 (2016) compared the outcomes of 1206 patients who received extended-hours HD for at least 60 days with 111,707 patients who received CHD exclusively. Extendedhours HD sessions were on average 6.7 hours in duration as compared with 3.5 hours for CHD sessions; both modalities were administered thrice weekly. Marginal structural modeling, which considered a patient’s likelihood of receiving a given dialysis modality as well as the likelihood for being censored during any 90-day interval, was used to account for the inevitable differences between patients receiving extendedhours HD and CHD. Weights to account for the administered HD modality were constructed by accounting for a variety of baseline comorbidity and demographic variables as well as timevarying variables such as previous dialysis history and laboratory data. Adjusted mortality while receiving extended-hours dialysis was 33% lower as compared with CHD. The findings remained robust in a wide array of sensitivity analyses including those that accounted for a lag effect of modality on death, the attribution of all deaths in anyone who had ever received extendedhours HD to this modality, and the local availability or nonavailability of extended-hours HD. This study examined the largest cohort of extended-hours HD recipients to date. It confirms the findings of other groups that showed a mortality benefit with extended-hours HD.6 Recognizing that patients who chose or are selected for extended-hours HD are likely to differ from those remaining on CHD, Rivara et al. used sophisticated analytic techniques to mitigate the impact of confounding and to capture the 1155

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inherently dynamic nature of a patient’s “voyage” through maintenance dialysis, which often involves multiple modality changes; such changes are related to evolving comorbidities and fluctuations in laboratory parameters which were analyzed as time-dependent covariates. Patients in this cohort were also followed up for up to 5 years, far longer than in previous studies in this area.6,7 Although difficult to completely elucidate from the data provided, there are several potential mechanisms to plausibly invoke a causal link between extended-hours HD and lower mortality. Extended-hours HD has been associated with a regression of left ventricular mass, a well-accepted surrogate for mortality and a widely used outcome in HD intensification trials.7,8 Assuming patients are judicious in their interdialytic sodium and fluid intake, the longer treatment times with overnight dialysis will generally lead to a reduction in the hourly ultrafiltration rate.6 The more gentle ultrafiltration afforded by extended-hours dialysis will minimize hemodynamic instability and permit the safe and complete removal of excess volume. As shown with all intensified regimens, extended-hours HD results in consistent reductions in serum phosphate concentration, thus providing the means of lowering a biomarker that has been associated with mortality.6–8 Prolonged dialysis will also result in the enhanced removal of a wider spectrum of solutes, including those with a higher molecular weight. However, the work by Rivara et al. also highlights the challenge of interpreting nonrandomized comparative effectiveness studies of dialysis modalities. The baseline characteristics strongly suggest that individuals who received extended-hours HD had a significant preponderance of some features that would augur a favorable prognosis (younger age, black race, higher body mass index) but also important comorbidities (diabetes, cardiovascular disease) that might portend worse outcomes. Although it is difficult to dissect how these opposing factors might collectively influence patient survival, there are several unmeasured 1156

factors that will persistently confound the relationship between dialysis modality and survival. Because overnight extended-hours HD will attract patients who are seeking to preserve employment opportunities, such programs will be a natural choice for young working patients, a highly select subgroup of the wider HD population that would tend to have a more favorable prognosis. Furthermore, a patient’s mere willingness to accept an intensified dialysis schedule might reflect a degree of selfmotivation, an intangible but highly potent contributor to favorable health outcomes. Adopting a regimen that involves longer session duration is a major commitment on the part of the patient. It is plausible that this decision correlates with greater health literacy, self-advocacy, and other healthpromoting behaviors (e.g., adherence to medications and diet). In the absence of an extended-hours program, such patients might do equally well on CHD. Finally, no information is provided about the dialysis provider’s policy, if one existed, regarding a patient’s eligibility for extended-hours HD. Given the late-night arrival and early-morning departure, as well as the possibility of lower staffing during the overnight hours, units might be understandably reluctant to allow their most vulnerable patients such as those with significant frailty or with cognitive impairment to receive extended-hours HD. Finally, the very availability of extended-hours HD at a given facility might have been a surrogate for other high-quality facilitybased patient care practices. Collectively, these factors likely explain the markedly lower crude mortality on extended-hours hemodialysis as compared with CHD (6.4 vs. 14.7 deaths/100 patient-years). Although this association was substantially attenuated in the adjusted analysis, even the most robust statistical strategy cannot completely account for the aforementioned confounders. How does this study impact the way clinicians counsel patients regarding dialysis intensification? Although data from a randomized trial would be ideal to provide clinicians and patients with a

definitive evidence base to support treatment decisions, we are concerned that such a trial may never take place. The failure of the Frequent Hemodialysis Network Nocturnal Trial to recruit its relatively modest target sample size for a trial based on surrogate outcomes, as well as aborted attempts to randomize patients to HD versus peritoneal dialysis, highlights the reluctance of patients to allow themselves to be randomized to treatment strategies that have such differing implications for their lifestyle.3,9 A trial that is designed to demonstrate a benefit on objective patient-relevant outcomes (i.e., survival, cardiovascular events) will likely require over 3000 patients with follow-up of at least 3 years. Given the high attrition from extended-hours dialysis observed in the study by Rivara et al., the sample size of such a trial would need to be inflated even further to account for expected crossovers. In the absence of clinical trial data on the imminent or long-term horizon, our practice is to carefully identify CHD recipients who are most likely to benefit from dialysis intensification (Table 1). These include patients with the following array of challenges on CHD: persistent volume overload, predialysis hypotension, frequent intradialytic hypotension, difficulty achieving small molecule adequacy, severe refractory hyperphosphatemia, and those with barriers to maintaining employment or pursuing education opportunities. Similarly, patients enjoying the benefits of intensified home HD but who are struggling with the burden of self-care should be considered for in-center Table 1 | Potential benefits of hemodialysis intensification Lower ultrafiltration rate Better small- and middle-molecule clearance Enhanced phosphate removal Regression of left ventricular hypertrophy Enhanced blood pressure control Improved quality of life Unique features of extended-hours hemodialysis Approximate doubling of dialysis time versus conventional hemodialysis Access to full care in the hemodialysis unit Administration during overnight hours

Kidney International (2016) 90, 1146–1163

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extended hours HD. All dialysis recipients, and especially those nearing dialysis, should receive individualized and comprehensive education about the array of modalities that might be available and feasible. This entails frank discussions about the conceivable benefits, shortcomings, and unknowns associated with each modality, including peritoneal dialysis and home HD. Dialysis units should optimally have the flexibility to allow patients a trial of a given intensified modality for a defined period (e.g., 2–4 weeks) with a firm option of returning to CHD if the trial is found to be unsatisfactory. In this regard, understanding the reasons for which many patients switch from extended-hours HD to a different modality (44% in the current study) is crucial. In conclusion, the study by Rivara et al. presents intriguing new data on the conceivable benefits of extended-hours HD.5 The suggestion of improved survival is yet another reason why this modality could represent an attractive option for some dialysis recipients. However, given the inherent shortcomings of the study, clinicians should be cautious in the way this treatment option is presented to patients. A balanced approach rooted in patient-centeredness should always govern discussions pertaining to dialysis modality and the potential value of dialysis intensification. DISCLOSURE

All of the authors declared no competing interests. REFERENCES 1. National Kidney Foundation. KDOQI Clinical Practice Guideline for Hemodialysis Adequacy: 2015 update. Am J Kidney Dis. 2015;66:884–930. 2. Culleton BF, Walsh M, Klarenbach SW, et al. Effect of frequent nocturnal hemodialysis vs conventional hemodialysis on left ventricular mass and quality of life: a randomized controlled trial. JAMA. 2007;298:1291–1299. 3. Rocco MV, Lockridge RS Jr., Beck GJ, et al. The effects of frequent nocturnal home hemodialysis: the Frequent Hemodialysis Network Nocturnal Trial. Kidney Int. 2011;80: 1080–1091. 4. Chertow GM, Levin NW, Beck GJ, et al. In-center hemodialysis six times per week versus three times per week. N Engl J Med. 2010;363:2287–2300. 5. Rivara MB, Adams SV, Kuttykrishnan S, et al. Extended-hours hemodialysis is associated with Kidney International (2016) 90, 1146–1163

lower mortality risk in patients with end-stage renal disease. Kidney Int. 2016;90:1312–1320. 6. Lacson E Jr., Xu J, Suri RS, et al. Survival with three-times weekly in-center nocturnal versus conventional hemodialysis. J Am Soc Nephrol. 2012;23:687–695. 7. Ok E, Duman S, Asci G, et al. Comparison of 4- and 8-h dialysis sessions in thrice-weekly in-centre haemodialysis: a prospective, case-controlled study. Nephrol Dial Transplant. 2011;26:1287–1296.

8. Wald R, Goldstein MB, Perl J, et al. The association between conversion to in-centre nocturnal hemodialysis and left ventricular mass regression in patients with end-stage renal disease. Can J Cardiol. 2016;32: 369–377. 9. Korevaar JC, Feith GW, Dekker FW, et al. Effect of starting with hemodialysis compared with peritoneal dialysis in patients new on dialysis treatment: a randomized controlled trial. Kidney Int. 2003;64:2222–2228.

Talking back: the podocytes and endothelial cells duke it out Agnes B. Fogo1 Thrombotic microangiopathy has numerous causes and may result in chronic kidney disease with secondary glomerulosclerosis. Detailed analyses of this interplay of lesions have been lacking. Buob et al. report on their adult, mostly Caucasian patients, showing frequent sclerosis, most often of collapsing type, with worse prognosis than in those without segmental scars. The complex interplay of glomerular cells and possible ways in which the endothelial cells may talk back to the podocytes, and vice versa, are discussed. Kidney International (2016) 90, 1157–1159; http://dx.doi.org/10.1016/j.kint.2016.08.031 Copyright ª 2016, International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

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he kidney is a magnificently complex organ with numerous highly specialized cells, which communicate with each other to effect normal renal excretory function and maintenance of whole organisms’ homeostasis, and in response to injury. Within the glomerular tuft, there are 3 resident cell types: podocytes, mesangial cells, and glomerular endothelial cells, which also may communicate with the parietal epithelial cells that line Bowman’s capsule. Complex communications between these cells allow 1 Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA

Correspondence: Agnes B. Fogo, Department of Pathology, Microbiology and Immunology, MCN C3310, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA. E-mail: agnes. [email protected]

numerous crosstalk and resulting injury patterns, which culminate in a finite number of patterns recognized by morphologic observations, with overlapping and/or distinct pathogenetic mechanisms. The extracellular matrix of the glomerular basement membrane is dynamically contributed to by both endothelial cells and podocytes, and also serves as a reservoir for signaling molecules that modify responses in health and injury. Thus, it is not surprising that injuries commencing in one kidney cell type can influence other cell types. Thrombotic microangiopathy (TMA) is the term used to describe a morphologic lesion with thrombosis within small vessels, which in the kidney predominantly affects the glomerulus and arterioles. In the early phase after injury, TMA morphologically manifests by fibrin 1157