Preparing for Hemodialysis

C H A P T E R

70 Preparing for Hemodialysis Robert T. Isom, Glenn M. Chertow Stanford University School of Medicine, Division of Nephrology, Palo Alto, CA, United States

Abstract Decisions regarding the initiation of renal replacement therapy (RRT)dwhether hemodialysis (HD), peritoneal dialysis, kidney transplantation, or palliative care is chosendare critical when considering combined efforts among nephrologists, patients, family members, and nonphysician health care personnel. The transition from management of progressive chronic kidney disease (CKD) to that of end-stage renal disease (ESRD) requires the nephrologist to have a clear understanding of the disease trajectory in the individual patient and to function as a teacher for the patient and members of the patient’s family, as well as for their professional and social networks. These functions involve an understanding of the patient both as an individual and as a member of a social milieu and require an appreciation of the patient’s culture, spirit, and belief systems. Although all therapeutic choices facing patients with advanced CKD have advantages and disadvantages, many of the steps in the transition to ESRD care are common to all the choices. In particular, recent advances in clinical science (based on evidence derived from observational studies and clinical trials) allow the nephrologist to advise patients regarding appropriate timing of initiation of RRT and factors related to successful creation of vascular access, which will promote the best health outcomes. The nephrologist, while delivering complex care at the time of a crucial transition, plays a key role in determining whether the start of RRT with HD will be characterized by a “smooth landing” or a “crash landing,” ultimately by serving as a coordinator of education and multidisciplinary consultation.

INTRODUCTION Patients with all forms of progressive chronic kidney disease (CKD) whose glomerular filtration rate (GFR) is expected to decline within their lifetime, to the point where life-threatening manifestations of advanced uremia are expected to develop, have a number of treatment and management options to consider. The different forms of renal replacement therapy (RRT) include hemodialysis (HD), peritoneal dialysis (PD), and kidney transplantation (KTx). The choice of RRT modality Chronic Renal Disease, Second Edition https://doi.org/10.1016/B978-0-12-815876-0.00070-X

should be tailored to the individual patient. The choice is generally based on a combination of medical and surgical comorbidities, anticipated life expectancy, psychosocial factors, and patient preference. KTx, when possible, remains the preferred treatment modality for almost all patients with end-stage renal disease (ESRD). Kidney transplant recipients, in aggregate, enjoy prolonged life expectancy and enhanced quality of life relative to patients undergoing either HD or PD.1 However, when transplantation is not an option for an individual patient, or if not available preemptively (before the initiation of dialysis), the patient and his or her nephrologist must decide between planning for PD, HD, or, in selected circumstances, emphasizing a more conservative, nondialytic approach. Palliative nephrology implies nonprovision of RRT in situations where, because of a patient’s cumulative comorbidities (or less commonly due to patient choice), dialysis of any type tends to provide only limited prolongation of life or functional rehabilitation, such that symptombased, comfort-directed measures may be more appropriate.2,3 For most younger (and healthier) patients with ESRD, goals of dialysis include prolongation of life expectancy and service as a bridge to KTx. For many older patients, however, dialysis itself is palliative care, in that its principal objective is to relieve symptoms rather than to necessarily prolong life. Planning for dialysis requires convincing a patient that he or she will derive meaningful quality and prolongation of life by submitting him or herself to an intrusive, mechanical form of support for a failing organ system, without which uremic symptoms and eventually death would ensue. The first step in this process involves educating the patient about the role of the kidneys in maintaining health and the anticipated effects on the patient’s health and survival associated with different degrees of impaired kidney function. The nephrologist cannot assume that the patient understands the roles of the kidneys in maintaining health or

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what signs and symptoms might develop in an individual patient as kidney function declines. (Indeed, even an experienced nephrologist may be fooled by patientto-patient variation in the expression and timing of symptoms.) The nephrologist must tailor his or her information delivery based on the patient’s intellectual capacity, educational background, culture, hopes for and fears about the future, and fixed beliefs, to integrate complex medical concepts. Not all patients, for example, can grasp the concept of estimated glomerular filtration rate (eGFR), although this parameter is increasingly noted on laboratory reports, and many patients will present for nephrology consultation with the chief complaint of having been told of a “low eGFR” by their referring internal medicine or family medicine physician, physician assistant, or nurse practitioner. Confusion surrounding parameters of kidney function, whether eGFR or serum creatinine concentration (S[Cr]), can place the nephrologist in an awkward position because the terms “glomerular” and “filtration” are foreign to most laypersons, and addressing the concern of a “low eGFR” to a patient’s full satisfaction may compel the nephrologist into a discussion of renal microanatomy, including details on the structure and function of the glomerulus. How else might a patient be able to understand what “eGFR” means? Understandably, without even a cursory discussion of this concept, patients may leave the consultation room still wondering, “What does my low eGFR actually mean?” Or, they may question “What is a glomerulus?” Some patients may be able to integrate this degree of physiologic discussion, if communicated skillfully by the nephrologist. For others, it may be more helpful to tell them to disregard the term “eGFR” and focus instead on something more tangible, such as “the kidneys’ percent ability to filter waste products” (conveniently, because an eGFR of 100 mL/min is not far off an expected, “normal” value for a young to middle-aged person). Ultimately, in terms that he or she can understand, the patient needs to learn that progressive CKD is associated with substantial morbidity and symptomatology, and if untreated in its most advanced form, is a lethal condition. Bearing in mind the patient’s cognitive function, capacity to understand, attention, cultural background, and ability to integrate medical terminology, the nephrologist must explain the different forms of RRT, emphasizing that these are treatments, not cures, for ESRD. Indeed, it is not unusual for a patient with ESRD to arrive for his or her first HD session and ask how long it will take for his or her kidneys to get better. Or he or she may ask, understandably, “Is there anything I can do to make my creatinine go down?” Many patients are understandably reluctant to go along with the recommended planning phases in preparation for dialysis initiation. Patients may repeatedly

delay or outright refuse dialysis planning. The idea of being tethered to a machine several times a week for necessary life support may seem painful, unnatural, overly time-consuming, and unacceptable. Although they may already have advanced CKD, patients are often free of the typical signs and symptoms of uremia, such that the stated benefits of dialysis (prolonging life and relieving symptoms), when viewed against the perspective of the hardships of the planned dialysis modality, remain abstract and difficult for a layperson to embrace. The first step in planning for HD, therefore, involves educating the patient and his or her sources of social support regarding the role of the kidneys in maintaining health and the anticipated impact of a progressive decline in kidney function on the patient’s health status and life expectancy. If the patient’s CKD is expected to progress to end-stage, he or she must be educated regarding the potential health benefits that would realistically be expected from dialysis. Patients should also have a good understanding of the trade-offs that would be encountered after they have started dialysis, in terms of dietary restriction, time commitment to the procedure, and subsequent impact on the lifestyle and occupation they may currently enjoy, as well as the physiologic limitations of what dialysis is and is not able to correct. The concept of “RRT” must be carefully explained to the patient, because HD and PD, strictly speaking, do not replace kidney function in its entirety. Although dialysis may diminish high serum levels of potassium, acid and by-products of nitrogenous (ingested protein) and muscle metabolism, it fails to correct a variety of reabsorptive, excretory, secretory, endocrine, metabolic, antiinflammatory, and other functions of the kidneys. As a result, even when patients are fully adherent with their prescribed dialysis regimen, they typically do not experience the comprehensive physiologic and lifestyle rehabilitation that only transplantation affords. In other words, although dialysis sustains life, it typically fails to restore health. When caregiver and patient agree on eventual provision of dialysis, a choice must be made between HD and PD. Although long-term survival among patients receiving HD and PD are generally similar, the argument has been made that when possible from the technical and psychosocial points of view, the initial modality of choice for most patients should be PD.4,5 This view is based on the observation that PD is associated with improved quality of life and patient independence, is less costly on an annual basis than HD, and is associated with longer preservation of residual kidney function. This is important because as is well known to nephrologists, maintenance of residual kidney function is associated with improved fluid and blood pressure control, phosphate and middle molecule clearance,

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INTRODUCTION

nutritional status, left ventricular hypertrophy and cardiovascular (CV) risk, decreased inflammatory markers, and prolonged survival.6e8 When the nephrologist and patient do agree on future implementation of HD as the optimal and preferred RRT modality, many factors must be addressed during the course of the patient’s declining kidney function, to allow optimization of outcomes at the time of initiation of HD, as well as during the ensuing months and years of maintenance therapy. We make the distinction to patients between a “smooth landing” and a “crash landing,” where crash landing may involve emergency hospitalization of the patient with decompensated uremic symptoms, severe metabolic disarray, pulmonary edema, possibly uremic pericarditis, and without preexisting vascular access, necessitating placement of a temporary vascular catheter, often in a critical care setting by less-experienced personnel. Outcomes under these circumstances are generally poordhospitalizations may be lengthy and costly, infection rates from emergency catheter placement are high, and long-term patient rehabilitation from having started dialysis in extremis, with globally decompensated signs and symptoms of uremia, may be suboptimal. Causes of a crash landing may include (a) lack of primary medical care and/or the patient being unaware of his or her disease until it becomes symptomatic, (b) late referral to nephrology services from the patient’s primary care provider, (c) the patient’s inability to come to terms with the progressive nature of his or her disease, leading to failure to follow the nephrologist’s recommendations, or (d) failure by the nephrologist and his or her treatment team to have a structured, guideline-based approach to management of the pre-ESRD patient. Ideally, preparation of the patient for HD should result in meeting several conditions. From the educational point of view, patients and families should have a reasonable understanding of the functional and symptomatic consequences of progressive kidney failure. They should also have a good understanding of the various modalities of RRT, with the eventual modality choice being tailored to the individual circumstances, taking into account medical and surgical comorbidities, age and projected life expectancy, lifestyle and occupation, social support system, and personal choice. Patients should have a reasonable set of expectations regarding what HD can and cannot replace for the failing kidneys. Patients should have a clear understanding of the scheduling and logistic requirements that will be expected of them and how new dietary restrictions will be imposed on them. For selected patients, because of either advanced age or other significant comorbid conditions, there should be an understanding that a palliative, conservative, symptom-based, and comfort-based approach may be reasonable.

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Appropriate measures to slow the progression of the patient’s CKD should be in place, targeting the underlying etiology of the patient’s CKD, potential implementation of a protein-restricted diet, and ongoing use (or de novo implementation) of inhibitors of the renine angiotensinealdosterone system (RAAS), even in late stage CKD. Importantly, with the newer generation potassium-binding agents now available, nephrologists should feel more emboldened to continue RAAS blockade further into the trajectory of a given patient’s CKD, without the fear of encountering critically significant hyperkalemia.9e12 The patient’s nutritional and functional status should be optimized. Guidelines regarding treatment of the anemia of CKD should be adhered to, with the goal of avoiding blood product administration before or at the time of dialysis initiation, particularly if patients are deemed to be (or will likely be considered) acceptable kidney transplant recipients. Because of the heightened risk of CV morbidity and mortality associated with moderate to advanced CKD and ESRD, modifiable risk factors for CV disease should be optimized, including coronary revascularization if significant, reversible ischemic heart disease is present. For those patients deemed to be medically and otherwise suitable for transplantation, they should, ideally, be seen and evaluated by a local transplant center and listed for eventual transplantation as soon as feasible. This should occur well before the actual time of dialysis initiation because an eGFR of 20 mL/min/1.73 m2 or less qualifies a patient for transplant listing with the United Network for Organ Sharing (UNOS). Waiting to refer for transplantation until dialysis is initiated, when eGFR is much lower than 20 mL/min/1.73 m2, essentially “robs” the patient of valuable waiting time (sometimes on the order of years, for those with more slowly progressive forms of nephropathy) that they could otherwise accrue on the deceased donor waiting list. Waiting to refer patients for transplantation until dialysis has been initiated will therefore produce the unintended effect of prolonging the waiting time for eventual transplantation, and potentially exposing patients to the interval development of dialysis-associated morbid events, not uncommonly rendering them subsequently unsuitable for transplantation. We recommend referral for transplantation when the eGFR is between 20e25 mL/min/1.73 m2 so that medical and psychosocial evaluations can be completed, the patient tentatively approved, and subsequently listed as soon as the referring nephrologist documents an eGFR consistently below 20 mL/min/1.73 m2 during serial monitoring. Perhaps most importantly, the patient should have a functional, permanent vascular access in place when HD is initiated. This requires early referral to a vascular

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surgeon, usually at least 4e6 months in advance of the anticipated time of starting HD. This provides sufficient time to allow maturation of a newly placed native arteriovenous fistula (AVF) (usually 3e6 months). Early vascular surgery referral also allows for the relatively high rate of primary failure of newly placed AV fistulae, leading to the need for repeated interventional procedures and/or revision surgeries to facilitate maturation of the fistula. If the first fistula created fails to develop in spite of optimal interventional support, the surgeon will need to place a new fistula at another site or place an arteriovenous graft (AVG) instead. Although fistulae are clearly preferable to grafts in terms of infectious risk and durability, both are vastly preferable to catheters, which are associated with the highest risks of infection, venous stenosis, and subclinical and clinically overt venous thromboembolic disease, including superior vena cava syndrome. As the steps outlined above are being followed, the nephrologist needs to formulate an ever-refined estimate of the time when HD will need to be initiated for the patient. This requires an appropriate schedule for laboratory monitoring, with attention focused most importantly on the patient’s evolving S[Cr] and eGFR, but with careful attention also being paid to serum potassium concentration, acidebase balance, serum phosphate concentration, and hemoglobin/hematocrit concentrations. From the clinical point of view, the patient should be seen at appropriate intervals by either the nephrologist or an advanced practice provider, so that a focused, renal-specific review of systems and physical examination can assess potential development of incipient signs or symptoms of uremia, which would prompt initiation of dialysis. If the above approach is followed, the patient should be able to initiate HD on an elective, outpatient basis. If eligible, patients should already be listed for KTx. The hemoglobin concentration should be at targets set by Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines, without blood transfusions. Patients should have a functional permanent vascular access, preferably an AVF. Patients should be free of severe, decompensated signs or symptoms of advanced kidney failure that would prompt emergent hospitalization for dialysis initiationdsuch as refractory hyperkalemia, encephalopathy, severe hypertension, congestive heart failure, or serositis (especially pericarditis). The considerations outlined, when properly adhered to, increase the likelihood of safe and successful initiation of HD, when the nephrologist has reached the conclusion that for the individual patient, benefits of dialysis have begun to outweigh the risks associated with the procedure, and that from the patient’s point of view, the lifestyle burden that maintenance dialysis will place on him or her and the family, when viewed

against the perspective of worsening symptoms and/ or death without provision of dialysis, now becomes acceptable. Patient education, CV risk factor management, anemia management, vascular access placement, and timing of the initiation of HD are all critical to patient care. Some of the issues touched on above, though relevant to the management and planning stages of dialysis preparation (such as delaying the progression of disease and the details of kidney transplant planning), are outside the scope of this chapter.

PATIENT EDUCATION A distressing and repeated observation is that the majority of patients starting HD have not been through a formal pre-ESRD teaching program designed to prepare them for transition to initiation of dialysis. Many patients report not having been made aware of modality choices other than thrice weekly in-center HD, including self-care in-center HD, home HD, nocturnal HD, PD, or KTx. The information gap regarding CKD and its treatment modalities appears more pronounced among African Americans.13,14 The majority of patients starting HD in the US continue to begin treatment with a central venous (tunneled) catheter, as opposed to a permanent arteriovenous vascular access, whether native vein or synthetic graft. Nevertheless, it has been repeatedly observed in multiple studies that formal pre-ESRD educational programs for patients and families result in a higher percentage of patients opting for home-based therapies; a higher percentage of patients beginning treatment with a mature, functioning vascular access, and more favorable nutritional status (assessed by S[Alb] or other parameters) at the time of dialysis start; and decreased need for emergent, hospital-based initiation of treatment, fewer hospitalizations at one year, and overall cost savings per patient during the first year of dialysis.15e21 Several studies have also demonstrated improved survival among patients managed before the initiation of dialysis by multidisciplinary approaches aimed at educating the patient regarding modality choice, dietary interventions, blood pressure control, and emphasis on timely vascular access placement.20,22,23 Devins et al. reported 20-year follow-up of a cohort of patients who had been randomized in the mid-1980s to predialysis psychoeducational interventions aimed at increasing patients’ knowledge of CKD and its treatment vs. usual care. These investigators found that patients who received predialysis CKD education survived a median of over 2 years longer than those assigned to usual care. Following initiation of dialysis, survival was 8 months

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CARDIOVASCULAR RISK FACTOR MANAGEMENT

longer in those having received CKD education, compared to the usual care group.24 Barriers to implementation of such predialysis educational programs are not clear, but probably include a combination of physician and institutional inertia, and the perception that implementation of such programs may prove prohibitively costly. Nevertheless, because of the evidence supporting implementation of such programs on patient outcomes and ESRD program-wide costs, the Centers for Medicare and Medicaid Services (CMS) has implemented financial incentives to foster growth of such programs. It is hoped that with ongoing, cumulative evidence demonstrating enhanced patient outcomes and cost savings, comprehensive predialysis patient education programs will become increasingly prevalent and become standard of care. Comprehensive education regarding treatment options in ESRD should not neglect a discussion of possible conservative, nondialytic management, such as nonprovision of RRT. However, when given a choice between prolongation of life with maintenance dialysis and nonprovision or RRT (which in nearly all patients with progressive CKD would temporally hasten their demise) most patients opt for dialysis, even bearing in mind the hardships associated with the procedure. For example, for the very elderly patient with advanced CKD or persons with multiple, significant comorbidities (e.g. active, metastatic cancer), especially when functional status is impaired and life expectancy correspondingly limited, conservative, nondialytic management focused on symptom control may be more appropriate. Kurella Tamura et al. published a study in which functional capacity and mortality were examined in a national cohort (n ¼ 3702) of nursing home residents initiating dialysis. Mortality one year after initiation of dialysis was a staggering 58%. Initiation of dialysis was associated with functional decline, regardless of the patient’s “functional trajectory” (the ability to perform activities of daily living) during the 3 months preceding initiation of dialysis. One year after starting dialysis, only one in eight patients maintained or improved his or her functional status relative to the start of dialysis.25 Elderly patients with multiple comorbidities who initiate HD have a higher likelihood of dying in an acute care facility, often in a critical care setting. The choice of conservative, nondialytic management for patients with progressive CKD recognizes that some patients may prefer a shorter life expectancy, with fewer procedures, less time-consuming therapies, and equivalent or improved quality of life.26 The choice of conservative, nondialytic management in advanced CKD implies an understanding between patient and provider that on the one hand, lack of provision of dialysis is likely to be associated with shortened

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life expectancy. How much so, of course, depends on the disease trajectory of the individual patient. Moreover, pursuing conservative, nondialytic management ideally should result in a concerted effort between the patient and a dedicated nephrology-sensitive palliative care team to address the many symptoms that inevitably develop as kidney function declines. Murtagh et al. reported on a UK-based cohort of 66 elderly patients with stage 5 CKD being managed conservatively. The mean age was 82 years, and mean eGFR was 11 mL/ min/1.73 m2. The most common symptoms reported by patients were fatigue, pruritus, dyspnea, edema, generalized pain, muscle cramps, restless leg syndrome, diminished appetite, inability to concentrate, and sleep disturbance.27 An individual office-based nephrologist, acting alone, cannot reasonably be expected to successfully address the many day-to-day issues that come up during the progressive decline of such patients. Students and trainees commonly form the notion that death from untreated uremia is a “slow, peaceful” way to die. As practitioners, we rarely have encountered such situations where patients seem to slip painlessly and quietly into a comatose state and then expire. More commonly, the terminal event in untreated uremiadespecially among those not followed closely in CKD clinic or who fail to adhere to dialysis planningdis either sudden cardiac death in the setting of electrolyte imbalance (for example hyperkalemia) or the more distressing picture of acute pulmonary edema. A carefully structured approach by a palliative care team well-versed in the specific needs of the patient with stage 5 CKD can address most of the symptoms such patients are likely to develop. Most importantly, with judicious use of diuretics, vasodilators, and narcotic analgesics (of which low-dose oxycodone, hydromorphone, and fentanyl may be best tolerated), it should be possible to alleviate the particularly troublesome signs and symptoms of volume overload leading to pulmonary edema, which might otherwise prompt patients (and distressed, on-looking family members) to reverse a deliberately decidedupon course and request emergency care including acute dialysis.28

CARDIOVASCULAR RISK FACTOR MANAGEMENT CV events account for more than 50% of premature deaths among patients receiving HD, including in particular heart failure, stroke, and sudden cardiac death. The excess burden of CVD applies to the predialysis population as well. Nephrologists caring for the patient with advanced CKD need to have a heightened awareness of the excess CV risk in this patient

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population. Where possible, nephrologists must address modifiable risk factors, so that as kidney function declines and the patient approaches the need for dialysis, mortality, and morbidity associated with CV risk can be attenuated. The last several years have seen an increased awareness of the contribution of nondialysis-requiring CKD, even at its early stages (albuminuria, or mild reductions in eGFR), to increased CV risk. Moreover, the association remains strong even in the absence of traditional risk factors such as diabetes, hypertension, dyslipidemia, and smoking.29 Foley et al. reported on a 5% sample of the US Medicare population (n ¼ 1,091,201), examining the relation between CKD and diabetes mellitus with respect to CV risk, defined as atherosclerotic heart disease, congestive heart failure, and overall mortality risk. Patients were divided into four groups: those without either diabetes or CKD (79%), those with diabetes but no CKD (16%), those with CKD but no diabetes (2.2%), and those with both diabetes and CKD (1.4%). Over a 2-year follow-up period, rates per 100 patient-years for developing atherosclerotic heart disease, heart failure, and all-cause mortality were higher for patients with CKD and no diabetes (35% vs. 25%, 30% vs. 18%, and 17% vs. 8%, respectively). For patients with both diabetes and CKD, event rates were higher still at 49%, 52%, and 19%, respectively.30 These findings were confirmed in a recent large Canadian study (n ¼ 1,268,029), again examining the interplay between diabetes and CKD, with regard to CV risk, specifically risk of myocardial infarction (MI), with the reference group against which DM and CKD risk were compared being those with prior MI. Risk of MI was highest in patients with prior MI, regardless of DM or CKD status. Here also, CKD proved to be a stronger predictor for MI than diabetes. In patients with more advanced CKD (GFR <45 mL/min/1.73 m2), or heavy proteinuria (>300 mg/g creatinine), the risk of MI was roughly twice that compared to the group with diabetes but without CKD (12.4 vs. 6.6 events per 1000 patientyears).31 Thus, the presence of CKD alone appears to be a stronger predictor of CV events and all-cause mortality than diabetes mellitus. The presence of both conditions is associated with even higher risk, particularly for atherosclerotic disease and heart failure. This risk of CVrelated mortality has been shown in multiple studies to increase exponentially as GFR declines, even applied to the earliest stages of CKD.32e34 The causes of this increased CV risk remain incompletely understood. In the CKD population, it has been estimated that traditional risk factors for CV-related morbidity and mortality account for only about 50% of risk.35 CKD-specific physiologic derangements contributing to this increased risk of CV events are still only

partially understood. Factors such as increased sympathetic hyperactivity, resistant hypertension, left ventricular hypertrophy, proteinuria and associated hypercoaguable states, oxidative stress, inflammation, malnutrition, and the effects of disordered mineral bone metabolism (hyperphosphatemia, vitamin D deficiency, and abnormal circulating levels of fibroblast growth factor-23 and soluble klotho), leading to vascular calcification and left ventricular hypertrophy, are believed to contribute to this risk.36e46 Preparation of the patient with advanced CKD for HD, therefore, involves early and careful attention on the nephrologist’s part toward treatment and optimization of modifiable risk factors that have been shown in well-designed studies (nearly all of which were implemented in patients with normal, near normal, or only mildly impaired kidney function) to reduce CV risk. Goals of management should be aimed at decreasing CV events during the evolution of CKD progression, preserving CV health during later stages of CKD, and to the extent that multiple CV risk factors also affect progression of CKD (such as hypertension, diabetes, and smoking), trying to delay progression of CKD where possible. As the patient approaches the time for planning RRT, the nephrologist should have a thorough knowledge of the patient’s CV status, including left and right ventricular function, ischemic burden, presence or absence of left ventricular hypertrophy, history of heart failure, and the presence or absence of significant valvular heart disease, as these may influence dialysis modality choice and help the clinician envision a dialysis regimen that optimizes hypertension control and minimizes risk of heart failure, stroke, atrial and ventricular arrhythmia, endocarditis, and sudden death. Although much has been learned over the past few decades regarding the putative mechanisms of increased CV risk in CKD, the relative contributions of these various physiologic derangements, and their interactions, remain areas of intense investigation, and many questions remain unanswered. Care must be taken to interpret available and emerging data to provide an evidence-based rationale for treatment aimed at reducing CV risk. What data from well-designed clinical trials can help guide the nephrologist during the care of the patient with progressive CKD to alleviate CV risk? The few CV clinical trials conducted specifically in patients with moderate to advanced CKD have focused on slowing progressive loss of kidney function. Few have focused on modification of CV risk. Indeed, most of the evidence on which we base our practice comes either from extrapolation of clinical trials conducted in the general population or from subgroup analyses of larger clinical trials.47

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The Study of Heart and Renal Protection trial, addressing the treatment of hypercholesterolemia, randomized 9270 patients (6247 with nondialysisrequiring CKD and 3023 with ESRD) to simvastatinezetimibe vs. placebo. Active cholesterol-lowering resulted in a 17% (95% CI 6e26%) reduction in the rate of major atherosclerotic events (nonfatal MI, nonhemorrhagic stroke, any arterial revascularization, or coronary death). Results remained statistically significant in patients with stage 4 CKD (corresponding rate reduction 22%, 95% CI 2e38%).48 Several subgroup analyses of heart failure trials have demonstrated consistent benefits of beta-adrenergic antagonists and inhibitors of the RAAS among patients with and without CKD, although few patients in these trials had advanced CKD.49e52 The net benefits and risks of aspirin and other antiplatelet agents in patients with advanced CKD are unknown. In a post hoc subgroup analysis of the Hypertension Optimal Treatment trial, CV events were reduced by 66% (95% CI 33e83%) and mortality was reduced by 49% (95% CI 6e73%) in patients treated with aspirin. Major bleeding events were modestly increased. A recent meta-analysis conducted by the Blood Pressure Lowering Treatment Trialists’ Collaboration pooled randomized clinical trials completed between 1995 and 2012 that compared two or more active blood pressuree lowering medications, active medications with placebo, or different targets for blood pressure lowering, aiming to determine the importance of blood pressure lowering (and the specific agents used) on CV outcomes. The primary outcome of the meta-analysis was major CV events, defined as the first episode of stroke, coronary heart disease, heart failure, and CV death. Of more than 150,000 participants from 25 clinical trials, 20% had CKD, defined as an eGFR below 60 mL/min/ 1.73 m2. Results showed statistically significant and substantial lowering of CV risk with blood pressure lowering, with no obvious difference by antihypertensive drug class. Unfortunately, fewer than one-half of one percent of patients included in this meta-analysis had eGFR below 30 mL/min/1.73 m2 at baseline.53 Although the evidence is relatively sparse, based on the data outlined above and our clinical experience, we usually advise the use of low-dose aspirin, statins, and antihypertensive therapy for CV risk reduction in patients with advanced CKD preparing for dialysis or KTx. We generally favor the use of RAAS inhibitors in combination with diuretic agents and/or betaadrenergic antagonists, given the potential to attenuate progression and the frequency with which we observe coincident volume overload and heart failure. We generally consider calcium channel blockers, alphaadrenergic antagonists, and other drugs as third or

fourth or fifth line agents for patients with refractory hypertension or other associated health conditions (such as benign prostatic hyperplasia with urinary retention). We recommend mindful limitation of salt intake, despite the confusion and ambiguity introduced with the recent Institute of Medicine report.54

ANEMIA MANAGEMENT We address certain points regarding the use of erythropoiesis stimulating agents (ESAs) and other agents to correct anemia associated with CKD, as they pertain to the preparation of the patient-planning initiation of HD. The story of the discovery of erythropoietin (EPO), its physiologic regulation, and mechanisms of action (not just on erythrocyte precursors but on target organs throughout the body) is an ongoing and exciting one, with original discoveries pointing to the existence of a circulating, erythropoiesis stimulating factor in the serum, dating to the end of the 19th century.55,56 The cloning of the EPO gene,57,58 followed soon after by the introduction of the use of recombinant human EPO to treat the anemia associated with ESRD59,60 revolutionized the field of clinical nephrology by greatly reducing the need for frequent red blood cell transfusions in patients receiving dialysis. Recognized complications of the frequent transfusions included transmission of infectious diseases (HIV and hepatitis B and C virus infections), systemic iron overload leading to hepatic and cardiac dysfunction, and anti-HLA allosensitization. Clinical use of ESAs eventually extended to the population of patients with nondialysis-requiring CKD, so that symptomatic anemia could be averted and allowing initiation of dialysis under conditions not requiring transfusion. The optimal target hematocrit or hemoglobin concentration has been a matter of much debate over the past several years, due to the unexpected findings of increased CV morbidity associated with higher hemoglobin concentrations, although specific adverse CV events have not been consistently observed in different trials. The reason(s) for CV morbidity related to ESA use is still a matter under intense investigation.61e63 We consider that optimal medical management of the patient with advanced CKD approaching HD should result, among other things, in the patient not requiring blood product administration during the course of their CKD leading up to dialysis initiation. More specifically, this recommendation applies to patients who meet criteria for future KTx. Not uncommonly, patients with limited or inadequate access to comprehensive CKD management eventually present with advanced uremia in the terminal phases of CKD, often accompanied by

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severe, symptomatic anemia, prompting transfusion when hospitalized and dialysis is initiated. Soon after the broad introduction of transplantation in the 1960s and 1970s, it was recognized that prior blood transfusion during a patient’s period of dialysis requirement resulted in the development of immune sensitization against HLA antigens, and that this resulted in longer waiting times for transplantation. These effects were reversed following widespread implementation of ESAs, beginning after the approval of recombinant erythropoietin (epoetin alfa, or EPO) in the late 1980s. Grimm et al. reported on a group of five dialysisdependent pediatric patients who, after the introduction of EPO and the subsequent elimination of “chronic antigenic stimulation” from blood transfusions, demonstrated marked reductions in anti-HLA antibody titers and a mean reduction in percent panel reactive antibodies from 80% to 56%, while a control group matched for age, prior transfusion dependence, and sensitization status, showed no reduction in anti-HLA titer or percent PRA.64 Subsequently, Vella et al. reported on a cohort of patients receiving dialysis before and then four years after introduction of EPO. Compared to patients receiving dialysis in the pre-EPO era, these authors noted a decrease in the number of transfusions per dialysis treatment from 0.095 to 0.06, representing a relative reduction of 36%. They also found a decrease in the number of patients being sensitized from 63% to 28%, and a resultant decrease in mean waiting time to transplant from 42 to 15 months during that era (current waiting times are considerably longer).65 More contemporary methodologies for assessing antiHLA antibodies have confirmed these earlier findings and highlighted the extent, magnitude, and specificity of anti-HLA antibody formation resulting from transfusion in dialysis patients. Yabu et al. recently analyzed data on patients from our center, linking local data with the US Renal Data System (USRDS), comparing transfused and nontransfused patients awaiting primary KTx, and who had at least two HLA antibody measurements using the Luminex single-antigen bead assay (including before and after transfusion, in the transfused cohort). Twenty percent of transfused patients vs. 4% of nontransfused patients demonstrated an interval increase of at least 10 anti-HLA antibodies, meeting the cutoff of >3000 mean fluorescent intensity (MFI). Of the 50 transfused patients, 6 (12%) demonstrated an increase of 30 anti-HLA antibodies above an MFI of 3000.66 Such findings underscore the important adverse effect of blood product administration on HLA sensitization in patients with advanced CKD. It is during the weeks and months preceding the initiation of dialysis that these issues become paramount. Prolonged waiting time on the transplant list due to sensitized status from

blood transfusion exposes the patient to increased risks of dialysis-related morbid events (primarily CV and/or infectious), which not uncommonly render the patient subsequently unsuitable for transplantation. A recent review of published studies in the postcyclosporine era has confirmed the deleterious effects of transfusion on anti-HLA sensitization, time to transplantation resulting from sensitization, and increased risk of rejection and decreased overall graft survival among patients sensitized from prior transfusion.67 Modification of prioritization (the Kidney Allocation System) introduced in December 2014 aims to correct the disadvantages faced by sensitized patients awaiting KTx. Avoiding transfusion in the months and weeks preceding dialysis initiation, nevertheless, remains advisable. Increased CV morbidity in clinical trial participants targeted to higher hemoglobin or hematocrit targets, along with the changes in CMS reimbursement patterns implemented in 2011, have resulted in the majority of patients being maintained at lower hemoglobin concentrations. At least among patients receiving maintenance HD, lower target hemoglobin concentrations have resulted in a higher frequency of blood transfusions since that time. Findings from the Dialysis Outcomes and Practice Patterns Study indicated a more than doubling of blood transfusions from 2.21% of patients transfused per month in September 2010 to 4.87% of patients transfused per month in September 2011. Data in the US using Medicare claims showed a similar increase in transfusions following introduction of the Prospective Payment System (“bundling”) and modification of product labels for ESAs highlighting CV risks. Legitimate concern has grown that an unintended effect of these changes in practice will lead to more patients being transfused, and therefore at risk for sensitization, with consequent prolongation of time to transplantation.68 Extending these observations and considerations to the predialysis population, we recommend careful adherence to KDOQI guidelines regarding anemia management. Goals include avoiding the development of symptomatic anemia, preventing over-correction of anemia (which has been shown to be associated with higher CV risk and possibly accelerated decline of GFR), and readying the patient for HD without prior need for transfusion, to the extent that this may affect HLA sensitization status and adversely affect time to transplantation.

VASCULAR ACCESS MANAGEMENT Experienced nephrologists who care for patients with ESRD will readily recognize that issues surrounding vascular access represent the “Achilles heel” for the patient requiring HD (Table 70.1). Options for vascular

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VASCULAR ACCESS MANAGEMENT

TABLE 70.1

Complications of Vascular Access Catheters

All catheters Patient discomfort, cosmetic inconvenience, adhesive dressing allergic reactions Heightened mortality compared with patients initiated with noncatheter vascular access Internal jugular and/or subclavian catheter (tunneled and nontunneled) Internal jugular vein thrombosis Subclavian vein thrombosis / interference with placement of permanent upper extremity vascular access Superior vena cava syndrome Distal catheter tip clot with risk of pulmonary embolus Septic phlebitis Catheter-associated bacteremia with or without metastatic infection endocarditis paraspinal abscess vertebral osteomyelitis septic joint Exit site infection with or without tunnel infection (abscess) Pneumothorax Femoral vein temporary catheter Retroperitoneal bleeding Inadvertent femoral artery cannulation with pseudoaneurysm formation Lower extremity DVT

access in maintenance HD patients include the native AVF, synthetic AVGs, and central venous catheters (CVCs). Preparing the patient with advanced CKD for initiation of maintenance HD necessarily involves a careful, patient-centered approach to timely placement of a suitable vascular access that is ready for use when initiation of dialysis is indicated. When possible, creation of an AVF is the preferred form of vascular access because compared with AVGs and CVCs, AVFs are associated with greater long-term patency rates, decreased need for interventional procedures to maintain patency, decreased rates of infection, decreased rates of hospitalization, decreased overall cost, and, importantly, decreased patient mortality. AVGs do not technically require time to “mature” (i.e. arterialize), although it may take several weeks before local inflammation subsides and the graft can be safely cannulated with minimal discomfort. Some practitioners recommend several weeks of healing without cannulation to allow for migration of endothelial cells

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although the optimal timing of first graft cannulation is unknown. Relative to AVFs, AVGs are more prone to thrombosis and outflow stenosis due to neointimal hyperplasia, leading to the need sometimes for interventional procedures (often multiple) to reestablish and maintain patency. CVCs can be placed and be ready for use on a sameday basis when the patient starts HD, yet are associated with multiple short-term and long-term complications (Table 70.1). Infection remains the most important drawback of CVCs. CVC-associated infection can be in the form of a relatively straightforward exit site infection, subcutaneous tunnel infection (which essentially is an abscess-equivalent and generally requires removal of the catheter and sometimes surgical drainage of the infected collection), and catheter-associated bacteremia. HD CVCeassociated bacteremias are associated with substantial morbidity and mortality. Sepsis and septic shock may develop in the context of dialysis CVCassociated bacteremia. Metastatic infection including endocarditis, paraspinal abscess, vertebral osteomyelitis, and septic joint are relatively frequent complications of CVC-associated bacteremia. In addition to infectious complications, long-term use of CVCs is associated with development of other vascular complications, including subclavian and internal jugular vein thrombosis, leading to the need for systemic anticoagulation. Superior vena cava syndrome may also develop in patients using CVCs. These vascular complications subsequently render future placement of noncatheter forms of access far more difficult. These observations have led to several initiatives and guideline-based recommendations to encourage efforts at timely and successful placement of AVFs. Nevertheless, in the US, the most common form of vascular access in incident HD patients remains the CVC. Foley et al. analyzed data regarding type of vascular access at the time of initiation of dialysis in patients starting dialysis for the period June 2005 through October 2007 (n ¼ 220,157), obtained from the Centers for Medicare and Medicaid Services Medical Evidence Report (Form CMS-2728). Only 13% of patients began dialysis with a functioning AVF; 4% began with an AVG; 16% had a CVC with maturing fistula; 3.3% had a CVC with a maturing graft; and the majority, 63.2%, had a CVC alone. Compared with those patients beginning dialysis with a functioning fistula, adjusted mortality hazard ratios (HRs) were 1.39 for AVGs, 1.49 for catheter with maturing AVF, 1.74 for catheter with maturing AVG, and 2.18 for catheter alone.69 Bray et al. reported on a prospective cohort of all patients starting dialysis in Scotland for the years 2009 through 2011 (n ¼ 2666). Patients dialyzing through a CVC alone were found to have a higher risk of all-cause mortality, including that attributed to CV death as well as infectious causes.

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The odds of dying from sepsis were 6.9-fold higher among those dialyzing through a CVC compared with those using an AVF or AVG.70 A review of 67 cohort studies including 586,337 patients similarly demonstrated higher risks for all-cause mortality, fatal infections, and CV events in patients dialyzing with a CVC opposed to either AVG or AVF.71 A critique of many of the observational studies on the relation between vascular access type and mortality risk has centered on the issue of selection bias. Specifically, it is unclear whether or not underlying health status plays a role in eventual type of vascular access at the time of dialysis initiation, which in turn would account for mortality risk. Grubbs et al., looking at 117,277 patients starting dialysis from the USRDS for the period 2005e2007, examined the relation between functional status and number of hospital days in the 2 years prior to dialysis initiation, with respect to type of vascular access at dialysis initiation and subsequent mortality risk. Confirming results from other studies, these authors demonstrated increased mortality risk compared with patients starting dialysis with an AVF, among those starting with an AVG (HR 1.20), catheter plus maturing AVF (HR 1.34), catheter plus “maturing” AVG (HR 1.46), and catheter alone (HR 1.95). They also showed that functional status was strongly associated with access type at dialysis initiation, with previously “sicker” patients more likely to start dialysis with a CVC, whereas the “healthier” patients were more likely to have had a functioning AVF. Mortality risk therefore appears to be modulated not just by type of access at dialysis initiation, but by underlying health status, which in turn appears to correlate with eventual form of access placement.72 In addition to underlying health status predating initiation of dialysis, age at initiation of dialysis is strongly associated with type of initial vascular access and subsequent mortality risk. Although the studies cited above show heightened mortality risk associated with CVC use in all patients starting HD regardless of age, when stratified according to access type (highest risk in catheter alone > catheter with maturing AVG > catheter with maturing AVF > AVG alone > AVF alone), DeSilva et al. analyzed data on 115,425 patients above the age of 67. For patients aged 67e79 years, the HR for mortality among those with an AVG as opposed to AVF as first access placed was only marginally worse (HR 1.10), and there was no difference in patients 80 years or older.73 These results suggest that the net benefit of AVF in older patients is attenuated, possibly related to the lower fraction of AVFs maturing to clinical use. Even among those elderly patients whose AVF does successfully mature, the prolonged use of CVCs pending AVF maturation exposes patients to the many infectious and CV-related adverse events associated

with CVCs, such that the strategy in vascular access planning (at least for the elderly CKD patient) has shifted from “fistula first” to “catheter last.” The technical challenges in creating a functional native AVF appear to be more pronounced in the elderly. Several studies have shown a higher rate of primary nonfunction of native AVF placement as patients’ age increases, with the result that a higher percentage of such patients will arrive at the need for dialysis requiring either AVG, catheter with maturing AVG, or catheter alone.74,75 A growing concern is that strict adherence to KDOQI guidelines during ESRD planning in the stage 4 CKD population, when applied to the elderly, may result in an increased rate of failed attempts at AVF creation, while waiting for later placement of an AVG may be a reasonable approach. Moreover, depending on the age of the patient, underlying health status, and trajectory of the progression of CKD, there are many patients with late-stage CKD who die before requiring initiating dialysis, raising concern that many well-intended and guideline-based referrals for access placement in selected patients are futile and current practice should be reassessed. Death with a functional (but neverused) AVF or AVG is an outcome that should ideally be avoided.76,77 Careful consideration must therefore be paid to the patient’s age, life expectancy, and underlying functional status when planning vascular access. Although the “fistula first” initiative represents a sound approach to vascular access planning for younger patients and those with more robust underlying functional status, increasingly, emphasis is being placed on “catheter last,” particularly in the elderly, in whom primary placement of an AVG may be an acceptable option. The reader is referred to recent elegant reviews summarizing the dilemmas, particularly surrounding the issue of vascular access placement, faced by the nephrologist caring for the elderly CKD patient.78,79 We recommend a patient-centered approach, bearing in mind age and functional status, particularly as we care for an ever-growing population of elderly patients with late stage CKD, in whom the anticipated probability of death prior to need for initiation of dialysis, the inherently high failure rate of primary AVF placement, and what appear to be equivalent mortality outcomes between AVF and AVG, all need to be part of the decision-making process. In younger and more robust patients, because of the overwhelming evidence implicating CVC use as a cause of increased all-cause, infectious, and CV mortality, and because of the confirmed benefit in nonelderly patients of AVF over AVG, we recommend adhering to standard guidelines emphasizing early referral to vascular surgery, at least 6 months before anticipated need for dialysis initiation, to allow maturation of the AVF. This approach also takes into account the relatively high rates of primary access

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TIMING OF THE INITIATION OF HEMODIALYSIS

failure in AVFs, leading to the need for interventional procedures and/or revision surgery, such that ample time is allowed for maturation of a functional AVF at the time of dialysis start. Standard recommendations regarding avoidance of blood draws or IV placements above the wrist, where possible, should be adhered to, as well as avoiding placement of peripherally inserted central catheters, as these carry the risk of phlebitis and thrombosis, which can interfere with creation or placement of permanent vascular access in the affected arm.

TIMING OF THE INITIATION OF HEMODIALYSIS Once the patient and nephrologist have agreed on eventual initiation of maintenance HD, the patient will logically ask, “when should I begin?” Without meaning to be facetious, one might reply to the patient, “not too early, but not too late”dand this of course would be an accurate response. A more refined and articulate answer might be, “When the benefits of dialysis to your health and survival begin to outweigh the risks and hardships associated with the procedure.” The goal should be to preserve patient autonomy as long as possible, free of the requirement for maintenance dialysis and its many restrictions on lifestyle, as long as this does not expose the patient to either short-term or longterm morbidity (or mortality) that would result from lack of provision of dialysis. For most patients with progressive CKD, once they start dialysis, there is “no turning back” (ability to safely come off dialysis for an extended period of time). Therefore, our responsibility is to give our best recommendations to the patient based on science, where available; art, to the extent that there is no “one size fits all” answer to this question; and compassion, bearing in mind that institution of our treatment plan will have wide-ranging lifestyle consequences for the patient and his or her family. How do we come up with a more rational answer to this question? Is there high-quality evidence on which we can we rely to inform our recommendations? Ultimately of course, the timing of dialysis initiation must be tailored to the individual patient. A common question from patients is, “At what creatinine will I need to start dialysis?” The S[Cr], or its derived eGFR for the patient in question, is only one of many considerations that come into play when deciding on the timing of dialysis initiation. For example, not all patients predictably develop dialysis-responsive uremic symptoms at the same level of eGFR. Occasionally, patients with relatively preserved eGFR (e.g. >10 mL/min/1.73 m2) and lack of traditional uremic symptoms may have problems with volume management and recurrent

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hospitalizations for pulmonary edema in spite of maximal medical therapy, due to significant comorbid structural heart diseasedmost commonly left ventricular hypertrophy with diastolic dysfunction, systolic heart failure, or pulmonary hypertension with severe right-sided congestive symptoms including anasarca. Such patients may benefit from earlier dialysis initiation, to the extent that serial ultrafiltration may help bring the patient closer to his or her optimal volume status and thereby break the cycle of frequent rehospitalizations for heart failure exacerbation. An important goal of managing the patient with advanced CKD is to avoid initiation of dialysis when the patient has become particularly decompensated requiring emergency hospitalization. The costs associated with “crash landing” initiations are necessarily much higher than outpatient, elective initiations, and significant morbidity may develop in the hospital setting including nosocomial infection. On the other hand, initiation of dialysis before true benefit accrues to the patient, intuitively does not make sense, only adds to cost of delivery of care and deprives the patient of whatever freedom from dialysist may reasonably persist with ongoing close medical supervision. A common observation during the past few decades had been a trend toward earlier start of patients on dialysis (both HD and PD), often at eGFRs greater than 10 mL/min/1.73 m2. This practice has probably been based on the supposition that earlier institution of therapy would enhance rehabilitation and prevent complications through a preemptive approach, avoiding the various manifestations uremic toxicity, before they become fully manifest. Hard evidence supporting such a practice, however, has been lacking. Key questions to be addressed include does timing of initiation of dialysis significantly affect patient morbidity and symptomatology? Does timing of initiation of dialysis affect patient mortality? What are the implications of practice guidelines regarding timing of dialysis initiation, in terms of global cost of care to society? The landmark Initiating Dialysis Early and Late (IDEAL) study examined these questions in some detail.80 IDEAL was a randomized, multicenter study that examined the effects on mortality from any cause among groups assigned to early-start dialysis (eGFR 10e14 mL/min/1.73 m2) vs. those in the late-start group (5e7 mL/min/1.73 m2). The primary outcome was death from any cause. Patients planning both HD and PD were included. Median time to start was 1.8 vs. 7.4 months in the early and late groups, respectively. The median time of follow-up was 3.5 years. The authors observed no significant difference in mortality between those assigned to early start (37.6%) vs. late start (36.6%). Moreover, there was no observed difference in the incidence of CV events, infectious

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disease complications, or other dialysis-related complications. A potential limitation of this study, however, is that a substantial number of patients (75.9%) assigned to the late-start group actually needed to start dialysis above the preassigned cutoff of 7 mL/min/1.73 m2, due to interval development of uremic symptoms. Whether or not a between-group mortality difference would have emerged had these patients actually waited to start dialysis until they reached the late-start eGFR cutoff of 5e7 mL/min/1.73 m2, is uncertain. In other words, one could criticize IDEAL in that it compared very early start with relatively early start, rather than late start, and the modest separation in kidney function between groups resulted in an underpowered study. Nevertheless, based on the IDEAL results, there is no clinical trialsebased evidence to support a very early preemptive initiation of dialysis strategy. It is noteworthy that left ventricular hypertrophy was present in a large fraction of IDEAL participants at the time of study enrollment. A substudy found no difference in left ventricular hypertrophy regression or progression at 12 months.81 There was no significant difference in mortality, CV events, infections, or access related complications, restricting analysis to those patients in IDEAL who eventually underwent HD as a modality choice. Fluid and electrolyte complications were more common, however, among patients randomized to the “late” start group.82 Whether or not these findings apply to a generally healthier population of prospective HD patientsdthose without diabetes and for whom the only significant comorbid condition in addition to CKD was hypertensiondwas examined in a large cohort of 81,176 patients starting in-center HD by Rosansky et al.83 The reference group included those patients assigned to dialysis initiation at an eGFR <5 mL/min/ 1.73 m2, who were compared across various strata of ever-increasing eGFRs at time of dialysis initiation, with the highest group being those with eGFR >15 mL/min/1.73 m2. Among these patients with limited comorbidity, unadjusted 1-year mortality for the reference group was 6.8%, while in the patients with eGFR >15 mL/min/1.73 m2 was 20.1%. Adjusted mortality hazards were progressively higher among patients starting dialysis at higher eGFR. These findings contradict those reported in the IDEAL study and suggest either that earlier start of dialysis may be harmfuldat least in this select group of nondiabetic patientsdor, most likely, that there is confounding by indication. In other words, patients sicker in ways that were not measured and/or adjusted for received dialysis earlier. Although confounding is likely to explain the findings reported by Rosansky et al., one should consider the possibility that early initiation of dialysis may in fact be harmful. In addition to risks associated

with creation or placement of vascular access, initiation of HD may accelerate loss of residual kidney function or lead to other untoward effects. Taken together, these observations suggest that in the majority of patients, initiation of HD can be delayed until eGFR is somewhere between 5e10 mL/min/ 1.73 m2, but that the ultimate decision should be patient-specific. Initiation of dialysis at eGFRs closer to 10 mL/min/1.73 m2 is reasonable if unequivocal symptoms of uremia have begun to develop. Special populations, such as those with heart failure, may also benefit from earlier initiation, for volume control. For the majority of patients, initiation of dialysis at eGFR greater than 10 mL/min/1.73 m2 appears to confer no survival benefit, is associated with increased cost, and in the nondiabetic subgroups, may actually be associated with higher 1-year mortality risk.

CONCLUSION Decisions regarding the initiation of RRT are critical in the relationships among nephrologists, patients, family members, and other health personnel. The transition from CKD to ESRD requires the nephrologist to have a clear understanding of the disease trajectory in the individual patient, and to function as a teacher for the patient and the important members of his or her family, and professional and social networks. Recent advances in clinical research allow the nephrologist to advise patients regarding timing of initiation of HD, and factors related to successful creation of vascular access, which will promote the best health outcomes. The nephrologist, while managing a complex set of medical problems in patients with late stages of CKD, can play a key role in determining the characteristics of the start of RRT with HD. Patient education, CV risk factor management, anemia management, vascular access placement, and timing the initiation of HD are all critical to patient care. When these issues are properly addressed, the safe and successful initiation of HD may be more likely.

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29. He J, et al. Risk factors for heart failure in patients with chronic kidney disease: the CRIC (chronic renal insufficiency cohort) study. J Am Heart Assoc 2017;6(5). 30. Foley RN, et al. Chronic kidney disease and the risk for cardiovascular disease, renal replacement, and death in the United States Medicare population, 1998 to 1999. J Am Soc Nephrol 2005;16(2): 489e95. 31. Tonelli M, et al. Risk of coronary events in people with chronic kidney disease compared with those with diabetes: a populationlevel cohort study. Lancet 2012;380(9844):807e14. 32. Tonelli M, et al. Chronic kidney disease and mortality risk: a systematic review. J Am Soc Nephrol 2006;17(7):2034e47. 33. Di Angelantonio E, et al. Chronic kidney disease and risk of major cardiovascular disease and non-vascular mortality: prospective population based cohort study. Br Med J 2010;341:c4986. 34. Briasoulis A, Bakris GL. Chronic kidney disease as a coronary artery disease risk equivalent. Curr Cardiol Rep 2013;15(3):340. 35. Kaisar M, Isbel N, Johnson DW. Cardiovascular disease in patients with chronic kidney disease. A clinical review. Minerva Urol Nefrol 2007;59(3):281e97. 36. Palmer SC, et al. Serum levels of phosphorus, parathyroid hormone, and calcium and risks of death and cardiovascular disease in individuals with chronic kidney disease: a systematic review and meta-analysis. JAMA 2011;305(11):1119e27. 37. Faul C, et al. FGF23 induces left ventricular hypertrophy. J Clin Investig 2011;121(11):4393e408. 38. Kahn MR, et al. Management of cardiovascular disease in patients with kidney disease. Nat Rev Cardiol 2013;10(5):261e73. 39. Garimella PS, Sarnak MJ. Cardiovascular disease in CKD in 2012: moving forward, slowly but surely. Nat Rev Nephrol 2013;9(2): 69e70. 40. Gansevoort RT, et al. Chronic kidney disease and cardiovascular risk: epidemiology, mechanisms, and prevention. Lancet 2013; 382(9889):339e52. 41. Menon MC, Ix JH. Dietary phosphorus, serum phosphorus, and cardiovascular disease. Ann N Y Acad Sci 2013;1301(1):21e6. 42. Quarles LD. Reducing cardiovascular mortality in chronic kidney disease: something borrowed, something new. J Clin Investig 2013;123(2):542e3. 43. Zoccali C, Yilmaz MI, Mallamaci F. FGF23: a mature renal and cardiovascular risk factor? Blood Purif 2013;36(1):52e7. 44. Major RW, et al. Cardiovascular disease risk factors in chronic kidney disease: a systematic review and meta-analysis. PLoS One 2018; 13(3):e0192895. 45. Rutherford E, Mark PB. What happens to the heart in chronic kidney disease? J R Coll Phys Edinb 2017;47(1):76e82. 46. Grabner A, Faul C. The role of fibroblast growth factor 23 and Klotho in uremic cardiomyopathy. Curr Opin Nephrol Hypertens 2016; 25(4):314e24. 47. Bansal N. Evolution of cardiovascular disease during the transition to end-stage renal disease. Semin Nephrol 2017;37(2): 120e31. 48. Baigent C, et al. The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): a randomised placebo-controlled trial. Lancet 2011;377(9784):2181e92. 49. Badve SV, et al. Effects of beta-adrenergic antagonists in patients with chronic kidney disease: a systematic review and metaanalysis. J Am Coll Cardiol 2011;58(11):1152e61. 50. Desai AS, et al. Incidence and predictors of hyperkalemia in patients with heart failure: an analysis of the CHARM Program. J Am Coll Cardiol 2007;50(20):1959e66. 51. Anand IS, et al. Proteinuria, chronic kidney disease, and the effect of an angiotensin receptor blocker in addition to an angiotensinconverting enzyme inhibitor in patients with moderate to severe heart failure. Circulation 2009;120(16):1577e84.

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52. Tokmakova MP, et al. Chronic kidney disease, cardiovascular risk, and response to angiotensin-converting enzyme inhibition after myocardial infarction: the Survival and Ventricular Enlargement (SAVE) study. Circulation 2004;110(24):3667e73. 53. Blood Pressure Lowering Treatment Trialists C, et al. Blood pressure lowering and major cardiovascular events in people with and without chronic kidney disease: meta-analysis of randomised controlled trials. Br Med J 2013;347:f5680. 54. Brian LS, Ann LY, Maria O, editors. Sodium intake in populations: assessment of evidence. The National Academies Press; 2013. 55. Jelkmann W. Erythropoietin after a century of research: younger than ever. Eur J Haematol 2007;78(3):183e205. 56. Bunn HF. Erythropoietin. Cold Spring Harb Perspect Med 2013;3(3): a011619. 57. Jacobs K, et al. Isolation and characterization of genomic and cDNA clones of human erythropoietin. Nature 1985;313(6005): 806e10. 58. Lin FK, et al. Cloning and expression of the human erythropoietin gene. Proc Natl Acad Sci U S A 1985;82(22):7580e4. 59. Winearls CG, et al. Effect of human erythropoietin derived from recombinant DNA on the anaemia of patients maintained by chronic haemodialysis. Lancet 1986;2(8517):1175e8. 60. Eschbach JW, et al. Correction of the anemia of end-stage renal disease with recombinant human erythropoietin. Results of a combined phase I and II clinical trial. N Engl J Med 1987;316(2):73e8. 61. Inrig JK, et al. Effect of hemoglobin target on progression of kidney disease: a secondary analysis of the CHOIR (Correction of Hemoglobin and Outcomes in Renal Insufficiency) trial. Am J Kidney Dis 2012;60(3):390e401. 62. Patel TV, Singh AK. Anemia in chronic kidney disease: new advances. Heart Fail Clin 2010;6(3):347e57. 63. Singh AK. What is causing the mortality in treating the anemia of chronic kidney disease: erythropoietin dose or hemoglobin level? Curr Opin Nephrol Hypertens 2010;19(5):420e4. 64. Grimm PC, et al. Effects of recombinant human erythropoietin on HLA sensitization and cell mediated immunity. Kidney Int 1990; 38(1):12e8. 65. Vella JP, et al. Sensitization to human leukocyte antigen before and after the introduction of erythropoietin. Nephrol Dial Transplant 1998;13(8):2027e32. 66. Yabu JM, et al. Sensitization from transfusion in patients awaiting primary kidney transplant. Nephrol Dial Transplant 2013;28(11): 2908e18. 67. Scornik JC, et al. An update on the impact of pre-transplant transfusions and allosensitization on time to renal transplant and on allograft survival. BMC Nephrol 2013;14:217.

68. Macdougall IC, Obrador GT. How important is transfusion avoidance in 2013? Nephrol Dial Transplant 2013;28(5):1092e9. 69. Foley RN, Chen SC, Collins AJ. Hemodialysis access at initiation in the United States, 2005 to 2007: still "catheter first". Hemodial Int 2009;13(4):533e42. 70. Bray BD, et al. Vascular access type and risk of mortality in a national prospective cohort of haemodialysis patients. QJM 2012; 105(11):1097e103. 71. Ravani P, et al. Associations between hemodialysis access type and clinical outcomes: a systematic review. J Am Soc Nephrol 2013;24(3): 465e73. 72. Grubbs V, et al. Health status as a potential mediator of the association between hemodialysis vascular access and mortality. Nephrol Dial Transplant 2014;29(4):892e8. 73. DeSilva RN, et al. Fistula first is not always the best strategy for the elderly. J Am Soc Nephrol 2013;24(8):1297e304. 74. Lazarides MK, et al. A meta-analysis of dialysis access outcome in elderly patients. J Vasc Surg 2007;45(2):420e6. 75. Lok CE, Foley R. Vascular access morbidity and mortality: trends of the last decade. Clin J Am Soc Nephrol 2013;8(7):1213e9. 76. O’Hare AM, et al. When to refer patients with chronic kidney disease for vascular access surgery: should age be a consideration? Kidney Int 2007;71(6):555e61. 77. Demoulin N, et al. Preparing renal replacement therapy in stage 4 CKD patients referred to nephrologists: a difficult balance between futility and insufficiency. A cohort study of 386 patients followed in Brussels. Nephrol Dial Transplant 2011;26(1):220e6. 78. Vachharajani TJ, et al. Elderly patients with CKD-dilemmas in dialysis therapy and vascular access. Nat Rev Nephrol 2014;10(2): 116e22. 79. Quinn RR, Ravani P. Fistula-first and catheter-last: fading certainties and growing doubts. Nephrol Dial Transplant 2014;29(4): 727e30. 80. Cooper BA, et al. A randomized, controlled trial of early versus late initiation of dialysis. N Engl J Med 2010;363(7):609e19. 81. Whalley GA, et al. Effect of early initiation of dialysis on cardiac structure and function: results from the echo substudy of the IDEAL trial. Am J Kidney Dis 2013;61(2):262e70. 82. Collins J, et al. Outcomes of patients with planned initiation of hemodialysis in the IDEAL trial. Contrib Nephrol 2011;171:1e9. 83. Rosansky SJ, et al. Early start of hemodialysis may be harmful. Arch Intern Med 2011;171(5):396e403.

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QUESTIONS AND ANSWERS

QUESTIONS AND ANSWERS Question 1 You are following a 62-year-old man with progressive CKD secondary to diabetic nephropathy. His current eGFR is 22 mL/min/1.73 m2. He comes to clinic to discuss renal replacement options. Which one of the following is true regarding his options for dialysis? A. PD is associated with enhanced survival compared to HD B. HD is a less costly form of RRT C. PD is associated with preservation of residual kidney function D. HD is associated with superior quality of life and patient independence Answer: C PD is associated with preservation of residual kidney function. This is important because persistence of residual kidney function is associated with improved fluid and blood pressure control, phosphate and middle molecule clearance, nutritional status, and attenuation of left ventricular hypertrophy and CV risk, decreased inflammatory markers, and prolonged survival.6e8 Answer A is incorrect as long-term survival among patients receiving HD and PD are generally similar. PD is typically associated with improved perception of quality of life and patient independence and is less costly on an annual basis than HD making Answers B and D incorrect.4,5

Question 2 In preparing for RRT, discussions should take place with the patient and family regarding which of the following: A. Symptomatic consequences of progressive kidney failure B. The different modalities of RRT including HD, PD, and KTx C. The expected scheduling and logistic requirements D. Dietary restrictions with which the patient will need to adhere E. All of the above Answer: E From the educational point of view, the patient and family should have a reasonable understanding of the functional and symptomatic consequences of progressive kidney failure. Patients and families should have a good understanding of the various modalities of RRT, with the eventual modality choice being tailored to the individual circumstances, taking into account

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medical and surgical comorbidities, age and projected life expectancy, lifestyle and occupation, social support system, and of course, personal choice. Patients should have a reasonable set of expectations regarding what HD can and cannot replace for the failing kidneys. Patients should have a clear understanding of the scheduling and logistic requirements that will be expected and how new dietary restrictions will be necessary. For selected patients, because of either advanced age or other significant co-morbid conditions, there should be an understanding that a conservative, symptom-based and comfort-driven approach may be preferred.

Question 3 Which one of the following is true regarding referring patients for KTx? A. Patients should be treated with HD for at least one year before they are referred for consideration of KTx B. Patients can be on the deceased donor waiting list when their eGFR is 20 mL/min/1.73 m2 C. Patients must be started on dialysis before they qualify for listing on the deceased donor waiting list D. Patients can be first placed on the deceased donor waiting list when their eGFR is 10 mL/min/ 1.73 m2 Answer: B For those patients deemed to be medically and otherwise suitable for transplantation, they should, ideally, be seen and evaluated by a local transplant center and listed for deceased donor transplantation. This should occur well before the actual time of dialysis initiation because an eGFR of 20 mL/min/1.73 m2 or less qualifies a patient for transplant listing with the UNOS making Answer B true and Answers A, C, and D incorrect. Waiting to refer for transplantation until dialysis is initiated, when eGFR is much lower than 20 mL/min/1.73 m2, essentially deprives the patient of valuable time (sometimes on the order of years, for those with more slowly progressive CKD) that could otherwise accrue on the deceased donor waiting list. This has the effect of prolonging the waiting time for eventual transplantation and exposing patients to potential interval development of dialysis-related morbid events, not uncommonly rendering them unsuitable for transplantation. Referral for transplantation is appropriate when eGFR is between 20e25 mL/min/1.73 m2, so that medical and psychosocial evaluations can be completed, the patient tentatively approved, and subsequently listed as soon as the referring nephrologist documents an eGFR consistently below 20 mL/min/1.73 m2 during serial monitoring.

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Question 4 A 54-year-old woman is followed for progressive kidney disease secondary to IgA nephropathy. She is scheduled to see you in a few hours. Which of the following are the goals in planning for HD? A. The hemoglobin concentration should be at targets defined by clinical practice guidelines without the need for transfusion B. Patients should have a functional permanent vascular access, preferably an AVF C. The patient should be followed at close intervals to avoid the need for an emergent inpatient start of HD treatment (“crash landing”) D. If eligible, patients should be listed for KTx when eGFR is 20 mL/min/1.73 m2 E. All of the above Answer: E The above-listed goals should all be part of the management of the patient being prepared for HD. When these are properly adhered to, the likelihood of safe and successful initiation of HD is increased. Patient education, CV risk factor management, anemia management, vascular access placement, and timing the initiation of HD are all critical to patient care.

Question 5 Which ONE of the following is true regarding formal pre-ESRD educational programs for patients and families? A. Families should not be included since it violates confidential patient information rules B. Education has no effect on type of dialysis selected by the patient C. Patients are started on dialysis earlier than necessary D. A higher percentage of patients begin dialysis with a mature functioning vascular access Answer: D Multiple studies have demonstrated that formal pre-ESRD educational programs for patients and families result in a higher percentage of patients opting for home-based therapies (Answer B is not true), a greater percentage of incident HD patients beginning treatment with a mature, functioning vascular access (Answer D is true and the correct answer), prolongation of time to need for initiation of dialysis (Answer C is incorrect), improved S[Alb] at the time of dialysis start, decreased need for emergent, hospital-based initiation of treatment, fewer hospitalizations at one year, and overall cost savings per patient during the first year of dialysis.15e19 Involvement of families,

with the permission of the patient, is critical to the success of any treatment plan for RRT, making Answer A not true.

Question 6 Which ONE of the following is true regarding the timing of the initiation of HD? A. Early-start dialysis (eGFR 10e14 mL/min/1.73 m2) results in lower mortality compared to late-start dialysis (eGFR 5e7 mL/min/1.73 m2) B. No significant difference in mortality is seen with late-start dialysis (eGFR 5e7 mL/min/1.73 m2) compared to early-start dialysis (eGFR 10e14 mL/ min/1.73 m2) C. Early-start dialysis (eGFR 10e14 mL/min/1.73 m2) results in a lower incidence of CV and infectious disease complications D. Early-start dialysis (eGFR 10e14 mL/min/1.73 m2) results in a lower incidence of dialysis-related complications Answer: B The landmark Initiating Dialysis Early and Late (IDEAL) trial was a randomized, multicenter randomized trial that evaluated effects on mortality from any cause among groups assigned to earlier initiation of dialysis (eGFR 10e14 mL/min) vs. those assigned to later initiation of dialysis (eGFR 5e7 mL/min).80 Patients planning both HD and PD were included. Median time to start was 1.8 vs. 7.4 months in the earlier and later initiation groups, respectively. The median time of follow-up was 3.5 years. There were no significant differences in mortality between those assigned to earlier initiation (37.6%) and later initiation (36.6%), making Answer B correct and Answer A incorrect. Moreover, there was no observed difference in the incidence of CV events, infectious disease complications, or other dialysis-related complications, making Answers C and D incorrect. A potential limitation of this study, however, is that a substantial number of patients (75.9%) assigned to the later initiation group were started on dialysis above the preassigned cutoff of 7 mL/min, due to interval development of uremic symptoms. Whether or not a between-group mortality difference would have emerged had these patients waited to start dialysis until they reached the late-start eGFR cutoff of 5e7 mL/min, is uncertain. In other words, one could criticize IDEAL in that it compared very early initiation with relatively early initiation, rather than late initiation, and the modest separation in kidney function between groups resulted in an underpowered study. Nevertheless, based on the IDEAL results, there is no clinical trials-based evidence to support a very early preemptive initiation of dialysis strategy.

VIII. THERAPEUTIC CONSIDERATIONS

QUESTIONS AND ANSWERS

Question 7 A 45-year-old woman presents to clinic for management of progressive CKD secondary to focal and segmental glomerulosclerosis. Her current eGFR is 20 mL/min/1.73 m2. Which ONE of the following statements is true regarding vascular access management in this patient? A. Native AVF is the preferred form of vascular access B. CVCs are not associated with any long-term complications C. In the US, the most common form of vascular access in incident HD patients is the AVF D. The patient should be referred for vascular access placement one month before anticipated start of dialysis Answer: A Answer A is correct because compared with synthetic AVGs and CVCs, AVFs are associated with greater longterm patency rates, decreased need for interventional

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procedures to maintain patency, decreased rates of infection, decreased rates of patient hospitalization, decreased overall cost, and importantly, decreased patient mortality. Answer B is incorrect as long-term use of CVCs is associated with development of vascular complications, including subclavian and internal jugular vein thrombosis. Superior vena cava syndrome may also develop in patients using CVCs. These vascular complications subsequently render future placement of noncatheter forms of access more difficult. In the US, the most common form of vascular access in incident HD patients remains the CVC, making Answer C incorrect.55 Answer D is incorrect as at least 6 months before anticipated need for dialysis initiation is needed to allow maturation of the AVF. This also takes into account the relatively high rates of primary access failure in AVFs, leading to the need for interventional procedures and/or revision surgery, such that ample time is allowed for maturation of a functional AVF at the time of dialysis start.

VIII. THERAPEUTIC CONSIDERATIONS