Planning for Hemodialysis

C H A P T E R

62 Planning for Hemodialysis Robert T. Isom and Glenn M. Chertow Stanford University School of Medicine, Division of Nephrology, Stanford, CA, USA

Patients with progressive forms of CKD whose glomerular filtration rate (GFR) is expected to decline within their lifetime, to the point where potentially 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. The choice of RRT modality should be tailored to the individual patient and is generally based on a combination of medical and surgical comorbidities, anticipated life expectancy, psychosocial factors and patient preference. Kidney transplantation, when possible, remains the preferred treatment modality for almost all patients with ESRD. 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 pre-­emptively (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 palliative approach. Palliative nephrology implies non-­ provision of RRT in situations where, because of a patient’s cumulative comorbidities, dialysis of any type tends to provide only limited prolongation of life or functional rehabilitation, such that symptom-based, comfort-directed measures may be more appropriate. Planning for dialysis requires convincing a patient that he or she will derive meaningful quality and prolongation of life by submitting themselves 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 P. Kimmel & M. Rosenberg (Eds): Chronic Renal Disease. DOI: http://dx.doi.org/10.1016/B978-0-12-411602-3.00062-7

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 what signs and symptoms might develop in an individual patient as kidney function declines. The nephrologist must tailor his or her information delivery based on the patient’s educational and cultural background, and intellectual capacity to integrate complex medical concepts. Not all patients, for example, can grasp the concept of 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 GFR” by their referring internist. This of course puts the nephrologist into an awkward position, since the term “glomerular” is foreign to laypeople, and addressing the concern of a “low GFR” 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 “GFR” means? Understandably, without even a cursory discussion of this concept, patients may leave the consultation room still wondering, “what does my low GFR actually mean?” or “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 helpful to tell them to disregard the term “GFR” and focus instead on something more tangible, like “the kidneys’ ability to filter out waste products.” 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 educational level, cultural background, and ability to comprehend and

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integrate medical terminology, the nephrologist must explain the different forms of RRT, emphasizing that these are treatments, not cures, for ESRD. For example, it is not unusual for a patient with ESRD to arrive for his or her first dialysis treatment, and ask how long it will take for their kidneys to get better, after being on dialysis. Or he or she may ask, understandably so, “is there anything I can do to make my creatinine go down?” Many patients are reluctant to go along with the recommended planning phases in preparation for dialysis initiation. Patients may repeatedly delay or refuse dialysis planning altogether. The idea of being tethered to a machine for necessary life support may seem painful, unnatural, overly time-consuming, and unacceptable to them. 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 (keeping the patient alive with a reasonable quality of life), 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 social support system regarding the role of the kidneys in maintaining health, and the anticipated impact of progressive decline in renal function on the patient’s health, quality of life, and life expectancy. If the patient’s CKD is expected to pro­ gress to ESRD, he or she must be educated regarding the potential health benefits that would realistically be anticipated from dialysis. Patients should also have a good understanding of the trade-offs that would be encountered as a patient on 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 “renal replacement therapy” must be carefully explained to the patient, since HD and PD, strictly speaking, do not replace kidney function. While 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 reabsoptive, excretory, endocrine, metabolic, anti-­ inflammatory 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, dialysis sustains life, but 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 is 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.2,3 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 persistence of residual kidney function is associated with improved fluid and blood pressure control, phosphate and middle molecule clearance, nutritional status, left ventricular hypertrophy and cardiovascular risk, decreased inflammatory markers, and prolonged survival.4–6 When the nephrologist and patient do agree on future implementation of HD, 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 “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 pre-existing vascular access, necessitating placement of a temporary vascular catheter, often in a critical care setting. Outcomes under these circumstances are generally poor – hospitalizations 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, is clearly suboptimal. Causes of a crash landing may include lack of primary medical care and/or the patient being unaware of his or her disease until it becomes symptomatic, late referral to nephrology services from the patient’s primary care provider, 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 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, 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 medical and surgical co-morbidities, age and projected life expectancy, lifestyle and occupation, social support system, and, of course, personal choice. Patients

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62.  Planning for Hemodialysis

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 co-morbid conditions, there should be an understanding that a palliative, conservative, symptom-based and comfort-based approach may be reasonable. 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 protein-restricted diet, as well as ongoing use (or de novo implementation) of inhibitors of the RAAS, even in late-stage CKD. The patient’s nutritional and functional status should be optimized. Guidelines regarding treatment of the anemia of CKD should be generally adhered to, with the primary goal of avoidance of 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 cardiovascular morbidity and mortality associated with moderate to advanced CKD and ESRD, modifiable risk factors for cardiovascular 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 deceased donor transplantation. This should occur well before the actual time of dialysis initiation, since 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 time (sometimes on the order of years, for those with more slowly progressive forms of nephropathy) 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. We recommend referral for transplantation when eGFR is between 20–25 mL/min/1.73 m2, so 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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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 surgeon, usually at least 4–6 months in advance of the anticipated time for starting HD. This provides sufficient time to allow maturation of a newly placed native arteriovenous fistula (usually 1 to 3 months). Early vascular surgery also takes into account the relatively high rate of primary failure of newly placed AV fistulae, leading to the need for sometimes 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. While 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, such as superior vena cava syndrome. As the steps outlined 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 S[K], acid– base balance, and S[P]. From the clinical point of view, the patient should be seen at appropriate intervals by either the nephrologist or a physician extender such as a dedicated nephrology nurse practitioner or physician assistant, so that a focused, renal-specific review of systems and physical examination can assess for 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 transplant-listed. The hemoglobin concentration should be at targets set by Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines without having been transfused. Patients should have a functional permanent vascular access, preferably an arteriovenous fistula. Patients should be free of severe, decompensated signs or symptoms of advanced kidney failure that would prompt emergent hospitalization for dialysis initiation – such as refractory hyperkalemia, encephalopathy, severe hypertension, congestive heart failure, pericarditis, or severe anemia requiring transfusion. 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 and

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costs associated with the procedure, and that from the patients’ point of view, the lifestyle burden that maintenance dialysis will place on themselves and family, when viewed against the perspective of worsening symptoms and/or death without provision of dialysis, now becomes acceptable. Patient education, cardiovascular risk factor management, anemia management, vascular access placement, and timing 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 incident HD patients have not been through a formal pre-ESRD teaching program designed to prepare them for eventual initiation of dialysis. Most patients report not having been made aware of modality choices other than center-based HD, including home HD, peritoneal dialysis, or transplantation. The information gap regarding CKD and its treatment modalities appears more pronounced among African Americans.7,8 The majority of incident HD patients in the US 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 greater percentage of patients opting for home-based therapies, a greater percentage of incident HD patients beginning treatment with a mature, functioning vascular access, prolongation of time to need for initiation of dialysis, 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.9–13 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.14,15 Devins et  al. in 2005 reported 20-year follow-up of a cohort of patients who had been randomized in the mid-1980s to pre-dialysis psychoeducational interventions aimed at increasing patients’ knowledge of CKD and its treatment versus usual care. These investigators found that patients who received pre-dialysis CKD education survived a median of over 2 years longer

than those assigned to usual care. Following initiation of dialysis, survival was 8 months longer in those having received CKD education, compared to the usual care group.16 Barriers to implementation of such pre-­ dialysis 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 pre-dialysis 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, non-dialytic management, such as non-provision of RRT. However, when given a choice between prolongation of life with maintenance dialysis, and non-provision or RRT (which in some patients could 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 co-morbidities (e.g. active, metastatic cancer), whose functional status is impaired and life expectancy correspondingly limited, conservative, non-dialytic management focused on symptom control may be more appropriate. Tamura et  al. in 2009 published a landmark study in which functional capacity and mortality were examined in a relatively large national cohort (n = 3702) of nursing home residents initiating dialysis. Mortality one year after initiation of dialysis was a staggering 58%. Initiation of dialysis was actually shown to be an independent predictor of functional decline, regardless of the patient’s “functional trajectory” (the ability to perform activities of daily living) during the three months preceding initiation of dialysis. One year after starting dialysis, only 1 in 8 patients maintained or improved his or her functional status relative to the start of dialysis.17 Elderly patients with multiple co-morbidities who initiate HD have a higher likelihood of dying in an acute care facility, often in a critical care setting. The choice of conservative, non-dialytic 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. The choice of conservative, non-dialytic management in advanced CKD implies an understanding between

VIII.  THERAPEUTIC CONSIDERATIONS

Cardiovascular Risk Factor Management

patient and provider that, on the one hand, lack of provision of dialysis is likely to be associated with shortened life expectancy. How much so, of course, depends on the status of the individual patient. Moreover, pursuing conservative, non-dialytic management necessitates 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. in 2007 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.18 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 uremia – especially among those not followed closely in CKD clinic or who fail to adhere to dialysis planning – is either sudden cardiac death in the setting of electrolyte imbalance (for example, hyperkalemia), or the more distressing picture of flash 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 lowdose 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 decided-upon course and request emergency care including acute dialysis.19

CARDIOVASCULAR RISK FACTOR MANAGEMENT Cardiovascular (CV) events account for more than 50% of premature deaths among patients receiving HD, including coronary artery disease, congestive heart failure, and sudden cardiac death. The excess burden of CVD applies to the pre-dialysis population as well.

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Nephrologists caring for the patient with advanced CKD need to have a heightened awareness of the excess cardiovascular risk in this patient 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 non-dialysis-requiring CKD, even at its early stages (albuminuria, or mild reductions in eGFR), to increased CV risk including CV death. Moreover, the association remains strong even in the absence of other traditional risk factors such as diabetes, hypertension, dyslipidemia, and smoking. Foley et  al. in 2005 reported on a 5% sample of the US Medicare population (n = 1,091,201), examining the relation between CKD and diabetes mellitus with respect to CV risk, defined as atherosclerotic heart disease, congestive heart failure, as well as 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, the rates per 100 patient-years for developing atherosclerotic heart disease, heart failure, and all-cause mortality were higher for those 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.20 These findings were confirmed in a recent large Canadian study (n = 1,268,029), again examining the mutual interplay between presence or absence of diabetes and CKD, with regard to cardiovascular risk, specifically risk of myocardial infarction, with the reference group against which DM and CKD risk were compared being those with prior myocardial infarction. In the different patient categories, risk of MI was greatest in those with prior MI, regardless of DM or CKD status. Here also, CKD proved to be a stronger predictor for myocardial infarction than diabetes. In patients with more advanced CKD (GFR <45  mL/min), or heavy proteinuria (>300 mg/g creatinine), the risk of MI compared to the diabetic group was doubled (12.4 vs. 6.6 events per 1000 patient-years).21 Thus, the presence of CKD alone appears to be a stronger predictor of cardiovascular 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 CV-related mortality has been shown in multiple studies to increase exponentially as GFR declines, even applying to the earliest stages of CKD.22–24 The causes of this increased CV risk remain incompletely understood. In the CKD population, it has been

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estimated that traditional risk factors for CV-related morbidity and mortality account for only 50% of risk.25 CKDspecific 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 its attendant hypercoaguable propensities, oxidative stress, inflammation, malnutrition, and the effects of disordered mineral bone metabolism (hyperphosphatemia, vitamin D deficiency, and increased circulating levels of fibroblast growth factor-23), leading to vascular calcification and left ventricular hypertrophy, are believed to contribute to this risk.26–33 Preparation of the patient with advanced CKD for HD therefore involves early and careful attention on the nephrologist’s part towards treatment and optimization of modifiable risk factors which 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 cardiovascular risk. Goals of management should be aimed at decreasing cardiovascular events during the evolution of CKD progression, laying the groundwork for as robust a cardiovascular health status as possible when the patient initiates HD, and to the extent that multiple cardiovascular risk factors also affect progression of CKD (such as hypertension, diabetes, smoking), trying to delay progression of CKD where possible. Moreover, as the patient approaches the time for planning for RRT, the nephrologist should have a thorough knowledge of the patient’s cardiovascular status, including left and right heart 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, arrhythmia and sudden death. Although much has been learned over the past few centuries regarding the putative mechanisms of increased cardiovascular 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 carefully interpret available and emerging data to provide an evidence-based rationale for treatment aimed at reducing cardiovascular risk. What data from well-designed clinical trials can help guide the nephrologist during the care of the patient with progressive CKD, to help alleviate cardiovascular risk? The few cardiovascular 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

cardiovascular 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. The Study of Heart and Renal Protection (SHARP) trial, addressing the treatment of hypercholesterolemia, randomized 9270 patients (6247 with non-dialysis requiring CKD and 3023 with ESRD) to simvastatinezetimibe versus placebo. Active cholesterol-lowering resulted in a 17% (95% CI 6 to 26%) reduction in the rate of major atherosclerotic events (non-fatal myocardial infarction, non-hemorrhagic stroke, any arterial revascularization or coronary death). Results remained statistically significant in subjects with stage 4 CKD (corresponding rate reduction 22%, 95% CI 2 to 38%).34 Several subgroup analyses of heart failure trials have demonstrated consistent benefits of beta adrenergic antagonists and inhibitors of the RAAS among subjects with and without CKD, although few patients in these trials had advanced CKD.35–38 The net benefits and risks of aspirin and other anti-platelet agents in patients with advanced CKD are unknown. In a post hoc subgroup analysis of the Hypertension Optimal Treatment (HOT) trial, cardiovascular events were reduced by 66% (95% CI 33 to 83%) and mortality was reduced by 49% (95% CI 6 to 73%) in patients treated with aspirin. Major bleeding events were modestly increased. More recently, a 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 pressure lowering medications, compared active medications with placebo or compared different targets for blood pressure lowering, aiming to determine the importance of blood pressure lowering (and the specific agents used) on cardiovascular outcomes. The primary outcome of the meta-analysis was major cardiovascular events, defined as the first episode of stroke, coronary heart disease, heart failure, and cardiovascular death. Of more than 150,000 participants from 25 clinical trials, 20% had CKD, defined as eGFR below 60 mL/min per 1.73 m2. Results showed statistically significant and substantial lowering of cardiovascular risk with blood pressure lowering, with no obvious difference by antihypertensive drug class. Unfortunately, fewer than one-half of 1% of patients included in this meta-analysis had eGFR below 30 mL/ min per 1.73 m2 at baseline.39 While 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 anti-hypertensive therapy for cardiovascular risk reduction in patients with advanced CKD preparing for dialysis or kidney transplantation. We generally

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Anemia Management

favor the use of RAAS inhibitors in combination with diuretic agents and/or beta adrenergic 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, alpha adrenergic 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 strongly recommend mindful limitation of salt intake, despite the confusion and ambiguity introduced with the recent Institute of Medicine report.40

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, now spanning the past three decades.41,42 The cloning of the EPO gene,43,44 followed soon after by the introduction of the use of recombinant human EPO to treat the anemia associated with ESRD45,46 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 (hepatitis B and C virus and HIV), 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 non-dialysis-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 decade, due to the unexpected findings of increased cardiovascular morbidity associated with higher hemoglobin concentrations, although specific adverse cardiovascular events have not been consistently observed in different trials. The reason(s) for cardiovascular morbidity related to ESA use is still a matter under intense investigation.47–49 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

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patients who meet criteria for future transplantation. 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 severe, symptomatic anemia, prompting transfusion when hospitalized and dialysis initiated. Soon after the 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 1989. Grimm et  al. in 1990 reported on a group of five dialysis-­ dependent pediatric patients who, after 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 and prior transfusion dependence, and sensitization status, showed no reduction in anti-HLA titer or %PRA.50 Subsequently, Vella et  al. in 1998 reported on a retrospective cohort of patients receiving dialysis before and then four years after introduction of EPO. Compared to patients receiving dialysis in the preEPO 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).51 More contemporary methodologies for assessing anti-HLA 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 non-transfused patients awaiting primary kidney transplant, 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 versus 4% of non-transfused patients demonstrated an interval increase of at least 10 anti-HLA antibodies, meeting the cutoff of >3000 mean fluorescent intensity (MFI). Six of the 50 transfused patients (12%) demonstrated an increase of 30 anti-HLA antibodies above an MFI of 3000.52

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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 dialysisrelated morbid events (primarily cardiovascular and/or infectious), which not uncommonly render the patient subsequently unsuitable for transplantation. A recent review of published studies in the post-­cyclosporine era has confirmed the deleterious effects of transfusion on anti-HLA sensitization, time to transplantation resulting from sensitization, as well as increased risk of rejection and decreased overall graft survival among patients sensitized from prior transfusion.53 The recent findings of increased cardiovascular 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 maintenance HD patients, this trend towards lower target hemoglobin or hematocrit has unfortunately resulted in a higher frequency of blood transfusions since that time. Findings from the Dialysis Outcomes and Practice Patterns Study (DOPPS) 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. 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, and potentially prolongation of time to transplantation.54 Extending these observations and considerations to the pre-dialysis population, we recommend careful adherence to KDOQI guidelines regarding anemia management. Goals are to avoid the development of symptomatic anemia, prevent over-correction of anemia (which has been shown to be associated with higher cardiovascular 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 HD patient (Table 62.1). Options for vascular access in chronic hemodialysis patients include the native

TABLE 62.1  Complications of Vascular Access Catheters All catheters: Patient discomfort, cosmetic inconvenience, adhesive dressing allergic reactions Heightened mortality compared with patients initiated with non-catheter vascular access Internal jugular and/or subclavian catheter (tunneled and non-tunneled): 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 +/− tunnel infection (abscess) Pneumothorax Femoral vein temporary catheter: Retroperitoneal bleeding Inadvertent femoral artery cannulation with pseudoaneurysm formation Lower extremity DVT

arteriovenous fistula (AVF), synthetic AVG, and central venous catheter (CVC). 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 patient 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, although the optimal timing of first graft cannulation is unknown. Relative to AVFs, AVGs are prone to thrombosis and outflow stenosis due to neointimal hyperplasia, leading to the need for sometimes repeated interventional procedures to re-establish and maintain patency. CVCs can be placed and be ready for use on a same-day basis when the patient starts HD, yet are

VIII.  THERAPEUTIC CONSIDERATIONS

Vascular Access Management

associated with multiple short- and long-term complications (Table 62.1). 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. Dialysis CVC-associated bacteremias are associated with substantial morbidity and mortality. Sepsis and septic shock may develop in the context of dialysis CVC-associated bacteremias. Metastatic infection including endocarditis, paraspinal abscess, vertebral osteomyelitis, and septic joint are common complications of CVC-associated bacteremias. In addition to infectious complications, long-term use of CVCs is associated with development of 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 non-catheter forms of access 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. in 2009 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 = 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 and maturing fistula, and 3.3% had a CVC with maturing graft. The majority, 63.2%, had a CVC alone. Compared with those patients beginning dialysis with a functioning fistula, adjusted mortality hazard ratios 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.55 Bray et  al. in 2012 reported on a prospective cohort of all patients starting dialysis in Scotland for the years 2009 through 2011 (n = 2666). Patients dialyzing through a CVC alone were found to have a higher risk of all-cause mortality, including that attributed to cardiovascular death as well as infectious causes. 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.56 A recent review of 67 cohort studies including 586,337 patients similarly demonstrated higher risks for all-cause mortality, fatal infections, and cardiovascular events in patients dialyzing with a CVC opposed to either AVG or AVF.57

759

A critique of many of the observational studies on the relationship 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 incident HD patients from the USRDS for the period 2005–2007, examined the relationship between health status, defined as functional status and number of hospital days in the two 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 (hazard ratio [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 health status, as defined above in the two years prior to dialysis initiation, strongly correlated with access type at dialysis initiation, with previously “sicker” patients more likely to start dialysis with a CVC, while 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.58 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. While the studies cited above show heightened mortality risk associated with CVC use in all patients starting HD, irrespective 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 67 to 79, the hazard ratio 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.59 These results suggest 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 the patient 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

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62.  Planning for Hemodialysis

elderly. Several studies have shown a higher rate of primary non-function 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.60,61 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 never-utilized) AVF or AVG is an outcome that should ideally be avoided.62,63 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 the 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.64,65 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 cardiovascular mortality, and because of the confirmed benefit in non-elderly patients of AVF over AVG, we recommend adhering to standard guidelines emphasizing early referral to vascular surgery, at least six months before anticipated need for dialysis initiation, 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. 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 (PICC), 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” – and 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- or long-term 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, and what evidencebased recommendations can we rely on? Ultimately, of course, the timing of dialysis initiation must be tailored to the individual patient. A common question from patients is, “at what creatinine level 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 GFR. Occasionally, patients with relatively preserved GFR (e.g. >10 mL/min) and lack of traditional uremic symptoms, may have problems with volume management and recurrent hospitalizations for pulmonary edema in spite of maximal medical therapy, due to significant co-morbid structural heart disease – most commonly left ventricular hypertrophy with diastolic dysfunction, systolic heart failure, or pulmonary hypertension with severe right-sided

VIII.  THERAPEUTIC CONSIDERATIONS

Timing of the Initiation of Hemodialysis

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 re-hospitalizations 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 greater 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 dialysis that may reasonably persist with ongoing close medical supervision. A common observation during the past two decades has been a trend towards earlier start of patients on dialysis (both HD and PD), 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 pre-emptive approach, avoiding the various manifestations of 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.66 IDEAL was a randomized, multi-center study which looked at the effects on mortality from any cause, among groups assigned to early-start dialysis (eGFR 10–14 mL/min/1.73 m2) versus those in the late-start group (5–7 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 versus 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%) versus late start (36.6%). Moreover, there was no observed difference in the incidence of cardiovascular events, ­ infectious disease complications, or other dialysisrelated 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 pre-assigned cutoff of

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7  mL/min, 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 5–7 mL/min, 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 trials-based evidence to support a very early pre-emptive 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. Substudy analysis found no difference in left ventricular hypertrophy (regression or progression) at 12 months.67 There was no significant difference in mortality, cardiovascular 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.68 Whether or not these findings apply to a generally healthier population of prospective HD patients – those without diabetes and for whom the only significant comorbid condition in addition to CKD was hypertension – was recently examined in a large cohort of 81,176 patients starting in-center HD.69 The reference group included those patients assigned to dialysis initiation at an eGFR <5 mL/min, who were compared across various strata of ever-increasing eGFRs at time of dialysis initiation, with the highest group those with eGFR ≥15 mL/min/1.73m2. Among these patients with limited co-morbidity, unadjusted 1-year mortality for the reference group was 6.8%, while in the patients with eGFR ≥15 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 harmful – at least in this select group of non-diabetic patients – or, 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. While 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 5–10 mL/ min/1.73 m2, but that the ultimate decision should be

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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 increase in cost, and in the non-diabetic subgroups may actually be associated with higher 1-year mortality risk.

CONCLUSION Decisions regarding the initiation of RRT are critical in the relationship between nephrologists, patients, family members and other health personnel. The transition between CKD and 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, professional and social network. Recent advances in clinical trials science 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, cardiovascular 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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62.  Planning for Hemodialysis

63. Demoulin N, Beguin C, Labriola L, Jadoul M. 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):220–6. 64. Vachharajani TJ, Moist LM, Glickman MH, Vazquez MA, Polkinghorne KR, Lok CE, et  al. Elderly patients with CKDdilemmas in dialysis therapy and vascular access. Nat Rev Nephrol 2014;10(2):116–22. 65. Quinn RR, Ravani P. Fistula-first and catheter-last: fading certainties and growing doubts. Nephrol Dial Transplant 2014;29(4):727–30. 66. Cooper BA, Branley P, Bulfone L, Collins JF, Craig JC, Fraenkel MB, et al. A randomized, controlled trial of early versus late initiation of dialysis. N Engl J Med 2010;363(7):609–19.

67. Whalley GA, Marwick TH, Doughty RN, Cooper BA, Johnson DW, Pilmore A, 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):262–70. 68. Collins J, Cooper B, Branley P, Bulfone L, Craig J, Fraenkel M, et al. Outcomes of patients with planned initiation of hemodialysis in the IDEAL trial. Contrib Nephrol 2011;171:1–9. 69. Rosansky SJ, Eggers P, Jackson K, Glassock R, Clark WF. Early start of hemodialysis may be harmful. Arch Intern Med 2011;171(5):396–403.

VIII.  THERAPEUTIC CONSIDERATIONS