Neurologic Complications of Chronic Kidney Disease

C H A P T E R

29 Neurologic Complications of Chronic Kidney Disease Stephen Seligera, Salina P. Waddyb a

Department of Medicine, Division of Nephrology, University of Maryland School of Medicine, Baltimore, MD, United States; bAtlanta Veterans Administration, Department of Neurology, Decatur, GA, United States association between renal function or albuminuria and cognitive impairment. Despite cognitive impairment being highly prevalent in the ESRD population, it is substantially underdiagnosed. In studies of HD patients,2,3 only 4% of patients with cognitive impairment had received a medical record diagnosis. As early stage CKD patients on average have much less frequent healthcare contact than HD patients, the likelihood of underdetection in earlier stage CKD patients is probably greater.

Abstract Neurologic outcomes in chronic kidney disease (CKD) patients are pervasive. The most common are cognitive impairment, stroke, seizures, and peripheral neuropathies. Despite a strong graded association between measures of renal function and cognitive function, cognitive impairment in CKD patients is largely undiagnosed. Annual and predialysis cognitive screening is critical to avoid adverse outcomes of missed diagnoses of cognitive impairment: medication noncompliance and inability to make informed decisions regarding initiating dialysis. Cerebrovascular disease, neurodegenerative disease, and inflammation contribute to a CKD model of accelerated vascular cognitive impairment. Risk of stroke increases significantly in CKD and ESRD patients, up to sevenfold during the month of dialysis initiation. Aggressive treatment with erythropoiesisstimulating agents increases stroke risk appreciably. For stroke prevention in atrial fibrillation, warfarin and doseadjusted newer anticoagulants appear effective in stage 3 CKD patients but are unproven or contraindicated in CKD stage 4 or higher. Management of uremic polyneuropathy, mononeuropathies, and uremic pruritus is described in this chapter.

Definitions of Cognitive Impairment (in the Non-CKD and CKD Populations)

INTRODUCTION Central and peripheral neurologic disorders in chronic kidney disease (CKD) patients are pervasive but are frequently underdiagnosed and their impact often underappreciated. The common neurologic complications in the CKD population are cognitive impairment, seizure, stroke, and peripheral neuropathies.1

COGNITIVE IMPAIRMENT IN CKD Cognitive impairment is highly prevalent in CKD patients. Multiple studies have confirmed a graded Chronic Renal Disease, Second Edition https://doi.org/10.1016/B978-0-12-815876-0.00029-2

Most studies describe the frequency of global cognitive impairment, measured on a test of overall cognitive function such as the Mini-Mental State Exam,4 or of impairment in individual cognitive domains, including memory, attention, language, visualespatial, calculations, and executive function. Executive function encompasses judgment and planning, including the ability to make informed healthcare decisions. Some studies measure diagnosed dementia, usually according to Diagnostic and Statistical Manual of Mental Disorders (DSM) IV criteria. Mild cognitive impairment (MCI) is impairment that is no longer consistent with normal aging but has not progressed to dementia. MCI most often involves early short-term memory loss (amnestic MCI) or impairment in one or more other cognitive domains such as language or executive function (nonamnestic MCI). MCI is often defined as performing 1.5e1.99 standard deviations below standardized norms on a given cognitive test,5,6 but the definition varies. The conversion rate from MCI to dementia is approximately 15% per year in elderly patients without CKD6 and is higher in those

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29. NEUROLOGIC COMPLICATIONS OF CHRONIC KIDNEY DISEASE

who carry the apolipoprotein E4 (APOE4) allele.7 APOE4 is a genetic factor that confers increased risk of Alzheimer disease (AD). Dementia is defined by DSM IV criteria as chronic persistent and usually progressive cognitive impairment in two or more cognitive domains (usually including memory) that substantially affects daily function, represents a decline in premorbid function, and is not due to concomitant acute delirium.8 Dementia is often defined in research studies as performing two or more standard deviations below population-defined norms in at least two cognitive domains. Dementia is the umbrella term for moderate to severe chronic cognitive impairment. AD is the most common type of dementia in the general US population and the most common neurodegenerative dementia. Hippocampal and cerebral atrophy are eventual prominent features of AD. Vascular dementia, due to both large- and small-vessel pathology and often accompanying white matter disease, is the second most common type, alone or in combination with AD. Dementia associated with Parkinson’s disease (sometimes called Lewy body disease), frontaletemporal dementia, and other dementia syndromes account for the remaining approximately 20% of dementias in patients without CKD.9 Delirium is a syndrome of acute cognitive impairment characterized by acute onset, inattention, disorganized thinking, and an altered state of consciousness, including sleepewake cycle disturbance. Other common symptoms include psychomotor agitation or retardation, memory loss, and disorientation. Delirium is defined by abrupt onset and fluctuating course, in contrast to the chronic insidious progressive nature of dementia. Delirium was previously believed to be transient. It is now established, however, that delirium often leads to sustained cognitive decline, especially in patients with preexisting dementia, and to a loss of on average one activity of daily living over 6 months of follow-up in non-CKD patients.10e12 Delirium is often due to an acute intercurrent medical condition such as a urinary tract infection, a medication side effect, or electrolyte imbalance. Interventions that result in bedrestriction or decreased mobility such as physical restraints, urinary catheters, or intravenous lines also increase the risk of delirium. Delirium is often multifactorial, so the actual cause may be difficult to ascertain. The presence of dementia increases the risk of delirium, and they often coexist. As delirium occurs three times as often in patients with dementia13 as in those without, the development of delirium should trigger suspicion of an underlying dementia. However, because the symptoms of delirium are difficult to distinguish from those of dementia, for patients with no previous diagnosis of cognitive impairment who develop delirium, it is

recommended to wait for a period of approximately a month after the delirium episode to conduct a full dementia assessment. The Confusion Assessment Method is the most commonly used instrument to assess the presence of delirium. The Confusion Assessment Method is a brief standardized validated instrument with questions regarding four features: (1) acute onset or fluctuating course, (2) inattention, (3) disorganized thinking, and (4) altered level of consciousness (such as hypervigilance, lethargy, or stupor). The diagnosis of delirium requires the presence of features 1 and 2, and either 3 or 4. Other symptoms may be present such as disorientation, psychomotor agitation or retardation, hallucinations, sleepewake cycle disturbance, and memory loss.14

Epidemiology of Cognitive Impairment in CKD The true population prevalence and incidence of cognitive impairment in CKD are difficult to estimate because most studies were not population based but conducted in clinic or referral populations. Among 80 stage 3e4 CKD clinic patients, 23% had severely impaired executive function and 28% scored poorly on delayed memory test.15 In the 2006 US Renal Data System Annual Data Report using Medicare claims data, the prevalence of dementia was 7.6% in the CKD cohort, increasing to 16.8% among patients aged 85 years or older.16 However, these rates are substantially underestimated because Medicare claims are an insensitive measure of dementia in populations in whom cognitive function is infrequently assessed. Multiple reports describe a graded cross-sectional relationship between estimated glomerular filtration rate (eGFR) and cognitive impairment. As renal function declines, so does cognitive function.17e20 In the Reasons for Geographic and Racial Differences in Stroke study, the prevalence of cognitive impairment increased with declining eGFR starting at eGFR<60 mL/min/1.73 m2 and paralleled the prevalence of cerebrovascular disease (Figure 29.1).18e20 In the Heart, Estrogen/Progesterone Study among menopausal women, each 10 mL/min/ 1.73 m2 decrement in eGFR corresponded to an approximately 15e25% increase in risk of impairment in executive function, language, and memory.19 Using a cognitive battery, the Chronic Renal Insufficiency Cohort study found that eGFR<30 compared with 45e59 mL/min/1.73 m2 was associated with greater impairment in most cognitive domains.20 The Systolic Blood Pressure Intervention Trial (SPRINT) was a study of intensive compared with standard blood pressure goals. Patients with diabetes and those with a history of stroke were excluded. Of the more than 9000 SPRINT participants, 2707 had complete

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443

30

Subjects (%)

25

Cognitive impairment Cerebrovascular disease

20 15 10 5 0

> = 100 90 – 99 80 – 89 70 – 79 60 – 69 50 – 59 40 – 49 30 – 39 20 – 29 10 – 19 Estimated GFR (in ml/min/1.73 m2)

FIGURE 29.1 Unadjusted prevalence of cognitive impairment and cerebrovascular disease by estimated glomerular filtration rate (eGFR). Reference 18, Copyright 2008 Elsevier Inc, reproduced with permission.

assessments of cognitive function. A subset of 637 participants underwent brain imaging. Mean age was 68 years, more than a third were women, and almost a third were Black. Mean eGFR was 70.8
20.9 mL/min/1.73 m2. Median urine albumin:creatinine ratio (UACR) was 9.7 mg/g. In this cross-sectional assessment, higher UACR was associated with worse global cognitive function, executive function, memory, and attention, in adjusted analyses. Increased urinary albumin excretion was associated with cognitive performance typical of older people. Lower eGFR was independently associated with worse global cognitive function and memory. In adjusted models, higher urinary albumin excretion was associated with larger abnormal white matter volume. There was no relationship detected between this parameter and eGFR. The findings suggested vascular disease may be associated with abnormal cognitive function in this population.21 A longitudinal relation between baseline eGFR and declines in global cognitive function and cognitive domains has also been reported.18,22e28 In the Cardiovascular Health Study, serum creatinine concentration (S[Cr]) >1.5 mg/dL in men and >1.3 mg/dL in women was associated with a 37% increased risk of incident dementia over 6 years.27 In the Health, Aging, and Body Composition (Health ABC) Study, adjusted odds ratios for cognitive decline were 1.32 for baseline eGFR 45e59 mL/ min/1.73 m2 and 2.43 for <45 mL/min/1.73 m2 (stage 3b CKD). In the Rush Memory and Aging Project, the effect on global cognitive function of 15 mL/min/1.73 m2 lower eGFR at baseline was similar to 3 years of aging and equivalent to about 75% of the effect of the APOE-4 allele, which confers up to twofold increased risk of AD.29 Baseline eGFR also predicted cognitive decline in the specific cognitive domains of memory and verbal fluency. Decline in eGFR over 5 years was associated

with decline in global cognition, verbal episodic memory, and abstract reasoning in the Maine-Syracuse Longitudinal Study of 590 community-dwelling individuals with mean age of 62 years, and mean baseline eGFR of 78.4 mL/min/1.73 m2. In that study, a decline in eGFR of 30 mL/min/1.73 m2 over 5 years was equivalent to a decline in global cognitive function of approximately 7 years of aging.28 Serum cystatin C concentration is another parameter used to measure renal function that has been studied in relation to cognitive impairment. Cystatin C colocalizes with amyloid in the brains of AD patients, and elevated serum cystatin C concentrations in the Health ABC study were shown to be associated with increased risk of baseline cognitive impairment and cognitive decline.30 Studies in animal models suggest that higher concentrations of cystatin C may have a protective effect against AD.31 Albuminuria may be a more sensitive biomarker for cognitive impairment than eGFR both cross-sectionally and longitudinally, because it is a measure of microvascular endothelial function and more likely to reflect similar vascular integrity in the cerebrovascular system.32e34 In the Action to Control Cardiovascular Risk in Diabetes-Memory in Diabetes (ACCORDMIND) trial,32 urinary albumin excretion, measured as albumin:creatinine ratio (ACR) >30 mg/mg, was associated with performance in the lowest tertile on a verbal memory test and was equivalent to 3.6 years of aging on the Digit Symbol Substitution Test of processing speed/executive function. In contrast, eGFR was not associated with any cognitive measure in that study. In the Nurses’ Health Study, ACR levels as low as 5 mg/ mg were associated with cognitive decline equivalent to 2e7 years of aging in global cognitive function, verbal memory, and verbal fluency.33

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Pathophysiology of Cognitive Impairment in CKD: the BraineKidney Connection The pathophysiology of cognitive impairment in CKD may be an accelerated model of vascular cognitive impairment, superimposed on and parallel with mechanisms leading to neurodegenerative disease such as AD. Cognitive impairment in CKD is nonlinear and multifaceted. Ischemic cerebrovascular disease, including smallvessel arteriolar disease, is central to the model as both a common intermediary outcome and a major contributor to chronic cognitive impairment. Chronic inflammation and underlying vascular endothelial pathology also appear to play substantial roles. The brain and kidneys can be considered end organs on parallel trajectories subject to shared cardiovascular risk factors and microvascular pathologic processes mediated by inflammatory35 and oxidative processes, occurring in similar low-resistance vascular beds and endothelial structures.36 Impaired endothelial function in the brain manifests as bloodebrain barrier defects,37,38 and increased susceptibility to microinfarcts, lacunar infarcts, and white matter changes.39 Similarly, impaired endothelial function in the kidney manifests as impaired glomerular filtration with secondary increased glomerular permeability, or proteinuria. Independently, the effects of uremic toxins, disrupted calciumephosphate metabolism, other metabolic disturbances, and a potential genetic predisposition to exaggerated inflammatory response may accelerate the rate of cognitive decline in CKD patients.40 At the cellular

and molecular level in the kidney, microvascular endothelial dysfunction in the glomerulus leads to abnormal glomerular permeability, which may trigger tubulointerstitial inflammation, secondary renal fibrosis, and progression of CKD.41 Mitochondrial dysfunction that triggers inflammation may be prevalent in CKD.42

Uremic Encephalopathy Uremic encephalopathy is a complication of both acute and chronic renal diseases. Uremic encephalopathy is characterized by a general sensorial clouding and may include other features such as headaches, dysarthria, gate instability, asterixis, action tremors, convulsions, and multifocal myoclonus.43,44 If untreated, uremic encephalopathy can progress to coma. Uremic encephalopathy is generally attributed to the accumulation of uremic toxins, although there may be additional CKD-related contributions related to hormonal dysregulation, hypertension, fluid and electrolyte disturbances, and drug toxicity. Symptoms of uremic encephalopathy generally improve with dialysis or renal transplantation.

Model of Pathways Leading to Cognitive Impairment in CKD Several models of the mechanisms of cognitive impairment in CKD patients have been proposed.45e47 Figure 29.2 describes a modified version of a model previously proposed by Kurella and Yaffe.47

Shared risk factors Age Non-white race Low education/low socioeconomic status Diabetes Hypertension Hyperlipidemia Genetics-APOE-4, renal disease, other Others

Nephrogenic risk factors Albuminuria Anemia Retention of uremic solutes Inflammation Oxidative stress Vascular calcification Hyponatremia Erythropoiesis-stimulating agents Others

Neurodegenerative disease

Microvascular disease

Stroke

Direct neuronal injury Increased stroke risk

Stroke

Cognitive impairment FIGURE 29.2

Mechanisms of cognitive impairment in chronic kidney disease patients. Adapted from reference 47. Copyright 2011 Macmillan Publishers Ltd, reproduced with permission.

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Risk Factors for Cognitive Impairment in CKD Shared risk factors that contribute to renal disease and low brain reserve appear in the top box (Figure 29.2). Risk factors for cognitive impairment in CKD patients are similar to those for dementia due to AD, vascular cognitive impairment, and combined types of dementia in the non-CKD population.48e50 Lifestyle factors including the Mediterranean diet51e53 and physical activity54 appear to protect against cognitive impairment and incident cognitive decline in the general population. APOE-4, presenilin-1, other genetic variants, and Sortilin-related receptor 1 protein predispose to neurodegeneration. The gene ABCA7 (ATP-binding cassette transporter) is associated with almost double the risk of AD in African Americans, an effect similar to that of the APOE-4 gene in white patients.55 Nephrogenic factors appear in the middle box (Figure 29.2). Both shared and nephrogenic risk factors increase the risk of neurodegenerative disease, microvascular disease including white matter disease, and macrovascular disease or stroke. Each of these outcomes can contribute to cognitive impairment via direct neuronal injury. The role of erythropoiesis-stimulating agents (ESAs) in mediating cognitive impairment in CKD patients is controversial. Higher doses of ESAs increase risk of stroke in CKD patients as delineated in the Trial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT) study,56 but these agents may also decrease risk of neuronal apoptosis and secondary cognitive impairment.57 In CKD populations, aging and nonvascular factors are overshadowed by a 10e15% annual stroke incidence,58 a high prevalence of cardiovascular risk factors including hypertension (80%) and diabetes (50e60%),16 markedly elevated levels of inflammatory markers and homocysteine,59 vascular endothelial dysfunction, cardiovascular events, and carotid atherosclerosis, all of which contribute to vascular dementia and neurodegenerative diseases such as AD60 (Figure 29.2). The additional contributions of factors secondary to CKD, such as uremia, anemia, higher circulating levels of guanidine compounds,61 endothelial dysfunction, and metabolic disturbances, are not well defined.45 In the Health ABC study, CKD accounted for approximately 10% of the cognitive impairment risk that was unexplained by demographic factors and comorbid conditions.26

Importance of Making the Diagnosis of Cognitive Impairment: Avoiding Adverse Outcomes of a Missed Diagnosis It is important for the clinician to become comfortable using brief cognitive screening instruments to make the

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diagnosis of cognitive impairment in CKD patients, to avoid multiple potential adverse outcomes of a missed diagnosis. Potential adverse outcomes related to missed diagnoses potentially include undetected medication and dietary noncompliance, secondary increased iatrogenic hospitalizations, and inability to make informed decisions regarding dialysis initiation. Dementia in CKD patients more than doubles the risk of death and is associated with a greater risk of death than in HD patients (hazard ratios [HRs] 2.26 and 1.86, respectively).16 Advantages of early diagnosis of dementia in non-CKD patients also apply to CKD patients. These include substantial savings for the family and society due to decreased crisis-driven hospitalizations and delayed nursing home entry by up to 1.5 years.62 Other advantages of early diagnosis are that it potentially (a) identifies the most likely causes of cognitive impairment, including potentially treatable causes such as depression, delirium, or recent subdural hematoma; (b) enables early treatment to potentially delay progression; (c) allows enrollment in clinical trials; (d) helps families understand the symptoms of cognitive impairment and associated behaviors and obtain help from dementia specialists in managing them; (e) provides families with appropriate referrals to the Alzheimer’s Association and dementia support groups; (f) enables improved management of comorbid conditions, decreases anxiety for patients and caregivers, and avoids crisis-driven acute and long-term care62; and (g) allows patients and families to plan together for future care and financial arrangements before dementia becomes advanced.

Cognitive Impairment Screening Instruments Cognitive impairment screening instruments vary in sensitivity and length. Several instruments allow brief screening in the clinic setting. Most of these instruments can be administered by nonhealthcare professionals (Table 29.1).47 The briefest test is the 3-minute MiniCog,63 which is insensitive to MCI but identifies most dementia cases. The Mini-Cog consists of immediate recall of three words, followed by clock-drawing and then uncued recall of the same three words. The 8minute Folstein’s Mini-Mental State Exam is the most commonly used brief instrument, but it is copyrighted and does not measure executive functions.4 Two longer assessment tools (8e10 minutes) provide more information and are more sensitive for diagnosing MCI and measuring executive function.64 The St. Louis Mental Status test (SLUMS) and the Montreal Cognitive Assessment (MOCA) are freely available. Both test the major cognitive domains of verbal memory, executive function, and visuospatial function.65 The MOCA is

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446 TABLE 29.1

29. NEUROLOGIC COMPLICATIONS OF CHRONIC KIDNEY DISEASE

Performance Characteristics of Selected Dementia Screening Instruments

Specificity

Positive Screen Cutpoint

Validation Reference Standard

85

85

Various

Clinical assessment for dementia

No

Less cultural bias. Evaluates executive function

Visuospatial executive function recall

76

89

2

Neuropsychological battery

No

Clock-drawing task plus uncued recall of three words

7e10

Orientation, recall attention visuospatial

71e92

56e96

23e25

Clinical assessment for dementia

No

Norms available. Copyrighted. Does not assess executive function well

St. Louis 7e10 University Mental Status Exam (SLUMS)

Orientation, recall attention visuospatial executive function

98e100

91e100

21.5

Clinical assessment for dementia

No

Evaluates executive function

Montreal Cognitive Assessment (MoCA)

Orientation, recall attention visuospatial, verbal fluency executive function

100

87

25

Neuropsychological battery

No

Evaluates executive function

Administration Domains Time (minutes) Evaluated

Sensitivity

Clock-drawing task

1e3

Visuospatial executive function

Mini-Cog

3e4

Mini-Mental State Exam (MMSE)

Instrument

10

Validated in CKD or ESRD

Comments

CKD, chronic kidney disease; ESRD, end-stage renal disease. Note: the sensitivity, specificity, and positive screen cutpoints listed above are for the general population, as most of the above tests have not been validated in patients with CKD. Adapted from reference 47. Copyright 2011 Macmillan Publishers Ltd, reproduced with permission.

now used as a global cognitive screening examination in ongoing and recently completed clinical trials, such as SPRINT, which has enrolled CKD participants.66 Because cognitive impairment is so common in CKD patients, annual cognitive screening is strongly recommended, especially before dialysis initiation to assess ability to make informed decisions.47

Diagnosis of Cognitive Impairment The most important component in the diagnosis of cognitive impairment is an accurate history. The onset, duration, fluctuation, and nature and severity of cognitive impairment must be clarified, including behavioral symptoms, functional impairment, and coexistent symptoms of depression or sleep disorders. Elucidating a comprehensive history often requires interviewing caregivers and multiple family members. A physical examination and neurologic examination also need to be performed. For patients with previously undiagnosed cognitive impairment, brain imaging with computed tomography or magnetic resonance imaging is recommended to rule out potentially remediable causes such as

subdural hematomas, brain tumors, and infection, and to detect stroke and severity and localization of brain atrophy and white matter disease. Brain imaging is critical if focal neurologic signs are present. Standard laboratory screening tests include complete blood count, chemistry panel, vitamin B12 level, and thyroid-stimulating hormone level to exclude common reversible hematologic or metabolic causes of cognitive dysfunction. For patients with high premorbid intelligence or for whom assessment of ability to make informed decisions is needed, a referral for detailed neuropsychologic testing is recommended. Depression commonly coexists with early dementia, and treatment with selective serotonin reuptake inhibitors is usually well tolerated. Delirium must be ruled out as a cause of acute cognitive impairment using the Confusion Assessment Method.14

Treatment of Cognitive Impairment in CKD Patients There have been no clinical trials in CKD patients of dementia medications that are currently used in the general population. Several treatment options are available,

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but their efficacy is controversial. These medications may be effective for 6e24 months in delaying the progression of cognitive impairment.7 Any reversal of symptoms is minimal. The two primary classes of dementia medications are cholinesterase inhibitors and N-methyl D-aspartate receptor antagonists. The cholinesterase inhibitors include donepezil, rivastigmine67 (available in oral form and as a patch), and galantamine.68 Their primary side effects are gastrointestinal disturbances. These include nausea and loose stools for approximately the first week, which usually resolve, mild anorexia and weight loss, dizziness, and, less frequently, insomnia. The medication should be withdrawn if severe nightmares occur, as they usually do not resolve. For CKD patients, a lower maximum dose of galanatime is recommended. Galantamine is contraindicated in end-stage renal disease (ESRD) patients. Memantine,69 the N-methyl D-aspartate receptor antagonist, causes fewer gastrointestinal side effects except constipation but can occasionally cause acute delirium after initial doses. The drug should be discontinued if this occurs. Dose reduction is recommended for patients with eGFR<30 mL/min/1.73 m2. Behavioral disturbances such as increased agitation or paranoia, associated with moderate to severe dementia, are common and very stressful for patients and their caregivers. To evaluate new behavioral symptoms, a full clinical assessment should be conducted to rule out pain or delirium secondary to an acute medical illness, especially urinary tract infections or medication changes. Behavioral disturbances can also be due to environmental triggers such as changes in location or caregivers, or to nursing shift changes in the chronic care setting. Only after behavioral management trials and treatment of acute medical conditions have been employed should pharmacologic treatment be considered under guidance from a dementia expert because medication effectiveness is not well established and side effects can be substantial.70 Atypical antipsychotics specifically are associated with modestly increased risk of cardiovascular disease and death.71 In the SPRINT MIND study, completed after the main study was stopped by the Data Safety Monitoring Board, the primary cognitive outcome was occurrence of probable dementia. Secondary cognitive outcomes included development of MCI and a composite outcome of MCI or probable dementia.72 Among the 9361 randomized participants, 91.5% completed at least one follow-up cognitive assessment after a median intervention period of approximately 3.3 years. After a median follow-up of a little more than 5 years, probable dementia developed in a lower proportion of participants in the intensive treatment group compared to the standard treatment group (HR, 0.83; 95% CI, 0.67e1.04). Intensive BP control

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was associated with reduced risk of MCI (HR, 0.81; 95% CI, 0.69e0.95) and the combined rate of MCI or probable dementia (HR, 0.85; 95% CI, 0.74e0.97). The intervention did not result in a detectable significant reduction in the risk of developing probable dementia, perhaps because of reduced power due to early termination of the study, and fewer than expected cases of dementia. In subsequent analyses, the effects were determined to be similar in subgroups. The study therefore holds great promise for prevention of dementia in the CKD population, but further work will be necessary to establish definitive conclusions and treatment recommendations.73

Health Policy Implications Currently, neither a cognitive history nor an assessment is required for CKD patients before, at, or any time after dialysis initiation. Given the rate of cognitive impairment in advanced CKD, many patients may lack adequate judgment to weigh the benefits and risks of initiating dialysis, or to withdraw from dialysis once initiated. Therefore there is a need to screen for cognitive impairment before dialysis initiation. The prognosis for HD patients with dementia is poor. In one study of nursing home ESRD patients, most experienced a rapid decline in physical function and more than half died 6 months after initiation.74 The 2010 Renal Physicians’ Association guidelines suggest that foregoing dialysis or withdrawing it from patients with advanced dementia is appropriate. Each case requires individual consideration and careful shared decision-making with patients and families.

Conclusion Several studies have confirmed a graded association between renal function and cognitive function. Symptomatic and subclinical ischemic cerebrovascular disease, neurodegenerative disease, and inflammation appear to play large roles in a proposed model of accelerated vascular cognitive impairment in CKD patients. Annual and predialysis cognitive screening in CKD patients is critical to confirm a diagnosis of cognitive impairment, avoid adverse outcomes of missed diagnoses, and improve clinician awareness of the potential effects of cognitive impairment on medication, fluid, and dietary compliance, and on the ability to make informed decisions regarding dialysis initiation. While much remains to be learned regarding the pathophysiology of cognitive impairment in patients with CKD, the public health implications of its substantial burden are immediate. The role and timing of intensive blood pressure control in CKD patients at risk of developing dementia requires further study.

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STROKE IN CHRONIC KIDNEY DISEASE Cerebrovascular disease including stroke is a common, serious, and disabling disease within the CKD population. An update to the definition of stroke by the American Heart Association and affirmed by the American Academy of Neurology states that stroke includes the following: central nervous system (CNS) infarction including silent CNS infarction, ischemic stroke, intracerebral hemorrhage (ICH) including silent cerebral hemorrhage, stroke caused by ICH, subarachnoid hemorrhage (SAH), stroke caused by SAH, stroke caused by cerebral venous thrombosis, and stroke not otherwise specified.75 Even though the definition of stroke is complex, studies in patients with CKD often focus on broadly defined stroke criteria, such as ischemic stroke, or ICH. Studies also include emerging data regarding CNS infarction (including silent CNS infarction). Both conditions can lead to cognitive impairment and cognitive deficits. Stroke is common in all stages of CKD but increases significantly as kidney function worsens. The incident stroke rate is 1.9e3.6 times higher (depending on age, eGFR, and race) for those with incident CKD compared to those without CKD, and the risk of stroke in stage 5 CKD is double that of stage 3. A critical period, studied in patients who were at least 67 years old and had Medicare as the primary payor, is the time before and after the initiation of dialysis. A year before initiation, the baseline stroke rate in CKD patients was 0.15%e0.20% of patients per month. Stroke rates began rising approximately 3 months before initiation of dialysis and increased two- to threefold during the month before initiation, peaking during the month after the start of dialysis. The findings suggest the transition from CKD care to ESRD therapy may be fraught and that care must be taken to decrease the incidence of stroke during this period.76 The rate of incident stroke in incident CKD Medicare patients ages 67e85 years as reported in the 2009 USRDS Annual Data Report is estimated at 9.0/100 patientyears (pt-yrs) (Figure 29.3). The incident stroke rate in prevalent CKD patients is about two-thirds of the rate in incident CKD patients, or about 5e6.0/100 pt-yrs overall. The effect of CKD on stroke risk is even greater in younger individuals. Using the Ingenix i3 database of community-dwelling individuals aged 50e64 years, stroke is 4.6e7.6 times more frequent in incident CKD patients than in non-CKD patients. The absolute incidence is lower in this younger cohort, ranging from approximately 1.6e2.2/100 pt-yrs, or about one quarter the rate of the older Medicare cohort. In both the incident and prevalent CKD cohorts, the risk of stroke

increases substantially with age and CKD stage. In CKD, the risk of incident stroke is also 50% higher for African Americans compared to white Medicare beneficiaries, similar to reports in non-CKD populations.58 Silent stroke describes lesions found incidentally on brain imaging in asymptomatic patients. Silent stroke increases the risk of subsequent stroke by over 10-fold (2.79/year compared to 0.21%/year) compared to those without previous silent stroke in the general population.77

Stroke Risk in CKD Results from several observational studies suggest that CKD patients are at significantly increased risk of acute stroke compared with those without CKD.74e79 This excess risk is not explained by common comorbid conditions or traditional vascular risk factors. In a meta-analysis of 21 published reports, CKD, defined as eGFR less than 60 mL/min/1.73 m2, was associated with a 43% greater risk of stroke (95% confidence interval [CI], 1.31e1.57).79 As GFR decreases the rate of stroke increases. A doseeresponse relationship was observed. Risk was increased 22% for patients with eGFR 40e59 and 77% for those with eGFR less than 40 mL/min/1.73 m2. Associations did not differ for hemorrhagic vs. ischemic stroke but were significantly greater for fatal stroke (relative risk [RR] 1.97) than for a combined outcome of fatal and nonfatal stroke (RR 1.37). However, overall heterogeneity was substantial across individual studies in a magnitude of reported associations and in types of patients studied (e.g., atrial fibrillation, postmenopausal women with coronary disease), methods of estimating renal function, and adjustment covariates included in statistical models. Albuminuria is an independent risk factor for stroke even after accounting for reduced GFR. For example, among community-dwelling older adults, microalbuminuria was associated with nearly doubled risk of incident stroke among those with and without decreased eGFR.80 These results were confirmed by a meta-analysis of 12 observational studies including 48,596 participants. Albuminuria was associated with a 92% greater RR of stroke compared to those without albuminuria. This association was significant in studies conducted in the general population, in diabetic and hypertensive patients, and in patients with prior stroke.81

Risk Factors and Mediators of Stroke Few studies have specifically examined the factors that predict stroke in CKD patients, or that may potentially mediate the relationship between CKD and stroke

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STROKE IN CHRONIC KIDNEY DISEASE

Medicare

Ingenix i3

Rate per 100 patient years

15

10

3.0 65 – 74 75 – 84 85+

50 – 54 55 – 59 60 – 64

2.0

1.0

5

0.0

0 No CKD/ After Stg 3–5 Stg 3 before CKD CKD

Stg 4

Stg 5

No CKD

Any CKD

FIGURE 29.3 Rate of incident of stroke in incident chronic kidney disease (CKD) and non-CKD patients, by age and CKD status. Reference 58. The data reported here have been supplied by the United States Renal Data System (USRDS). The interpretation and reporting of these data are the responsibility of the author(s) and in no way should be seen as an official policy or interpretation of the US government.

(Figure 29.4). In general, estimated associations between CKD and stroke are attenuated after adjustment for multiple vascular risk factors and prevalent cardiac disease, raising the possibility that these associations represent the effect of unmeasured or residual confounding by other vascular risk factors or comorbidity severity. Alternatively, shared susceptibility to adverse end-organ effects in the brain and kidneys from vascular disease could identify individuals vulnerable to both stroke and renal disease.36 This seems a plausible explanation for the increased stroke risk in patients with microalbuminuria and intact GFR, for whom low-level elevations in albuminuria may identify systemic vasculopathy with increased risk of major vascular events. For patients with more impaired renal function, a direct causal effect of CKD on stroke risk is plausible, with potential mediators including retained uremic

toxins, and metabolic consequences of decreased renal function including hyperhomocysteinemia and altered mineral metabolism, increased oxidative stress and inflammation, and anemia. The role of these factors in the pathogenesis of stroke in CKD patients has not been examined in detail in epidemiologic studies, although evidence indicates that hyperphosphatemia is associated with greater cardiovascular mortality in CKD, and greater serum phosphate concentration is associated with increased stroke risk in the general population.82,83 Evidence indicates that CKD may interact synergistically with anemia to contribute to stroke risk. Among 3015 adult diabetic participants in a combined sample of four general population cohorts, anemia in CKD was associated with an 81% greater risk of stroke compared to those without anemia. In contrast, anemia

CKD and Stroke – pathologic mechanisms Comorbidity: HTN DM CHF Afib CKD

Cerebrovascular atherosclerosis and arteriosclerosis

Acute stroke

Anemia Hyperphosphatemia Hyperhomocyteinemia

Endothelial dysfunction Microinflammation Oxidative stress

FIGURE 29.4

Pathologic mechanisms of chronic kidney disease (CKD) and stroke. Afib, atrial fibrillation; CHF, congestive heart failure; DM, diabetes mellitus; HTN, hypertension.

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did not predict incident stroke among participants without CKD.84 Physiological studies suggest that chronic anemia can cause adverse remodeling of the left ventricle and the peripheral arteries, leading to maladaptive cardiac hypertrophy and arteriosclerosis.85 The resulting vascular stiffening may contribute to endorgan damage including cerebral ischemic injury such as acute stroke.

Erythropoiesis-Stimulating Agents and Stroke Risk Given the epidemiological and physiologic data linking anemia to excess stroke risk in CKD, pharmacological correction of anemia with ESAs might be expected to be an effective preventive therapy. In addition to stimulating erythropoiesis, ESAs show direct neuroprotective effects in experimental models of cerebral ischemia.86 Conversely, ESAs may have direct and indirect effects that could plausibly increase the risk of stroke, including increased blood pressure, acute endothelial dysfunction, platelet activation, and decreased cerebral blood flow due to rapid changes in red cell mass. Results of large randomized clinical trials and observational studies conducted among CKD patients suggest that ESAs, especially when dosed to target high hemoglobin levels, increase the risk of stroke to a clinically significant degree. In the TREAT study, diabetic nonedialysis-dependent CKD patients with anemia were randomized to weekly darbepoetin with a goal hemoglobin of 13 g/dL or to placebo. During followup, the RR of fatal or nonfatal stroke (a secondary trial endpoint) was 92% greater in the active than in the control group.56 In a post hoc multivariate analysis, this effect of treatment on stroke risk was similar to the effect of prior stroke. This analysis failed to find an effect of on-treatment changes in blood pressure, hemoglobin, or platelet count with risk of stroke.87 In contrast, no excess stroke risk was identified among 1432 anemic CKD patients in the Correction of Hemoglobin and Outcomes in Renal Insufficiency (CHOIR) trial randomized to epoetin alfa with high (13.5 g/dL) vs. normal (11 g/dL) hemoglobin targets.88 However, this trial was terminated early for futility, and the number of observed stroke events was too small to allow conclusions regarding the cerebrovascular safety of the intervention. In an observational case-control study among Veterans Administration outpatients with non-dialysisdependent CKD and anemia, those with prior ESA treatment were 30% more likely to be stroke cases, after adjustment for potential confounders.89 The association between ESA use and stroke was particularly strong

(odds ratio 1.85) among CKD patients with evidence of cancer under active oncology care, whereas no significant association was observed among CKD patients without cancer (odds ratio 1.07). ESA-treated CKD patients with active cancer received initial ESA doses 2.5e4 times higher than those without cancer, despite similar pretreatment hemoglobin concentrations. Whether their greater stroke risk compared to ESAtreated patients without cancer is explained by the higher ESA dosing they received, or by other stroke risk factors concurrent in cancer patientsdsuch as greater inflammation or increased thrombotic potentialdis unclear. Patients with active cancer were specifically excluded from both the TREAT and the CHOIR studies.

Primary and Secondary Stroke Prevention No RCTs have been designed specifically to test the efficacy of stroke prevention strategies in patients with nonedialysis-dependent CKD. However, limited data regarding treatment effects are derived from post hoc subgroup analyses of RCTs conducted in the general population, from RCTs in CKD populations of therapies designed to prevent all cardiovascular events (for which stroke was a secondary or tertiary outcome), and from observational cohort studies. For patients with symptomatic severe (70% diameter reduction) carotid stenosis, carotid endarterectomy (CEA) has long been established as an effective intervention for secondary stroke prevention.90 However, observational studies have suggested that none dialysis-dependent CKD patients have a much higher risk of perioperative mortality and other complications after CEA,91,92 raising questions about the riskebenefit tradeoff in these patients. In a post hoc subgroup analysis of data from the North American Symptomatic Carotid Endarterectomy Trial (NASCET), patients with stage 3 CKD (mean eGFR 49 mL/min/1.73 m2) had a fourfold higher risk of cardiac complications than those with normal renal function, but no excess risk of mortality.93 However, they also experienced a markedly greater benefit from CEA than from standard medical therapy, with an 82% RR reduction of recurrent stroke. In contrast, CKD patients with moderate carotid stenosis (50e69% diameter reduction) experienced no significant benefit in stroke reduction. Atrial fibrillation is an important risk factor for stroke in the general population, and risk of stroke is 40% greater among atrial fibrillation patients who also have CKD stage 3B or higher.94 Warfarin therapy has been the mainstay of stroke prevention among atrial fibrillation patients estimated to be at high stroke risk. However, reports have suggested that warfarin use in

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STROKE IN CHRONIC KIDNEY DISEASE

maintenance dialysis patients may be associated with a paradoxically increased risk of stroke,95 especially hemorrhagic stroke,96 raising concerns about its safety in nonedialysis-dependent CKD patients. Hart et al. performed a post hoc subgroup analysis of the Stroke Prevention in Atrial Fibrillation (SPAF) 3 trial, which compared adjusted-dose warfarin with combination aspirin plus fixed low-dose warfarin among high-risk atrial fibrillation patients.97 Among the 805 participants with stage 3 CKD (42%) (mean eGFR 49 mL/min/ 1.73 m2), adjusted-dose warfarin reduced the risk of ischemic stroke or systemic thromboembolism by 76%, an effect size similar to that among participants with normal eGFR. No excess risk of major hemorrhage was observed with adjusted-dose warfarin in the CKD participants. As the renal impairment was relatively modest, whether the same riskebenefit ratio favoring warfarin also applies to more advanced CKD is unclear. Somewhat discrepant results were reported from an observational cohort study among patients with nonvalvular atrial fibrillation, using Danish national patient registry data.98 CKD not requiring renal replacement therapy was identified by diagnosis codes, not by renal function measurement, likely resulting in significant underascertainment. Warfarin use was associated with a 16% lower risk of stroke or systemic thromboembolism (RR 0.84), but this association did not meet the conventional threshold of significance (p ¼ 0.07). However, warfarin-treated participants were at a 36% greater risk for major bleeding after other risk factors were accounted for. Warfarin has been a mainstay of oral anticoagulation, but the new oral anticoagulants (NOACs) such as dabigatran,99 rivaroxaban,100 and apixaban101 are increasingly being used, as they have been shown to be efficacious for non-CKD patients. In addition, the NOACs provide increased simplicity for healthcare management because they do not require laboratory monitoring, have fewer drugedrug interactions, and necessitate fewer dietary restrictions (compared to vitamin K in warfarin use). However, NOAC use can be complex in CKD patients because NOACs rely at least partly on renal excretion for elimination. Use of NOACs has not been studied in clinical trials specifically designed with CKD patients. Importantly, the major trials that demonstrated efficacy for SPAF excluded patients with advanced (typically stage 4 or higher CKD) renal impairment.102 Eikelboom et al. conducted a post hoc subgroup analysis of the Apixaban Versus Acetylsalicylic Acid to Prevent Stroke in Atrial Fibrillation Patients Who Have Failed or are Unsuitable for Vitamin K Antagonist Treatment trial, which compared apixaban with aspirin among chronic atrial fibrillation patients who were not candidates for warfarin.103 Apixaban was dose-reduced among patients with S[Cr] greater

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than 1.5 mg/dL. Results suggested a similar treatment advantage of apixaban over aspirin among patients with stage 3 CKD (mean eGFR 49 mL/min/1.73 m2) compared with non-CKD patients, with a RR reduction of 68%. There was no excess risk of major bleeding with apixaban among CKD patients. In the Apixaban for Reduction In Stroke and Other Thromboembolic Events in Atrial Fibrillation trial comparing apixaban to warfarin, the effect of apixaban also did not differ significantly by renal function.104 (Patients with creatinine clearance less than 30 mL/min were excluded.) Apixaban, compared with warfarin, reduced the risk of hemorrhage among participants with eGFR less than 50 mL/min/1.73 m2 (HR 0.48; 95% CI 0.37e0.64) to a greater extent than among those with intact renal function. Additional studies regarding the safety and efficacy of apixaban in various levels of renal disease have demonstrated the net benefit of apixaban over warfarin.105 Similar evidence for a favorable riskebenefit ratio in CKD patients was reported for rivaroxaban vs. warfarin in a post hoc subgroup analysis of the Rivaroxaban OnceDaily, Oral, Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET-AF) trial.106,107 Dabigatranda direct thrombin inhibitordis contraindicated in those with eGFR less than 30 mL/min/ 1.73 m2. A subgroup analysis did not find any difference in the effect of dabigatran compared to warfarin for the prevention of stroke or thromboembolism among those with eGFR 30e50 mL/min/1.73 m2 compared to 80 mL/min/1.73 m2.108 However, the relative benefit and risk of dabigatran in stroke prevention in CKD stage 3 patients is a topic of ongoing uncertainty and debate.109 There is no readily available method for monitoring drug concentrations or anticoagulant effects of dabigatran. Unlike warfarin, for which there is extensive experience in reversing, monitoring, and fine-tuning the degree of anticoagulation, the NOACs have emerging methods for reversing anticoagulant effects, which include the development of new medications and development of NOAC-specific strategies. Idarucizumab is a Food and Drug Administrationeapproved monoclonal antibody fragment to reverse dabigatran. Other types of pro-coagulant clotting agents, known as bypass agents, are being studied and used by some to reverse numerous types of NOACs.110 Use of these newer reversal agents need additional study in patients with CKD as concerns about the safety of NOACs in those with renal impairment exist. In addition to the safety concerns in CKD, there are challenges to reversal agent availability, due to lack of widespread stocking of the newer agents and the high price of the reversal agents.

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HMG CoA-reductase inhibitors have been demonstrated to reduce the risk of both initial and recurrent stroke in the general population. However, two large multicenter trials in maintenance HD patients showed no reduction in total stroke with rosuvastatin or atorvastatin vs. placebo, and a doubling of fatal stroke with atorvastatin in the Deutsche Diabetes Dialyze Study (4D) trial.111,112 The Study of Heart and Renal Protection (SHARP) trial examined the effects of simvastatin 20 mg plus ezetimibe 10 mg daily vs. placebo on atherosclerotic events among CKD patients, including those requiring RRT (roughly one-third of the total sample).113 The risk of nonhemorrhagic stroke was reduced by 25% in the active treatment group (RR 0.75; 95% CI, 0.60e0.94). The effects of stroke risk were not reported separately for study participants with nonedialysis-dependent CKD, although there was a significant effect on all atherosclerotic events in this subgroup (RR 0.78). Additional evidence for the effect of statins is provided by subgroup analyses of general population clinical trials. A meta-analysis estimated a summary RR reduction of 39% for fatal and nonfatal strokes (RR 0.61; 95% CI, 0.38e0.98) with statin therapy compared to placebo. However, most included clinical trials constituting this meta-analysis intentionally excluded patients with advanced CKD. Statin therapy did not result in excess risk of major adverse effects, including myalgias, cancer, or abnormal liver or muscle enzyme concentrations. Antiplatelet agents such as glycoprotein IIb/IIIa inhibitors or clopidogrel are recommended for primary and secondary prevention of stroke among patients at high vascular risk.114 However, no clinical trials have specifically examined their effectiveness or safety in CKD patients. There are only limited data from secondary subgroup analyses of clinical trials. A meta-analysis found an “uncertain effect” of these agents on risk of stroke in CKD patients (RR 0.66; CI, 0.16e2.78).115 The risk of minor bleeding was increased by 70% in CKD patients randomized to antiplatelet drugs.

Thrombolytic Therapy Since the late 1990s, tissue plasminogen activator (tPA, or specifically alteplase) has been an important and increasingly utilized treatment for acute stroke, in the general population.116 Guidelines by the American Heart Association and American Stroke Association regarding the treatment of acute ischemic stroke have informed the field regarding the use of alteplase.117 There are several recent outcomes that are important to patients with kidney dysfunction in terms of both efficacy and safety. Participants with a lower eGFR (less than 60 mL/min/1.73 m2) received less benefit from the administration of alteplase, compared to

participants with normal eGFR at 24 hours (coefficient 2.3, 95% CI 3.7 to 0.9; p ¼ 0.002) and at 7 days (coefficient 3.5, 95% CI 5.3 to 1.7; p < 0.001). With modeling, each 10 mL/min/1.73 m2 decline in eGFR was associated with a 0.4 decrease in NIHSS improvement in the setting of alteplase use.118 There are concerns regarding the potential for bleeding and hemorrhage risk that occurs in CKD patients with use of tPA. The safety of tPA in CKD was recently studied by Ovbiagele et al. through the retrospective Get With the Guidelines-Stroke Program (GWTG-Stroke).119 The CKD patients had a higher unadjusted odd of symptomatic intracranial hemorrhage or serious systemic hemorrhage, while also being more likely to die in the hospital (adjusted odds ratio, 1.22; 95% CI: 1.14e1.32) or have an unfavorable functional status at discharge (adjusted odds ratio, 1.13; 95% CI: 1.07e1.19), compared to patients with normal kidney function. This was further studied and confirmed through a meta-analysis of seven studies, which included 7168 CKD patients with IS and treated with tPA to show that there was a higher risk of symptomatic ICH and mortality, while also having an increased risk of poor outcome at 3 months.120

SPRINT The SPRINT trial results showed that the intensive target resulted in a significantly lower rate of major cardiovascular events and death from any cause.66 CKD patients comprised 28% of study participants.121 A SPRINT-CKD subgroup analysis showed that the intensive treatment target had a lower rate of cardiovascular events (HR, 0.81; 95% CI, 0.63e1.05) and all-cause death (HR, 0.72; 95% CI, 0.53e0.99) than the standard treatment group.

Conclusion Patients with nonedialysis-dependent CKD (whether defined by reduced eGFR or albuminuria cutoffs) are at a significantly increased risk of acute stroke compared with individuals without evidence of renal disease. This may represent a direct causal relationship of renal disease on stroke risk, or shared susceptibilities to endorgan damage in both the brain and the kidneys among patients with vascular risk factors or established vascular diseases. Although anemia is associated with a marked increase in stroke risk in CKD patients, and is a plausible mediator for the CKD/stroke association, aggressive correction of anemia with ESAs increases the risk of stroke appreciably. However, the precise mechanisms that mediate this risk, and the relative contributions of ESA dose vs. achieved or targeted

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NEUROLOGICAL AND MUSCULAR DISEASE

hemoglobin levels in increasing risk, remain unclear. A post hoc subgroup analysis suggests a large benefit in secondary prevention of stroke with CEA in selected patients with stage 3 CKD, although at the cost of greater perioperative complications. Statins, warfarin, and dose-adjusted oral anticoagulants in patients with atrial fibrillation appear at least as effective among stage 3 CKD patients as among non-CKD patients for stroke prevention. However, no clinical trial data support the use of warfarin or newer anticoagulants among patients with CKD stage 4 or higher. Use of newer anticoagulants is contraindicated for patients with stage 5 CKD. There is emerging evidence regarding the use of these newer NOAC and DOAC agents in addition to strategies to optimize efficacy, while providing the drug safely in addition to the recent introduction of reversal agents. Data are insufficient to indicate a benefit in stroke prevention of glycoprotein IIb/IIIa inhibitors or clopidogrel as antiplatelet therapy.

NEUROLOGICAL AND MUSCULAR DISEASE Peripheral neuropathies and myopathies are common complications of renal dysfunction and contribute significantly to disability and reduced quality of life. While these conditions are typically more prevalent and more severe in ESRD, it is important to recognize that they often become clinically relevant during the latter stages of CKD. Data on the prevalence of these conditions in CKD are very limited, and it is likely that many of these conditions are either underdiagnosed or misdiagnosed.

Uremic Somatic Polyneuropathy Somatic polyneuropathy is a highly prevalent and potentially disabling complication of advanced CKD.43,44,122 Somatic polyneuropathy is characterized by mixed sensory and motor dysfunction in a symmetrical, length-dependent distribution and typically presents with lower extremity pain, hypoesthesia, and/or paresthesias. Sensory dysfunction expands proximally as the disease progresses and is eventually complicated by weakness and muscle wasting. Estimates of the prevalence of uremic somatic polyneuropathy vary greatly.16,123 This likely relates, in part, to the relatively high prevalence of nonuremic polyneuropathies in CKD populations, which confound diagnosis. Diabetes mellitus is the most common nonuremic etiology of polyneuropathy in CKD populations, although contributions from other nonuremic sources such as alcohol

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use, amyloidosis, and systemic vasculitides should always be considered in the evaluation of such patients.44 The pathogenesis of somatic polyneuropathy in CKD patients remains incompletely understood and may be multifactorial. Advanced stage disease nerve biopsies typically demonstrate axonal degeneration and secondary segmental demyelination.124 Accordingly, nerve conduction studies characteristically show significant reductions in sensory and motor amplitudes, with more moderate reductions in conduction velocities.125 Early theories attributed uremic axonal damage to CKD-related accumulation of “middle molecules,” i.e., renally cleared mid-range molecular weight substances such as b2-microglobulin and parathyroid hormone.126 However, this hypothesis remains unproven, and parathyroid hormone is the only middle molecule for which some evidence of neurotoxicity exists.127,128 More recent work indicates that hyperkalemia may play an important role in pathogenesis.129,130 Management of uremic somatic polyneuropathy includes dialysis and supportive medical therapy. Adequate dialysis generally prevents neuropathic progression, but complete clinical reversibility is uncommon.131 Accordingly, rapid symptom progression remains an important indicator of dialysis insufficiency. Medical management includes nutritional supplementation (with drugs such as biotin, pyridoxine, cobalamin, thiamine), routine foot care, and pain management with tricyclic antidepressants (such as amitriptyline) and anticonvulsants (such as pregabalin).43,44,122 The potential role of hyperkalemia in neurotoxicity has also led to efforts to reduce interdialytic potassium concentrations by dietary therapy.130 Proper management of uremic somatic polyneuropathy also includes diagnosis and treatment of other conditions, which may contribute to polyneuropathy, such as diabetes mellitus and alcohol use. Renal transplantation remains the only treatment that consistently reverses uremic somatic polyneuropathy. Neurological recovery after renal transplantation is often dramatic and rapid, with measurable improvements in nerve conduction velocities days after surgery.132 Clinical recovery is often achieved within several months of transplantation in mild cases but may take longer in more severe cases.133

Uremic Autonomic Neuropathy Dysfunction of autonomic nerves can also occur in patients with advanced CKD.43,44,122 Common autonomic manifestations include postural and interdialytic hypotension, cardiac arrhythmias, impaired sweating, gastrointestinal dysmotility, and sexual dysfunction. Because CKD-related autonomic neuropathies do not

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always coexist with somatic polyneuropathies, it is not clear if they are manifestations of the same or separate processes.134 Parasympathatic dysfunction tends to predominate in CKD-related autonomic neuropathy, whereas sympathetic dysfunction tends to be more common in diabetes-related disease.43 While the true burden and clinical significance of CKD-related autonomic neuropathy is unknown, it is important to note that studies in dialysis patients associate autonomic dysfunction with sudden cardiac death.135,136 Diagnosis of autonomic neuropathy in CKD patients can be challenging, due to the nonspecific nature of clinical symptoms and an incomplete correlation between symptoms and common clinical diagnostics, such as resting ReR interval variation and blood pressure responses to sustained handgrip.134 For example, diagnosis of gastrointestinal dysfunction due to autonomic neuropathy in CKD patients can be particularly challenging because CKD-related uremic toxins, ischemia, and decreased clearance of gastrointestinal hormones may produce similar symptoms. Similarly, diagnosis of sexual dysfunction related to autonomic neuropathy in male and female CKD patients requires exclusion of other factors commonly associated with CKD, including vascular disease, hormonal dysregulation, nutritional deficiencies, depression, and medications.137e139 As with uremic somatic polyneuropathy, renal transplantation provides the most effective treatment for uremic autonomic neuropathy.122 Specific medical therapies include sildenafil for erectile dysfunction, midodrine for hypotension, and renally dosed metoclopramide for impaired gastrointestinal mobility.140

Uremic Mononeuropathies Carpal tunnel syndrome (CTS) is the most common mononeuropathy related to CKD.43,44,122 CTS results from median nerve compression in the carpal tunnel of the wrist and typically presents as weakness or paresthesias in the hand, and dull, aching discomfort in the hand, forearm, or upper arm.141 These symptoms are often exacerbated by repetitive actions, sustained hand positions, and sleep and are mitigated by position changes and hand shaking. Initial sensory symptoms may progress to weakness and atrophy as axonal loss occurs. Diagnosis of CTS is typically clinical, with confirmation provided by electrophysiologic testing when needed.141 Nerve conduction studies characteristically show reductions in distal median conduction velocities due to axonal compression. Conduction amplitudes are typically preserved in the early stages of CTS but may be reduced in later stages if axonal loss occurs. CTS is a long-term complication of renal insufficiency and typically presents after dialysis initiation. The

prevalence of CTS increases with dialysis duration, affecting up to 30% of patients treated with dialysis for more than 10 years.142 The increased prevalence of CTS in CKD and ESRD populations is primarily attributed to amyloidosis from b2-microglobulin accumulation,143,144 although uremic tumoral calcinosis and complications of arteriovenous fistula creation are also implicated.145,146 Treatment of mild CTS involves conservative strategies, such as activity modification and nocturnal splinting.141 Corticosteroid injections may improve symptoms, although relapse is common and procedure-related median nerve injury is a risk. Surgical decompression of the carpal tunnel is indicated for patients with severe symptoms. Renal transplantation remains the only definitive preventive therapy.144

Uremic Pruritus Pruritus is a common complication of advanced CKD.147,148 While uremic pruritus (UP) is often associated with dialysis, most patients develop symptoms before dialysis initiation. UP is usually episodic and more intense at night. Pruritic sensation can be generalized or localized, and patients typically present with skin excoriations. Aside from being an obvious threat to quality of life, UP may have greater implications. The recent large DOPPS II study associated UP with sleep disorders and increased mortality.149 The pathogenesis of UP is incompletely understood and likely multifactorial. Potential contributing factors include calcium and phosphorus metabolic abnormalities, uremic toxin accumulation, cytokine dysregulation and systemic inflammation, cutaneous xerosis, damage and dysregulation of peripheral and somatic nerves, intrinsic opioid system dysregulation, and common comorbid conditions such as advanced age, diabetes mellitus, iron deficiency anemia, and viral hepatitis.147,148 The management of UP remains challenging. To date, there are no definitive therapies for UP short of renal transplant. General treatment strategies include skin emollients, mineral metabolism regulation, and dialysis optimization.147,148 Gabapentin, ultraviolet phototherapy, and nalfurafine, a k-opioid receptor agonist, have also been shown to be effective and well tolerated.150e152 Erythropoietin and previously common therapies such as antihistamines and serotonin receptor antagonists have not been proven effective.147

Uremic Myopathy Uremic myopathy is a general term used to describe the constellation of functional and structural muscle abnormalities commonly associated with chronic

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REFERENCES

uremia.153 Uremic myopathy is characterized by proximal weakness, muscle atrophy, limited exercise tolerance, and rapid fatigability.154 Symptoms typically appear when GFR is below 25 mL/min/1.73 m2, and disease progression tends to parallel the decline in renal function.153 Patients affected by uremic myopathy generally have normal creatine kinase levels, and electromyography studies and tissue biopsies only occasionally show muscle fiber atrophy.153,155 The pathogenesis of uremic myopathy is not completely understood but has been linked to factors such as uremic toxins, insulin resistance, carnitine deficiency, and hyperparathyroidism.153 Care must be taken to rule out contributions from simple water and electrolyte disturbances, which can underlie similar presentations. Management of uremic myopathy includes provision of adequate HD, correction of anemia, exercise therapy, nutritional supplementation, and treatment of secondary hyperparathyroidism.153 While both CKD and dialysis therapy lead to disorders in carnitine metabolism that may contribute to muscular dysfunction, the benefits of carnitine supplementation in these conditions remain incompletely established.156,157 However, given the favorable safety profile of carnitine and the potentially debilitating nature of muscular dysfunction, carnitine supplementation on a trial basis may be recommended for patients who do not respond to standard therapy.156,157

Conclusion CKD is associated with several forms of neuromuscular disease that can significantly diminish quality of life. Many of these conditions first become clinically significant in patients with advanced or long-standing CKD. Proper diagnosis and treatment of these conditions is challenging but is an important component in the comprehensive care of CKD patients. Additional work is needed to further characterize the prevalence and clinical course of these conditions in CKD populations.

SUMMARY Neurologic outcomes in CKD patients are prevalent. The most common neurologic complications in CKD patients are cognitive impairment, stroke, and peripheral neuropathies. Despite a strong graded association between measures of renal function and cognitive function, cognitive impairment in CKD patients is largely undiagnosed. Annual and predialysis cognitive screening is critical to avoid adverse outcomes of missed diagnoses of cognitive impairment, such as medication

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noncompliance and inability to make informed decisions regarding initiating dialysis. Early dementia diagnosis decreases anxiety for patients and caregivers, avoids crisis-driven acute and long-term care, and allows patients and families to plan for future care and financial arrangements. Cerebrovascular disease, uremic encephalopathy, neurodegenerative disease, and inflammation contribute to a model of accelerated vascular cognitive impairment in patients with CKD. Aggressive treatment with ESAs increases stroke risk appreciably. Warfarin and dose-adjusted newer anticoagulants appear effective for stroke prevention in stage 3 CKD patients with atrial fibrillation, but such therapy is unproven or contraindicated in higher CKD stages. Neuromuscular disease in advanced CKD patients, such as uremic peripheral neuropathies, uremic myopathy, and pruritucan significantly diminish patient perception of quality of life. Proper diagnosis and treatment of these conditions is a challenging but important component in the comprehensive care of CKD patients.

References 1. Murray AM, Seliger S, Stendhal JC. Neurologic complications of chronic kidney disease. In: Chronic Renal Disease. San Diego: Academic Press; 2015. p. 249e65 [chapter 21]. 2. Kurella M, Mapes DL, Port FK, Chertow GM. Correlates and outcomes of dementia among dialysis patients: the dialysis outcomes and practice patterns study. Nephrol Dial Transplant 2006;21(9): 2543e8. 3. Murray AM, Tupper DE, Knopman DS, Gilbertson DT, Pederson SL, Li S. Cognitive impairment in hemodialysis patients is common. Neurology 2006;67(2):216e23. 4. Folstein MF, Folstein SE, McHugh PR. “Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975;12(3):189e98. 5. Petersen RC. Mild cognitive impairment as a diagnostic entity. J Intern Med 2004;256(3):183e94. 6. Petersen RC, Doody R, Kurz A, Mohs RC, Morris JC, Rabins PV. Current concepts in mild cognitive impairment. Arch Neurol 2001;58(12):1985e92. 7. Petersen RC, Thomas RG, Grundman M, Bennett D, Doody R, Ferris S. Vitamin E and donepezil for the treatment of mild cognitive impairment. N Engl J Med 2005;352(23):2379e88. 8. American Psychiatric Association. Diagnostic and statistical manual of mental disorders (DSM-IV). 4th ed. Washington, DC: American Psychiatric Association; 1994. p. 124e33. 9. Plassman BL, Langa KM, Fisher GG, Heeringa SG, Weir DR, Ofstedal MB. Prevalence of cognitive impairment without dementia in the United States. Ann Intern Med 2008;148(6):427e34. 10. Murray AM, Levkoff SE, Wetle TT, Beckett L, Cleary PD, Schor JD. Acute delirium and functional decline in the hospitalized elderly patient. J Gerontol 1993;48(5):M181e6. 11. Gross AL, Jones RN, Habtemariam DA, Fong TG, Tommet D, Quach L. Delirium and long-term cognitive trajectory among persons with dementia. Arch Intern Med 2012;172(17):1324e31. 12. Pandharpande PP, Girard TD, Jackson JC, Morandi A, Thompson JL, Pun BT. BRAIN-ICU Study Investigators. Longterm cognitive impairment after critical illness. N Engl J Med 2013;369(14):1306e16.

V. COMPLICATIONS OF CHRONIC KIDNEY DISEASE

456

29. NEUROLOGIC COMPLICATIONS OF CHRONIC KIDNEY DISEASE

13. Inouye SK. Delirium in older persons. N Engl J Med 2006;354(11): 1157e65. 14. Inouye SK, van Dyck CH, Alessi CA, Balkin S, Siegal AP, Horwitz RI. Clarifying confusion: the confusion assessment method. A new method for detection of delirium. Ann Intern Med 1990;113(12):941e8. 15. Kurella TM, Chertow GM, Luan J, Yaffe K. Cognitive impairment in chronic kidney disease. J Am Geriatr Soc 2004;52(11):1863e9. 16. Renal U.S. Data system USRDS 2006 annual data report: atlas of chronic kidney disease & end-stage renal disease in the United States. Bethesda, MD: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; 2006. 17. Elias MF, Elias PK, Seliger SL, Narsipur SS, Dore GA, Robbins MA. Chronic kidney disease, creatinine and cognitive functioning. Nephrol Dial Transplant 2009;24(8):2446e52. 18. Kurella TM, Wadley V, Yaffe K, McClure LA, Howard G, Go R. Kidney function and cognitive impairment in US adults: the reasons for geographic and racial differences in stroke (REGARDS) study. Am J Kidney Dis 2008;52(2):227e34. 19. Kurella TM, Yaffe K, Shlipak MG, Wenger NK, Chertow GM. Chronic kidney disease and cognitive impairment in menopausal women. Am J Kidney Dis 2005;45(1):66e76. 20. Yaffe K, Ackerson L, Kurella TM, Le Blanc P, Kusek JW, Sehgal AR. Chronic kidney disease and cognitive function in older adults: findings from the chronic renal insufficiency cohort cognitive study. J Am Geriatr Soc 2010;58(2):338e45. 21. Weiner DE, Gaussoin SA, Nord J, Auchus AP, et al. Cognitive function and kidney disease: baseline data from the Systolic Blood Pressure Intervention Trial (SPRINT). Am J Kidney Dis 2017;70: 357e67. 22. Feng L, Yap KB, Yeoh LY, Ng TP. Kidney function and cognitive and functional decline in elderly adults: findings from the Singapore longitudinal aging study. J Am Geriatr Soc 2012;60(7): 1208e14. 23. Slinin Y, Paudel ML, Ishani A, Taylor BC, Yaffe K, Murray AM. Kidney function and cognitive performance and decline in older men. J Am Geriatr Soc 2008;56(11):2082e8. 24. Etgen T, Sander D, Chonchol M, Briesenick C, Poppert H, Fo¨rstl H. Chronic kidney disease is associated with incident cognitive impairment in the elderly: the INVADE study. Nephrol Dial Transplant 2009;24(10):3144e50. 25. Buchman AS, Tanne D, Boyle PA, Shah RC, Leurgans SE, Bennett DA. Kidney function is associated with the rate of cognitive decline in the elderly. Neurology 2009;73(12):920e7. 26. Kurella TM, Chertow GM, Fried LF, Cummings SR, Harris T, Simonsick E. Chronic kidney disease and cognitive impairment in the elderly: the health, aging, and body composition study. J Am Soc Nephrol 2005;16(7):2127e33. 27. Seliger SL, Siscovick DS, Stehman-Breen CO, Gillen DL, Fitzpatrick A, Bleyer A. Moderate renal impairment and risk of dementia among older adults: the cardiovascular health cognition study. J Am Soc Nephrol 2004;15(7):1904e11. 28. Davey A, Elias MF, Robbins MA, Seliger SL, Dore GA. Decline in renal functioning is associated with longitudinal decline in global cognitive functioning, abstract reasoning and verbal memory. Nephrol Dial Transplant 2013;28:1810e9. 29. Qiu C, Kivipelto M, Aguero-Torres H, Winblad B, Fratiglioni L. Risk and protective effects of the APOE gene towards Alzheimer’s disease in the Kungsholmen project: variation by age and sex. J Neurol Neurosurg Psychiatry 2004;75(6):828e33. 30. Yaffe K, Lindquist K, Shlipak MG, Simonsick E, Fried L, Rosano C. Cystatin C as a marker of cognitive function in elders: findings from the Health ABC study. Ann Neurol 2008;63(6):798e802. 31. Tizon B, Ribe EM, Mi W, Troy CM, Levy E. Cystatin C protects neuronal cells from amyloid-beta-induced toxicity. J Alzheimer’s Dis 2010;19(3):885e94.

32. Murray AM, Barzilay JI, Lovato JF, Williamson JD, Miller ME, Marcovina S. Biomarkers of renal function and cognitive impairment in patients with diabetes. Diabetes Care 2011;34(8):1827e32. 33. Sajjad I, Grodstein F, Kang JH, Curhan GC, Lin J. Kidney dysfunction and cognitive decline in women. Clin J Am Soc Nephrol 2012; 7(3):437e43. 34. Fried L. Albuminuria and cognitive impairment. Clin J Am Soc Nephrol 2012;7(3):376e8. 35. Himmelfarb J. Uremic toxicity, oxidative stress, and hemodialysis as renal replacement therapy. Semin Dial 2009;22(6):636e43. 36. Seliger SL, Longstreth WT. Lessons about brain vascular disease from another pulsating organ, the kidney. Stroke 2008;39(1):5e6. 37. Wardlaw JM, Sandercock PA, Dennis MS, Starr J. Is breakdown of the blood-brain barrier responsible for lacunar stroke, leukoaraiosis, and dementia? Stroke 2003;34(3):806e12. 38. Kalimo H. Does chronic brain edema explain the consequences of cerebral small-vessel disease? Stroke 2003;34(3):806e12. 39. Weiner DE, Bartolomei K, Scott T, Price LL, Griffith JL, Rosenberg I. Albuminuria, cognitive functioning, and white matter hyperintensities in homebound elders. Am J Kidney Dis 2009;53(3):438e47. 40. Buraczynska M, Ksiazek P, Zukowski P, Benedyk-Lorens E, Orlowska-Kowalik G. Complement factor H gene polymorphism and risk of cardiovascular disease in end-stage renal disease patients. Clin Immunol 2009;132(2):285e90. 41. Rodriguez-Iturbe B, Garcia GG. The role of tubulointerstitial inflammation in the progression of chronic renal failure. Nephron Clin Pract 2010;116(2):c81e8. 42. Manfredi AA, Rovere-Querini P. The mitochondrion e a Trojan horse that kicks off inflammation? N Engl J Med 2010;362(22): 2132e4. 43. Rizzo MA, Frediani F, Granata A, Ravasi B, Cusi D, Gallieni M. Neurological complications of hemodialysis: state of the art. J Nephrol 2012;25(2):170e82. 44. Brouns R, De Deyn PP. Neurological complications in renal failure: a review. Clin Neurol Neurosurg 2004;107(1):1e16. 45. Bugnicourt JM, Godefroy O, Chillon JM, Choukroun G, Massy ZA. Cognitive disorders and dementia in CKD: the neglected kidney-brain axis. J Am Soc Nephrol 2013;24(3):353e63. 46. Murray AM. Cognitive impairment in the aging dialysis and chronic kidney disease populations: an occult burden. Adv Chron Kidney Dis 2008;15(2):123e32. 47. Kurella TM, Yaffe K. Dementia and cognitive impairment in ESRD: diagnostic and therapeutic strategies. Kidney Int 2011; 79(1):14e22. 48. Casserly I, Topol E. Convergence of atherosclerosis and Alzheimer’s disease: inflammation, cholesterol, and misfolded proteins. Lancet 2004;363(9415):1139e46. 49. Mielke MM, Rosenberg PB, Tschanz J, Cook L, Corcoran C, Hayden KM. Vascular factors predict rate of progression in Alzheimer disease. Neurology 2007;69(19):1850e8. 50. Luchsinger JA, Reitz C, Honig LS, Tang MX, Shea S, Mayeux R. Aggregation of vascular risk factors and risk of incident Alzheimer disease. Neurology 2005;65(4):545e51. 51. Scarmeas N, Stern Y, Mayeux R, Manly JJ, Schupf N, Luchsinger JA. Mediterranean diet and mild cognitive impairment. Arch Neurol 2009;66(2):216e25. 52. Feart C, Samieri C, Rondeau V, Amieva H, Portet F, Dartigues JF. Adherence to a Mediterranean diet, cognitive decline, and risk of dementia. J Am Med Assoc 2009;302(6):638e48. 53. Tsivgoulis G, Judd S, Letter AJ, Alexandrov AV, Howard G, Nahab F. Adherence to a Mediterranean diet and risk of incident cognitive impairment. Neurology 2013;80(18):1684e92. 54. Schmidt W, Endres M, Dimeo F, Jungehulsing GJ. Train the vessel, gain the brain: physical activity and vessel function and the impact on stroke prevention and outcome in cerebrovascular disease. Cerebrovasc Dis 2013;35(4):303e12.

V. COMPLICATIONS OF CHRONIC KIDNEY DISEASE

REFERENCES

55. Reitz C, Jun G, Naj A, Rajbhandary R, Vardarajan BN, Wang LS. Variants in the ATP-binding cassette transporter (ABCA7), apolipoprotein E 4, and the risk of late-onset Alzheimer disease in African Americans. J Am Med Assoc 2013;309(14):1483e92. 56. Pfeffer MA, Burdmann EA, Chen CY, Cooper ME, de Zeeuw D, Eckardt KU. A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease. N Engl J Med 2009;361(21):2019e32. 57. Maiese K, Li F, Chong ZZ. New avenues of exploration for erythropoietin. J Am Med Assoc 2005;293(1):90e5. 58. Renal U.S. Data System. USRDS 2009 Annual Data Report: Atlas of chronic kidney disease & end-stage renal disease in the United States. Bethesda, MD: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; 2009. 59. Seshadri S, Beiser A, Selhub J, Jacques PF, Rosenberg IH, D’Agostino RB. Plasma homocysteine as a risk factor for dementia and Alzheimer’s disease. N Engl J Med 2002;346(7):476e83. 60. Gorelick PB. Risk factors for vascular dementia and Alzheimer disease. Stroke 2004;35(11 Suppl. 1):2620e2. 61. De Deyn PP, Vanholder R, Eloot S, Glorieux G. Guanidino compounds as uremic (neuro)toxins. Semin Dial 2009;22(4):340e5. 62. Weimer DL, Sager MA. Early identification and treatment of Alzheimer’s disease: social and fiscal outcomes. Alzheimer’s Dementia 2009;5(3):215e26. 63. Borson S, Scanlan J, Brush M, Vitaliano P, Dokmak A. The minicog: a cognitive “vital signs” measure for dementia screening in multi-lingual elderly. Int J Geriatr Psychiatry 2000;15(11):1021e7. 64. Tariq SH, Tumosa N, Chibnall JT, Perry MH, Morley JE. Comparison of the Saint Louis University mental status examination and the mini-mental state examination for detecting dementia and mild neurocognitive disorder–a pilot study. Am J Geriatr Psychiatry 2006;14(11):900e10. 65. Nasreddine ZS, Phillips NA, Bedirian V, Charbonneau S, Whitehead V, Collin I. The Montreal Cognitive Assessment, MoCA: a brief screening tool for mild cognitive impairment. J Am Geriatr Soc 2005;53(4):695e9. 66. The SPRINT Research Group. A randomized trial of intensive versus standard blood-pressure control. N Engl J Med 2015;373: 2103e16. 67. Rivastigmine [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corp.; 2013. 68. Galantamine [package insert]. Titusville, NJ: Janssen Pharmaceuticals, Inc.; 2014. 69. Memantine [package insert]. St. Louis, MO: Forest Pharmaceuticals, Inc.; 2012. 70. Schneider LS, Tariot PN, Dagerman KS, Davis SM, Hsiao JK, Ismail MS. Effectiveness of atypical antipsychotic drugs in patients with Alzheimer’s disease. N Engl J Med 2006;355(15): 1525e38. 71. Ballard C, Waite J. The effectiveness of atypical antipsychotics for the treatment of aggression and psychosis in Alzheimer’s disease. Cochrane Database Syst Rev 2006;(1):CD003476. 72. SPRINT MIND Investigators for the SPRINT Research Group, Williamson JD, Pajewski NM, Auchus AP, Bryan RN, et al. Effect of intensive vs standard blood pressure control on probable dementia: a randomized clinical trial. J Am Med Assoc 2019;321(6): 553e61. 73. Yaffe K. Prevention of cognitive impairment with intensive systolic blood pressure control. J Am Med Assoc 2019;321(6):548e9. 74. Kurella TM, Covinsky KE, Chertow GM, Yaffe K, Landefeld CS, McCulloch CE. Functional status of elderly adults before and after initiation of dialysis. N Engl J Med 2009;361(16):1539e47. 75. Sacco RL, Kasner SE, Broderick JP, et al. An updated definition of stroke for the 21st century: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2013;44:2064e89.

457

76. Murray AM, Seliger S, Lakshminarayan K, et al. Incidence of stroke before and after dialysis initiation in older patients. J Am Soc Nephrol 2013;24(7):1166e73. 77. Moss AH. Revised dialysis clinical practice guideline promotes more informed decision-making. Clin J Am Soc Nephrol 2010; 5(12):2380e3. 78. Kobayshi S, Okada K, Koide H, Bokura H, Yamaguchi S. Subcortical silent brain infarction as a risk factor for clinical stroke. Stroke 1997;28(10):1932e9. 79. Lee M, Saver JL, Chang KH, Liao HW, Chang SC, Ovbiagele B. Low glomerular filtration rate and risk of stroke: meta-analysis. BMJ 2010;341:c4249. 80. Aguilar MI, O’Meara ES, Seliger S, Longstreth WT, Hart RG, Pergola PE. Albuminuria and the risk of incident stroke and stroke types in older adults. Neurology 2010;75(15):1343e50. 81. Lee M, Saver JL, Chang KH, Liao HW, Chang SC, Ovbiagele B. Impact of microalbuminuria on incident stroke: a meta-analysis. Stroke 2010;41(11):2625e31. 82. Covic A, Kothawala P, Bernal M, Robbins S, Chalian A, Goldsmith D. Systematic review of the evidence underlying the association between mineral metabolism disturbances and risk of all-cause mortality, cardiovascular mortality and cardiovascular events in chronic kidney disease. Nephrol Dial Transplant 2009;24(5):1506e23. 83. Foley RN, Collins AJ, Ishani A, Kalra PA. Calcium-phosphate levels and cardiovascular disease in community-dwelling adults: the Atherosclerosis Risk in Communities (ARIC) Study. Am Heart J 2008;156(3):556e63. 84. Vlagopoulos PT, Tighiouart H, Weiner DE, Griffith J, Pettitt D, Salem DN. Anemia as a risk factor for cardiovascular disease and all-cause mortality in diabetes: the impact of chronic kidney disease. J Am Soc Nephrol 2005;16(11):3403e10. 85. London G. Pathophysiology of cardiovascular damage in the early renal population. Nephrol Dial Transplant 2001;16(Suppl. 2): 3e6. 86. Brines M, Cerami A. Emerging biological roles for erythropoietin in the nervous system. Nat Rev Neurosci 2005;6(6):484e94. 87. Skali H, Parving HH, Parfrey PS, Burdmann EA, Lewis EF, Ivanovich P. Stroke in patients with type 2 diabetes mellitus, chronic kidney disease, and anemia treated with Darbepoetin Alfa: the Trial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT) experience. Circulation 2011;124(25):2903e8. 88. Singh AK, Szczech L, Tang KL, Barnhart H, Sapp S, Wolfson M, Reddan D, Investigators CHOIR. Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med 2006;355(20): 2085e98. 89. Seliger SL, Zhang AD, Weir MR, Walker L, Hsu VD, Parsa A. Erythropoiesis-stimulating agents increase the risk of acute stroke in patients with chronic kidney disease. Kidney Int 2011;80(3): 288e94. 90. Furie KL, Kasner SE, Adams RJ, Albers GW, Bush RL, Fagan SC. Guidelines for the prevention of stroke in patients with stroke or transient ischemic attack: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2011;42(1):227e76. 91. Debing E, Van den Brande P. Chronic renal insufficiency and risk of early mortality in patients undergoing carotid endarterectomy. Ann Vasc Surg 2006;20(5):609e13. 92. Sidawy AN, Aidinian G, Johnson ON, White PW, DeZee KJ, Henderson WG. Effect of chronic renal insufficiency on outcomes of carotid endarterectomy. J Vasc Surg 2008;48(6):1423e30. 93. Mathew A, Eliasziw M, Devereaux PJ, Merino JG, Barnett HJ, Garg AX. Carotid endarterectomy benefits patients with CKD and symptomatic high-grade stenosis. J Am Soc Nephrol 2010; 21(1):145e52.

V. COMPLICATIONS OF CHRONIC KIDNEY DISEASE

458

29. NEUROLOGIC COMPLICATIONS OF CHRONIC KIDNEY DISEASE

94. Go AS, Fang MC, Udaltsova N, Chang Y, Pomernacki NK, Borowsky L. Impact of proteinuria and glomerular filtration rate on risk of thromboembolism in atrial fibrillation: the Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) study. Circulation 2009;119(10):1363e9. 95. Chan KE, Lazarus JM, Thadhani R, Hakim RM. Warfarin use associates with increased risk for stroke in hemodialysis patients with atrial fibrillation. J Am Soc Nephrol 2009;20(10):2223e33. 96. Winkelmayer WC, Liu J, Setoguchi S, Choudhry NK. Effectiveness and safety of warfarin initiation in older hemodialysis patients with incident atrial fibrillation. Clin J Am Soc Nephrol 2011; 6(11):2662e8. 97. Hart RG, Pearce LA, Asinger RW, Herzog CA. Warfarin in atrial fibrillation patients with moderate chronic kidney disease. Clin J Am Soc Nephrol 2011;6(11):2599e604. 98. Olesen JB, Lip GY, Kamper AL, Hommel K, Køber L, Lane DA. Stroke and bleeding in atrial fibrillation with chronic kidney disease. N Engl J Med 2012;367(7):625e35. 99. Connolly SJ, Wallentin L, Ezekowitz MD, et al. The long-term multicenter observational study of dabigatran treatment in patients with atrial fibrillation (RELY-ABLE) study. Circulation 2013;128(3):237e43. 100. Bansilal S, Bloomgarden Z, Halperin JL, et al. Efficacy and safety of rivaroxaban in patients with diabetes and nonvalvular atrial fibrillation: the rivaroxaban once daily, oral, direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and embolism trial in atrial fibrillation (ROCKET AF trial). Am Heart J 2015;170(4):675e82. 101. Granger CB, Alexander JH, McMurray JJ, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011; 365(11):981e92. 102. Connolly SJ, Eikelboom J, Joyner C, et al. Apixaban in patients with atrial fibrillation. N Engl J Med 2011;364(9):806e17. 103. Eikelboom JW, Connolly SJ, Gao P, Paolasso E, De Caterina R, Husted S. Stroke risk and efficacy of apixaban in atrial fibrillation patients with moderate chronic kidney disease. J Stroke Cerebrovasc Dis 2012;21(6):429e35. 104. Hohnloser SH, Hijazi Z, Thomas L, Alexander JH, Amerena J, Hanna M. Efficacy of apixaban when compared with warfarin in relation to renal function in patients with atrial fibrillation: insights from the ARISTOTLE trial. Eur Heart J 2012;33(22):2821e30. 105. Pelliccia F, Rosanio S, Marazzi G, et al. Efficacy and safety of novel anticoagulants versus vitamin K antagonists in patients with mild and moderate to severe renal insufficiency: focus on apixaban. Int J Cardiol 2016;225:77e81. 106. Halperin JL, Hankey GJ, Wojdyla DM, et al. Efficacy and safety of rivaroxaban compared with warfarin among elderly patients with nonvalvular atrial fibrillation in the rivaroxaban once daily, oral, direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and embolism trial in atrial fibrillation (ROCKET AF). Circulation 2014;130:138e46. 107. Fox KA, Piccini JP, Wojdyla D, Becker RC, Halperin JL, Nessel CC. Prevention of stroke and systemic embolism with rivaroxaban compared with warfarin in patients with non-valvular atrial fibrillation and moderate renal impairment. Eur Heart J 2011; 32(19):2387e94. 108. Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139e51. 109. Knauf F, Chanknos M, Berns JS, Perazella MA. Dabitragan and kidney disease: a bad combination. Clin J Am Soc Nephrol 2013;8: 1591e7. 110. Cuker A, Burnett A, Triller D, et al. Reversal of direct oral anticoagulants: guidance from the anticoagulation forum. Am J Hematol 2019;94(6):697e709.

111. Fellstrom BC, Jardine AG, Schmieder RE, Holdaas H, Bannister K, Beutler J. Rosuvastatin and cardiovascular events in patients undergoing hemodialysis. N Engl J Med 2009;360(14):1395e407. 112. Wanner C, Krane V, Marz W, Olschewski M, Mann JF, Ruf G. Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis. N Engl J Med 2005;353(3):238e48. 113. Baigent C, Landray MJ, Reith C, Emberson J, Wheeler DC, Tomson C. The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): a randomised placebocontrolled trial. Lancet 2011;377(9784):2181e92. 114. Palmer SC, Craig JC, Navaneethan SD, Tonelli M, Pellegrini F, Strippoli GF. Benefits and harms of statin therapy for persons with chronic kidney disease: a systematic review and metaanalysis. Ann Intern Med 2012;157(4):263e75. 115. Palmer SC, Di ML, Razavian M, Craig JC, Perkovic V, Pellegrini F. Effects of antiplatelet therapy on mortality and cardiovascular and bleeding outcomes in persons with chronic kidney disease: a systematic review and meta-analysis. Ann Intern Med 2012; 156(6):445e59. 116. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med 1995;333:1581e8. 117. Jauch EC, Saver JL, Adams Jr HP, Bruno A, Connors JJ, Demaerschalk BM, Khatri P, McMullan Jr PW, Qureshi AI, Rosenfield K, Scott PA, Summers DR, Wang DZ, Wintermark M, Yonas H, American Heart Association Stroke Council, Council on Cardiovascular Nursing, Council on Peripheral Vascular Disease, Council on Clinical Cardiology. Guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2013;44(3):870e947. 118. Power A, Epstein D, Cohen D, et al. Renal impairment reduces the efficacy of thrombolytic therapy in acute ischemic stroke. Cerebrovasc Dis 2013;35(1):45e52. 119. Ovbiagele B, Schwamm LH, Smith EE, Grau-Sepulveda MV, Saver JL, Bhatt DL, Hernandez AF, Peterson ED, Fonarow GC. Patterns of care quality and prognosis among hospitalized ischemic stroke patients with chronic kidney disease. J Am Heart Assoc 2014;3(3):e000905. 120. Jung JM, Kim HJ, Ahn H, Ahn IM, Do Y, Choi JY, Seo WK, Oh K, Cho KH, Yu S. Chronic kidney disease and intravenous thrombolysis in acute stroke: a systematic review and meta-analysis. J Neurol Sci 2015;358(1e2):345e50. 121. Cheung AK, Rahman M, Reboussin DM, Craven TE, Greene T, Kimmel PL, et al. Effects of intensive BP control in CKD. J Am Soc Nephrol 2017;28(9):2812e23. 122. Krishnan AV, Pussell BA, Kiernan MC. Neuromuscular disease in the dialysis patient: an update for the nephrologist. Semin Dial 2009;22(3):267e78. 123. Krishnan AV, Kieman MC. Neurological complications of chronic kidney disease. Nat Rev Neurol 2009;5:542e51. 124. Dyck PJ, Johnson WJ, Lambert EH, O’Brien PC. Segmental demyelination secondary to axonal degeneration in uremic neuropathy. Mayo Clin Proc 1971;46(6):400e31. 125. Laaksonen S, Metsarinne K, Voipio-Pulkki LM, Falck B. Neurophysiologic parameters and symptoms in chronic renal failure. Muscle Nerve 2002;25(6):884e90. 126. Babb AL, Ahmad S, Bergstrom J, Scribner BH. The middle molecule hypothesis in perspective. Am J Kidney Dis 1981;1(1):46e50. 127. Massry SG. Parathyroid hormone: a uremic toxin. Adv Exp Med Biol 1987;223:1e17. 128. Vanholder R, De SR, Hsu C, Vogeleere P, Ringoir S. Uremic toxicity: the middle molecule hypothesis revisited. Semin Nephrol 1994;14(3):205e18.

V. COMPLICATIONS OF CHRONIC KIDNEY DISEASE

REFERENCES

129. Bostock H, Walters RJ, Andersen KV, Murray NM, Taube D, Kiernan MC. Has potassium been prematurely discarded as a contributing factor to the development of uraemic neuropathy? Nephrol Dial Transplant 2004;19(5):1054e7. 130. Krishnan AV, Phoon RK, Pussell BA, Charlesworth JA, Bostock H, Kiernan MC. Altered motor nerve excitability in end-stage kidney disease. Brain 2005;128(Pt 9):2164e74. 131. Ogura T, Makinodan A, Kubo T, Hayashida T, Hirasawa Y. Electrophysiological course of uraemic neuropathy in haemodialysis patients. Postgrad Med J 2001;77(909):451e4. 132. Oh SJ, Clements RS, Lee YW, Diethelm AG. Rapid improvement in nerve conduction velocity following renal transplantation. Ann Neurol 1978;4(4):369e73. 133. Bolton CF. Electrophysiologic changes in uremic neuropathy after successful renal transplantation. Neurology 1976;26(2):152e61. 134. Vita G, Messina C, Savica V, Bellinghieri G. Uraemic autonomic neuropathy. J Auton Nerv Syst 1990;30(Suppl.):S179e84. 135. Jassal SV, Coulshed SJ, Douglas JF, Stout RW. Autonomic neuropathy predisposing to arrhythmias in hemodialysis patients. Am J Kidney Dis 1997;30:219e23. 136. Tozawa M, Iseki K, Yoshi S, Fukiyama K. Blood pressure variability as an adverse prognostic risk factor in end-stage renal disease. Nephrol Dial Transplant 1999;14:1976e81. 137. Palmer BF. Sexual dysfunction in uremia. J Am Soc Nephrol 1999; 10:1381e8. 138. Foy CG, Newman JC, Berlowitz DR, Russell LP, Kimmel PL, SPRINT Study Research Group, et al. Blood pressure, sexual activity, and dysfunction in women with hypertension: baseline findings from the systolic blood pressure intervention trial (SPRINT). J Sex Med 2016;13(9):1333e46. 139. Foy CG, Newman JC, Berlowitz DR, Russell LP, Kimmel PL, SPRINT Study Research Group, et al. Blood pressure, sexual activity, and erectile function in hypertensive men: baseline findings from the systolic blood pressure intervention trial (SPRINT). J Sex Med 2019;16(2):235e47. 140. Barri YM, Golper TA. Gastrointestinal disease in dialysis patients. Waltham, MA: UpToDate; 2012. 141. Bland JD. Carpal tunnel syndrome. BMJ 2007;335(7615):343e6. 142. Hirasawa Y, Ogura T. Carpal tunnel syndrome in patients on long-term haemodialysis. Scand J Plast Reconstr Surg Hand Surg 2000;34(4):373e81.

459

143. Drueke TB. Beta2-microglobulin and amyloidosis. Nephrol Dial Transplant 2000;15(Suppl. 1):17e24. 144. Floege J, Ketteler M. Beta2-microglobulin-derived amyloidosis: an update. Kidney Int Suppl 2001;78:S164e71. 145. Cofan F, Garcia S, Combalia A, Segur JM, Oppenheimer F. Carpal tunnel syndrome secondary to uraemic tumoral calcinosis. Rheumatology 2002;41(6):701e3. 146. Thermann F, Kornhuber M. Ischemic monomelic neuropathy: a rare but important complication after hemodialysis access placement–a review. J Vasc Access 2011;12(2):113e9. 147. Manenti L, Tansinda P, Vaglio A. Uraemic pruritus: clinical characteristics, pathophysiology and treatment. Drugs 2009;69(3):251e63. 148. Narita I, Iguchi S, Omori K, Gejyo F. Uremic pruritus in chronic hemodialysis patients. J Nephrol 2008;21(2):161e5. 149. Pisoni RL, Wikstrom B, Elder SJ, Akizawa T, Asano Y, Keen ML. Pruritus in haemodialysis patients: international results from the dialysis outcomes and practice patterns study (DOPPS). Nephrol Dial Transplant 2006;21(12):3495e505. 150. Gunal AI, Ozalp G, Yoldas TK, Gunal SY, Kirciman E, Celiker H. Gabapentin therapy for pruritus in haemodialysis patients: a randomized, placebo-controlled, double-blind trial. Nephrol Dial Transplant 2004;19(12):3137e9. 151. Gilchrest BA, Rowe JW, Brown RS, Steinman TI, Arndt KA. Relief of uremic pruritus with ultraviolet phototherapy. N Engl J Med 1977;297(3):136e8. 152. Wikstrom B, Gellert R, Ladefoged SD, Danda Y, Akai M, Ide K. Kappa-opioid system in uremic pruritus: multicenter, randomized, double-blind, placebo-controlled clinical studies. J Am Soc Nephrol 2005;16(12):3742e7. 153. Campistol JM. Uremic myopathy. Kidney Int 2002;62(5):1901e13. 154. Moore GE, Parsons DB, Stray-Gundersen J, Painter PL, Brinker KR, Mitchell JH. Uremic myopathy limits aerobic capacity in hemodialysis patients. Am J Kidney Dis 1993;22(2): 277e87. 155. Diesel W, Emms M, Knight BK, Noakes TD, Swanepoel CR, van Zyl Smit R. Morphologic features of the myopathy associated with chronic renal failure. Am J Kidney Dis 1993;22(5):677e84. 156. Calo LA, Vertolli U, Davis PA, Savica V. L carnitine in hemodialysis patients. Hemodial Int 2012;16:428e34. 157. Guarnieri G, Situlin R, Biolo G. Carnitine metabolism in uremia. Am J Kidney Dis 2001;4(Suppl. 1):S63e7.

V. COMPLICATIONS OF CHRONIC KIDNEY DISEASE

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29. NEUROLOGIC COMPLICATIONS OF CHRONIC KIDNEY DISEASE

QUESTIONS AND ANSWERS Question 1 You are seeing a 75-year-old woman with stage 4 CKD in clinic for the first time for a scheduled followup. She is living with her husband in assisted living. He reports that she became more agitated yesterday and was up most of the night. Today she seems more confused and initially refused to get dressed, which is unusual for her. She has no fever but her appetite is poor. There has been no recent change in her medications. On examination, she is uncooperative, has difficulty tracking, and is easily distracted. The remainder of her exam is normal. What would be your next step? A. Use the Mini-Cog to assess cognitive function B. Obtain a urine culture and serum electrolytes C. Use the Confusion Assessment Method to assess cognitive function D. B and C E. Refer to a neurologist, psychiatrist, or geriatrician Answer: D This patient is presenting with classic symptoms of delirium: acute onset confusion, decreased attention, disrupted sleepewake cycle, and agitation. As she is living in assisted living, she may also have underlying dementia but has never been diagnosed with cognitive impairment. It is not possible to differentiate delirium from dementia on an initial evaluation. The best steps are to use the Confusion Assessment Method to confirm the diagnosis of delirium and obtain a urine culture and electrolytes. Urinary tract infection and serum electrolyte disturbance are two very common causes of delirium in the elderly, the latter being especially common in CKD. Medication change is another common cause, but her medications have not changed.

Question 2 Which of these statements is true? A. Dementia in CKD patients more than doubles the risk of death B. Brain imaging is recommended for most new cases of cognitive impairment C. High cystatin C, albuminuria, and eGFR <45 mL/ min/1.73.m2 are associated with an increased risk of cognitive impairment D. Delirium in the hospitalized elderly usually results in long-term cognitive and functional decline E. All are true Answer: E

All of these statements are true. Of note delirium in the hospitalized elderly rarely complete reverses, especially in those with underlying dementia.

Question 3 A 65-year-old man with stage 3 CKD (eGFR 45 mL/ min/1.73 m2) has an ischemic stroke affecting the right middle cerebral artery territory. A duplex ultrasound study demonstrates high-grade (>70%) stenosis in the right internal carotid artery. Which of the following statements is correct regarding the role of CEA in this patient? A. This patient is at no greater risk for postoperative complications than a patient with similar comorbidity but without CKD B. The benefit in ipsilateral stroke recurrence from CEA is similar to the benefit in patients with CKD and moderate-grade (50%e69%) carotid stenosis C. CEA compared with standard medical therapy reduces the risk of ipsilateral stroke by approximately 80% D. The benefit in prevention of recurrent stroke from CEA is similar to the benefit in patients with stage 5 CKD Answer: C A subgroup analysis from the NASCET clinical trial suggests that patients with stage 3 CKD and symptomatic high-grade internal carotid artery stenosis have an 82% lower risk of recurrent ipsilateral stroke with CEA compared with standard medical therapy. In contrast, no significant difference in stroke risk was observed with CEA among patients with moderate stenosis. This same analysis, and additional observational cohort studies, suggests an increased risk of postoperative cardiac complications (myocardial infarction, congestive heart failure, arrhythmia, and potentially death) in CKD patients undergoing CEA compared with patients with eGFR > 60 mL/min/1.73m2. There are no data from clinical trials regarding effects of CEA vs. medical therapy in patients with stage 5 CKD.

Question 4 Which of the following statements about stroke risk in patients with nonedialysis-dependent CKD is true: A. Lower eGFR but not greater albuminuria is associated with an increased risk of acute stroke B. Patients with nonedialysis-dependent CKD and anemia are at greater risk for acute stroke than those with CKD but no anemia C. ESAs reduce the risk of acute stroke in nonedialysisdependent CKD patients with anemia

V. COMPLICATIONS OF CHRONIC KIDNEY DISEASE

QUESTIONS AND ANSWERS

D. HMG CoA-reductase inhibitors (statins) are not effective in stroke prevention among patients with nonedialysis-dependent CKD E. In patients with stage 3 CKD and atrial fibrillation, oral factor Xa inhibitors (e.g., apixaban) are less effective for stroke prevention than in patients without CKD Answer: B Meta-analyses of observational studies suggest that both albuminuria and lower eGFR are risk factors for acute stroke, independent of traditional vascular risk factors. Data from observational studies suggest that anemia is associated with greater risk of stroke among patients with nonedialysis-dependent CKD. However, the results of interventional and observational studies suggest that ESAs, especially when administered at high doses and/or targeting high hemoglobin concentrations, increase rather than reduce stroke risk. A summary of post hoc subgroup analyses of clinical trials involving statins suggest that statins reduce the risk of fatal and nonfatal strokes among patients with none dialysis-dependent (primarily stage 3) CKD; these results are supported by the SHARP study, which found a 25% lower risk of nonhemorrhagic stroke among none dialysis-dependent and dialysis-dependent CKD patients treated with simvastatin combined with ezetimibe. Post hoc subgroup analyses of clinical trials of oral factor Xa inhibitors suggest patients with stage 3 CKD have the same reduction in risk of stroke as those with preserved renal function, at least when reduced doses for lower renal function are used. These medications are contraindicated in patients with more advanced CKD.

Question 5 A 70-year-old man with long-standing CKD due to hypertension presents with 3 weeks of tingling and dull pain in the distal portions of both feet. His GFR is approximately 10e15 mL/min/1.73 m2 and has declined only minimally over the past year. His exam is significant for decreased sensation to monofilament and vibration. He has repeatedly said that he is not interested in initiating dialysis. He does not have diabetes mellitus and does not drink alcohol. Which one of the following is the best initial treatment for his symptoms? A. B. C. D.

Ibuprofen Amitriptyline Oxycodone Sertraline

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E. Tramadol Answer: B The patient’s presentation is consistent with uremic polyneuropathy. Amitriptyline, a tricyclic antidepressant, is regarded as a first-line agent for treatment of painful uremic polyneuropathy. Anticonvulsants such as pregabalin and valproate are also regarded as effective. While opioids such as tramadol and oxycodone may provide effective pain relief, potential problems with addiction, abuse, and overdose generally preclude their use as initial therapy. NSAIDs such as ibuprofen are contraindicated in CKD due to adverse effects on renal function. There are also theoretical concerns that NSAID-induced prostacyclin inhibition may impair nerve circulation and worsen nerve injury.

Question 6 A 52-year-old woman with advanced CKD due to diabetes mellitus has been experiencing daily episodes of itching for the past 2 weeks. The itching has been most intense at night and is interrupting sleep. Her GFR has declined significantly over the past 12 months and is now approximately 15 mL/min/1.73 m2. Her exam is significant for dry, flaking skin with patches of erythema and excoriation on her arms and abdomen. She is scheduled for vascular access placement in the coming week in anticipation of hemodialysis initiation in the coming months. Which one of the following is the best initial treatment for her symptoms? A. B. C. D. E.

Odansetron Oxycodone Diphenhydramine Topical emollient Cetirizine

Answer: D The patient’s presentation is consistent with UP. Topical emollients are safe and inexpensive and have been shown to be very effective in reducing pruritic symptoms. Other potentially effective treatments include gabapentin, UVB phototherapy, and nalfurafine, a k-opioid receptor agonist. Antihistamines such as diphenhydramine and cetirizine are widely used in the treatment of uremic pruritus, but their effectiveness is controversial. 5-HT3 receptor agonists such as odansetron have not been proven effective. Opiates such as oxycodone are frequently associated with pruritic side effects and are not effective treatments for uremic pruritus.

V. COMPLICATIONS OF CHRONIC KIDNEY DISEASE