Neurologic Complications of Chronic Kidney Disease

C H A P T E R

21 Neurologic Complications of Chronic Kidney Disease Anne M. Murraya, Stephen Seliger b and John C. Stendahlc a

Division of Geriatrics, Department of Medicine, Hennepin County Medical Center, Minneapolis, MN, USA, b Department of Medicine, Division of Nephrology, University of Maryland School of Medicine, Baltimore, MD, USA, c Department of Medicine, Hennepin County Medical Center, Minneapolis, MN, USA

INTRODUCTION Neurologic disorders in CKD patients are pervasive, including the central and peripheral nervous systems, but are frequently underdiagnosed and their impact often underappreciated. The most common neurologic complications in the CKD population are cognitive impairment, stroke and peripheral neuropathies.

COGNITIVE IMPAIRMENT IN CKD Cognitive impairment is now recognized as highly prevalent in CKD patients. Multiple studies have confirmed a graded association between renal function (whether assessed or albuminuria) and cognitive impairment. Cognitive impairment is also highly prevalent in the ESRD population, but substantially underdiagnosed. In two studies of HD patients,1,2 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.

Definitions of Cognitive Impairment (in the Non-CKD and CKD Populations) Most studies describe the frequency of global cognitive impairment, measured on a test of overall cognitive P. Kimmel & M. Rosenberg (Eds): Chronic Renal Disease. DOI: http://dx.doi.org/10.1016/B978-0-12-411602-3.00021-4

function such as the Mini-Mental State Exam,3 or of impairment in individual cognitive domains, including memory, attention, language, visual-spatial, calculations, and executive function. Executive function encompasses judgment and planning, including the ability to make informed healthcare decisions pertaining to dialysis initiation. 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 (non-amnestic MCI). MCI is often defined as performing 1.5–1.99 standard deviations below standardized norms on a given cognitive test,4,5 but the definition varies across studies. The conversion rate from MCI to dementia is approximately 15% per year in elderly patients without CKD5 and is higher in those who carry the APOE4 allele.6 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.7 Dementia is often defined in research studies as performing 2 or more standard deviations below population-defined

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norms in at least 2 cognitive domains. Importantly, dementia is the umbrella term for moderate to severe chronic cognitive impairment. Alzheimer disease (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), frontal–temporal dementia, and other dementia syndromes account for the remaining approximately 20% of dementias in patients without CKD.8 Delirium is a syndrome of acute cognitive impairment characterized by acute onset, inattention, disorganized thinking, and an altered state of consciousness, including sleep–wake 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 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 pre-existing dementia, and to a loss of on average one activity of daily living over 6 months of follow-up in non-CKD patients.9–11 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 bed-restriction or decreased mobility such as physical restraints, urinary catheters or intravenous lines also increase the risk of delirium. Delirium is very 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 dementia12 as in those without, it can be considered a litmus test for undiagnosed dementia in hospitalized elderly patients. 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 1 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, 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, sleep–wake cycle disturbance and memory loss.13

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 3 to 4 CKD clinic patients in a study by Kurella Tamura et  al., 23% had severely impaired executive function and 28% scored poorly on delayed memory tests.14 In the 2006 United States 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.15 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 eGFR and cognitive impairment. As renal function declines, so does cognitive function.16–19 In the Reasons for Geographic and Racial Differences in Stroke (REGARDS) 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 21.1).17–19 In the Heart, Estrogen/Progesterone Study among menopausal women, each 10  mL/ min/1.73 m2 decrement in eGFR corresponded to an approximately 15–25% increase in risk of impairment in executive function, language, and memory.18 Using a cognitive battery, the Chronic Renal Insufficiency Cohort (CRIC) study found that eGFR <30 compared with 45–59 mL/min/1.73 m2 was associated with greater impairment in most cognitive domains.19 A longitudinal relation between baseline eGFR and declines in global cognitive function and cognitive domains has also been reported.17,20–26 In the Cardiovascular Health Study, 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.25 In the Health, Aging and Body Composition (Health ABC) Study, adjusted odds ratios for cognitive decline were 1.32 for baseline eGFR 45–59 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 2-fold increased risk of AD.27 Baseline

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Cognitive Impairment in CKD

251

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 21.1  Unadjusted prevalence of cognitive impairment and cerebrovascular disease by estimated glomerular filtration rate (GFR). Source: American Journal of Kidney Diseases (Kurella TM, Wadley V, Yaffe K, McClure LA, Howard G, Go R, et al. Kidney function and cognitive impairment in US adults: the Reasons for Geographic and Racial Differences in Stroke (REGARDS) Study. 52:227–234), Copyright 2008 Elsevier Inc, reproduced with permission.

eGFR also predicts cognitive decline in the specific cognitive domains of memory and verbal fluency.27 Most recently, decline in eGFR over 5 years was significantly associated with decline in global cognition, verbal episodic memory and abstract reasoning in the Maine-Syracuse Longitudinal Study of 590 communitydwelling 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.26 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.28 More recent studies in animal models suggest that higher concentrations of cystatin C may have a protective effect against AD.29 Albuminuria may be a more sensitive biomarker for cognitive impairment than eGFR both cross-sectionally30 and longitudinally,31 because it is a measure of microvascular endothelial function and more likely to reflect similar vascular integrity in the cerebrovascular system.32 In the Action to Control Cardiovascular Risk in Diabetes-Memory in Diabetes (ACCORD-MIND) trial,30 urinary albumin excretion, measured as albumin/creatinine ratio (ACR) >30  µ/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. More recently in the Nurses Health Study, ACR levels as low as 5 µ/mg were associated with cognitive decline equivalent to 2 to 7 years of aging in global cognitive function, verbal memory, and verbal fluency.31

Pathophysiology of Cognitive Impairment in CKD: The Brain–Kidney Connection The pathophysiology of cognitive impairment in CKD may be a “natural” 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 small-vessel 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 the 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 inflammatory33 and oxidative processes, occurring in similar low-resistance vascular beds and endothelial structures.34 Impaired endothelial function in the brain manifests as blood–brain barrier defects,35,36 and increased susceptibility to microinfarcts, lacunar infarcts, and white matter changes.37 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

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calcium-phosphate metabolism, other metabolic disturbances, and a potential genetic predisposition to exaggerated inflammatory response38 may accelerate the rate of cognitive decline in CKD patients. At the cellular and molecular level in the kidney, microvascular endothelial dysfunction in the glomerulus leads to abnormal glomerular permeability, which some propose may trigger tubulointerstitial inflammation, and secondary renal fibrosis and progression of CKD.39 Mitochondrial dysfunction that triggers inflammation may be especially prevalent in CKD.40

Uremic Encephalopathy Uremic encephalopathy is a complication of both acute and chronic renal disease. 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.41,42 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.43–45 Figure 21.2 describes a modified version of a previously proposed model by Kurella and Yaffe.45

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 21.2). 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.46–48 Lifestyle factors including the Mediterranean diet49–51 and physical activity52 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 recently identified 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.53 Nephrogenic factors appear in the middle box (Figure 21.2). Both shared and nephrogenic risk factors

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 21.2.  Mechanisms of cognitive impairment in CKD patients. Source: Adapted from Kurella TM, Yaffe K. Dementia and cognitive impairment in ESRD: diagnostic and therapeutic strategies. Kidney International, 2011, 79:14–22. Copyright 2011 Macmillan Publishers Ltd, reproduced with permission.

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Cognitive Impairment in CKD

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,54 but these agents may also decrease risk of neuronal apoptosis and secondary cognitive impairment.55 In CKD populations, aging and non-vascular factors are overshadowed by a 10–15% annual stroke incidence,56 a high prevalence of cardiovascular risk factors including hypertension (80%) and diabetes (50–60%),15 markedly elevated levels of inflammatory markers and homocysteine,57 vascular endothelial dysfunction, cardiovascular events, and carotid atherosclerosis, all of which contribute to vascular dementia and neurodegenerative diseases such as AD58 (Figure 21.2). The additional contributions of factors secondary to CKD, such as uremia, anemia, higher circulating levels of guanidine compounds,59 endothelial dysfunction, and metabolic disturbances, are not well defined.43 In the Health ABC study, CKD accounted for approximately 10% of the cognitive impairment risk that was unexplained by demographic factors and comorbid conditions.24 Factors associated with HD treatment, such as cerebral hypoperfusion and brain edema also contribute to high levels of cognitive impairment, but are not included in Figure 21.2 as the focus is on pre-dialysis CKD patients.

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 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 non-compliance, 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 2.26 and 1.86, respectively).15 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 crisisdriven hospitalizations and delayed nursing home entry by up to 1.5 years.60

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Other advantages of early diagnosis are that it 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 care,60 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 non-healthcare professionals (Table 21.1).45 The briefest test is the 3-minute MiniCog,61 which is insensitive to mild cognitive impairment, 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 8-minute Folstein’s Mini-Mental State Exam is the most commonly used brief instrument,3 but it is copyrighted and does not measure executive functions. Two longer assessment tools (8–10 minutes) provide more information and are more sensitive for diagnosing mild cognitive impairment and measuring executive function.62 The St. Louis Mental Status test (SLUMS) and the Montreal Cognitive Assessment (MOCA) are freely available, and both test the major cognitive domains of verbal memory, executive function and visuospatial function.63 The MOCA is now used as a global cognitive screening exam in ongoing clinical trials, such as the Systolic Blood Pressure Intervention Trial (SPRINT trial) which has enrolled CKD participants. 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.45

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

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TABLE 21.1  Performance Characteristics of Selected Dementia Screening Instruments

Instrument

Administration Domains Time (Minutes) Evaluated

Sensitivity

Positive Screen Specificity Cutpoint

Validation Reference Standard

Validated in CKD or ESRD No

Comments

Clock 1–3 drawing task

Visuospatial executive function

85

85

Various

Clinical assessment for dementia

Less cultural bias. Evaluates executive function

Mini-Cog

3–4

Visuospatial executive function recall

76

89

2

Neuropsychological No battery

Clock drawing task plus uncued recall of three words

Mini-Mental State Exam (MMSE)

7–10

Orientation, recall attention visuospatial

71–92

56–96

23–25

Clinical assessment for dementia

No

Norms available. Copyrighted. Does not assess executive function well

St. Louis University Mental Status Exam (SLUMS)

7–10

Orientation, recall attention visuospatial executive function

98–100

91–100

21.5

Clinical assessment for dementia

No

Evaluates executive function

Montreal Cognitive Assessment (MoCA)

10

Orientation, recall attention visuospatial, verbal fluency executive function

100

87

25

Neuropsychological No battery

Evaluates executive function

Source: Adapted from Kidney International (Kurella TM, Yaffe K. Dementia and cognitive impairment in ESRD: diagnostic and therapeutic strategies. 79:14–22). Copyright 2011 Macmillan Publishers Ltd, reproduced with permission. Abbreviations: 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.

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.13

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, but their efficacy is controversial. These medications may be effective for 6 to 24 months in delaying the progression of cognitive impairment.6 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, rivastigmine64 (available in oral form and as a patch), and galantamine.65 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

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The Epidemiology of Stroke in Chronic Kidney Disease

nightmares occur, as they usually do not resolve. For CKD patients, a lower maximum dose of galanatime is recommended. Galantamine is contraindicated in ESRD patients. Memantine,66 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 are 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, since medication effectiveness is not well established and side-effects can be substantial.67 Atypical antipsychotics specifically are associated with modestly increased risk of cardiovascular disease and death.68

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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 pre-dialysis 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 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 EPIDEMIOLOGY OF STROKE IN CHRONIC KIDNEY DISEASE

Currently, neither a cognitive history nor an assessment is required for CKD patients before, at, or any time after dialysis initiation. Dementia is not listed as a comorbid condition on the Centers for Medicare & Medicaid Services Medical Evidence Report (form CMS-2728) required at dialysis initiation for Medicare entitlement. Given the high 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. This emphasizes the critical 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.69 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.70

The rate of incident stroke in incident CKD Medicare patients ages 67–85 years as reported in the 2009 USRDS annual data report is estimated at 9.0/100 patient-years (pt-yrs) (Figure 21.3). The incident stroke rate is 1.9–3.6 times higher (depending on age, eGFR and race) for those with incident CKD compared to those without CKD, and the risk in stage 5 CKD is double that of stage 3. The incident stroke rate in prevalent CKD patients is about twothirds of the rate in incident CKD patients, or about 5 to 6.0/100 pt-yrs overall. The effect of CKD on stroke risk is even stronger in younger individuals. Using the Ingenix i3 database of community-dwelling individuals aged 50 to 64 years old, stroke is 4.6–7.6 times more frequent for incident CKD patients than for non-CKD patients. The absolute incidence is lower in this younger cohort, ranging from approximately 1.6 to 2.2/100 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. Risk of incident stroke is also 50% higher for African Americans compared to white Medicare beneficiaries, similar to reports in non-CKD populations.56 Silent stroke describes lesions found incidentally on brain imaging in asymptomatic patients. Silent stroke increases the risk of subsequent stroke by over 10 times (2.79/year compared to 0.21%/year) compared to those without previous silent stroke in the general population.71 Although similar studies in CKD patients are lacking, silent stroke could be used to identify those who may benefit the most from preventive stroke measures in the CKD population.

Conclusion

Stroke Risk in CKD

Several studies have confirmed a graded association between renal function and cognitive function.

Results from several observational studies suggest that CKD patients are at significantly increased risk of

Health Policy Implications

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Rate per 100 patient years

15

10

Medicare

3.0

65 – 74 75 – 84 85+

2.0

50 – 54 55 – 59 60 – 64

1.0

5

0

Ingenix i3

0.0

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

Stg 4

Stg 5

No CKD

Any CKD

FIGURE 21.3  Rate of incident of stroke in incident CKD and non-CKD patients, by age and CKD status. Source: US Renal Data System, USRDS 2009 Annual Data Report: Atlas of Chronic Kidney Disease and End-Stage Renal Disease in the United States, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 2009. 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.

acute stroke compared with those without CKD.69–72 This excess risk is not explained by common comorbid conditions or traditional vascular risk factors. In a recent meta-analysis of 21 published reports, CKD as defined by eGFR less than 60 mL/min/1.73 m2 was associated with a 43% greater risk of stroke (95% confidence interval [CI], 1.31–1.57).72 A dose–response relationship was observed. Risk was increased 22% for patients with eGFR 40 to 59 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.73 These results were confirmed by a recent meta-analysis of 12 observational studies comprising 48,596 participants. Albuminuria was associated with a 92% greater relative risk of stroke compared to those without albuminuria, and this association was significant in studies conducted in the general population, in diabetic and hypertensive patients, and in patients with prior stroke.74 Increased risk of stroke is especially marked during the period of transition to maintenance dialysis therapy. In a retrospective cohort study using USRDS data,

Murray et  al. examined the risk over time of hospitalized stroke among older Medicare-insured adults who initiated maintenance HD or PD.75 Stroke rates increased approximately 90 days before initiation of maintenance HD, peaking at 8.4% per year within the month after initiation. Rates rapidly declined within 2 months after initiation but remained twice as high as pre-dialysis rates. The peri-initiation increase was most marked for patients who initiated dialysis as inpatients. This temporal increase in stroke risk may reflect potential adverse effects of the dialysis procedure itself. Alternatively, patients transitioning to dialysis are more likely to have a combination of pre-existing cerebrovascular disease and advanced CKD, such as low vascular reserve in both the brain and kidneys, making them susceptible at-risk patients for both stroke and renal disease.

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 (Figure 21.4). 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.34 This seems a plausible explanation for the increased stroke risk in patients with microalbuminuria and intact GFR, for whom lowlevel elevations in albuminuria may identify systemic vasculopathy with increased risk of major vascular

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The Epidemiology of Stroke in Chronic Kidney Disease

257

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

CKD

Acute stroke

Anemia hyperphosphatemia hyperhomocysteinemia

Endothelial dysfunction microinflammation oxidative stress

FIGURE 21.4  Pathologic mechanisms of CKD and stroke. Afib: atrial fibrillation, CHF: congestive heart failure, DM: diabetes mellitus, HTN: hypertension.

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,76 and greater S[P] is associated with increased stroke risk in the general population.77 Evidence indicates that CKD may interact synergistically with anemia to contribute to stroke risk. For example, 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 did not predict incident stroke among participants without CKD.78 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.79 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.80 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 non-dialysis-dependent CKD patients with anemia were randomized to weekly darbepoeitin with a goal hemoglobin of 13 g/dL or to placebo. During follow-up, the relative risk of fatal or non-fatal stroke (a secondary trial endpoint) was 92% greater in the active than in the control group.54 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.81 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 epoeitin alfa with high (13.5 g/dL) vs. normal (11 g/dL) hemoglobin targets. 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.

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In an observational case-control study among Veterans Administration outpatients with nondialysis-dependent CKD and anemia, those with prior ESA treatment were 30% more likely to be stroke cases, after adjustment for potential confounders.82 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, while 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 2.5 to 4 times higher than those without cancer, despite similar pretreatment hemoglobin concentrations. Whether their greater stroke risk compared to ESA-treated patients without cancer is explained by the higher ESA dosing they received, or by other stroke risk factors concurrent in cancer patients – such as greater inflammation or increased thrombotic potential – is unclear. Of note, 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 non-dialysis-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.83 However, observational studies have suggested that nondialysis-dependent CKD patients have a much higher risk of perioperative mortality and other complications after CEA,84,85 raising questions about the risk– benefit 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 4-fold higher risk of cardiac complications than those with normal renal function, but no excess risk of mortality.86 However, they also experienced a markedly greater benefit from CEA than from standard medical therapy, with an 82% relative risk reduction of recurrent stroke. In contrast, CKD patients with moderate carotid stenosis (50–69% diameter reduction) experienced no significant benefit in stroke reduction. Atrial fibrillation is a major stroke risk factor in the general population, and risk of stroke is 40% greater among atrial fibrillation patients who also have CKD

stage 3B or higher.87 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 maintenance dialysis patients may be associated with a paradoxically increased risk of stroke,88 especially hemorrhagic stroke,89 raising concerns about its safety in non-dialysis-dependent CKD patients. Hart et  al.90 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. 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 risk–benefit 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.91 CKD not requiring renal replacement therapy was identified by diagnosis codes, not by renal function measurement, likely resulting in significant under-ascertainment. Warfarin use was associated with a 16% lower risk of stroke or systemic thromboembolism (relative risk 0.84), but this association did not meet the conventional threshold of significance (P = 0.07). However, warfarin-treated participants were at a 36% greater risk for major bleeding after other risk factors were accounted for. Newer oral anticoagulants such as dabigatran, rivaroxaban, and abixaban have been shown to be efficacious in stroke prevention in atrial fibrillation in non-CKD patients, and do not require laboratory monitoring. However, these medications rely at least partly on renal excretion for elimination, and have not been studied in clinical trials specifically designed with CKD patients. In the major landmark trials demonstrating efficacy, patients with advanced (typically stage 4 or higher CKD) renal impairment were excluded. 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 (AVERROES) trial, which compared apixaban with aspirin among chronic atrial fibrillation patients who were not candidates for warfarin. Apixiban was dose-reduced among patients with S[Cr] greater than 1.5  mg/dL. Results suggested a similar treatment advantage of apixaban

V.  COMPLICATIONS OF CHRONIC KIDNEY DISEASE

The Epidemiology of Stroke in Chronic Kidney Disease

over aspirin among patients with stage 3 CKD (mean eGFR 49 mL/min/1.73 m2) compared with non-CKD patients, with a relative risk reduction of 68%. There was no excess risk of major bleeding with apixaban among CKD patients.92 In the Apixaban for Reduction In Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial comparing apixaban to warfarin, the effect of apixaban also did not differ significantly by renal function (patients with creatinine clearance less than 30 mL/min were excluded). Apixiban vs. warfarin reduced the risk of hemorrhage among participants with eGFR less than 50 mL/ min/1.73 m2 (hazard ratio 0.48; 95% CI 0.37–0.64) to a greater extent than among those with intact renal function.93 Similar evidence for a favorable risk– benefit ratio in CKD patients was reported for rivaroxaban vs. warfarin in a post-hoc subgroup analysis of 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.94 Dabigatran – a direct thrombin inhibitor – is 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 dagitraban compared to warfarin for the prevention of stroke or thromboembolism among those with eGFR 30 to 50 mL/min/1.73 m2 compared to ≥80 mL/min/1.73 m2.95 However, the relative benefit and risk of dabigatran in stroke prevention in CKD stage 3 patients is a topic of ongoing uncertainty and debate.96 There is no readily available method for monitoring drug concentrations or anticoagulant effects of dabigatran, nor are there established methods for reversing anticoagulant effects, raising concerns about the safety of this therapy in those with renal functional impairment. 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,97,98 and a doubling of fatal stroke with atorvastatin in the Deutsche Diabetes Dialyse Studie (4D) trial.98 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).99 The risk of non-hemorrhagic stroke was reduced by 25% in the active treatment group (relative risk 0.75; 95% CI, 0.60–0.94). The effects of stroke risk were not reported separately for study participants with non-dialysis-dependent CKD, although there was a significant effect on all atherosclerotic events in this subgroup (relative risk 0.78). Additional evidence

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for the effect of statins is provided by subgroup analyses of general population clinical trials. A recent metaanalysis estimated a summary relative risk reduction of 39% for fatal and non-fatal strokes (RR 0.61; 95% CI, 0.38–0.98) with statin therapy vs. placebo.100 However, most included clinical trials constituting this metaanalysis 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. However, no prior 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 recent meta-analysis found an “uncertain effect” of these agents on risk of stroke in CKD patients (relative risk 0.66; CI, 0.16–2.78).101 The risk of minor bleeding was increased by 70% in CKD patients randomized to antiplatelet drugs.

Conclusion Patients with non-dialysis-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 end-organ 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 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 hemoglobin levels in increasing risk, remain unclear.102 A single post-hoc subgroup analysis suggests a large benefit in secondary prevention of stroke with carotid endarterectomy in selected patients with stage 3 CKD, although at the cost of greater perioperative complications. Statins, warfarin, and dose-adjusted oral anticoagulants in 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. Data are insufficient to indicate a benefit in stroke prevention of glycoprotein IIb/IIIa inhibitors or clopidogrel as anti-platelet therapy.

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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.41,42,103 Somatic polyneuropathy is characterized by mixed sensory and motor dysfunction in a symmetrical, length-dependent distribution and typically presents with lower extremity pain, hypesthesia, and/ or paresthesias. Sensory dysfunction expands proximally as the disease progresses and is eventually complicated by weakness and muscle wasting. Estimates on the prevalence of uremic somatic polyneuropathy vary greatly.15,104 This likely relates, in part, to the relatively high prevalence of non-uremic polyneuropathies in CKD populations which confound diagnosis. Diabetes mellitus is the most common non-uremic etiology of polyneuropathy in CKD populations, although contributions from other non-uremic sources such as alcohol, amyloidosis, and systemic vasculitides should always be considered.42 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.105 Accordingly, nerve conduction studies characteristically show significant reductions in sensory and motor amplitudes, with more moderate reductions in conduction velocities.106 Early theories attributed uremic axonal damage to CKD-related accumulation of “middle molecules,” i.e., renally cleared mid-range molecular weight substances such as β2-microglobulin and parathyroid hormone.107 However, this hypothesis remains unproven, and parathyroid hormone is the only middle molecule for which some evidence of neurotoxicity exists.108,109 More recent work indicates that hyperkalemia may play an important role in pathogenesis.110,111 Management of uremic somatic polyneuropathy includes dialysis and supportive medical therapy. Adequate dialysis generally prevents neuropathic progression, but complete clinical reversibility is uncommon.112

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).41,42,103 The potential role of hyperkalemia in neurotoxicity has also led to efforts to reduce interdialytic potassium concentrations by dietary therapy.111 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.113 Clinical recovery is often achieved within several months of transplantation in mild cases and may take longer in more severe cases.114

Uremic Autonomic Neuropathy Dysfunction of autonomic nerves can also occur in advanced CKD.41,42,103 Common autonomic manifestations include postural and interdialytic hypotension, cardiac arrhythmias, impaired sweating, gastrointestinal dysmotility, and sexual dysfunction.115 Because CKD-related autonomic neuropathies do not always coexist with somatic polyneuropathies, it is not entirely clear if they are manifestations of the same or separate processes.115 Interestingly, parasympathatic dysfunction tends to predominate in CKD-related autonomic neuropathy, while sympathetic dysfunction tends to be more common in diabetes-related disease.41 While the true burden and clinical significance of CKD-related autonomic neuropathy is not known, it is important to note that studies in dialysis patients associate autonomic dysfunction with sudden cardiac death.116,117 Diagnosis of autonomic neuropathy in CKD patients can be challenging due to the non-specific nature of clinical symptoms and an incomplete correlation between symptoms and common clinical diagnostics, such as resting R–R interval variation and blood pressure responses to sustained handgrip.115 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. In a similar fashion, 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,

V.  COMPLICATIONS OF CHRONIC KIDNEY DISEASE

Neurological and Muscular Disease

depression, and medications.118 As with uremic somatic polyneuropathy, renal transplantation provides the most effective treatment for uremic autonomic neuropathy.103 Specific medical therapies include sildenafil for erectile dysfunction,103 midodrine for hypotension,103 and renally-dosed metoclopramide for impaired gastrointestinal mobility.119

Uremic Mononeuropathies Carpal tunnel syndrome (CTS) is the most common mononeuropathy related to CKD.41,42,103 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.120 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.120 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.121 The increased prevalence of CTS in CKD and ESRD populations is primarily attributed to amyloidosis from β2-microglobulin accumulation,122,123 although uremic tumoral calcinosis and complications of arteriovenous fistula creation are also implicated.124,125 Treatment of mild CTS involves conservative strategies, such as activity modification and nocturnal splinting.120 Corticosteroid injections have been shown to 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, although modifications to dialysis techniques such as high-flux biocompatible membranes and purified, bicarbonate-buffered dialysates have also demonstrated protective merit.123

Uremic Pruritus Pruritus is a common complication of advanced CKD.126,127 While uremic pruritus (UP) is often associated with dialysis, most patients develop symptoms

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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 detriment to quality of life, UP may have greater implications. The recent large DOPPS II study associated UP with sleep disorders and increased mortality.128 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.126,127 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.126,127 Gabapentin, ultraviolet phototherapy, and nalfurafine, a κ-opioid receptor agonist, have also been shown to be effective and well tolerated.129–131 Erythropoietin and previously common therapies such as antihistamines and serotonin receptor antagonists have not been proven effective.126 The potential benefits of dialysis membrane improvements remain controversial, especially since the prevalence of UP does not clearly differ between HD and PD patients.126

Uremic Myopathy Uremic myopathy is a general term used to describe the constellation of functional and structural muscle abnormalities commonly associated with chronic uremia.132 Uremic myopathy is characterized by proximal weakness, muscle atrophy, limited exercise tolerance, and rapid fatigability.133 Symptoms typically appear when GFR is below 25 mL/min/1.73 m2, and disease progression tends to parallel the decline in renal function.132 Patients affected by uremic myopathy generally have normal creatine kinase levels, and electromyography studies and tissue biopsies only occasionally show muscle fiber atrophy.132,134 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.132 Care must be taken to rule out contributions from simple water and electrolyte disturbances, which can present in similar fashion. Management of uremic myopathy includes adequate HD, correction of anemia, exercise therapy, nutritional supplementation, and treatment of secondary hyperparathyroidism.132 While both CKD and dialysis therapy lead to

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disorders in carnitine metabolism that may contribute to muscular dysfunction, the benefits of carnitine supplementation in these conditions remains incompletely established.135,136 However, given the favorable safety profile of carnitine and the potentially debilitating nature of muscular dysfunction, carnitine supplementation on a trial basis is recommended for patients who do not respond to standard therapy.135,136

Conclusion Renal dysfunction 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 longstanding CKD. Proper diagnosis and treatment of these conditions is a challenging, but important component in the comprehensive management 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 pervasive. The most common 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 pre-dialysis cognitive screening is critical to avoid adverse outcomes of missed diagnoses of cognitive impairment, such as medication non-compliance 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 CKD model of accelerated vascular cognitive impairment. Risk of stroke increases significantly in CKD, from up to 7-fold during the month of dialysis initiation. Aggressive treatment with erythropoiesis-stimulating agents increases stroke risk appreciably. For stroke prevention in atrial fibrillation, warfarin and dose-adjusted newer anticoagulants appear effective in stage 3 CKD patients, but are unproven or contraindicated in CKD stage 4 or higher. Neuromuscular disease in advanced CKD such as uremic peripheral neuropathies, uremic myopathy and pruritus can significantly diminish quality of life. Proper diagnosis and treatment of these conditions is a challenging, but important component in the comprehensive management of CKD patients.

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