commentary
REFERENCES 1.
2.
3.
4.
5.
6.
7.
Bostom AG, Kronenberg F, Ritz E. Predictive performance of renal function equations for patients with chronic kidney disease and normal serum creatinine levels. J Am Soc Nephrol 2002; 13: 2140–2144. Wang X, Vrtiska TJ, Avula RT et al. Age, kidney function, and risk factors associate differently with cortical and medullary volumes of the kidney. Kidney Int 2014; 85: 677–685. Chapman AB, Bost JE, Torres VE et al. Kidney volume and functional outcomes in autosomal dominant polycystic kidney disease. Clin J Am Soc Nephrol 2012; 7: 479–486. Al-Said JM, O’Neill WC. Reduced kidney size in patients with simple renal cysts. Kidney Int 2003; 64: 1059–1064. Al-Said J, Moghazi S, Brumback M et al. Reduced renal function in patients with simple renal cysts. Kidney Int 2004; 65: 2303–2308. Rule AD, Sasiwimonphan K, Lieske JC et al. Characteristics of renal cystic and solid lesions based on contrast-enhanced computed tomography of potential kidney donors. Am J Kidney Dis 2012; 59: 611–618. Grantham JJ. Solitary renal cysts: worth a second look? Am J Kidney Dis 2012; 59: 593–594.
8.
9.
10.
11.
12.
13.
Feldt-Rasmussen B, Hegedus L, Mathiesen ER. Kidney volume in type I (insulin-dependent) diabetic patients with normal or increased urinary albumin excretion: effect of long-term improved metabolic control. Scand J Clin Lab Invest 1991; 51: 31–36. Baumgartl HJ, Sigl G, Banholzer P et al. On the prognosis of IDDM patients with large kidneys. Nephrol Dial Transplant 1998; 13: 630–634. Bakker J, Olree M, Kaatee R et al. Renal volume measurements: accuracy and repeatability of US compared with that of MR imaging. Radiology 1999; 211: 623–628. Johnson S, Rishi R, Andone A et al. Determinants and functional significance of renal parenchymal volume in adults. Clin J Am Soc Nephrol 2011; 6: 70–76. Nyengaard JR, Bendtsen TF. Glomerular number and size in relation to age, kidney weight, and body surface in normal men. Anat Rec 1992; 232: 194–201. Hoy W, Douglas-Denton R, Hughson M et al. A stereologic study of glomerular number and volume: preliminary findings in a multiracial study of kidneys at autopsy. Kidney Int 2003; 63: 31–37.
see clinical investigation on page 693
Cognitive impairment in chronic kidney disease: keep vascular disease in mind David A. Drew1 and Daniel E. Weiner1 Cognitive impairment is a major cause of morbidity in people with chronic kidney disease (CKD) and is associated with worse survival. Prior data suggest a relationship between vascular disease and cognitive impairment in individuals with CKD. Clinicians should be aware of the high rates of cognitive impairment that occur in all stages of CKD, which, although sometimes subtle, may impact comprehension and decision making and may herald future, more debilitating impairment. Kidney International (2014) 85, 505–507. doi:10.1038/ki.2013.437
Cognitive impairment is a major cause of morbidity in chronic kidney disease (CKD). Individuals with cognitive impairment often have lower quality of life, have more difficulty adhering to medications, and have worse survival.1 Importantly, cognitive deficits become both more 1 Division of Nephrology, Department of Medicine, Tufts Medical Center, Boston, Massachusetts, USA Correspondence: Daniel E. Weiner, Tufts Medical Center, 800 Washington Street, Box #391, Boston, Massachusetts 02111, USA. E-mail: [email protected]
Kidney International (2014) 85
prevalent and more severe at lower levels of kidney function.2 For patients with kidney failure treated with dialysis, this translates to a prevalence of cognitive impairment anywhere from 30 to 70%.3,4 Reflecting the complex medical issues present in people with CKD, the cause of cognitive impairment is probably multifactorial in this population. As in the general population, aging patients with kidney disease can be at risk for developing Alzheimer’s disease, which initially affects memory most
prominently; however, rates of Alzheimer’s in CKD patients appear similar to those in age- and sex-matched controls, therefore not explaining an observed excess of cognitive impairment.5 In contrast, cerebrovascular disease is common in all stages of CKD, with the highest rates occurring in those treated with dialysis. Brain magnetic resonance imaging in dialysis patients confirms a high burden of white matter disease, atrophy, and cerebral infarcts, even in those without a known history of stroke.6 Supporting the hypothesis that cerebrovascular disease is most responsible for cognitive impairment in people with CKD are several factors: (1) Neurocognitive manifestations of cerebrovascular disease predominantly affect executive function domains rather than memory, and most prior studies of individuals with CKD reveal that executive function is more severely affected than other cognitive domains.3,4,7,8 (2) Systemic cardiovascular disease (CVD) and CVD risk factors are associated with significantly worse executive function.7 (3) In earlier stages of CKD, higher levels of albuminuria, probably representing systemic vascular burden, are associated with both worse executive functioning and brain magnetic resonance image findings.5,9,10 (4) More intensive dialysis with more effective clearance of uremic solutes does not improve cognitive function.11 In addition to a high burden of traditional CVD risk factors among individuals with CKD, nontraditional risk factors such as inflammation may be more prominent in individuals with CKD and may also predispose to cardiovascular and cerebrovascular disease (Figure 1). Few data exist on how inflammation in individuals with CKD may contribute to abnormal brain function. Attempting to address these questions, Seidel et al.12 (this issue) performed a cross-sectional study evaluating cognitive performance in 119 patients with CKD stages 3–5D as well as 54 control subjects, all of whom had an estimated glomerular 505
commentary
filtration rate greater than 60 ml/min per 1.73 m2 but an otherwise similar burden of vascular disease risk factors. A battery of ten neurocognitive tests was used, the results of which were converted into a global cognitive score as well as three subscores comprising memory, executive function, and language domains. Although similar overall with respect to many characteristics, including age, education, and several vascular disease risk factors, there were several key differences between the CKD group and controls in this study, including the rate of transient ischemic attack or stroke (6% in CKD versus 0% in control) and the levels of brain natriuretic peptide and fibrinogen (both higher in CKD). As would be expected, the CKD group performed modestly worse on multiple measures of cognition when compared with the control group. Thirty percent of the CKD group had poor global cognitive performance (defined as one standard deviation worse than the control group), while 18% had memory deficits and 38% executive deficits. In unadjusted comparisons, performance did not vary significantly by CKD stage, a finding that could be explained by the younger age of stage 5D patients compared with CKD stage 3–5 (55 versus 65 years), possibly suggesting that the effects of kidney failure on cognitive function are similar to 10 years of aging. After adjustment for age, sex, and education, CKD stage was a strong predictor of global cognitive performance (with more advanced CKD associated with worse performance), but not of individual cognitive domains. Interestingly, the authors found a relationship between higher self-reported depression scores (using the Hospital Anxiety and Depression Scale) and lower global cognitive performance,12 a finding consistent with previous reports in dialysis that have demonstrated an association between depression symptoms and both poorer self-perceived and measured cognitive performance.13,14 The association was attenuated with adjustment for markers of disease severity such as blood pressure, hemoglobin A1c, CKD stage, and dyslipidemia, suggesting that comorbid conditions are involved in both depression and cognitive performance. 506
Traditional risk factors: • Dyslipidemia • Hypertension • Diabetes and hyperglycemia • Older age
Large- and small-vessel cerebrovascular disease
Non traditional risk factors: • Inflammation (C-reactive protein, fibrinogen) • Anemia • Mineral and bone disorder
Neuronal damage
Cognitive impairment
Other factors: • Education level • Depression • Psychiatric disease
Figure 1 | Proposed mechanisms of cognitive impairment in chronic kidney disease.
Notably, one recent randomized clinical trial conducted in 72 hemodialysis patients with sleep disturbances evaluated the effectiveness of cognitive-behavioral therapy, a non-pharmacologic intervention for depression, and noted a significant improvement in depression scores as well as inflammatory markers in the group treated with cognitive-behavioral therapy, potentially suggesting a mechanistic link among inflammation, sleep disturbances, depression, and cognition.15 In sum, the relationship between depression and cognitive performance is intriguing and deserves further attention for future study, as, unlike many other risk factors, depression is potentially modifiable, although few studies have assessed treatments for depression in hemodialysis patients. Next, Seidel et al. examined vascular disease risk factors and their association with cognitive performance. A key finding was that higher hemoglobin A1c (HbA1c) was associated with poorer global cognitive performance; this finding persisted even in models that adjusted for a previous history of CVD events as well as other traditional risk factors such as dyslipidemia, smoking, body mass index, and systolic blood pressure.12 HbA1c has been linked with cognitive performance in people with type 2 diabetes, but this has not previously been extended to patients with advanced CKD. Unfortunately, it is difficult to interpret what this finding means for patients with CKD, as HbA1c measurement in kidney disease remains poorly validated, with recent studies demonstrating that HbA1c measurement does not accurately reflect long-term blood sugar levels and thus may
substantially underestimate the degree of hyperglycemia in this population.16 Future studies of cognition could be well served by consideration of alternative measures of glycemic control to investigate this potentially important risk factor. An additional finding was an association between a higher fibrinogen level and worse memory and executive function, a finding that was attenuated in the main multivariable model. Fibrinogen, a marker of inflammation, is associated with cognitive performance in the general population, specifically with poorer performance on tests that identify vascular dementia,17 and, in individuals with stage 3–4 CKD, higher levels of fibrinogen are associated with CVD outcomes.18 Therefore, it was unexpected that the association between fibrinogen and memory was the more robust association in this study, raising the question of residual confounding. C-reactive protein (CRP), another wellstudied marker of inflammation, was not assessed in this study. Although both higher CRP and rising CRP over time are associated with the development of cognitive impairment in elderly populations,19 few studies have looked at CRP and cognitive performance in kidney disease despite the association of high CRP with a multitude of cardiovascular outcomes. Well-designed longitudinal studies that include multiple measures of inflammation will probably be required to better explore the impact of inflammation and its modifiers on cognitive performance. Kidney International (2014) 85
commentary
In sum, even when compared with a population enriched for CVD and CVD risk factors, individuals with CKD performed modestly worse on a cognitive battery testing multiple domains. Despite the many caveats associated with a crosssectional study as well as this study’s modest sample size, these findings, when viewed in the context of existing data, suggest that risk factors for cerebrovascular disease may be particularly important in the pathogenesis of cognitive impairment in people with CKD. Critically, clinicians should be aware of the high rates of cognitive impairment that occur even in earlier stages of CKD. Although initial cognitive deficits may be subtle, these deficits may herald future, more debilitating impairment. Future studies should evaluate whether treatments targeting vascular disease risk factors, possibly including inflammation, can prevent or slow the development of cognitive impairment in individuals with CKD. DISCLOSURE
The authors declared no competing interests. ACKNOWLEDGMENTS
D.A.D is funded by the American Society of Nephrology Research Fellowship Program. D.E.W work on cognition in kidney disease is funded via National Institute of Diabetes and Digestive and Kidney Diseases (National Institutes of Health) grant R01-DK090401.
REFERENCES 1.
2.
3.
4.
5.
6.
7.
Griva K, Stygall J, Hankins M et al. Cognitive impairment and 7-year mortality in dialysis patients. Am J Kidney Dis 2010; 56: 693–703. Kurella M, Chertow GM, Luan J et al. Cognitive impairment in chronic kidney disease. J Am Geriatr Soc 2004; 52: 1863–1869. Sarnak MJ, Tighiouart H, Scott TM et al. Frequency of and risk factors for poor cognitive performance in hemodialysis patients. Neurology 2013; 80: 471–480. Murray AM, Tupper DE, Knopman DS et al. Cognitive impairment in hemodialysis patients is common. Neurology 2006; 67: 216–223. Seliger SL, Siscovick DS, Stehman-Breen CO et al. Moderate renal impairment and risk of dementia among older adults: the Cardiovascular Health Cognition Study. J Am Soc Nephrol 2004; 15: 1904–1911. Drew DA, Bhadelia R, Tighiouart H et al. Anatomic brain disease in hemodialysis patients: a cross-sectional study. Am J Kidney Dis 2013; 61: 271–278. Weiner DE, Scott TM, Giang LM et al. Cardiovascular disease and cognitive function in maintenance hemodialysis patients. Am J Kidney Dis 2011; 58: 773–781.
Kidney International (2014) 85
8.
9.
10.
11.
12.
13.
Kalirao P, Pederson S, Foley RN et al. Cognitive impairment in peritoneal dialysis patients. Am J Kidney Dis 2011; 57: 612–620. Weiner DE, Bartolomei K, Scott T et al. Albuminuria, cognitive functioning, and white matter hyperintensities in homebound elders. Am J Kidney Dis 2009; 53: 438–447. Barzilay JI, Fitzpatrick AL, Luchsinger J et al. Albuminuria and dementia in the elderly: a community study. Am J Kidney Dis 2008; 52: 216–226. Kurella Tamura M, Unruh ML, Nissenson AR et al. Effect of more frequent hemodialysis on cognitive function in the Frequent Hemodialysis Network Trials. Am J Kidney Dis 2013; 61: 228–237. Seidel UK, Gronewold J, Volsek M et al. The prevalence, severity, and association with HbA1c and fibrinogen of cognitive impairment in chronic kidney disease. Kidney Int 2014; 85: 693–702. Sorensen EP, Sarnak MJ, Tighiouart H et al. The kidney disease quality of life cognitive function subscale and cognitive performance in maintenance hemodialysis patients. Am J Kidney Dis 2012; 60: 417–426.
14.
15.
16.
17.
18.
19.
Agganis BT, Weiner DE, Giang LM et al. Depression and cognitive function in maintenance hemodialysis patients. Am J Kidney Dis 2010; 56: 704–712. Chen H-Y, Cheng I-C, Pan Y-J et al. Cognitivebehavioral therapy for sleep disturbance decreases inflammatory cytokines and oxidative stress in hemodialysis patients. Kidney Int 2011; 80: 415–422. Peacock T, Shihabi Z, Bleyer A et al. Comparison of glycated albumin and hemoglobin A1c levels in diabetic subjects on hemodialysis. Kidney Int 2008; 73: 1062–1068. van Oijen M, Witteman JC, Hofman A et al. Fibrinogen is associated with an increased risk of Alzheimer disease and vascular dementia. Stroke 2005; 36: 2637–2641. Weiner DE, Tighiouart H, Elsayed EF et al. The relationship between nontraditional risk factors and outcomes in individuals with stage 3 to 4 CKD. Am J Kidney Dis 2008; 51: 212–223. Jenny NS, French B, Arnold AM et al. Longterm assessment of inflammation and healthy aging in late life: the Cardiovascular Health Study All Stars. J Gerontol A Biol Sci Med Sci 2012; 67: 970–976.
see clinical investigation on page 686
Better prevention than cure: optimal patient preparation for renal replacement therapy Xiaoyan Huang1,2 and Juan Jesu´s Carrero1,3 A generous proportion of end-stage renal disease patients may not be adequately prepared for initiation of renal replacement therapy (RRT). Here we review potential benefits of early patient referral to nephrologists and optimal preparation for RRT. We place this evidence in the context of the epidemiological study by Kurella Tamura et al., which shows that voluntary community kidney disease screening and education is associated with better patient preparation and, importantly, improved survival upon initiation of RRT. Kidney International (2014) 85, 507–510. doi:10.1038/ki.2013.438
1 Divisions of Renal Medicine and Baxter Novum, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden; 2Division of Nephrology, Peking University Shenzhen Hospital, Peking University, Shenzhen, China and 3Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden Correspondence: Juan Jesu´s Carrero, Divisions of Renal Medicine and Baxter Novum, Karolinska University Hospital at Huddinge K56, Karolinska Institutet, SE-14186 Stockholm, Sweden. E-mail: [email protected]
The population prevalence of chronic kidney disease (CKD) exceeds 12% and is more than 50% in high-risk subpopulations. Nonetheless, awareness remains low in the community and among many physicians. In patients who progress to end-stage renal disease (ESRD), renal replacement therapy (RRT) is a life-saving necessity. Preparation for ESRD initiation has received increasing attention for disease 507
REFERENCES 1.
2.
3.
4.
5.
6.
7.
Bostom AG, Kronenberg F, Ritz E. Predictive performance of renal function equations for patients with chronic kidney disease and normal serum creatinine levels. J Am Soc Nephrol 2002; 13: 2140–2144. Wang X, Vrtiska TJ, Avula RT et al. Age, kidney function, and risk factors associate differently with cortical and medullary volumes of the kidney. Kidney Int 2014; 85: 677–685. Chapman AB, Bost JE, Torres VE et al. Kidney volume and functional outcomes in autosomal dominant polycystic kidney disease. Clin J Am Soc Nephrol 2012; 7: 479–486. Al-Said JM, O’Neill WC. Reduced kidney size in patients with simple renal cysts. Kidney Int 2003; 64: 1059–1064. Al-Said J, Moghazi S, Brumback M et al. Reduced renal function in patients with simple renal cysts. Kidney Int 2004; 65: 2303–2308. Rule AD, Sasiwimonphan K, Lieske JC et al. Characteristics of renal cystic and solid lesions based on contrast-enhanced computed tomography of potential kidney donors. Am J Kidney Dis 2012; 59: 611–618. Grantham JJ. Solitary renal cysts: worth a second look? Am J Kidney Dis 2012; 59: 593–594.
8.
9.
10.
11.
12.
13.
Feldt-Rasmussen B, Hegedus L, Mathiesen ER. Kidney volume in type I (insulin-dependent) diabetic patients with normal or increased urinary albumin excretion: effect of long-term improved metabolic control. Scand J Clin Lab Invest 1991; 51: 31–36. Baumgartl HJ, Sigl G, Banholzer P et al. On the prognosis of IDDM patients with large kidneys. Nephrol Dial Transplant 1998; 13: 630–634. Bakker J, Olree M, Kaatee R et al. Renal volume measurements: accuracy and repeatability of US compared with that of MR imaging. Radiology 1999; 211: 623–628. Johnson S, Rishi R, Andone A et al. Determinants and functional significance of renal parenchymal volume in adults. Clin J Am Soc Nephrol 2011; 6: 70–76. Nyengaard JR, Bendtsen TF. Glomerular number and size in relation to age, kidney weight, and body surface in normal men. Anat Rec 1992; 232: 194–201. Hoy W, Douglas-Denton R, Hughson M et al. A stereologic study of glomerular number and volume: preliminary findings in a multiracial study of kidneys at autopsy. Kidney Int 2003; 63: 31–37.
see clinical investigation on page 693
Cognitive impairment in chronic kidney disease: keep vascular disease in mind David A. Drew1 and Daniel E. Weiner1 Cognitive impairment is a major cause of morbidity in people with chronic kidney disease (CKD) and is associated with worse survival. Prior data suggest a relationship between vascular disease and cognitive impairment in individuals with CKD. Clinicians should be aware of the high rates of cognitive impairment that occur in all stages of CKD, which, although sometimes subtle, may impact comprehension and decision making and may herald future, more debilitating impairment. Kidney International (2014) 85, 505–507. doi:10.1038/ki.2013.437
Cognitive impairment is a major cause of morbidity in chronic kidney disease (CKD). Individuals with cognitive impairment often have lower quality of life, have more difficulty adhering to medications, and have worse survival.1 Importantly, cognitive deficits become both more 1 Division of Nephrology, Department of Medicine, Tufts Medical Center, Boston, Massachusetts, USA Correspondence: Daniel E. Weiner, Tufts Medical Center, 800 Washington Street, Box #391, Boston, Massachusetts 02111, USA. E-mail: [email protected]
Kidney International (2014) 85
prevalent and more severe at lower levels of kidney function.2 For patients with kidney failure treated with dialysis, this translates to a prevalence of cognitive impairment anywhere from 30 to 70%.3,4 Reflecting the complex medical issues present in people with CKD, the cause of cognitive impairment is probably multifactorial in this population. As in the general population, aging patients with kidney disease can be at risk for developing Alzheimer’s disease, which initially affects memory most
prominently; however, rates of Alzheimer’s in CKD patients appear similar to those in age- and sex-matched controls, therefore not explaining an observed excess of cognitive impairment.5 In contrast, cerebrovascular disease is common in all stages of CKD, with the highest rates occurring in those treated with dialysis. Brain magnetic resonance imaging in dialysis patients confirms a high burden of white matter disease, atrophy, and cerebral infarcts, even in those without a known history of stroke.6 Supporting the hypothesis that cerebrovascular disease is most responsible for cognitive impairment in people with CKD are several factors: (1) Neurocognitive manifestations of cerebrovascular disease predominantly affect executive function domains rather than memory, and most prior studies of individuals with CKD reveal that executive function is more severely affected than other cognitive domains.3,4,7,8 (2) Systemic cardiovascular disease (CVD) and CVD risk factors are associated with significantly worse executive function.7 (3) In earlier stages of CKD, higher levels of albuminuria, probably representing systemic vascular burden, are associated with both worse executive functioning and brain magnetic resonance image findings.5,9,10 (4) More intensive dialysis with more effective clearance of uremic solutes does not improve cognitive function.11 In addition to a high burden of traditional CVD risk factors among individuals with CKD, nontraditional risk factors such as inflammation may be more prominent in individuals with CKD and may also predispose to cardiovascular and cerebrovascular disease (Figure 1). Few data exist on how inflammation in individuals with CKD may contribute to abnormal brain function. Attempting to address these questions, Seidel et al.12 (this issue) performed a cross-sectional study evaluating cognitive performance in 119 patients with CKD stages 3–5D as well as 54 control subjects, all of whom had an estimated glomerular 505
commentary
filtration rate greater than 60 ml/min per 1.73 m2 but an otherwise similar burden of vascular disease risk factors. A battery of ten neurocognitive tests was used, the results of which were converted into a global cognitive score as well as three subscores comprising memory, executive function, and language domains. Although similar overall with respect to many characteristics, including age, education, and several vascular disease risk factors, there were several key differences between the CKD group and controls in this study, including the rate of transient ischemic attack or stroke (6% in CKD versus 0% in control) and the levels of brain natriuretic peptide and fibrinogen (both higher in CKD). As would be expected, the CKD group performed modestly worse on multiple measures of cognition when compared with the control group. Thirty percent of the CKD group had poor global cognitive performance (defined as one standard deviation worse than the control group), while 18% had memory deficits and 38% executive deficits. In unadjusted comparisons, performance did not vary significantly by CKD stage, a finding that could be explained by the younger age of stage 5D patients compared with CKD stage 3–5 (55 versus 65 years), possibly suggesting that the effects of kidney failure on cognitive function are similar to 10 years of aging. After adjustment for age, sex, and education, CKD stage was a strong predictor of global cognitive performance (with more advanced CKD associated with worse performance), but not of individual cognitive domains. Interestingly, the authors found a relationship between higher self-reported depression scores (using the Hospital Anxiety and Depression Scale) and lower global cognitive performance,12 a finding consistent with previous reports in dialysis that have demonstrated an association between depression symptoms and both poorer self-perceived and measured cognitive performance.13,14 The association was attenuated with adjustment for markers of disease severity such as blood pressure, hemoglobin A1c, CKD stage, and dyslipidemia, suggesting that comorbid conditions are involved in both depression and cognitive performance. 506
Traditional risk factors: • Dyslipidemia • Hypertension • Diabetes and hyperglycemia • Older age
Large- and small-vessel cerebrovascular disease
Non traditional risk factors: • Inflammation (C-reactive protein, fibrinogen) • Anemia • Mineral and bone disorder
Neuronal damage
Cognitive impairment
Other factors: • Education level • Depression • Psychiatric disease
Figure 1 | Proposed mechanisms of cognitive impairment in chronic kidney disease.
Notably, one recent randomized clinical trial conducted in 72 hemodialysis patients with sleep disturbances evaluated the effectiveness of cognitive-behavioral therapy, a non-pharmacologic intervention for depression, and noted a significant improvement in depression scores as well as inflammatory markers in the group treated with cognitive-behavioral therapy, potentially suggesting a mechanistic link among inflammation, sleep disturbances, depression, and cognition.15 In sum, the relationship between depression and cognitive performance is intriguing and deserves further attention for future study, as, unlike many other risk factors, depression is potentially modifiable, although few studies have assessed treatments for depression in hemodialysis patients. Next, Seidel et al. examined vascular disease risk factors and their association with cognitive performance. A key finding was that higher hemoglobin A1c (HbA1c) was associated with poorer global cognitive performance; this finding persisted even in models that adjusted for a previous history of CVD events as well as other traditional risk factors such as dyslipidemia, smoking, body mass index, and systolic blood pressure.12 HbA1c has been linked with cognitive performance in people with type 2 diabetes, but this has not previously been extended to patients with advanced CKD. Unfortunately, it is difficult to interpret what this finding means for patients with CKD, as HbA1c measurement in kidney disease remains poorly validated, with recent studies demonstrating that HbA1c measurement does not accurately reflect long-term blood sugar levels and thus may
substantially underestimate the degree of hyperglycemia in this population.16 Future studies of cognition could be well served by consideration of alternative measures of glycemic control to investigate this potentially important risk factor. An additional finding was an association between a higher fibrinogen level and worse memory and executive function, a finding that was attenuated in the main multivariable model. Fibrinogen, a marker of inflammation, is associated with cognitive performance in the general population, specifically with poorer performance on tests that identify vascular dementia,17 and, in individuals with stage 3–4 CKD, higher levels of fibrinogen are associated with CVD outcomes.18 Therefore, it was unexpected that the association between fibrinogen and memory was the more robust association in this study, raising the question of residual confounding. C-reactive protein (CRP), another wellstudied marker of inflammation, was not assessed in this study. Although both higher CRP and rising CRP over time are associated with the development of cognitive impairment in elderly populations,19 few studies have looked at CRP and cognitive performance in kidney disease despite the association of high CRP with a multitude of cardiovascular outcomes. Well-designed longitudinal studies that include multiple measures of inflammation will probably be required to better explore the impact of inflammation and its modifiers on cognitive performance. Kidney International (2014) 85
commentary
In sum, even when compared with a population enriched for CVD and CVD risk factors, individuals with CKD performed modestly worse on a cognitive battery testing multiple domains. Despite the many caveats associated with a crosssectional study as well as this study’s modest sample size, these findings, when viewed in the context of existing data, suggest that risk factors for cerebrovascular disease may be particularly important in the pathogenesis of cognitive impairment in people with CKD. Critically, clinicians should be aware of the high rates of cognitive impairment that occur even in earlier stages of CKD. Although initial cognitive deficits may be subtle, these deficits may herald future, more debilitating impairment. Future studies should evaluate whether treatments targeting vascular disease risk factors, possibly including inflammation, can prevent or slow the development of cognitive impairment in individuals with CKD. DISCLOSURE
The authors declared no competing interests. ACKNOWLEDGMENTS
D.A.D is funded by the American Society of Nephrology Research Fellowship Program. D.E.W work on cognition in kidney disease is funded via National Institute of Diabetes and Digestive and Kidney Diseases (National Institutes of Health) grant R01-DK090401.
REFERENCES 1.
2.
3.
4.
5.
6.
7.
Griva K, Stygall J, Hankins M et al. Cognitive impairment and 7-year mortality in dialysis patients. Am J Kidney Dis 2010; 56: 693–703. Kurella M, Chertow GM, Luan J et al. Cognitive impairment in chronic kidney disease. J Am Geriatr Soc 2004; 52: 1863–1869. Sarnak MJ, Tighiouart H, Scott TM et al. Frequency of and risk factors for poor cognitive performance in hemodialysis patients. Neurology 2013; 80: 471–480. Murray AM, Tupper DE, Knopman DS et al. Cognitive impairment in hemodialysis patients is common. Neurology 2006; 67: 216–223. Seliger SL, Siscovick DS, Stehman-Breen CO et al. Moderate renal impairment and risk of dementia among older adults: the Cardiovascular Health Cognition Study. J Am Soc Nephrol 2004; 15: 1904–1911. Drew DA, Bhadelia R, Tighiouart H et al. Anatomic brain disease in hemodialysis patients: a cross-sectional study. Am J Kidney Dis 2013; 61: 271–278. Weiner DE, Scott TM, Giang LM et al. Cardiovascular disease and cognitive function in maintenance hemodialysis patients. Am J Kidney Dis 2011; 58: 773–781.
Kidney International (2014) 85
8.
9.
10.
11.
12.
13.
Kalirao P, Pederson S, Foley RN et al. Cognitive impairment in peritoneal dialysis patients. Am J Kidney Dis 2011; 57: 612–620. Weiner DE, Bartolomei K, Scott T et al. Albuminuria, cognitive functioning, and white matter hyperintensities in homebound elders. Am J Kidney Dis 2009; 53: 438–447. Barzilay JI, Fitzpatrick AL, Luchsinger J et al. Albuminuria and dementia in the elderly: a community study. Am J Kidney Dis 2008; 52: 216–226. Kurella Tamura M, Unruh ML, Nissenson AR et al. Effect of more frequent hemodialysis on cognitive function in the Frequent Hemodialysis Network Trials. Am J Kidney Dis 2013; 61: 228–237. Seidel UK, Gronewold J, Volsek M et al. The prevalence, severity, and association with HbA1c and fibrinogen of cognitive impairment in chronic kidney disease. Kidney Int 2014; 85: 693–702. Sorensen EP, Sarnak MJ, Tighiouart H et al. The kidney disease quality of life cognitive function subscale and cognitive performance in maintenance hemodialysis patients. Am J Kidney Dis 2012; 60: 417–426.
14.
15.
16.
17.
18.
19.
Agganis BT, Weiner DE, Giang LM et al. Depression and cognitive function in maintenance hemodialysis patients. Am J Kidney Dis 2010; 56: 704–712. Chen H-Y, Cheng I-C, Pan Y-J et al. Cognitivebehavioral therapy for sleep disturbance decreases inflammatory cytokines and oxidative stress in hemodialysis patients. Kidney Int 2011; 80: 415–422. Peacock T, Shihabi Z, Bleyer A et al. Comparison of glycated albumin and hemoglobin A1c levels in diabetic subjects on hemodialysis. Kidney Int 2008; 73: 1062–1068. van Oijen M, Witteman JC, Hofman A et al. Fibrinogen is associated with an increased risk of Alzheimer disease and vascular dementia. Stroke 2005; 36: 2637–2641. Weiner DE, Tighiouart H, Elsayed EF et al. The relationship between nontraditional risk factors and outcomes in individuals with stage 3 to 4 CKD. Am J Kidney Dis 2008; 51: 212–223. Jenny NS, French B, Arnold AM et al. Longterm assessment of inflammation and healthy aging in late life: the Cardiovascular Health Study All Stars. J Gerontol A Biol Sci Med Sci 2012; 67: 970–976.
see clinical investigation on page 686
Better prevention than cure: optimal patient preparation for renal replacement therapy Xiaoyan Huang1,2 and Juan Jesu´s Carrero1,3 A generous proportion of end-stage renal disease patients may not be adequately prepared for initiation of renal replacement therapy (RRT). Here we review potential benefits of early patient referral to nephrologists and optimal preparation for RRT. We place this evidence in the context of the epidemiological study by Kurella Tamura et al., which shows that voluntary community kidney disease screening and education is associated with better patient preparation and, importantly, improved survival upon initiation of RRT. Kidney International (2014) 85, 507–510. doi:10.1038/ki.2013.438
1 Divisions of Renal Medicine and Baxter Novum, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden; 2Division of Nephrology, Peking University Shenzhen Hospital, Peking University, Shenzhen, China and 3Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden Correspondence: Juan Jesu´s Carrero, Divisions of Renal Medicine and Baxter Novum, Karolinska University Hospital at Huddinge K56, Karolinska Institutet, SE-14186 Stockholm, Sweden. E-mail: [email protected]
The population prevalence of chronic kidney disease (CKD) exceeds 12% and is more than 50% in high-risk subpopulations. Nonetheless, awareness remains low in the community and among many physicians. In patients who progress to end-stage renal disease (ESRD), renal replacement therapy (RRT) is a life-saving necessity. Preparation for ESRD initiation has received increasing attention for disease 507
