Abstracts
Impairment of cognitive functions occurs frequently in chronic kidney disease (CKD). The conditions most associated with this decline are depression, delirium, mild cognitive impairment and dementia. The mechanisms involved have not been established yet, but some factors, as neuronal damage by uremic toxins, cerebrovascular ischemic lesions, oxidative stress, chronic inflammation, anemia, hyperhomocysteinemia, the endothelial dysfunction may play a critical role. The neuropsychological performance improves with the initiation of dialysis, although some cognitive dysfunctions remain even after treatment, especially in the areas of attention, cognitive flexibility, memory and learning. Kidney transplantation may improve and even reverse some cognitive deficits detected in the dialysis period, despite some compromise in verbal memory and executive functions remain after transplantation. The diagnosis of cognitive decline in patients with CKD may have an important impact on the management and prognosis. This paper presents an update on the decline of cognitive function in patients with CKD.
cognition disorders; dialysis; kidney failure, chronic; kidney transplantation
Prejuízos das funções cognitivas ocorrem com frequência na doença renal crônica (DRC). As condições mais associadas a esses prejuízos são depressão, delirium, comprometimento cognitivo leve e demência. Os mecanismos envolvidos ainda não estão estabelecidos, mas alguns fatores, como dano neuronal induzido pelas toxinas urêmicas, lesões cerebrovasculares isquêmicas, estresse oxidativo, inflamação crônica, anemia, hiper-homocisteinemia e disfunção endotelial, podem ser importantes. O desempenho neuropsicológico tende a melhorar com o início da diálise, apesar de algumas disfunções cognitivas permanecerem alteradas mesmo após a instituição do tratamento, principalmente nos domínios de atenção, flexibilidade cognitiva, memória e aprendizagem. O transplante renal pode melhorar e, inclusive, reverter alguns déficits cognitivos, apesar de prejuízos na memória verbal e nas funções executivas poderem permanecer. O diagnóstico do declínio cognitivo nos pacientes renais crônicos pode ter impacto no manejo e no prognóstico. Este artigo apresenta uma atualização sobre declínio das funções cognitivas nos pacientes com DRC.
cognição; diálise; insuficiência renal crônica; transplante de rim
Introduction
The term "cognition" covers aspects of brain function related to various domains
such as attention, language, memory, learning, reasoning, decision making, and
problem solving. Cognitive impairment can be understood as a decline in patient
baseline functions possibly at a level severe enough to interfere with the
performance of activities of daily living by the individual. Cognitive
involvement and dementia are commonly seen in patients with chronic kidney
disease (CKD), particularly in subjects with advanced stage disease, but are
poorly recognized by nephrologists.11. Kurella Tamura M, Yaffe K. Dementia and cognitive impairment in
ESRD: diagnostic and therapeutic strategies. Kidney Int 2011;79:14-22. PMID:
20861818 DOI: http://dx.doi.org/10.1038/ki.2010.336
http://dx.doi.org/10.1038/ki.2010.336...
However, individuals with disease in any stage are susceptible to cognitive
disorders22. Bugnicourt JM, Godefroy O, Chillon JM, Choukroun G, Massy ZA.
Cognitive disorders and dementia in CKD: the neglected kidney-brain axis. J Am
Soc Nephrol 2013;24:353-63. DOI:
http://dx.doi.org/10.1681/ASN.2012050536
http://dx.doi.org/10.1681/ASN.2012050536...
associated with increased
risk of death, lower levels of compliance to proposed treatment, higher
incidence of cerebrovascular disease, and prolonged hospitalization.11. Kurella Tamura M, Yaffe K. Dementia and cognitive impairment in
ESRD: diagnostic and therapeutic strategies. Kidney Int 2011;79:14-22. PMID:
20861818 DOI: http://dx.doi.org/10.1038/ki.2010.336
http://dx.doi.org/10.1038/ki.2010.336...
,33. McQuillan R, Jassal SV. Neuropsychiatric complications of chronic
kidney disease. Nat Rev Nephrol 2010;6:471-9. DOI:
http://dx.doi.org/10.1038/nrneph.2010.83
http://dx.doi.org/10.1038/nrneph.2010.83...
,44. Nasser Mel T, Shawki S, El Shahawy Y, Sany D. Assessment of
cognitive dysfunction in kidney disease. Saudi J Kidney Dis Transpl
2012;23:1208-14.
The identification of cognitive deficits may produce positive impacts on patient
outcome, particularly when the impairment is secondary to potentially treatable
conditions such as depression and delirium.11. Kurella Tamura M, Yaffe K. Dementia and cognitive impairment in
ESRD: diagnostic and therapeutic strategies. Kidney Int 2011;79:14-22. PMID:
20861818 DOI: http://dx.doi.org/10.1038/ki.2010.336
http://dx.doi.org/10.1038/ki.2010.336...
The prevalence of depression symptoms in
patients with end-stage renal disease (ESRD) ranges between 20% and 25%,55. Cukor D, Coplan J, Brown C, Friedman S, Cromwell-Smith A,
Peterson RA, et al. Depression and anxiety in urban hemodialysis patients. Clin
J Am Soc Nephrol 2007;2:484-90. DOI:
http://dx.doi.org/10.2215/CJN.00040107
http://dx.doi.org/10.2215/CJN.00040107...
ranking them second only to hypertension
in the roster of comorbidities observed in patients with ESRD.55. Cukor D, Coplan J, Brown C, Friedman S, Cromwell-Smith A,
Peterson RA, et al. Depression and anxiety in urban hemodialysis patients. Clin
J Am Soc Nephrol 2007;2:484-90. DOI:
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,66. Cukor D, Peterson RA, Cohen SD, Kimmel PL. Depression in
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Delirium is a syndrome characterized by rapid onset of alternating consciousness
and cognitive function alterations caused by the physiologic dysfunctions
introduced by a medical condition.77. American Psychiatric Association. Diagnostic and Statistical
Manual of Mental Disorders. 4th ed. Washington: American Psychiatric
Association; 2000.
Psychomotor and sleep architecture disorders are commonly seen in patients
suffering from delirium.33. McQuillan R, Jassal SV. Neuropsychiatric complications of chronic
kidney disease. Nat Rev Nephrol 2010;6:471-9. DOI:
http://dx.doi.org/10.1038/nrneph.2010.83
http://dx.doi.org/10.1038/nrneph.2010.83...
The
predisposing factors for delirium in patients with CKD include sensory loss,
cerebrovascular disease, subclinical metabolic disorders, and polypharmacy.
Hospitalization and alterations in the metabolism of certain drugs (opioids,
psychotropic drugs, antibiotics, antiviral medication) and their toxic
metabolites also boost occurrences of delirium.33. McQuillan R, Jassal SV. Neuropsychiatric complications of chronic
kidney disease. Nat Rev Nephrol 2010;6:471-9. DOI:
http://dx.doi.org/10.1038/nrneph.2010.83
http://dx.doi.org/10.1038/nrneph.2010.83...
,88. Helmer C, Stengel B, Metzger M, Froissart M, Massy ZA, Tzourio C,
et al. Chronic kidney disease, cognitive decline, and incident dementia: the 3C
Study. Neurology 2011;77:2043-51. PMID: 22116945 DOI:
http://dx.doi.org/10.1212/WNL.0b013e31823b4765
http://dx.doi.org/10.1212/WNL.0b013e3182...
In addition to potentially reversible conditions, mild cognitive involvement and
dementia have also been correlated with mental function decline. CKD has been
strongly correlated with vascular dementia in particular.99. Cheng KC, Chen YL, Lai SW, Mou CH, Tsai PY, Sung FC. Patients
with chronic kidney disease are at an elevated risk of dementia: a
population-based cohort study in Taiwan. BMC Nephrol 2012;13:129. DOI:
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When
compared to the general population, the prevalence of cognitive impairment is
higher in individuals with renal failure and even more significant in patients
on dialysis.1111. Gaxatte C, Daroux M, Bloch J, Puisieux F, Deramecourt V,
Boulanger E. Cognitive impairment and chronic kidney disease: which links?
Nephrol Ther 2011;7:10-7. In qualitative terms, mild
cognitive involvement is similar to dementia, although its impact on the
performance of activities of daily living is not as significant as the one
produced by dementia.
Dementia appears to complicate the management of patients with ESRD and has been
correlated with poorer prognosis.11. Kurella Tamura M, Yaffe K. Dementia and cognitive impairment in
ESRD: diagnostic and therapeutic strategies. Kidney Int 2011;79:14-22. PMID:
20861818 DOI: http://dx.doi.org/10.1038/ki.2010.336
http://dx.doi.org/10.1038/ki.2010.336...
Patients with dementia present deficits in at least two of the following
cognitive functional areas: memory, executive function, attention, visuospatial
skills, speed of information processing, and language. Signs of decline in lower
functional levels materialize as compromised performance in various areas of the
affected individual's life, such as work and interpersonal relationships.77. American Psychiatric Association. Diagnostic and Statistical
Manual of Mental Disorders. 4th ed. Washington: American Psychiatric
Association; 2000. Murray et al.1212. Murray AM, Tupper DE, Knopman DS, Gilbertson DT, Pederson SL, Li
S, et al. Cognitive impairment in hemodialysis patients is common. Neurology
2006;67:216-23. DOI:
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looked into the neuropsychological
performance of 338 hemodialysis patients through memory, language, and executive
function tests and found that over a third of the subjects had three times the
prevalence of dementia estimated for the general population.
However, dementia is not limited to cases of advanced kidney disease. Patients
initially diagnosed with moderate renal disease without dementia had higher
incidences of vascular dementia over six years of follow-up1010. Seliger SL, Siscovick DS, Stehman-Breen CO, Gillen DL,
Fitzpatrick A, Bleyer A, Kuller LH. Moderate renal impairment and risk of
dementia among older adults: the Cardiovascular Health Cognition Study. J Am Soc
Nephrol 2004;15:1904-11. DOI:
http://dx.doi.org/10.1097/01.ASN.0000131529.60019.FA
http://dx.doi.org/10.1097/01.ASN.0000131...
in association with higher serum creatinine levels.
Given the context, this paper aims to present an update on the most frequent cognitive alterations seen in CKD patients and further emphasize the relevance of the topic in nephrology care.
What are the mechanisms involved in the cognitive dysfunctions of patients with CKD?
Most studies suggest that CKD severity and progression of cognitive decline
go hand in hand.1313. Kurella M, Chertow GM, Luan J, Yaffe K. Cognitive impairment in
chronic kidney disease. J Am Geriatr Soc 2004;52:1863-9. PMID: 15507063 DOI:
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followed a group
of patients for four years and correlated the estimated glomerular
filtration rate (GFR) decreases in CKD patients aged 55 years and older with
greater functional and global cognitive decline.
Helmer et al.88. Helmer C, Stengel B, Metzger M, Froissart M, Massy ZA, Tzourio C,
et al. Chronic kidney disease, cognitive decline, and incident dementia: the 3C
Study. Neurology 2011;77:2043-51. PMID: 22116945 DOI:
http://dx.doi.org/10.1212/WNL.0b013e31823b4765
http://dx.doi.org/10.1212/WNL.0b013e3182...
studied a cohort of 7,839 patients aged 65 and older and did not report
increases in the risk of cognitive impairment or dementia in association
with low estimated GFR. In the seven-year follow-up, however, more rapid
declines in the GRF were associated with global cognitive impairment and
increased incidence of vascular dementia. In any case, other recent studies
comparing patients with CKD and subjects without renal disease have
confirmed the correlation between all stages of CKD and greater risk of
cerebral function impairment.22. Bugnicourt JM, Godefroy O, Chillon JM, Choukroun G, Massy ZA.
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uremic toxins, the risk of cognitive involvement and dementia in these
patients may be due to the high prevalence of symptomatic and asymptomatic
brain ischemia.22. Bugnicourt JM, Godefroy O, Chillon JM, Choukroun G, Massy ZA.
Cognitive disorders and dementia in CKD: the neglected kidney-brain axis. J Am
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This vascular
mechanism may explain the association between the risk factors affecting
both the brain and the kidneys and its potential exacerbation in renal
disease.88. Helmer C, Stengel B, Metzger M, Froissart M, Massy ZA, Tzourio C,
et al. Chronic kidney disease, cognitive decline, and incident dementia: the 3C
Study. Neurology 2011;77:2043-51. PMID: 22116945 DOI:
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By their
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Figure 1 shows a schematic
representation of the pathophysiological mechanisms related to cognitive
dysfunction in CKD patients.
Dialysis and cognition
Although underdiagnosed, the prevalence of cognitive impairment is
significant among individuals with CKD on dialysis.1616. Radic J, LjuticD, RadicM, KovacicV, Sain M, CurkovicKD. The
possible impact of dialysis modality on cognitive function in chronic dialysis
patients. Neth J Med 2010;68:153-7. PMID: 20421655 A recent study found that patients on dialysis
performed more poorly than the general population on tasks assessing
executive function, a finding correlated with vascular disease and vascular
risk factors.2727. Sarnak MJ, Tighiouart H, Scott TM, Lou KV, Sorensen EP, Giang
LM, et al. Frequency of and risk factors for poor cognitive performance in
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Normal scores on the
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do
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LM, et al. Frequency of and risk factors for poor cognitive performance in
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Individuals on hemodialysis had low scores in logical reasoning, verbal
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The risk of multi-infarct dementia
in elderly patients on hemodialysis appears to be seven times greater than
in the general population, possibly due to increased prevalence of
comorbidities such as diabetes mellitus, atherosclerosis, and hypertension
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Similarly to hemodialysis patients, most individuals on peritoneal dialysis
have moderate to severe cognitive impairment, especially in areas related to
executive function, decision-making, and capacity for abstraction. Such
impairment may interfere with the self-administration of dialysis and
compliance with complex medication regimens.3131. Kalirao P, Pederson S, Foley RN, Kolste A, Tupper D, Zaun D, et
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Patients doing well on hemodialysis, in good nutritional
condition, and clinically stable do not appear to differ significantly from
their counterparts in equal condition on peritoneal dialysis.1616. Radic J, LjuticD, RadicM, KovacicV, Sain M, CurkovicKD. The
possible impact of dialysis modality on cognitive function in chronic dialysis
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Dialysis processes directly contribute to cognitive involvement by inducing
brain ischemia. Acute decreases in intravascular volumes and fluid exchanges
occurring during dialysis sessions may cause edema and diminish cerebral
perfusion.1616. Radic J, LjuticD, RadicM, KovacicV, Sain M, CurkovicKD. The
possible impact of dialysis modality on cognitive function in chronic dialysis
patients. Neth J Med 2010;68:153-7. PMID: 20421655 More specifically,
patients with acute kidney injury are more susceptible to cerebral
hypoperfusion during intermittent hemodialysis than patients with ESRD.3333. Regolisti G, Maggiore U, Cademartiri C, Cabassi A, Caiazza A,
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Neuropsychological performance tends to improve after the introduction of
dialysis, and patients on dialysis have lesser cognitive deficits than
untreated individuals and patients with uremia. Short-term memory improves
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despite the possible persistence of other cognitive dysfunctions in the
domains of attention, cognitive flexibility, memory, and learning.3434. Pliskin NH, Yurk HM, Ho LT, Umans JG. Neurocognitive function in
chronic hemodialysis patients. Kidney Int 1996;49:1435-40. PMID: 8731111 DOI:
http://dx.doi.org/10.1038/ki.1996.202
http://dx.doi.org/10.1038/ki.1996.202...
Cognitive function and kidney transplantation
Studies have described memory improvements after renal transplantation and
reversion of some neuropsychological deficits, memory impairments in
particular, detected during dialysis.3535. Griva K, Thompson D, Jayasena D, Davenport A, Harrison M, Newman
SP. Cognitive functioning pre- to post-kidney transplantation-a prospective
study. Nephrol Dial Transplant 2006;21:3275-82. DOI:
http://dx.doi.org/10.1093/ndt/gfl385
http://dx.doi.org/10.1093/ndt/gfl385...
Although in a study published in 1984 Fennel et
al.3636. Fennell RS 3rd, Rasbury WC, Fennell EB, Morris MK. Effects of
kidney transplantation on cognitive performance in a pediatric population.
Pediatrics 1984;74:273-8. indicated that
improvements in cognitive performance were not sustained in children and
adolescents, the benefits of kidney transplantation do not seem to be
transient or limited to the early stages of the post-transplant period, and
may persist for at least a year after the procedure.3737. Harciarek M, Biedunkiewicz B, Lichodziejewska-Niemierko M,
Debska-Slizien A, Rutkowski B. Continuous cognitive improvement 1 year following
successful kidney transplant. Kidney Int 2011;79:1353-60. PMID: 21389973 DOI:
http://dx.doi.org/10.1038/ki.2011.40
http://dx.doi.org/10.1038/ki.2011.40...
,3838. Radić J, Ljutić D, Radić M, Kovačić V, Dodig-Ćurković K, Šain M.
Kidney transplantation improves cognitive and psychomotor functions in adult
hemodialysis patients. Am J Nephrol 2011;34:399-406. DOI:
http://dx.doi.org/10.1159/000330849
http://dx.doi.org/10.1159/000330849...
Improvements in cognition may be observed in intelligence tests after renal
transplantation, both in adults and children.3535. Griva K, Thompson D, Jayasena D, Davenport A, Harrison M, Newman
SP. Cognitive functioning pre- to post-kidney transplantation-a prospective
study. Nephrol Dial Transplant 2006;21:3275-82. DOI:
http://dx.doi.org/10.1093/ndt/gfl385
http://dx.doi.org/10.1093/ndt/gfl385...
,3939. Icard P, Hooper SR, Gipson DS, Ferris ME. Cognitive improvement
in children with CKD after transplant. Pediatr Transplant 2010;14:887-90. DOI:
http://dx.doi.org/10.1111/j.1399-3046.2010.01359.x
http://dx.doi.org/10.1111/j.1399-3046.20...
Nevertheless, after transplantation patients may still have to endure
deficits in verbal memory and executive function.4040. Gelb S, Shapiro RJ, Hill A, Thornton WL. Cognitive outcome
following kidney transplantation. Nephrol Dial Transplant 2008;23:1032-8. DOI:
http://dx.doi.org/10.1093/ndt/gfm659
http://dx.doi.org/10.1093/ndt/gfm659...
Despite the improvements in the metabolic factors
associated with CKD, cognitive impairment is thought to persist as a
consequence of the patients' remaining clinical comorbidities.4040. Gelb S, Shapiro RJ, Hill A, Thornton WL. Cognitive outcome
following kidney transplantation. Nephrol Dial Transplant 2008;23:1032-8. DOI:
http://dx.doi.org/10.1093/ndt/gfm659
http://dx.doi.org/10.1093/ndt/gfm659...
Evidence suggests that kidney transplantation and dialysis positively impact the cognitive status of patients with CKD. However, the literature does not support the prescription of dialysis based solely on the presence of cognitive impairment. Patients with chronic kidney disease might benefit from therapies devised specifically to improve cognitive performance, such as cognitive rehabilitation, but no specific studies have been carried out on the matter. Likewise, little research has been done on the efficacy and safety of drug therapies for dementia and mild cognitive impairment in the context of kidney disease; management, therefore, must be individualized.
Closing remarks
Depression, delirium and dementia are commonly seen in any stage of CKD, and are
generally associated with complications and poorer prognosis.1212. Murray AM, Tupper DE, Knopman DS, Gilbertson DT, Pederson SL, Li
S, et al. Cognitive impairment in hemodialysis patients is common. Neurology
2006;67:216-23. DOI:
http://dx.doi.org/10.1212/01.wnl.0000225182.15532.40
http://dx.doi.org/10.1212/01.wnl.0000225...
CKD appears to be a risk factor for
cognitive impairment and dementia. Renal disease severity walks hand in hand
with loss of neurocognitive function.99. Cheng KC, Chen YL, Lai SW, Mou CH, Tsai PY, Sung FC. Patients
with chronic kidney disease are at an elevated risk of dementia: a
population-based cohort study in Taiwan. BMC Nephrol 2012;13:129. DOI:
http://dx.doi.org/10.1186/1471-2369-13-129
http://dx.doi.org/10.1186/1471-2369-13-1...
Although evidence suggests that hemodialysis improves cognition in patients with CKD,44. Nasser Mel T, Shawki S, El Shahawy Y, Sany D. Assessment of cognitive dysfunction in kidney disease. Saudi J Kidney Dis Transpl 2012;23:1208-14. a significant, yet underestimated, portion of the individuals on hemodialysis presents moderate to severe cognitive impairment. There appears to be no difference in the cognitive disorders affecting patients with CKD treated with hemodialysis or peritoneal dialysis.1616. Radic J, LjuticD, RadicM, KovacicV, Sain M, CurkovicKD. The possible impact of dialysis modality on cognitive function in chronic dialysis patients. Neth J Med 2010;68:153-7. PMID: 20421655
The identification of patients with cognitive impairment is an important step in
the process to improve quality of life and mitigate the morbidities associated
with this condition. The ideal time to assess cognitive function and the choice
of screening scale must take the patient's clinical status into account.11. Kurella Tamura M, Yaffe K. Dementia and cognitive impairment in
ESRD: diagnostic and therapeutic strategies. Kidney Int 2011;79:14-22. PMID:
20861818 DOI: http://dx.doi.org/10.1038/ki.2010.336
http://dx.doi.org/10.1038/ki.2010.336...
Evaluations should take little time, as
is the case with the administration of the MMSE,2828. Folstein MF, Folstein SE, McHugh PR. "Mini-mental state". A
practical method for grading the cognitive state of patients for the clinician.
J Psychiatr Res 1975;12:189-98. PMID: 1202204 DOI:
http://dx.doi.org/10.1016/0022-3956(75)90026-6
http://dx.doi.org/10.1016/0022-3956(75)9...
the best known and studied screening test for dementia. However,
neuropsychological testing requires more time and may be needed in more thorough
investigations of the cognitive domains.
The reasons behind the onset of cognitive impairment in patients with CKD are yet
unclear, but evidence indicates the involvement of factors such as inflammation,
endothelial dysfunction, atherosclerosis, oxidative stress, anemia,
hyperhomocysteinemia, and uremic toxins.1818. Vianna HR, Soares CM, Tavares MS, Teixeira MM, Silva AC.
Inflammation in chronic kidney disease: the role of cytokines. J Bras Nefrol
2011;33:351-64. DOI:
http://dx.doi.org/10.1590/S0101-28002011000300012
http://dx.doi.org/10.1590/S0101-28002011...
,2121. Troen AM, Scott TM, D'Anci KE, Moorthy D, Dobson B, Rogers G, et
al.; FACT Study Investigators. Cognitive dysfunction and depression in adult
kidney transplant recipients: baseline findings from the FAVORIT Ancillary
Cognitive Trial (FACT). J Ren Nutr 2012;22:268-76. DOI:
http://dx.doi.org/10.1053/j.jrn.2011.07.009
http://dx.doi.org/10.1053/j.jrn.2011.07....
,2323. Rios DR, Carvalho Md, Lwaleed BA, Simões e Silva AC, Borges KB,
Dusse LM. Hemostatic changes in patients with end stage renal disease undergoing
hemodialysis. Clin Chim Acta 2010;411:135-9. PMID: 19945449 DOI:
http://dx.doi.org/10.1016/j.cca.2009.11.022
http://dx.doi.org/10.1016/j.cca.2009.11....
More studies
are needed to shed light on the possible strategies that may be used to delay or
prevent the onset of cognitive impairment in patients with chronic kidney
disease.
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» http://dx.doi.org/10.1038/ki.1996.202 -
35Griva K, Thompson D, Jayasena D, Davenport A, Harrison M, Newman SP. Cognitive functioning pre- to post-kidney transplantation-a prospective study. Nephrol Dial Transplant 2006;21:3275-82. DOI: http://dx.doi.org/10.1093/ndt/gfl385
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» http://dx.doi.org/10.1038/ki.2011.40 -
38Radić J, Ljutić D, Radić M, Kovačić V, Dodig-Ćurković K, Šain M. Kidney transplantation improves cognitive and psychomotor functions in adult hemodialysis patients. Am J Nephrol 2011;34:399-406. DOI: http://dx.doi.org/10.1159/000330849
» http://dx.doi.org/10.1159/000330849 -
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» http://dx.doi.org/10.1093/ndt/gfm659
Publication Dates
-
Publication in this collection
Apr-Jun 2014
History
-
Received
15 July 2013 -
Accepted
24 Oct 2013