Nephrol Dial Transplant (2021) 37: ii55 –ii62 doi: 10.1093/ndt/gfab261 LEADING EUROPEAN NEPHROLOGY NEPHROLOGY DIALYSIS TRANSPLANTATION Albuminuria as a risk factor for mild cognitive impairment and dementia—what is the evidence? REVIEW 1 2 Boris Bikbov , Maria José Soler , Vesna Pesic3, Giovambattista Capasso4,5, Robert Unwin 6 , Matthias Endres7, Giuseppe Remuzzi1, Norberto Perico1, Ron Gansevoort8, Francesco Mattace-Raso9, Annette Bruchfeld 10, Andreja Figurek11 and Gaye Hafez 12; the CONNECT Action (Cognitive Decline in Nephro-Neurology European Cooperative Target) 1 Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy, 2Division of Nephrology Autonomous University of Barcelona, Hospital Universitari Vall d’Hebron, Barcelona, Spain, 3Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia, 4Department Translational Medical Sciences, Univ. Campania “L. Vanvitelli”, Naples, Italy, 5BIOGEM, Insititute Molecular Biology and Genetics, Ariano Irpino, Italy, 6Department of Renal Medicine, University College London, London, UK, 7Klinik und Hochschulambulanz für Neurologie, Charité-Universitätsmedizin Berlin, Berlin, Germany, 8Department of Internal Medicine, University Medical Center Groningen, Groningen, The Netherlands, 9Department of Internal Medicine, Erasmus MC University Medical Center, Rotterdam, The Netherlands, 10Unit of Renal Medicine, Linköping and Karolinska University Hospital, Stockholm, Sweden, 11Institute of Anatomy, University of Zurich, Zurich, Switzerland and 12Department of Pharmacology, Faculty of Pharmacy, Altinbas University, Istanbul, Turkey, Correspondence to: Boris Bikbov; E-mail: boris@bikbov.ru GRAPHICAL ABSTRACT C The Author(s) 2021. Published by Oxford University Press on behalf of ERA. V This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/ by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re- use, please contact journals.permissions@oup.com 1 ABSTRACT The interest in studying the interplay between CKD and Kidney dysfunction can profoundly influence many organ sys- MCI or dementia has been determined by its potential for tems, and recent evidence suggests a potential role for increased practical application, with the main question being whether albuminuria in the development of mild cognitive impairment the treatment of CKD can prevent MCI and dementia. (MCI) or dementia. Epidemiological studies conducted in dif- Unfortunately, so far the answer is unknown, and more re- ferent populations have demonstrated that the presence of in- search and clinical studies will be needed to resolve it. Previous creased albuminuria is associated with a higher relative risk of studies have suggested that albuminuria is related to MCI and MCI or dementia both in cross-sectional analyses and in studies dementia, and in this review we summarize the available with long-term follow-up. The underlying pathophysiological evidence, point out existing gaps in our knowledge and make mechanisms of albuminuria’s effect are as yet insufficiently some suggestions on what might be done to fill them. studied, with several important knowledge gaps still present in a complex relationship with other MCI and dementia risk factors. ASSOCIATION OF INCREASED ALBUMINURIA WITH Both the kidney and the brain have microvascular similarities MCI AND DEMENTIA that make them sensitive to endothelial dysfunction involving The first published clinical studies demonstrating an associa- different mechanisms, including oxidative stress and inflamma- tion between albuminuria and dementia were confined mainly tion. The exact substrate of MCI and dementia is still under in- to elderly populations [5–9]. In one early investigation in older vestigation, however available experimental data indicate that adults from the Cardiovascular Health Cognition Study elevated albuminuria and low glomerular filtration rate are as- (n ¼ 2316), Barzilay et al. found a cross-sectional association sociated with significant neuroanatomical declines in hippo- between increasing albuminuria and dementia. This association campal function and grey matter volume. Thus, albuminuria remained significant after adjustment for factors associated may be critical in the development of cognitive impairment and with dementia, such as hypertension, diabetes and prevalent its progression to dementia. In this review, we summarize the cardiovascular disease. The authors suggested that the associa- available evidence on albuminuria’s link to MCI and dementia, tion of albuminuria and dementia may be partly explained by point to existing gaps in our knowledge and suggest actions to the many anatomical microvascular similarities found in the overcome them. The major question of whether interventions brains of people with dementia and in the kidneys of patients that target increased albuminuria could prevent cognitive de- with albuminuria [6]. The Prevention of Renal and Vascular cline remains unanswered. Our recommendations for future re- End-Stage Disease study conducted in a general population search are aimed at helping to plan clinical trials and to solve (n ¼ 4095) found that elevated albuminuria, but not estimated the complex conundrum outlined in this review, with the ulti- glomerular filtration rate (eGFR), was associated with worse mate goal of improving the lives of patients with chronic kidney cognitive function. However, this association was only present disease. in the younger cohort (lower tertile of age: 42 6 4 years old). Furthermore, younger subjects with an increase in albuminuria during the 6 years before cognitive function testing performed Keywords: albuminuria, chronic kidney disease, dementia, significantly worse on testing than those with stable albumin- glomerular filtration rate, mild cognitive impairment uria. The authors suggested that the stronger association of al- buminuria with cognitive function in younger versus older INTRODUCTION participants is plausible, because at a young age the prevalence Kidney dysfunction can have a profound effect on many organ of interacting comorbid conditions that might confound this systems, and chronic kidney disease (CKD) is recognized as a association is low [7]. Similarly, a high urinary albumin-to- creatinine ratio (UACR) was significantly associated with the major risk factor for not only broader cardiovascular diseases presence of imaging markers of cerebral small vessel disease in [1], but also for pre-eclampsia, premature delivery and low middle-aged and elderly participants of the general population- birth weight [2]. Recently, evidence has emerged for a relation- based Rotterdam Study [10], and with an increase of the white ship between CKD and mild cognitive impairment (MCI) or matter hyperintensities (reflecting deteriorating cerebral white dementia, and this review aims to summarize different aspects matter due to myelin breakdown) volume to the intracranial of this still poorly understood association. The magnitude of volume ratio in the Hisayama Study [11]. More recently, this as- the problem is large, with almost 700 million persons world- sociation has been confirmed in the population-based AGES– wide affected by CKD [3] and almost 51 million with Reykjavik Study (mean age 75 years), showing that participants Alzheimer’s disease or other dementias [4]. The burden of both with incident albuminuria (UACR >30 mg/g) had 21% more CKD, MCI and or dementia increases with age, but apart from white matter hyperintensity volume progression compared an aging population, there are additional factors that drive both with participants without incident albuminuria [12]. Recent conditions and lead to an increase in their age-standardized studies, including a prospective Atherosclerosis Risk in prevalence rates (which accounts for both population growth Communities (ARIC) study [13], the Hisayama Study [14] and and aging) over the past 30 years: CKD and dementia have others, also found that increased albuminuria is consistently shown an increase of 9.4% and 5.7%, respectively, whereas car- associated with the incidence of dementia. diovascular disease, cancer and chronic respiratory diseases de- In diabetic patients, albuminuria has been linked to acceler- creased by 4.4%, 6.6% and 16.9%, respectively [4]. ated cognitive decline. Microvascular cerebral disease manifests 2 B. Bikbov et al. as impaired vasoreactivity, hypoperfusion and decreased me- information processing speed domain. HIV patients treated tabolism, which may lead to hypoxia and brain tissue loss. with combination antiretroviral therapy and a history of In middle-aged adults with diabetes and preserved baseline microalbuminuria had worse cognitive performance for the eGFR (90 mL/min/1.73 m2), cognitive function assessed by information processing speed domain, possibly because of the the Digit Symbol Substitution Test was worse in participants presence of cerebral small vessel disease [20]. with persistent and progressive albuminuria compared with Of particular interest is the analysis of cognitive function in participants with no albuminuria. Moreover, the eGFR decline the nephrotic syndrome (NS) characterized by heavy protein- was greater in those with persistent albuminuria compared with uria >3.5 g/24 h (accompanied by oedema, hypercholesterolae- those with increasing albuminuria, suggesting a dose effect. mia, hypoalbuminaemia and prothrombotic state) and usually These findings were independent of both baseline eGFR and a normal eGFR that allows separation of the effects of protein- eGFR decline [15]. Mehta et al. used 3D magnetization pre- uria and reduced eGFR. Unfortunately, literature data are scant. pared rapid acquisition with gradient echo magnetic resonance In children with NS, different studies have demonstrated an imaging (MRI) at 3T to evaluate the effect of subclinical levels altered quality of life [21], behavioural abnormalities (mostly of albuminuria on grey matter (GM) in type 2 diabetes mellitus hyperkinesis) [22], ‘thought problems’ and ‘internalizing prob- (DM). These authors found a link between UACR and GM lems’, without mood changes or attention problems [23]. volume changes in type 2 DM subjects compared with age- However, the interpretation of these findings is confounded by matched controls. Of note, even subclinical levels of concurrent factors. Thus, psychological stress may trigger pro- UACR 5 mg/g were associated with an early decline in brain teinuria in children with steroid-sensitive NS [24] and mood health. This study also found that the lesions at the GM level be- changes could be associated with corticosteroid therapy for NS gin early when UACR is within accepted normal limits, but [23]. In adults with NS, a study conducted in Taiwan suggested there is clearly a continuum [16]. In contrast, in the Memory in a correlation between NS and ischaemic stroke [25]. Diabetes substudy of the Action to Control Cardiovascular Risk in Diabetes study of middle-aged and older adults with type 2 ROLE OF LOW EGFR IN COGNITIVE DM, albuminuria at baseline and its persistence during follow- IMPAIRMENT AND DEMENTIA up were not independently associated with an increase in There are conflicting data on the role of eGFR in the impair- abnormal white matter hyperintensity volume when analyses ment of separate cognitive domains [26]. This also concerns the were adjusted for systolic blood pressure (SBP) [17]. The de- evidence correlating low eGFR with overt dementia. Thus, in a cline in cognitive function in association with albuminuria retrospective community-based cohort study on geriatric appeared to be mediated by other risk factors such as elevated patients, increased albuminuria and low eGFR have been sug- SBP, older age, oxidative stress, obesity and increased arterial gested as risk factors for dementia [27]. However, the large- stiffness. Later studies by Freedman et al. demonstrated that in scale population Helseundersøkelsen i Nord-Trøndelag study African-Americans, type 2 DM, mildly elevated UACR and did not reveal a significant association between isolated low slightly reduced eGFR were associated with poorer mental proc- eGFR and dementia [28]. Moreover, the Rotterdam study [10] essing speed and working memory [18]. These results identified and the AGES–Reykjavik study [12] have documented, respec- a subgroup of African-Americans with type 2 DM at higher risk tively, that low eGFR is independently associated with lower ce- for developing reduced cognitive function, and suggested possi- rebral blood flow, and that a faster eGFR decline (>3 mL/min/ ble treatment pathways for reducing the burden of cognitive 1.73 m2/year) is associated with increased risk for developing impairment-related disability. In patients with early diabetes manifestations of cerebral small vessel disease. from the Glycaemia Reduction Approaches in Diabetes study These controversial results could be partially explained by (n ¼ 4998), participants with albuminuria or eGFR <60 mL/ the different methods used for GFR evaluation. Of note, the min/1.73 m2 had significantly lower test scores for information widely accepted eGFR equations are based on serum creatinine processing speed and perception, executive function and ability level that can be affected by non-renal factors, including de- to categorize information, and for verbal learning and memory creased muscle mass in elderly patients. To overcome this limi- compared with participants without renal disease. These find- tation, the ARIC study estimated GFR by three methods and ings remained statistically significant after adjustment for hy- found that only low eGFR calculated by equations based on cys- pertension, dyslipidaemia and waist circumference [19]. tatin C and b2-microglobulin was associated with higher de- The association of microalbuminuria and cognitive function mentia incidence, but not low eGFR based on serum creatinine has also been investigated in patients with human immunodefi- [13]. This study also demonstrated the cumulative hazard in ciency virus (HIV). Patients with HIV without severe DM and/ participants who had both increased UACR (>30 mg/g) and or hypertension, hepatitis C virus infection, past or ongoing low cystatin C-based eGFR (<60 mL/min/1.73 m2), suggesting neurological diseases (notably acquired immunodeficiency syn- that both of these CKD markers are independent factors for de- drome defining neurological events) and/or alcohol or illicit mentia development [13]. The higher serum levels of cystatin C drug addiction were selected for the study. After adjustment itself (corresponding to lower eGFR) were related to cognitive for factors associated with HIV-associated neurocognitive impairment measured by the Mini-Mental State Examination disorders and/or microalbuminuria (i.e. age, educational level, in another study conducted in Japan [29]. Together, these hypertension and CD4þ T-cell nadir), patients with previous results suggest that apart from decreased eGFR, other factors re- microalbuminuria had a worse cognitive performance for the lated to higher cystatin C levels such as diabetes, higher levels of Albuminuria and cognitive impairment 3 FIGURE 1: Hippocampal structural and functional changes in animal models of kidney disease. GD, gyrus dentatus. C-reactive protein (CRP) and white blood cell count [30] could impairment [35]. Studies in vivo performed using 3T-MRI play a role in development of MCI or dementia that may further scans showed that patients with CKD had smaller cerebral GM complicate the evaluation of its relationship to albuminuria. and hippocampal volume accompanied by decreased cortical thickness [36]. Also, disturbed calcium metabolism in CKD is PATHOPHYSIOLOGY OF COGNITIVE associated with numerous neuropathological findings, includ- IMPAIRMENT AND DEMENTIA IN ing arteriosclerosis, microaneurysms and microvascular calci- ALBUMINURIC PATIENTS nosis, and the hippocampus is not spared from these pathological changes. Brain autopsy from subjects with CKD The multiple mechanisms explaining MCI and dementia in kid- has demonstrated microvascular calcinosis in the CA4 hippo- ney dysfunction include vascular lesion and impaired cerebral blood flow autoregulation, neuroinflammation, effect of urae- campal region [37]. These neuroanatomical changes correlated mic neurotoxins and kidney neurotrophins, and have been de- with poorer cognitive performance. scribed in detail elsewhere [31, 32]. Below we highlight the less Furthermore, in an animal model of CKD, a reduction in studied pathways that link albuminuria and cognitive impair- synaptic proteins in the hippocampus was demonstrated at a ment. Albuminuria and an eGFR decrease could contribute to a molecular level. In unilateral ureteric obstruction (UUO) mice, reduction of hippocampal volume with concomitant a model of CKD, synapsin-1, synaptophysin and synaptotag- microvascular damage, resulting in significant hippocampal an- min, together with glutamate NMDAR2B and AMPA recep- atomical and functional decline (Figure 1). The hippocampus is tors, were all reduced compared with controls [38]. Even part of the limbic system of the brain and, among other though the effect of albumin on neurocognitive parameters de- physiological roles, is involved in the processes of formation, cay cannot be directly linked to CKD in this particular model, consolidation and memory retrieval [33]. The hippocampus is the study clearly demonstrates not only behavioural cognitive composed of several subregions including ‘cornu ammonis’ decline, but also reduced functional markers of excitatory hip- parts 1–4 (CA1–CA4), the ‘dentate gyrus’ and the ‘subiculum’. pocampal synapses [38], which should be investigated further CA regions contain three neuronal layers with pyramidal excit- in albuminuria models. Also, histological examination in UUO atory cells and are connected by several neural circuits with mice showed hyperphosphorylation of tau protein in the other parts of the hippocampus. The dentate gyrus is consid- hippocampus. ered to be one of only two regions in the brain capable of adult Several lines of evidence show that functional performance neurogenesis and is thought to be involved in the maintenance in memory tests in animal models of CKD is associated with of cognitive function, in particular spatial and non-spatial hippocampal decay and atrophy. Compared with the sham-op- memory. However, different factors could be affecting it and a erated group, in a mouse with CKD induced by UUO, weak deficient rate of adult neurogenesis could potentially contribute performance was demonstrated in several behavioural learning to many neurological and psychiatric conditions. and memory tests: novel object recognition test, Y-maze test Brain atrophy has been associated with physiological aging; and puzzle box test [38]. Spatial learning deficits were also dem- however, in patients with CKD, a higher prevalence of brain at- onstrated in the five-sixths nephrectomy (5/6Nx) CKD mouse rophy has been found, even at relatively young patients with model that resulted in increased escape latency during acquisi- mean age 60 6 12 years [34]. In CKD patients, decline in GM tion trials in the Moris water maze task and correlated with volume seems to be more rapid and followed by cognitive increased neuro-inflammatory markers in hippocampal tissue 4 B. Bikbov et al. [39]. Unilateral nephrectomy (UniNx) and two-thirds electro- Various mediators have been suggested to cause endothelial coagulation of the other renal cortex of C57BL/6 mice was dysfunction. Particularly, kidney dysfunction induces nitric ox- associated with lower performance in the radial arm water ide deficiency due to disturbances in L-arginine metabolism, maze test, and the UniNx mice made significantly more errors eventually affecting the maintenance of the microcirculation compared with sham-operated controls [40]. Cognitive impair- and BBB [49]. A key mechanism that may link albuminuria and ment was accompanied by increased numbers of pyknotic BBB damage is a loss of the glycocalyx, a polysaccharide layer neuronal cells in the hippocampus of the CKD mice. that lines the luminal endothelial surface and that acts as a Neuroanatomical and functional changes in the hippocam- barrier [50]. Degradation of the glycocalyx in response to endo- pus of CKD patients and in animal models of CKD could be thelial activation, as may occur in kidney disease, can lead to al- associated with reduced hippocampal neurogenesis. In patients buminuria and increased microvascular permeability in organs with MCI, a lower number of neuroblast cells was found in the other than the kidney, including the brain [50]. The cross-talk dentate gyrus of the hippocampus, while a higher expression between kidney and brain may also involve the renin–angiotensin level of these cells correlated with better cognitive scores [41]. system [51], and the evidence from in vivo and clinical studies Several factors could contribute to this, including chronic showing that the treatment with angiotensin-converting en- oxidative stress and increased glucocorticoid levels that reduce zyme inhibitors and AT1 receptor blockers, beside exerting differentiation and proliferation of hippocampal neuronal stem renoprotection, also has beneficial actions in neurodegenerative cells, probably as a result of accumulation of mitochondrial disorders [52]. oxidative stress [42, 43]. Accumulation of a critical marker of oxidative stress, 8-hydroxy-2’-deoxyguanosine, in hippocampal CONTROVERSIES IN THE RELATIONSHIP neuronal cells was found in an animal model of CKD [40]. BETWEEN ALBUMINURIA AND MCI AND Endoplasmic reticulum (ER) stress is also thought to contribute DEMENTIA significantly to neuronal dysfunction and its role in the Several controversies exist in the relationships between in- hippocampal dysfunction seen in CKD has been examined. The creased albuminuria and cognitive impairment, leaving the expression level of glucose-regulated protein 78, a typical ER questions about its causal role. First, these two conditions share stress marker, showed a pronounced increase in the hippocam- some important risk factors. Compared with the general popu- pus. Furthermore, 4-hydroxy-2-nonenal-protein adducts, a lation [53] or even other CKD patients with normal urinalysis marker of oxidative stress, was also increased in the hippocam- [6, 54], patients with albuminuria are generally older and have pus 8 weeks after 5/6Nx [44]. more comorbidities, including higher prevalence of diabetes In UUO mice, increased levels of the inflammatory markers and cardiovascular disease, higher smoking rate and higher CRP and tumour necrosis factor-a (TNF-a) in serum were BP—each of these can affect brain function over time. In fact, detected, accompanied by elevated levels of the Nrf2 transcrip- the Cardiovascular Health Cognition Study demonstrated the tion factor and 8-hydroxyguanosine in the hippocampus [38]. role of such confounders in patients who had doubling of Oxidant/antioxidant imbalance and up-regulation of TNF-a albuminuria over time: after adjustment for cardiovascular and interleukin-1b (IL-1b) gene expression in hippocampal tis- disease and demographic factors the relative risk of dementia sue were also detected in 5/6Nx mice. These changes were ac- development was substantially attenuated, and the risk of mild companied by increased proteinuria and a reduction in cognitive decline becomes non-significant [6]. Diabetes alone creatinine clearance [39]. Also, microglial activation should be increases the odds of cognitive decline by 1.2- to 1.7-fold, considered as a source of neurotoxicity and release of pro- depending on the examination tool used [55, 56]. Even young inflammatory factors that could contribute to cognitive impair- patients with type 1 diabetes, who had good glycaemic control ment. Exposure of primary cultured microglia to serum albu- and few comorbidities, over 18 years of follow-up demonstrated min resulted in release of TNF-a, transforming growth factor- a decline in psychomotor and motor speed (but not in memory b1 and higher inducible nitric oxide synthase expression [45]. or intelligence tests). In this cohort several major predictors of Finally, blood–brain barrier (BBB) breakdown is an early cognitive dysfunction have been revealed, including a rise in se- event in the aging human brain that begins in the hippocampus rum creatinine or the need for dialysis, but the role of albumin- and may contribute to cognitive impairment [46]. The BBB uria has not been studied [57]. breakdown in the hippocampus and its CA1 and dentate gyrus Second, albuminuria may be the result of systemic endothe- subdivisions worsened with MCI, and correlated with injury to lial dysfunction that also plays an independent role in MCI and BBB-associated pericytes seen in a mouse model of CKD [47]. dementia development [58, 59]. Notably, both the kidney and Furthermore, it is known that small vessels in the kidney and brain have low vascular resistance systems and can maintain brain are exposed to high blood flow volumes during the car- stable continuous high-volume perfusion that is resistant to diac cycle [48]. Therefore, it has been hypothesized that kidney fluctuations in systemic BP, although this feature makes both disease (as reflected in increased albuminuria) and cerebral organs sensitive to disturbances in endothelial function and small vessel disease (cognitive impairment) are both signs of autoregulation, and stiffness of central arteries [48]. The design systemic small vessel disease affecting different organs with ana- of studies performed so far is hampered by the inability to eval- tomical and haemodynamic similarities. Moreover, endothelial uate endothelial dysfunction and its role on MCI or dementia, dysfunction, regardless of the cause, leads to leakage of proteins since most studies analyse ‘CKD in general’ without any into the interstitial space in both kidney and brain tissues [49]. fine-grain distinction by the primary cause of CKD or types of Albuminuria and cognitive impairment 5 macro- and microvascular abnormalities that may be present. Table 1. Recommendations for further clinical studies on relationship The data on cognitive decline in different diseases that affect between albuminuria and MCI or dementia kidney structure are lacking, and only analyses with a mixture 1. Collect data about comorbidities and risk factors (DM, hypertension, of primary (glomerular diseases) and secondary (diabetes, hy- smoking, etc.) that could lead to development of MCI or dementia. pertensive nephropathy, etc.) kidney aetiologies are currently 2. Account for the primary kidney disease that has led to albuminuria available. The dilemma of whether kidney dysfunction in development. 3. Account for markers of systemic inflammation (CRP) at baseline and primary nephropathies leads to systemic endothelial dysfunc- during follow-up. tion that subsequently increases the risk of MCI and dementia, 4. Evaluate the effect of change in albuminuria, eGFR, blood pressure, or whether the primary systemic endothelial dysfunction per se glucose level, body mass index on MCI or dementia during follow-up. is due to diseases affecting multiple organs and leads to the le- 5. Evaluate in CKD patients the effect of non-pharmacological interven- sion in both kidney and brain, remains unresolved. Moreover, tions (additional physical activity, cognitive training, etc.) that could lead to prevention of MCI and dementia. there are only a few, and not always unidirectional [6], pub- 6. Apply in the same study several tests/questionnaires that evaluate lished data on whether an increase or decrease of albuminuria different cognitive domains and include tests that allow to cross-validate over time has any impact on progression of MCI and dementia. impairment in a single cognitive domain. Third, incident cognitive dysfunction can be limited by 7. Use imaging techniques to identify instrumental signs of brain dysfunc- tion in CKD patients. intensive BP control as demonstrated in the systolic blood pres- 8. Estimate indicators of endothelial autoregulation disturbances sure intervention trial memory and cognition in decreased hy- (measuring flow-mediated dilatation), stiffness of central arteries pertension (SPRINT MIND) study [60] in which the (measuring pulse wave velocity) and retinal vessels analysis to evaluate intensively treated group (SBP <120 mmHg) had a substan- the role of vascular system in development of MCI or dementia in CKD tially lower hazard ratio (HR) at 0.81 [95% confidence interval patients. 9. Evaluate joint effect of albuminuria and eGFR on MCI or dementia in (CI) 0.69–0.95] for development of MCI compared with the prospective studies. Use equations for calculation of eGFR based on standard treatment group (SBP <140 mmHg). However, this both serum creatinine and cystatin C. effect should be studied further in relation to overt kidney dis- 10. In case of dementia as outcome, report the exact nosological form ease, because in subgroup analysis the patients with CKD had a (Alzheimer’s disease, vascular dementia, Lewy body dementia and HR of 1.00 (95% CI 0.77–1.31) for this endpoint (even if no dis- frontotemporal dementia) and provide study findings for each of them. tinction between low eGFR and albuminuria in patients has been carried out), suggesting that the onset of cognitive impair- ment can be reduced by intensive BP control only in patients with several tests in the same patients that allow to study the without CKD. The relationship between BP and albuminuria is role of albuminuria and other factors in the complex landscape complex, and a secondary analysis of the SPRINT trial [54] has of MCI and dementia domains. All these conundrums will need shown that in the intensively treated group the association of al- to be addressed in future studies (Table 1). buminuria and stroke was not significant [1.25 (95% CI 0.69– 2.28)], while in the standard treatment group this association CONCLUSIONS was present [3.44 (95% CI 2.11–5.61)]. The effect of risk factors We have summarized evidence that delineates some of the pos- correction that may improve cognitive status in the general sible pathophysiological mechanisms and clinical significance population [61, 62]—namely, additional physical activity, cog- of albuminuria for MCI and dementia. Despite the availability nitive training, a Mediterranean diet, obesity correction, reduc- of strong evidence for an association between albuminuria and tion of social isolation and smoking cessation—remain MCI or dementia, several important knowledge gaps exist, unknown in CKD patients, and the benefits of their correction leaving unresolved the major questions about a causal relation- have never been studied considering the relationship between ship and the effectiveness of interventions targeting albumin- albuminuria and MCI or dementia. uria per se to prevent cognitive decline. Our recommendations Finally, MCI is a rather broad term, covering different cogni- for future research aim to help in planning clinical trials and tive domains [31], including memory, reaction time, attention, to solve this complex conundrum, with the ultimate goal to executive function, concentration, visuospatial performance improve the outcomes in patients with kidney damage. and others. Dementia is also non-heterogeneous condition that has distinct nosologic forms, including Alzheimer’s disease, vas- ACKNOWLEDGEMENTS cular dementia, Lewy body dementia and frontotemporal de- This publication is based upon work from the Cognitive mentia. The widely used Montreal Cognitive Assessment Decline in Nephro-Neurology: European Cooperative Target (MoCA) covers different domains of cognitive abilities, but it (CONNECT) Action CA19127, supported by European may have different results for some domains compared with Cooperation in Science and Technology (COST), www.cost. other tests. For example, only 7% of patients had abnormal trail eu. The extended information about the action is available at making test (TMT), which examines executive function (visual www.connectcost.eu. attention and task switching), while 44% had abnormal MoCA, and proteinuria was substantially higher in those with abnormal TMT (median protein-to-creatinine ratio 150 versus 43 g/mol, FUNDING respectively) [63]. Only some of the studies discussed here have This article is published as part of a supplement financially applied a comprehensive evaluation of all cognitive domains supported by the COST Action CA19127-Cognitive 6 B. Bikbov et al. Decline in Nephro-Neurology: European Cooperative Target disease, 1990–2017: a systematic analysis for the Global Burden of Disease (CONNECT). Study 2017. Lancet 2020; 395: 709–733 4. Vos T, Lim SS, Abbafati C et al. Global burden of 369 diseases and injuries in 204 countries and territories, 1990–2019: a systematic analysis for the CONFLICT OF INTEREST STATEMENT Global Burden of Disease Study 2019. 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