L

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ACKNOWLEDGMENTS I would like to thank my supervisor Monica Bivol, for her expertise and assistance during this project. I am truly grateful for her patient guidance and the fruitful discussions we’ve had. I would also like to thank all the patients that agreed to participate and contribute to the results of this study. I also extend my sincere thanks the medical staff from the Dialysis Department at Akershus University Hospital, for giving me the opportunity to work with this project and for greeting me with warmth and understanding during the time I spent in the Department. And last, but not at least, I would like to thank to my parents for their loving support while I complete my education as a medical doctor.

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ABSTRACT Background 10% of the worldwide population is affected by chronic kidney disease (CKD). There is increasing evidence in the last decade that CKD patients have a high risk of cognitive impairment (CI). Purpose The present study investigates cognitive performance in relation to the transplantation status of patients with end-stage CKD undergoing hemodialysis (HD). Method 46 patients undergoing chronic HD were randomly chosen and divided in 2 groups: transplantable (n=23) and not transplantable (n=23). The patients were evaluated using the Montreal Cognitive Assessment Scale, the Zung self Rating Assessment Scale, and the Edmonton Symptom Assessment Scale. Results 70% of transplantable patients had reduced cognitive performance (mild and severe) and 30% had severe CI, versus 90% of not transplantable patients with CI and 26% with severe CI. The clinical status self-reported was very poor in both groups, but worse in the transplanted group. No difference in metabolic complication or non-specific inflammation was found Conclusion Cognitive impairment largely affects the population with terminal kidney failure undergoing hemodialysis independent of kidney transplantation status. A routine screening of cognitive function should be done in these patients, preferably before starting renal replacement therapy. Benefits and risks of dialysis should be assessed carefully.

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ABBREVIATIONS ACR Albumin Creatinine Ratio Alb. Albumine CI Cognitive Impairment 95% CI 95% Confidence Interval CKD Chronic Kidney Disease CRP C Reactive Protein ESAS Edmonton Symptom Assessment Scale ESRD End Stage Renal Disease GFR Glomerular Filtration Rate MMSE Mini Mental Status Exam MoCa Montreal Cognitive Assessment Scale n Number of Patients OR Odd ratio SD Standard Deviation of the Mean

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TABLE OF CONTENTS ACKNOWLEDGMENTS...............................................................................................................................page1ABSTRACT.......................................................................................................................................................page2 ABBREVIATIONS..........................................................................................................................................page3 INTRODUCTION.............................................................................................................................................page5

I.Backgroundforchoiceofthisproject..............................................................................page5 II.Generalbackground..............................................................................................................page5 III.Chronickidneyfailure(CKD)............................................................................................page5 IV.ClasifficationofkidneyfailurebasertpåGFR........................................................... page6 V.MetaboliccomplicationofCKD..........................................................................................page7 VI.Cognitivefunction..................................................................................................................page7 VII.Evaluationofcognitivefunction....................................................................................page8 VIII.Evaluationofpatientswithchronicillness............................................................. page8 IX.PosibblelinkbetweenCKDandcognitivefunction.................................................page9 X.Workinghypethesisandaimofthestudy.....................................................................page9

METHODS........................................................................................................................................................page10

I.Clinicalstudy...............................................................................................................................page10 II.Literaturereview......................................................................................................................page11

RESULTS...........................................................................................................................................................page12

I.RESULTSOFTHECLINICALSTUDY..................................................................................page12 1.Generaldata..............................................................................................................page12 2.CognitivefunctionassessedbyMoCaassessmentscale........................ page12 3.RiskofdepressionevaluatedbytheZUNGDepressionScale(SDS) page134.ClinicalsymptomsevaluatedbyESAS............................................................page13 5.Laboratoryresults...................................................................................................page15

II.RESULTSOFTHELITERATURERESEARCH................................................................page16 DISCUSSION.....................................................................................................................................................page17CONCLUSIONS...............................................................................................................................................page18REFERENCES..................................................................................................................................................page19 Annex1..............................................................................................................................................................page23 Annex2..............................................................................................................................................................page24 Annex3..............................................................................................................................................................page25

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INTRODUCTION I. BACKGROUND FOR CHOICE OF THIS PROJECT

My first encounter with kidney failure was as a student in the emergency room. My interest for this condition developed when I realized that kidney failure is a worldwide problem that will only get worse as the global population grows older. The reason behind the progression of kidney insufficiency is not clearly understood, though non-infectious related chronic inflammation is one of the main theories. As any other illness, chronic kidney disease can bring along severe complications like cognitive impairment. Each small study could bring the knowledge one step further.

Between September 2014 and September 2015 I participated in the study presented in this report, done on patients with terminal kidney failure undergoing chronic hemodialysis at Akershus University Hospital. This study is a small brick in a big project that aims to reveal the mechanisms behind the initiation and activation of inflammation and its consequences in patients with kidney failure. The background of the project was the observation that patients with chronic kidney disease (CKD) have a higher risk of developing cognitive impairment (CI) and so the main question was how extensive is the CI in this population? Furthermore, could CI be related to the degree of inflammation, clinical state, risk of depression or metabolic complications of CKD? In parallel I also did a literature search on CKD and CI. II. GENERAL BACKGROUND

The prevalence of age-related health problems, like chronic kidney failure (CKD) or cognitive impairment (CI) are becoming an important public health concern as the world population ages (1, 2). Projections by the World Health Organization indicate that by 2050 the number of individuals older then 60 years will be 22% of the world’s population. Over 2 million people with CKD are today receiving renal replacement therapy worldwide, and that number will only grow.

Cognitive dysfunction increases in prevalence with CKD severity, affecting up to 70% of patients. Both CKD and CI are serious conditions that have a tremendously negative impact on quality of life (3). The impact on every day activities is even more pronounced when both conditions affect the same patient.

Therefore we need to learn and understand more about cognitive dysfunction in patients with terminal kidney failure. III. CHRONIC KIDNEY FAILURE

The kidney is a vital organ in the human body. The kidney’s main purpose is to keep the composition of the blood balanced by filtering toxins and water from the bloodstream. The kidney is also the main regulator of blood pressure. Approximately 20% of the circulate volume is filtered in the kidney per minute. Therefore, a decline of kidney

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function has severe hemodynamic and metabolic consequences for the whole body. CKD is a condition that describes gradual loss of renal function due to different

diseases, either localized only in the kidney (like glomerulonephritis), or systemic diseases (like diabetes, lupus, vasculites and so on).

There is no precise method to measure kidney function today, except by directly measure of glomerular filtration rate (GFR) using radioactive agents like Technetium 99 or Cr-EDTA. These are time-consuming and invasive methods. Serum creatinine concentration is generally used as a proxy for kidney function, but is not reliable since creatinine concentration is dependent of muscular mas (4). Serum Cystatin C measurement is also widely used. It is proved to be a more reliable measurement of kidney function in patients that are very young or very old (5). Additional tools like estimated GFR based on either creatinine or Cystatin C are also used on a daily basis worldwide, mainly to classify the degree of CKD. These are mathematical formulas where in addition to creatinine or Cystatin C level, the age, race and weight is also taken into consideration.

A GFR below 60 mL/min/1.72m2 measured at least 90 days apart and not due to a transient condition, satisfies the definition of CKD. Kidney damage, detected either by imaging, persistent proteinuria or by other urine abnormalities that can be traced back to the kidneys, lasting over a period of 90 days also satisfies the definition of CKD. IV. CLASSIFICATION OF KIDNEY FAILURE BASED ON GFR

According to the Kidney Disease Outcomes Quality InitiativeTM (6), CKD is divided into five stages based on the estimated GFR value as shown in the table 1. Stage 3 CKD is divided further into 2 sub-stages A and B, to underline the increased cardiovascular risk and risk of CKD progression at lower eGFR values. Patients with stage 3A CKD are considered to be at low risk for progression to kidney failure, while patients in stage 3B and 4 are considered to be at high risk for progression to kidney failure.

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V. CKD METABOLIC COMPLICATIONS

As mentioned already, there is no treatment available today that can stop the progression of CKD. But a close watch of the metabolic complications, as well as treatment of the main disease, can prolong the development of end stage of kidney failure. The main metabolic complications due to failure of kidney function are normocytic anemia, hyperkalemia, hyperphosphatemia, hyperuremia, but also renal bone disease. Correction of these complications gives better life quality in the last stages of kidney failure.

It is generally accepted today that inflammation is activated in CKD (7), but the mechanisms behind this activation remain unclear. Chronic inflammation, not related to infections, is also considered a complication of terminal kidney failure, and it is measured by non-specific markers of inflammation as CRP and albumin. VI. COGNITIVE FUNCTION

Cognitive function describes the acquisition of knowledge and understanding through thought, experience and senses. It encompasses processes such as attention, memory, evaluation, reasoning, problem solving and language.

Cognitive impairment (CI) is a term that describes any barrier to the cognition process (8). The term is reserved for irreversible changes in mental abilities, either congenital or caused by environmental factors such as structural injury, neurological disorders or mental illness. People with CI may have difficulty with remembering, learning new things, concentrating, or making decisions that affect their everyday life. In mild CI there are minor changes that allow the patient to function satisfactory in their daily life, while in severe CI (also called dementia) the patients are unable to function independently.

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There is no one disease or condition that causes CI, nor is it limited to any specific age group – though age is the primary risk factor. Other risk factors include family history, socioeconomic status, depression, brain injury, exposure to pesticides or toxins, physical inactivity, and chronic conditions such as Parkinson’s disease, heart disease, stroke, and diabetes. One risk factor that has received increasing attention over the past decade is chronic kidney disease. The heavy burden of CI in patients with terminal stage of kidney failure only recently become increasingly recognized (9). There are few studies showing that patients with advanced kidney failure (stage IV, V and VD) have high prevalence of moderate CI despite normal global cognitive function (10). VII. EVALUATION OF COGNITIVE FUNCTION

There are many ways to measure the cognitive status and performance of patients. Some tests, such as the mini mental status exam (MMSE) and the 6-Item screener, assess global cognitive function, whereas other tests assess individual domains (memory, language, visuospatial ability and executive function). In the present study was used a modified MMSE, Montreal Cognitive Assesment Scale (MoCa), validated with higher sensitivity to detect CI (11). This test (shown in annex1) assesses congnitive function from many angles: visuospatial, executive, memory, attention, language, orientation, delayed recall and abstract perspective VIII. EVALUATION OF PATIENT WITH CHRONIC ILLNESS

Chronic kidney failure is a condition that patients who are not eligible for kidney transplantation have to live for the rest of their life. For patients that are transplantable, however, the chronic illness condition is only transient. This difference is believed to have an impact on long-term outcome.

The burden of chronic illness carries with it psychosocial impairment that impact clinical symptoms as well as depression tendency (12). Based on this background, in the present study the patients were also evaluated with 2 other validated questionnaires. The Edmonton Symptom Assement Scale (ESAS, annex 2) was used to gain from the patients perspective (subjective) an overall picture over 10 main symptoms graded from 1 (no symptom) to 10 (severe symptom) that comes along with chronic illness: pain, tiredness, nausea, depression, angst, dizziness, appetite, physical shape, dyspnea, itch. The test also gives the patient the possibility to write in symptoms not on the questionnaires. The Zung Self Rating Depression Scale (SDS, annex 3) was also used in the present study as one the oldest validated tool for objective reveal of risk for depression (13). The test consists of 20 questions graded from minimum 1 point to maximum 4 points, with complex interrogation covering area of physical, physical and emotional aspects of daily life. IX. POSSIBLE LINK BETWEEN CKD AND COGNITIVE FUNCTION

There are studies showing that patients with advanced kidney failure (stage IV, V

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and VD) have high prevalence of moderate CI despite normal global cognitive function (10). It has also been shown that impaired kidney function might be a risk factor for subclinical brain infarcts, and the prevalence of cerebral events is higher in advanced kidney failure (14). Moreover, in patients with CKD there has been proved by imagistic methods that the white brain matter is reduced (15). Although still controversial, white matter damage/reduction is now thought to be due to chronic ischemia or hypoperfusion (16). Both subclinical brain infarcts and white matter damage have been linked to cognitive decline in the general population and high risk of depression (17).

It is also well known the hemodynamic variability and complications during hemodialysis treatment can cause blood pressure to drop rapidly, causing temporary loss of consciousness (18). The risk of blood pressure falls are more frequent and severe in patients with long-term hypertension, diabetes, obesity, dyslipidemia, smokers and chronic inflammation.

Therefore, the damage of cerebral small vessels, and so CI, in patients with kidney failure may be due to systemic disease like diabetes or hypertension, affecting simultaneously both kidney and brain. But slowly progressive cerebral damage might be also due to activation of inflammation during the progression of CKD, hemodynamic variation and acute hemodynamic insufficiency that dialysis patient may experience during the treatment or metabolic complications generated of CKD. Risk of depression and poor clinical shape might also play an important role in development of CI. X. WORKING HYPOTHESIS AND AIM OF THE STUDY

The aim of the literature research was to learn more about the facets of CI as they relate to CKD in terms underlying diseases and comorbid conditions and common risk factors.

It is well known that not all the patients progressing to end stage of kidney failure can be transplanted due to the associated comorbidity that characterizes an aging population. These patients remain dependent on dialysis treatment the rest of their lives.

We hypothesized that cognitive dysfunction could be a feature of aging population that is not eligible for kidney transplantation. We also hypothesized that this group of patients have more clinical symptoms, have higher risk to develop depression and have higher non- specific inflammation.

The results of both literature research and this clinical study would try to answer to the main question if screening for cognitive impairment should be part of the routine investigation in patients with CKD before entering into renal replacement therapy?

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METHODS I. CLINICAL STUDY

The study was performed in accordance with Helsinki Declaration and under the approval of the Norwegian National Research Ethical Committee and Local Research Council. 46 patients with CKD stage VD undergoing hemodialysis at the Akershus University Hospital were randomly included based on written consent in this study. The patients were interviewed using 3 validated scales as following: The Montreal Cognitive Assessment query (MoCa, annex 1) to assess cognitive function, the Zung Self Rating Depression Scale (SDS, annex 3) to evaluate the depressive tendencies, and the Edmonton Symptom Assessment Scale (ESAS, annex 2) to assess the daily symptoms of these patients.

The MoCa query was conducted according to the instructions, with the interviewer scoring the test while it was performed. The scale rates up to 30 points. Normal cognitive function is considered for a score from 26 to 30. Range between 19 to 25 points revealed mild CI, while score below 18 points express severe (CI).

The SDS scale rates up to maximum 80 points and score below 50 is considered normal, while mild depression is considered for score from 50 to 69 and severe depression for a score over 70. We defined as risk to develop depression a total score from 40 to 49.

The ESAS self-evaluates 10 symptoms graded from 1 (no symptom/ best shape) to 10 (severe symptom/ worst shape). Score from 2 to 4 was defined as low, from 5 to 7 was defined as moderate and from 8 to 10 was defined as severe symptom.

The SDS and the ESAS were completed by the patients themselves when possible, with assistance rendered when requested. In those cases, the interviewer conducted the questionnaires orally. The SDS and ESAS forms were scored after the interview. All the questionnaires were done during the dialysis treatment. 2 patients did not answer the SDS scale and 1 patient did not answer ESAS scale due to tiredness.

The patients were further divided into two groups as following: group 1 (N=23) with patients found eligible for a kidney transplant and group 2 (N=23) with patients found not eligible for kidney transplantation.

The following usual laboratory blood samples were also assessed before start of hemodialysis treatment: creatinine (µmol/l), Hb (g/dl), phosphate (mmol/l), potassium (mmol/l), urea (mmol/l) as expression of metabolic complications of kidney failure, and uric acid (µmol/l), CRP (mg/l) and albumin (g/l) as non-specific markers of inflammation. The measurements were done at the hospital laboratory by validated methods.

Data are presented as mean ± SD. Statistical analyse was done using SigmaPlott software. P values ≤0.05 are considered statistically significant. II. LITERATURE REVIEW

A systematic review of studies regarding CKD and cognitive impairment was

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conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (19). The Norwegian Electronic Health Library McMasterPlus pyramid and PubMed database were used to identify relevant literature, studies and information on cognitive impairment and chronic kidney disease. Only relevant studies and reviews were included in this literature review. Search terms used are as following: 1) Cognitive impairment AND CKD; 2) Cognitive impairment AND “chronic kidney disease”; 3) Dementia AND CKD; 4) Dementia AND “chronic kidney disease”

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RESULTS I. RESULTS OF THE CLINICAL STUDY

1. GENERAL DATA Overall mean age was 62,2 ± 16 years (13 female and 33 males). Age distribution

was 52,3 ± 15 years in transplantable (4 female and 19 males) and 72 ± 9 years in non- transplantable group (9 female and 14 males).

2. COGNITIVE FUNCTION assessed by MoCa assessment scale. Overall results (table 2) surprisingly showed that only 19,5% out of a total 46

patients scored in the normal range, while 87,7% of them had mild (56,2%), and respective severe (28,2%) CI.

When patients were divided into 2 groups depending on whether they are found

eligible for kidney transplantation (group1) or not (group 2), the results (fig.1A) show that in group 1 only 30,4 % had normal cognitive function compare to the group 2 where only 8,7% had normal cognitive function, while the rest: 69,6% in group 1 and 91,3% in group 2 had cognitive dysfunction.

When CI was further divided in mild and moderate (fig. 1B), 39,1% (n=9) had mild and 30,4% (n=7) had severe CI in transplantable. In the non-transplantable, the proportion was even worse: 65,2% (n=16) had mild and 26% (n=5) had severe CI. There were more patients with severe CI in the group 1 then in the group 2.

Finally, when looking at the mean ± SE of the scores between the 2 groups, there was no significant difference. In the group 1 with normal cognitive function the score was 28,3± 0,6 versus 28,5±1,5 in the group 2. The patients with mild CI scored 23±0,6 in the group 1 and 22±0,4 in the group 2, while those with severe CI scored 15±1 in group 1 and 15± 0,4 in group 2 (p>0,5).

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3. RISK OF DEPRESSION evaluated by the ZUNG Self Rating Depression Scale (SDS). 2 of a total 46 study patients did not answer to this questionnaire. Overall results showed that none of the patients interviewed had depression, all scored under 50 points. Risk to develop depression was defined as a total score from 40 to 49, and 25% of the patients (n=11) rated in this rage. When divided in groups, 19% (4 of 21 patients) in the group 1 and 26% in the group 2 (6 of 23 patients) rated between 40 and 49.

When look at the self-reported depression symptom from ESAS, overall results showed that 56% of the patients did not feel depressed. When divided in groups, 80% patients from group1, versus 60% in the group 2 did not felt depressed. 4. CLINICAL SYMPTOMS evaluated by Edmonton Symptom Assessment Scale (ESAS). Overall results (table 3) showed again surprisingly findings. The majority of patients were severely affected by the reduced physical shape. Only 6,6% were in normal shape and as much as 46,6% reported severe reduced physical shape. Moreover, lack of appetite (only 26,6 % had normal appetite), fatigue (only 28,6 % did not feel fatigue) and itch (only 40% reported no itch) were symptoms that highly affected these patients. On the other hand, over 50% of the patients had no nausea, angst, dizziness, depression, pain or dyspnea, as showed in table 3.

When divided into group1 (transplantable) and group 2 (not transplantable), the self- assessment of symptoms showed again, unexpected, that the transplantable patiets (table 4) were more affected of reduced appetite, fatigue, pain, dizziness and nausea compare to non- transplantable patients from group 2 (table 5).

In addition, no patient (0%) from group1 reported normal physical shape, compared to 8,7% in group 2. Symptoms like pain and dizziness were reported as severe in group 1, while in group 2 none of the patients reported severe symptoms.

Only 7 patients reported other symptoms, interestingly 1 patient reported reduced

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memory in group1, compare to 4 patients in group 2. Each patient from both groups also reported peripheral edema.

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5.LABORATORY RESULTS Mean ± SE for serum creatinine, Hb, phosphate, potassium, urea as an expression of metabolic complications of kidney failure, and uric acid, CRP and albumin as expression of non-specific inflammation are shown in table 6. There was no difference between the studied groups, but there was a tendency that activation of inflammation was lower in the group 1 (CRP 6,65± 2,1 and albumin 39,2 ± 1, p=0.08 and respective p= 0,06) then in group 2 (CRP 13,39 ± 3, and albumin 36 ± 1,2)

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Table 7 shows the summary of the findings for the all cross-sectional and longitudinal studies relevant for our study

Name of the Study Number of Participants

Cognitive Tests

Results

Jassal et al., 2010: Rancho Bernardo Study

1,345

-MMSE -Trails B -Category Fluency

For men: ACR >30 mg/g associated with greater decline in MMSE and Category Fluency Scores.

Sasaki et al., 2011: Osaki-Tajiri Project

497

Clinical Dementia Rating

CKD associated with incident dementia (OR 5.3, 95%CI 1.7-16.2)

Tamura et al., 2011: REGARDS

19,399

6 Item Screener Doubling ACR increased the risk of cognitive impairment by 7% (OR 1.30, 95%CI 1.02-1.66)

Helmer et al., 2012: The Three City Study

7,839

MMSE No association between eGFR and cognitive impairment.

Szerlip et al., 2015: Health and Aging Brain among Latino Elders study.

437

Neuro-psychological assessment.

For men: Association between eGFR <60 and cognitive impairment (OR 9.6, 95%CI 1.3-74.3)

Kurella et al., 2005: Heart Estrogen/ Progestin Replacement Study

1,015 -Modified MMSE -Trails B -Verbal tests

The risk for cognitive impairment increased between 10-25% for each eGFR decrease of 10 mL/min/1.73 m2

Hailpern et al., 2007: Third National Health and Nutrition Examination Survey

4,849

Computerized Cognitive Tests

Moderate CKD associated with poorer learning/concentration (OR 2.41, 95%CI 1.30-5.63) and with impairment in visual attention (OR 2.74, 95%CI 1.01-7.40)

Tamura et al., 2008: REGARDS

23,405

6 Item Screener CKD associated with an increased prevalence of cognitive impairment (OR 1.23, 95%CI 1.06-1.43)

Elias et al., 2009: Maine-Syracuse Longitudinal Study

923

Neuro-psychological assessment

CKD (eGFR <60) associated with performing in the lowest quartile of the global composite (OR 1.97, 95%CI 1.25-3.10)

Yaffe et al., 2010: Chronic Renal Insufficiency Cohort Study

825

-Modified MMSE -Trails A + B -Category Fluency

Advanced CKD patients more likely to have clinically significant cognitive impairment than mild to moderate group (OR 2.0, 95%CI 1.1-3.9)

Yang et al., 2011 228

Cognitive Abilities Screening Instrument (CASI)

Positive (but weak) correlation between CASI score and eGFR. (R=0.18, P=0.008)

Tamura et al., 2011: Chronic Renal Insufficiency Cohort Study

3,591 Modified MMSE eGFR < 30 associated with cognitive impairment (OR 1.47, 95%CI 1.05-2.05)

Wang et al., 2015: Hypertension and Ageing Project of Chengdu

395

MMSE CKD associated with cognitive impairment (OR 2.76, 95%CI 1.10-7.15)

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II. RESULTS OF THE LITERATURE RESEARCH In table 7 the findings for all cross-sectional and longitudinal studies that aimed to

assess the cognitive function in patients with kidney failure are summarized. The summary lists the first author, year of publication, name of the study, number

of participants, the methods used for evaluation of cognitive function and the main conclusion of the study.

The relevant studies taken into consideration here contain several methodological limitations that could explain the variation of the study outcome. The number of participants in each study varies wildly. Most of the data were gathered from studies and screening projects investigating a wide range of issues, and so the cognitive screening measurements were targeted only to identify cognitive dysfunction and not to grade to mild or severe CI. The most common screening instrument in all the studies was by far the MMSE, which is widely accepted to be an excellent screening for global cognitive function, but it`s sensitivity is limited.

The studied revealed that the incidence of CI is very high in CKD population and the risk is growing with CKD progression. The majority of the studies done on patients with terminal kidney failure reveal an incidence of CI above 50% up to 70% in this population (11). DISCUSSION

It is widely accepted today that patients with chronic illness in general have a higher risk of developing cognitive dysfunction. A number of studies in the last decade have shown that prevalence and risk of developing cognitive impairment (CI) is high in elderly populations, as the literature search revealed (table 7). Cross-sectional studies and a meta-analysis review articles suggested that CKD is an independent risk factor for cognitive decline.

There are a few studies showing that patients with advanced kidney failure (stage IV, V and VD) have high prevalence of moderate CI (10,11). A prevalence of CI above 50% up to 70% has been reported (11), but the link between kidney failure and cognitive impairment is not yet known. Such a high rate of CI in end-stage kidney failure raises the question if that could be due to patients not found eligible for kidney transplantation that presumably are more affected of comorbidity and CI then those transplantable.

There is no previous study in our knowledge that evaluated before the distribution of CI in stage VD kidney failure in relation with kidney transplantation status.

The first novel finding of this study was an extremely high prevalence of 70% cognitive dysfunction, mild and severe all together, in transplantable dialysis patients and 91% in not transplantable ones (table 2, fig. 1A). Extent of cognitive impairment was much higher in not transplanted population (only 9% normal) than previously reported (11). The overall cognitive dysfunction in dialysis population in our study was 80%, at least 10% higher then reported by others. It has been previously shown that impaired kidney function might be a risk for subclinical brain infarcts. The prevalence of cerebral events (14) as well as white brain matter damage (15), are higher in advanced kidney failure. There is not known weather cerebral damage precedes initiation of dialysis treatment or succeed it. Both subclinical brain infarcts and white matter damage have been linked to cognitive decline in the general population (17) and could explain this extremely high incidence of CI in dialysis population independent of transplantation status.

The second novel finding of the present study was high extent of severe cognitive impairment: 30% in transplantable and 26% in not transplantable (table 2, fig.1B). It seems that there is no big difference between transplantable and not transplantable, unexpected and in contrary with the general image that patients found eligible for kidney

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transplantation do not have as much comorbidity as not transplantable patients. Such a high rate of severe reduction of cognitive performance independent of transplantation status that we have seen here could be the consequence of hemodynamic variability and blood pressure drop in hemodialysis treatment, symptomatically or not (18). The risk of blood pressure falls is more often and severe in patients with long-term hypertension and metabolic syndrome (diabetes, obesity, dyslipidemia, smokers), representing 70% of general dialysis population (34). Therefore the damage of cerebral small vessels in patients with kidney failure may be due to those conditions that affect simultaneously both kidney and brain.

Another important finding of this study was very low percentage of patients was in good physical shape when self-evaluated with ESAS scale. Only 6.6% from our studied dialysis population (table 3), and 0% from the transplantable group had good physical performance (table 4). As reported in life-quality studies on chronic illness (2, 33) there are a large number of symptoms that patients have to deal with on daily basis. The “better” clinical shape of not transplantable (table 4 and 5) patients might be due to a total higher rate of cognitive dysfunction.

The burden of chronic illness carries with it psychosocial impairments that influence the clinical symptoms as well as depression tendency (12). Our study revealed contradictory results related to evaluation of depression by SDS test, the oldest validated tool for risk for depression (13). On one hand, there was no difference in the risk of depression in the study groups (SDS). On the other hand, evaluation of self-reported depression by ESAS showed that 81% from transplantable and 61% from not transplantable group had no depression.

Correction of metabolic disequilibrium seen in patients with CKD can improve cognitive performance. Especially correction of renal anemia seems to improve cognitive function (35). In the present study, serum parameters for evaluation of metabolic complication related to CKD were the same independent of transplantation status (table 6). There is also increasing evidence that in patients with end-stage renal failure the non-specific inflammation is highly activated, but the mechanisms behind this activation remain unclear (7). Slowly progressive of cerebral damage might also be due to activation of inflammation during the progression of CKD (36). This study found no difference in inflammation activation independent of transplantation status (table 6). There was observed a tendency of lower CRP and higher Alb serum values in transplantable group (6,65 ±2,1 for CRP and 39,2 ±1 for Alb) compare to non-transplantable patients (13,39 ± 3,2 for CRP and 36 ± 1,2 for Alb, p=0,08 and respective 0.06), but did not reach statistic significance.

Limits of the study: The number of patients included was low and therefore none of the differences observed reached statistic significance. The gender distribution was in male favor. There are a lot of bias factors that were not taken into consideration like previously cerebral events, compliance, blood pressure drops during the dialysis treatment just to name some.

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CONCLUSIONS The main novel finding of the present study was that independent of kidney transplantation status, 2/3 of transplantable patients suffer of cognitive impairment. Larger studies need to be done in order to confirm these results. We recommend that a routinely screening of cognitive function should be done in these patients, preferably before starting renal replacement therapy. Benefits and risks of dialysis should be assessed carefully.

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19

Annex2

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Annex3

21