Home About us Current issue Back issues Submission Instructions Advertise Contact Login   

Search Article 
  
Advanced search 
 
Saudi Journal of Kidney Diseases and Transplantation
Users online: 252 Home Bookmark this page Print this page Email this page Small font sizeDefault font size Increase font size 
 


 
Table of Contents   
ORIGINAL ARTICLE  
Year : 2018  |  Volume : 29  |  Issue : 6  |  Page : 1333-1341
Impact of correction of anemia in end-stage renal disease patients on cerebral circulation and cognitive functions


Department of Internal Medicine, Division of Nephrology, Kasr El Aini Hospital, Cairo University, Cairo, Egypt

Click here for correspondence address and email

Date of Submission11-Nov-2017
Date of Decision08-Jan-2018
Date of Acceptance14-Jan-2018
Date of Web Publication27-Dec-2018
 

   Abstract 

End-stage renal disease (ESRD) patients have been associated with accelerated vascular disease of the cerebral circulation due to uremic toxins. Furthermore, anemia increases cerebral oxygen extraction fraction which impairs the cerebral vasodilatory capacity. We evaluated the effect of correction of anemia on cerebral blood flow by measuring the mean blood flow velocity, resistance index (RI), and pulsatility index (PI) in the middle cerebral artery (MCA) in relation to cognitive functions. We measured the mean blood flow velocity, RI, and PI in MCA of 120 ESRD patients when the hemoglobin (Hb) ranges between 8 and 10 g/dL and after correction of anemia to two Hb ranges between 10–11.5 g/dL and 11.5–12.5 g/dL in the same patients using transcranial Doppler (TCD) ultrasound in relation to cognitive functions assessment by Mini–Mental State Examination. We observed that there is a mild-to-moderate cognitive impairment in hemodialysis (HD) patients associated with anemia. With the improvement of anemia, the cognitive functions improved. There was an improvement of blood flow of MCA with improvement of Hb. The improvement was obvious at Stage 3 (Hb 11.5–≤12.5 g/dL) in comparison to Stage 2 (Hb 10–<11.5 g/dL) with P <0.001 at all. The optimal Hb for HD patients ranges from 11.5 to ≤12.5 g/dL which associated with better improvement of cognitive function and cerebral circulation investigated by TCD ultrasound for MCA.

How to cite this article:
Shaker AM, Mohamed OM, Mohamed MF, El-Khashaba SO. Impact of correction of anemia in end-stage renal disease patients on cerebral circulation and cognitive functions. Saudi J Kidney Dis Transpl 2018;29:1333-41

How to cite this URL:
Shaker AM, Mohamed OM, Mohamed MF, El-Khashaba SO. Impact of correction of anemia in end-stage renal disease patients on cerebral circulation and cognitive functions. Saudi J Kidney Dis Transpl [serial online] 2018 [cited 2019 Jan 18];29:1333-41. Available from: http://www.sjkdt.org/text.asp?2018/29/6/1333/248306

   Introduction Top


End-stage renal disease (ESRD) patients undergoing hemodialysis (HD) are known to have associated accelerated vascular disease and premature atherosclerosis of the cerebral circulation due to uremic toxins and traditional risk factors of atherosclerosis.[1] Anemia increases cerebral oxygen extraction fraction in HD patients that might impair the cerebral vasodilator capacity.[2] Cognitive impairment is common in ESRD and is associated with poor outcomes, and anemia may lead to cerebral ischemia and cognitive impairment and dementia in these patients.[3] Cognitive impairment that is caused by or associated with different neurologic or systemic illnesses may be characterized by impairments in specific cognitive domains.


   Patients and Methods Top


Study population and data collection were recruited from the Dialysis Unit in Kasr El Aini Hospital. This prospective case-control study was performed in a cohort of 120 clinically stable maintenance HD patients ([60 males, 60 females; mean ± standard deviation (SD) age: 39.8 ± 10.7 years] as well as 60 age-matched healthy controls (30 males, 30 females; mean ± SD age: 41.2 ± 11.4 years). Controls were age and sex matched and had no abnormal clinical or laboratory findings. The study included patients >18 years and <60 years. All the patients had regular HD for 4 h a day three times a week for >6 months and <24 months’ duration. All patients had a native arteriovenous fistula. Blood flow rate was 250–400 mL/min and the bicarbonate dialysis fluid flow rate was 500–800 mL/min. Dialysis efficiency [single pool Kt/V (sp Kt/V)] and ultrafiltration volume (mean of the last 3 recorded values) were retrieved from patients’ files. Epoetin alpha and iron saccharate (Ferosac®) were prescribed according to the National Kidney Foundation/Kidney Disease Outcomes Quality Initiative guidelines for anemia therapy. Antihypertensive medications were not changed in any hypertensive cases during the study period.

Our study excluded patients with recent cere-brovascular accident (hemorrhagic and non-hemorrhagic) within six months, history of gastrointestinal blood loss, those who received blood transfusions, cases with atrial fibrillation, cases with tertiary hyperparathyroidism, chronic liver disease patients, and diabetes.

The study protocol was approved by the Institutional Review Board of Cairo University. Written informed consent was obtained from each participant before enrollment.

Hemoglobin (Hb) was measured monthly. The study was divided into three stages: Stage 1 when Hb level was from 8 to <10 g/dL, Stage 2 when HB level was from 10 to <11.5 g/dL, and Stage 3 when Hb level was from 11.5 g/dL to 12.5 g/dL for the same patient.

Transcranial Doppler (TCD) ultrasonography was done for the same patient three times during the study. The mean blood flow velocity, resistance index (RI), and pulsatility index (PI) in the middle cerebral artery (MCA) of the patients were measured.

Assessment of cognitive function was done three times during the study before and after correction of anemia using the Mini-Mental State Examination (MMSE) which is the most widely used cognitive test. All patients were followed up by serum blood urea nitrogen, creatinine, sodium, potassium, calcium, phosphorus, parathyroid hormone, aspartate amino-transferase, alanine aminotransferase, albumin, bilirubin total and direct, prothrombin concentration, international normalized ratio, and lipid profile (cholesterol, triglycerides, low-density lipoprotein, and high-density lipoprotein). Iron indices including serum iron, total iron-binding capacity (TIBC), and ferritin were measured. Transferrin saturation (TSAT) was calculated by dividing the serum iron concentration over the TIBC multiplied by 100. The quality of dialysis was assessed during the study period by calculating Kt/V for all the patients.

Blood sampling was taken just before HD. Fasting blood samples (12 h) were obtained from controls in the morning and from HD patients before the first dialysis session of the midweek (mean Kt/V, a marker of dialysis adequacy, was 1.27 ± 0.02).

TCD ultrasound was done 48 h following HD sessions, with same operator, same machine, and same pulse repetition frequency (PRF) for the same patient three times during the study in association with MMSE for assessment of cognitive functions.


   Statistical Analysis Top


Precoded data were entered on the computer using Microsoft Office Excel Software program (2010) for windows. Data were then transferred to the Statistical Package for the Social Sciences Software (SPSS) program version 21.0 (SPSS Inc., Chicago, IL, USA) to be statistically analyzed. Data were summarized using range, mean, and SD for quantitative variables and frequency and percentage for qualitative ones. Comparison between groups was performed using independent sample t-test for quantitative variables and Chi-square test or Fisher’s exact test for qualitative ones. Repeated measures analysis of variance test was performed for paired quantitative variables with post hoc Bonferroni test. Pearson correlation coefficients were calculated to signify the association between different quantitative variables. P <0.05 was considered statistically significant, and <0.01 was considered highly significant. Graphs were used to illustrate some information.


   Results Top


The study was conducted in 120 maintenance HD patients (60 males, 60 females; mean ± SD age: 39.8 ± 10.7 years) and 60 age-matched healthy controls (30 males, 30 females; mean ± SD age: 41.2 ± 11.4 years). There was no significant difference in age between the maintenance HD patients and healthy controls. The duration of dialysis range was from nine to 21 months, with a mean 13.4 ± 3.1 months. Hypertension was the cause of renal failure in 35% of causes, chronic obstructive uropathy 15%, and unknown cause 25%. Other causes included systemic lupus erythematosus, non-steroidal anti-inflammatory drug abuse, chronic pyelonephritis, preeclampsia, and focal segmental glomerulosclerosis [Figure 1].
Figure 1: Cause of renal failure of the cases.
FSGS: Focal segmental glomerulosclerosis, SLE: Systemic lupus erythematosus, NSAID: Nonsteroidal anti-inflammatory drugs.


Click here to view


The time needed to reach Stage 2 during the study ranges from two months to four months, with mean 2.7 ± 0.7 months, and Stage 3 ranges from three months to six months, with mean 5 ± 0.8 months.

The percentage of cases who received iron loading dose was 40%, and iron maintenance doses were 60% at Stage 1, 80% of cases received iron maintenance dose at Stage 2, and 65% of cases received iron maintenance dose at Stage 3. All cases whose TSAT was <30%, received iron loading dose.

The doses of erythropoietin given per week during three stages of the study and the percentage of these cases are given in [Table 1].
Table 1: The percentage of cases who were received erythropoietin dose per week during three stages of the study.

Click here to view


The range and mean of resistivity index (RI), PI, and mean blood flow velocity of TCD of MCA was improved with improvement of Hb during three stages of the study [Table 2].
Table 2: The range of resistivity index, pulsatility index, and mean blood flow velocity of transcranial Doppler of middle cerebral artery improved.

Click here to view


There were no relevant changes of range, mean, and SD of peak systolic velocity and end-diastolic velocity of TCD of MCA of the cases during the three stages of the study [Figure 2] and [Figure 3].
Figure 2: Changes of mean of peak systolic velocity of transcranial Doppler of MCA of the cases during the three stages of the study with improvement of Hb.
MCA: Middle cerebral artery, Hb: Hemoglobin.


Click here to view
Figure 3: Changes of mean of end-diastolic velocity of transcranial Doppler of MCA of the cases during the three stages of the study with improvement of Hb.
MCA: Middle cerebral artery, Hb: Hemoglobin.


Click here to view


The range, mean, and SD of cognitive function scoring of MMSE of the cases during three stages of the study were calculated, and it showed improvement of mean of cognitive function of cases with improvement of Hb during three stages of the study [Figure 4].
Figure 4: Changes of mean of cognitive function scoring of MMSE of the cases during the three stages of the study with improvement of Hb.
MMSE: Mini–Mental State Examination, Hb: Hemoglobin.


Click here to view


The comparison between mean and standard deviation of cases and controls regarding RI, PI, mean blood flow velocity, regarding peak systolic velocity and end-diastolic velocity of TCD of MCA showed statistically significant difference with normal readings in control group (P <0.001) during three stages in the study [Table 3].
Table 3: The comparison between mean and standard deviation of cases and controls regarding resistance index, pulsatility index, mean blood flow velocity, peak systolic velocity, and end-diastolic velocity of transcranial Doppler of middle cerebral artery shows statistically significant difference with good readings in control group (P <0.001) during three stages in the study.

Click here to view


The comparison between mean and SD of cases and controls regarding cognitive funtion scoring of MMSE during the study showing statistically significant difference (P <0.001) with normal score in control group [Table 3].

The comparison between changes in RI, PI, and mean blood flow velocity of TCD of MCA by time for cases during three stages of the study showed that there was no statistically significant difference between Stage 1 and Stage 2. There was a statistically significant difference between Stage 1 and Stage 3. There was a statistically significant difference between Stage 2 and Stage 3 [Table 4].
Table 4: The comparison between changes in resistivity index, pulsatility index, and mean blood flow velocity of transcranial Doppler of middle cerebral artery by time for cases during three stages of the study

Click here to view


The comparison between changes in peak systolic velocity and end-diastolic velocity of TCD of MCA during three stages of the study showed no statistically significant difference between three stages.

The comparison between changes of cognitive function scoring of MMSE by time for cases during three stages of the study showed that there was no statistically significant difference between Stage 1 and Stage 2, but there was statistically significant difference between Stage 1 and Stage 3 and between Stage 2 and Stage 3 [Table 5].
Table 5: The comparison between changes of cognitive function scoring of Mini-Mental State Examination by time for cases during three stages of the study.

Click here to view


The study showed statistically significant strong inverse correlation between age of the cases and mean blood flow velocity at three stages of the study. There was no statistically significant correlation between dialysis duration and mean blood flow velocity at three stages of the study.

Furthermore, the study showed no statistically significant correlation between age and dialysis duration of cases in relation to RI and PI of TCD of MCA and cognitive function scoring of MMSE during three stages.


   Discussion Top


In this study, we aimed to evaluate the effect of the changes of degree of anemia on cerebral blood flow among HD patients. We have noticed that there is a high frequency of mild-to-moderate cognitive impairment in HD patients, especially if associated with anemia. Our findings were in agreement with Sarnak et al in their cross-sectional cohort study of 314 HD patients who underwent detailed cognitive assessment. There was a high frequency of impaired cognitive performance in HD patients.[4] Furthermore, Odagiri et al in their cross-sectional study, 154 HD outpatients and 852 participants were assessed their cognitive function using MMSE. The HD patients showed a higher prevalence of cognitive impairment in older groups (50 years and older). In conclusion, an older adult with CKD, lower level of kidney function was associated with lower cognitive function on most domains.

In our study, chronic anemia was associated with impaired cognitive function, and during gradual improvement of anemia, there was an improvement of cognitive function. Wood et al in their cross-sectional design investigated the association between Hb and cognitive dysfunction in adult patients. This study investigated the level at which Hb must decline to contribute to cognitive dysfunction using cut off values of 12, 10, or 8 g/dL. There was a significant difference between Hb groups and their performance on the collective cognitive measures (P = 0.026).[6] Our findings also were in agreement with Petranović et al, in their study examining the relationship between anemia levels and cognitive function. The results showed that anemia significantly undermines cognitive functions in adult patients (P <0.01).[7]

There was an improvement of blood flow of MCAs with improvement of Hb during the study which showed a decrease of mean blood flow velocity, RI, and PI and an increase of end-diastolic velocity which all indicate better blood flow with the increase of Hb in cases during the study. Our findings were in agreement with Haktanir et al study that described Doppler sonography measurement of cerebral blood flow in anemia secondary to chronic renal failure and to compare the results with data gathered from healthy controls in 27 patients with chronic anemia resulting from chronic renal failure and 20 healthy controls. Statistical significance was observed, and the data were correlated with Hb level. From the assessed Doppler parameters, only cerebral blood flow and right and net vertebral artery blood flows had a significant difference (P <0.05) and showed a negative correlation with Hb level.[8]

There was a correlation between improvement of cognitive function and improvement of cerebral circulation measured by TCD of MCA during the study. Furthermore, Keage et al in their study showed the contribution of cerebrovascular dysfunction to the manifestation of dementia and cognitive impairment.[9] Pase et al in their study of 160 healthy adults aged 50–70 years, cerebral blood flow velocity was measured in the MCA using TCD while neuropsychological performance was measured using a computerized cognitive test battery. Arterial aging was associated with increased pulsatile hemodynamic stress in the brain. However, this was not associated with impaired neuropsychological performance.[10]

We have noted the lack of complications such as a stroke, cardiovascular complications and uncontrolled hypertension when Hb increased to 12.5 g/dL. We have noticed the improvement of cognitive function and mean blood flow velocity, RI and PI with TCD of MCA during the study. The improvement was obvious at Stage 3 (Hb 11.5–≤12.5 g/dL) in comparison to Stage 2 (Hb 10–< 11.5 g/dL) with P <0.001 in all. This finding indicates that optimal Hb for HD patients ranges from 11.5 to ≤12.5 g/dL. Our findings were in agreement with a cohort study of Regidor et al which showed that in 58,058 maintenance HD patients, Hb levels between 12 and 13 g/dL were associated with the greatest survival.[11] Our findings are in agreement with Macdougall et al study.[12] In this data from 8209 HD patients for the relative risk of death at different Hb concentrations. The greatest mortality was seen in patients with a Hb <9 g/dL, while the lowest death rate was seen in patients with Hb levels between 12 and 13 g/dL (64% reduced mortality; P = 0.015). Survival advantage associated with Hb of around 11–12 and 12–13 and ≥13 g/dL was maintained and was highly significant (P <0.0001).[12] They reported that there is a significant relationship between achieved Hb and mortality with no increase in risk seen with higher Hb levels (10–-11 g/dL). Our study was in agreement with Avram et al study.[13] This study enrolled 529 HD and 326 peritoneal dialysis patients. Mean enrolment Hb levels of HD patients were 9.44 ± 1.9 g/dL. Survivals of HD (P = 0.05) patients with Hb levels ≥12 g/dL were higher than those with Hb levels <12 g/dL. Hb <12 g/dL was a better predictor of mortality in nondiabetics than diabetics, particularly in HD patients. The relative risk of mortality of patients on HD with Hb <12 g/dL was 2.13-fold (P = 0.008) higher compared to those with Hb ≥12 g/dL (P = 0.035).[13] In conclusion, one can say that Hb is a predictor of long-term survival in HD patients. Patients with Hb levels that are higher than current treatment recommendations (>12 g/dL) may benefit from long-term survival. However, Singh et al in the CHOIR study reported an increased risk from targeting an Hb of 13.5 g/dL (and achieving an Hb of 12.6 g/dL) and no incremental quality-of-life benefit with a target of 13.5 g/dL versus the lower target of 11.3 g/dL. The CHOIR study enrolled 1432 patients and randomized about half to a target Hb of 13.5 g/dL (achieved mean: 12.6 g/dL) and half to a lower target of 11.3 g/dL. The results showed that the higher Hb group had a significantly higher risk of the composite end point (death, myocardial infarction, heart failure, and stroke; hazard ratio of 1.34, P <0.03). The recommendation of CHOIR study was to maintain Hb level <12 g/dL for HD patients.[14]


   Conclusions Top


There is a high frequency of mild-to-moderate cognitive impairment in HD patients associated with anemia. Chronic anemia was associated with impaired cognitive function while gradual improvement of anemia was associated with improvement of cognitive function. We have noted a decrease of complications such as a stroke, cardiovascular complications, and uncontrolled hypertension with increase of Hb to 12.5 g/dL. Thus, our study shows that optimal Hb for HD patients ranges from 11.5 to ≤12.5 g/dL and is associated with improvement of cognitive function.

Conflicts of interest: None declared.

 
   References Top

1.
Farhoudi M, Abedi Azar S, Abdi R. Brain hemodynamics in patients with end-stage renal disease between hemodialysis sessions. Iran J Kidney Dis 2012;6:110-3.  Back to cited text no. 1
    
2.
Li H, Wang SX. Intravenous iron sucrose in Chinese hemodialysis patients with renal anemia. Blood Purif 2008;26:151-6.  Back to cited text no. 2
    
3.
Murray AM, Tupper DE, Knopman DS, et al. Cognitive impairment in hemodialysis patients is common. Neurology 2006;67:216-23.  Back to cited text no. 3
    
4.
Sarnak MJ, Tighiouart H, Scott TM, et al. Frequency of and risk factors for poor cognitive performance in hemodialysis patients. Neurology 2013;80:471-80.  Back to cited text no. 4
    
5.
Odagiri G, Sugawara N, Kikuchi A, et al. Cognitive function among hemodialysis patients in Japan. Ann Gen Psychiatry 2011; 10:20.  Back to cited text no. 5
    
6.
Wood SM, Meyers CA, Faderl S, Kantarjian HM, Pierce SA, Garcia-Manero G. Association of anemia and cognitive dysfunction in patients with acute myelogenous leukemia and myelodysplastic syndrome. Am J Hematol 2011;86:950-2.  Back to cited text no. 6
    
7.
Petranović D, Taksić V, Dobrila-Dintinjana R, et al. Correlation of anaemia and cognitive functions measured by the complex reactio-meter drenovac. Coll Antropol 2008;32:47-51.  Back to cited text no. 7
    
8.
Haktanir A, Demir S, Acar M, et al. Doppler sonographic evaluation of cerebral blood flow in anemia resulting from chronic renal failure. J Ultrasound Med 2005;24:947-52.  Back to cited text no. 8
    
9.
Keage HA, Churches OF, Kohler M, et al. Cerebrovascular function in aging and dementia: A systematic review of transcranial Doppler studies. Dement Geriatr Cogn Dis Extra 2012;2:258-70.  Back to cited text no. 9
    
10.
Pase MP, Grima NA, Stough C, Scholey A, Pipingas A. Association of pulsatile and mean cerebral blood flow velocity with age and neuropsychological performance. Physiol Behav 2014;130:23-7.  Back to cited text no. 10
    
11.
Regidor DL, Kopple JD, Kovesdy CP, et al. Associations between changes in hemoglobin and administered erythropoiesis-stimulating agent and survival in hemodialysis patients. J Am Soc Nephrol 2006;17:1181-91.  Back to cited text no. 11
    
12.
Macdougall IC, Tomson CR, Steenkamp M, Ansell D. Relative risk of death in UK haemodialysis patients in relation to achieved haemoglobin from 1999 to 2005: An observational study using UK renal registry data incorporating 30,040 patient-years of follow-up. Nephrol Dial Transplant 2010;25:914-9.  Back to cited text no. 12
    
13.
Avram MM, Blaustein D, Fein PA, Goel N, Chattopadhyay J, Mittman N. Hemoglobin predicts long-term survival in dialysis patients: A 15-year single-center longitudinal study and a correlation trend between prealbumin and hemoglobin. Kidney Int Suppl 2003;87:S6-11.  Back to cited text no. 13
    
14.
Singh AK, Szczech L, Tang KL, et al. Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med 2006; 355:2085-98.  Back to cited text no. 14
    

Top
Correspondence Address:
Dr. Amr Mohamed Shaker
Department of Internal Medicine, Division of Nephrology, Kasr El Aini Hospital, Cairo University, Cairo
Egypt
Login to access the Email id


DOI: 10.4103/1319-2442.248306

PMID: 30588964

Rights and Permissions


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]



 

Top
   
 
 
    Similar in PUBMED
    Search Pubmed for
    Search in Google Scholar for
    Email Alert *
    Add to My List *
* Registration required (free)  
 


 
    Abstract
   Introduction
   Patients and Methods
   Statistical Analysis
   Results
   Discussion
   Conclusions
    References
    Article Figures
    Article Tables
 

 Article Access Statistics
    Viewed131    
    Printed0    
    Emailed0    
    PDF Downloaded33    
    Comments [Add]    

Recommend this journal