|Year : 2018 | Volume
| Issue : 2 | Page : 34-39
Does brain-derived neurotrophic factor play a role in depression in hemodialysis patients?
Montasser M.H Zeid1, Akram A Deghady2, Osama A Elkholy3, Yasmine S Naga1, Eman M.M Farag1
1 Department of Internal Medicine and Nephrology, Alexandria University, Egypt
2 Department of Clinical and Chemical Pathology, Alexandria University, Alexandria, Egypt
3 Department of Neuropsychiatry Medicine, Alexandria University, Alexandria, Egypt
|Date of Submission||16-Oct-2017|
|Date of Acceptance||12-Nov-2017|
|Date of Web Publication||4-Sep-2018|
Eman M.M Farag
Specialist in the Department of Internal Medicine and Nephrology, Alexandria University Students’ Hospital, Egypt 11 Ibn Elkady Street, Victoria, El Raml, Alexandria
Source of Support: None, Conflict of Interest: None
Background Many end-stage renal disease (ESRD) patients undergoing hemodialysis (HD) suffer from depressive disorders as well as anxiety. These often underdiagnosed conditions not only decrease the quality of life of patients but also increase their mortality. Decrease in brain-derived neurotrophic factor (BDNF) has emerged as a marker of depression that can be used for the diagnosis and follow-up of depression in the general population.
Objectives The aim of the present study was to study the role of BDNF in depression in HD patients.
Patients and methods A single-center, cross-sectional study was carried out including 50 depressed (group I) and 35 nondepressed (group II) ESRD patients on maintained HD according to the Hospital Anxiety and Depression Scale. BDNF levels were measured in all patients.
Result The mean BDNF level was significantly lower in depressed HD patients (2556.0±1498.15 pg/ml) in comparison with group II (9017.14±4249.60 pg/ml), with a P value less than 0.001. Serum BDNF level was also correlated negatively with both the anxiety (rs=−0.440, P<0.001) and the depression score (rs=−0.693, P<0.001) in the total sample. In addition, BDNF was a significant predictor of depression with a high area under the receiver operating characteristics curve (ROC curve) (AUC) (95% confidence interval=0.939–0.998, P<0.001).
Conclusion Anxiety and depression are closely linked in ESRD patients. BDNF is significantly lower in depressed HD patients and correlates negatively with both depression and anxiety. It is a useful biomarker in the detection of depression, a common often undiagnosed and undertreated condition, in ESRD.
Keywords: brain-derived neurotrophic factor, depression, Hospital Anxiety and Depression Scale, hemodialysis
|How to cite this article:|
Zeid MM, Deghady AA, Elkholy OA, Naga YS, Farag EM. Does brain-derived neurotrophic factor play a role in depression in hemodialysis patients?. J Egypt Soc Nephrol Transplant 2018;18:34-9
|How to cite this URL:|
Zeid MM, Deghady AA, Elkholy OA, Naga YS, Farag EM. Does brain-derived neurotrophic factor play a role in depression in hemodialysis patients?. J Egypt Soc Nephrol Transplant [serial online] 2018 [cited 2018 Dec 11];18:34-9. Available from: http://www.jesnt.eg.net/text.asp?2018/18/2/34/240583
| Introduction|| |
Depressive disorders are the most common psychiatric ailment in end-stage renal disease (ESRD) patients undergoing hemodialysis (HD) ,,. Depression starts in earlier stages of chronic kidney diseases and increases in frequency as chronic kidney disease progresses. Renal replacement therapy modality affects the prevalence of depression, with lower rates in transplant recipients, but with similarly high rates in HD and peritoneal dialysis patients . Depression in HD patients is associated with multiple adverse outcomes including poor compliance with treatment, withdrawal from dialysis, more hospitalizations, and mortality rates ,,.
In addition to depression, HD patients frequently suffer from anxiety often together with depression . Anxiety adds to the distress experienced by dialysis patients, significantly worsening their quality of life ,.
There are multiple methods available for the detection of depression including numerous questionnaires and emerging biomarkers . The Hospital Anxiety and Depression Scale (HADS)  can measure both anxiety and depression in outpatient populations and it has been validated in ESRD patients .
Brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family of growth factors , is a secretory protein regulating the development and function of neural circuits ,. According to multiple studies, neurotrophins, especially BDNF, play a role in the development and treatment of depressive disorders ,. It is hypothesized that the lack of BDNF leads to less neuronal plasticity , which may contribute toward the structural alterations and volume decrease in the limbic system and the prefrontal cortex often found in depressed patients ,.
Clinically, multiple studies have reported low levels of BDNF in depressed patients, which increase in response to treatment of antidepressant and psychotherapy, making it a potentially valuable marker for the detection and follow-up of depressed patients ,,.
A study by Shin et al. , found that HD patients had significantly higher plasma BDNF levels than healthy control individuals, putting into question the role of BDNF in detecting depression in this setting. The aim of the present study was to assess the role of BDNF in depressed HD patients.
| Patients and methods|| |
After obtaining the approval of the ethics committee of the Faculty of Medicine of the Alexandria University, eighty five ESRD patients (50 depressed and 35 nondepressed as classified by the HADS score) on maintenance HD for at least 6 months were recruited from the dialysis units of the Alexandria University Hospitals.
The HADS is a 14-item self-report scale measuring the presence of symptoms of both anxiety (seven items) and depression (seven items) during the past week. Each item is scored from 0 to 3; thus, the final score for each subscale is between 0 and 21. The HADS consists of depression (HADS-D) and anxiety (HADS-A) subscales .
An informed consent from the patients was obtained before carrying out the study. Patients with advanced liver disease, autoimmune diseases, those with a history of cerebrovascular stroke, those who were using hypnotics, and those with difficulty in communications were excluded.
Data including name, age, sex, past medical history, and data obtained from clinical examination were recorded at enrollment. Routine laboratory investigations were also recorded.
Serum level of BDNF was measured using the enzyme-linked immunosorbent assay technique kit based on standard sandwich enzyme-linked immune-sorbent assay technology .
Statistical analysis of the data
Data were fed to the computer and analyzed using IBM SPSS software package version 20.0 (IBM Corp., Armonk, New York, USA) . Qualitative data were described using number and percent. Quantitative data were described using range (minimum and maximum), mean, SD, and median. The Kolmogorov–Smirnov test was used to verify the normality of distribution. Student t-test was used to compare normally distributed data and the Mann–Whitney test was used to compare abnormally distributed data. Spearman’s coefficient was used to correlate quantitative variables. ROC was used to assess the performance of BDNF levels for the detection of depression. Significance of the obtained results was judged at the 5% level .
| Results|| |
The present study included 85 ESRD patients on MHD from the dialysis unit of Alexandria Main University Hospital [50 depressed (group I) and 35 nondepressed (group II)]. The studied variables are summarized in [Table 1]. The depressed group (group I) included significantly more women than group II (60 vs. 34%, P=0.02), but there was no significant difference in the age and duration dialysis.
|Table 1 Comparison between the two studied groups according to different variables|
Click here to view
The mean hemoglobin level was significantly higher in group I (9.88±1.06 g/dl) in comparison with group II (9.25±1.03 g/dl), with a P value 0.007, whereas the mean serum albumin level was significantly lower in group I (3.79±0.35 g/dl) in comparison with group II (3.97±0.42 g/dl), with a P value 0.039. Other measured laboratory values including the urea reduction ratio were not significantly different in the two groups studied ([Table 1]). In addition, the mean BDNF level was significantly lower in group I (2556.0±1498.15 pg/ml) in comparison with group II (9017.14±4249.60 pg/ml), with a P value less than 0.001 as shown in [Table 1].
According to HADS, the mean depression score was significantly higher in group I (13.10±3.09) in comparison with group II (3.31±1.62), with a P value less than 0.001, and the mean anxiety score was also significantly higher in group I (10.94±4.44) in comparison with group II (5.40±3.84), with a P value less than 0.001 as shown in [Table 1].
Depression and anxiety scores ([Table 2]) were significantly correlated in group I (rs=0.364, P=0.009), group II (rs=0.508, P=0.002), and the total sample (rs=0.662, P<0.001). There was a statistically significant negative correlation between serum BDNF level and both the depression score (rs=−0.693, P <0.001) and the anxiety score (rs=−0.440, P<0.001) in the total sample.
|Table 2 Significant correlations between brain-derived neurotrophic factor and Hospital Anxiety and Depression Scale score|
Click here to view
The AUC of the ROC curve was calculated to assess the predictive value of BDNF in detecting depression in the studied patients. When a cutoff value of up to 4700 pg/ml was used, BDNF was a statistically significant predictor of depression with an AUC of 0.968, a specificity of 97.14%, and a sensitivity of 88% as shown in [Figure 1] and [Table 3].
|Figure 1 Receiver operating chara cteristics (ROC) curve for brain-derived neurotrophic factor (BDNF) in the assessment of depression (groups I and II). AUC, area under the curve. *Significant if less than 0.05 in all.|
Click here to view
|Table 3 Agreement (sensitivity, specificity) for brain-derived neurotrophic factor in the assessment of depression (groups I and II)|
Click here to view
| Discussion|| |
Depression and anxiety are major, underappreciated problems in ESRD patients on HD. The causes of depression in ESRD include psychosocial factors (such as feelings of hopelessness, perceptions of loss and lack of control, job loss, and altered family and social relationships) and biological factors such as inflammation and uremia.
Anemia is one of the factors that was associated with depression as found by Afsar  and Teles et al.  in studies carried out on HD patients. In contrast, the hemoglobin level in the present study was significantly higher in group I (9.88±1.06 g/dl) in comparison with group II (9.25±1.03 g/dl), with a P value of 0.007. In our study, both groups had low hemoglobin compared with the recommended hemoglobin target by KDIGO guidelines, but the difference between the two groups, although significant, was small.
Although dialysis adequacy may seem to be a potential factor that can cause depression and anxiety in HD patients, its role has not been shown in our study. The mean urea reduction ratio was insignificantly higher in group I (63.84±6.05%) in comparison with group II (63.83±7.51%), with a P value of 0.994. Other studies also failed to find a link between dialysis adequacy and depression. In a cross-sectional study by Najafi and colleagues on 127 HD patients assessed for anxiety and depression using HADS, the authors found that there was no statistically significant correlation between depression and anxiety on the one hand and dialysis adequacy assessed by urea reduction ratio and Kt/V on the other .
Nutritional state is another important determinant of depression. In the present study, the mean serum albumin level was significantly lower in group I (3.79±0.35 g/dl) in comparison with group II (3.97±0.42 g/dl), with a P value 0.039. This finding is consistent with the finding of Simic and colleagues that low albumin is found more in depressed HD patients than nondepressed ones and they speculated that depression is one component of the MIA (malnutrition, inflammation, atherosclerosis) syndrome . In another study by Huang et al.  on non-HD population, they found that serum albumin levels of the group with major depressive disorder were significantly lower than nondepressed controls and that the severity of depression is correlated negatively to the serum albumin level independent of malnutrition.
Other nonspecific markers of malnutrition have also been linked to depression including low phosphorus and uric acid levels. In the present study, uric acid level was lower in group I (7.51±1.59 mg/dl) in comparison with group II (7.93±1.35 mg/dl), but this was not statistically significant, with a P value of 0.206. In a study by Wen and colleagues on a non-HD population, serum uric acid levels were measured in 124 patients with depression, 660 patients with different types of other mental disorders, and 42 healthy participants. The study reported that a lowered uric acid level is another characteristic of depression. This may be explained by the fact that low uric acid may be a marker of poor nutrition .
The mean phosphorus level was insignificantly higher in group I (6.0±1.53 mg/dl) in comparison with group II (5.88±1.82 mg/dl), with a P value 0.733. In contrast, Teles et al.  found a strong correlation between low levels of phosphorus and depression and concluded that low phosphorus was an independent factor associated with depression in HD patients. This finding was not obtained in our study probably because all the patients in our cohort had high phosphorus levels.
The mean intact parathyroid hormone was higher in group II (942.12±583.96 pg/ml) in comparison with group I (731.36±309.18 pg/ml), but the difference was not statistically significant, with a P value 0.311. However, in the general population, depression is associated with higher intact parathyroid hormone levels. This has been attributed to lower 25-hydroxy vitamin D, indicating low sun exposure. This may indicate that hyperparathyroidism secondary to vitamin D deficiency is another risk factor for depression in these patients .
The mean anxiety score was significantly higher in group I (10.94±4.44) in comparison with group II (5.40±3.84), with a P value less than 0.001. The high concordance rate between anxiety and depression has been well documented. Although they are different entities, depressed persons often experience symptoms of anxiety and those with a history of anxiety disorder often develop depression. Although no causal relationship has been established between the two disorders, still many patients suffer from both . In our study, there was a statistically significant positive correlation between anxiety and depression score in group I, group II, and the total sample. This result is consistent with a study by Sapilak and Steciwko  carried out on a group of 400 individuals undergoing HD, which showed that depression occurred in 60.4% of patients, whereas 53.3% of respondents showed symptoms of anxiety.
The serum BDNF level ranged from 500 to 6000 pg/ml in group I, whereas it ranged from 4000 to 20000 pg/ml in group II. The mean BDNF level was significantly higher in group II (9017.14±4249.60 pg/ml) in comparison with group I (2556.0±1498.15 pg/ml), with a P value less than 0.001, as shown in [Table 1]. There was a statistically insignificant negative correlation between serum BDNF level and depression score in group I and group II, but there was a statistically significant negative correlation between serum BDNF level and depression score in the total sample as shown in [Table 2]. Although Shin et al.  found higher plasma BDNF levels in HD patients in comparison with healthy controls. A meta-analysis of studies examining the role of BDNF levels in depression found that the mean level in depressed patients was 1444±1117 versus 2318 ±2145 pg/ml in nondepressed individuals, levels that are lower than the levels found in both groups in our study . Although levels are higher in HD patients because of decreased clearance, BDNF may still be used in depression detection by adjusting the cutoff level in this population. ROC curve analysis ([Figure 1]) found that BDNF at a cutoff value of up to 4700 pg/ml was a statistically significant predictor of depression with an AUC of 0.968, a specificity of 97.14%, and a sensitivity of 88%. In addition, a study by Lee and Kim  pointed to a more important role of BDNF levels in serum or plasma in monitoring clinical response or improvement of depressive symptoms rather than just as a diagnostic marker of major depression, and yet, this assumption has not been tested in HD patients.
Although there was no significant correlation between serum BDNF level and anxiety score in group I and group II, there was a statistically significant negative correlation between serum BDNF level and anxiety score in the total sample. Similarly, a review by Suliman et al.  reported that BDNF levels appear to be reduced in individuals with an anxiety disorder. However, this correlation may be because of the associated depression rather than evidence of a link between BDNF level and anxiety.
Limitations of our study include the small number of patients and the lack of normal controls (i.e. non-HD population). The cross-sectional design of the study also did not enable us to assess the change in the level over time, with dialysis, and after treatment.
| Conclusion|| |
Anxiety and depression are closely linked in ESRD patients. BDNF is significantly lower in depressed HD patients and correlates negatively with both depression and anxiety. It is a useful biomarker in the detection of depression, a common often undiagnosed and undertreated condition, in ESRD.
The authors received no financial support for the research, authorship, and/or publication of this article.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Watnick S, Kirwin P, Mahnensmith R, Concato J. The prevalence and treatment of depression among patients starting dialysis. Am J Kidney Dis 2003; 41:105–110.
Kimmel PL, Thamer M, Richard CM, Ray NF. Psychiatric illness in patients with end-stage renal disease. Am J Med 1998; 105:214–221.
Al Dukhayel A. Prevalence of depressive symptoms among hemodialysis and peritoneal dialysis patients. Int J Health Sci 2015; 9:9–16.
Palmer S, Vecchio M, Craig JC, Tonelli M, Johnson DW, Nicolucci A et al.
Prevalence of depression in chronic kidney disease: systematic review and meta-analysis of observational studies. Kidney Int 2013; 84:179–191.
Drayer RA, Piraino B, Reynolds CF, Houck PR, Mazumdar S, Bernardini J et al.
Characteristics of depression in hemodialysis patients: symptoms, quality of life and mortality risk. Gen Hosp Psychiatry 2006; 28:306–312.
Hedayati SS, Bosworth HB, Briley LP, Sloane RJ, Pieper CF, Kimmel PL et al.
Death or hospitalization of patients on chronic hemodialysis is associated with a physician-based diagnosis of depression. Kidney Int 2008; 74:930–936.
Abbas Tavallaii S, Ebrahimnia M, Shamspour N, Assari S. Effect of depression on health care utilization in patients with end-stage renal disease treated with hemodialysis. Eur J Intern Med 2009; 20:411–414.
Kring DL, Crane PB. Factors affecting quality of life in persons on hemodialysis. Nephrol Nurs J 2009; 36:15–24.
Cukor D, Coplan J, Brown C, Friedman S, Cromwell-Smith A, Peterson RA et al.
Depression and anxiety in urban hemodialysis patients. Clin J Am Soc Nephrol 2007; 2:484–490.
Cukor D, Coplan J, Brown C, Friedman S, Newville H, Safier M et al.
Anxiety disorders in adults treated by hemodialysis: a single-center study. Am J Kidney Dis 2008; 52:128–136.
Strawbridge R, Young AH, Cleare AJ. Biomarkers for depression: recent insights, current challenges and future prospects. Neuropsychiatr Dis Treat 2017; 13:1245–1262.
Zigmond A, Snaith R. The hospital anxiety and depression scale. Acta Psychiatr Scand 1983; 67:361–370.
Loosman WL, Siegert CEH, Korzec A, Honig A. Validity of the Hospital Anxiety and Depression Scale and the Beck Depression Inventory for use in end-stage renal disease patients. Br J Clin Psychol 2010; 49:507–516.
Hallbook F, Ibanez CF, Persson H. Evolutionary studies of the nerve growth factor family reveal a novel member abundantly expressed in Xenopus ovary. Neuron 1991; 6:845–858.
Park H, Poo MM. Neurotrophin regulation of neural circuit development and function. Nat Rev Neurosci 2013; 14:7–23.
Zagrebelsky M, Korte M. Form follows function: BDNF and its involvement in sculpting the function and structure of synapses. Neuropharmacology 2014; 76:628–638.
Brunoni AR, Lopes M, Fregni F. A systematic review and meta-analysis of clinical studies on major depression and BDNF levels: implications for the role of neuroplasticity in depression. Int J Neuropsychopharmacol 2008; 11:1169–1180.
Hashimoto K. Brain-derived neurotrophic factor as a biomarker for mood disorders: an historical overview and future directions. Psychiatry Clin Neurosci 2010; 64:341–357.
Stein DJ, Daniels WM, Savitz J, Harvey BH. Brain-derived neurotrophic factor: the neurotrophin hypothesis of psychopathology. CNS Spectr 2008; 13:945–949.
Drevets W, Price JL, Furey ML. Brain structural and functional abnormalities in mood disorders: Implications for neurocircuitry models of depression. Brain Struct Funct 2008; 213:93–118.
Macqueen G, Yucel K, Taylor VH, Macdonald K, Joffe R. Posterior hippocampal volumes are associated with remission rates in patients with major depressive disorder. Biol Psychiatry 2008; 64:880–883.
Molendijk M, Spinhoven P, Polak M, Bus B, Penninx B, Elzinga B. Serum BDNF concentrations as peripheral manifestations of depression: evidence from a systematic review and meta-analyses on 179 associations. Mol Psychiatry 2014; 19:791–800.
Sen S, Duman R, Sanacora G. Serum brain-derived neurotrophic factor, depression, and antidepressant medications: meta-analyses and implications. Biol Psychiatry 2008; 64:527–532.
Shin SJ, Yoon HE, Chung S, Kim YG, Kim DJ. Plasma brain-derived neurotrophic factor in hemodialysis patients. Int J Med Sci 2012; 9:772–777.
Gonul AS, Akdeniz F, Taneli F, Donat O, Eker C, Vahip S. Effect of treatment on serum brain-derived neurotrophic factor levels in depressed patients. Eur Arch Psychiatry Clin Neurosci 2005; 255:381–386.
Kirkpatrick LA, Feeney BC. A simple guide to IBM SPSS statistics for version 20.0. Student ed. Belmont, CA: Wadsworth, Cengage Learning; 2013.
Kotz S, Balakrishnan N, Read CB, Vidakovic B. Encyclopedia of statistical sciences. 2nd ed. Hoboken, NJ: Wiley-Interscience; 2006.
Afsar B. The relationship between depressive symptoms and erythropoietin resistance in stable hemodialysis patients with adequate iron stores. Int J Artif Organs 2013; 36:314–319.
Teles F, Azevedo VF, Miranda CT, Miranda MP, Teixeira Mdo C, Elias RM. Depression in hemodialysis patients: the role of dialysis shift. Clinics (Sao Paulo) 2014; 69:198–202.
Najafi A, Keihani S, Bagheri N, Ghanbari Jolfaei A, Mazaheri Meybodi A. Association between anxiety and depression with dialysis adequacy in patients on maintenance hemodialysis. Iran J Psychiatry Behav Sci 2016; 10:e4962.
Simic Ogrizovic S, Jovanovic D, Dopsaj V, Radovic M, Sumarac Z, Bogavac SN et al.
Could depression be a new branch of MIA syndrome? Clin Nephrol 2009; 71:164–172.
Huang SY, Chiu CC, Shen WW, Chang HC, Wu PL, Su KP. Hypoalbuminemia in drug-free patients with major depressive disorder compared with a dietary matched control group: a clinical meaning beyond malnutrition. Eur Neuropsychopharmacol 2005; 15:227–230.
Wen S, Cheng M, Wang H, Yue J, Wang H, Li G et al.
Serum uric acid levels and the clinical characteristics of depression. Clin Biochem 2012; 45:49–53.
Hoogendijk WJ, Lips P, Dik MG, Deeg DJ, Beekman AT, Penninx BW. Depression is associated with decreased 25-hydroxyvitamin D and increased parathyroid hormone levels in older adults. Arch Gen Psychiatry 2008; 65:508–512.
Sapilak BJ, Steciwko A. Depression and anxiety disorders occurring during renal replacement therapy - how to deal with the patient (based on 3-year own research). Polska Medycyna Rodzinna 2004; 6:1345–1346.
Lee B, Kim Y. The roles of BDNF in the pathophysiology of major depression and in antidepressant treatment. Psychiatry Investig 2010; 7:231–235.
Suliman S, Hemmings SM, Seedat S. Brain-Derived Neurotrophic Factor (BDNF) protein levels in anxiety disorders: systematic review and meta-regression analysis. Front Integr Neurosci 2013; 7:55.
[Table 1], [Table 2], [Table 3]