Abstract
Background
Neurotrophins are related with depressive disorders. Significant neurotrophins variations occur during renal replacement therapy, but whether peri-hemodialysis availability is associated with depression in patients with Chronic Kidney Disease (CKD) is yet unclear.
Aim
To determine dynamic concentrations of neurotrophins in the peri-hemodialysis range and their association with depressive symptoms in patients with CKD.
Methods
Pre-, and post-hemodialysis plasma concentrations of brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF), as well as their plasma clearance rates, were determined (multiplexing) in patients with stage 5 CKD. Depressive symptoms, as assessed by the Beck Depression Inventory-II (BDI-II), were determined. Finally, the bioavailability of BDNF and NGF was related to the score of depressive symptoms.
Results
Fifty-three patients were divided according to depressive symptoms. Pre-hemodialysis plasma BDNF was lower in patients with depressive disorder; whereas basal BDNF value >220 pg/mL independently reduced the risk for depressive disorder (Odds Ratio 0.23, p = 0.047) at uni- and multivariate analysis. Post-hemodialysis concentration and clearance rate of neurotrophins were not related with depressive symptoms.
Conclusion
Higher plasma BDNF before hemodialysis reduces the risk of mild depression in patients with CKD under renal replacement therapy.
Keywords: Plasma brain-derived neurotrophic factor, hemodialysis, depression, chronic renal failure
Introduction
The prevalence of depressive disorder between populations with Chronic Kidney Disease (CKD) is 20 to 39%; and it may increase all-cause mortality risk (RR 1.59) [1], as well as the impact on the quality of life, hospitalization rate and length, nutritional status and therapy compliance [2,3]. Therefore, early identification of depressive disorders between the CKD population is relevant; although not always easy, since concomitant neurovegetative and neurocognitive symptoms occurring in CKD are hard to discriminate from depressive disorders.
Metabolic alterations in CKD may facilitate the development of depressive disorders, such as the continuous production of pro-inflammatory and pro-oxidative mediators, as well as the dysfunction of the hypothalamic-pituitary-adrenal axis, imbalance in glucose homeostasis and insulin lifetime [2,4]. There has been increasing evidence regarding the role of neurotrophic factors in the pathophysiology of depression, particularly in the context of CKD.
Neurotrophins are peptides related to the survival, growth, plasticity and functional capacities of neurons in the central and peripheral nervous system [5]. Among the neurotrophins, brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) are the most abundant in the brain [6]. Both have been involved in the pathophysiology of depression [7–9].
A decrease in plasma BDNF from 19.4% up to 42% has been described during renal replacement therapy in the population with CKD [10–13]. Such variation is taught to occur due to transport mechanisms in the semipermeable membrane [14]. Interestingly, Kielstein et al. found lower plasma BDNF in patients with depression on hemodialysis and described a negative correlation between BDNF and a score of the Beck Inventory for Depression [15] However, other studies with comparable designs show inconsistent results [16,17].
Despite the significant variations in neurotrophins during renal replacement therapy, previous studies targeting depressive disorders in CKD have not considered the peri-hemodialysis bioavailability of neurotrophins and whether it may affect depressive symptoms. This study aimed to determine dynamic concentrations of neurotrophins during hemodialysis and whether it may associate with depressive symptoms in patients with CKD.
Experimental procedures
An observational, cross-sectional, analytical, comparative study was performed in patients older than 18 years old, with CKD5 on regular hemodialysis program in Hemodialysis Unit from “Centro Medico Nacional 20 de Noviembre” and “Clínica de Especialidades Dr. Pisanty Ovadia”, ISSSTE, Mexico City. Patients were excluded if evidence of active infection, neoplasia, liver disease, autoimmune disease, renal transplantation, hemodynamic instability or use of immuno-modulators; as well as diagnosis of depression, use of antidepressants or other drugs that potentially affect the nervous system.
Clinical-demographic information was collected on the hemodialysis session date. Depressive symptoms were rated through the Beck Depression Inventory II (BDI-II). Blood sampling was performed at the shortest interdialytic period. Plasma concentrations of BDNF and NGF were determined in patients with CKD5, before and immediately after hemodialysis, by multiplexing assay. Finally, the concentrations of BDNF and NGF were related to the depressive symptoms.
Sample size was calculated through comparison of means for two independent groups, as follows: [2 ⋅ (Zα/2 + Zβ)2⋅σ2]/Δ2. For statistical analysis, qualitative variables were resumed as frequency and percentages; and quantitative data were expressed as mean, standard deviation and interquartile range. Normal distribution of data was determined through Shapiro–Wilks normality test. Qualitative variables were compared by x2 analysis or Fisher’s exact test, as appropriate according to the frequency of the observations. Mann–Whitney U was used to analyze quantitative data. Uni- and multi-variate analyses were performed to estimate potential associations and confounders. All statistical tests were with the SPSS v.21. p < 0.05 was considered statistically significant.
We respect the recommendations issued by the Nuremberg Code, the Universal Declaration of Human Rights, the Declaration of Helsinki and the Belmont report. In addition, we follow the regulations of Ley General de Salud en Materia de Investigación en Salud. All participants signed informed consent. The study protocol was revised and authorized by the Institutional Ethical and Research Review Board, ID number 413.2018.
Results
The study population was constituted of 48 patients, mean aged of 47 years old, 53% males, with glomerulonephritis as the most frequent etiology of CKD and high blood pressure as the most frequent co-morbidity. Complete clinical–demographic characteristics are shown in (Table 1).
Table 1.
Clinical-demographic characteristics of the study population (n = 53).
| All (n = 28) | w/o depression (n = 25) | Mild depression | p-value | ||
|---|---|---|---|---|---|
| Age (years old) | 47 ± 14.2 | 45 ± 13.4 | 51 ± 14.2 | 0.23 | |
| Gender (male; n[%]) | 28 (52.8) | 15 (53.6) | 13 (52.0) | 0.56 | |
| BMI (kg/m2) | 22.2 ± 4.5 | 21.9 ± 4.9 | 22.7 ± 4.5 | 0.30 | |
| Etiology | Glomerulonephritis | 23 (43.4) | 13 (46.4) | 10 (40.0) | 0.63 |
| Undetermined | 10 (18.9) | 6 (21.4) | 4 (16.0) | 0.44 | |
| DM nephropathy | 10 (18.9) | 4 (14.3) | 8 (32.0) | 0.11 | |
| Angiosclerosis | 5 (9.4) | 3 (10.7) | 2 (8.0) | 0.55 | |
| Fabry disease | 2 (3.8) | 0 (0) | 2 (8.0) | 0.22 | |
| PKD | 2 (3.8) | 1 (3.6) | 0 (0) | 0.53 | |
| Preeclampsia | 2 (3.8) | 1 (3.6) | 0 (0) | 0.53 | |
| Comorbidities | DM | 10 (18.9) | 3 (10.7) | 10 (40.0) | 0.01 |
| SAH | 31 (54.5) | 19 (67.8) | 21 (84.0) | 0.14 | |
| Hypothyroidism | 4 (7.5) | 2 (7.1) | 4 (16.0) | 0.28 | |
| Previous PD | 25 (47.2) | 16 (57.1) | 8 (32.0) | 0.06 | |
| RRT time (months) | 36 (35, 133) | 99 (41, 168) | 48 (34, 82) | 0.07 | |
The diagnosis of depression was made through the Beck Depression Inventory II (BDI-II). Patients were classified as normal (score 0–9), or mild depression (score 10–16). Quantitative data with normal distribution were expressed with mean ± standard deviation, otherwise, they were resumed as median (p25, p75); then, compared by non-paired, 2-tailed t-test, Mann–Whitney U. Categorical data were summarized as n(%) and analyzed by Chi Square or Fisher’s exact test, as appropriate according to the frequency of the observations. Bold p-values indicate statistical significance (p < 0.05) regarding data comparison from the groups w/o depression vs. Mild depression.
BMI: Body Mass Index; DM: Diabetes Mellitus; SAH: systemic arterial hypertension; PKD: polycystic kidney disease; PD: peritoneal dialysis; RTT: renal replacement treatment.
According to the Beck Depression Inventory II (BDI-II), the rating score ranged between 2 and 16, with mild depression present in 36.1% of the cases. When comparing subgroups according to depression, similar characteristics, but a higher prevalence of Diabetes Mellitus in the subgroup with Mild Depression, was found (Table 1).
Regarding biochemical profile, the subgroup with Mild Depression showed significantly lower plasma creatinine and higher platelet count (Table 2). Hemodialysis reduced plasma nitrogen compounds and potassium, whereas no differences between Depression subgroups were observed (Table 2).
Table 2.
Biochemical characteristics.
| All (n = 28) | w/o depression (n = 25) | Mild depression | p-value | ||
|---|---|---|---|---|---|
| Before HD | Urea (mg/dL) | 156.6 ± 53.2 | 157.0 ± 49.0 | 156.0 ± 61.0 | 0.95 |
| BUN (mg/dL) | 73.1 ± 24.8 | 73.3 ± 23.1 | 72.8 ± 28.6 | 0.95 | |
| Cr (mg/dL) | 10.6 ± 2.9 | 11.6 ± 2.6 | 8.8 ± 2.4 | 0.01 | |
| Albumin (g/dL) | 4.1 ± 0.4 | 4.1 ± 0.27 | 4.0 ± 0.52 | 0.24 | |
| Na (meq/dL) | 138 ± 3.6 | 138 ± 3.6 | 137 ± 3.4 | 0.53 | |
| K (meq/dL) | 5.7 ± 1.1 | 5.5 ± 0.8 | 5.8 ± 1.3 | 0.40 | |
| Hemoglobin (mg/dL) | 10.7 ± 1.8 | 11.0 ± 1.6 | 10.2 ± 1.9 | 0.17 | |
| Platelets (cel/mm3) | 215 ± 77 | 193 ± 56 | 254 ± 95 | 0.02 | |
| Leukocytes (cel/mm3) | 5.5 ± 1.74 | 5.7 ± 1.6 | 5.1 ± 1.8 | 0.32 | |
| After HD | Urea (mg/dL) | 60.7 ± 22.2 | 60.2 ± 18.8 | 61.7 ± 28.1 | 0.85 |
| BUN (mg/dL) | 28.4 ± 10.3 | 28.1 ± 8.7 | 28.8 ± 13.1 | 0.85 | |
| K (meq/dL) | 3.9 ± 0.5 | 3.8 ± 0.54 | 4.03 ± 0.45 | 0.25 | |
The diagnosis of depression was made through the Beck Depression Inventory II (BDI-II). Patients were classified as normal (score 0–9), or mild depression (score 10–16). Quantitative data with normal distribution were expressed with mean ± standard deviation. Non-paired, 2-tailed t-test was applied as appropriate. Bold p-values indicate statistical significance (p < 0.05) regarding data comparison from the groups w/o depression vs. Mild depression.
Cr: serum creatinine; BUN: blood ureic nitrogen; HD: hemodialysis.
Baseline plasma BDNF was lower in patients with mild depression (373 vs. 220 pg/ml, p < 0.05), and no significant changes in NGF were observed (Figure 1).
Figure 1.
Neurotrophins and depression. Plasma concentration of BDNF and NGF in patients with depression and without depression. *p < 0.05.
Plasma BDNF and NGF median values showed non-significant increase after the hemodialysis (BDNF pre-dialysis 334.5 [p25 187.8, p75 462.4 pg/ml vs post-dialysis 421.0, p25 239.5 p75 520.5 pg/ml; NGF pre-dialysis10.0 (p25 2.0, p75 21.3 pg/ml) vs post-dialysis 11.5 (p25 4.0, p75 27.8 pg/ml). Delta is shown in Table 3.
Table 3.
HD-related change in neurotrophins and mild depression.
| All | w/o depression (n = 28) | Mild depression (n = 25) | p-value | |
|---|---|---|---|---|
| (%)Δ BDNF | 1.5 | 1.0 | 2.0 | 0.29 |
| (%)Δ NGF | 2.0 | 2.0 | 1.0 | 0.54 |
The value Δ (pre- vs post-HD) is the % of change from values of pre- vs post-hemodialytic serum neurotrophins. Data are shown as median (p25, p75). Non-paired, 2-tailed Mann–Whitney U was applied. Statistical significance was considered as p < 0.05.
BDNF: brain-derived neural factor; NGF: nerve growth factor.
Higher baseline plasma BDNF significantly protected against Mild depression (Odds Ratio 0.23, p = 0.04), independently from age, sex, comorbidities, time under renal replacement therapy, dialysis dose, and ultrafiltered volume (Table 4).
Table 4.
Risk analysis of BDNF and mild depression.
| Odds ratio | 95% confidence interval | Univariate | Multivariate | |
|---|---|---|---|---|
| MODEL 1 | ||||
| Before HD | 0.24 | 0.01 to 0.75 | 0.04* | - |
| After HD | 0.55 | 0.13 to 2.37 | 0.39 | – |
| MODEL 2* | ||||
| Before HD | 0.16 | 0.28 to 0.80 | 0.04* | 0.03* |
| After HD | 0.51 | 0.02 to 13.10 | 0.39 | 0.39 |
| MODEL 3* | ||||
| Before HD | 0.10 | 0.15 to 0.77 | 0.04* | 0.03* |
| After HD | 0.63 | 0.12 to 3.26 | 0.39 | 0.59 |
| MODEL 4* | ||||
| Before HD | 0.01 | 0.01 to 0.59 | 0.04* | 0.01* |
| After HD | 0.99 | 0.98 to 1.00 | 0.39 | 0.17 |
Cut-off values: BDNF pre-HD 220 pg/ml and post-HD 354 pg/mL.
Model 1: not adjusted.
Model 2: adjusted for age (47 years) and sex.
Model 3: adjusted for age, sex and comorbidities (DM and SAH).
Model 4: adjusted for age, sex and comorbidities (DM, SAH), BMI (22.2 kg/m2), time on TRR (36 months), KTV (1.09), platelets (215 cel/mm3), UF (10.60 mL/kg/hr) and albumin (4.1 g/dL).
For uni- and multi-variated regression analyses, bold p-values and (*) indicate statistical significance (p < 0.05) regarding the OR (CI 95%) of BDNF to predict Mild depression.
DM: Diabetes Mellitus; SAH: systemic arterial hypertension; RRT: renal replacement therapy; KTV: dialysis dose; BDNF: brain-derived neurotrophic factor.
Discussion
The main finding of the present study was a higher pre-dialytic concentration of BDNF, which resulted protective against mild depression in patients with CKD under RRT. This result supports the relation of neurotrophins with depression in patients with CKD; with a particular role for BDNF, since NGF did not significantly variate in relation to depression.
Our data are similar to previous findings reported by Kielstein [15], while other studies have failed to demonstrate a relation between neurotrophin and depression in patients with CKD under RRT [10,18]. We measured plasma BDNF and NGF through multiplex assay, which provides precise and reliable results; however, inconsistencies with other reports may be due to methodological differences regarding the type of RRT used [12,13,19], the biological sample where neurotrophins were determined, such as plasma or serum, and other design variations. Recently, Stanisławska et al. used a very similar methodology but were unable to find a significant relation between plasma BDNF and the score of Beck Depression Inventory II (BDI-II) in patients with CKD under hemodialysis [20]. Such discrepancies may be explained by differences in age of the study population, time in HD, previous use of PD, urea baseline levels, and methods to measure BDNF. Therefore, further comprehensive and long-term prospective studies are required for a better understanding of the role of BDNF within depression in patients with CKD under RRT.
The 36% prevalence of depression obtained in the present study resembles that observed in other reports, ranging from 20 to 50% [2–4,21–23]. In addition, a higher prevalence of type 2 DM was observed between the subgroup with mild depression; being consistent with findings from Khaledi et al. where 1 out of 4 adults with type 2 Diabetes Mellitus concomitantly experienced depression [24].
The subgroup with mild depression was also characterized by a higher platelet count and lower concentration of serum creatinine. Interestingly, relations between platelet count with depression and BDNF levels are plausible since platelet concentration of BDNF is 50 to 100 times higher than brain concentration and may be released after activation of alpha granules [25,26]. While lower creatinine observed in mild depression may reflect the relative malnutrition in the population with CKD and depressive disorders. In the present study, mild depression did not result associated with expected clinical-demographic factors previously described, such as systemic arterial hypertension, gender or age [18,21,27–30], as well as many characteristics related with dialysis [27].
Our data analysis suggests that BDNF reduces the risk of depressive disorder, remaining significant even after multivariate adjustment by clinical and demographic parameters. This effect may be related to its participation in neuronal plasticity, growth, neurogenesis, synaptogenesis and neuronal maturation [31–34]. Therefore, normal or high concentrations of BDNF may favor the adaptability of the neural microenvironment. Consistent with our data, some publications showed that BDNF values returned to normal after antidepressant drug therapy [11,18,35,36], although it is not known whether CKD may affect the antidepressant effect on neurotrophins.
Characterization of BDNF′s role in depression within CKD under RRT highlights early diagnostic and therapeutic implications. Comparatively, BDNF seemed to exert a significant impact on depressive symptoms in the CKD population under RRT, which was not evident for NGF. Such performance suggests the ability of BDNF as a marker of depression, which may be explained by its neuroprotective effect and the modulation of mechanisms related to depression, such as insulin resistance, oxidative stress, and inflammation in patients with CKD [37]. Likewise, lower BDNF levels are frequently related to the presence and severity of depressive symptoms, as well as cognitive impairment in the population under hemodialysis [8,38–40]. On the other hand, the relation of NGF with neuronal health and/or depression in patients with CKD and RRT is less conclusive, limiting its reliability as a candidate marker [8].
Based on previous reports describing a significant circulating BDNF removal between 19.4% to 42%, after RRT [12,13]; we further explored whether BDNF clearance induced by RRT may be related with mild depression in patients with CKD. Non-significant increase of 2% of BDNF after RRT was observed, which did not affect the prevalence of mild depression. Possible explanations for a lack of BNDF clearance include differences in dialysis dose [10,13] and/or type of RRT.
Our study explored the relation of neurotrophins with depression in patients with CKD under RRT, including the influence of several dialytic parameters. In addition, our study design and methods allow for exploring the role of neurotrophins like BDNF as potential biomarkers, offering practical implications for clinical practice and the development of new therapies to improve the comfort of hemodialysis patients. However, some limitations of the present study should be considered. First, although Beck Depression Inventory II (BDI-II) has been validated in Mexican Spanish [41,42], this tool may overestimate the prevalence of depression [1]. Second, the study was carried out in a third-level hospital, which attends to a particular population mostly young aged, some of them included in a renal transplant register program, with mild depression. Cases with severe depression were not possible to be recruited. Third, the hospital provides constant emotional advice and support for all the patients with CKD under RRT, which is not replicated in similar cohorts from other hospitals.
After considering potential sampling and/or measurement bias, it can be concluded that higher pre-dialytic plasma levels of BDNF might reduce the risk of mild depression in patients with CKD under RRT, without a significant influence of BDNF clearance by RRT.
Acknowledgements
The authors acknowledge to Rebeca de los Santos for the critical review of the methodological analysis.
Funding Statement
This research received financial support from E015 Programa Presupuestal, Investigación y Desarrollo Tecnológico en Salud. ISSSTE.
Authors contributions
J.A.S-C, N.P.C-N, E.R-A, A.D.Z-L, M.G.O-M and D.M-T participated in study design and data analyses. E.V-G, A.H-P, G.M-T, Y.B-F, J.A.P-J, collected information and performed statistical analyses J.G-S and S.G wrote the first manuscript draft and final review. All the authors reviewed and approved the final manuscript.
Disclosure statement
No potential conflict of interest was reported by the author(s).
Data availability statement
The datasets generated and/or analyzed during the current study are not publicly available due to institutional data use guidelines but are available from the authors on reasonable request.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The datasets generated and/or analyzed during the current study are not publicly available due to institutional data use guidelines but are available from the authors on reasonable request.