Serum metabolomics of end-stage renal disease patients with depression: potential biomarkers for diagnosis

Figures & data

Table 1. Demographic and clinical characteristics of the three groups.

Indicators	Healthy control (n = 12)	ESRD patients without depression (n = 17)	ESRD patients with depression (n = 17)
Age (year)	57.00 ± 11.51	50.18 ± 10.65	50.82 ± 13.45
Hypertension history (month)	0.00 ± 0.00	73.82 ± 61.47**	66.76 ± 85.80*
Diabetes history (month)	0.00 ± 0.00	52.24 ± 88.69	43.06 ± 98.23
History of nephropathy (month)	0.00 ± 0.00	42.00 ± 38.29**	30.71 ± 43.41*
Heart disease history (month)	0.00 ± 0.00	0.29 ± 1.21	7.76 ± 16.40
SBP (mmHg)	126.33 ± 4.50	163.53 ± 23.15**	171.12 ± 33.06**
DBP (mmHg)	80.33 ± 2.67	94.24 ± 9.75**	101.59 ± 16.19**
Dialysis frequency (times/week)	0.00 ± 0.00	2.53 ± 1.01**	2.12 ± 1.11**
WBC (×10^9/L)	5.79 ± 1.55	7.22 ± 2.53	6.62 ± 3.48
Neutrophils (%)	58.56 ± 8.17	69.23 ± 9.82*	78.24 ± 11.20^**△
RBC (× 10^12/L)	4.67 ± 0.35	3.73 ± 0.63**	3.17 ± 1.13**
Hb (g/L)	142.50 ± 13.36	109.71 ± 17.09**	92.29 ± 25.84**
TC (mmol/L)	4.72 ± 0.92	3.25 ± 1.57*	4.30 ± 1.68
TG (mmol/L)	1.25 ± 0.68	3.13 ± 1.50**	2.02 ± 1.46
Albumin (g/L)	44.88 ± 3.66	38.39 ± 2.92**	124.34 ± 280.64
Cr (μmol/L)	59.10 ± 12.43	985.87 ± 342.62**	915.14 ± 213.44**
BUN (mmol/L)	5.38 ± 1.43	21.37 ± 5.85**	28.72 ± 7.23^**△△
K^+ (mmol/L)	4.04 ± 0.51	4.78 ± 0.56**	4.67 ± 0.81*
Phosphorus (mmol/L)	1.09 ± 0.12	1.82 ± 0.47**	1.97 ± 0.82**
Ca^2+ (mmol/L)	2.32 ± 0.15	2.15 ± 0.32	2.07 ± 0.33*
Anxiety scores	4.33 ± 5.66	7.41 ± 3.40	21.29 ± 4.91^**△△
Depression scores	3.75 ± 3.11	9.00 ± 3.06**	22.88 ± 4.20^**△△

SBP: systolic blood pressure; DBP: diastolic blood pressure; WBC: white blood cells; N: neutrophils; RBC: red blood cells; Hb: hemoglobin; TC: cholesterol; TG: triglycerides; Cr: serum creatinine; BUN: blood urea nitrogen. *p < 0.05, **p < 0.01 compared with healthy controls; ^Δp < 0.05, ^ΔΔp < 0.01 compared with ESRD patients without depression.

Figure 1. The score plots of PCA model in positive-ion mode (A, C) and negative-ion mode (B, D); A(A1) and B(B1) show health controls, ESRD patients without depression and ESRD patients with depression; C(C1) and D(D1) show ESRD patients without depression and ESRD patients with depression.

Figure 2. The score plots of PLS-DA model in positive-ion mode (A, C) and negative-ion mode (B, D); A(A1) and B(B1) show health controls, ESRD patients without depression and ESRD patients with depression; C(C1) and D(D1) show ESRD patients without depression and ESRD patients with depression.

Figure 3. The score plots of the three groups of SPLS-DA model in positive-ion mode (A, C) and negative-ion mode (B, D); A(A1) and B(B1) show health controls, ESRD patients without depression and ESRD patients with depression; C(C1) and D(D1) show ESRD patients without depression and ESRD patients with depression.

Table 2. Characteristic compounds of ESRD patients without depression vs. ESRD patients with depression.

Compound name	ESI^+/-	FC	Raw.pval	Vip	Trend
5′-Deoxy-5-fluorocytidine	+	5.44E + 00	2.63E-02	2.0509	↑
Dehydrogenated ticlopidine	+	3.12E + 01	1.91E-02	2.1539	↑
N-Desmethylpromazine	+	1.21E-03	1.54E-02	2.2204	↓
Leucyl-phenylalanine	+	3.97E-02	3.61E-02	1.9432	↓
Cladribine	+	7.96E + 00	4.88E-02	1.8341	↑
Pregnenolone	+	2.99E-03	4.59E-02	1.8561	↓
Bevantolol	+	3.23E-02	4.65E-02	1.8518	↓
Tetracosanoic acid	+	9.62E + 03	2.29E-02	2.0964	↑
6-Thioguanosine monophosphate	+	2.33E + 01	4.91E-02	1.8318	↑
Farnesyl pyrophosphate	+	6.39E + 00	3.84E-02	1.9205	↑
Alfuzosin	+	1.89E-02	6.96E-03	2.4468	↓
Cephapirin	+	1.58E + 01	2.22E-02	2.1062	↑
Thiamin pyrophosphate	+	8.73E + 00	2.14E-02	2.1175	↑
Cabergoline	+	1.12E-02	2.37E-02	2.0853	↓
Almitrine	+	9.89E-02	4.63E-02	1.853	↓
Probucol	+	2.65E-02	2.12E-02	2.121	↓
LysoPC(22:4)	+	4.05E-02	4.55E-02	1.86	↓
PA(34:2)	+	2.27E-02	3.31E-03	2.6358	↓
PG(36:1)	+	1.43E-03	4.15E-02	1.8936	↓
CL(i-36:0/18:2)	+	6.71E-02	7.02E-03	2.4442	↓
Phosphoric acid	−	4.63E-02	2.38E-02	1.893	↓
4-Methylcatechol	−	4.15E-02	2.90E-02	1.8329	↓
Dihydrothymine	−	2.92E + 01	1.68E-04	2.9428	↑
3-Methyl-2-oxovaleric acid	−	9.25E-02	6.13E-03	2.2528	↓
Urocanic acid	−	9.61E-02	4.87E-02	1.6664	↓
5-ethyl-5-methyl-2,4-oxazolidinedione	−	4.65E-09	3.66E-02	1.76	↓
L-Glutamic acid	−	2.44E + 01	4.10E-04	2.7978	↑
Gentisic acid	−	2.57E-09	4.69E-02	1.6791	↓
2,5-Furandicarboxylic acid	−	7.19E-09	3.21E-02	1.8021	↓
L-3-Phenyllactic acid	−	7.29E + 00	4.87E-02	1.666	↑
Uric acid	−	1.42E-09	4.02E-02	1.7302	↓
N-Acetyl-L-aspartic acid	−	2.37E-02	4.40E-03	2.3306	↓
Serotonin	−	2.28E-02	1.74E-02	1.9826	↓
Vanylglycol	−	4.72E-03	2.77E-02	1.8473	↓
2-Phosphoglyceric acid	−	5.67E-02	2.84E-03	2.4274	↓
Homocitrulline	−	6.07E + 00	2.78E-03	2.4319	↑
Hydroxyphenylacetylglycine	−	6.80E + 00	7.71E-03	2.1971	↑
1-Hydroxylorcaserin	−	1.32E-09	2.63E-02	1.8631	↓
Propenoylcarnitine	−	2.18E-09	4.28E-02	1.7091	↓
cyclic 6-Hydroxymelatonin	−	3.23E + 01	4.43E-04	2.7843	↑
Desacetyl-nitazoxanide	−	1.06E + 01	1.96E-02	1.9492	↑
Deoxyartemsinin	−	1.77E + 01	3.81E-04	2.8099	↑
Malaoxon	−	5.64E-02	1.52E-02	2.0206	↓
5-HEPE	−	7.48E-02	1.90E-02	1.9573	↓
15(S)-Hydroxyeicosatrienoic acid	−	2.00E-02	2.33E-02	1.8993	↓
5′-O-Desmethyl omeprazole	−	4.06E-02	4.61E-04	2.7776	↓
17-HDoHE	−	8.61E-02	1.29E-02	2.0645	↓
5-(4′-Hydroxyphenyl)-gamma-valerolactone-4′-O-glucuronide	−	8.97E + 00	2.34E-02	1.8971	↑
Hydromorphone-3-sulphate	−	5.47E + 00	4.59E-02	1.686	↑
6-Thioxanthine 5′-monophosphate	−	8.21E-02	7.36E-03	2.2084	↓
Hydroxylansoprazole	−	8.92E-09	4.68E-02	1.6799	↓
Eletriptan N-oxide	−	6.01E-02	2.20E-02	1.9162	↓
Carboxycelecoxib	−	6.03E-02	3.38E-02	1.7851	↓
Zileuton O-glucuronide	−	2.53E-09	1.50E-02	2.0241	↓
Hesperetin 3′-O-glucuronide	−	7.95E + 00	3.72E-02	1.7551	↑
DG(30:1)	−	7.01E + 00	8.44E-03	2.1747	↑
Enkephalin L	−	1.01E + 01	3.51E-02	1.7733	↑

Table 2 shows the qualitative results and related information of screening differential metabolites in the positive- and negative-ion mode.

Figure 4. Thermogram of the relative content of differential metabolites: (A) is three groups; (B) shows ESRD patients without depression and ESRD patients with depression. (C) Shows the analytical heat map of the 50 metabolite contents with the largest differences between the three groups. (D) Shows the analytical heat map of the 50 metabolite contents with the largest difference between the two groups.

Figure 5. Scores of metabolite pathways involved by differential metabolites in ESRD patients without depression vs. ESRD patients with depression. The size and color of each circle are based on pathway impact value and p value, respectively.

Table 3. Different metabolite pathway in ESRD patients without depression versus ESRD patients with depression.

	Total	Expected	Hits	Raw p	Holm adjust	FDR	Impact
Alanine, aspartate and glutamate metabolism	24	0.2393	2	0.02301	1	1	0.17664
Tyrosine metabolism	76	0.75779	3	0.038024	1	1	0.01825
Glycerophospholipid metabolism	39	0.38887	2	0.056434	1	1	0.10429
Histidine metabolism	44	0.43872	2	0.069917	1	1	0.06816
D-Glutamineand D-glutamate metabolism	11	0.10968	1	0.10458	1	1	0.11230
Citrate cycle (TCA cycle)	20	0.19942	1	0.18227	1	1	0.04844
Thiamin metabolism	24	0.23930	1	0.21468	1	1	0.02865
Glycolysis or Gluconeogenesis	31	0.30910	1	0.26847	1	1	0.00068
Pyruvate metabolism	32	0.31907	1	0.27586	1	1	0.00459
Glycerolipid metabolism	32	0.31907	1	0.27586	1	1	0.01247
Terpenoid backbone biosynthesis	33	0.32904	1	0.28317	1	1	0.05141
Glutathione metabolism	38	0.37889	1	0.31871	1	1	0.01095
Valine, leucine and isoleucine degradation	40	0.39884	1	0.33245	1	1	0.03781
Pyrimidine metabolism	60	0.59826	1	0.45599	1	1	0.01492
Aminoacyl-tRNA biosynthesis	75	0.74782	1	0.53393	1	1	0.05634
Arginine and proline metabolism	77	0.76776	1	0.54348	1	1	0.03582
Tryptophan metabolism	79	0.78770	1	0.55284	1	1	0.05734
Purine metabolism	92	0.91732	1	0.60933	1	1	0.00969
Steroid hormone biosynthesis	99	0.98712	1	0.63685	1	1	0.02542

Table 3 shows the relative impact scores of metabolic pathways enriched by different compounds in ESRD patients with or without depression.

Table 4. The metabolites for the diagnosis of ESRD with depression (AUC ≥0.90).

Compound	AUC	TPR	FPR	95% CI
5-ethyl-5-methyl-2,4-oxazolidinedione	0.934	0.9	0.8	0.834–0.986
Gentisic acid	0.965	0.9	0.9	0.896–1.000
2,5-Furandicarboxylic acid	0.931	0.9	0.8	0.829–0.986
Uric acid	0.931	0.9	0.8	0.834–0.990
Serotonin	0.931	0.9	0.9	0.822–0.986
2-Phosphoglyceric acid	0.924	0.8	0.9	0.811–0.986
N-Desmethylpromazine	0.965	0.9	0.9	0.900–1.000
Leucyl-phenylalanine	0.938	0.9	0.9	0.834–0.990
Propenoyl carnitine	0.934	0.9	0.8	0.832–0.990
Malaoxon	0.927	0.9	0.8	0.803–0.990
Pregnenolone	0.976	0.9	0.9	0.917–1.000
Bevantolol	0.948	0.9	0.9	0.861–1.000
6-Thioxanthine 5′-monophosphate	0.924	0.9	0.9	0.789–1.000
Hydroxyl ansoprazole	0.924	0.9	0.8	0.824–0.986
Alfuzosin	0.931	0.8	0.9	0.823–0.986
Zileuton O-glucuronide	0.958	0.9	0.9	0.867–1.000
Cabergoline	0.952	0.9	0.8	0.849–0.997
Probucol	0.931	0.9	0.8	0.815–0.986
PA(34:2)	0.945	0.9	0.9	0.839–1.000
PG(36:1)	0.955	0.9	0.9	0.875–1.000

TPR: true-positive rate; FPR: false-positive rate; 95% CI: 95% confidence interval.

Figure 6. Biochemical transformation of differential metabolites. ESRD patients with depression compared with ESRD patients without depression, red metabolites have increased and green metabolites decreased.

Data availability statement

The study data can be accessed from the corresponding author Ran J.H. or Li J.F. by request.