Association of plasma ortho-tyrosine/para-tyrosine ratio with responsiveness of erythropoiesis-stimulating agent in dialyzed patients

Figures & data

Table 1. Clinical parameters of dialysis patients

Group	Non-ESA-HD	ESA-HD	CAPD
n	8	40	21
Age (years)	72 (22)	77 (16)	58 (25)^a,b
Male/female	5/3	12/28	12/9
Dialysis duration (months)	40 (43)	34 (63)	8 (10)^b,c
Restdiuresis (ml)	200 (550)	200 (575)	1500 (1300)^b,c
Kt/Vurea	1.72 (0.61)	1.67 (0.33)	2.00 (0.71)^a,b
ESA-dose (μg/week)	–	15 (15)	5 (20)^d
ESA-dose/body weight (μg/kg/week)	–	0.2500 (0.2604)	0.0405 (0.2487)^b
ERI1 (μg/kg/week/g/l)	–	0.0023 (0.0025)	0.0003 (0.0026)^b
ERI2 (μg/kg/week/%)	–	0.0073 (0.0076)	0.0011 (0.0078)^b
ERI3 (μg/kg/week/T/l)	–	0.0630(0.0642)	0.0101 (0.0734)^b
Hemoglobin (g/l)	122 (21)	113 (11)	116 (16)
Hematocrit (%)	35.4 ± 4.3	33.7 ± 2.9	35.3 ± 4.2
RBC (T/l)	3.84 ± 0.52	3.59 ± 0.38	3.80 ± 0.59
MCV (fl)	92.4 ± 5.2	94.2 ± 5.8	93.5 ± 7.7
MCH (pg)	30.74 (3.23)	31.53 (2.85)	30.40 (4.49)
MCHC (g/l)	334 (30)	330 (13)	327 (14)
Body weight (kg)	72.8 (26.6)	64.3 (17.5)	80.0 (45.8)^b
Height (m)	1.60 (0.15)	1.63 (0.10)	1.70 (0.13)^b
BMI (kg/m^2)	28.40 (8.24)	25.24 (5.92)	26.73 (13.21)
Se-Na^+ (mmol/l)	140 (8)	140 (5)	141 (4)
Se-K^+ (mmol/l)	5.00 (2.10)	4.80 (0.97)	4.30 (0.55)^b,c
Se-Ca^2+ (mmol/l)	2.04 ± 0.28	2.17 ± 0.15	2.26 ± 0.25^a
Se-PO4^3− (mmol/l)	1.52 (0.92)	1.43 (0.54)	1.71 (0.56)
PTH (pmol/l)	43.79 (46.25)	32.15 (31.51)	25.93 (36.20)
Se-iron (μmol/l)	11.8 (4.4)	10.3 (6.1)	12.1 (4.6)
Se-transferrin (g/l)	1.5 ± 0.3	1.6 ± 0.3	2.0 ± 0.3^b,c
Transferrin saturation (%)	33.38 (14.93)	26.38 (21.18)	23.04 (10.68)^c
Se-ferritin (μg/l)	999 ± 331	1056 ± 494	392 ± 246^b,c
Se-creatinine (μmol/l)	570 (289)	522 (228)	468 (291)
hsCRP (mg/l)	10.5 (10.3)	9.7 (9.8)	6.2 (6.1)
Se-total protein (g/l)	63.5 ± 7.3	64.2 ± 5.2	65.0 ± 7.1
Se-albumin (g/l)	36.1 ± 4.6	38.4 ± 3.2	39.5 ± 5.0
Se-total cholesterol (mmol/l)	4.35 (0.61)	4.64 (1.42)	5.03 (1.33)^a
Se-HDL-cholesterol (mmol/l)	0.96 (0.32)	1.12 (0.52)	0.94 (0.46)^d
Calculated se-LDL-cholesterol (mmol/l)	2.51 (0.61)	2.81 (1.07)	3.00 (1.20)
Se-non-HDL-cholesterol (mmol/l)	3.30 (0.88)	3.50 (1.11)	4.10 (1.42)^a,d
Se-triglyceride (mmol/l)	1.79 (1.36)	1.38 (0.79)	2.46 (2.24)^b
Systolic blood pressure (mmHg)	125 (10)	120 (20)	120 (30)
Diastolic blood pressure (mmHg)	70 (16)	70 (10)	70 (13)
No. of antihipertensive drugs	3 (2)	3 (3)	3 (4)^a,b
RAAS-inhibitors (%)	50	55	90^a,b
Diabetes (%)	63	48	43
CVD (%)	75	83	71
Cerebrovascular disease (%)	38	33	14
PAD (%)	50	33	10^a

RBC, red blood cell count; MCV, mean corpuscular volume; MCH, mean corpuscular hemoglobin; MCHC, mean corpuscular hemoglobin concentration; BMI, body mass index; BSA, body surface area; se-, serum; PTH, parathormone; hsCRP, high sensitivity C-reactive protein; RAAS, renin angiotensin aldosterone system; CVD, cardiovascular disease; PAD, peripheral artery disease. ERI₁, ESA-dose/body weight/Hb; ERI₂, ESA-dose/body weight/Htc; ERI₃, ESA-dose/body weight/RBC.

^aP < 0.05, as compared to group non-ESA-HD. ^bP < 0.01, as compared to group ESA-HD. ^cP < 0.01, as compared to group non-ESA-HD. ^dP < 0.05, as compared to group ESA-HD. Data represent the median (interquartile range) or mean ± SD.

Figure 1. Level of plasma para-tyrosine (A) and ortho-tyrosine (B) in controls (CONTR), hemodialyzed patients without ESA-treatment (non-ESA-HD), hemodialyzed patients with ESA-treatment (ESA-HD), and patients with peritoneal dialysis (CAPD). para-Tyr, para-tyrosine; ortho-Tyr, ortho-tyrosine.

Figure 2. Correlations between [A] plasma ortho-tyrosine or [B] plasma ortho-tyrosine/para-tyrosine and ESA-dose/body weight. Correlations between [C] plasma ortho-tyrosine or [D] plasma ortho-tyrosine/para-tyrosine and ERI₁ = ESA-dose/body weight/hemoglobin. ortho-Tyr, ortho-tyrosine; para-Tyr, para-tyrosine.

Table 2. Predictors of ESA-demand (plasma para-tyrosine/phenylalanine ratio included)

	Model 1			Model 2
Dependent	Independent predictor	β	P	Independent predictor	β	P
ESA-dose	Restdiuresis	−0.256	0.038	Restdiuresis	−0.256	0.038
ESA-dose/body weight	Restdiuresis	−0.329	0.007	Restdiuresis	−0.329	0.007
ERI1	Restdiuresis	−0.302	0.014	Restdiuresis	−0.302	0.014
ERI2	Restdiuresis	−0.304	0.013	Restdiuresis	−0.304	0.013
ERI3	Restdiuresis	−0.299	0.015	Restdiuresis	−0.299	0.015

Model 1: se-Ca²⁺, se-PO₄³⁻, PTH, restdiuresis, se-ferritin, and plasma para-tyrosine/phenylalanine.

Model 2: age, dialysis duration, hsCRP, restdiuresis, se-ferritin, and plasma para-tyrosine/phenylalanine.

ERI₁, ESA-dose/body weight/hemoglobin; ERI₂, ESA-dose/body weight/hematocrit; ERI₃, ESA-dose/body weight/red blood cell count.

Method: stepwise.

Table 3. Predictors of ESA-demand (plasma ortho-tyrosine/phenylalanine ratio included)

	Model 1			Model 2
Dependent	Independent predictor	β	P	Independent predictor	β	P
ESA dose	–	–	–	–	–	–
ESA-dose/body weight	Restdiuresis	−0.298	0.030	Restdiuresis	−0.298	0.030
ERI1	Restdiuresis	−0.275	0.046	Restdiuresis	−0.275	0.046
ERI2	Restdiuresis	−0.277	0.045	Restdiuresis	−0.277	0.045
ERI3	Restdiuresis	−0.273	0.048	Restdiuresis	−0.273	0.048

Model 1: se-Ca²⁺, se-PO₄³⁻, PTH, restdiuresis, se-ferritin, and plasma ortho-tyrosine/phenylalanine.

Model 2: age, dialysis duration, hsCRP, restdiuresis, se-ferritin, and plasma ortho-tyrosine/phenylalanine.

ERI₁, ESA-dose/body weight/hemoglobin; ERI₂, ESA-dose/body weight/hematocrit; ERI₃, ESA-dose/body weight/red blood cell count.

Method: stepwise.

Table 4. Predictors of ESA-demand (plasma ortho-tyrosine/para-tyrosine ratio included)

	Model 1			Model 2
Dependent	Independent predictor	β	P	Independent predictor	β	P
ESA-dose	ortho-Tyr/para-Tyr	0.418	0.002	ortho-Tyr/para-Tyr	0.366	0.007
ESA-dose/body weight	ortho-Tyr/para-Tyr	0.394	0.004	ortho-Tyr/para-Tyr	0.394	0.004
ERI1	ortho-Tyr/para-Tyr	0.330	0.016	ortho-Tyr/para-Tyr	0.330	0.016
ERI2	ortho-Tyr/para-Tyr	0.343	0.012	ortho-Tyr/para-Tyr	0.343	0.012
ERI3	ortho-Tyr/para-Tyr	0.310	0.024	ortho-Tyr/para-Tyr	0.310	0.024

Model 1: se-Ca²⁺, se-PO₄³⁻, PTH, restdiuresis, se-ferritin, and plasma ortho-tyrosine/para-tyrosine.

Model 2: age, dialysis duration, hsCRP, restdiuresis, se-ferritin, and plasma ortho-tyrosine/para-tyrosine.

ERI₁, ESA-dose/body weight/hemoglobin; ERI₂, ESA-dose/body weight/hematocrit; ERI₃, ESA-dose/body weight/red blood cell count.

Method: stepwise.

ortho-Tyr, ortho-tyrosine; para-Tyr, para-tyrosine.

Figure 3. Time kinetics of plasma ortho-tyrosine level when DA is not administered (ESA−) and when administered (ESA+). *, end of HD, at ESA+ the time of DA administration. Pairwise comparisons of ESA− and ESA+ at each time point were not significant. Data represent mean ± SD. ortho-Tyr, ortho-tyrosine.

Figure 4. Possible mechanism of development of ESA-hyporesponsiveness in ESRF patients via inhibition of intracellular signaling pathways. * According to the findings of Ruggiero et al.²²