Effects of parathyroidectomy on plasma PTH fragments and heart rate variability in stage 5 chronic kidney disease patients

Figures & data

Table 1. Demographics, clinical characteristics and laboratory results in controls and stage 5 CKD patients.

Variables	Controls (n = 164)	Stage 5 CKD Patients (n = 354)	p Value^a	Stage 5 CKD Patients
				iPTH ≤ 50 (n = 30)	50 < iPTH ≤ 150 (n = 53)	150 < iPTH ≤ 300 (n = 41)	300 < iPTH ≤ 800 (n = 37)	800 < iPTH ≤ 1500 (n = 80)	iPTH > 1500 (n = 113)	p value^b (ANOVA)
Demographics
Age (years)	42.99 ± 14.46	49.57 ± 11.76	<.001	53.27 ± 12.29	50.55 ± 13.14	52.63 ± 12.35	51.14 ± 10.37	48.96 ± 10.87	46.95 ± 11.34	.026
Male/Female	60/104	192/162	<.001	19/11	27/26	27/14	18/19	39/41	62/51	.426
BMI (kg/m^2)	22.76 ± 3.05	22.34 ± 3.32	.172	22.59 ± 4.17	21.92 ± 3.36	22.14 ± 3.34	23.28 ± 3.13	23.08 ± 3.05	21.75 ± 3.16	.057
SBP (mmHg)	119.28 ± 14.65	142.37 ± 23.66	<.001	153.77 ± 18.54	149.83 ± 22.78	151.32 ± 31.91	141.89 ± 25.87	135.77 ± 20.54	137.37 ± 20.25	<.001
DBP (mmHg)	75.43 ± 10.27	85.34 ± 13.59	<.001	85.97 ± 16.99	84.74 ± 12.48	87.32 ± 13.21	85.32 ± 15.83	82.70 ± 11.78	86.60 ± 13.61	.417
Dialysis mode, n (%)
Predialysis	0 (0.00)	30 (8.47)	/	5 (16.67)	8 (15.09)	10 (24.39)	5 (13.51)	2 (2.50)	0 (0.00)	/
Hemodialysis	0 (0.00)	281 (79.38)	/	22 (73.33)	37 (69.81)	23 (56.10)	27 (72.97)	66 (82.50)	106 (93.81)	<.001
Peritoneal dialysis	0 (0.00)	44 (12.43)	/	3 (10.00)	8 (15.09)	8 (19.51)	5 (13.51)	12 (15.00)	8 (7.08)	.317
Dialysis vintage (months)	0.00 (0.00–0.00)	66.50 (25.75–108.00)	/	18.00 (4.75–41.25)	16.00 (4.50–36.50)	24.00 (0.50–72.00)	60.00 (13.00–106.00)	84.00 (60.00–120.00)	96.00 (72.00–120.00)	<.001
Comorbidities, n (%)
Diabetic mellitus	0 (0.00)	35 (9.89)	/	8 (26.67)	6 (11.32)	4 (9.76)	8 (21.62)	7 (8.75)	2 (1.77)	<0.001
Hypertension	15 (0.09)	285 (80.51)	<.001	27 (90.00)	47 (88.68)	33 (80.49)	31 (83.78)	56 (70.00)	91 (80.53)	0.079
Cause of ESKD, n (%)
CGN	0 (0.00)	268 (75.71)	/	19 (63.33)	37 (69.81)	26 (63.41)	25 (67.57)	70 (87.50)	91 (80.53)	.008
DN	0 (0.00)	22 (6.21)	/	6 (20.00)	6 (11.32)	5 (12.20)	3 (8.11)	1 (1.25)	1 (0.89)	<.001
HN	0 (0.00)	39 (11.02)	/	14 (46.67)	10 (18.87)	11 (26.83)	3 (8.11)	1 (1.25)	0 (0.00)	/
PKD	0 (0.00)	12 (3.39)	/	1 (3.33)	2 (3.77)	2 (4.88)	4 (10.81)	1 (1.25)	2 (1.77)	.129
Other	0 (0.00)	51 (14.41)	/	4 (13.33)	8 (15.09)	6 (14.63)	8 (21.62)	7 (8.75)	18 (15.93)	.564
Medication history, n (%)
CCB	0 (0.00)	192 (54.24)	/	22 (73.33)	36 (67.92)	30 (73.17)	15 (40.54)	33 (41.25)	56 (49.56)	<.001
ACEI/ARB	0 (0.00)	80 (22.60)	/	8 (26.67)	12 (22.64)	8 (19.51)	10 (27.03)	17 (21.25)	25 (22.12)	.961
β-receptor blocker	0 (0.00)	136 (38.42)	/	12 (40.00)	20 (37.74)	15 (36.59)	13 (35.14)	29 (36.25)	47 (41.59)	.970
Phosphate binder	0 (0.00)	194 (54.80)	/	22 (73.33)	30 (56.60)	19 (46.34)	22 (59.46)	41 (51.25)	60 (53.10)	.280
Active Vitamin D sterols	0 (0.00)	200 (56.50)	/	17 (56.67)	28 (52.83)	21 (51.22)	25 (67.57)	46 (57.50)	63 (55.75)	.753
Cinacalcet	0 (0.00)	49 (13.84)	/	0 (0.00)	1 (1.89)	4 (9.76)	7 (18.92)	19 (23.75)	18 (15.93)	/
Laboratory values
Hemoglobin (g/L)	139.57 ± 15.39	100.34 ± 20.74	<.001	105.60 ± 16.35	99.06 ± 20.83	89.32 ± 18.00	99.41 ± 24.83	102.41 ± 18.99	102.38 ± 21.38	.007
Hematocrit (%)	41.75 ± 4.21	31.05 ± 6.40	<.001	32.37 ± 4.88	30.25 ± 6.36	27.39 ± 5.46	30.56 ± 7.53	31.72 ± 5.94	32.08 ± 6.56	.001
Glucose (mmol/L)	5.22 ± 0.75	5.04 ± 1.86	.109	6.34 ± 2.86	6.01 ± 2.28	5.58 ± 2.60	4.70 ± 0.97	4.77 ± 1.29	4.33 ± 0.93	<.001
Albumin (g/L)	47.88 ± 4.92	38.08 ± 4.93	<.001	37.99 ± 7.17	38.81 ± 5.59	36.75 ± 5.65	37.81 ± 4.30	38.59 ± 4.54	37.98 ± 3.96	.401
Creatinine (μmol/L)	68.09 ± 16.13	919.64 ± 305.19	<.001	832.66 ± 346.73	878.40 ± 329.08	997.33 ± 380.43	944.98 ± 380.71	952.10 ± 281.35	902.62 ± 227.48	.181
Urea (mmol/L)	5.17 ± 1.56	24.10 ± 8.19	<.001	24.49 ± 7.82	23.90 ± 8.37	27.20 ± 8.60	26.34 ± 10.44	22.97 ± 7.23	23.02 ± 7.58	.030
TC (mmol/L)	4.82 ± 0.90	4.27 ± 1.16	<.001	4.62 ± 1.55	4.21 ± 1.10	4.13 ± 1.18	4.59 ± 1.06	4.23 ± 1.12	4.20 ± 1.10	.233
TG (mmol/L)	1.33 ± 1.20	1.88 ± 1.51	<.001	1.60 ± 0.84	1.80 ± 1.30	1.73 ± 1.19	2.21 ± 1.71	2.21 ± 1.91	1.71 ± 1.43	.122
Ca (mmol/L)	2.34 ± 0.11	2.38 ± 0.28	.013	2.21 ± 0.39	2.25 ± 0.15	2.18 ± 0.25	2.31 ± 0.31	2.51 ± 0.21	2.49 ± 0.24	<.001
Adjusted Ca (mmol/L)	2.16 ± 0.14	2.42 ± 0.27	<.001	2.26 ± 0.42	2.28 ± 0.13	2.26 ± 0.22	2.36 ± 0.28	2.54 ± 0.20	2.53 ± 0.22	<.001
Phosphorus (mmol/L)	1.18 ± 0.15	2.08 ± 0.57	<.001	1.63 ± 0.77	1.86 ± 0.55	1.96 ± 0.63	2.15 ± 0.62	2.21 ± 0.39	2.23 ± 0.50	<.001
ALP (U/L)	69.65 (56.03, 82.98)	126.80 (77.38, 371.75)	<.001	68.95 (60.00, 92.40)	70.00 (52.90, 88.80)	75.60 (62.05, 103.70)	108.30 (71.50, 160.85)	161.05 (114.55, 300.53)	462.00 (303.00, 791.00)	<.001
Ln (ALP)	4.24 ± 0.29	5.15 ± 0.99	<.001	4.30 ± 0.33	4.24 ± 0.34	4.38 ± 0.36	4.76 ± 0.68	5.30 ± 0.76	6.11 ± 0.78	<.001
iPTH (pg/mL)	31.72 (22.97, 41.13)	930.40 (160.65, 1792.50)	<.001	24.96 (17.65, 38.74)	93.36 (67.20, 114.70)	207.60 (164.25, 250.95)	608.70 (393.75, 728.55)	1131.50 (945.58, 1285.75)	2344.00 (1875.50, 3241.00)	<.001
Ln (iPTH)	3.40 ± 0.47	6.29 ± 1.56	<.001	3.15 ± 0.64	4.49 ± 0.32	5.33 ± 0.22	6.28 ± 0.33	7.02 ± 0.17	7.82 ± 0.37	<.001
(1-84) PTH (pg/mL)	23.05 (16.81, 33.61)	448.60 (99.62, 850.45)	<.001	21.26 (12.38, 35.90)	64.81 (49.68, 82.35)	124.90 (99.93, 150.05)	302.00 (235.75, 369.30)	549.40 (456.35, 645.57)	1156.00 (865.85, 1523.00)	<.001
Ln [ (1-84) PTH]	3.13 ± 0.48	5.70 ± 1.42	<.001	2.86 ± 1.03	4.15 ± 0.35	4.83 ± 0.35	5.66 ± 0.32	6.30 ± 0.22	7.08 ± 0.43	<.001
(7-84) PTH (pg/mL)	6.29 (3.79, 9.98)	468.20 (54.22, 922.55)	<.001	5.62 (–0.01, 9.99)	24.70 (17.22, 34.34)	72.70 (58.35, 92.75)	261.40 (167.45, 338.30)	589.65 (481.20, 667.10)	1201.00 (959.00, 1738.50)	<.001
Ln [ (7-84)PTH]	1.87 ± 0.88	5.47 ± 1.80	<.001	1.74 ± 0.89	3.14 ± 0.58	4.28 ± 0.45	5.45 ± 0.47	6.33 ± 0.23	7.14 ± 0.43	<.001
(1-84) PTH/iPTH	0.79 ± 0.17	0.58 ± 0.18	<.001	0.85 ± 0.33	0.72 ± 0.10	0.63 ± 0.14	0.55 ± 0.10	0.49 ± 0.07	0.49 ± 0.09	<.001

Data are presented as means ± SD or median (interquartile range) for continuous variables and as n (%) for categorical variables. CKD: chronic kidney disease; PTH: parathyroid hormone; BMI: body mass index; SBP: systolic blood pressure; DBP: diastolic blood pressure; CGN, chronic glomerulonephritis; DN, diabetic nephropathy; HN, hypertensive nephropathy; PKD: polycystic kidney disease; CCB, calcium channel blocker; ACEI/ARB, angiotensin converting enzyme inhibitors/angiotensin receptor blocker; ALP, alkaline phosphatase; Ca, calcium; TC: total cholesterol; TG: triglyceride.

^aControls vs. CKD5 patients. ^bAnalysis of variance of 6 groups in CKD5 patients.

Figure 1. Baseline HRV indices in CKD5 patients and healthy controls. CKD5 patients were divided into 6 groups according to plasma iPTH levels: 1: iPTH ≤ 50pg/mL (n = 30); 2: 50 < iPTH ≤ 150pg/mL (n = 53); 3: 150 < iPTH ≤ 300pg/mL (n = 41); 4: 300 < iPTH ≤ 800pg/mL (n = 37); 5: 800 < iPTH ≤ 1500pg/mL (n = 80); 6: iPTH >1500pg/mL (n = 113). MHR: mean 24-h heart rate; Mean NN: mean normal-to-normal R-R intervals; SDNN: standard deviation of the normal-to-normal R-R intervals; SDANN: standard deviation of 5-min average of normal R-R intervals; rMSSD: root-mean square of differences between adjacent normal R-R interval; pNN50: percentage of adjacent NN intervals differing by more than 50 milliseconds; VLF: very-low frequency; LF: low-frequency; HF: high-frequency.

Table 2. Influencing factors of HRV in CKD5 patients analyzed by multiple stepwise regression.

Dependent Variable	Independent Variable	Unstandardized Coefficient	Standardized Coefficient	95% CI	p Value	Adjusted R^2
MHR (bpm)	BMI	0.41	0.13	(0.09, 0.74)	.013	0.13
	Creatinine	0.00	0.11	(0.00, 0.01)	.032
	Ln (ALP)	2.21	0.21	(1.08, 3.34)	<.001
	Adjusted Ca	7.99	0.21	(3.82, 12.16)	<.001
Mean NN (ms)	Ln (iPTH)	–12.20	–0.16	(–21.20, −3.20)	.008	0.05
	Adjusted Ca	–51.04	–0.12	(–100.36, −1.72)	.043
SDNN (ms)	Hb	0.25	0.17	(0.09, 0.41)	.003	0.14
	Glu	–2.50	–0.15	(–4.40, −0.60)	.010
	Alb	0.99	0.15	(0.27, 1.70)	.007
	Ln [(1-84) PTH]	–6.98	–0.31	(–9.44, −4.52)	<.001
SDANN (ms)	Hb	0.22	0.16	(0.07, 0.37)	.005	0.16
	Glu	–2.44	–0.15	(–4.20, −0.68)	.007
	Alb	1.07	0.18	(0.42, 1.72)	.001
	Ln [(1-84) PTH]	–7.01	–0.34	(–9.28, −4.73)	<.001
rMSSD (ms)	TG	–0.94	–0.13	(–1.69, −0.18)	.015	0.03
	Adjusted Ca	–5.64	–0.15	(–9.74, −1.54)	.007
pNN50 (%)	Age	0.07	0.14	(0.01, 0.12)	.015	0.03
	Adjusted Ca	–2.47	–0.11	(–4.82, −0.11)	.040
Ln (VLF)	Age	–0.53	–0.17	(–0.87, −0.19)	.002	0.20
	Dialysis vintage	0.00	–0.14	(–0.01, 0.00)	.024
	Hb	–0.02	–0.22	(–0.02, −0.01)	<.001
	Glu	–0.11	–0.13	(–0.21, −0.02)	.017
	Creatinine	0.00	–0.11	(0.00, 0.00)	.050
	Ln (iPTH)	–0.32	–0.31	(–0.45, −0.20)	<.001
Ln (LF)	Sex	–0.43	–0.16	(–0.72, −0.14)	.003	0.08
	Age	–0.01	–0.11	(–0.03, −0.00)	.041
	Ln (iPTH)	–0.21	–0.24	(–0.30, −0.11)	<.001
Ln (HF)	Sex	–0.36	–0.12	(–0.68, −0.03)	.031	0.04
	Dialysis vintage	0.00	0.14	(0.00, 0.01)	.027
	Ln (iPTH)	–0.20	–0.20	(–0.32, −0.07)	.002
Ln (LF/HF)	Dialysis vintage	–0.00	–0.21	(–0.01, −0.00)	<.001	0.04

Multiple stepwise regression models with adjustment for age, sex, BMI, SBP, dialysis vintage and Hb, Glu, Alb, Ln (ALP), TC, TG, Creatinine, adjusted Ca, P, Ln (iPTH), Ln [(1-84) PTH], Ln [(7-84) PTH] and (1-84) PTH/iPTH. CKD: chronic kidney disease; PTH: parathyroid hormone; BMI: body mass index; SBP: systolic blood pressure; Hb: hemoglobin; Glu: glucose; ALP, alkaline phosphatase; TC: total cholesterol; TG: triglyceride; Ca, calcium; P: phosphorus; MHR: mean 24-h heart rate; Mean NN: mean normal-to-normal R-R intervals; SDNN: standard deviation of the normal-to-normal R-R intervals; SDANN: standard deviation of 5-min average of normal R-R intervals; rMSSD: root-mean square of differences between adjacent normal R-R interval; pNN50: percentage of adjacent NN intervals differing by more than 50 milliseconds; VLF: very-low frequency; LF: low-frequency; HF: high-frequency; CI: confidence interval.

Figure 2. Comparisons of laboratory indices in PTX patients. PTX: parathyroidectomy; Hb: hemoglobin; Alb: albumin; Ca: calcium; P: phosphorus; ALP: alkaline phosphatase; iPTH: intact parathyroid hormone.

Table 3. Pre- and post-PTX HRV indices in CKD5 patients.

Variable	Pre-PTX	Post-PTX	p Value
MHR (bpm)	88.97 ± 9.70	78.60 ± 9.63	<.001
Time domain
Mean NN (ms)	684.33 ± 74.87	774.50 ± 100.70	<.001
SDNN (ms)	66.40 ± 18.64	100.27 ± 22.84	<.001
SDANN (ms)	56.20 ± 16.41	86.80 ± 26.15	<.001
rMSSD (ms)	17.63 ± 6.68	23.23 ± 10.19	.010
pNN50 (%)	2.37 ± 2.78	5.54 ± 6.25	.015
Frequency domain
Ln (VLF)	5.40 ± 0.93	5.90 ± 0.85	.004
Ln (LF)	3.98 ± 1.35	4.70 ± 1.2242	.014
Ln (HF)	2.80 ± 1.64	3.75 ± 1.4944	.020
Ln (LF/HF)	0.96 ± 0.79	0.62 ± 0.69	.089

Data are presented as means ± SD or median (interquartile range) for continuous variables. HRV: heart rate variability; PTX: parathyroidectomy; CKD: chronic kidney disease; MHR: mean 24-h heart rate; Mean NN: mean normal-to-normal R-R intervals; SDNN: standard deviation of the normal-to-normal R-R intervals; SDANN: standard deviation of 5-min average of normal R-R intervals; rMSSD: root-mean square of differences between adjacent normal R-R interval; pNN50: percentage of adjacent NN intervals differing by more than 50 milliseconds; VLF: very-low frequency; LF: low-frequency; HF: high-frequency.

Figure 3. Correlations between the changes of plasma PTH fragments levels and HRV indices in PTX patients before and after operation. Linear correlations between SDNN and Ln (iPTH) (A), Ln[(1-84) PTH] (B) and Ln [(7-84) PTH] (C) in post-PTX patients. Linear correlation between SDANN and Ln[(1-84) PTH] (D) in post-PTX patients (p = .042). PTX: parathyroidectomy; iPTH: intact parathyroid hormone. Δ: subtracting the values before PTX from the values of post-PTX; |Δ|: absolute value.