Performing Only One Cardiovascular Reflex Test Has a High Positive Predictive Value for Diagnosing Autonomic Neuropathy in Patients with Chronic Renal Failure on Hemodialysis

Abstract

Background. Autonomic neuropathy is an important cause of morbidity and mortality in patients with chronic renal failure (CRF) on hemodialysis. Generally, cardiovascular reflex tests are used to determine autonomic neuropathy. Our purpose in this study was to determine the frequency of autonomic neuropathy in patients with CRF on hemodialysis by using cardiovascular reflex tests and compare the sensitivity of each test. Methods. The authors performed five tests: heart rate response to the Valsalva maneuver, heart rate variation during deep breathing, heart rate response to standing up, blood pressure response to standing up, and blood pressure response to hand grip exercise in order to determine autonomic neuropathy. Each test subject was evaluated as normal, borderline, and abnormal and scored as 0, 1, and 2, respectively. Subjects with a total score ≥ 5 were considered to have autonomic neuropathy. Forty subjects with CRF on hemodialysis were included in this study. None of the subjects had diabetes mellitus or any other etiology that could cause autonomic neuropathy. Results. Thirty-five of 40 subjects (87.5%) had abnormal autonomic tests. In 35 subjects, the relationship between autonomic neuropathy and biochemical parameters, effects of treatment with vitamin D and erythropoietin, and urea reduction rate were studied. No relationship was found between autonomic neuropathy and age, time on hemodialysis, urea reduction rate, albumin, ferritin, calcium, inorganic phosphorus, intact parathyroid hormone, hemoglobin levels, and treatment with vitamin D and erythropoietin. The abnormal test results were as follows: 20 subjects (50%) in the heart rate response to the Valsalva Maneuver, 31 (77.5%) in the heart rate variation during deep breathing, 28 (70%) in the heart rate response to standing up, 6 (15%) in the blood pressure response to standing up, and 31 subjects (77.5%) in the blood pressure response to hand grip exercise tests. Among these five tests, the two most abnormal tests were the heart rate variation during deep breathing and the blood pressure response to hand grip exercise. Conclusion. Patients with CRF on hemodialysis frequently have autonomic neuropathy. For the diagnosis and follow-up of patients, five cardiovascular autonomic reflex tests are generally used. In this study, it was determined that performing only one test instead of all five tests has a high sensitivity and is more practicable in terms of determining autonomic neuropathy.

Keywords:

• autonomic neuropathy
• chronic renal failure
• cardiovascular reflex test

INTRODUCTION

Autonomic nervous system abnormalities are major causes of morbidity and mortality in patients with chronic renal failure (CRF) on hemodialysis and are generally considered a part of polyneuropathy. Postural hypotension, impotents, gastrointestinal disturbance, gastrointestinal motility, and sweating abnormalities are common symptoms. The most frequent complication in patients with CRF on hemodialysis is intradialytic hypotension, and it has been suggested that intradialytic hypotension is mostly related to autonomic neuropathy.[1–6] The pathogenesis of autonomic neuropathy is unclear, but a reduced response to norepinephrines by the end organ and the toxic effect of metabolic toxins are considered to be some of the causes. Five cardiovascular reflex tests are generally used to determine autonomic neuropathy: the heart rate response to the Valsalva Maneuver, the heart rate variation during deep breathing, the heart rate response to standing up, the blood pressure response to standing up, and the blood pressure response to hand grip exercise.[7],[8] The purpose of this study was to determine the frequency of autonomic neuropathy in patients with CRF on hemodialysis by using cardiovascular reflex tests and compare the sensitivity of each test.

PATIENTS AND METHODS

Patients

The study was performed in 40 patients with CRF on hemodialysis with a female/male ratio of 16/24. Patients with end-stage renal failure undergoing regular hemodialysis treatment three times a week for 3–4 hours was enrolled. Seven of 40 patients had hypertension; in the remaining 33 patients, blood pressure was well controlled without antihypertensive drugs.

Because the study population was small, it would be beneficial to study the type of antihypertensive drug, effect of blood pressure, gender, and smoking on autonomic neuropathy. None of the patients had either a history or a laboratory finding suggesting diabetes mellitus or any other etiologic cause of autonomic neuropathy. Patients with a history or laboratory finding suggesting uncontrolled hypertension, myocardial infarction, congestive heart failure, adrenocortical failure, amyloidosis, porphyries, neurological abnormalities, reflex sympathic dystrophy, chronic alcohol abuse, and other central effective drugs were excluded. All patients were dialyzed with Braun Dialog volumetric control machines using a hallow fiber polysulfone dialyzer. The blood flow rate ranged from 300 to 450 mL/min, the dialysate flow rate was 500 mL/min, and the dialysate temperature was 37°C. The ultra filtration rate was adjusted to reach the dry weight in the preset dialysis time. The dialysate composition was 140 mmol/L sodium, 2 mmol/L potassium, 35 mmol/ bicarbonate, 105 mmol/L chloride, 1.5 mmol/L calcium, 0.25 mmol/L magnesium, and 11 mmol/L glucose. The five cardiovascular reflex tests were performed for each patient after 30 minutes of rest before hemodialysis. Informed consent was obtained from all patients.

Parasympathetic Tests

1. Heart Rate Response to the Valsalva Maneuver. The subject was asked to sit quietly, blow into a mouthpiece attached to a pressure gauge to a pressure of 40 mm Hg, and maintain that pressure for 15 seconds. During and after the maneuver, an electrocardiogram (ECG) was continuously recorded. The ratio of the longest R-R interval to the shortest R-R interval during or immediately after the strain period was calculated and expressed as the Valsalva ratio (VR). The value ≥ 1, and 21 was considered normal.[7], [8]

2. Heart Rate Variation during Deep Breathing. The subject sat quietly and breathed deeply and evenly at a rate of six breaths/minute. Heart rate was continuously recorded, and the difference between the maximum and minimum heart rate was divided into the average heart rate and multiplied by 100. Differences ≥ 15 were considered normal.[7],[8]

3. Heart Rate Response to Standing Up. While the subject was lying down, the ECG was recorded, and after the subject stood up, the ratio of the R-R interval of the 30th beat to the R-R interval of the 15th was calculated (30/15 ratio). The value ≥ 1, and 40 was considered normal.[7],[8]

Sympathetic Tests

1. Blood Pressure Response to Standing Up. After the subject lay for five minutes, blood pressure was measured, and measured again after standing up. Differences ≤ 10 mm Hg was considered normal.[7],[8]

2. Blood Pressure Response to Hand Grip Exercise (Heart Rate Response to Isometric Exercise). First, the maximum willing contraction capacity was evaluated. The exercise was maintained for five minutes with 30 percent of maximum value. Blood pressure was measured each minute, and the difference in diastolic blood pressure before and after the test was calculated. Values ≥16 mmHg were considered normal.[7],[8]

Tests results were evaluated as normal, borderline, and abnormal, as shown in Table 1 and were scored 0, 1, and 2, respectively. Subjects with a total score ≥ 5 were considered to have autonomic neuropathy.[7],[8]

Table 1 Evaluation of cardiovascular reflex tests

Tests	Normal	Borderline	Abnormal
VR	≥ 1.21	1.11–1.20	≤ 1.10
HRVDDB	≥ 15	11–14	≤ 10
HRRSU	≥ 1.04	1.01–1.03	≤ 1.00
BPRSU	≤ 10	11–29	≥ 30
BPRHE	≥ 16	11–15	≤ 10

VR: Valsalva ratio; HRVDDB: heart rate variation during deep breathing; HRRSU: heart rate response to standing up; BPRSU: blood pressure response to standing up; BPRHE: blood pressure response to hand grip exercise.

Statistical Analysis

Comparisons of hemoglobin and calcium levels of patients with or without autonomic neuropathy were performed by Student's t-test. Comparisons of age, time on hemodialysis, the mean urea reduction rate at the last three months, creatinine, albumin, ferritin, inorganic phosphorus, and intact parathyroid hormone levels of patients with or without autonomic neuropathy were analyzed by Mann-Whitney U test. Comparisons of treatment with vitamin D and erythropoietin of patients with or without autonomic neuropathy were evaluated by Fisher's Exact chi-square test. A p value <0.05 was considered as statistically significant. In patients with autonomic neuropathy, the most abnormal two tests were evaluated together, and the positive and negative predictive values were calculated as follows:

• Positive Predictive Value (PPV) = the number of patients with autonomic neuropathy who had abnormal test, divided by the number of patients with autonomic neuropathy who had abnormal test + number of patients without autonomic neuropathy who had abnormal test

• Negative Predictive Value (NPV) = the number of patients without autonomic neuropathy who didn't have abnormal test, divided by the number of patients without autonomic neuropathy who didn't have abnormal test + number of patients with autonomic neuropathy who didn't have abnormal test

RESULTS

Patients

Patients' characteristics and biochemical parameters are shown in Table 2.

Table 2 Patients' characteristics and biochemical parameters

	Autonomic neuropathy
Characteristic	+ (35/40)	– (5/40)	Minimum	Maximum	p value
Age, years	48.74 ± 10.55	42.20 ± 9.25	32	64	0.190
Ferritin, ng/mL	336.00 ± 256.50	386.03 ± 260.83	17	887	0.638
Hemoglobin, g/dL	10.00 ± 1.42	9.92 ± 0.64	5.9	13.8	0.578
Creatinine, mg/dL	8.32 ± 0.91	8.81 ± 1.73	4	11	0.269
Intact parathyroid hormone, pg/mL	269.34 ± 139.42	245.40 ± 159.51	40	461	0.713
Time on hemodialysis, month	44.94 ± 38.39	6.20 ± 49.51	4	188	0.538
Albumin, g/dL	4.46 ±0.54	4.16 ± 0.43	3.3	5.5	0.234
Calcium, mg/dL	9.55 ± 0.60	9.65 ± 0.64	8.6	10.6	0.645
Inorganic phosphorus, mg/dL	5.47 ± 0.79	5.58 ± 0.65	3.8	6.5	0.854
Urea reduction rate	0.654 ± 0.065	0.654 ± 0.061	0.56	0.85	0.399

Cardiovascular Reflex Tests

Forty patients were evaluated according to the cardiovascular tests results; 35 subjects had a ≥ 5 total score, and a diagnosis of autonomic neuropathy was made. The most abnormal test for the parasympathetic and sympathetic tests were heart rate variation during deep breathing (31/40) and blood pressure response to hand grip exercise (31/40), respectively. The cumulative results are shown in Tables 3 and 4.

Table 3. Parasympathetic and Sympathetic Tests Results

	Parasympathetic						Sympathetic
	VR		HRRSU		HRVDDB		BPRSU		BPRHE
	%	N	%	N	%	N	%	N	%	N
Normal	27.5	11	10	4	12.5	5	72.5	29	20	8
Borderline	22.5	9	20	8	10	4	12.5	5	2.5	1
Abnormal	50	20	70	28	77.5	31	15	6	77.5	31
Total	100	40	100	40	100	40	100	40	100	40

VR: Valsalva ratio; HRVDDB: heart rate variation during deep breathing; HRRSU: heart rate response to standing up; BPRSU: blood pressure response to standing up; BPRHE: blood pressure response to hand grip exercise.

Table 4. Parasympathetic and Sympathetic Tests Results

	Parasympathetic			Sympathetic
	VR	HRRSU	HRVDDB	BPRSU	BPRHE
Sensitivity	54	77	86	17	86
Specifity	80	80	80	100	80
PPV	95	97	97	100	97
NPV	20	33	44	14	44

VR: Valsalva ratio; HRVDDB: heart rate variation during deep breathing; HRRSU: heart rate response to standing up; BPRSU: blood pressure response to standing up; BPRHE: blood pressure response to hand grip exercise; PPV: positive predictive value; NPV: negative predictive value.

DISCUSSION

Autonomic neuropathy is a well-known complication of CRF and is generally considered to be part of polyneuropathy. The incidence of autonomic neuropathy is around 50%. The pathogenesis of autonomic neuropathy, however, isn't clearly known.[9],[10] The effect of hemodialysis on developing autonomic neuropathy is controversial: some authors suggested that autonomic neuropathy is ameliorated after beginning hemodialysis, while others suggested that it isn't.[5],[11],[12] In this study, the incidence of autonomic neuropathy was 87.5%, which was higher than the results in the literature. Vita et al. suggested that uremic autonomic function disorders weren't related to age and time on dialysis but were related to the severity and time of CRF.[13] Mallamaci et al. didn't establish a relationship between parathyroid hormone and autonomic nervous system tests.[5] Zoccali et al. studied the effects of long-time hemodialysis on autonomic neuropathy with heart rate variation during deep breathing and atropine tests. They showed parasympathetic dysfunction with both tests but didn't establish a relationship between time on hemodialysis and parasympathetic tests.[14] Campese et al. didn't find any relationship between the Valsalva maneuver and anemia in patients with autonomic neuropathy.[15] Ewing et al. studied the relationships between levels of urea, creatinine, time on dialysis, and both heart rate response to the Valsalva maneuver and blood pressure response to hand grip exercise, but they couldn't establish a relationship.[16] However, Pfeiffer et al. established a relationship between age and autonomic neuropathy.[17]

In the current study, the authors didn't establish a relationship between autonomic neuropathy and age, time on hemodialysis, urea reduction rate, albumin, ferritin, calcium, inorganic phosphorus, intact parathyroid hormone, hemoglobin levels, and treatment with vitamin D and erythropoietin. However, this study population was small for the analysis of the risk factor for autonomic neuropathy and should be evaluated in a large study population. In general, cardiovascular reflex tests are used to determine autonomic neuropathy. The tests for the parasympathetic nervous system are the heart rate response to the Valsalva maneuver, the heart rate variation during deep breathing, and the heart rate response to standing up; the sympathetic tests are the blood pressure response to standing up and the blood pressure response to hand grip exercise.[7],[8]

Many studies demonstrated that there is an abnormal parasympathetic response in patients with predialytic stage CRF and patients with CRF on hemodialysis.[5],[18–25] Heidbreder et al. evaluated the heart rate response to the Valsalva maneuver, the heart rate variation during deep breathing, and the heart rate response to standing up in 31 patients with CRF and 35 patients with CRF on hemodialysis. They didn't find any differences between the two groups but found an abnormal heart rate response in two groups when compared with the control group.[4] Campanese et al. evaluated the Valsalva response in 21 patients with CRF, 16 patients with CRF on hemodialysis, and the control group with 60 subjects. They didn't find any difference between two groups but found differences between two groups and the normal control group.[15]

Unlike parasympathetic autonomic neuropathy, there were different study results in terms of sympathetic autonomic neuropathy. Some studies demonstrated sympathetic autonomic neuropathy in patients with CRF; on the other hand, other studies suggested that sympathetic function is normal in patients with CRF.[11],[15],[16],[18],[20–30] The present authors compared the relation between five cardiovascular reflex tests and biochemical parameters, effect of treatment with vitamin D and erythropoietin, and urea reduction rate. They didn't find a relationship between the five cardiovascular reflex tests and age, time on hemodialysis, urea reduction rate, albumin, ferritin, calcium, inorganic phosphorus, intact parathyroid hormone, hemoglobin levels, and treatment with vitamin D and erythropoietin. Though the study population was small, it would be beneficial to study biochemical parameters, effect of treatment with vitamin D and erythropoietin, and urea reduction rate in a larger sample. According to the five cardiovascular reflex tests, 35 out of 40 subjects (87.5%) had abnormal autonomic tests. The abnormal test results were as follows: 20 subjects (50%) in the heart rate response to the Valsalva maneuver, 31 (77.5%) in the heart rate variation during deep breathing, 28 (70%) in the heart rate response to standing up, 6 (15%) in the blood pressure response to standing up, and 31 subjects (77.5 %) in the blood pressure response to the hand grip exercise test. The most abnormal parasympathetic and sympathetic tests are heart rate variation during deep breathing and the blood pressure response to hand grip exercise test, respectively, and the positive predictive value for each test is 97. In conclusion, patients with CRF on hemodialysis frequently had autonomic neuropathy. In general, for the diagnosis and follow-up of patients, five cardiovascular autonomic reflex tests are used; however, in this study, it was determined that performing only one test instead of five has a high sensitivity and positive predictive value and is more practicable in terms of determining autonomic neuropathy.