European Journal of Cardiovascular Medicine

Chronic Kidney Disease (CKD) is characterized by a steady and permanent decline in kidney function, typically over months to years. It is often associated with comorbid conditions such as hypertension (HTN) and diabetes mellitus (DM), which are the important causes of CKD. CKD involves the advanced damage of nephrons, the functional units of the kidney, leading to compensatory hypertrophy and hyperfiltration in the remaining nephrons. Over time, this hyperfiltration damages the glomeruli, leading to proteinuria and further decrease in kidney function. “The disease is classified into five stages based on the glomerular filtration rate (GFR), with stage 5 representing kidney failure or end-stage renal disease (ESRD). CKD is a long-term condition characterized by the gradual loss of kidney function over time, leading to the accumulation of waste products and fluid imbalances in the body. It is typically defined by a GFR of less than 60 mL/min/1.73 m² for three months or more, irrespective of the underlying cause.” CKD is allied with substantial morbidity and death, specifically due to its strong association with cardiovascular disease.  The worldwide incidence of CKD is predicted to be between 10-15% of the adult people, with greater rates detected in older adults and individuals with DM and HTN. Primary recognition and management are crucial in slowing the development of the disease and decreasing the risk of problems. ^[1] The incidence of CKD differs worldwide, with an estimated 10-15% of the adult populace exaggerated. CKD prevalence is notably higher in older adults and individuals with risk features such as HTN and DM.^[2-4] “Autonomic dysfunction is a common and important complication of CKD, because it contributes to the high incidence of cardiovascular morbidity and mortality.^[5] Autonomic dysfunction in CKD means increased sympathetic nervous system activity & depressed parasympathetic activity.^[5] Incidence of cardiovascular autonomic dysfunction increases as the renal functional reserve decreases.^[5] Cardiac Autonomic Neuropathy (CAN) consisting of resistant HTN, orthostatic & intradialytic hypotension, reduced heart rate (HR) variability, impaired spontaneous baroreflex sensitivity poses an increased risk of sudden cardiac death.^[5] Autonomic dysfunction affects various body systems including gastrointestinal, genitourinary, and other body systems leading to significant morbidity.^[6] Assessment of autonomic function has demonstrated abnormalities in 60% of patients with CKD, particularly relating to measure of parasympathetic function, such as HR response to deep breathing and Valsalva maneuver.^[6] Ewing’s Cardiovascular Reflex Tests (CRT) are used to assess autonomic dysfunction, which is common in patients with CKD. Autonomic dysfunction in CKD is associated with increased cardiovascular morbidity and mortality.”

Ewing’s CRT are crucial in assessing autonomic dysfunction, predominantly in subjects with CKD. The HR Response (to“Valsalva Maneuver” evaluates the change in HR during forced expiration against a closed airway; a blunted response indicates autonomic dysfunction, commonly observed in CKD due to impaired autonomic regulation of the heart.^[7] The HR Response to Deep Breathing assesses the difference in HR with respiration, which is typically decreased in CKD subjects with autonomic neuropathy, reflecting impaired parasympathetic function.^{[7, 8]} The Blood Pressure (BP) Response to Standing is utilized to detect postural hypotension, where a significant drop in BP upon standing is a indication of autonomic dysfunction often seen in CKD subjects.^{[9, 10]} CKD is classified into various types depending on the underlying cause, disease progression, and the extent of kidney damage. The classification is essential for diagnosis, management, and prognosis. ^{[7, 10]} CKD encompasses various types, each with distinct etiologies and pathophysiologies. Diabetic Kidney Disease (Diabetic Nephropathy) is the most prevalent reason of CKD, particularly in subjects with DM. It is marked by albuminuria, a declining GFR, and an elevated risk of cardiovascular events. ^[11] Hypertensive Nephropathy occurs as both a cause and a consequence of CKD, were prolonged HTN damages renal blood vessels, gradually impairing kidney function ^[12] Glomerulonephritis represents a set of diseases categorized by irritation of the glomeruli, the kidney’s filtering units. This condition can be primary, originating in the kidneys, or secondary, resulting from systemic diseases such as lupus.^[13] Polycystic Kidney Disease is a genetic disorder leading to the growth of numerous cysts in the kidneys, causing progressive enlargement and loss of function, making it one of the most common inherited kidney disorders.^[14]” Chronic Interstitial Nephritis involves long-term inflammation of the kidney's interstitial tissue, often resulting from prolonged medication use, infections, or systemic diseases like sarcoidosis.^[15] Obstructive Nephropathy arises from circumstances that block urine flow, such as kidney stones, tumours, or an enlarged prostate, with chronic obstruction leading to kidney damage and CKD.^[16] Chronic Pyelonephritis is caused by recurrent kidney infections, leading to chronic inflammation, scarring, and progressive renal damage.^[17] Lastly, Vascular Kidney Disease includes conditions such as renal artery stenosis or atherosclerosis that reduce blood flow to the kidneys, causing ischemic damage and contributing to the development of CKD.^[18] The aim of the study was to evaluate “CAN” using Ewing’s CRT in patients with CKD.

As per inclusion and exclusion criteria the patients were enrolled in the study after counselling and written informed consent taken in their own language. The diagnosis of CKD depends on eGFR values.  The stages of CKD were classified as follows: Stage 1: Kidney damage with normal or increased GFR (>90mL/min/1.73m²) Stage 2: Mild reduction in GFR (60-89mL/min/1.73m²) Stage 3a: Moderate reduction in GFR (45-59mL/min/1.73m²) Stage 3b: Moderate reduction in GFR (30-44mL/min/1.73m²) Stage 4: Severe reduction in GFR (15-29mL/min/1.73m²) Stage 5: Kidney failure (GFR < 15 mL/min/1.73m²)

Cardiovascular autonomic reflex tests were conducted to assess autonomic function, with ECG electrodes attached to the participants to monitor HR changes during specific tasks. These tests, commonly known as Ewing’s score, were valid and reliable for detecting CAN. The total scoring of Ewing’s score was based on the results from five tests, including: Valsalva manoeuvre, HR response to deep breathing, HR response to standing, BP response to standing up, BP response to a sustained handgrip

Valsalva manoeuvre: The “patient was asked to sit quietly and then to blow into the mouthpiece attached to the manometer, holding it at a pressure of 40mmHg for 15 seconds while a continuous ECG was recorded. The manoeuvre was repeated 3 times with a 1-minute interval, and the results were expressed as the Valsalva ratio, calculated as the longest R-R interval after the manoeuvre divided by the shortest R-R interval during the manoeuvre. The mean of the 3 Valsalva ratios was taken as the final value.

Heart rate response to standing: The test was performed with the patient lying down quietly on a couch while the HR was continuously recorded on an electrocardiograph. The patient was then asked to stand unaided, and the point of starting to stand was marked on the ECG paper. The shortest R-R interval around the 15th beat and the longest R-R interval around the 30th beat after starting to stand were marked and measured with a ruler. The HR response was expressed as the 30:15 ratio.

Deep breathing test (DBT):  The patient was asked to breathe deeply at 6 breaths per minute for 1 minute, with the ECG recorded throughout the period of deep breathing. The onset of each inspiration and expiration was marked on the ECG paper. The maximum and minimum R-R intervals during each breathing cycle were measured and converted to beats per minute. The result of the test was expressed as the difference between maximum and minimum HRs for the 6 measured cycles in beats per minute.”

Blood pressure response to standing: The “patient's BP was measured with a sphygmomanometer while the patient was lying quietly, and again 1 minute after standing up. The postural fall in BP was taken as the difference between the systolic pressure lying down and the systolic pressure standing up. The test was repeated 3 times, and the mean was calculated.

Blood pressure response to sustained handgrip:  The baseline BP was taken before the manoeuvre. A handgrip dynamometer was used to determine the maximum voluntary contraction (MVC). The patient was asked to maintain the handgrip for 4 minutes, with BP recorded at the 1st, 2nd, and 4th minutes of contraction. The rise in DBP above the baseline was noted.

Autonomic dysfunction was classified according to the Ewing & Clarke criteria as follows: Normal: All tests were normal, Early Parasympathetic: One of the three tests of parasympathetic function was abnormal. Definite Parasympathetic: Two or more of the three tests of parasympathetic function were abnormal. Combined Damage: One or both tests of sympathetic function were abnormal in addition to parasympathetic damage. Borderline tests were interpreted as normal.”

Age The mean age of the study subjects was 58.33±12.61 years. The highest proportion of individuals (31.25%) was observed in the 51–60years age group, followed by 23.96% in the 61–70years category. The 41–50years group comprised 16.67% of the study population, while 15.63% of participants were aged between 71–80 years. Younger individuals aged 30–40 years represented 8.33% of the total sample, and only 4.17% of the patients belonged to the 81–90years age bracket.

Sex Out of the total 96 CKD patients included in the study, 54 (56.25%) were male and 42 (43.75%) were female. This indicates a slight male predominance in the study population.

Duration of diabetes Among the 96 patients with CKD included in the study, 67 individuals (69.79%) had a history of diabetes for 5-10 years, whereas 29 participants (30.21%) had a duration of diabetes of more than 10 years.

Stages of CKD Among the 96 patients evaluated, the majority (54.17%) were in Stage 4 CKD, followed by 23.96% in Stage 5. Stage 3B accounted for 15.63% of the sample, while only 6.25% of participants were in Stage 3A (Graph no.1)

Graph no. 1 Distribution of CKD stages

Valsalva maneuver

A total of 60 participants (62.5%) demonstrated a normal Valsalva response, whereas 36 participants (37.5%) exhibited an abnormal response (Table no 1).

Table 1: Distribution of Valsalva maneuver

Standing HR Response of the total participants, 65 individuals (67.71%) exhibited a normal heart rate response upon standing, while 31 participants (32.29%) showed an abnormal response (Table 2).

Table 2: Distribution of standing HR response

Deep Breathing HR Response

A normal deep breathing HR response was observed in 56 participants (58.33%), whereas 40 participants (41.67%) exhibited an abnormal response (Table 3).

Table 3: Distribution of deep breathing HR response

BP Response to Standing

Among the 96 patients with CKD, 72 individuals (75.00%) exhibited a normal BP response upon standing, while 24 individuals (25.00%) demonstrated an abnormal response (Table 4).

Table 4: Distribution of BP response to standing

Sustained Handgrip BP Response

Out of the 96 participants, 73 individuals (76.04%) exhibited an abnormal response, whereas only 23 participants (23.96%) demonstrated a normal response (Table 5).

Table 5: Distribution of sustained handgrip BP response

CAN grades

The majority of participants (47.92%) were found to have early parasympathetic involvement, indicating that one of the three parasympathetic function tests was abnormal. This was followed by combined autonomic damage, seen in 19 patients (19.79%), characterized by abnormal sympathetic function tests in addition to parasympathetic dysfunction. Definite parasympathetic neuropathy, where two or more parasympathetic tests were abnormal, was identified in 8 participants (8.33%). A total of 23 patients (23.96%) exhibited normal autonomic function (Graph no. 2).

Graph no 2. Distribution of CAN grades

Correlation between eGFR and CAN parameters

The analysis revealed no statistically significant correlations between eGFR and any of the autonomic function tests. Specifically, the correlation between eGFR and the Valsalva maneuver was weakly positive (r = 0.035, p = 0.7325), while that with standing heart rate response (r = 0.022, p = 0.8256) and blood pressure response to standing (r = 0.013, p = 0.8966) were also negligible and not significant. A weak negative correlation was observed between eGFR and the deep breathing heart rate response (r = –0.109, p = 0.2873), and similarly with the sustained handgrip blood pressure response (r = –0.050, p = 0.6244); however, these associations did not reach statistical significance (Table 6).

Table 6: Correlation between eGFR and CAN parameters.

Association between Valsalva maneuver and duration of diabetes of the 67 patients with diabetes duration less than 10 years, 46 (68.66%) exhibited a normal Valsalva response, while 21 (31.34%) had an abnormal response. In contrast, among the 29 patients with diabetes for 10 years or more, only 14 (48.28%) had a normal response, whereas 15 (51.72%) showed abnormal Valsalva results. The observed association approached but did not reach statistical significance (p = 0.0596). These findings suggest a trend toward a higher prevalence of abnormal Valsalva responses in patients with longer duration of diabetes, indicative of increasing parasympathetic dysfunction over time. Although the p-value is slightly above the conventional threshold for statistical significance (p < 0.05), the pattern observed may reflect a clinically meaningful relationship between prolonged hyperglycemia and the development of CAN (Graph no 3).

Graph no 3. Association between standing HR response and duration of diabetes

Among those with a diabetes duration of less than 10 years (n = 67), a normal standing HR response was observed in 50 patients (74.63%), while 17 patients (25.37%) had an abnormal response. In contrast, among those with diabetes for 10 years or more (n = 29), only 15 patients (51.72%) had a normal response, whereas 14 patients (48.28%) exhibited an abnormal response. This difference was statistically significant (p = 0.0283) (Graph no 4).

Graph no 4. Association between standing HR response and duration of diabetes

Association between deep breathing HR response and duration of diabetes

In patients with DM duration less than 10 years (n = 67), 44 individuals (65.67%) demonstrated a normal response, whereas 23 (34.33%) had an abnormal response. Conversely, among those with DM for 10 years or more (n = 29), only 12 (41.38%) exhibited a normal response, while 17 (58.62%) showed abnormal results. This association was statistically significant (p = 0.0275) (Graph no 5).

Graph no 5. Association between deep breathing HR response and duration of diabetes

Association between BP response to standing and duration of diabetes

Among the 67 patients with diabetes duration less than 10 years, 53 (79.10%) demonstrated a normal BP response, while 14 (20.89%) had an abnormal response. In contrast, among patients with diabetes for 10 years or more (n = 29), 19 (65.52%) had a normal response and 10 (34.48%) exhibited abnormal results. Although there is a visible trend suggesting a greater proportion of abnormal BP responses with longer diabetes duration, the association was not statistically significant (p = 0.1605) (Graph no 6).

Graph no 6. Association between BP response to standing and duration of diabetes

Association between sustained handgrip BP response and duration of diabetes

In patients with DM duration less than 10 years (n = 67), 18 individuals (26.87%) showed a normal response, while 49 (73.13%) had an abnormal response. Among those with diabetes for 10 years or more (n = 29), only 5 (17.24%) exhibited a normal response and 24 (82.76%) had abnormal findings. The observed association between diabetes duration and abnormal handgrip response was not statistically significant (p = 0.3126) (Graph no 7).

Graph 7. Association between sustained handgrip BP response and duration of diabetes

Association between CAN grades and duration of diabetes.

Among patients with diabetes for less than 10 years (n = 67), 22 individuals (32.84%) exhibited normal autonomic function, 31 (46.27%) showed early parasympathetic dysfunction, 7 (10.45%) had definite parasympathetic involvement, and 7 (10.45%) presented with combined sympathetic and parasympathetic damage. In contrast, among patients with a diabetes duration of 10 years or more (n = 29), only 1 patient (3.45%) had normal autonomic function, while 15 (51.72%) exhibited early parasympathetic involvement, 1 (3.45%) had definite parasympathetic dysfunction, and a striking 12 patients (41.38%) demonstrated combined autonomic damage. The association between CAN grade and diabetes duration was found to be highly statistically significant (p = 0.0003) (Table 7).

Table 7: Association between CAN grades and duration of diabetes

CAN is a serious and often overlooked complication in patients with CKD, particularly those with coexisting DM. The present study, conducted on 96 CKD patients, aimed to assess the prevalence and severity of CAN using Ewing’s cardiovascular reflex tests and to explore its correlation with eGFR and duration of diabetes.

In the present study, the mean age of the participants was 58.33 ± 12.61 years, with the highest proportion (31.25%) belonging to the 51–60years age group. These findings are comparable to those reported by Doulgerakis D et al., who observed a mean age of 59.5 ± 14.6 years in their study on autonomic dysfunction in CKD patients^{. [19]} This similarity in age distribution suggests that autonomic disturbances are more commonly observed among middle-aged and elderly individuals, likely due to the cumulative burden of chronic comorbidities such as diabetes and hypertension over time. A slight male predominance was observed in our study, consistent with the study by Mirg S et al. (56.25% Vs 73.3%), ^[20] which reported higher prevalence of CKD in males. This could be attributed to gender-related differences in health-seeking behavior, risk factor exposure (such as smoking and hypertension), and possibly biological susceptibility.

Most patients in the study were in Stage 4 CKD (54.17%), followed by Stage 5 (23.96%). This high proportion of advanced CKD may have contributed to the high prevalence of autonomic dysfunction observed in our population. Although our study did not find a statistically significant correlation between eGFR and individual autonomic test parameters, a similar trend was observed in studies such as Thapa L et al. ^[21] who reported progressive deterioration in autonomic function with declining eGFR, particularly in patients with coexisting diabetes mellitus.

Regarding the assessment of CAN, abnormal responses were seen in 37.5% for the Valsalva maneuver, 32.29% for the standing heart rate response, and 41.67% for deep breathing heart rate variability. These findings point towards parasympathetic dysfunction, which typically precedes sympathetic involvement in the course of diabetic autonomic neuropathy. These results are in line with the early work of Ewing et al., ^[22] and Dimitropoulos G et al., ^[23] who emphasized the utility of these cardiovascular reflex tests in identifying early parasympathetic damage. Additionally, sustained handgrip, a test for sympathetic function, was abnormal in 76.04% of participants in our study. Similar findings were reported by Kiran Kumar T et al., ^[24] who found sympathetic involvement in a large proportion of CKD patients, suggesting that uremia and associated metabolic derangements may impair sympathetic nervous system activity.

Grading of CAN in our study revealed that nearly half the participants (47.92%) had early parasympathetic involvement, while 19.79% had combined autonomic dysfunction. Only 23.96% exhibited normal autonomic function. This distribution is consistent with studies by Vinik et al., ^[25] who emphasized the stepwise progression of autonomic neuropathy, with early parasympathetic involvement followed by combined sympathetic and parasympathetic damage over time, particularly in patients with poorly controlled or long-standing diabetes.

The duration of diabetes showed a significant association with multiple autonomic function parameters. Among patients with diabetes duration ≥10 years, abnormal responses were significantly more common in the standing HR response (48.28%, p = 0.0283) and deep breathing HR response (58.62%, p = 0.0275), indicating progressive parasympathetic dysfunction with longer diabetes duration. Although the association between Valsalva response and diabetes duration was not statistically significant (p = 0.0596), it approached the conventional threshold for significance, suggesting a clinically relevant trend. These observations support the findings of Birajdar SV et al., ^[26] who demonstrated a strong relationship between diabetes duration and autonomic dysfunction, particularly parasympathetic abnormalities.

While the blood pressure response to standing and handgrip did not show statistically significant associations with diabetes duration (p = 0.1605 and p = 0.3126, respectively), a clear trend was noted, with a higher proportion of abnormal responses among those with a longer duration of diabetes. These results mirror those of Spallone et al. ^[27] who reported that sympathetic dysfunction tends to occur later and progresses more gradually compared to parasympathetic dysfunction.

Finally, the association between CAN grade and diabetes duration was highly significant (p = 0.0003). Among patients with diabetes duration <10 years, 32.84% had normal autonomic function, compared to only 3.45% in those with duration ≥10 years. Moreover, combined autonomic dysfunction was significantly more prevalent (41.38%) in the latter group. This underscores the cumulative impact of chronic hyperglycemia and diabetic metabolic derangements on autonomic nervous system integrity. Vinik AI and Ziegler D ^[25] and Pop-Busui R ^[28] similarly observed that the prevalence and severity of CAN increased markedly with longer diabetes duration, especially in individuals with poor glycemic control and concomitant complications such as CKD. Collectively, the findings of this study highlight a high prevalence of subclinical and clinical CAN in patients with CKD, with more severe dysfunction seen in those with longer-standing diabetes. The absence of a significant correlation between eGFR and autonomic dysfunction suggests that routine screening for CAN should not be limited to patients with advanced renal disease alone. Moreover, given the silent and progressive nature of CAN, especially in the diabetic CKD population, early and periodic screening using Ewing’s tests can aid in timely diagnosis and intervention, potentially mitigating cardiovascular morbidity and mortality.

Significant prevalence of CAN was observed in CKD patients, with early parasympathetic and combined autonomic dysfunction being common. Advancing CKD stages showed a clear trend of worsening autonomic function, despite no statistically significant correlation with eGFR. Duration of diabetes mellitus was a strong, statistically significant predictor of autonomic dysfunction, particularly affecting parasympathetic activity. Early and routine screening for CAN is essential in CKD patients, especially those with long-standing diabetes, to reduce cardiovascular risk. Simple bedside tests like Ewing’s cardiovascular reflex battery can aid in early detection and improve patient prognosis.

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