A Clinical and Electrophysiological Study of Peripheral Neuropathies in Predialysis Chronic Kidney Disease Patients and Relation of Severity of Peripheral Neuropathy with Degree of Renal Failure

Study procedure

Two hundred consecutive CKD patients with serum creatinine >2 mg/dl who had given consent to participate in the study were divided into two groups. Group 1 included 100 predialysis CKD patients with serum creatinine between 2 and 4.9 mg/dL (mild-to-moderate renal failure). Group 2 included 100 predialysis patients with serum creatinine ≥5 mg/dl (severe renal failure). Each group was further subdivided into two subgroups: each subgroup included 50 diabetic patients and 50 nondiabetic patients.

Detailed history was elicited pertaining to symptoms of peripheral neuropathy and diabetes mellitus. Detailed general physical examination and neurological examination were done and documented. Biochemical investigations including blood urea, serum creatinine, and blood sugars were measured in all the patients as per the standard methods used in the department of biochemistry.

Nerve conduction studies

All cases were subjected to NCSs using Medelec Synergy and Natus machines. NCS procedure was done for both motor conductions and sensory conductions. Median nerve, ulnar nerve, common peroneal nerve, and posterior tibial nerve were assessed for motor conductions. Median nerve, ulnar nerve, and sural nerve were assessed for sensory conductions. In motor conductions, distal latency, conduction velocity, amplitude, and F wave were assessed. In sensory conductions, distal latency, conduction velocity, and amplitude were assessed.

Motor nerve conduction studies procedure

The gain was normally set at 2–5 mV per division for the motor conduction studies.[14] The recording electrodes were placed on the muscle being studied. The belly-tendon montage was used commonly. The center of the muscle belly (over the motor endplate) was used for placing the active recording electrode (also known as G1) and the reference electrode (also known as G2) was placed distally, over the tendon of the muscle. The nerve that supplies the muscle was used for placing the stimulator, where the cathode was placed close to the recording electrode. The duration of the electrical pulse was generally set to 200 ms for the motor NCSs. To achieve supramaximal stimulation, current in the range of 20–50 mA was used. The underlying nerve fibers were brought to action potential as the current was steadily increased from a baseline, usually by 5–10 mA. The summation of all the underlying individual muscle fiber action potentials was represented by the compound muscle action potential (CMAP). When all the nerve fibers have been excited and the supramaximal stimulation has been achieved, the CMAP will no longer increase in size.

For median nerve motor conduction studies, the recording electrode was placed over the motor point of the abductor pollicis brevis muscle, at the midpoint of a line drawn from the first metacarpophalangeal joint to the insertion of the tendon of the flexor carpi radialis muscle, and the reference electrode was placed over the distal interphalangeal joint. Midarm, antecubital fossa, and wrist were sites of stimulation for median nerve motor conduction studies. For ulnar nerve motor conduction studies, the recording electrode was placed over the motor point of the abductor digiti minimi muscle, at the midpoint of a line between the fifth metacarpophalangeal joint and the pisiform bone, with the reference electrode over the middle phalanx of digit V. Axilla, above elbow, ulnar groove, and medial wrist were sites of stimulation for ulnar nerve motor conduction studies. For the posterior tibial nerve, the CMAP was recorded by placing the active electrode over the middle of the adductor hallucis muscle, and the reference electrode over the proximal phalanx of digit I. The posterior tibial nerve was stimulated below the medial malleolus and in the popliteal fossa. For common peroneal nerve motor conduction studies, the recording electrode was placed in the middle of the extensor digitorum brevis muscle. The common peroneal nerve was stimulated at the ankle, 80 mm proximal to the recording electrode, lateral to the tendon of tibialis anterior muscle, and below the knee 20–50 mm distal to the proximal part of the caput fibula.

Latency was described as the time from the stimulus to the initial CMAP deflection from the baseline. The CMAP amplitude was measured from the baseline to the negative peak. Conduction velocity was calculated using the formula as follows: Distance between the proximal and distal stimulation sites/proximal latency − distal latency. The standardized normal adult values of motor NCSs in both upper and lower extremities as per our electrophysiology laboratory are shown in Table 1.[15]

Table 1 Motor nerve conduction studies: Standardized normal adult values in both upper and lower extremities

The F response also known as the late motor response occurs after the CMAP.[16] Normal minimal F latency was 25–30 ms in median and ulnar nerves, while it was 45–59 ms in common peroneal and posterior tibial nerves.

Sensory conduction studies

Median and ulnar sensory nerve action potentials (SNAPs) were obtained orthodromically, stimulating from the index finger (median nerve) or the little finger (ulnar nerve) and recording at the wrist. Sural SNAPs were obtained antidromically, recording behind the lateral malleolus and stimulating on the dorsal aspect of the calf, 140 mm proximal to the recording site. The responses were averaged at least 10 times. The standardized normal adult values of sensory NCSs in both upper and lower extremities as per our electrophysiology laboratory are shown in Table 2.[17]

Table 2 Sensory nerve conduction studies: standardized normal adult values in both upper and lower extremities

Based on electrophysiological parameters, peripheral neuropathy patterns were subclassified into axonal neuropathy, demyelinating neuropathy, and mixed neuropathy. In axonal neuropathy, CMAPs decrease, conduction velocities are normal or slightly decreased but never <75% of the lower limit of normal, and distal latencies are normal or slightly prolonged but never >130% of the upper limit of normal. In demyelinating neuropathy, CMAPs are usually normal with marked slowing of conduction velocity (slower than 75% of the lower limit of normal) and/or marked prolongation of distal latency (longer than 130% of the upper limit of normal). It was classified as mixed neuropathy if it has features of both axonal neuropathy and demyelinating neuropathy. Degree of severity of peripheral neuropathy was divided into three groups: normal, early damage, and definite damage, according to the number of peripheral nerves involved. Normal or no peripheral damage was defined if NCSs were normal or only one peripheral nerve was involved. Early damage, if two or three peripheral nerves were involved, and definite damage, if more than three peripheral nerves were involved.

Statistical analysis

The data were collected and tabulated using Microsoft excel 2010 version. Data were analyzed using SPSS version 20. All the continuous variables were expressed as mean ± standard deviation (SD) or median with interquartile range as appropriate. All categorical variables were expressed as frequencies (percentage). Independent t-test and ANOVA test were applied to compare nominal data between the groups and P < 0.05 was considered statistically significant.

Demographic characteristics

The mean age in the present study was 53.2 ± 13.2 years. Males (n = 136, 68%) outnumbered females (n = 64, 32%). Mean duration of CKD was 2.2 ± 1.6 years. The mean serum creatinine and blood urea of 200 predialysis patients were 4.9 ± 2.6 mg/dl and 95.7 ± 53.2 mg/dl, respectively. The prevalence of peripheral neuropathy in the present study was 45% based on clinical symptoms and 90% based on electrophysiological parameters.

The mean duration of diabetes mellitus in diabetic subgroups (n = 100) was 7.3 ± 2.8 years.

Symptoms and signs of 200 predialysis patients are shown in Table 3. On comparing symptoms and signs of two groups of predialysis patients, patients with severe renal failure (Group 2) showed statistically significant positive symptoms (P < 0.001), absent ankle jerk (P = 0.023), impaired pain and temperature sensation (P = 0.048), and impaired vibration and joint position sense (P = 0.034).

Table 3 Symptoms and signs of 200 predialysis chronic kidney disease patients who participated in the study

Electrophysiological parameters of 200 predialysis patients

Nerve conduction abnormalities in 200 predialysis patients are shown in Table 4. Comparison of electrophysiological parameters of 200 predialysis patients, 100 patients with serum creatinine of 2–4.9 mg/dl (Group 1), and 100 patients with serum creatinine of ≥5 mg/dl (Group 2) is shown in Table 5. Among 200 predialysis CKD patients, 126 patients (63%) had definite damage and 54 patients (27%) had early damage. The most common patterns of peripheral neuropathy in 200 predialysis patients were pure axonal sensorimotor neuropathy pattern (53%) followed by mixed sensorimotor neuropathy pattern (30%).

Table 4 Nerve conduction abnormalities in 200 predialysis chronic kidney disease patients

Table 5 Comparison of electrophysiological parameters of 200 predialysis chronic kidney disease patients who participated in the study

Predialysis patients with mild-to-moderate renal failure (Group 1)

Mean age was 57.4 ± 12.9 years. Males (n = 70, 70%) outnumbered females (n = 30, 30%). Mean serum creatinine and blood urea in Group 1 were 2.7 ± 0.6 mg/dl and 67.4 ± 35.3 mg/dl, respectively. The prevalence of peripheral neuropathy was 30% based on clinical symptoms and 88% based on electrophysiological parameters.

Among 100 patients in Group 1, 54 patients (54%) had definite damage, 34 patients (34%) had early damage, and 12 patients (12%) had no evidence of significant peripheral neuropathy. In diabetic subgroup (n = 50), definite damage was seen in 36 (72%) patients and early damage was seen in 14 (28%) patients. In nondiabetic subgroup (n = 50), definite damage was seen in 18 (36%) patients, early damage was seen in 20 (40%) patients, and 12 (24%) patients had no significant peripheral neuropathy. The most common patterns of peripheral neuropathy were pure axonal sensorimotor neuropathy (44%) followed by mixed sensorimotor neuropathy pattern (40%).

On comparing symptoms and signs of two subgroups of Group 1, diabetic subgroup showed statistically significant absent ankle jerk (P = 0.012).

On comparing electrophysiological data between two subgroups of Group 1, diabetic subgroup showed statistically significant prolonged median nerve motor distal latency (P < 0.001), low median nerve motor conduction velocity (P = 0.001), prolonged median nerve F wave (P = 0.006), low ulnar nerve motor conduction velocity (P < 0.001), low ulnar nerve motor amplitude (P = 0.003), prolonged ulnar nerve F wave (P < 0.001), low common peroneal nerve motor conduction velocity (P < 0.001), low common peroneal nerve motor amplitude (P = 0.008), prolonged posterior tibial nerve motor distal latency (P = 0.044), low posterior tibial nerve motor conduction velocity (P < 0.001), low posterior tibial nerve motor amplitude (P < 0.007), prolonged posterior tibial F wave (P = 0.002), low median nerve sensory conduction velocity (P = 0.031), low ulnar nerve sensory conduction velocity (P = 0.025), low ulnar nerve sensory amplitude (P = 0.001), low sural nerve sensory conduction velocity (P = 0.021), and low sural nerve sensory amplitude (P = 0.004). Patients without diabetes mellitus showed statistically significant prolonged ulnar nerve motor distal latency (P = 0.020).

Predialysis patients with severe renal failure (Group 2)

Mean age was 49.0 ± 12.3 years. Males (n = 66, 66%) outnumbered females (n = 34, 34%). Mean serum creatinine and blood urea in Group 2 were 7.1 ± 1.9 mg/dl and 123.9 ± 53.4 mg/dl, respectively. The prevalence of peripheral neuropathy was 60% based on clinical symptoms and 92% based on electrophysiological parameters.

Among 100 patients in Group 2, 70 patients (70%) had definite damage, 22 patients (22%) had early damage, and 8 patients (8%) had no evidence of significant peripheral neuropathy. In diabetic subgroup, definite damage was seen in 47 (94%) patients and 3 (6%) patients had no significant peripheral neuropathy. In nondiabetic subgroup (n = 50), definite damage was seen in 23 (46%) patients, early damage was seen in 22 (44%) patients, and 5 (10%) patients had no significant peripheral neuropathy. The most common patterns of peripheral neuropathy were pure axonal sensorimotor neuropathy (52%) followed by mixed sensorimotor neuropathy pattern (30%).

There was no statistically significant difference on comparing symptoms and signs of two subgroups of Group 2.

On comparing electrophysiological data between two subgroups of Group 2, diabetic subgroup showed statistically significant prolonged median nerve motor distal latency (P = 0.004), low median nerve motor conduction velocity (P = 0.004), low median nerve motor amplitude (P = 0.022), prolonged median nerve F wave (P = 0.022), prolonged ulnar nerve motor distal latency (P = 0.007), low ulnar nerve motor conduction velocity (P = 0.001), prolonged ulnar nerve motor F wave (P = 0.002), low common peroneal nerve motor conduction velocity (P = 0.001), low common peroneal nerve motor amplitude (P < 0.001), absent common peroneal nerve F wave (P < 0.001), low posterior tibial nerve motor conduction velocity (P < 0.001), low posterior tibial nerve motor amplitude (P = 0.001), absent posterior tibial F wave (P < 0.001), low median nerve sensory conduction velocity (P = 0.005), low median nerve sensory amplitude (P < 0.001), low ulnar nerve sensory amplitude (P < 0.001), low sural nerve sensory distal latency (P < 0.001), low sural nerve sensory conduction velocity (P < 0.001), and low sural nerve sensory amplitude (P < 0.001). Patients without diabetes mellitus showed statistically significant prolonged median nerve sensory distal latency (P = 0.016), prolonged ulnar nerve sensory distal latency (P = 0.002), and low ulnar nerve sensory conduction velocity (P = 0.010).

Electrophysiological parameters in predialysis chronic kidney disease patients

Comparison of electrophysiological parameters in 200 predialysis CKD patients with other published international studies[1922] is shown in Table 6. Data regarding electrophysiological parameters in predialysis CKD patients are sparse in Indian literature.

Table 6 Comparison of electrophysiological parameters in predialysis patients as reported in published studies

On comparing electrophysiological parameters of predialysis patients, motor distal latency and motor conduction velocity were similar to other published studies, but motor amplitudes were low in the present study. Sample size in the present study was large, when compared to other published studies.

Most common nerves involved in the present study were sural nerve, median sensory nerve, and ulnar sensory nerve. Most common motor nerves involved in the present study were common peroneal nerve, posterior tibial nerve followed by median nerve, and ulnar nerve. Lower limbs were most commonly affected than upper limbs, which indicate a length dependent pattern of peripheral neuropathy. As length-dependent pattern of neuropathy is seen in uremic neuropathy, lower limbs are involved early in CKD. Upper limb nerves are later involved as renal failure worsens theoretically. Similar pattern was seen in the present study also. Sensory nerves were commonly affected than motor nerves in the present study. These results were similar to other published international studies.[1922]

According to Aggarwal et al.,[18] mean nerve conduction velocities (m/s) of right median, ulnar, common peroneal, and posterior tibial nerves were 51.34 ± 6.07, 53.04 ± 5.91, 44.72 ± 6.14, and 44.2 ± 5.17, respectively, in predialysis patients, which were almost similar to the present study. In predialysis patients (n = 200), mononeuropathy was seen in 6 patients in the form of carpal tunnel syndrome.

Ulnar nerve sensory amplitude and conduction velocity, median nerve sensory amplitude, median nerve motor amplitude, and conduction velocity were statistically significant electrophysiological parameters to differentiate severe renal failure group of patients from mild-to-moderate renal failure group of patients.

The prevalence of peripheral neuropathy was 88% in mild-to-moderate renal failure group and 92% in severe renal failure group. This showed that the prevalence of peripheral neuropathy increases as renal failure worsens. In addition, severity of peripheral neuropathy was also more in severe renal failure group of patients which was similar to other Indian study by Aggarwal et al.[18]

Diabetic CKD patients showed more severe and high prevalence of peripheral neuropathy when compared to nondiabetic CKD patients (97% vs. 83%), which was almost similar in both Group 1 and Group 2. As peripheral neuropathy depends on blood sugar level in addition to uremia, diabetic CKD patients showed higher prevalence and severity of peripheral neuropathy.

In the present study, statistically most significant electrophysiological parameters differentiating diabetics and nondiabetics in mild-to-moderate renal failure group were median nerve motor distal latency, ulnar nerve motor conduction velocity, ulnar nerve F wave, common peroneal nerve motor conduction velocity, posterior tibial nerve motor conduction velocity, and ulnar nerve sensory amplitude. Statistically most significant electrophysiological parameters differentiating diabetics and nondiabetics in severe renal failure group were common peroneal nerve F wave, posterior tibial F wave, median nerve sensory amplitude, ulnar nerve sensory amplitude, sural nerve sensory distal latency, sural nerve sensory conduction velocity, sural nerve sensory amplitude, common peroneal nerve motor conduction velocity, common peroneal nerve motor amplitude, and ulnar nerve motor conduction velocity. Indian literature comparing diabetic CKD patients and nondiabetic CKD patients is sparse.

Pure axonal sensorimotor neuropathy and mixed sensorimotor neuropathy were most common patterns in predialysis CKD patients.

Limitations of the present study

1. This study is a hospital-based study, so it is not an accurate measure of community-based prevalence of neuropathy in predialysis CKD patients.

2. Electrophysiologic parameters might be slightly altered due to the presence of edema in CKD patients.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.