Introduction
Chronic Kidney Disease (CKD) has emerged as a critical global health priority, currently affecting an estimated 10-16% of the world’s population [1]. Characterized by persistent structural or functional renal abnormalities and a glomerular filtration rate (GFR) falling below 60ml/min/1.73m2 for more than three months, the disease signifies a progressive collapse of essential homeostatic mechanisms. Beyond the primary failure of fluid and electrolyte regulation, the advancement of CKD leads to the systemic accumulation of uremic retention solutes, which act as potent neurotoxins [2]. While dialysis and transplantation have become standard global interventions, the neurological sequelae of the uremic state remain remarkably prevalent. Specifically, peripheral neuropathy (PN) stands as the most frequent neurologic complication, with reports suggesting that 70-100% of patients on dialysis experience neuropathic symptoms despite reaching conventional targets for dialysis adequacy [3]. This suggests a "uremic paradox" where the clearance of small molecules like urea and creatinine does not necessarily correlate with the mitigation of nerve damage.
The clinical manifestation of uremic neuropathy typically involves a length-dependent, sensory-predominant pattern, including paresthesias, numbness, and debilitating pain in the distal extremities. Although this association was recognized as early as the 19th century, the precise molecular mechanisms and epidemiological shifts continue to evolve [4]. Pathogenesis is now understood to be multifactorial, involving the accumulation of middle molecules and protein-bound toxins, such as indoxyl sulfate and p-cresyl sulfate, which interfere with neuronal mitochondrial function and axonal metabolism. These biochemical insults are further compounded by chronic systemic inflammation and microvascular ischemia due to the calcification of the vasa nervorum, leading to a progressive loss of nerve fiber density [5-6]. While Nerve Conduction Studies (NCS) can detect reduced velocities and prolonged latencies before clinical symptoms manifest, these diagnostic tools remain underutilized in routine clinical practice, particularly in high-volume settings like North India. In the Indian clinical landscape, the prevalence and patient discomfort associated with PN are frequently overshadowed by the management of more acute, life-threatening renal complications [6].
Despite the profound impact of PN on patient morbidity, mortality, and overall quality of life including its links to gait instability, cardiovascular autonomic dysfunction, and adverse mental health outcomes significant knowledge gaps persist [7]. Reported prevalence rates vary widely due to heterogeneous diagnostic methodologies and a lack of standardized electrophysiological profiling across different CKD stages. Furthermore, the correlation between specific renal biochemical markers and the severity of nerve dysfunction remains insufficiently delineated in Indian literature [7-8]. This study, therefore, seeks to address these gaps by systematically evaluating the electrophysiological profile of CKD patients through comprehensive Nerve Conduction Studies. By quantifying the frequency and characterizing the nuances of nerve injury, this research aims to provide a framework for earlier risk stratification and more tailored therapeutic interventions in the management of uremic neuropathy.
Materials and Methods
1. Study Design and Setting
This cross-sectional study was conducted at the Sri Guru Ram Das Institute of Medical Sciences and Research, Amritsar, from July 2024 to December 2025. The study protocol was designed to evaluate the prevalence and electrophysiological characteristics of peripheral neuropathy (PN) in patients diagnosed with Chronic Kidney Disease (CKD), correlating these findings with the severity of renal impairment.
2. Patient Selection and Sample Size
The study population included adult patients (≥18 years) admitted to the inpatient wards or attending the Nephrology/Medicine outpatient departments. Based on a previous prevalence of 45% [9] and a 95% confidence interval with an absolute error of 10%, the initial sample size was calculated at 95. Accounting for a 10% non-response rate, a final cohort of 105 patients was enrolled via consecutive sampling. Patients meeting the KDIGO criteria for CKD (eGFR 60 ml/min/1.73m2 for >3 months) were included in the study. Whereas patients with Acute Kidney Injury (AKI), malignancy, pregnancy, current chemotherapy, or congenital nephropathy were excluded to eliminate confounding variables of nerve damage.
3. Diagnostic Criteria and Stratification
CKD was staged according to KDIGO guidelines using clinical history, Urine Albumin-to-Creatinine Ratio (UACR), and abdominal ultrasonography to assess corticomedullary differentiation and renal echogenicity. Renal function was quantified using the Cockcroft–Gault Equation: eGFR= (140-Age) x Weight (kg)/72xSerum Creatinine (mg/dl) x [0.85 if female]
4. Clinical and Neurological Assessment
Comprehensive neurological screening was performed using the Michigan Neuropathy Screening Instrument (MNSI), consisting of a 13-point symptom questionnaire and a structured physical examination.
Sensory Evaluation: Systematic testing of touch, pain, temperature, and vibration (128 Hz tuning fork) was conducted.
Motor Evaluation: Assessments included muscle power grading and deep tendon reflexes, specifically the ankle reflex (with the Jendrassik maneuver where necessary).
Protective Sensation: The 10-point Semmes-Weinstein Monofilament test was applied to five plantar sites per foot.
5. Electrophysiological Protocol
Nerve Conduction Studies (NCS) were performed on all four limbs using a standardized electrophysiology system. To ensure accuracy, limb temperature was maintained using heat packs to prevent artificially prolonged latencies or altered amplitudes.
Motor Studies: Evaluated the Median, Ulnar, Common Peroneal, and Tibial nerves, measuring Distal Latency, CMAP Amplitude, and Conduction Velocity (CV).
Sensory Studies: Assessed the Median, Ulnar, and Sural nerves for SNAP Amplitudes and CV. Symmetry was evaluated by comparing contralateral limbs; an amplitude discrepancy of >50% was considered abnormal.
| Study Type | Nerve | Amplitude | CV (m/s) | Distal Latency (ms) |
| Sensory (SNAP) | Ulnar | >17 µV | >50 | <3.1 |
| Median | >20 µV | >50 | <3.3 | |
| Sural | >6 µV | >40 | <4.4 | |
| Motor (CMAP) | Median | >4.0 mV | >49 | <4.4 |
| Ulnar | >6.0 mV | >49 | <3.3 | |
| Post. Tibial | >4.0 mV | >41 | <5.8 |
6. Data Management and Ethical Considerations
All clinical data, including serum creatinine, urea, and UACR, were recorded on a standardized proforma. Written informed consent was obtained from all participants in their vernacular language. Ethical clearance was secured from the Institutional Ethics Committee (SGRD/IEC/2024-370) prior to study commencement.
Statistical Analysis
The corrected data was organized into a master-chart and managed using Microsoft Excel. Initially, univariate analysis was performed to calculate frequencies for categorical variables and measures of central tendency and dispersion for continuous variables. Bivariate analysis was subsequently conducted using the Chi-square test to examine relationships between categorical variables, while the unpaired t-test was employed for quantitative comparisons. Statistical significance was defined by a p-value of less than 0.05.
Results
1. Demographic and Clinical Baseline
The study cohort (N=105) was predominantly male (61.9%), with the largest age group falling between 60–79 years (46.67%). The distribution across advanced CKD stages is relatively balanced, with Stage 3 being the most frequent (38.1%), followed by Stages 5 (31.4%) and 4 (30.5%). Whereas, sensory symptoms are the most common clinical manifestation (32.4%), while objective neurological signs like absent ankle jerks (11.4%) and autonomic symptoms (7.6%) occur less frequently. Biochemically, the participants showed significantly elevated renal parameters, with a mean serum urea of 124.81±53.22 mg/dl and creatinine of 6.88±1.95 mg/dl (Table 2).
| Parameter | Classification | Frequency (n) | Percentage (%) |
| Gender | Male / Female | 65 / 40 | 61.9 / 38.1 |
| Primary Age Group | 60–79 Years | 49 | 46.67 |
| CKD Severity | Stage 3 / 4 / 5 | 40 / 32 / 33 | 38.1 / 30.5 / 31.4 |
| Clinical Presentation | Sensory Symptoms | 34 | 32.4 |
| Absent Ankle Jerk | 12 | 11.4 | |
| Autonomic Symptoms | 8 | 7.6 | |
| Renal Markers | Urea (mg/dl) | Creatinine (mg/dl) | Range (Min–Max) |
| Mean±SD | 124.81±53.22 | 6.88±1.95 | 43.8–238.0/5.1-13.9 |
2. Electrophysiological Nerve Conduction Profile
Nerve conduction studies (NCS) revealed widespread abnormalities across motor and sensory pathways. The Median and Ulnar sensory nerves showed the highest rates of latency prolongation (54.3% and 61.0%) and velocity slowing (47.6% and 55.2%), respectively. Motor nerve involvement is primarily characterized by a reduction in amplitude rather than a decline in conduction velocity. The Posterior Tibial (56.2%) and Ulnar (55.2%) nerves were the most frequently affected motor pathways, primarily exhibiting decreased compound muscle action potential (CMAP) amplitudes. This pattern is highly suggestive of axonal loss as the primary underlying pathology in the motor system (Table 3).
| Nerve Type | Nerve Tested | Increased Latency n (%) | Decreased Amplitude n (%) | Decreased Velocity n (%) |
| Motor | Median | 30 (28.6) | 52 (49.5) | 22 (21.0) |
| Ulnar | 22 (21.0) | 58 (55.2) | 28 (26.7) | |
| Post. Tibial | 25 (23.8) | 59 (56.2) | 30 (28.6) | |
| Sensory | Sural | 35 (33.3) | 66 (62.9) | 36 (34.3) |
| Median | 57 (54.3) | 36 (34.3) | 50 (47.6) | |
| Ulnar | 64 (61.0) | 44 (41.9) | 58 (55.2) |
3. Prevalence and Patterns of Peripheral Neuropathy (PN)
The data in Table 4 reveals a high diagnostic yield for peripheral neuropathy within the study population, with nerve conduction studies identifying neuropathic involvement in 71.4% (n=75) of participants. Electrophysiological phenotyping confirms a predominant pure axonal sensory-motor pathology in 45.7% of cases, significantly outweighing mixed axonal-demyelinating patterns (25.7%). Clinically, a sensorimotor presentation emerged as the most frequent subtype (40.9%), while the distribution of limb involvement underscores a length-dependent progression; combined upper and lower limb involvement was the most prevalent topographic pattern (39.1%), followed by isolated lower limb impairment (20.0%). These findings collectively characterize uremic neuropathy in this cohort as a primarily axonal, symmetric polyneuropathy that scales in complexity from distal lower extremities to generalized limb involvement.
| Category | Phenotype | Frequency (n) | Percentage (%) |
| Overall Status | Neuropathy Present | 75 | 71.4 |
| Pathological Type | Pure Axonal Sensory Motor | 48 | 45.7 |
| Mixed (Axonal + Demyelinating) | 27 | 25.7 | |
| Clinical Pattern | Sensorimotor | 43 | 40.9 |
| Sensory Only | 20 | 19.1 | |
| Motor Only | 12 | 11.4 | |
| Limb Involvement | Both Upper and Lower | 41 | 39.1 |
| Lower Limb Only | 21 | 20.0 | |
| Upper Limb Only | 13 | 12.3 |
4. Correlation with CKD Progression
The analysis reveals a highly significant, stage-dependent escalation in both the prevalence and complexity of peripheral neuropathy as renal function declines (p<0.0001). While overall prevalence climbs from 55.0% in Stage 3 to 84.8% in Stage 5, the clinical phenotype undergoes a distinct transition: isolated sensory deficits predominate in early stages (35% in Stage 3), whereas advanced disease is characterized by a shift toward sensorimotor involvement (69.7% in Stage 5) and emerging motor-only impairment. Furthermore, the underlying pathology mirrors this progression, with pure axonal damage remaining the primary driver across all stages, though mixed axonal-demyelinating patterns nearly double in frequency as patients transition into end-stage renal disease. These findings emphasize that advancing CKD not only increases the likelihood of nerve damage but also drives a shift toward more severe, multi-system neurological impairment.
| Feature | Stage 3 (n=40) | Stage 4 (n=32) | Stage 5 (n=33) | p-value |
| PN Prevalence | 22 (55.0%) | 25 (78.1%) | 28 (84.8%) | < 0.0001 |
| Pattern | ||||
| Sensorimotor | 8 (20.0%) | 17 (53.1%) | 18 (69.7%) | < 0.0001 |
| Sensory Only | 14 (35.0%) | 4 (12.5%) | 2 (6.1%) | < 0.0001 |
| Motor Only | 0 (0.0%) | 4 (12.5%) | 8 (25.0%) | < 0.0001 |
| Type | ||||
| Pure Axonal | 15 (37.5%) | 15 (46.9%) | 18 (54.5%) | < 0.0001 |
| Mixed | 7 (17.5%) | 10 (31.3%) | 10 (30.3%) | < 0.0001 |
Discussion
Peripheral neuropathy is a well-recognized but frequently underdiagnosed complication of chronic kidney disease, contributing significantly to functional disability and diminished quality of life. This study utilized nerve conduction studies (NCS) to delineate the electrophysiological profile of neuropathy across various CKD stages, offering critical insights into the prevalence and patterns of uremic nerve damage.
The study cohort exhibited a clear male predominance (61.9% Table 2), aligning with findings by Mallipeddi et al.,[10] (64%) and Jasti et al.,[9] (23-24%). While some literature suggests a higher susceptibility in males with Alagesan & Mohan, [11] reporting neuropathy in 48.6% of males versus 16.3% of females our data found no statistically significant sex-based difference. This suggests that the higher number of male cases in the present study likely reflects the higher general prevalence of CKD in men rather than a biological predisposition to uremic nerve injury.
The mean age of participants was 56.5±16.9 years, with nearly half older than 60. Age emerged as a critical non-modifiable risk factor, consistent with the cumulative vulnerability hypothesis. Advancing age likely compounds uremic neurotoxicity, as older axons are less resilient to metabolic stress [12]. Our findings mirror those of Jhee et al.,[13] who identified age as an independent predictor of neuropathy in non-dialysis CKD patients.
A significant finding was the diagnostic gap between clinical symptoms and objective testing: Clinical sensory symptoms were reported by only 32.4% of participants, whereas motor weakness was entirely absent on physical examination. NCS identified neuropathy in 71.4% of the cohort (Table 4). This discrepancy highlights the subclinical nature of uremic neuropathy. As noted by Jasti et al.,[9] only 45% of patients presented with symptoms, 90% exhibited electrophysiological abnormalities. Reliance on clinical examination alone significantly underestimates the true disease burden. The study identified pure axonal sensory-motor neuropathy as the dominant pattern (45.7%), followed by mixed patterns (25.7%, Table 5).
Electrophysiological Features includes Motor Nerves preserved conduction velocities but reduced amplitudes Whereas sensory nerves prolonged latencies and significantly slowed velocities. These results support the hypothesis that uremic toxins such as middle-molecular-weight compounds and advanced glycation end products primarily disrupt axonal metabolic integrity and transport [14]. Demyelination appears to be a secondary phenomenon resulting from a loss of trophic support rather than a primary insult to Schwann cells [14].
Neuropathy predominantly affected both upper and lower limbs (39.1% Table 4), following a length-dependent (stocking-glove) pattern. Longer axons have higher metabolic demands and are further from the neuronal cell body, making distal segments in the lower extremities the first targets of uremic injury. The sural nerve emerged as a sensitive early indicator, consistent with Fatima et al.,[15] who found sural abnormalities in 66% of their cohort [58 Table 3]. The study demonstrated a compelling and statistically robust correlation (p=0.0001) between the progression of renal dysfunction and the severity of nerve damage. This dose-response relationship was evidenced by a substantial rise in neuropathy prevalence as disease severity advanced, increasing from 55% in Stage 3 patients to 84.8% in those at Stage 5. These findings underscore how the cumulative burden of uremic toxins as Glomerular Filtration Rate (GFR) declines, the escalating retention of neuroactive solutes exerts a dose-dependent toxic effect. This reinforces the findings of Mathew et al.,[16] suggesting that the transition from Stage 3 to Stage 4/5 represents a period of accelerated neurological risk.
Beyond the large-fiber involvement typically captured by nerve conduction studies, current literature highlights a significant concurrent burden of autonomic and small-fiber neuropathy in the chronic kidney disease population. Cardiovascular autonomic dysfunction is particularly prevalent, affecting up to 62% of non-diabetic patients and suggesting that uremia exerts a direct toxic effect on the autonomic nervous system. Furthermore, histopathological evidence reveals a marked reduction in intraepidermal nerve fiber density, indicating that small-fiber loss often precedes the large-fiber changes detectable by standard electrophysiological testing [17,18].
Conclusion
The current study establishes that peripheral neuropathy is an extensively prevalent yet frequently subclinical complication of advanced renal failure, affecting 71.4% of the cohort despite clinical symptoms manifesting in only 32.4% of cases. The findings characterize uremic neuropathy as a primarily pure axonal sensory-motor polyneuropathy that adheres to a length-dependent topographic distribution, with the sural nerve serving as a critical early indicator of damage. Most notably, a robust, stage-dependent correlation (p<0.0001) was identified, where neuropathy prevalence escalated from 55% in Stage 3 to 84.8% in Stage 5, accompanied by a transition from isolated sensory deficits to more severe sensorimotor impairment. Ultimately, these results underscore that advancing CKD acts as a primary driver of progressive axonal degeneration, necessitating the integration of routine electrophysiological screening into standard clinical monitoring to detect and manage neurological deterioration before it results in significant functional disability.
Declarations
Ethical Approval and Consent to Participate
All procedures performed in this case series were conducted in accordance with the ethical standards of the institutional research committee and the 1964 Declaration of Helsinki and its later amendments. Ethical approval was obtained from the Institutional Ethics Committee (SGRD/IEC/2024-370). Written informed consent was obtained from all individual participants or their legal guardians included in the study prior to any procedures.
Consent for Publication
Written informed consent for the publication of clinical details and accompanying images was obtained from the patients or their legal representatives. All data has been meticulously anonymized to ensure patient confidentiality and privacy.
Availability of Data and Materials
The datasets generated and analyzed during the current study are available from the corresponding author upon reasonable request, in compliance with institutional data sharing policies and ethical restrictions.
Competing Interests
The authors declare that they have no financial or non-financial competing interests that could inappropriately influence or bias the integrity of this research.
Funding
This research received no specific grant or financial support from any funding agency in the public, commercial, or not-for-profit sectors.
Authors’ Contributions
All authors contributed significantly to the study's conception, design, data acquisition, and analysis. Each author participated in drafting the manuscript and performing critical revisions for intellectual content. The final version of the manuscript has been reviewed and approved by all authors for submission.