This study investigated the distribution of sudomotor function across stages of CKD. Both hands and feet ESC showed a significant decrease, and the prevalence of pathological hands and feet ESC increased with CKD progression, regardless of diabetes status. Diabetic CKD subjects had more impaired sudomotor function compared to non-diabetic CKD patients.
The small unmyelinated C fibers, similar in structure to the nerve fibers responsible for thermal perception, are also vulnerable to injury from metabolic derangements [17]. Sudomotor function reflects the activity of these small unmyelinated C fibers, allowing the assessment of peripheral sympathetic function through the measurement of sweat gland response using Sudoscan [17]. In diabetic patients, Sudoscan has been validated against other tools for neuropathy detection, including small-fiber neuropathy and autonomic dysfunction [15, 19]. Additionally, Sudoscan has shown comparable diagnostic accuracy for intraepidermal nerve fiber density in diabetic distal symmetric polyneuropathy [10]. Casellini et al. demonstrated a significant correlation between Sudoscan score and clinical neuropathy scores and autonomic function testing based on heart rate variability [15]. Selvarajah et al. also observed a strong correlation between hands and feet ESC and scores from nerve conduction and cardiovascular autonomic reflex tests [20].
Uremic peripheral neuropathy is prevalent among CKD patients and typically affects large-diameter axons, resulting in demyelination and axonal degeneration. This neuropathy is characterized by symptoms such as numbness, weakness, and reduced reflexes, leading to physical dysfunction and decreased quality of life in both diabetic and non-diabetic patients [2, 4, 7]. A study involving 176 dialysis patients found that a pathological hands or feet ESC, measured by Sudoscan, was associated with a higher risk of intra-dialytic hypotension [18].
Studies have suggested that small-fiber involvement in uremic neuropathy is more prevalent than previously reported. Thermal sensation abnormalities have been observed in 30% of the CKD population, and these abnormalities do not correlate with large fiber dysfunction. This indicates that small fiber neuropathy can be considered a distinct form of uremic neuropathy [21]. In fact, the prevalence of small-fiber sensory neuropathy (67.5%) is higher compared to that of large-fiber neuropathies (37.5%) in patients with advanced CKD [22]. Furthermore, it has been widely accepted that uremic peripheral neuropathy is only observed in patients with advanced CKD [2, 3]. However, recent studies have shown that neuropathy affects a significant proportion of patients with CKD stages 3 [7, 23].
Previous studies examining the application of the Sudoscan score in CKD have mainly focused on diabetic patients and had a limited number of cases. For example, Freedman et al. demonstrated a significant association between average hands and feet ESC and eGFR in African Americans (but not in Caucasians) after adjusting for age, gender, BMI, and HbA1c in a cohort of 390 participants with diabetes [12]. The mean eGFR for African Americans and Caucasians in this study was 87.95 and 82.7 mL/min/1.73m², respectively, and the percentages of patients with GFR < 60 mL/min/1.73m² were only 9% and 16%, respectively. In another study of 2833 Hong Kong Chinese adults with diabetes, a low Sudoscan nephropathy score (calculated via the machine's built-in algorithms) was significantly associated with low eGFR, even after adjusting for disease vintage, gender, BMI, blood pressure, HbA1c, cholesterol, and use of anti-hypertensive drugs [13]. In this study, the majority of participants did not have CKD (n = 2670), and only 163 patients had CKD, with a mean eGFR of 42.1 mL/min/1.73m² and a median urine albumin-to-creatinine ratio of 35.8 mg/mmol (0.32 g/g). In our study, we confirm the positive association between ESC and eGFR in both diabetic and non-diabetic patients with pre-dialysis CKD. Furthermore, after adjusting for CKD-associated factors, renal function itself was not found to be an independent predictor of hands and feet ESC.
In the present study, age, BMI, hemoglobin, and albumin were found to be significantly associated with hands or feet ESC in the fully adjusted model among diabetic patients. These findings are consistent with previous studies on peripheral neuropathy. Hypoalbuminemia and anemia have been reported to be associated with peripheral neuropathy in diabetic patients [24, 25]. Furthermore, the association between albumin and diabetic neuropathy was found to be stronger in patients with a higher BMI (≥ 24 kg/m2) compared to those with a lower BMI (< 24 kg/m2) [26]. In patients who initiated dialysis, the use of erythropoietin-stimulating agents significantly improved nerve conduction [27], and in pediatric patients with iron deficiency anemia, peripheral neuropathy was observed to reverse after iron treatment [28]. These findings suggest that malnutrition and anemia are likely universal factors contributing to peripheral neuropathy.
To the best of our knowledge, our study recruited the largest cohort for the measurement of sudomotor function across various stages of CKD. However, there are several limitations to consider. Firstly, there is a lack of nerve conduction studies and documentation of clinical symptoms and signs. Secondly, we did not rule out other potential causes of neuropathy, such as chronic inflammation, autoimmune disease, or chemotherapy agent use, which could potentially impact sudomotor function. Thirdly, relevant factors associated with uremic neuropathy, such as parathyroid hormone, thiamine, zinc, biotin, or β2-microglobulin, were not included in our study.