Uremic neuropathy is a common under-investigated complication in patients with ESKD on dialysis. Uremic neuropathy occurs in 60–100% of dialysis patients ; it has a lower prevalence in non-dialysis CKD (ND-CKD) patients, which was reported to be 64% in one study . Patients are mostly diagnosed late after being symptomatic in advanced axonal neuropathy, which is generally an irreversible nerve damage stage .
Aggarwal and his colleagues found that the prevalence of neuropathy increased with severity of renal dysfunction; among patients with ND-CKD .
Regarding nerve affection distribution, nerves of lower limbs are usually involved before upper-limb nerves . It was proved that the dorsal sural nerve was the most affected nerve in different kinds of peripheral neuropathy . Consequently, it is essential to detect early neuropathic changes by electrophysiological study and timely start proper treatment to retard nerve damage progression and prevent subsequent functional disability .
In this study, 55.6% of the patients had clinical neuropathy, which is consistent with Hassan and his colleagues, who found that two-thirds of CKD patients suffer from uremic neuropathy at the beginning of dialysis . Remarkably, 44.4% of our patients did not have clinical manifestations of neuropathy, but they were found to have diagnostic electrophysiological findings of neuropathy (subclinical asymptomatic neuropathy). Therefore, early screening for neuropathy is crucial in ND-CKD patients regardless of the presence or absence of clinical features .
In our study, lower-limb nerves (common peroneal, posterior tibial; MNCV and CMAP amplitude and sural nerves) were severely affected than the upper-limb nerves, and these results are well-matched with the clinical manifestations of uremic neuropathy, which typically involve the lower limbs more than the upper limbs . Also, Krishnan and Kiernan have described a change in sural sensory potential as the most sensitive nerve conduction abnormality in patients with CKD . Additionally, the decrease in CMAP amplitude suggests that the demyelinating process is associated with axonal degeneration . Also, the sural nerve was undetectable in diabetic CKD patients, and this could be explained by the effect of diabetes [29, 30], taking into consideration that all the enrolled patients in our study have a long-standing type 2 diabetes mellitus (12.5 (± 6.22) years).
Regarding motor affection in the upper-limb nerves, the ulnar nerve MNCV was affected while the median nerve was in the normal range; this contrasts with what Hassan and his colleagues found in anemic pre-dialysis patients, the ulnar nerve was normal at the beginning of their study while median, peroneal and tibial nerves were affected . Another study reported that the facial nerve was more sensitive to uremic neuropathy than median and peroneal nerves while the ulnar nerve was the least involved in patients with end-stage renal disease of varying severity and duration (the frequency was 82, 68, 36 and 22%, respectively) .
Uremic toxins are believed to participate in the pathogenesis of uremic neuropathy; subsequently, both peritoneal and hemodialysis have proven partial reduction of uremic neuropathy progression . Early studies noticed a decrease in neuropathy occurrence with either increased frequency or dose of dialysis . Ghazan and his colleagues found that intensive home hemodialysis (5–6 nights/week) clears more uremic toxins than other conventional renal replacement therapy improving neurological symptoms . Similarly, another study found that daily hemodialysis enhanced improvement of neuromuscular function in ESKD patients more than conventional thrice-weekly hemodialysis . This improvement may be due to frequent daily elimination of the smaller sized molecules (urea and creatinine) and converting more toxic substances to the less harmful smaller molecules . Likewise, conventional thrice-weekly hemodialysis usually results in fluctuations in body fluid volume and solutes, which is different from normal body hemostasis. Increasing dialysis frequency may simulate the normal renal physiology in the healthy population lower fluctuations of solute concentrations and body fluid volume .
In our study, we had made our best to ensure that all the patients received the same dialysis dose. All patients underwent conventional thrice-weekly hemodialysis with almost similar dialysis doses regarding the length of treatment, frequency of dialysis, and hemodialyzer that diminishes the possibility of neurophysiological improvement because of hemodialysis only.
Upon initiation of the study, we noticed low MNCV of ulnar, common peroneal, and posterior tibial nerves. After 3-month hemodialysis (thrice weekly) with ESA therapy, both ulnar and posterior tibial nerves showed improvement that was statistically significant in the ulnar nerve (MNCV P = 0.016 and CMAP P = 0.067). Also, NCS of the radial nerve's sensory branch was within the normal range upon initiation of the study and showed statistically significant improvement after 3-month hemodialysis with ESA therapy (SNCV P = 0.009). On the other hand, patients in group B (who did not receive ESA) had no improvement in almost all electrophysiological studies.
These results concur with Hassan and his colleagues, who found significant improvement of MNCV of the median, peroneal, and tibial nerves (p = 0.04, p = 0.03, p = 0.04, respectively) after 5 months of ESA therapy . Also, Sobh and his colleagues described a significant increase in MNCV in six patients who underwent chronic hemodialysis with 3 months of ESA therapy .
Diabetic patients are predisposed to diabetic neuropathy and vasculopathy; their peripheral nervous system becomes more affected, especially the sensory part, in the uremic patients . This may explain the marked affection of CKD diabetic patients that was observed upon initiation of the study in comparison to non-diabetic CKD patients. After 3-month hemodialysis with ESA therapy, we recorded a significant improvement of ulnar and posterior tibial nerves (MNCV and CMAP amplitude) in non-diabetic CKD patients. On the other hand, diabetic CKD patients did not show improvement in almost all nerves after hemodialysis with ESA therapy.
We suggest that the absence of diabetic patients' improvement may be explained by the additional harmful effect of uncontrolled diabetes on peripheral nerves. Furthermore, the findings of improvement in motor more than sensory parameters after 3 months of treatment of ESA may be attributed to the early and augmented affection of sensory nerves by both diabetic and uremic neuropathies . These findings coincide with Hosseini-Zare MS and his colleagues, who found that although ESA therapy had corrected the anemia in mild-to-moderate CKD patients with diabetic neuropathy, neurophysiological parameters did not improve after 6 months of ESA therapy .
The improvement in nerve conduction velocity could be related to ESA's direct action through EPO receptors on human neuronal cells . Campana and colleagues revealed the presence of EPO receptors in Schwann cells and axons in the peripheral nervous system of animal models . Similarly, Keswani and his colleagues found that acrylamide-treated rats (a neurotoxic substance causes severe motor and sensory axonal degeneration) were given ESA showed significantly less sensory and motor axonal degeneration compared to those were given a placebo , suggesting that ESA prevents axonal degeneration.