Peripheral neuropathy response to erythropoietin in type 2 diabetic patients with mild to moderate renal failure

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Abstract

This study assessed the added effect of 6 months of erythropoietin (EPO) administration in patients suffering from diabetic neuropathy with mild to moderate chronic kidney disease (CKD) managed with gabapentin.

Twenty diabetic patients with mild to moderate CKD were included; 12 in gabapentin and 8 in EPO + gabapentin group. The subjects underwent nerve conduction studies (NCS) at the initiation of the investigation and after 6-month treatment. NCS were made in deep and superficial peroneal, tibial, and sural nerves.

After 6 months, in both the groups, proximal motor latency (PML) nonsignificantly improved in deep peroneal and tibial nerves; conversely, dorsal motor latency (DML) got slightly impaired in these two nerves. A nonsignificant disruption and improvement was observed in deep peroneal and tibial motor nerve conduction velocity (MNCV), respectively, in gabapentin group. Although the F-wave of tibial and deep peroneal nerves remained stable in gabapentin group, a nonsignificant improvement was observed in EPO + gabapentin group. H-reflex of tibial nerve and all the evaluated parameters of sural and superficial peroneal nerves remained constant in all patients.

Thus, it can be concluded that 6-month administration of EPO + gabapentin, or gabapentin alone in mild to moderate CKD patients with diabetic neuropathy could not improve nerve performance.

Introduction

Peripheral neuropathy is one of the most common complications of diabetes mellitus (DM) causing significant morbidity and mortality [1]. A total of 20–30% of the diabetic patients suffer from peripheral neuropathy [2] affecting sensory, autonomic, and motor neurons of peripheral nervous system [3].

Neurophysiological examinations play important roles in the assessment of diabetic neuropathy progression and also lead us to distinguish muscular from neuropathic diseases [4]. Nerve damage typically manifests as painless loss and sensation change that may be detected just by clinical tests [3]. Pain and paresthesia as the common symptoms of sensorimotor neuropathy typically initiate from the most distal extremities (fingers and toes) [1]. It seems that most of the diabetic patients suffer from length-dependent polyneuropathy [5]. Most of these patients have a slowing nerve conduction velocity due to nerve demyelination and reduction of large myelinated fibers. Axons loss leads to decrease in nerve action potential in diabetic patients [6]. The accelerated form of neuropathy has been observed in patients suffering from both renal failure and DM [7]. Gabapentin as an anticonvulsant drug, although not approved by FDA, has been commonly used to relieve diabetic neuropathy and has improved the quality of life of these patients [8]. Most of the advanced chronic kidney disease (CKD) and dialysis patients suffer from peripheral neuropathy recognized as uremic neuropathy. Uremic neuropathy is a distal symmetrical involvement of motor and sensory nerves that affects legs more than arms [9]. The clinical features of uremic neuropathy include weakness and length-dependent sensory impairment [10]. Electrophysiological studies demonstrated moderate slowing of nerve conduction velocity in these patients [11]. The pathogenesis of uremic neuropathy is not clearly understood; however, it is assumed to be owing to certain toxins [9].

Erythropoietin (EPO) is a glycoprotein, which is mainly produced in peritubular renal cortex [11]. The progenitor cells of bone marrow contain EPO receptors provoking erythroid cell proliferation and increasing red blood cell (RBC) mass [12]. Anemia is a common complication of CKD, especially among patients with diabetes. EPO is the drug of choice to treat anemia in these patients [12], [13]. Additionally, EPO may play an important role in the development of neural progenitor cell [14] and promote neuron-angiogenesis and differentiation [15], [16]. The higher amounts of EPO in cerebrospinal fluid of premature infants, when compared with new-born children suggest potential nerve productive effect of EPO [17]. Some studies have shown that EPO administration improved autonomic and peripheral neuropathies in patients with moderate and advanced diabetic nephropathy [18], [19].

This study was designed to assess the added effect of 6-month EPO administration in patients suffering from diabetic neuropathy with mild to moderate renal failure managed with gabapentin.

Section snippets

Patients

During the 2 years of this study, 200 patients with type 2 DM, who suffered from peripheral neuropathy and referred to nephrology clinics of Imam-Khomeini Hospital Complex affiliated to Tehran University of Medical Sciences, were evaluated. Their glomerular filtration rate (GFR) was assessed according to modified diet renal disease (MDRD) formula. To exclude patients with uremic neuropathy, only subjects with mild to moderate CKD (estimated GFR of >30 mL/min) were considered. The medical history

Results

A total of 24 patients were included in the study, out of which 4 patients were excluded. The excluded subjects comprised one in the EPO + gabapentin group due to patient death and three in the gabapentin group (one patient death and two diagnosed to have malignancy). Thus, 20 patients with a mean age of 63.30 ± 8.29 years (range: 51–81 years), mean body weight of 71.63 ± 13.3 kg (range: 52–110 kg), mean SCr of 1.6 ± 0.44 mg/dL (range: 0.9–2.2 mg/dL), and mean estimated GFR of 38.12 ± 5.59 mL/min/1.73 m2

Discussion

Chronic hyperglycemia is associated with microvascular changes and endoneural hypoxia, and sensitizes diabetic nerves to ischemia [20]. Diabetic neuropathy, as an outstanding high-frequent complication, causes significant morbidity in diabetic patients. This disorder sometimes results in tissue necrosis and leads to limb amputation. Moreover, it was proved that in diabetic neuropathy, the most distal sensory fibers in the lower extremities are affected more frequently than the upper extremities

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