Early nerve fibre regeneration in individuals with type 1 diabetes after simultaneous pancreas and kidney transplantation

Abstract

Aims/hypothesis: The study aimed to assess the impact on neuropathy of simultaneous pancreas and kidney transplantation (SPK) in individuals with type 1 diabetes.

Methods: This longitudinal observational study examined neuropathic symptoms, deficits, quantitative sensory testing, neurophysiology, corneal confocal microscopy and skin biopsy results in 32 healthy (non-diabetic) control participants, 29 individuals with type 1 diabetes and severe diabetic peripheral neuropathy [DPN] and 36 individuals with type 1 diabetes after SPK.

Results: Following SPK, HbA_1c, eGFR, triacylglycerols and HDL improved significantly (all p < 0.05). Compared with the DPN group, which remained unchanged over the 36 month study period, corneal confocal microscopy assessments improved over 36 months following SPK, with increasing corneal nerve fibre density of 5/mm² (95% CI 1.8, 8.2; p = 0.003) and corneal nerve fibre length of 3.2 mm/mm² (95% CI 0.9, 5.5; p = 0.006). The Neuropathy Symptom Profile and peroneal nerve conduction velocity also improved significantly by 36 months compared with DPN (2.5; 95% CI 0.7, 4.3; p = 0.008 and 4.7 m/s; 95% CI 2.2, 7.4; p = 0.0004, respectively), but with a temporal delay compared with the corneal confocal microscopy assessments. Intraepidermal nerve fibre density did not change following SPK; however, mean dendritic length improved significantly at 12 (p = 0.020) and 36 (p = 0.019) months. In contrast, there were no changes in the Neuropathy Disability Score, quantitative sensory testing or cardiac autonomic function assessments. Except for a small decrease in corneal nerve fibre density in the healthy control group, there were no changes in any other neuropathy measure in the healthy control or DPN groups over 36 months.

Conclusions/interpretation: SPK is associated with early and maintained small nerve fibre regeneration in the cornea and skin, followed by an improvement in neuropathic symptoms and peroneal nerve conduction velocity.

Keywords: Corneal confocal microscopy; Diabetic neuropathy; Pancreas and kidney transplantation; Skin biopsy.

Fig. 1

Longitudinal least mean squares change from baseline values confirms early and sustained improvement in (a) CNFD and (b) CNFL, with a later improvement in (c) NSP score, (d) peroneal NCV and (e) sural nerve amplitude. *p < 0.05, **p < 0.01 vs baseline; ^†p < 0.01, ^††p < 0.001 SPK vs DPN over the time course; all statistical comparisons by mixed model repeated measures analysis. HC, healthy control; NCV, nerve conduction velocity

Fig. 2

Percentage change from baseline values in (a) CNFD, (b) CNFL, (c) NSP score, (d) peroneal NCV and (e) sural nerve amplitude. HC, healthy control; NCV, nerve conduction velocity

Fig. 3

Corneal confocal images of the sub-basal nerve plexus in (a) a control participant and (b–f) an SPK patient at baseline (b) and at 6 (c), 12 (d), 24 (e) and 36 (f) months, showing small fibre regeneration. Scale bars, 50 μm

Fig. 4

Representative examples of 50 μm skin biopsy sections immunostained for (a–d) PGP9.5 and (e–h) GAP-43 from a healthy control participant (a, e) and an SPK patient (b–d, f–h) . (a) The healthy control sample shows numerous long branching intraepidermal nerve fibres (IENFs) reaching the upper epidermis and a well-developed subepidermal nerve plexus. IENFs in an SPK patient at baseline (b) are sparse and short, showing (c) elongation and (d) branching after 12 months. Red arrows indicate nerves crossing the basement membrane and blue arrows show the terminal part of the IENF. (e) GAP-43 immunostained nerve fibres from the same healthy individual as in (a) are long and branching and those from an SPK patient at baseline (f) and at 12 (g) and 24 (h) months after SPK show a similar pattern as those stained for PGP9.5. Scale bars in (a) and (e), 50 μm; scale bars in (b–d) and (f–h), 25 μm