Corneal microstructural changes, and nephropathy, in participants with diabetes mellitus with and without peripheral neuropathy: a systematic review and meta-analysis

The aim of this review is to evaluate corneal microstructural changes and nephropathy in participants with diabetic peripheral neuropathy (DPN+) and without (DPN-) in each of type 1 (T1DM) and type 2 diabetes (T2DM). A systematic review of primary studies was conducted that quantified corneal sub-basal nerve plexus parameters using laser scanning in vivo corneal confocal microscopy (CCM) and DPN+ in at least five humans with diabetes mellitus. CCM parameters examined were corneal nerve fibre density (NFD), nerve branch density (NBD) and nerve fibre length (NFL). Weighted mean difference (+/- standard error) is reported. Twenty-six studies were included in this meta-analysis (18 for T1DM, 14 for T2DM). This comprised 1,357 participants with T1DM (573,784; DPN+, DPN-), 1,119 with T2DM (598,521; DPN+, DPN-) and 1,032 non-diabetic controls. Compared to T2DM, T1DM participants had larger differences in NFD (8.54 +/- 0.83 vs 3.61 +/- 0.41), NBD (11.92 +/- 1.93 vs 3.56 +/- 1.03) and NFL (4.24 +/- 0.41 vs 1.65 +/- 0.18) between DPN+ and DPN- groups. T1DM participants also had larger differences than T2DM participants in NBD (-21.26 +/- 2.90 vs -6.15 +/- 1.69) and NFL (-4.25 +/- 0.59 vs -2.65 +/- 0.31) between DPN- and non-diabetic controls, but smaller, insignificant difference, in NFD (-5.93 +/- 0.90 vs -6.39 +/- 0.92). eGFR was significantly different between DPN+ and DPN- in T1DM (p < 0.00001) but not in T2DM (p = 0.46). When comparing DPN- to DPN+, ACR was reduced in T1DM (-2.72 +/- 1.14) and T2DM (-20.85 +/- 8.91). Corneal sub-basal nerve changes and glomerular nephropathy likely precede peripheral neuropathy in T1DM and T2DM, with greater corneal neuropathy in T1DM. The current evidence suggests that CCM may be useful for monitoring the progression of diabetic neuropathy and nephropathy.