Choroidal and retinal thinning in chronic kidney disease independently associate with eGFR decline and are modifiable with treatment

In patients with chronic kidney disease (CKD), there is an unmet need for novel biomarkers that reliably track kidney injury, demonstrate treatment-response, and predict outcomes. Here, we investigate the potential of retinal optical coherence tomography (OCT) to achieve these ends in a series of prospective studies of patients with pre-dialysis CKD (including those with a kidney transplant), patients with kidney failure undergoing kidney transplantation, living kidney donors, and healthy volunteers. Compared to health, we observe similar retinal thinning and reduced macular volume in patients with CKD and in those with a kidney transplant. However, the choroidal thinning observed in CKD is not seen in patients with a kidney transplant whose choroids resemble those of healthy volunteers. In CKD, the degree of choroidal thinning relates to falling eGFR and extent of kidney scarring. Following kidney transplantation, choroidal thickness increases rapidly (~10%) and is maintained over 1-year, whereas gradual choroidal thinning is seen during the 12 months following kidney donation. In patients with CKD, retinal and choroidal thickness independently associate with eGFR decline over 2 years. These observations highlight the potential for retinal OCT to act as a non-invasive monitoring and prognostic biomarker of kidney injury.

restricted to participants with follow up scan at 12 months (B).

Supplementary table 7. Summary of univariable logistic regression models evaluating relationship between each chorioretinal metric (total macular volume and choroidal thickness
[locations one, two and three]) and the primary outcomes of a decline in eGFR of ≥10 at one year and ≥20% at two years.Two sided analyses.Abbreviations: CI -confidence interval; dfdegrees of freedom; eGFR -estimated glomerular filtration rate; OR -odds ratio.p values <0.05 are in bold. of an eGFR decline of ≥10% at one year.The table illustrates the effect of sequentially adding covariates to each logistic regression model.Based on its AIC and the likelihood ratio test statistic obtained when it was compared individually to the other five models, the model selected for the final analysis was Model 6. Please note: the odds ratios and 95% confidence intervals depicted for total macular volume refer to the effect of a 1 mm 3 increase in total macular volume, not a 1 mm 3 decrease -as is depicted elsewhere in the manuscript.

Supplementary table 9.
Comparison of multivariable logistic regression models evaluating the relationship between total macular volume and the odds of an eGFR decline of ≥20% at two years.The table illustrates the effect of sequentially adding covariates to each logistic regression model.Based on its AIC and the likelihood ratio test statistic obtained when it was compared individually to the other five models, the model selected for the final analysis was Model 6. Please note: the odds ratios and 95% confidence intervals depicted for total macular volume refer to the effect of a 1 mm 3 increase in total macular volume, not a 1 mm 3 decrease -as is depicted elsewhere in the manuscript.Two sided analyses.Abbreviations: AIC -Akaike Information Criterion; BP -blood pressure; CI -confidence interval; eGFR -estimated glomerular filtration rate; PCR -protein:creatinine ratio.
Choroidal thickness and kidney histology.Scatter dot plots of OCTderived choroidal thickness at location I (left panels), location II (centre panels) and location III (right panels) in relation to extent of interstitial fibrosis and tubular atrophy (IFTA, A) and glomerulosclerosis (B) from paired native kidney biopsies, n=46.Analysis by two-sided Pearson correlation coefficients.
, outer inferior; IN, inner nasal; IS, inner superior; IT, inner temporal; II, inner inferior; IC, inner circle.T, temporal; TS, temporal-superior; NS, nasal-superior; N, nasal; NI, nasal-inferior; TI, temporal-inferior; PMB, papillo-macular bundle; N/T, nasal-temporal ratio; G, average RNFL thickness.Lines represent mean. A. Macular volume vs. pre transplant ***p<0.001at 1 month, 3 months.12 months, *p=0.016 at 6 months.B. *p<0.05,**p<0.01,*** p<0.001 vs. pre-transplant.Analysis by two-sided mixed-effects model with Sidak correction for multiple comparisons.nasal; NI, nasal-inferior; TI, temporal-inferior; PMB, papillo-macular bundle; N/T, nasaltemporal ratio; G, average RNFL thickness.Lines represent mean. A. Location I vs. predonation *p=0.041 at 3 months, *p=0.012 at 6 months , *p=0.040 at 12 months; Location II vs. pre-donation **p=0.010at 3 months, **p=0.003at 6 months, **p=0.004at 12 months; change from pre-donation (microns) Location III vs. pre-donation *p=0.030 at 3 months, **p=0.005at 6 months, **p=0.005at 12 months.Two-sided analysis by mixed-effects model with Sidak correction for multiple comparisons.(right panel) from healthy volunteers who underwent OCT scanning at 0900, 1200 and 1600 (C).Line represents mean.CV -coefficient of variation, Analyses by linear regression, coefficient of variation and ANOVA.rings of diameters 1, 3, and 6mm, respectively.The inner and outer rings are further divided into quadrants: temporal, nasal, superior, and inferior.Retinal thickness is defined as the area bounded by internal limiting membrane (ILM, red) and Bruch's membrane (BM, blue).ON, outer nasal; OS, outer superior; OT, outer temporal; OI, outer inferior; IN, inner nasal; IS, inner superior; IT, inner temporal; II, inner inferior; IC, inner circle.B.Left panel is a CLSO image centred over the optic nerve head with line of cross-section (green) circled around the peri-papillary region.Right panel is an OCT image demonstrating retinal thickness from the circular cross-section around the optic nerve head in the left image.The green line running from left to right corresponds to the direction of cross-section of the green circle in left panel.Retinal nerve fibre layer (RNFL) thickness as defined by the red and cyan lines which is measured for 7 regions: T, temporal;TS, temporal-superior; NS, nasalsuperior; N, nasal; NI, nasal-inferior; TI, temporal-inferior.PMB, papillo-macular bundle.Using these values, two additional measures are calculated: N/T, nasal-temporal ratio; G, average RNFL thickness.C. CSLO (left panel) and horizontal line OCT scan with Enhanced Depth Imaging (EDI, right panel).Choroidal thickness was defined as the distance between the outer hyper-reflective line of the retinal pigment epithelium (RPE) (RPE/basement membrane complex) to the choroidal-scleral junction and was measured at 3 locations: I = 2 mm nasal to the fovea, II = subfoveal, III = 2 mm temporal to the fovea as shown.The corresponding locations on the macula are indicated by yellow arrows.