In this longitudinal study of young people with type 1 diabetes, normal AER, and no retinopathy at baseline, greater retinal venular LDR and lower venular tortuosity predicted incident renal dysfunction independent of established risk factors including diabetes duration, glycemic control, BP, and total cholesterol. We also confirmed our recent findings that lower arteriolar LDR and greater arteriolar tortuosity were associated with incident retinopathy (data not shown) (14
We recently proposed that, in the diabetic milieu, neuroretinal hypoxia leads to a compensatory increase in afferent blood flow through increased vessel density (earlier arteriolar branching resulting in lower arteriolar LDR) and a corresponding increase in arteriolar tortuosity (14
). Although this described the afferent changes in blood flow, it is important to understand the adaptations at the efferent (venular) end and their significance.
Whereas arteriolar changes may best represent localized organ tissue changes (14
), venular changes may better reflect systemic compensation and maladaptation. Determinants of resistance to blood flow within a vascular network include the individual blood vessel size (caliber and length), the organization of the vascular network (series and parallel), and the flow characteristics (laminar versus turbulent). Although the microcirculation provides most of the systemic vascular resistance, it has low Reynolds numbers and therefore turbulence at this level is unlikely to occur. In this setting, hydrostatic and oncotic pressures, viscosity, and wall shear stress would be most influential. Hyperglycemia causes significant hemodynamic and rheological changes (19
), including increased retinal blood flow (20
) and blood viscosity (19
). Furthermore, changes to particulate components of blood include greater platelet aggregation (19
) and increased leukocyte numbers with higher integrin-mediated adhesion properties promoting leukostasis (11
). We propose that decreased venular network complexity together with early vascular tone dysregulation and non-Newtonian influences contribute to increased capillary hydrostatic pressure, greater wall shear stress, and vessel damage. Thus, individuals with a simplified venular network may be at greater risk of microvascular complications such as renal dysfunction.
Baseline characteristics () demonstrated overall narrower arteriolar calibers in those with renal dysfunction. However, longer diabetes duration was associated with wider vessel calibers (both arteriolar and venular). This may describe the natural history of microvascular changes in diabetes: 1
) early impairment of microvascular autoregulation with inappropriate vasoconstriction, 2
) subsequent compensatory dilation, 3
) loss of smooth muscle cells and pericytes (or podocytes in the kidney), and 4
) loss of wall structural integrity and, finally, irreversible dilation. Early hyperglycemia results in a downregulation of large-conductance, calcium-activated potassium channels necessary for vascular smooth muscle cell relaxation, leading to early vasoconstriction and neuroretinal hypoxia (21
). Diabetic rat models demonstrated a similar dysregulation in the renal microvasculature early in diabetes with severe insulin deficiency. It has been speculated that tissue hypoxia beyond a certain threshold may override the vasoconstrictive effect of diabetes (12
). Finally, large population-based studies associated wider retinal venules with proteinuria in adults with type 1 diabetes of longer duration (13
Changes in vessel caliber are most influential in the acute regulation of blood flow. According to the Poiseuille equation, vessel resistance is inversely proportional to the vessel radius to the fourth power (r4
). Thus, even small changes in the diameter of arterioles and venules can lead to significant changes in blood flow and capillary pressures. Capillary hypertension has been associated with both retinopathy (12
) and nephropathy (22
). Classical renal micropuncture studies demonstrated that glomerular hypertension ensued in diabetes models even in the setting of normal BP (23
). Diabetes led to an impairment of glomerular circulatory autoregulation, with greater vasodilatation of the afferent arteriole than the efferent arteriole, which resulted in greater intraglomerular capillary pressure (23
). Ultimately, this exposes the glomeruli to increased intracapillary pressure, increased shear stress, and mechanical stretch. Mechanical stretch has been observed to favor an accumulation of extracellular matrix (24
) and a decrease in podocyte number through effects on cell proliferation, apoptosis, and cell adhesion to the basement membrane (22
). In this setting, even minor increments in systemic BP would exacerbate glomerular hypertension in a self-perpetuating cycle of ongoing hypertensive injury with impaired microvascular autoregulation. The efficacy of ACE inhibitors in retarding the progression of DN may in part be due to their vasodilatory effect on the efferent glomerular arteriole, thus decreasing glomerular capillary pressure (25
Although we observed higher BP in those with baseline renal dysfunction (), BP measured at each visit did not predict renal dysfunction in GEE longitudinal analysis (). A longer follow-up period may be required to examine this relationship with adequate statistical power.
In our study, A1C was an independent predictor of early renal dysfunction in keeping with previous reports (26
). Loss of capillary autoregulation, higher glomerular capillary pressure, and decrease in podocytes are related to the severity and chronicity of hyperglycemia (22
This study of normotensive young people with no intercurrent medications provides an insight into the preclinical renal dysfunction associated with diabetes and may assist in identifying those at greatest risk where early intervention may yield greatest benefit. The lack of a statistically significant association between BP and incident renal dysfunction in our multivariate models contrasts with previous findings regarding retinopathy (27
). It is noteworthy that a significantly greater proportion of those who developed incident renal dysfunction also developed incident retinopathy. Thus, changes in BP may only become apparent later in the course of renal disease where capillary bed autoregulation may no longer be able to compensate for metabolic demands. This also suggests that retinal hypoxic demands may have a greater influence in BP autoregulation than changes in renal microvasculature. This is consistent with our previous observations between BP and retinopathy in young people with type 1 diabetes (27
Our findings suggest that a simplified venular network (i.e., greater LDRv and lower STv) results in a greater risk of early renal dysfunction. As previously described, lower LDR can result from shorter axial length due to earlier branching points and/or wider vessel calibers (14
Our current software does not report vessel length; however, our results suggest venular axial length was increased in view of the wider venules observed with longer diabetes duration. These early venular differences may represent greater tissue metabolic demands, mechanical stress, and an increased propensity for early nephropathy. Our measures of tortuosity and LDR had good reproducibility; however, branching angles are particularly vulnerable to parallax error as reflected in the relatively low intraobserver correlation. Not unexpectedly, therefore, there were no significant associations in GEE models between branching angles and renal dysfunction.
The strengths of this study include the longitudinal design, a large patient cohort with multiple visits per individual, and standardized, quantitative evaluation of retinal vascular measures by a single grader masked to participants’ clinical status. Our young cohort without comorbidities avoids confounders present in older groups with established complications and medical therapy. The use of GEEs allowed inclusion of every available patient visit in the analysis and accounts for uneven follow-up and missing data. The reproducibility of LDR and ST measures (ICCs ranging from 0.80 to 0.96) was comparable with retinal vascular caliber measurements in the Atherosclerosis Risk on Community study (ICCs ranging from 0.79 to 0.83) (28
). Repeated longitudinal LDR and ST measures would strengthen this study. This cohort from a tertiary referral center may be biased toward closer monitoring, tighter metabolic control, and, thus, underrepresentation of early renal dysfunction; conversely, this underscores the robust nature of the measures studied.
Limitations of our measurements include the use of the central retinal field only and the lack of reporting absolute values for vessel length. Therefore, we cannot generalize our findings to the whole microvascular bed involving peripheral retinal areas that need further study both structurally and functionally. The spherical nature of the retinal surface cannot be accurately assessed in two-dimensional photographs and has an inherent degree of parallax error when evaluating branching angles. Nevertheless, our results demonstrate the potential utility of novel quantitative measurements of retinal vascular geometry from this central field, which is practical and reproducible, in people with diabetes.
In summary, retinal vascular geometry parameters, specifically retinal venular LDR and tortuosity, are independent predictors of incident renal dysfunction in young people with type 1 diabetes. These noninvasive retinal measures may further our understanding of early mechanistic pathways for microvascular complications. Functional studies examining blood flow would complement these findings. Future studies replicating these findings in other populations are needed. Our study highlights the role of venular LDR and tortuosity as tools for risk stratification of individuals at high risk for microvascular complications, and in monitoring of disease progression and therapeutic benefits.