Retinal Microvascular Function Predicts Chronic Kidney Disease in Patients With Cardiovascular Risk Factors
May 15, 2023
Abstract
1. Background and aims
Endothelial dysfunction is a precursor to atherosclerosis and is implicated in the coexistence between cardiovascular disease (CVD) and chronic kidney disease (CKD). We examined whether retinal microvascular dysfunction is present in subjects with renal impairment and predictive of long-term CKD progression in patients with CVD.
2. Methods
In a single-center prospective observational study, 253 subjects with coronary artery disease and CVD risk factors underwent dynamic retinal vessel analysis. Retinal microvascular dysfunction was quantified by measuring retinal arteriolar and venular dilatation in response to flicker light stimulation. Serial renal function assessment was performed over a median period of 9.3 years using estimated GFR (eGFR).
3. Results
Flicker light-induced retinal arteriolar dilatation (FI-RAD) was attenuated in patients with baseline eGFR <90 mL/min/1.73 m2, compared to those with normal renal function (eGFR ≥90 mL/min/1.73 m2 ) (1.0 [0.4–2.1]% vs. 2.0 [0.8–3.6]%; p < 0.01). In patients with normal renal function, subjects with the lowest FI-RAD responses exhibited the greatest annual decline in eGFR. In uni- and multivariable analysis, among subjects with normal renal function, a 1% decrease in FI-RAD was associated with an accelerated decline in eGFR of 0.10 (0.01, 0.15; p = 0.03) and 0.07 mL/min/1.73 m2 per year (0.00, 0.14; p = 0.06), respectively. FI-RAD was not predictive of CKD progression in subjects with baseline eGFR <90 mL/min/1.73 m2.
4. Conclusions
Retinal arteriolar endothelial dysfunction is present in patients with CVD who have early-stage CKD and serves as an indicator of long-term CKD progression in those with normal renal function.
Keywords
Endothelial function; Retinal circulation; Microvascular dysfunction; Renal impairment; Chronic kidney disease; Dynamic vessel analysis.
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Introduction
Cardiovascular disease (CVD) remains the greatest contributor to increased morbidity and mortality among patients with advanced chronic kidney disease (CKD) [1]. Patients with CKD carry a disproportionately high burden of comorbid cardiovascular disorders and are more likely to die of CVD than progress to end-stage kidney disease (ESKD) [2,3]. The coexistence of CKD with CVD is felt to be due to the impact of established cardiovascular risk factors, along with non-traditional contributors including volume overload and endothelial dysfunction [4].
Vascular endothelial dysfunction, a sentinel event in the development of focal and systemic vascular disease, is a common occurrence in CKD [5] and is associated with adverse clinical outcomes [6]. Impaired endothelial function, as indicated by brachial artery flow-mediated dilation, laser Doppler flowmetry, and aortic pulse wave velocity, has been reported in CKD [7–9]. However, these methods are indirect, imprecise, or time-consuming, and generally measure endothelial function in larger vessels [10,11]. Given that microvascular endothelial dysfunction is an important characteristic of CKD, the establishment of the extent and identification of patients with microvascular endothelial dysfunction may provide insights into the development and progression of kidney disease.
Retinal microvascular endothelial vasodilatation, a nitric oxide-dependent phenomenon, provides a direct measure of vascular reactivity in the retinal microcirculation [12]. Real-time changes in retinal vascular caliber can now be quantified in response to diffuse luminance flicker using advances in retinal imaging. Previous studies have concluded that flicker light-induced retinal vasodilation may be more effective in predicting incident cardiovascular outcomes than static retinal fundus images [13,14]. Our group has shown that attenuated retinal arteriolar endothelial function is an independent predictor of major adverse cardiovascular events (MACE) and all-cause mortality in patients with or at high risk of coronary artery disease (CAD) [15]. Despite the strong association between retinal microvascular endothelial dysfunction and CAD, its implication in CKD remains unknown [16]. Accordingly, we sought to determine whether flicker light-induced retinal microvascular endothelial function is attenuated in subjects with renal impairment, and whether diminished retinal microvascular function is predictive of long-term CKD progression.
Patients and methods
1. Study design and patient population
The study protocol was approved by the Austin Health Human Research Ethics Committee (Reference H2009/03371) by the ethical guidelines of the 1975 Declaration of Helsinki. Written informed consent was obtained from all patients. Subjects were prospectively recruited between 2009 and 2010 from Austin Health, a teaching hospital of the University of Melbourne, Australia. All participants (n = 253) underwent static and dynamic retinal vascular assessment and serum biomarker evaluation. Inclusion criteria comprised at least two traditional cardiovascular risk factors or clinically stable CAD. Traditional cardiovascular risk factors included diabetes mellitus, dyslipidemia, hypertension, cigarette smoking, or a family history of premature CAD. Clinically stable CAD was defined by symptoms of myocardial ischemia and a positive functional study, or at least one coronary angiographic stenosis ≥50%. Exclusion criteria comprised subjects with ESKD, or conditions prohibiting adequate retinal vascular assessment, including cataracts, previous narrow-angle glaucoma, or epilepsy.
2. Static and dynamic retinal vascular imaging
Retinal examinations were conducted in a sound and temperature-controlled environment between 8 and 10 a.m. following a 12-h period of fasting. Vasoactive medications, caffeinated drinks, and nicotine were withheld for at least 12 h before the examination to minimize the influence on vessel caliber. Following pupillary dilatation with 1% topical tropicamide, digital color images were acquired with a Canon CF-60UVi fundus camera (Canon, Tokyo, Japan). Two photographic fields, centered on the optic disc and macula, were obtained for each eye. Using a standardized computer-based algorithm (IVAN, University of Wisconsin, USA) arteriole and venule diameters were measured in 60◦ digital grey-scale (red-free) fundus photographs. For each photograph, the six largest arterioles and venules traversing a zone between 0.5- and 1-disc diameter from the optic disc margin were measured and summarised as the central retinal artery and vein equivalents (CRAE and CRVE) [17]. The arteriovenous ratio (AVR) was defined as the ratio of the CRAE to the CRVE. Focal arteriolar narrowing (FAN) and arteriovenous nicking (AVN) were quantified based on the methods developed by Hubbard and colleagues [17]. All images were acquired by a single investigator (AA) and analyzed independently by the Centre for Eye Research Australia (Melbourne, Australia).
Flicker light-induced retinal vasodilatation was quantified using the Dynamic Vessel Analyzer (Imedos Systems UG, Jena, Germany) attached to a Zeiss FF450 fundus camera (Carl Zeiss Meditec, Germany) [16]. After pupillary dilation and 10 min of rest in a darkened room, dynamic retinal vessel analysis was performed with the patient in a seated position. In the upper or lower temporal quadrants, arteriolar and venular segments within 0.5-to-2-disc diameters from the optic disc margin were selected for continuous diameter recording. Measurements along the selected segment, preferably 1.0–1.5 mm in length, commenced at a frequency of 25 Hz, enabling 25 readings of vessel diameter per second. After 50 s of baseline measurement, flicker light provocation at 12.5 Hz was applied for 20 s, followed by 80 s of steady illumination to enable baseline vessel recovery [18]. Two identical provocation and illumination cycles were subsequently repeated, yielding a total experimental time of 350 s [19,20]. Measurement cycles were recorded in both eyes and averaged to calculate the maximum flicker light-induced retinal arteriolar (FI-RAD) and venular dilatation (FI-RVD), expressed as the percentage change in vessel diameter from baseline [21]. The intraclass correlation coefficients for retinal arteriolar and venular diameter have been previously reported by our group as 0.99 and 0.98, respectively [19]. FI-RAD and FI-RVD measurements have also shown to be highly reproducible, with intraclass correlation coefficients of 0.82 and 0.79, respectively [19,20]. All retinal measurements were performed by a single investigator (AA) trained in DVA assessment.
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3. Plasma biochemistry and endothelin-1 and assays
Venous blood samples were obtained from all fasted participants following retinal vessel assessment. Blood samples were stored on ice and centrifuged at 3000 revolutions per minute for 10 min at 4 ◦C. Plasma was collected and stored at − 80 ◦C until extraction. Plasma endothelin-1 (ET-1) was quantified using a previously described radioimmunoassay, with an intra-assay coefficient of variation of 7% [22]. Laboratory assays were conducted independently and without knowledge of clinical parameters (Austin Pathology, Austin Health, Melbourne, Victoria).
4. Follow-up procedures and renal outcomes
Serum creatinine was measured at the time of enrolment and over three further time points throughout the study. The timing of serial creatine measurements, beyond the baseline reading, was determined by clinical necessity according to the subject’s managing physicians. Serum creatinine values reflective of an acute kidney injury were excluded from the analysis. Acute kidney injury was defined according to the KDIGO (Kidney Disease Improving Global Outcomes) criteria as a 26.5 μmol/L or 1.5-fold increase in serum creatinine above the subject’s baseline [23]. A persistently elevated serum creatinine for two consecutive measures ≥30 days apart was accepted as the subject’s new baseline. For patients with serial creatinine measurements over multiple consecutive days, the median value was selected for inclusion. The estimated glomerular filtration rate (eGFR) was calculated according to the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation [24]. Clinical follow-up was conducted by investigators (JT and EW) blinded to clinical details at enrolment and included a review of hospital and physicians’ medical records. Adjudication of renal outcomes was performed by a committee of investigators (JT, EW, and AA) blinded to clinical details, with any disagreement resolved by consensus.
5. Statistical analyses
Normally distributed continuous parameters are expressed as mean ± standard deviation (SD), while those with a skewed distribution are reported as the median with interquartile range (IQR; 25th to 75th percentile). The normality of data was assessed using the Shapiro-Wilk statistic. Baseline patient characteristics, retinal parameters, and measures of endothelial function, stratified by baseline eGFR, were evaluated using the unpaired t-test, the Mann-Whitney U test, or the chi-squared statistic, as appropriate. The baseline relationship between eGFR and FI-RAD was assessed using Pearson’s correlation coefficient.
To investigate each participant’s decline in renal function over the study duration, a linear mixed effects model with unstructured covariance was fitted. Participants were entered as random coefficients and slope, while baseline eGFR group (≥90 versus <90 mL/min/1.73 m2 ) and time (in years) were entered as fixed effects. Due to the significant interaction between the eGFR group and time, all further analyses were stratified by the eGFR group.
To examine the effect of retinal arteriolar microvascular dysfunction with longitudinal changes in renal function (eGFR), FI-RAD values were converted into a categorical variable by tertile. A linear mixed effects model with unstructured covariance was fitted (random coefficients and slope) with the interaction between FI-RAD tertile and time (both as fixed effects).
Multivariable linear regression analysis was conducted to examine the association between clinical characteristics and retinal parameters with long-term eGFR decline (eGFR slope). Each participant’s eGFR decline was derived from a mixed effects linear model with random coefficients and slope. A multivariable model was developed using backward stepwise regression using variables with p ≤ 0.10 on univariable analysis. Analyses were performed separately for subjects with baseline eGFR ≥90 and < 90 mL/min/1.73 m2.
Statistical analyses were performed using SPSS version 23 for Windows (SPSS Inc., Chicago, IL, USA) and Stata version 16.1 for Mac (StataCorp, College Station, Texas, USA). Two-tailed p values ≤ 0.05 were considered statistically significant.
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Discussion
In the current prospective study, we examined the relationship between retinal microvascular endothelial dysfunction and renal impairment in patients with cardiovascular risk factors. We evaluated whether retinal microvascular endothelial dysfunction can predict long-term kidney impairment in this group of patients. The major finding of our study was that retinal arteriolar endothelial dysfunction, as quantified by FI-RAD, was significantly associated with early-stage CKD and predicted its progression; in subjects with normal renal function (eGFR ≥90 mL/min/1.73 m2 ), an incremental relationship was observed, whereby the lowest FI-RAD responses were associated with the greatest annual decline in eGFR. Retinal venular endothelial dysfunction, as measured by FI-RVD, was not associated with renal impairment or predictive of long-term CKD progression.
The retina offers a unique opportunity to directly and non-invasively assess the health of the human microcirculation in vivo. Given that the retinal and renal microcirculation share numerous morphological and physiological properties [25], the retinal assessment provides a central insight into the microvascular processes that underlie the pathogenesis of both retinopathy and kidney glomerular dysfunction [26]. Previous studies mostly used “static” (ie. single timepoint) retinal images to investigate the relationship between a range of retinal microvascular changes and CKD [27,28]. For example, static measurements of retinal arteriolar narrowing and venular dilatation, have been reported in established CKD risk factors, such as hypertension [29] and diabetes [30], with cross-sectional studies further describing a direct association between retinal arteriolar narrowing and CKD [31,32]. Similarly, large population-based studies have described an independent link between retinopathy signs (ie. microaneurysms, retinal hemorrhages) and renal dysfunction [26], with retinopathy serving as an independent risk factor for end-stage kidney disease in diabetic cohorts [33]. Mechanistically, the aforementioned retinal microvascular changes and those evaluated in this study reflect small vessel damage, precipitated by age, diabetes, hypertension, and inflammation [34]. However, a meta-analysis of studies suggests that retinal vessel diameter is not associated with CKD [35].
Our study extends these observations but uses a different approach by measuring “dynamic” changes in retinal vessel caliber, a marker of microvascular endothelial dysfunction. We show that dynamic retinal arteriolar changes to flicker light is associated with renal dysfunction at baseline and predictive of its progression over time. Thus, we establish retinal microvascular endothelial dysfunction as a precursory state to cumulative damage in both the retinal and renal microvascular networks.
We further attempted to evaluate the value of FI-RAD in predicting long-term kidney disease progression. In our cohort of patients with normal renal function (eGFR ≥90 mL/min/1.73 m2 ), a significant positive association emerged at baseline, whereby adjusted eGFR was greater with each successively higher tertile of FI-RAD. Over a median period of 9.3 years, a further gradient was observed in this same cohort, with the lowest tertile of FI-RAD associated with the greatest annual decline in eGFR. Notably, neither of these correlations was observed in patients with already impaired renal function. Taken together, our findings support the novel concept that attenuated FI-RAD may serve as a biomarker for the future development of kidney impairment in patients with CVD risk factors and normal renal function. Our data further validate the principle that retinal arteriolar endothelial dysfunction precedes the static morphological changes that characterize retinopathy and possibly, CKD. Interestingly, attenuation of FI-RAD has been documented in the early stages of other pathological processes. We recently reported no significant difference in FI-RAD between subjects with stable CAD, compared to those presenting with acute coronary syndrome [15]. Likewise, reduced FI-RAD responses have also been observed in pre-diabetic subjects without retinopathy, highlighting the potential of dynamic retinal vessel analysis as an early indicator of cardiovascular disease [36].
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In contrast, we observed no significant difference in FI-RVD in patients with and without CKD at baseline. These findings support earlier reports, whereby no correlation has been observed between any renal indices and FI-RVD, maximum venous dilatation, or dilatation amplitude [37]. Whilst the relationship between FI-RVD and baseline CKD has remained consistent, the predictive capacity of FI-RVD for long-term cardiovascular outcomes has been mixed. In the current study, FI-RVD was not predictive of long-term CKD progression. Additionally, we have previously reported that FI-RAD, but not FI-RVD, was predictive of long-term major adverse cardiovascular events in subjects with or at risk of CAD [15]. On the other hand, in a recent cohort of haemodialysed end-stage kidney disease patients, only FI-RVD was found to be an independent predictor of all-cause mortality [38]. Physiologically, the discrepancy in FI-RVD outcomes data may be related to its biochemical sensitivity. In a cohort of subjects with hypercholesterolemia and impaired retinal vasodilatation, only FI-RVD improved after a single low-density lipoprotein apheresis, implying that the retinal venules, and not the arterioles, respond to abrupt alterations in the microcirculation [39]. Accordingly, the physiological status of the patient must be accounted for when extrapolating FI-RVD as a single measure in time.
To explore a mechanistic link between retinal microvascular and renal glomerular dysfunction, we quantified serum concentrations of the potent vasoconstrictor, endothelin-1. We observed a significant elevation in endothelin-1 in subjects with eGFR <90 mL/min/1.73 m2 and a steeper decline in eGFR slope (p = 0.107) in participants with preserved renal function. Supportive evidence from animal models has demonstrated a role for endothelin-1 in modulating retinal hemodynamics via action on pericyte contractility [40], with human studies revealing a positive correlation between plasma endothelin-1 levels and the extent of diabetic retinal microangiopathy [41]. In the renal glomerulus, endothelin-1 has been implicated in the pathophysiological mechanisms linking podocyte impairment and proteinuria in diabetic and hypertensive nephropathy [42,43]. Collectively, the coexistence of endothelin-1 and nitric oxide in the human ophthalmic artery [44], with dysfunction of these opposing endothelial mediators seen in hypertension and diabetes, suggests an important role in the regulation of vascular tone in the pathophysiology of retinal microvascular complications. Dynamic retinal vessel analysis opens a direct window into evaluating endothelial function and nitric oxide production locally, whilst facilitating indirect insight into other morphologically similar microvascular beds, including the renal glomerulus. Therapies that enhance endothelial nitric oxide synthase, such as the SGLT2 inhibitors [45], improve systemic microvascular endothelial function, thereby resulting in better renal function and reduced MACE [46]. Further therapeutic studies targeting the retinal and renal microvascular networks would help establish a definitive role for endothelin-1 and nitric oxide in the development of retinal and glomerular microvascular injury.
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Limitations
Our study has several limitations that warrant discussion. First, functional retinal parameters were quantified at the time of participant enrolment, and not re-measured during the follow-up period. Accordingly, we assume a long-term correlation between baseline retinal variables and serial serum creatinine measurements. To elicit a more causative association, serial assessments of FI-RAD would be required over the lifespan of the study. Second, we cannot account for any lifestyle or pharmacological interventions that influenced long-term renal or retinal microvascular function. Future studies evaluating the modifiability of dynamic retinal vessel parameters would, however, be essential in ascertaining whether improvements in FI-RAD delay long-term CKD progression. Third, additional indicators of renal dysfunction, including albuminuria, microalbuminuria, and the albumin-to-creatine ratio, were not measured at baseline or during the follow-up period. Accordingly, there may have been a small number of patients with normal renal function (eGFR ≥90 mL/min/1.73 m2 ), who possessed subclinical evidence of kidney injury at enrolment. The inclusion of such subjects in the eGFR ≥90 mL/min/1.73 m2 cohort may have confounded our long-term analysis, given these patients were already predisposed to kidney disease. Finally, our cohort was modest in size, thereby necessitating larger validation studies to establish clinical viability. Nonetheless, our study represents the largest cohort of its kind, with robust, long-term follow-up serving as its major strength.
Conclusion
In summary, the present study demonstrates an association between attenuated retinal arteriolar endothelial function and early-stage kidney disease. Our results further support the hypothesis that impaired retinal arteriolar dilatation to flicker light stimulation, a nitric oxide-dependent response, serves as an early indicator of kidney disease progression in subjects with normal renal function. Overall, these findings highlight the promising utility of dynamic retinal vessel analysis in stratifying patients who have CAD and cardiovascular risk factors who are at high risk of CKD.
The Efficacy and Safety of Cistanche in chronic kidney disease
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Research has shown that Cistanche extract offers a range of therapeutic benefits, including anti-inflammatory and antioxidant properties, which may be important in managing CKD. These properties help to reduce inflammation and oxidative stress within the kidneys, which are key factors in the development and progression of CKD.
Several studies have investigated the efficacy and safety of Cistanche extract in CKD. One study found that supplementation with Cistanche extract improved renal function in CKD rats by decreasing levels of serum creatinine and urea. Another study demonstrated that Cistanche extract had protective effects against kidney damage in diabetic nephropathy rats by reducing oxidative stress markers.
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In conclusion, Cistanche extract shows promise as a safe and effective therapy for managing CKD due to its anti-inflammatory and antioxidant properties. However, further research is needed to establish its long-term safety and efficacy, as well as its optimal dosages and treatment protocols for this condition.
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James D. Theuerle a,b, Ali H. Al-Fiadh a,b, Edmond Wong a, Sheila K. Patel b, Gizem Ashraf a, Thanh Nguyen c,d, Tien Yin Wong e, Francesco L. Ierino f, Louise M. Burrell a,b, Omar Farouque a,b,
a. Department of Cardiology, Austin Health, Melbourne, Australia
b. Department of Medicine, Austin Health, The University of Melbourne, Melbourne, Australia
c. The Centre for Eye Research Australia, Royal Victorian Eye, and Ear Hospital, Melbourne, Australia
d. Ophthalmology, Department of Surgery, The University of Melbourne, Melbourne, Australia
e. Singapore Eye Research Institute, Singapore National Eye Centre, Duke-NUS Medical School, National University of Singapore, Singapore
f. Department of Nephrology, St. Vincent’s Hospital, Melbourne, Australia
