Retinal arteriolar narrowing as marker of renal dysfunction: potential value and limitations

A consistent body of evidence points toward the presence of a close relationship between advanced retinopathy (documented by the evidence of hemorrhages, microaneurysms, hard and soft exudates) and kidney dysfunction in both diabetic and nondiabetic patients [1–5]. Whether and to what extent this is the case also for the association between early retinal and renal alterations is more controversial. In the Atherosclerosis Risk in Communities study, for example, development of renal dysfunction (defined as an increase in serum creatinine of at least 0.4 mg/dl or a death or hospitalization due to kidney disease) was unrelated to retinal arteriolar-venular ratio in a large population sample (more than 10 000) followed for a 6-year period [6]. This was also the case for the 1394 elderly participants enrolled in the Cardiovascular Health study, in which the presence of retinal arteriolar abnormalities (arterovenous nicking, focal arteriolar narrowing or lowest quartile of arteriolar-venular ratio) was not associated with deterioration of renal function (i.e. a 0.3 mg/dl increase in serum creatinine or ≥20% decrease in estimated glomerular filtration rate) during the 4-year follow-up period [7]. Similar findings were obtained by our group in a recent study, in which the relationships of arteriolar-venular ratio with microalbuminuria and estimated glomerular filtration rate were assessed in about 400 middle-aged essential hypertensive patients [8]. Overall, the two above-mentioned markers of renal damage, either as continuous or categorical variables, did not show significant differences across quartiles of artero-venous ratios, a finding which was further confirmed by the lack of correlation between microalbuminuria, estimated glomerular filtration rate and retinal arteriolar-venular ratio. At variance from the above-mentioned studies, however, data collected in diabetic populations provide evidence that in the initial clinical phases of renal disease, early retinal abnormalities (as assessed by standardized quantitative image analysis techniques) take place, supporting the view that the assessment of retinal caliber may have a predictive value as far as the risk of nephropathy is concerned. This is confirmed by the results of the Wisconsin Epidemiologic study of Diabetic Retinopathy, a population-based cohort of 557 patients with type 1 diabetes, showing a significant and direct relationship between retinal venular caliber and incident macroproteinuria and renal insufficiency (estimated glomerular filtration rate <60 ml/min per 1.73 m2) over a 16-year period, independent of other traditional risk factors [9]. Similar findings have been reported in the type 2 diabetic cohort of the same study, in which the average caliber of retinal venules (i.e. central retinal venular equivalent) but not of retinal arterioles was independently related to the incidence and progression of diabetic nephropathy [10]. In the present issue of the Journal, two studies provide evidence on a close link between the presence of retinal microvascular disease and markers of early renal dysfunction such as a reduced estimated glomerular filtration rate and microalbuminuria. Both studies advance the hypothesis that retinal vessel examination, based on new imaging technologies, may be of help in identifying patients with subclinical renal disease. In the first study, carried out in a large multiethnic population-based sample living in Singapore, Sabanayagam et al. [11] show that the presence of a generalized retinal arteriolar narrowing, a vascular phenotype reflecting both functional and structural changes from a variety of cardiovascular risks, including high blood pressure, increases the likelihood of chronic kidney disease, defined by an estimated glomerular filtration rate less than 60 ml/min per 1.73 m2. In the second study, Ritt et al. [12] examine the relationship between wall-to-lumen ratio of retinal arterioles, assessed using scanning laser Doppler flowmetry, and markers of early renal microvascular damage in a selected group of 39 nondiabetic overweight and obese individuals. Despite some methodological limitations that deserve a critical appraisal, both papers offer a new piece of information on the clustering of early retinal changes and subclinical renal damage. The report by Sabanayagam et al. [11] confirms and expands previous evidence on the clinical value of computerized assessment of retinal vessel caliber by showing that retinal arteriolar narrowing (defined as the lowest central retinal arteriolar equivalent quartile) may be regarded as a reliable marker of renal dysfunction in both normotensive and hypertensive individuals. There are two main findings of the study. One, the prevalence of chronic renal disease was related to central retinal arteriolar equivalent values, being highest (7.8%) in the first quartile (i.e. the quartile with the lowest retinal arterial caliber), intermediate in the second (5.0%) and third (4.5%) quartiles and lowest in the fourth quartile (3.8%). Two, looking at the combined effects of hypertension and arteriolar narrowing, an approximately six-fold higher prevalence of renal disease was found in hypertensive patients in the lowest central retinal arteriolar equivalent quartile as compared with their normotensive counterparts, suggesting that the combined presence of hypertension and retinal narrowing is strongly related to renal disease, independently of ethnicity, sex, age and conventional risk factors. Some limitations of the study should also be highlighted, however. First, as recognized by the authors, the cross-sectional design of the study is not the best approach for testing the hypothesis. Second, definition of the kidney disease phenotype was based on a single determination of serum creatinine and may have misclassified renal status in patients with transient rather than chronic renal dysfunction. Indeed, findings from a large Canadian registry have shown that low estimated glomerular filtration rate values at a first determination were confirmed in subsequent testing performed within at least 30 days in less than two-thirds of the individuals surveyed [13]. Important strengths of the study balancing the above-mentioned limitations include the analysis of three different ethnic groups, a comprehensive and sophisticated statistical approach aimed at avoiding possible interference of several confounders and the standardized procedures for measurement of retinal vascular caliber independently performed from an excellence reading center. Finally, the results of the present study are strengthened by the similar findings obtained by the same group of investigators in a population-based cohort of 3280 adults of Malay ethnicity [14]. In this Asian cohort, arteriolar narrowing was found to be associated with chronic kidney disease or micro/macroalbuminuria. The contribution by Ritt et al. [12] focuses on the relation of retinal arteriolar remodeling, as assessed by an innovative methodology based on scanner laser Doppler flowmetry, with two distinct parameters of vascular damage, that is, microalbuminuria and changes in vascular reactivity to infusion of the nitric oxide synthase inhibitor N-monomethyl-L-arginine (L-NMMA). The results show an independent association between wall-to-lumen ratio of retinal arterioles and urinary albumin-to-creatinine excretion ratio. In addition, they demonstrate that wall-to-lumen ratio of retinal arterioles is inversely related to the aortic augmentation index changes brought about by the infusion of L-NMMA. Both findings support the concept that an increased wall-to-lumen ratio of retinal arterioles reflects the presence of vascular damage generalized to the whole cardiovascular system. Microalbuminuria is a marker of impaired renal function and, more generally, of endothelial dysfunction; and an established risk factor for cardiovascular morbidity and mortality and for end-stage renal disease [15]. Some implications of this study need to be briefly emphasized. The assessment of retinal arteriolar structure and geometry by scanner laser Doppler flowmetry represents an important innovative advance in detecting subclinical microvascular damage. The present study, conducted on a relatively small group of individuals characterized by a narrow spread in demographic and clinical characteristics and without overt cardiovascular and renal disease, hypertension or diabetes, reinforces previous findings showing the relationship between increased wall-to-lumen ratio of retinal arterioles and established markers of vascular damage and suggests that this new approach may have a pivotal role in stratifying cardiovascular risk. In summary, although the clinical and prognostic value of early microvascular retinal abnormalities assessed either by clinical ophthalmology or qualitative evaluation of eye ground photography still remains questionable, the development and, more importantly, the implementation in clinical practice of new standardized quantitative imaging analysis techniques may provide new perspectives in the difficult task of assessing the impact of hypertension and other major cardiovascular risk factors on retinal vascular network.

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