High Levels of Serum Cystatin C and Chronic Kidney Disease Linked to Age-Related Macular Degeneration

February 27, 2009 — Serum cystatin C level and chronic kidney disease may have a link to incidence of age-related macular degeneration (AMD) that is independent of smoking and other risk factors, according to a population-based cohort study reported in the February issue of the Archives of Ophthalmology.

"Serum cystatin C has been used to estimate glomerular filtration rate to define the presence of CKD," write Ronald Klein, MD, MPH, from the University of Wisconsin School of Medicine and Public Health, Madison, and colleagues. "It is abundant in retinal pigment epithelium (RPE) cells and has been hypothesized through its effects on cathepsins to have a role in the pathogenesis of AMD."

The goal of this study was to examine the associations of the serum cystatin C level and chronic kidney disease with the incidence and progression of AMD during 15 years of follow-up in 4926 participants of the Beaver Dam Eye Study.

The participants were residents of Beaver Dam, Wisconsin, and were 43 to 84 years old at the time of their baseline examination, which took place between March 1, 1988, and September 14, 1990. Follow-up examinations were done at 5-year intervals. The 15-year follow-up examination was performed from March 31, 2003, through April 30, 2005, and included 2119 survivors of the original study cohort.

Casual blood specimens were obtained at each examination to determine white blood cell count, serum blood urea nitrogen, glomerular filtration rate, and cystatin C. The glomerular filtration rate from serum creatinine was estimated using the Modification of Diet in Renal Disease (Study) prediction equation. Mild chronic kidney disease was defined as a glomerular filtration rate of more than 45 mL/min/1.73 m² to 60 mL/min/1.73 m² or less. Moderate to severe chronic kidney disease was defined as a glomerular filtration rate of 45 mL/min/173 m² or more. Gross proteinuria concentration was determined using a dipstick test on a casual urine sample. AMD was determined by grading photographs of the macula.

The 15-year cumulative incidence of early AMD was 14.3%; pure geographic atrophy, 1.3%; exudative AMD, 2.0%; and progression of AMD, 12.2%. The prevalence and 15-year cumulative incidence and progression of AMD were similar in men and women and increased with age.

After controlling for age and other risk factors, the level of serum cystatin C at baseline was associated with the incidence of early AMD (odds ratio [OR] per log standard deviation, 1.16; 95% confidence interval [CI], 1.01 - 1.35) and exudative AMD (OR, 1.42; 95% CI, 1.03 - 1.96). However, baseline cystatin C was not associated with geographic atrophy (OR, 0.89; 95% CI, 0.56 - 1.41) or progression of AMD.

Mild chronic kidney disease was associated with the 15-year cumulative incidence of early AMD (OR per log standard deviation, 1.36; 95% CI, 1.00 - 1.86). However, it was not associated with the incidence of other AMD endpoints.

The statistically significant relationship of mild chronic kidney disease with early AMD but not with exudative AMD, geographic atrophy, or progression of AMD that was found in the Beaver Dam Eye Study is consistent with data from earlier studies, the authors comment.

"The Blue Mountains Eye Study showed that after adjusting for age, sex, and other risk factors, individuals with moderate CKD are 3 times as likely to develop early AMD compared with individuals with no or mild CKD (OR [95% CI], 3.2 [1.8 - 5.7]; P<.001)," the study authors write. "When using the same definition of CKD (based on the Cockcroft-Gault equation) as used in the Blue Mountains Eye Study, while controlling for other factors in a multivariable model, we found a relationship of CKD to incident early AMD (OR [95% CI], 1.53 [1.10 - 2.11]; P = .01) but not to incident exudative AMD (1.38 [0.68 - 2.66]; P = .37)."

The authors warn that the low frequency of chronic kidney disease and pure geographic atrophy "limit our ability to detect (or reject) meaningful relations" and that some findings that appear to be of potential biological significance may be entirely owing to chance, given the number of associations examined. Finally, they point out the possibility that no significant relationships between some risk factors and AMD were found because individuals with these factors who developed AMD did not live to participate in the follow-up examination.

They conclude that confirmation of their findings in other studies and a better understanding of the biological processes underlying these findings are needed.

This study was supported by the National Eye Institute, the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institutes of Health, and Senior Scientific Investigator Awards from Research to Prevent Blindness. The authors have disclosed no relevant financial relationships.

Arch Ophthalmol. 2009;127:146-152.