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Cystatin C, Other Markers of Kidney Disease, and Incidence of Age-Related Cataract

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Cystatin C, Other Markers of Kidney Disease, and Incidence of Age-Related Cataract EPIDEMIOLOGY Cystatin C, Other Markers of Kidney Disease, and Incidence of Age-Related Cataract Barbara E. K. Klein, MD, MPH; Michael D. Knudtson, MS; Peter Brazy, MD; Kristine E. Lee, MS; Ronald Klein, MD, MPH Objective: To investigate the 15-year incidence of 3 spe- dence interval [CI], 1.09-1.41) and posterior subcapsu- cific types of age-related cataract as related to cystatin C lar (OR, 1.24; 95% CI, 1.02-1.50) cataracts. One SD and other measures of kidney function. increase in the logarithm of blood urea nitrogen and cre- atinine were associated with 15-year incidence of pos- Methods: Examinations of a population-based cohort terior subcapsular cataract (OR, 1.22; 95% CI, 1.04- (n=4926) occurred at 5-year intervals for 15 years. As- 1.42 and OR, 1.26; 95% CI, 1.03-1.54, respectively). sessment of medical history, examination, and photo- graphs of the lens after pupil dilation were performed at Conclusion: Increased levels of cystatin C are associ- each examination. Protocols for photography and grad- ated with increased risk of specific types of age-related ing were used. Laboratory measures were from speci- cataract. Whether the associations are due to the meta- mens collected at baseline. bolic changes associated with decreased renal function, common genes, or both awaits further research. Results: In multivariable analyses, a 1-SD increase in the logarithm of cystatin C was associated with 15-year in- cidence of cortical (odds ratio [OR], 1.24; 95% confi- Arch Ophthalmol. 2008;126(12):1724-1730 ATARACTS, THE MOST COM- lected in the urine and does not reappear mon cause of visual impair- in the blood. It is produced by all nucle- ment and blindness world- ated cells in the body. Its production rate wide, are concomitants of is not affected by the subject’s diet, but its aging.1-3 Age-related cata- levels are affected by either hyperthyroid- Cracts (ARC) are associated with many risk ism or hypothyroidism and they fluctuate factors including a variety of environmen- with other markers of inflammation such tal and personal exposures such as life- as C-reactive protein.24,25 Serum cystatin C style habits, diseases, and metabolic char- concentration appears to correlate more acteristics.4-18 Those with severe kidney closely with GFR than serum creatinine and disease appear to be at increased risk of ARC; is more sensitive in identifying subjects with mild kidney dysfunction may also en- mild renal insufficiency.26 hance the risk of cataract.19-23 Serum creati- Cystatin C has also been linked to other nine and blood urea nitrogen (BUN) are systemic diseases27,28 but, to our knowl- used as markers of renal function or glo- edge, has not been examined regarding the merular filtration rate (GFR) in standard development of ARC. Our purpose is to de- clinical practice. These markers are imper- termine whether measures of cystatin C and fect because their levels in the blood are af- other measures of kidney function are as- fected by factors other than GFR such as di- sociated with incidence of ARC during a 15- etary protein, state of hydration, and renal year interval in the population of adults who tubular reabsorption or secretion. Research- participated in the Beaver Dam Eye Study. Author Affiliations: ers have identified another endogenous sub- Departments of Ophthalmology stance that appears to be a better noninva- METHODS and Visual Sciences sive marker of GFR, cystatin C. This (Drs B. E. K. Klein and R. Klein, Mr Knudtson, and Ms Lee) and substance is a low–molecular weight pro- POPULATION Medicine, Nephrology Section tein that is a member of the cystatin super- (Dr Brazy), University of family of cysteine protease inhibitors. It is The population and recruitment methods for Wisconsin School of Medicine filtered by the kidney and then metabo- the full cohort have been described in previ- and Public Health, Madison. lized by the tubules so it cannot be col- ous articles.29-37 In brief, a private census of the (REPRINTED) ARCH OPHTHALMOL / VOL 126 (NO. 12), DEC 2008 WWW.ARCHOPHTHALMOL.COM 1724 ©2008 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 population of Beaver Dam, Wisconsin, was performed from Sep- LABORATORY ANALYSES tember 15, 1987, to May 4, 1988, to identify all residents in the city or township of Beaver Dam aged 43 to 84 years. A total Casual blood specimens were obtained at the time of the base- of 5924 eligible individuals were identified and invited for a line examination. An aliquot of serum was used immediately baseline examination between March 1, 1988, and September for determination of total cholesterol,39 blood glucose,40 and 14, 1990.29 The Tenets of the Declaration of Helsinki were fol- BUN. Whole-blood glycosylated hemoglobin was determined lowed, institutional review board approval was granted, and in- using affinity chromatography (Isolab Inc, Akron, Ohio) from formed consent was obtained from each subject. Examina- casual blood samples. Cystatin C, creatinine, and high- tions were completed for 4926 persons. The most common sensitivity C-reactive protein (hsCRP) were measured in 2007 reason for nonparticipation after the baseline examination was from serum specimens that had been collected at baseline and death. Ninety-nine percent of the population was white, as clas- frozen at −80°C since that time. Laboratory methodologies re- sified by the examiner. Comparisons between participants and lating to measurement of these markers are provided below. nonparticipants at the baseline have been presented else- Serum BUN levels were measured using the colorimetric where.29 In brief, nonparticipants (dead or alive) were older, method (the Berthelot reaction) on a Technicon RA-1000 Au- had fewer years of education, were less likely to be currently toAnalyzer (Technicon Instruments, Tarrytown, New York). employed, had poorer visual acuity, were more likely to have Creatinine levels were measured in serum by rate reflec- cardiovascular disease, had diabetes, smoked more, and had tance spectrophotometry using thin-film adaptation of the cre- higher systolic blood pressures. atine amidinohydrolase method on the Vitros analyzer (Johnson & Johnson Clinical Diagnostics Inc, Rochester, New York) at TIMING OF STUDY VISITS the Collaborative Studies Clinical Laboratory at Fairview- University Medical Center (Minneapolis, Minnesota). The ref- Visits occurred at 5-year intervals from the baseline examina- erence range in adult women was 0.4 to 1.1 mg/dL (to convert tion for 3 follow-up evaluations. Of the 5924 enumerated per- to micromoles per liter, multiply by 76.25) and in adult men sons aged 43 to 84 years, 4926 participated in baseline exami- was 0.5 to 1.2 mg/dL. The laboratory coefficient of variability nations from 1988 to 1990. Of these, 3684 (81.1%) participated (CV) was 2.2%. in 5-year follow-up examinations from 1993 to 1995. Of the Cystatin C levels were determined using the Dade Behring 3334 surviving participants in the baseline and second exami- BN100 nephelometer (Deerfield, Illinois) as follows: a solu- nation, 2764 (82.9%) participated in the 10-year follow-up. Of tion of polystyrene particles coated with antibodies specific to the 2480 surviving participants who were examined at the base- human cystatin C was incubated with diluted specimen. A re- line, 5-, and 10-year follow-ups, 2119 (85.4%) participated in action occurred between the bound antibody and the cystatin the 15-year follow-up. Comparison of participants and non- C in the specimen, resulting in particle aggregation and an in- participants at each examination phase have been detailed else- crease in light absorbance. The cystatin C concentration of the where.29-31 test specimen was determined by comparing its absorbance For the current incidence analyses, participants had to have change to that of a calibration curve. The interassay precision attended the baseline examination, not had the cataract type was determined at 2 control levels: 1.72 mg/L (CV, 6.4%) and of interest at baseline, provided a blood specimen, partici- 0.78 mg/L (CV, 5.2%). pated at the first 5-year follow-up, and may have participated The level of hsCRP was measured in serum using a latex- in 1 or more subsequent examinations. Gradable lens photo- particle enhanced immunoturbidimetric assay kit (Kamiya Bio- graphs had to be available for each relevant visit. A total of 3097 medical Company, Seattle, Washington) and was read on the persons contributed to at least 1 analysis. Roche/Hitachi 911 (Roche Diagnostics, Indianapolis, Indi- ana). The reference range was 0 to 0.5 mg/L (to convert to nano- moles per liter, multiply by 9.524). The interassay CV range EXAMINATION, INTERVIEW, in our laboratory was 4.5%. Proteinuria was measured with a AND GRADING PROTOCOLS dipstick on a casual urine specimen obtained at the baseline examination. The same protocols, with few additions or deletions, were used at each examination phase. A brief medical history, including DEFINITIONS use of medication, was obtained. Photographs of the lens were taken after pharmacologic dilation. Slitlamp photographs were In analyses using a categorical cutpoint, the following were con- taken to grade the degree of nuclear sclerosis. Retroillumina- sidered abnormally high: serum cystatin C higher than 0.95 tion photographs were taken to grade the presence and sever- mg/L; serum creatinine higher than 1.1 mg/dL for women and ity of cortical and posterior subcapsular cataracts. The proto- 1.2 mg/dL for men; serum BUN of 20 mg/dL or higher (to con- cols for the photography and grading procedures were based vert to millimoles per liter, multiply by 0.357); protein levels on detailed codified rules.38 Graders were masked as to sub- of 30 mg/dL or higher in urine were considered proteinuria.
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