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 creatinine 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 photographs 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 incidence 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- ractsC (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

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©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 nanomoles 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. ject identity. Scores for nuclear sclerosis were based on com- Smoking and diabetes histories were obtained as part of a medi- parison with standard photographs, which resulted in a 5-step cal questionnaire. Persons who did not have diabetes but whose severity scale based on the opacity of the nucleus. Severities glycosylated hemoglobin or casual blood glucose met age- and greater than standard (3) were considered nuclear cataracts. sex-specific criteria were included as cases of diabetes.41,42 Scores for cortical and posterior subcapsular cataracts were based on the estimated amount of involvement based on the total involvement of segments of a grading grid placed under the film STATISTICAL METHODS image. Cortical opacities involving more than a weighted av- erage of 5% of the total lens were considered cortical cata- We examined the relationships between serum cystatin C, cre- racts. Posterior subcapsular opacities involving more than 5% atinine, BUN, and the presence of gross proteinuria to the in- of any of the 9 individual grid segments were considered pos- cidence of 3 types of ARC over 15 years. The SAS version 9 (SAS terior subcapsular cataracts.38 Analyses were based on cataract Institute, Cary, North Carolina) was used for analyzing the data. incidence of the first eye to develop a lesion. Persons without Multivariate odds ratios (ORs) and 95 percent confidence in- gradable photographs in either eye were excluded. tervals were calculated from discrete linear logistic hazard mod-

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©2008 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 Table 1. Comparing Participants With Incidence Data to Persons Who Refused the First Follow-up Examination

Refused First Have Incidence Data Follow-up Examination Age-Adjusted Characteristic No. (%) Mean (SD) No. (%) Mean (SD) P Value P Value Age, y 3097 59.0 (9.9) 684 62.6 (11.7) Ͻ.001 Sex Female 1713 (55.3) 405 (59.2) .06 .35 Male 1384 (44.7) 279 (40.8) Smoking history Never 1381 (44.6) 285 (41.8) .02 Ͻ.001 Past 1107 (35.8) 231 (33.9) Current 608 (19.6) 166 (24.3) Heavy drinking history Never 2597 (84.0) 540 (79.5) .01 Ͻ.001 Past 423 (13.7) 117 (17.2) Current 73 (2.4) 22 (3.2) Systolic blood pressure, mm Hg 3096 130.1 (19.2) 684 135.9 (21.8) Ͻ.001 Ͻ.001 Diastolic blood pressure, mm Hg 3096 78.3 (10.4) 684 78.3 (12.1) .89 .07 Glycosylated hemoglobin, % 3092 6.0 (1.5) 681 6.1 (1.6) .01 .03 Diabetes No 2880 (93.3) 627 (91.9) .21 .28 Yes 207 (6.7) 55 (8.1) CRP, mg/La 3078 3.9 (8.7) 674 4.0 (5.6) .80 .93 Total cholesterol, mg/dLb 3093 232.9 (43.0) 681 239.0 (44.6) Ͻ.001 .01 BMI 3088 28.8 (5.4) 679 28.9 (5.5) .81 .37 Oral steroid use No 3007 (98.3) 658 (97.6) .21 .32 Yes 51 (1.7) 16 (2.4) Cystatin C, mg/L 2920 0.87 (0.19) 635 .94 (.30) Ͻ.001c Ͻ.001c Cystatin C Ͼ0.95 mg/L No 2213 (75.8) 411 (64.7) Ͻ.001 .06 Yes 707 (24.2) 224 (35.3) BUN, mg/dLd 3094 17.1 (4.9) 681 17.5 (6.0) 0.67c .05c BUN Ն20 mg/dLd No 2292 (74.1) 489 (71.8) 0.22 .55 Yes 802 (25.9) 192 (28.2) Creatinine, mg/dLe 3078 .89 (.20) 674 .91 (0.27) 0.24c .80c High creatininef No 2832 (92.0) 606 (89.9) .08 .87 Yes 246 (8.0) 86 (10.1) Proteinuria, Ն30 mg/dL No 3001 (97.1) 653 (96.7) .66 .67 Yes 91 (2.9) 22 (3.3)

Abbreviations: BMI, body mass index (calculated as weight in kilograms divided by height in meters squared); BUN, blood urea nitrogen; CRP, C-reactive protein. a To convert to nanomoles per liter, multiply by 9.524. b To convert to millimoles per liter, multiply by 0.0259. c P values calculated for the log-transformed variable. d To convert to millimoles per liter, multiply by 0.357. e To convert to micromoles per liter, multiply by 88.4. f High creatinine defined as more than 1.2 mg/dL for men and more than 1.1 mg/dL for women.

els.43 These analytical approaches allowed persons who were cholesterol, heavy drinking history, and history of use of right-censored (censored at the 10- or 15-year examination due oral steroids as additional confounders. Models were also to death, nonparticipation, or cataract surgery) to contribute further stratified by baseline diabetes status, but because no information to the estimates. interactions were detected, we include only the results for The distributions of serum cystatin C, creatinine, and the unstratified analyses in the Tables. BUN levels were highly skewed, so we include them in our models after log-transforming them. We present ORs per increase in standard deviation in the risk factor for continu- RESULTS ous measures. We also tested for a threshold effect of cystatin C, creatinine, and BUN using predefined values described above. Analyses first controlled for age in 4 cat- Characteristics of participants are seen in Table 1. Base- egories of 10-year bands and sex. We considered smoking line serum cystatin C was significantly higher in those history, glycosylated hemoglobin, serum hsCRP, serum total not participating in follow-up examinations. There were

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©2008 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 Table 2. Continuous Models of Each Kidney Variable as Risk Factor for Incident Cataract Type

Age/Sex Adjusted Multivariatea Adjusted

Risk Factor by Cataract Type OR (95% CI) P Value OR (95% CI) P Value Nuclear Log of cystatin C 1.13 (1.01-1.27) .04 1.09 (0.97-1.23) .16 Log of BUN 0.90 (0.82-0.99) .04 0.94 (0.85-1.04) .20 Log of creatinine 0.87 (0.75-1.01) .07 0.92 (0.80-1.07) .29 Cortical Log of cystatin C 1.24 (1.09-1.40) Ͻ.001 1.24 (1.09-1.41) .001 Log of BUN 1.03 (0.93-1.14) .62 1.05 (0.94-1.17) .39 Log of creatinine 0.92 (0.78-1.08) .29 0.95 (0.81-1.11) .51 Posterior subcapsular Log of cystatin C 1.30 (1.08-1.56) .01 1.24 (1.02-1.50) .03 Log of BUN 1.21 (1.04-1.41) .02 1.22 (1.04-1.42) .02 Log of creatinine 1.20 (0.98-1.48) .08 1.26 (1.03-1.54) .03

no other significant differences in the kidney-related vari- a ables between participants and nonparticipants among Table 3. Pearson Correlation Matrix of Logarithms of Kidney Variables the characteristics in Table 1. We examined whether each measure of kidney func- Cystatin C BUN Creatinine tion was associated with the individual cataract types, controlling first for only age and sex (Table 2). Increased Cystatin C 1.00 0.34 0.43 levels of serum cystatin C and decreased levels of BUN BUN 1.00 0.44 Creatinine 1.00 were associated with incident nuclear cataract. Serum cystatin C was associated with incidence of cortical cata- Abbreviation: BUN, blood urea nitrogen. ract. Increased levels of serum cystatin C and BUN were a For all correlations, P Ͻ .001. associated with incident posterior subcapsular cataract. After adjusting for smoking, glycosylated hemoglobin, posterior subcapsular cataract in continuous models. hsCRP, serum total cholesterol, history of use of sys- These findings are unique in 2 ways: (1) the relation- temic steroids, and heavy drinking, higher levels of se- ships are specific for cataract type and (2) a relationship rum creatinine were also significantly related to incident with serum cystatin C is found. Clayton and col- posterior subcapsular cataract. Because the continuous mea- leagues21 studied 931 patients with cataracts and 325 pa- sures of kidney function were relatively highly correlated tients without. Patients with cataracts had higher mean (Table 3), we did not include them in the same models. blood urea levels than the comparison group. The rela- Limiting the analyses to include only those without dia- tive rarity of posterior subcapsular cataract may ex- betes did not alter the specific variables associated with plain, in part, why that specific cataract type was not re- cataracts; the ORs were similar for those with and with- ported. Cortical cataract, while more common, is less out diabetes (data not shown). Alternative analyses in which likely to result in decreased vision and may therefore be cut points for high (abnormal) values for the kidney vari- overlooked. Many studies do not have specific grading ables were used and yielded similar associations for cys- for the presence of each particular type of ARC, so use tatin C for both cortical and posterior subcapsular cata- of the more generic term cataract may have obscured the ract and for BUN and posterior subcapsular cataract specificity of cataract type in previous reports. compared with the continuous models (Table 4). Pro- We performed multivariable analyses using cataract teinuria was not significantly associated with any cata- surgery as an endpoint. We found similar relationships ract type. of the kidney variables to this outcome as we found for posterior subcapsular cataract (data not shown). This is COMMENT consistent with the finding that the relative risk for cataract surgery is greatest for persons with posterior sub- We find that higher levels of serum cystatin C, adjusted capsular cataract.23 for age and sex, is associated with the odds of incident An association between kidney disease and cataract posterior subcapsular and cortical cataract over a 15- or cataract surgery in persons with diabetes has been re- year interval and that the ORs remained significant after ported.23,44 In this long-term incidence study, we found further controlling for smoking, serum cholesterol, gly- that the relationship of kidney function to cataract was cosylated hemoglobin, hsCRP, heavy drinking, and use not markedly different between those with and without of systemic steroids. This is true even when analyses are diabetes, suggesting that it is kidney function itself rather restricted to persons without diabetes. Higher levels of than diabetic kidney disease specifically that puts the lens serum BUN and serum creatinine are also associated with at risk. We have evaluated the association of markers of

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©2008 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 Table 4. Categorical Models of Each Kidney Variable as Risk Factor for Incident Cataract Type

Age/Sex Adjusted Multivariatea Adjusted Cases, Risk Factor by Cataract Type Level, mg/dL No. No. OR (95% CI) P Value OR (95% CI) P Value Nuclear Cystatin C Յ0.95 1972 504 Referent Referent Ͼ0.95 539 213 1.13 (0.92-1.38) .24 1.05 (0.85-1.29) .68 BUNb Ͻ20 1986 542 Referent Referent Ն20 662 209 0.93 (0.77-1.12) .45 0.96 (0.79-1.17) .70 Creatininec 2445 699 Referent Referent Men and women Low 203 52 0.67 (0.49-0.94) .02 0.70 (0.50-0.97) .03 High Proteinuria None/trace 2567 730 Referent Referent Ն30 78 21 1.29 (0.78-2.14) .33 1.10 (0.65-1.86) .71 Cortical Cystatin C Յ0.95 1966 384 Referent Referent Ͼ0.95 551 158 1.35 (1.09-1.67) .01 1.32 (1.05-1.65) .02 BUNb Ͻ20 2003 413 Referent Referent Ն20 650 163 1.11 (0.91-1.36) .31 1.10 (0.90-1.35) .36 Creatininec 2446 534 Referent Referent Men and women Low 207 42 0.91 (0.65-1.27) .57 0.87 (0.62-1.23) .44 High Proteinuria None/trace 2574 555 Referent Referent Ն30 74 21 1.81 (1.11-2.96) .02 1.57 (0.94-2.60) .08 Posterior subcapsular Cystatin C Յ0.95 2125 142 Referent Referent Ͼ0.95 650 75 1.52 (1.12-2.07) .01 1.39 (1.01-1.91) .04 BUNb Ͻ20 2176 147 Referent Referent Ն20 744 90 1.73 (1.32-2.28) Ͻ.001 1.68 (1.27-2.22) Ͻ.001 Creatininec 2690 214 Referent Referent Men and women Low 230 23 1.15 (0.73-1.81) .54 1.18 (0.75-1.86) .48 High Proteinuria None/trace 2831 227 Referent Referent Ն30 85 10 1.83 (0.94-3.57) .07 1.65 (0.84-3.24) .15

Abbreviations: BUN, blood urea nitrogen; CI, confidence interval; OR, odds ratio. a Multivariate adjusted for age, sex, smoking history, glycosylated hemoglobin, C-reactive protein, total cholesterol, heavy drinking history, and use of oral steroids. b To convert to millimoles per liter, multiply by 0.357. c To convert to micromoles per liter, multiply by 88.4; low is 1.2 or less for men, 1.1 or less for women; high, 1.2 or more for men, 1.1 or more for women.

kidney function and the specific cataract types in data Cystatin C levels are elevated with mild degrees of re- from past examinations. While we found a relationship nal insufficiency, whereas serum creatinine levels are not.26 between posterior subcapsular cataract and BUN in the The metabolic abnormalities present in the early stages past, the relationship was not statistically significant and of kidney dysfunction are not the result of retained waste therefore not reported. During the longitudinal follow products or the failure to maintain the homeostasis of up, the number of cases of cataract, particularly poste- body fluids. These abnormalities are the result of the ad- rior subcapsular cataract, has increased. This likely ac- aptations made to maintain the homeostasis. The circu- counts for the significance we now find of BUN and cre- lating levels of parathyroid hormone are elevated in re- atinine. sponse to a normal intake of calcium and phosphorus. There are plausible explanations underlying the bio- Sodium regulatory hormones like atrial natriuretic pep- logical mechanisms that may account for our findings. tide are elevated in persons with unrestricted sodium in- It is possible that systemic metabolic acidosis itself is a take. The capacity to buffer and excrete acid loads is re- risk factor for cataract. Many persons with kidney dys- duced, and excess acid is buffered in tissues like bone. function are chemically acidotic and it may be that even The clinical expression of these adaptive and abnormal low levels of acidosis affect the lens. In addition, a spe- processes is often delayed until a later stage of kidney dys- cific kidney functional abnormality, renal tubular aci- function. However, in this study, we may be identifying dosis, is associated with lens epithelial abnormalities that complications (ie, cortical and posterior subcapsular cata- have been postulated to lead to loss of lens transpar- racts) that occur in response to some metabolic factor ency.45 We did not have specific measures of systemic aci- during an early stage of kidney disease. dosis or information to estimate anion gap. We had a single Oxidative stress may, in part, explain the association blood pH measure at baseline, and this was not associ- of the markers of kidney disease with cataracts. Patients ated with any type of cataract (data not shown). with kidney failure are in a state of oxidative stress.46-49

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©2008 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 Oxidative stress may lead to carbamylation of lens pro- Author Contributions: Dr B. E. K. Klein had full access teins, a process that has been suggested to cause cata- to all the data in the study and takes responsibility for the ract.50 Thus, markers of kidney function are likely to be integrity of the data and the accuracy of the data analysis. indicators of oxidative stress, and there may be a rela- Financial Disclosure: None reported. tionship of the severity of kidney disease and oxidative Funding/Support: This study was supported by grant stress across the range of function reflected in the val- EY06594 from the National Eye Institute; Senior Scien- ues of the quantitative markers. tific Awards (Drs B. E. K. Klein and R. Klein) from Re- Cystatins, naturally occurring inhibitors of cysteine search to Prevent Blindness provided further additional proteinases,51 are found in various cell types and body support for data analyses. fluids52,53 and are considered a component of serum proteins. Serum cystatin C is used currently in other studies as a marker of kidney dysfunction and has been as- REFERENCES sociated with microvascular and macrovascular disease,27,28,54 but its usefulness as a predictor of impor- 1. Thylefors B, Negrel AD, Pararajasegaram R, Dadzie KY. Global data on blindness. 55 Bull World Health Organ. 1995;73(1):115-121. tant cardiovascular events is not certain. While some 2. Rahmani B, Tielsch JM, Katz J, et al. The cause-specific prevalence of visual im- suggest that cataract and cardiovascular disease share risk pairment in an urban population: the Baltimore Eye Survey. Ophthalmology. 1996; factors,56-58 the findings are not universal,59 so there may 103(11):1721-1726. be limited usefulness in comparing new biomarkers for 3. Congdon N, Vingerling JR, Klein BE, et al. Prevalence of cataract and pseudophakia/ these events in different systems and hoping for parallel aphakia among adults in the United States. Arch Ophthalmol. 2004;122(4): 487-494. findings. 4. Klein BE, Klein R, Jensen SC, Ritter LL. Are sex hormones associated with age- We have been considering cystatin C levels as a marker related maculopathy in women? the Beaver Dam Eye Study. Trans Am Ophthal- of kidney function. However, cystatin C, being nearly mol Soc. 1994;92:289-295. ubiquitous, is found in tissue and fluid in the eye (aque- 5. Hiller R, Sperduto RD, Ederer F. Epidemiologic associations with cataract in the 51 1971-1972 National Health and Nutrition Examination Survey. Am J Epidemiol. ous humor, cornea, retina, sclera, and lens epithelium). 1983;118(2):239-249. Cystatin C has been found to be inhibited by reactive al- 6. Klein BE, Klein R, Ritter LL. Relationship of drinking alcohol and smoking to preva- dehydes that may lead to the abnormal accumulation of lence of open-angle glaucoma: the Beaver Dam Eye Study. Ophthalmology. 1993; proteins, and it has been postulated that this process may 100(11):1609-1613. lead to cataracts.60 7. Christen WG, Manson JE, Seddon JM, et al. A prospective study of cigarette smoking and risk of cataract in men. JAMA. 1992;268(8):989-993. Limitations of our study include the lack of other, 8. Klein BE, Klein R, Moss SE. Prevalence of cataracts in a population-based study perhaps more sensitive, measures of renal function of persons with diabetes mellitus. Ophthalmology. 1985;92(9):1191-1196. such as inulin clearance or iothalamate excretion. Such 9. Klein BE, Klein R, Lee KE, Danforth LG. Drug use and five-year incidence of age- testing was beyond the resources of this study. Medical related cataracts: the Beaver Dam Eye Study. Ophthalmology. 2001;108(9): 1670-1674. care, specifically cataract surgery for nuclear cataract, 10. De Juan E Jr, Sternberg P Jr, Michels RG. Penetrating ocular injuries: types of selectively eliminated persons (eyes) for incidence fol- injuries and visual results. Ophthalmology. 1983;90(11):1318-1322. low-up. It is also possible that systemic conditions that 11. Duke-Elder S. System of Ophthalmology, Volume 14 . St Louis, MO: CV Mosby; we were unaware of or could not detect may have con- 1972. founded the relationships we studied. We do not know 12. Wong TY, Klein BE, Klein R, Tomany SC. Relation of ocular trauma to cortical, nuclear, and posterior subcapsular cataracts: the Beaver Dam Eye Study. Br J the extent to which medications and other environmen- Ophthalmol. 2002;86(2):152-155. tal exposures influenced both markers of kidney func- 13. West SK, Duncan DD, Munoz B, et al. Sunlight exposure and risk of lens opaci- tion and cataract, although we have included the factors ties in a population-based study: the Salisbury Eye Evaluation project. JAMA. 1998; that we think would most likely have influenced our 280(8):714-718. 14. Taylor HR, West SK, Rosenthal FS, et al. Effect of ultraviolet radiation on cata- findings. ract formation. N Engl J Med. 1988;319(22):1429-1433. In summary, we have found that markers of kidney 15. Klein BE, Cruickshanks KJ, Klein R. Leisure time, sunlight exposure and cataracts. function are related to incidence of posterior subcapsu- Doc Ophthalmol. 1994-1995;88(3-4):295-305. lar cataract, a lesion that is associated with significant im- 16. Iyengar SK, Klein BE, Klein R, et al. Identification of a major locus for age- pairment of visual acuity, and to incident cortical cata- related cortical cataract on chromosome 6p12-q12 in the Beaver Dam Eye Study. Proc Natl Acad Sci U S A. 2004;101(40):14485-14490. ract. We also found that the severity of kidney dysfunction, 17. He´on E, Paterson AD, Fraser M, et al. A progressive autosomal recessive cata- as reflected in higher serum levels of cystatin C, BUN, ract locus maps to chromosome 9q13-q22. Am J Hum Genet. 2001;68(3): and creatinine, is associated with progressively in- 772-777. creased risk. The mechanisms of oxidative stress, other 18. Klein BE, Klein R, Lee KE, Knudtson MD, Tsai MY. Markers of inflammation, vas- cular endothelial dysfunction, and age-related cataract. Am J Ophthalmol. 2006; metabolic changes related to kidney function, common 141(1):116-122. genetic etiologies for kidney dysfunction and lens pa- 19. Klein BE, Klein R, Lee KE. Renal function abnormalities and incident cataract af- thology, or all of these are possible and require further ter a five-year interval: the Beaver Dam Eye Study. Curr Eye Res. 1998;17(7): study. 720-725. 20. Durant JS, Frost NA, Trivella M, Sparrow JM. Risk factors for cataract subtypes wa- terclefts and retrodots: two case-control studies. Eye. 2006;20(11):1254-1267. Submitted for Publication: March 31, 2008; final revi- 21. Clayton RM, Cuthbert J, Duffy J, et al. Some risk factors associated with cata- sion received June 3, 2008; accepted June 25, 2008. ract in SE Scotland: a pilot study. Trans Ophthalmol Soc U K. 1982;102(pt 3): Correspondence: Barbara E. K. Klein, MD, MPH, De- 331-336. partment of Ophthalmology and Visual Sciences, Uni- 22. Vrabec R, Vatavuk Z, Pavlovic D, et al. Ocular findings in patients with chronic renal failure undergoing haemodialysis. Coll Antropol. 2005;29(suppl 1):95-98. versity of Wisconsin Madison, 610 N Walnut St, Fourth 23. Klein BE, Klein R, Moss SE. Incidence of cataract surgery in the Wisconsin Epi- Floor Wisconsin Alumni Research Foundation (WARF), demiologic Study of Diabetic Retinopathy. Am J Ophthalmol. 1995;119(3): Madison, WI 53726 ([email protected]). 295-300.

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©2008 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 24. Manetti L, Pardini E, Genovesi M, et al. Thyroid function differently affects se- 43. Hosmer DW Jr, Lemeshow S. Special topics. In: Applied Logistic Regression. rum cystatin C and creatinine concentrations. J Endocrinol Invest. 2005;28 New York, NY: John Wiley & Sons; 1989:238-245. (4):346-349. 44. Peduzzi M, Debbia A, Monzani A, et al. Prevalence of cataracts in a population- 25. Knight EL, Verhave JC, Spiegelman D, et al. Factors influencing serum cystatin based study of patients with diabetes mellitus. Dev Ophthalmol. 1989;17:75- C levels other than renal function and the impact on renal function measurement. 78. Kidney Int. 2004;65(4):1416-1421. 45. Usui T, Hara M, Satoh H, et al. Molecular basis of ocular abnormalities associ- 26. Coll E, Botey A, Alvarez L, et al. Serum cystatin C as a new marker for noninva- ated with proximal renal tubular acidosis. J Clin Invest. 2001;108(1):107-115. sive estimation of glomerular filtration rate and as a marker for early renal 46. Himmelfarb J, Stenvinkel P, Ikizler TA, Hakim RM. The elephant in uremia: oxi- impairment. Am J Kidney Dis. 2000;36(1):29-34. dant stress as a unifying concept of cardiovascular disease in uremia. Kidney 27. Niccoli G, Conte M, Bona RD, et al. Cystatin C is associated with an increased Int. 2002;62(5):1524-1538. coronary atherosclerotic burden and a stable plaque phenotype in patients with 47. Ikizler TA, Morrow JD, Roberts LJ, et al. Plasma F2-isoprostane levels are el- ischemic heart disease and normal glomerular filtration rate [published online evated in chronic hemodialysis patients. Clin Nephrol. 2002;58(3):190-197. ahead of print November 5, 2007]. Atherosclerosis. 2008;198(2):373-380. doi: 48. Mezzano D, Pais EO, Aranda E, et al. Inflammation, not hyperhomocysteinemia, 10.1016/j.atherosclerosis.2007.09.022. is related to oxidative stress and hemostatic and endothelial dysfunction in uremia. 28. Sarnak MJ, Katz R, Stehman-Breen CO, et al. Cystatin C concentration as a risk Kidney Int. 2001;60(5):1844-1850. factor for heart failure in older adults. Ann Intern Med. 2005;142(7):497-505. 49. Costagliola C, Iuliano G, Menzione M, et al. Systemic human diseases as oxida- 29. Klein R, Klein BE, Linton KL, De Mets DL. The Beaver Dam Eye Study: visual acuity. tive risk factors in cataractogenesis II: chronic renal failure. Exp Eye Res. 1990; Ophthalmology. 1991;98(8):1310-1315. 51(6):631-635. 30. Klein R, Klein BE, Lee KE. Changes in visual acuity in a population: the Beaver 50. Hasan A, Smith JB, Qin W, Smith DL. The reaction of bovine lens alpha A- Dam Eye Study. Ophthalmology. 1996;103(8):1169-1178. crystallin with aspirin. Exp Eye Res. 1993;57(1):29-35. 31. Klein R, Klein BE, Lee KE, Cruickshanks KJ, Chappell RJ. Changes in visual acu- 51. Barka T, van der Noen H. Expression of the cysteine proteinase inhibitor cys- ity in a population over a 10-year period: the Beaver Dam Eye Study. Ophthalmology. tatin C mRNA in rat eye. Anat Rec. 1994;239(3):343-348. 2001;108(10):1757-1766. 52. Barka T, van der Noen H. Expression of the cysteine proteinase inhibitor cys- 32. Klein R, Klein BE. The Beaver Dam Eye Study: Manual of Operations. Spring- tatin C gene in rat heart: use of digoxigenin-labeled probes generated by poly- field, VA: US Dept of Commerce; 1991. National Technical Information Service merase chain reaction directly for in situ and northern blot hybridizations. J His- Accession No. PB 91-149823/AS. tochem Cytochem. 1993;41(12):1863-1867. 33. Klein R, Klein BE. The Beaver Dam Eye Study II: Manual of Operations. Spring- 53. Henskens YM, Veerman EC, Mantel MS, van der Velden U, Nieuw Amerongen AV. field, VA: US Dept of Commerce; 1995. National Technical Information Service Cystatins S and C in human whole saliva and in glandular salivas in periodontal health Accession No. PB 95-273827. 34. Klein R, Davis MD, Magli YL, Segal P, Klein BE, Hubbard L. The Wisconsin age-related and disease. JDentRes. 1994;73(10):1606-1614. maculopathy grading system. Ophthalmology. 1991;98(7):1128-1134. 54. Ix JH, Shlipak MG, Chertow GM, Whooley MA. Association of cystatin C with 35. Klein R, Davis MD, Magli YL, Segal P, Klein BE. The Wisconsin Age-Related Macu- mortality, cardiovascular events, and incident heart failure among persons with lopathy Grading System. Springfield, VA: US Dept of Commerce; 1991. National coronary heart disease: data from the Heart and Soul Study. Circulation. 2007; Technical Information Service Accession No. PB 91-184267/AS. 115(2):173-179. 36. Klein R, Klein BE, Linton KL. Prevalence of age-related maculopathy: the Beaver 55. Shlipak MG, Ix JH, Bibbins-Domingo K, Lin F, Whooley MA. 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Evidence for inactivation of cyste- Elevated cystatin C concentration and progression to pre-diabetes: the Western ine proteases by reactive carbonyls via glycation of active site thiols. Biochem J. New York study. Diabetes Care. 2007;30(7):1724-1729. 2006;398(2):197-206.

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