Showing papers by "Ronald Klein published in 2011"

Prevalence of Age-Related Macular Degeneration in the US Population

Abstract: Objective To examine the prevalence of age-related macular degeneration (AMD) in non-Hispanic white, non-Hispanic black, Mexican American, and other racial/ethnic groups. Design A US nationally representative, population-based, cross-sectional study involving a total of 5553 persons aged 40 years and older from the 2005-2008 National Health and Nutrition Examination Survey. The main outcome measure was AMD determined by the grading of 45° digital images from both eyes using a standardized protocol. Results In the civilian, noninstitutionalized, US population aged 40 years and older, the estimated prevalence of any AMD was 6.5% (95% confidence interval, 5.5-7.6) and the estimated prevalence of late AMD was 0.8% (95% confidence interval, 0.5-1.3). Non-Hispanic black persons aged 60 years and older had a statistically significantly lower prevalence of any AMD than non-Hispanic white persons aged 60 years and older (odds ratio = 0.37; 95% confidence interval, 0.21-0.67). Conclusions Overall, the prevalence of any AMD in the 2005-2008 National Health and Nutrition Examination Survey was 6.5%, which is lower than the 9.4% prevalence reported in the 1988-1994 Third National Health and Nutrition Examination Survey. While this finding might be explained in part by possible methodological differences, these estimates are consistent with a decreasing incidence of AMD and suggest important public health care implications.

Tinnitus and its risk factors in the Beaver Dam offspring study.

Abstract: Objective: To assess the prevalence of tinnitus along with factors potentially associated with having tinnitus. Design: Data were from the Beaver Dam Offspring Study, an epidemiological cohort study of aging. Study Sample: After a personal interview and audiometric examination, participants (n = 3267, ages 21–84 years) were classified as having tinnitus if in the past year they reported having tinnitus of at least moderate severity or that caused difficulty in falling asleep. Results: The prevalence of tinnitus was 10.6%. In a multivariable logistic regression model adjusting for age and sex, the following factors were associated with having tinnitus: hearing impairment (Odds Ratio (OR) = 3.20), currently having a loud job (OR = 1.90), history of head injury (OR = 1.84), depressive symptoms (OR = 1.82), history of ear infection (men, OR = 1.75), history of target shooting (OR = 1.56), arthritis (OR = 1.46), and use of NSAID medications (OR = 1.33). For women, ever drinking alcohol in the past year...

Quantitative and qualitative retinal microvascular characteristics and blood pressure

Abstract: ObjectiveThe present study examined the effects of blood pressure on a spectrum of quantitative and qualitative retinal microvascular signs.MethodsRetinal photographs from the Singapore Malay Eye Study, a population-based cross-sectional study of 3280 (78.7% response) persons aged 40–80 years, were

The Prevalence of Hearing Impairment and Associated Risk Factors: The Beaver Dam Offspring Study

Abstract: Hearing impairment (HI) is one of the most common chronic conditions in older adults affecting at least 29 million Americans.1 Population-based epidemiological prevalence estimates range from 20.6% in adults ages 48–59 years to 90% in adults over 80 years old.2 The ten-year incidence of HI in these two age groups has been estimated to be 22% and 100% respectively.3 Furthermore, severity of this condition has been shown to be associated with poorer quality of life, communication difficulties, impaired activities of daily living, dementia, and cognitive dysfunction.4,5 Besides older age and male sex, environmental factors such as loud noise, socioeconomic status (SES), and ear infections have been associated with HI.1,3,6–8 Traditional cardiovascular disease (CVD) risk factors may also be important contributors to worse hearing, although the findings from different epidemiological cohorts have been inconsistent. Associations have been found between HI and history of smoking,6,9 CVD including myocardial infarction and stroke,6,10 higher blood pressure or hypertension,10,11 and diabetes.6,12 Most data regarding the association of CVD risk factors and HI have come from the study of cohorts of older persons, after noise and occupational exposures have ceased. Fewer studies have focused on risk factors for HI in younger adults where there may be other competing exposures. Recent reports from the NHANES (age range 20–69 years) have shown that those with increased occupational and firearm noise exposure, increased pack-years of smoking, and the presence of diabetes are more likely to have HI.8,13 Epidemiological data are needed to characterize the burden of HI across all adult age groups, especially in those under age 60 years. In addition, to investigate associations between CVD risk factors and HI, both pure-tone and speech audiometry (word recognition in competing message (WRCM)) were used in analytic modeling as there may be both peripheral and central dysfunction in HI. Identifying possible modifiable risk factors may allow for early interventions to delay the onset of HI and diminish the impact on quality of life.

Meta-analysis of Dense Genecentric Association Studies Reveals Common and Uncommon Variants Associated with Height

Abstract: Height is a classic complex trait with common variants in a growing list of genes known to contribute to the phenotype. Using a genecentric genotyping array targeted toward cardiovascular-related loci, comprising 49,320 SNPs across approximately 2000 loci, we evaluated the association of common and uncommon SNPs with adult height in 114,223 individuals from 47 studies and six ethnicities. A total of 64 loci contained a SNP associated with height at array-wide significance (p < 2.4 x 10(-6)), with 42 loci surpassing the conventional genome-wide significance threshold (p < 5 x 10(-8)). Common variants with minor allele frequencies greater than 5% were observed to be associated with height in 37 previously reported loci. In individuals of European ancestry, uncommon SNPs in IL11 and SMAD3, which would not be genotyped with the use of standard genome-wide genotyping arrays, were strongly associated with height (p < 3 x 10(-11)). Conditional analysis within associated regions revealed five additional variants associated with height independent of lead SNPs within the locus, suggesting allelic heterogeneity. Although underpowered to replicate findings from individuals of European ancestry, the direction of effect of associated variants was largely consistent in African American, South Asian, and Hispanic populations. Overall, we show that dense coverage of genes for uncommon SNPs, coupled with large-scale meta-analysis, can successfully identify additional variants associated with a common complex trait.

Glycated Hemoglobin and the Risk of Kidney Disease and Retinopathy In Adults with and Without Diabetes

Abstract: OBJECTIVE Glycated hemoglobin was recently recommended for use as a diagnostic test for diabetes. We examined the association between 2010 American Diabetes Association diagnostic cut points for glycated hemoglobin and microvascular outcomes (chronic kidney disease, end-stage renal disease [ESRD], and retinopathy) and formally tested for the presence of risk thresholds in the relationships of glycated hemoglobin with these outcomes. RESEARCH DESIGN AND METHODS Prospective cohort and cross-sectional analyses of 11,357 participants (773 with a history of diagnosed diabetes) from the Atherosclerosis Risk in Communities (ARIC) Study. RESULTS During a median of 14 years of follow-up of individuals without diagnosed diabetes at baseline, clinical categories of glycated hemoglobin were associated with risk of chronic kidney disease, with adjusted hazard ratios (HRs) of 1.12 (0.94–1.34) and 1.39 (1.04–1.85) for glycated hemoglobin 5.7–6.4% and ≥6.5%, respectively, as compared with <5.7% ( P trend = 0.002). The corresponding HRs for ESRD were 1.51 (0.82–2.76) and 1.98 (0.83–4.73), respectively ( P trend = 0.047). In the absence of diagnosed diabetes, glycated hemoglobin was cross sectionally associated with the presence of moderate/severe retinopathy, with adjusted odds ratios of 1.42 (0.69–2.92) and 2.91 (1.19–7.11) for glycated hemoglobin 5.7–<6.5% and ≥6.5%, respectively, compared with <5.7% ( P trend = 0.011). Risk associations were stronger among individuals with a history of diabetes. We did not observe significant thresholds in the associations of glycated hemoglobin with kidney disease risk or retinopathy. CONCLUSIONS These data from a community-based, biracial population support the use of new 2010 American Diabetes Association glycated hemoglobin cut points for the diagnosis of diabetes.

Determinants of Hearing Aid Acquisition in Older Adults

Abstract: Objectives. We determined factors associated with hearing aid acquisition in older adults.Methods. We conducted a population-based, prospective study that used information from 3 examinations performed on study participants as part of the Epidemiology of Hearing Loss Study (1993–2005). We included participants (n = 718; mean age = 70.5 years) who exhibited hearing loss at baseline or the first follow-up and had no prior history of hearing aid use. We defined hearing loss as a pure tone threshold average (PTA) at 0.5, 1, 2, and 4 kilohertz in the better ear of greater than 25 decibels Hearing Level.Results. The 10-year cumulative incidence of hearing aid acquisition was 35.7%. Associated factors included education (college graduate vs all others: hazard ratio [HR] = 2.5; 95% confidence interval [CI] = 1.5, 4.1), self-perception of hearing (poor vs good or better: HR = 2.5; 95% CI = 1.3, 5.0), score on a perceived hearing handicap inventory (+ 1 difference: HR = 1.1; 95% CI = 1.0, 1.1), and PTA (+ 5 dB diff...

Candidate gene association study for diabetic retinopathy in persons with type 2 diabetes: the Candidate gene Association Resource (CARe).

Abstract: Diabetic retinopathy (DR) is the leading cause of blindness in working-age Americans1,2 and is increasing in prevalence as rates of type 2 diabetes (T2D) soar worldwide.3,4 The frequency and severity of DR are heterogeneous within and across ethnic groups,5 even with adjustment for risk factors such as duration of diabetes and glycemic control.2,6,7 There are people who have a long duration of diabetes without DR and those who have severe DR despite relatively good glycemic control. For these reasons, genetic risk factors are thought to play a role in DR. Heritability has been estimated to be as high as 27% for DR and 52% for proliferative diabetic retinopathy (PDR).8–10 However, genetic association studies for DR have been thus far limited mostly to studies of one or a modest number of candidate genes.11,12 Most reported associations have not been consistently reproduced.11,13,14 In contrast to DR, genetic association studies for T2D have revealed many consistently associated genes. Genes that increase T2D risk may also predispose to development of retinopathy. In the case of diabetic nephropathy (DN), a TCF7L2 variant increases the risk of developing DN beyond the risk of diabetes.15 Because there is evidence that DR shares risk factors and pathophysiological mechanisms with DN and macrovascular diabetic complications,6,16–21 genes associated with DN and atherosclerotic vascular disease may also be associated with DR. The Candidate gene Association Resource (CARe) is a collaboration for association analyses of genotypes and cardiovascular disease phenotypes.22 It comprises >40,000 participants from nine cohorts who have been genotyped for 49,320 single nucleotide polymorphisms (SNPs) from approximately 2,000 candidate genes postulated or known to increase risk of cardiovascular, metabolic, and inflammatory diseases.23 It includes 2691 T2D participants with fundus photographs of multiple ethnicities. Thus, the CARe framework provides an opportunity to investigate genetic associations for DR with a candidate gene approach. CARe genotyped many genes previously associated with DR,24,25 DN,25–27 and T2D.28–34 The first purpose of this study was to investigate whether these genes are also associated with the presence of DR in CARe. The second purpose was to determine whether the remaining genes included in the CARe genotyping platform, which were also chosen as potential cardiovascular disease genes, are associated with DR.

Olfactory impairment in older adults: five-year incidence and risk factors.

Abstract: Objectives/Hypothesis: The objective of this study was to determine the five-year incidence of olfactory impairment and associated risk factors in a general population of older adults. Study Design: Longitudinal population-based study. Methods: Participants (n = 1,556) in the population-based Epidemiology of Hearing Loss Study had olfaction measured at the 5- and 10-year examinations (1998–2000 and 2003–2005, respectively). Olfactory ability was measured by the San Diego Odor Identification Test. Results: The five-year incidence of olfactory impairment was 12.5%. Incidence rates increased with age for men and women. In a multivariate model, age (odds ratio [OR] = 1.79, 95% CI, 1.61–2.00; for every five-year increase), a history of nasal polyps (OR = 2.33, 95% CI, 1.13–4.59), a history of deviated septum (OR = 2.05, 95% CI, 1.14–3.56), and a history of heavy alcohol use (OR = 1.84, 95% CI, 1.13–2.93) were associated with an increased risk of olfactory impairment, whereas use of lipid-lowering agents (OR = 0.68, 95% CI, 0.46–0.99; yes vs. no), exercising at least once a week (OR = 0.69, 95% CI, 0.48–0.98), and oral steroid use (OR = 0.37, 95% CI, 0.11–0.94) were associated with a decreased risk. Conclusions: The five-year incidence of olfactory impairment is high in this population of older adults. Modifiable risk factors associated with impairment suggest some impairment could be amenable to prevention or treatment. Laryngoscope, 2011

Retinal Venular Diameter as an Early Indicator of Progression to Proliferative Diabetic Retinopathy With and Without High-Risk Characteristics in African Americans With Type 1 Diabetes Mellitus

Abstract: Objective To examine the relationship between retinal arteriolar and venular diameter and the 6-year progression of diabetic retinopathy (DR) in African Americans with type 1 insulin-dependent diabetes mellitus. Methods Included were 468 African Americans with type 1 diabetes mellitus who participated in the New Jersey 725 and who had undergone a 6-year follow-up examination. Seven standard field retinal photographs were obtained at both examinations. Computer-assisted grading, from digitized images of field 1 of baseline retinal photographs, was accomplished to determine the average diameter of retinal arterioles (central retinal arteriolar equivalent [CRAE]) and venules (central retinal venular equivalent [CRVE]). Retinal vessel diameter was examined in relation to the 6-year incidence and/or progression of DR. Results For right and left eyes, mean (SD) CRAE was 168.8 (16.0) μm and mean CRVE was 254.2 (25.2) μm. Both CRAE and CRVE were correlated between eyes ( P Conclusion Larger retinal venular diameter is an independent and early indicator of progression to either PDR or PDR with high-risk characteristics in African Americans with type 1 diabetes mellitus.

The Cost‐Effectiveness of Three Screening Alternatives for People with Diabetes with No or Early Diabetic Retinopathy

Abstract: Diabetic retinopathy (DR)—a complication involving the retinal microvasculature resulting in damage to the retina from ischema, neovascularization, hemorrhage, and edema—develops in virtually all people with diabetes mellitus and can progress to more advanced stages threatening permanent visual impairment and blindness (American Academy of Ophthalmology Retina Panel 2008). In 2004, DR was the estimated cause of 195,000 prevalent cases of visual impairment and blindness in the United States (The Eye Diseases Prevalence Research Group 2004). Screening to increase detection of DR progression and timely treatment can reduce the risk of permanent visual impairment. Based on clinical and cost-effectiveness evidence from the 1990s, the American Academy of Ophthalmology (AAO), the American Optometric Association, and the American Diabetes Association currently all recommend annual dilated evaluations by an eye-care professional (annual eye evaluations) for all patients with diabetes (Dasbach et al. 1991; Javitt et al. 1994; Javitt 1995; Javitt and Aiello 1996; Fodera 1999; Fong et al. 2003; American Academy of Ophthalmology Retina Panel 2008). This recommendation is likely most cost-effective for patients with advanced DR or elevated hemoglobin A1c (HbA1c) levels, but annual evaluation may be costly for those with no DR or with microaneurysms (MA) only. For lower-risk patients with diabetes, Vijan, Hofer, and Hayward (2000) found that less frequent evaluations provide nearly equivalent benefits as annual ones at lower costs (Vijan, Hofer, and Hayward 2000). In 2006, nearly 9.1 million Americans had type 2 diabetes with limited or no signs of DR (National Center for Health Statistics 2005–2006). After accounting for the rate of compliance with current screening recommendations and the costs of evaluation by an eye-care professional, a change from annual evaluations to biennial evaluations could save approximately U.S.$200 million in health expenditures annually with limited risks to health. However, Vijan, Hofer, and Hayward (2000) did not account for noncompliance with recommendations or for the benefits of detecting other ocular disorders. These limitations may have influenced their results because only 64 percent of people with diabetes aged 30 or older comply with current recommendations and because people with diabetes are at higher risk for incident glaucoma, cataract, and possibly vision-threatening age-related macular degeneration (AMD) than people without diabetes (Klein et al. 1995; Bonovas, Peponis, and Filioussi 2004; Clemons et al. 2005; National Center for Health Statistics 2005–2006). Furthermore, advocates for annual evaluation argue that the annual recommendation is easier to communicate, creating less risk of noncompliance. Over the past decade, retinal digital photography (telemedicine) has emerged as a lower cost alternative to annual evaluation by an eye-care professional. Telemedicine uses digital retinal photography to enable screening in nonophthalmologic settings. Images are electronically transferred to a grading center for evaluation, and patients with evidence of mild to severe DR are referred to an eye-care professional for a full evaluation. Telemedicine has shown better sensitivity (98 percent) and specificity (86 percent) in detecting DR than ophthalmoscopy (Moss et al. 1985; Ahmed et al. 2006) and usually costs less from both the health care and societal perspectives than dilated eye examinations because of lower provider reimbursements and lower patient productivity losses from time lost to treatment. Because 82 percent of people with diabetes visit a primary care provider annually, telemedicine could also potentially increase the annual probability of screening for DR compared with clinical eye evaluations (National Center for Health Statistics 2005–2006). Unfortunately, telemedicine currently has a limited ability to detect prevalent eye conditions other than AMD, such as cataract, glaucoma, or uncorrected refractive error (URE, a presenting acuity of 20/40 or worse that can be easily corrected with glasses or contact lenses). The much greater ability of clinical eye evaluation to detect these conditions may result in either annual or biennial evaluation being more cost-effective than telemedicine. We designed this study to provide additional information regarding the most cost-effective screening alternatives for people with diabetes who are at low risk of progression when accounting for imperfect compliance with screening recommendations and the ability of eye evaluation to detect other common visual disorders. We estimated the cost-effectiveness of four possible methods of managing this patient population: patient self-referral following visual symptoms, annual eye evaluation, biennial eye evaluation, and annual telemedicine screening in primary care settings. Our results can be used to evaluate the management practice that is most likely to be cost-effective at different societal valuations of the gains from medical therapy and to inform what additional research may be required to update recommendations.

A 32 kb critical region excluding Y402H in CFH mediates risk for age-related macular degeneration

Abstract: Complement factor H shows very strong association with Age-related Macular Degeneration (AMD), and recent data suggest that multiple causal variants are associated with disease. To refine the location of the disease associated variants, we characterized in detail the structural variation at CFH and its paralogs, including two copy number polymorphisms (CNP), CNP147 and CNP148, and several rare deletions and duplications. Examination of 34 AMD-enriched extended families (N = 293) and AMD cases (White N = 4210 Indian = 134; Malay = 140) and controls (White N = 3229; Indian = 117; Malay = 2390) demonstrated that deletion CNP148 was protective against AMD, independent of SNPs at CFH. Regression analysis of seven common haplotypes showed three haplotypes, H1, H6 and H7, as conferring risk for AMD development. Being the most common haplotype H1 confers the greatest risk by increasing the odds of AMD by 2.75-fold (95% CI = [2.51, 3.01]; p = 8.31×10(-109)); Caucasian (H6) and Indian-specific (H7) recombinant haplotypes increase the odds of AMD by 1.85-fold (p = 3.52×10(-9)) and by 15.57-fold (P = 0.007), respectively. We identified a 32-kb region downstream of Y402H (rs1061170), shared by all three risk haplotypes, suggesting that this region may be critical for AMD development. Further analysis showed that two SNPs within the 32 kb block, rs1329428 and rs203687, optimally explain disease association. rs1329428 resides in 20 kb unique sequence block, but rs203687 resides in a 12 kb block that is 89% similar to a noncoding region contained in ΔCNP148. We conclude that causal variation in this region potentially encompasses both regulatory effects at single markers and copy number.

Serum cystatin C and the incidence of type 2 diabetes mellitus

Abstract: To examine the association of serum cystatin C with the incidence of type 2 diabetes mellitus over a 15 year follow-up period The 15 year cumulative incidence of diabetes was measured in a cohort of Beaver Dam Eye Study participants (n = 3,472, 1988–2003) A person was defined as developing diabetes (a positive history of diabetes mellitus treated with insulin, oral hypoglycaemic agents and/or diet, or elevations in glycosylated haemoglobin levels) in the absence of diabetes at baseline The relation of cystatin C and other risk factors to incident type 2 diabetes was determined using discrete time extension of the proportional hazards model The 15 year cumulative incidence of diabetes was estimated to be 96% After controlling for age, sex, body mass index, smoking status, glycosylated haemoglobin, proteinuria, chronic kidney disease status and hypertension status, serum cystatin C at baseline was associated with the 15 year cumulative incidence of type 2 diabetes (OR per log of cystatin C unit 219, 95% CI 102–468) These findings show a positive relationship of serum cystatin C levels with the incidence of type 2 diabetes mellitus independently of confounding risk factors The findings strongly suggest the need for further evaluation of the potential importance of cystatin C in the pathogenesis of type 2 diabetes mellitus

Retinal Microvascular Signs and Functional Loss in Older Persons The Cardiovascular Health Study

Abstract: Background and Purpose—We hypothesized that retinal microvascular signs are associated with executive dysfunction, slow gait, and depressive mood, which are characteristic features of microvascular disease affecting frontal subcortical regions of the brain. Methods—In the Cardiovascular Health Study, 1744 participants (mean age, 78) free of stroke had retinal photographs and carotid ultrasound during the 1997 to 1998 visit. We examined the cross-sectional association of retinal signs with the digit-symbol substitution test (DSST) score, gait speed, the Center for Epidemiologic Studies–Depression score, and depressive mood, defined as Center for Epidemiologic Studies–Depression score >9 or antidepressant use. Results—After adjusting for potential confounders, retinal signs were associated with lower DSST score (generalized arteriolar narrowing and arteriovenous nicking), slower gait (retinopathy), and depressive mood (generalized arteriolar narrowing). A higher number of retinal signs was associated with l...

Physical Activity, Television Viewing Time, and Retinal Microvascular Caliber The Multi-Ethnic Study of Atherosclerosis

Abstract: Physical activities and sedentary behaviors are 2 broad classes of behavior that may be clearly distinguished from each other and have different patterns of determinants. The authors examined the associations of physical activity and television viewing time with retinal vascular caliber among US adults (n = 5,893) from 4 racial/ethnic groups in the Multi-Ethnic Study of Atherosclerosis (2002-2004) that included non-Hispanic whites, blacks, Hispanics, and Chinese. Physical activity and television viewing time were assessed by using a questionnaire, and vascular calibers (arteriolar and venular) were measured from digital retinal photographs. Those in the lowest quartile of physical activity had wider retinal venular caliber compared with those in the highest quartile in multivariate models adjusted for demographic, cardiovascular, behavioral, and inflammatory risk factors. This was noted in non-Hispanic whites and Hispanics but not in blacks or Chinese. For television viewing time, non-Hispanic whites (but not the other racial/ethnic groups) who were in the highest quartile of television viewing time had wider retinal venular caliber compared with those in the lowest quartile. No associations were noted with arteriolar caliber. Lower levels of physical activity (among non-Hispanic whites and Hispanics) and higher levels of television viewing time (among whites) are associated with wider retinal venules.

Retinal arteriolar caliber and urine albumin excretion: the Multi-Ethnic Study of Atherosclerosis

Abstract: Background. Changes in retinal microvascular caliber, which occur prior to onset of retinopathy, may indicate presence of kidney damage. Methods. This study examined the association between retinal arteriolar [central retinal artery equivalent (CRAE)] and venular caliber [central retinal venule equivalent (CRVE)] and presence of albuminuria (micro- or macroalbuminuria) among participants of the Multi-Ethnic Study of Atherosclerosis (MESA), a cohort of adults aged 45–84 years without baseline clinical cardiovascular disease. During the second MESA exam, digital fundus photography was completed in 5897 participants who provided spot urine specimens. Albuminuria was defined by spot urine albumin/creatinine ratios ≥30 mg/g. Multivariable adjusted odds of albuminuria by quintiles of CRAE and CRVE were determined using logistic regression. Analyses were repeated after stratifying by presence of type 2 diabetes. Results. Albuminuria was noted in 11.5% (n = 675) and included 584 subjects with microalbuminuria and 91 with macroalbuminuria. A significant U-shaped pattern was seen with higher prevalence of albuminuria across quintile extremes in CRAE (15.7, 8.8 and 10.6% in CRAE Quintiles 1, 3 and 5, respectively; P <0.0001). After adjustment for covariates, both narrower CRAE [odds ratios (OR) 1.55; 95% confidence interval (CI) 1.17–2.04, Quintile 1 versus 3) and wider CRAE (OR 1.44; 95% CI 1.07–1.93, Quintile 5 versus 3) were significantly associated with albuminuria. Associations appeared substantially stronger in adults with than without type 2 diabetes but the interaction term for diabetes and CRAE on presence of albuminuria did not meet statistical significance (P = 0.3). No association was noted between CRVE quintiles and albuminuria. Conclusions. Albuminuria is associated with narrower and wider arteriolar caliber. Future studies should determine whether variation in arteriolar caliber predicts incident albuminuria and whether associations are mediated by hypertension and diabetes. Such information could further clarify early microvascular processes in the pathogenesis of kidney disease.