[Show abstract][Hide abstract] ABSTRACT: Diabetes mellitus is a disease with considerable morbidity and mortality worldwide. Breakdown of the blood-retinal barrier and leakage from the retinal vasculature leads to diabetic macular edema, an important cause of vision loss in patients with diabetes. Although epidemiologic studies and randomized clinical trials suggest that glycemic control plays a major role in the development of vascular complications of diabetes, insulin therapies for control of glucose metabolism cannot prevent long-term retinal complications. The phenomenon of temporary paradoxical worsening of diabetic macular edema after insulin treatment has been observed in a number of studies. In prospective studies on non-insulin-dependent (type 2) diabetes mellitus patients, a change in treatment from oral drugs to insulin was often associated with a significant increased risk of retinopathy progression and visual impairment. Although insulin therapies are critical for regulation of the metabolic disease, their role in the retina is controversial. In this study with diabetic mice, insulin treatment resulted in increased vascular leakage apparently mediated by betacellulin and signaling via the epidermal growth factor (EGF) receptor. In addition, treatment with EGF receptor inhibitors reduced retinal vascular leakage in diabetic mice on insulin. These findings provide unique insight into the role of insulin signaling in mediating retinal effects in diabetes and open new avenues for therapeutics to treat the retinal complications of diabetes mellitus.
Preview · Article · Jul 2013 · American Journal Of Pathology
[Show abstract][Hide abstract] ABSTRACT: To evaluate the concordance of cancer diagnosis from self- and registry reports.
Self-reported diagnosis information from participants in a cohort study was compared with linkage data from the Wisconsin Cancer Reporting System.
Overall, there was good agreement between self- and registry-reported cancers, with 90% of all matches being considered an exact match. Concordance varied by cancer site; agreement was excellent for breast (85.4%) and prostate (78.9%) cancers.
While self-reported cancer diagnoses for some cancers such as breast and prostate cancer are important sources of information and may be reliable substitutes when registry data are incomplete or not available, a combination of self and registry reports with mortality information may yield the most accurate information about cancer for purposes of health care planning and conducting epidemiologic studies.
Preview · Article · Oct 2010 · WMJ: official publication of the State Medical Society of Wisconsin
[Show abstract][Hide abstract] ABSTRACT: To estimate the ten-year incidence of dry eye in an older population and examine its association with various risk factors.
The 43 to 86 year old population of Beaver Dam, WI, was examined in 1988 to 1990 (n = 4926) and 1993 to 1995 (n = 3722). Dry eye data were first collected in 1993 to 1995. Subsequent examinations or interviews occurred in 1998 to 2000 (n = 2827) and 2003 to 2005 (n = 2124). The incidence cohort comprised 2414 subjects not reporting dry eye in 1993 to 1995. Risk factor information, ascertained in 1993 to 1995, included demographics, medical history, cardiovascular disease risk factors, medications, and life-style factors. Ten-year cumulative incidence was estimated by the product-limit method.
Over the 10-year period, 482 subjects developed a history of dry eye for an incidence of 21.6% (95% confidence interval, 19.9 to 23.3%). Incidence increased significantly (p < 0.001) with age. Incidence was greater in women (25.0%) than men (17.2%, p < 0.001). After adjusting for age, incidence was greater (p < 0.05) in subjects with arthritis, allergy or thyroid disease not treated with hormone, using antihistamines, antianxiety medications, antidepressants, oral steroids or vitamins, and poorer self-rated health. Incidence was less (p < 0.05) in subjects consuming alcohol. It was not significantly associated with blood pressure, hypertension, serum total or high density lipoprotein cholesterol, body mass, diabetes, gout, osteoporosis, cardiovascular disease, smoking, caffeine use, or taking calcium channel blockers or anticholesterol medications. In a multivariable model with time-varying covariates, increased incidence was associated with age, female gender, poorer self-rated health, antidepressant or oral steroid use, and thyroid disease untreated with hormone. It was lower for those using angiotensin-converting enzyme inhibitors or with a sedentary lifestyle.
Dry eye incidence is substantial. However, there are few associated risk factors. Some drugs (antihistamines, antianxiety drugs, antidepressants, oral steroids) are associated with greater risk, while angiotensin-converting enzyme inhibitors may be associated with lower risk.
No preview · Article · Aug 2008 · Optometry and Vision Science
[Show abstract][Hide abstract] ABSTRACT: To describe the 15-year incidence of retinal vein occlusion (central retinal vein occlusion and branch retinal vein occlusion) and associated risk factors.
A population-based study where branch retinal vein occlusion and central retinal vein occlusion were detected at baseline (n = 4068, 1988-1990) and three 5-year follow-up examinations by grading 30 degrees color fundus photographs.
The 15-year cumulative incidences of branch retinal vein occlusion and central retinal vein occlusion were 1.8% and 0.5%, respectively. Using a generalized estimating equation model, incident retinal vein occlusion was related to baseline age (odds ratio [OR] per 10 years, 1.70; 95% confidence interval [CI], 1.36-2.12), history of barbiturate use (OR, 5.30; 95% CI, 2.28-12.31), focal retinal arteriolar narrowing (OR, 2.45; 95% CI, 1.29-4.66), glaucoma (OR, 3.17; 95% CI, 1.50-6.69), serum ionized calcium level (OR per 0.4 mg/dL, 0.43; 95% CI, 0.23-0.79), serum phosphorus level (OR per 0.3 mg/dL, 1.15; 95% CI, 1.01-1.30), and serum creatinine level (OR for > or = 1.4 vs < 1.4 mg/dL, 1.61; 95% CI, 1.00-2.59). Migraine headache history was associated with branch retinal vein occlusion (OR, 1.99; 95% CI, 1.08-3.67). Diabetes history was associated with central retinal vein occlusion (OR, 6.35; 95% CI, 1.90-21.27).
Incident retinal vein occlusion is not infrequent in the population, especially after age 65 years. The relationships of barbiturate use, serum creatinine level, serum ionized calcium level, and serum phosphorus level with incident retinal vein occlusion require further assessment in other large population-based studies.
Preview · Article · May 2008 · Archives of ophthalmology
[Show abstract][Hide abstract] ABSTRACT: To describe the frequency of orthostatic hypotension and hypertension and associations with risk factors in a cohort of persons with long-term Type 1 diabetes (n=440) participating in the Wisconsin Epidemiologic Study of Diabetic Retinopathy.
Evaluations included detailed medical history, electrocardiography (ECG), and laboratory tests. Blood pressure (BP) was measured in supine and standing positions. Standing decrease in systolic (SBP) or diastolic (DBP) BP of at least 20 or 10 mmHg, respectively, was defined as orthostatic hypotension; increase of SBP from <140 to >or=140 mmHg or DBP from <90 to >or=90 mmHg was defined as orthostatic hypertension.
Prevalence of orthostatic hypotension and orthostatic hypertension was 16.1% and 15.2%, respectively. Some ECG measurements of cardiac autonomic dysfunction were significantly associated with orthostatic hypotension. Association between SBP and orthostatic hypotension and orthostatic hypertension were significant [odds ratio, 1.02 (95% confidence interval, or CI, 1.01-1.05) and 1.02 (95% CI, 1.01-1.04), per 1 mmHg, respectively] after adjusting for confounders. Interaction between SBP and age was observed. SBP was significantly associated with orthostatic hypotension and orthostatic hypertension in people <or=40 years old [1.35 (1.02-1.78) and 1.12 (1.05-1.18), respectively].
Results showed that measurements derived from the ECG can help describe an individual at increased risk of having postural BP changes. Moreover, SBP was associated with postural BP changes among individuals who were <40 years of age with long-term Type 1 diabetes.
Full-text · Article · Apr 2008 · Journal of diabetes and its complications
[Show abstract][Hide abstract] ABSTRACT: The purpose of this study was to examine the relationship of glycemic control and exogenous and endogenous insulin levels with all-cause and cause-specific mortality (ischemic heart disease and stroke) in an older-onset diabetic population.
The Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR) is an ongoing, prospective, population-based cohort study of individuals with diabetes first examined in 1980-1982. A stratified sample of all individuals with diabetes diagnosed at 30 years of age or older was labeled "older-onset" (n = 1,370). Those participating in the 1984-1986 examination phase (n = 1,007) were included in the analysis. Endogenous insulin was determined by measurements of plasma C-peptide (in nanomoles per liter), and exogenous insulin was calculated in units per kilogram per day. Glycemic control was determined by levels of glycosylated hemoglobin (HbA(1)).
After 16 years of follow-up, 824 individuals died (all-cause mortality); 358 deaths involved ischemic heart disease and 137 involved stroke. C-peptide and HbA(1) were significantly associated with all-cause and ischemic heart disease mortality in our study. The hazard ratio (95% CI) values for all-cause mortality were 1.12 (1.07-1.17) per 1% increase in HbA(1), 1.20 (0.85-1.69) per 1 unit x kg(-1) x day(-1) increase in exogenous insulin, and 1.15 (1.04-1.29) per 1 nmol/l increase in C-peptide and for ischemic heart disease mortality were 1.14 (1.06-1.22), 1.50 (0.92-2.46), and 1.19 (1.02-1.39) for HbA(1), exogenous insulin, and C-peptide, respectively, after adjusting for relevant confounders. C-peptide was associated with stroke mortality only among men (1.65 [1.07-2.53]).
Our results show that individuals with higher endogenous insulin levels are at higher risk of all-cause, ischemic heart disease, and stroke mortality.
[Show abstract][Hide abstract] ABSTRACT: To describe the relationship of retinal arteriolar and venular calibers to the long-term incidence of microvascular and macrovascular complications in people with type 2 diabetes.
Population-based prospective study.
One thousand three hundred seventy persons diagnosed to have diabetes at > or =30 years of age in south central Wisconsin participated in the baseline examination from 1980 to 1982, 987 in the 4-year follow-up, and 533 in the 10-year follow-up.
Computer-assisted grading was used to determine the average caliber of retinal arterioles (central retinal arteriolar equivalent [CRAE]) and retinal venules (central retinal venular equivalent [CRVE]) at all examinations.
Incidence and progression of diabetic retinopathy; incidence of proliferative diabetic retinopathy and macular edema; incidence of nephropathy, neuropathy, and lower extremity amputation; and ischemic heart disease, stroke, and overall mortality.
While adjusting for other factors, smaller CRAE was associated with the 14-year cumulative incidence of lower extremity amputation (odds ratio [OR], first vs. second to fourth quartiles, 2.20; 95% confidence interval [CI], 1.14-4.24; P = 0.02), 22-year all-cause mortality (hazard ratio [HR], 1.18; 95% CI, 1.02-1.38; P = 0.03), and 22-year stroke mortality (HR, 1.47; 95% CI, 1.04-2.07; P = 0.03) but not with the other end points. Larger CRVE was associated with the 14-year incidence of diabetic nephropathy (OR, fourth vs. first to third quartiles, 2.08; 95% CI, 1.47-2.94; P<0.001) and 22-year stroke mortality (HR, 1.71; 95% CI, 1.20-2.44; P = 0.003) but with none of the other end points.
Retinal vessel caliber is independently associated with risk of incident nephropathy, lower extremity amputation, and stroke mortality in persons with type 2 diabetes. Measurement of retinal vessel caliber from photographs may provide additional information for the prediction of these events.
[Show abstract][Hide abstract] ABSTRACT: Retinopathy is relatively common in nondiabetic populations, and its long-term prognostic implications are not certain. For this reason, the authors hypothesized that retinal alterations were associated with all-cause and cause-specific mortality in nondiabetic individuals participating in the Beaver Dam Eye Study in Wisconsin. Included in the analysis were 4,294 nondiabetic subjects aged 43-84 years examined at baseline (1988-1990). Retinopathy was classified into four groups by using retinal photographs: 1) no retinopathy, 2) presence of retinal hemorrhages only, 3) presence of retinal microaneurysms only, and 4) presence of moderate or worse retinopathy. The authors analyzed survival during 14 years of follow-up and in 5-year intervals by using time-varying covariates. Baseline prevalence of retinopathy was 7.7%. Adjusting for age, sex, and significant confounders, they observed that moderate retinopathy at baseline was associated with all-cause (hazard ratio = 1.76, 95% confidence interval: 1.16, 2.69) and ischemic heart disease (hazard ratio = 3.17, 95% confidence interval: 1.73, 5.78) mortality after 14 years of follow-up. In the 5-year-interval analysis, the presence of hemorrhages only was significantly related to increased all-cause (hazard ratio = 1.49, 95% confidence interval: 1.05, 2.12) and ischemic heart disease (hazard ratio = 2.43, 95% confidence interval: 1.48, 4.01) mortality. Study results suggest that retinal changes have possible prognostic implications regarding survival of persons without diabetes.
Full-text · Article · Oct 2007 · American Journal of Epidemiology
[Show abstract][Hide abstract] ABSTRACT: Hyperglycemia is implicated in the development and progression of microvascular complications in type 1 diabetes. In contrast, the association between hyperglycemia and macrovascular complications or mortality in type 1 diabetes is not clear. The authors studied a population-based cohort of 879 individuals with type 1 diabetes from Wisconsin, free of cardiovascular disease and end-stage renal disease at the baseline examination (1980-1982). The main outcome of interest was all-cause (n=201) and cardiovascular (n=132) mortality as of December 31, 2001. Elevated glycosylated hemoglobin levels were associated with all-cause and cardiovascular mortality, independent of duration of diabetes, smoking, hypertension, and proteinuria. The multivariable relative risks comparing the highest quartile of glycosylated hemoglobin (>or=12.1%) with the lowest quartile (<or=9.4%) were 2.42 (95% confidence interval: 1.54, 3.82; p-trend=0.0006) for all-cause mortality and 3.28 (95% confidence interval: 1.77, 6.08; p-trend<0.0001) for cardiovascular mortality. This association was present among both sexes and persisted in subgroup analyses by categories of diabetes duration, smoking, body mass index, proteinuria, and retinopathy. These data suggest that hyperglycemia is associated with all-cause and cardiovascular mortality among individuals with type 1 diabetes.
Preview · Article · Aug 2007 · American Journal of Epidemiology
[Show abstract][Hide abstract] ABSTRACT: The purpose of this study was to evaluate the relationship of severe hypoglycemia and smoking in a population-based cohort of individuals with long-term type 1 diabetes.
This was a cross-sectional analysis of the population-based cohort of the Wisconsin Epidemiologic Study of Diabetic Retinopathy. The analyses in this report were limited to 537 type 1 diabetic individuals with complete data who participated in the last examination phase (2000-2001). Severe hypoglycemia was defined as having one or more episodes of loss of consciousness or overnight hospitalization attributable to hypoglycemia in a 1-year period before the examination.
The prevalence of severe hypoglycemia in this population was 14.3%. In univariate analysis, current smokers had a greater chance of having severe hypoglycemia compared with never smokers (odds ratio 2.40 [95% CI 1.30-4.40]). When we controlled for relevant confounders such as age, sex, A1C, waist-to-hip ratio, orthostatic hypotension, alcohol consumption, intensive insulin treatment, past history of severe hypoglycemia, and late complications of diabetes (nephropathy, neuropathy, and retinopathy), the association remained statistically significant, with current smoking presenting approximately 2.6 times greater odds of developing severe hypoglycemia.
Current smokers with type 1 diabetes have higher odds of severe hypoglycemia episodes.
[Show abstract][Hide abstract] ABSTRACT: The incidence of recently defined outcome of chronic kidney disease (CKD) has not been widely reported in type 1 diabetes.
To examine the prospective association between baseline glycosylated hemoglobin levels and the 16-year incidence of CKD and end-stage renal disease (ESRD) in type 1 diabetes.
Prospective cohort study of type 1 diabetes individuals.
Community based in southwestern Wisconsin.
547 younger-onset type 1 diabetes individuals who were free of CKD at baseline (1984-86).
Development of CKD (defined as estimated glomerular filtration rate<60 ml/min/1.73 m(2) or ESRD [history of dialysis or renal transplantation]) over 16-year follow-up period, among individuals free of CKD at baseline. Alternate outcome was 16-year incident ESRD.
After 16 years of follow-up, there were 158 cases of CKD and 37 cases of ESRD in our cohort. The 16-year cumulative incidence of CKD was 31.7 percent. Elevated glycosylated hemoglobin levels were associated with incident CKD and ESRD in separate models. Multivariable odds ratio (OR) [95% confidence intervals (CI)] comparing the highest quartile of glycosylated hemoglobin (11-15.3%) to the lowest quartile (6-8.6%) was 6.44 (3.61-11.51), p-trend<0.0001 for incident CKD and 21.87 (2.84-168.39), p-trend<0.0001 for ESRD.
Higher baseline glycosylated hemoglobin levels are independently associated with incident CKD and ESRD, among individuals with type 1 diabetes.
No preview · Article · Mar 2007 · Experimental and Clinical Endocrinology & Diabetes
[Show abstract][Hide abstract] ABSTRACT: Current recommendations, largely based on studies in type 2 diabetes, suggest lower target blood pressures (BPs) for individuals with diabetes than for the general population. However, the effect of lower BP on renal outcomes in type 1 diabetes is uncertain. In a population-based cohort of type 1 diabetes adults (mean age: 33.1 years) based in Wisconsin, of which the distribution of baseline BP was in the low-normal range, we examined the relationship between decreasing categories of systolic and diastolic BP and the 16-year incidence of proteinuria (n=232 of 604) and estimated glomerular filtration rate of <60 mL/min/1.73 m(2) (n=158 of 547). Decreasing BP categories had lower relative risk (RR) of developing incident proteinuria (RR comparing decreasing quartiles of systolic BP: 1.00, 0.76, 0.58, 0.73; P for trend=0.03; RR comparing decreasing quartiles of diastolic BP: 1.00, 0.81, 0.66, 0.42; P for trend <0.0001) and incident estimated glomerular filtration rate <60 mL/min/1.73 m(2) (RR comparing decreasing quartiles of systolic BP: 1.00, 0.83, 0.61, 0.65; P for trend=0.03; RR comparing decreasing quartiles of diastolic BP: 1.00, 0.84, 0.82, 0.43; P for trend=0.001). These associations were independent of glycemic control and several putative confounding factors. Subjects with either systolic BP <120 mm Hg or diastolic BP <70 mm Hg had significantly lower RR (95% confidence interval) of incident proteinuria (0.63 [0.48 to 0.82]) and incident estimated glomerular filtration rate <60 mL/min/1.73 m(2) (0.60 [0.43 to 0.82]); corresponding population-attributable risks for these outcomes were 26.7% and 29.5%, respectively. Our study suggests that lower BP levels, even below the accepted normal range, are protective against kidney disease in adults with type 1 diabetes. Interventional trials are desirable to clarify the clinical significance of this association.
[Show abstract][Hide abstract] ABSTRACT: To examine the association of ambulatory blood pressure (ABP) and ambulatory pulse rate (APR) with diabetic retinopathy (DR) in persons with type 1 diabetes in the Renin-Angiotensin System Study (RASS), a multicenter primary diabetic nephropathy (DN) prevention trial.
One hundred ninety-four normotensive RASS participants in 3 centers who are 16 years of age or older with type 1 diabetes mellitus (DM) of 2 to 20 years' duration.
Ambulatory blood pressure and APR were monitored using standardized protocols. Patients were defined as nondippers if the night-to-day ratios for both systolic and diastolic blood pressures were >0.9. Diabetic retinopathy was determined by masked grading of 30 degrees color stereoscopic fundus photographs of 7 standard fields using the Early Treatment Diabetic Retinopathy Study severity scale.
Severity of DR.
No DR was present in 32%, mild nonproliferative DR (NPDR) was present in 55%, and moderate to severe NPDR or proliferative DR was present in 13% of the cohort. Neither 24-hour systolic ABP or diastolic ABP, daytime systolic or diastolic ABP, nor nighttime diastolic ABP were related to severity of DR. Statistically significant associations were found between nighttime systolic ABP and mean ABP and DR. Among those with no DR, 19% were nondippers; for those with mild NPDR, 28% were nondippers; and for those with severe NPDR or proliferative DR, 36% were nondippers (P = 0.08). The ratio of nighttime to daytime APR, but not the 24-hour APR or daytime or nighttime APR, was related positively to the severity of DR. In multivariable analyses, only the nighttime systolic ABP was related to severity of DR (P<0.05).
These data suggest that ABP, especially during the night, may provide a better measure than clinical BP regarding the relationship of BP to the severity of retinopathy in normotensive persons with type 1 DM without clinical DN.
[Show abstract][Hide abstract] ABSTRACT: To describe retinal vascular caliber and correlates in people with type 2 diabetes.
Thirteen hundred seventy persons diagnosed to have diabetes at or after 30 years of age in an 11-county area in south central Wisconsin from 1980 to 1982.
Retinal photographs of 7 standard fields were taken; light box grading was done to determine retinopathy severity. Computer-assisted grading was done from a digitized image of field 1 to determine the central retinal arteriolar equivalent (CRAE; arteriolar caliber) and central retinal venular equivalent (CRVE; venular caliber).
Retinal arteriolar and venular calibers.
In multivariable analyses in persons with panretinal photocoagulation excluded, while controlling for refractive error, CRAE was associated independently with age (per 10 years, beta = -2.0 microm), mean arterial blood pressure (BP) (per 10 mmHg, beta = -2.2 microm), smoking status (current vs. never smoked, beta = 5.6 microm), and intraocular pressure (IOP) (per 1 mmHg, beta = 0.2 microm). The CRVE was associated independently with age (per 10 years, beta = -2.5 microm), mean arterial BP (per 10 mmHg, beta = -2.1 microm), smoking status (current vs. never smoked, beta = 11.6 microm), pack-years smoked (per 10 pack-years, beta = 1.0 microm), body mass index (per kg/m2, beta = 0.3 mm), pulse rate (per 10 beats/minute, beta = 1.5 microm), retinopathy severity (per 1 level, beta = 1.05 microm), and IOP (per 10 mmHg, beta = -0.5 microm). Smaller CRAEs and CRVEs were found in eyes with panretinal photocoagulation treatment than in eyes without such treatment.
In persons with type 2 diabetes, variations in retinal vascular caliber are related to various systemic and ocular factors. Understanding these relationships may provide further insights into early retinal vascular changes in diabetes.
[Show abstract][Hide abstract] ABSTRACT: To examine the relationship of retinopathy in persons without diabetes mellitus to the 15-year cumulative incidence of diabetes mellitus and hypertension.
A total of 3,402 persons 43 to 86 years of age without diabetes mellitus (1,879 without diabetes or hypertension) at the time of a baseline examination in 1988-1990 had follow-up examinations in 1993-1995, 1998-2000, and/or 2003-2005. Diabetes mellitus was defined by a combination of history, serum glucose levels, and glycosylated hemoglobin levels, and hypertension was defined as systolic blood pressure >/=140 mm Hg or diastolic blood pressure >/=90 mm Hg and/or use of antihypertensive medications. Retinopathy at baseline was determined by masked gradings of stereoscopic fundus photographs using standardized protocols.
Retinopathy was present in 7.3% of the nondiabetic persons in the cohort and 5.4% of the nondiabetic, nonhypertensive cohort at baseline. The 15-year cumulative incidence of diabetes was 12.5% and of hypertension 54.1%. While controlling for age, persons with retinopathy were more likely to develop diabetes mellitus (odds ratio, 95% confidence interval, P value: 1.70, 1.17-2.48, P = .005) and hypertension (1.62, 1.18-2.23, P = .003) than persons without retinopathy. While controlling for other risk factors (eg, blood pressure, glucose level, cardiovascular disease history), the associations of retinopathy with incident diabetes mellitus (1.35, 0.90-2.03, P = .15) and hypertension (1.48, 1.05-2.07, P = .02) became attenuated but remained statistically significant for hypertension. In stratified analyses, retinopathy was associated with incident diabetes in persons younger than 65 years (1.80, 1.12-2.89, P = .02)
While controlling for other risk factors, retinopathy in nondiabetic individuals is associated with the incidence of hypertension and, in younger persons, with the incidence of diabetes mellitus.
Full-text · Article · Feb 2006 · Transactions of the American Ophthalmological Society
[Show abstract][Hide abstract] ABSTRACT: To examine the association of ankle-brachial blood pressure index (ABI) with prevalence of age-related maculopathy (ARM).
A cross-sectional cohort study.
ABI was measured in 2447 subjects aged 53 to 97 years. ARM was determined from 30-degree color stereoscopic fundus photographs.
Low ABI (< or =0.9) was present in 5.4% of subjects. Early ARM was present in 22.1% of subjects with and 18.8% without low ABI. Late ARM was present in 5.3% of subjects with and 1.7% without low ABI. This result was not statistically significant.
Low ABI does not appear to be a risk factor for ARM.
No preview · Article · Jan 2006 · American Journal of Ophthalmology
[Show abstract][Hide abstract] ABSTRACT: Few epidemiological data exist regarding the correlation of anatomic measures of diabetic retinopathy and nephropathy, especially early in the disease processes. The aim of this study was to examine the association of severity of diabetic retinopathy with histological measures of diabetic nephropathy in normoalbuminuric patients with type 1 diabetes. The study included participants (n = 285) in the Renin-Angiotensin System Study (RASS; a multicenter diabetic nephropathy primary prevention trial) who were aged >/=16 years and had 2-20 years of type 1 diabetes with normal baseline renal function measures. Albumin excretion rate (AER), blood pressure, serum creatinine, and glomerular filtration rate (GFR) were measured using standardized protocols. Diabetic retinopathy was determined by masked grading of 30 degrees color stereoscopic fundus photographs of seven standard fields using the Early Treatment Diabetic Retinopathy Study (ETDRS) severity scale. Baseline renal structural parameters, e.g., fraction of the glomerulus occupied by the mesangium or mesangial fractional volume [Vv(Mes/glom)] and glomerular basement membrane width, were assessed by masked electron microscopic morphometric analyses of research percutaneous renal biopsies. No retinopathy was present in 36%, mild nonproliferative diabetic retinopathy in 53%, moderate to severe nonproliferative diabetic retinopathy in 9%, and proliferative diabetic retinopathy in 2% of the cohort. Retinopathy was not related to AER, blood pressure, serum creatinine, or GFR. All renal anatomical end points were associated with increasing severity of diabetic retinopathy, while controlling for other risk factors. These data demonstrate a significant association between diabetic retinopathy and preclinical morphologic changes of diabetic nephropathy in type 1 diabetic patients.