Poor Glycemic Control in Diabetes and The Risk of Incident Chronic Kidney Disease Even in The Absence of Albuminuria and Retinopathy: The Atherosclerosis Risk in Communities (Aric) Study

Abstract

Background

Diabetic nephropathy is the leading cause of kidney failure in the US. The extent to which elevated glycated hemoglobin (HbA1c) is associated with increased risk of chronic kidney disease (CKD) in the absence of albuminuria and retinopathy, the hallmarks of diabetic nephropathy, is uncertain.

Methods

HbA1c was measured in 1,871 adults with diabetes followed for 11 years in the Atherosclerosis Risk in Communities Study. Incident CKD was defined as an estimated glomerular filtration rate (GFR) below 60 mL/min/1.73 m² after 6 years of follow-up or a kidney disease-related hospitalization. We categorized HbA1c into 4 clinically relevant categories. Retinopathy and albuminuria were measured midway through follow-up.

Results

Higher HbA1c was strongly associated with risk of CKD in models adjusted for demographics, baseline GFR and cardiovascular risk factors. Compared to HbA1c values of <6.00%, HbA1cs of 6.00-7.00%, 7.00%-8.00%, and >8.00% had adjusted relative hazards of CKD of 1.4 (95% CI: 0.97-1.91), 2.5 (1.70-3.66) and 3.7 (2.76-4.90), respectively. Risk of CKD was higher among individuals with retinopathy and albuminuria, the association between HbA1c and incident CKD was observed even among those participants without either abnormality: adjusted relative hazards =1.46 (0.80-2.65), 1.17 (0.43-3.19) and 3.51 (1.67-7.40); p-trend=0.004.

Conclusion

We observed a positive association between HbA1c and incident CKD that was strong, graded, independent of traditional risk factors and present even in the absence of albuminuria and retinopathy. Hyperglycemia is an important indicator of risk of both diabetic nephropathy (with albuminuria or retinopathy) and of less specific forms of CKD.

Background

More than 26 million US adults have chronic kidney disease (CKD), defined by decreased glomerular filtration rate (GFR) or increased urinary albumin excretion.¹ CKD is associated with an increased risk of cardiovascular disease (CVD) morbidity and mortality.^2-7 As a major risk factor for CVD, the National Kidney Foundation⁸ and the American Heart Association⁹ place individuals with CKD in the highest risk group for intervention.

Diabetes is a leading cause of kidney failure in the U.S., accounting for more than 40% of all incident end-stage renal disease (ESRD) cases.^{10,11 12} Diabetes increases the risk for end-stage renal disease (ESRD) including disease that is a direct complication of diabetes as well as ESRD due to causes other than diabetes.¹³ Diabetes is closely associated with microvascular disease, often manifesting as retinopathy or albuminuria.^{14, 15} However, approximately one-third of individuals with diabetes have decreased kidney function without either albuminuria or retinopathy.¹⁶

Increased glycated hemoglobin (hemoglobin A1c, HbA1c) is related to the development of microvascular disease in diabetes, and their reduction is at the center of the clinical management of hyperglycemia. Randomized studies among individuals with type 1 diabetes have shown that intensive treatment slows progression of microvascular complications (nephropathy, retinopathy, neuropathy) as well as reduces the development and progression of microalbuminuria.¹⁷

The continuous relationship between HbA1c levels and incidence of moderate CKD among individuals with diabetes, however, has not been well quantified. It is also unknown whether moderately elevated HbA1c levels predict a decline in kidney function in the absence of detectable microvascular disease, as evidenced by albuminuria and/or retinopathy. An improved understanding from observational data of the risks and consequences of diabetes in the absence of albuminuria and retinal damage is particularly important given recent concerns about tight glycemic control and risk of mortality among certain high risk individuals with diabetes.¹⁸

We examined the long-term independent association between moderately elevated levels of HbA1c and incident CKD in a population-based observational sample of adults with diabetes and evaluated the consistency of this association among those with and without albuminuria and/or retinopathy.

Methods

Study population

Data were taken from the Atherosclerosis Risk in Communities (ARIC) Study. This prospective biracial observational cohort of 15,792 individuals (including 2,187 persons with diabetes) between the ages of 45 and 64 (mean age: 54 (SD 5.8), 55% female, 74% white, 26% African American at baseline) was recruited from a probability sample of four U.S. communities (Forsyth County, NC; Jackson, MS; suburban Minneapolis, MN; and Washington County, MD). Participants took part in examinations starting with a baseline visit (visit 1) between 1987 and 1989. Individuals had 3 follow-up examinations in approximately three year intervals at community clinics, as well as annual follow-up telephone interviews between visits. Hospitalized events were ascertained continuously from ARIC's inception through December 31, 2004. Details of the ARIC cohort have been published elsewhere.¹⁹

In the present study, we included all participants with diabetes at the second ARIC visit (visit 2: 1990-1992), the only visit in which HbA1c was measured. Diabetes mellitus was defined as a fasting glucose of ≥ 126 mg/dL, nonfasting glucose of ≥ 200 mg/dL, self-reported physician diagnosis of diabetes mellitus or use of oral hypoglycemic medication or insulin. A total of 1,054 (56%) of 1,871 of individuals were identified based on self-reported diabetes. A total of 1,655 (88%) individuals were identified based on elevated plasma glucose: 1,556 (83%) with fasting plasma glucose of at least 126 mg/dL and an additional 99 (7%) with a nonfasting glucose of at least 200 mg/dL. Only 216 (11.5%) individuals reported having diabetes without also having an elevated plasma glucose.

We excluded participants who were missing HbA1c values at visit 2 (n=28), missing serum creatinine values at ARIC visit 1 or visit 2 (n=20), those with an estimated GFR < 60 mL/min/1.73 m² at either ARIC visit 1 or visit 2 (n=229), participants who reported a race other than white or African American (n=3) and African Americans from the Minnesota and Washington County study centers (n=8). Analyses are based on the remaining 1,871 study participants. The study was approved by the institutional review boards at each of the sites, and written informed consent was obtained from all participants.

Data collection

Demographic and health behavior data, medical history, and measurements of height, weight and blood pressure were obtained during each clinical examination. Blood was drawn at all clinic visits as described previously.²⁰

HbA1c was assayed from stored whole blood samples from the second ARIC visit using Tosoh high-performance liquid chromatography instruments in a secondary reference laboratory of the National Glycohemoglobin Standardization Program at the University of Minnesota Medical Center, Fairview, and certified by the International Federation of Clinical Chemists.^21-23 HbA1c measurements were available for 2,159 (98.7%) of 2,187 participants with diabetes. HbA1c concentrations were recalibrated to correct for an upwards bias that was observed in a previous validation study comparing samples before and after long-term storage.²²

A modified kinetic Jaffe method was used to measure serum creatinine at ARIC visit 2 and visit 4. Serum creatinine concentration was corrected for interlaboratory differences and indirectly calibrated to the Cleveland Clinic measurement by subtraction of 0.24 mg/dL from the visit 2 values and the addition of 0.18 mg/dL to the visit 4 values and then used to estimate GFR.^{3, 24} Estimated GFR was calculated using the simplified Modification of Diet in Renal Disease equation developed at the Cleveland Clinic: estimated GFR = 186.3 × (serum creatinine [mg/dL]^-1.154) × (age^-0.203) × (0.742 if female) × (1.21 if African American).²⁵

Three seated blood pressure measurements were taken by certified technicians using a random-zero sphygmomanometer after 5 minutes of rest. The mean of the second and third readings was recorded. Enzymatic methods were used to obtain total plasma cholesterol, high-density lipoprotein (HDL) cholesterol and triglycerides while low-density lipoprotein (LDL) cholesterol was calculated from these using the Friedewald equation.²⁶

Smoking status was determined by self-reported cigarette smoking. Prevalent CHD was defined as a history of physician-diagnosed myocardial infarction, evidence of a prior myocardial infarction by electrocardiogram (presence of a major or minor Q-wave abnormality with T-wave or ST-segment abnormality) or self-reported prior coronary revascularization procedure. Self-reported medication use (eg: antihypertensives, or antidiabetics) was verified by bottle inspection.

Urinary albumin excretion was measured from a spot urine sample at ARIC visit 4 (1996-1998) as the ratio of albumin to creatinine (ACR, in mg/g). Albuminuria was defined as ACR ≥30 mg/g (which includes both the categories of micro- and maroalbuminuria). Retinography was conducted at ARIC visit 3 (1993-1995) in one randomly selected eye of each participant. A modification of the Airlie House classification system was used to grade lesions typical of diabetic retinopathy from a 45° color fundus photograph of one eye from each participant. Severity scores were assigned as follows: level 10, none; level 20, minimal nonproliferative retinopathy (microaneurysms only or blot hemorrhages only); level 35, early nonproliferative retinopathy (microaneurysms and at least one of the following: venous loops, soft exudate or hard exudate, and questionable intraretinal microvascular abnormalities or venous beading); levels 43 to 47, moderate to severe nonproliferative retinopathy (microaneurysms and at least one of the following: intraretinal microvascular abnormalities, venous beading, hemorrhages, and microaneursyms exceeding those in standard photograph 2A); level ≥60, proliferative retinopathy. We considered a severity score of 20 or higher to be presence of retinopathy.^27-29

Outcomes

Incident CKD was defined as an estimated GFR below 60 mL/min/1.73 m² at visit 4 (1996-1998, approximately 6 years after visit 2), or kidney disease noted during a hospitalization.³⁰ All hospitalizations and deaths among ARIC participants were ascertained through review of medical records, annual follow-up interviews and death certificates. Identification of hospital events was limited to those taking place in acute care hospitals and did not include events occurring in nursing homes, psychiatric hospitals, or other locations. Deaths were recorded regardless of location, and death certificates were abstracted for both underlying and contributory causes of death. Hospitalizations identified through active surveillance and used to identify cases included:_hospitalizations (discharges or deaths) coded for chronic renal disease, (International Classification of Diseases, Ninth Revision [ICD-9] codes 581-583 or 585-588), hypertensive renal disease (403), hypertensive heart and renal disease (404), unspecified disorder of kidney and ureter (593.9), diabetes with renal manifestations (250.4), kidney transplantation, renal dialysis, or adjustment/fitting of catheter (V42.0, V45.1, or V56), hemodialysis (39.95) or peritoneal dialysis (54.98), without acute renal failure (584, 586, 788.9, and 958.5) as the primary or secondary hospitalization code.³¹

Statistical analysis

We categorized HbA1c into categories (<6%, 6-7%, 7-8%, or >8%) corresponding to current ADA guideline categories.³² Baseline characteristics of the population were compared across CKD status and HbA1c categories using chi-squared and t tests. Incidence rates of CKD during follow-up were compared across HbA1c categories. Follow-up time was calculated from the time of the second ARIC examination to the first date of CKD diagnosis, defined as the earliest of either the fourth examination (if GFR decline was indicated), or the discharge date of a CKD-related hospitalization. Participants were censored at the earliest time of either death, withdrawal, or on December 31, 2004. Adjusted hazard ratios and their 95% confidence intervals for the time to development of CKD were computed using Cox proportional hazards models after first testing the assumption of proportionality of hazards over time. Models were developed comparing participants by HbA1c category as well as by continuous HbA1c. The continuous association between HbA1c and incident CKD was estimated from a Poisson regression model including a fourth-order polynomial for HbA1c, adjusted to the incidence rate for a 60 year old white male with a baseline eGFR of 90 mL/min/1.73 m². Multivariable models included age, race, gender, study center, baseline eGFR, BMI, hypertension status, use of antihypertensives, prevalent coronary heart disease (CHD), smoking status, LDL- and HDL-cholesterol and triglyceride concentrations. Analyses were repeated after stratification by the presence of albuminuria at visit 4 and retinopathy at visit 3 among participants for whom these data were available (n= 1,231).

All statistical analyses were conducted using Stata statistical software Version 9.2³³ or SAS Version 9.1.³⁴

Results

Among the 1,871 participants, higher HbA1c values were directly associated with female sex, African American race, higher estimated GFR, fasting glucose, prevalent CHD, hypertension, use of antihypertensives and antidiabetics, body mass index, and triglycerides (Table 1). Higher HbA1c category also was associated with lower HDL concentrations.

Table 1. Characteristics of the cohort of 1879 Individuals with Diabetes by HbA1c Category at Baseline.

Hemoglobin A1c Category
Characteristic: % or Mean (SD)	< 6.00% (n=770)	6.00- 7.00% (n=407)	7.00-8.00% (n=193)	> 8.00% (n=501)	p-trend
HbA1c (%)		5.28 (0.43)	6.46 (0.31)	7.73 (0.28)	10.15 (1.50)
HbA1c median (IQR)		5.29 (4.97-5.61)	6.46 (6.14-6.67)	7.52 (7.31-7.73)	9.86 (8.90-11.24)
Progressed to Incident CKD		11.8	16.5	23.8	31.3	<0.001
Male, %		52	49.6	44.0	41.3	0.002
Age (y)		58 (5.7)	58 (5.8)	59 (5.7)	57 (5.7)	0.977
African American, %		29.5	40.5	35.8	55.3	<0.001
Serum creatinine (mg/dL)		0.89 (0.18)	0.89 (0.17)	0.87 (0.18)	0.85 (0.19)	0.0004
eGFR, mL/min/1.73 m2		89 (18)	91 (18)	91 (18)	97 (23)	<0.0001
Mildly decreased (60-89 mL/min/1.73 m2) eGFR, %		60.5	55.3	54.9	42.3	<0.001
Fasting Glucose (mg/dL)		134 (24)	156 (27)	195 (48)	270 (67)	<0.0001
Use of blood sugar medication, %		14.7	39.8	68.2	74.8	<0.001
Prevalent CHD*,%		8.1	9.8	16.8	12.2	0.002
Blood Pressure Category, %	Normal	33.9	33.91	36.3	34.33	0.937
	Pre-hypertension	39.7	42.5	38.3	41.4	0.726
	Stage 1 hypertension	18.7	17.4	18.7	17.8	0.945
	Stage 2 hypertension	7.7	6.1	6.7	6.8	0.793
Systolic blood pressure (mm Hg)		128 (20)	128 (18)	128 (20)	128 (20)	0.9795
Diastolic blood pressure (mm Hg)		74 (11)	73 (10)	72 (10)	72 (11)	0.0472
Hypertensive, % (stage 1 or 2 or on antihypertensives)		52.6	60.7	54.4	59.1	0.025
Smoking status	Current, %	20.3	20.2	18.7	19.0	0.917
	Former, %	41.5	38.3	38.0	37.0	0.383
	Never, %	38.2	41.5	43.2	44.0	0.184
BMI* (kg/m2)		30.2 (5.5)	32.3 (6.2)	31.3 (6.0)	31.6 (5.9)	<0.0001
LDL cholesterol* (mg/dL)		134 (38)	136 (38)	133(44)	140 (40)	0.0702
HDL cholesterol* (mg/dL)		44 (14)	41 (13)	43 (15)	43 (14)	0.0043
Triglycerides* (mg/dL)		164 (110)	169 (92)	188 (118)	200 (179)	<0.0001

^*numbers of missing values (n): prevalent CHD (33) BMI (7); LDL (87); HDL (6); Triglycerides (3)

Abbreviations: HbA1c: glycated hemoglobin; eGFR: estimated glomerular filtration rate;

A total of 361 cases of incident CKD occurred during a mean follow-up of 11 years (incidence rate = 17.0 CKD cases per 1,000 person-years). A total of 120 cases were identifed based on a follow-up eGFR<60 mL/min/1.73 m² and 292 participants were based on a kidney-related hospitalization or death (51 met both criteria). Figure 1 compares the cumulative risk of developing CKD by HbA1c category. From lowest to highest category, 11.8%, 16.5%, 23.8% and 31.3% of participants developed CKD over the length of the study (log rank p<0.001). The incidence rate was progressively higher with higher category of HbA1c (Table 2). Cases detected by decreased estimated GFR at visit 4 (6-years after the baseline HbA1c) are indicated by the steeper rise of the cumulative incidence curve at this follow-up time. The trend for higher risk of decreased kidney function remained after adjustment for age, race and sex as shown by the graded association across the entire range of HbA1c levels (Figure 2, which caps HbA1c concentrations at an upper limit for the overall sample).

Figure 1. Kaplan-Meier Survival Estimates for HbA1c by Category.

Table 2. Incidence of CKD by HbA1c Category.

		Hemoglobin A1c Category
	Total	< 6.00%	6.00- 7.00%	7.00-8.00%	> 8.00%	p-trend
Mean HbA1c (SD)	7.07 (2.16)	5.28 (0.43)	6.46 (0.31)	7.53 (0.28)	10.15 (1.50)
CKD defined by Visit 4 estimated GFR < 60 mL/min/1.73 m2 or ICD-hospitalization
Events/n	361/1,871	91/770	67/407	46/193	157/501
Incidence/1000 person-yrs	17.00	9.87	14.15	21.87	30.29	<0.001
Unadjusted HR (95% CI)†	1.25 (1.20-1.30)*	1.00	1.44 (1.05-1.97)	2.30 (1.61-3.28)	3.39 (2.62-4.39)	<0.001
Adjusted HR (95% CI)‡	1.31 (1.25-1.38)*	1.00	1.37 (0.97-1.91)	2.49 (1.70-3.66)	3.67 (2.76-4.90)	<0.001
CKD defined by Visit 4 estimated GFR < 60 mL/min/1.73 m2
Events/n	120/1,871	39/770	30/407	12/193	39/501
Incidence/1000 person-yrs	14.92	11.20	16.35	14.83	20.37	0.013
Unadjusted HR (95% CI)†	1.10 (1.02-1.18)*	1.00	1.48 (0.92-2.39)	1.41 (0.74-2.70)	1.72 (1.10-2.70)	0.021
Adjusted HR (95% CI)‡	1.13 (1.03-1.25)*	1.00	1.31 (0.78-2.20)	1.27 (0.63-2.56)	1.63 (0.95-2.79)	0.084
CKD defined by ICD-hospitalization only
Events/n	292/1,871	62/770	49/407	41/193	140/501
Incidence/1000 person-yrs	13.58	6.68	10.20	19.09	26.56	0.676
Unadjusted HR (95% CI)†	1.29 (1.23-1.35)*	1.00	1.54 (1.06-2.24)	2.97(2.00-4.40)	4.36 (3.23-5.88)	<0.001
Adjusted HR (95% CI)‡	1.33 (1.26-1.40)*	1.00	1.43 (0.96-2.12)	3.12 (2.04-4.77)	4.53 (3.26-6.30)	<0.001

^*per 1% increase in HbA1c

^†HR=Hazard Ratio; CI=Confidence Interval

^‡Adjusted for age, race, gender, study center, baseline estimated GFR, BMI, hypertension status, use of antihypertensive agents, prevalent coronary heart disease, smoking status, LDL- and HDL-cholesterol and triglyceride concentrations

Figure 2. Adjusted Incidence Rates (IR) of CKD by HbA1c.

Incidence rates (and 95% confidence intervals (shaded area) of CKD by HbA1c concentration. The curve represents minimally adjusted incidence rates based on a Poisson regression model including a fourth-order polynomial for HbA1c, adjusted to the incidence rate for a 60 year old white male with a baseline eGFR of 90 mL/min/1.73 m². The histogram represents the frequency distribution of HbA1c in the study sample.

The association of HbA1c and risk of CKD remained after further adjustment for other CKD risk factors including study center, BMI, hypertension, use of antihypertensive medications, prevalent CHD, smoking status, LDL- and HDL-cholesterol, and triglyceride concentrations (Table 2). Individuals with HbA1c between 6and 7%, between 7% and 8%, and greater than 8% had 1.37 (95% CI: 0.97-1.91), 2.49 (95% CI: 1.70-3.66) and 3.67 (95% CI: 2.76-4.90) times the hazards, respectively, of progressing to incident CKD compared to individuals with diabetes and HbA1cs of 6.0% or less. In analyses of HbA1c as a continuous risk factor, each 1% higher HbA1c level was associated with a 31% higher risk of developing CKD. The association was observed for both components of the combined case definition of incident CKD, though the association was somewhat weaker in analyses limited to events detected by a decrease in estimated GFR at visit 4 (HR 1.13, 95% CI 1.03-1.25, per 1% higher HbA1c) than for kidney-related hospitalizations (HR 1.33, 95% CI 1.26-1.40, per 1% higher HbA1c). The association was not appreciably altered when controlling for total cholesterol, white blood cell count or use of angiotensin-converting enzyme inhibitors at baseline (results not shown). The association remained in analyses setting the time of incident CKD to the midpoint between the two visit dates for cases defined by a decrease in estimated GFR (results not shown).

Stratified Analyses

Individuals who had developed either retinopathy or albuminuria by visits 3 and 4 respectively, (Table 3) were at much higher risk of CKD than those with neither abnormality.

Table 3. Adjusted Hazard Ratio of Incident CKD, by HbA1c Category, by Albuminuria and Retinopathy Status^**.

		Hemoglobin A1c Category
	Total	< 6.00%	6.00- 7.00%	7.00-8.00%	> 8.00%	p-trend
Albuminuria (93/251§)
Events/n	103/270	15/61	14/58	13/31	61/120
Incidence/1000 person-yrs	34.53	20.81	30.32	40.49	48.73	<0.001
Adjusted HR (95% CI)‡	1.27 (1.14-1.41)*	1.00	0.83 (0.38-1.84)	2.19 (0.96-5.00)	2.54 (1.35-4.79)	<0.001
No Albuminuria (116/972§)
Events/n	129/1,035	49/504	32/239	16/100	32/192
Incidence/1000 person-yrs	9.78	7.55	10.47	12.66	13.46	<0.001
Adjusted HR (95% CI)‡	1.20 (1.08-1.32)*	1.00	1.34 (0.83-2.15)	1.75 (0.94-3.27)	2.21 (1.32-3.70)	0.002
Retinopathy (135/467§)
Events/n	152/512	23/127	19/92	22/66	88/227
Incidence/1000 person-yrs	26.14	15.11	17.67	29.78	35.51	<0.001
Adjusted HR (95% CI)‡	1.27 (1.17-1.37)*	1.00	1.01 (0.52-1.97)	2.23 (1.18-4.20)	2.73 (1.65-4.50)	<0.001
No Retinopathy (123/960§)
Events/n	134/1,015	56/526	34/248	13/89	31/152
Incidence/1000 person-yrs	10.75	8.55	11.08	12.21	17.38	<0.001
Adjusted HR (95% CI)‡	1.22 (1.10-1.35)*	1.00	1.12 (0.71-1.77)	1.49 (0.75-2.96)	2.44 (1.48-4.01)	0.001
Neither Albuminuria nor Retinopathy (66/675§)
Events/n	73/707	31/393	22/173	6/58	14/83
Incidence/1000 person-yrs	8.05	6.10	9.95	8.17	13.42	<0.001
Adjusted HR (95% CI)‡	1.27 (1.08-1.51)*	1.00	1.46 (0.80-2.65)	1.17 (0.43-3.19)	3.51 (1.67-7.39)	0.004
Both Albuminuria and Retinopathy (56/104§)
Events/n	64/116	4/12	6/12	6/12	48/80
Incidence/1000 person-yrs	53.15	30.77	44.06	47.41	59.16	<0.001
Adjusted HR (95% CI)‡	1.14 (0-.96-1.36)*	1.00	0.74 (0.16-3.39)	2.09 (0.43-10.05)	2.13 (0.63-7.28)	0.104

^*per 1% increase in HbA1c;

^**Albuminuria was measured at the 6-year follow-up visit and retinopathy at the 3-year follow-up visit;

^†HR=Hazard Ratio; CI=Confidence Interval;

^‡Adjusted for age, race, gender, study center, baseline estimated GFR, BMI, hypertension status, use of antihypertensive agents, prevalent coronary heart disease, smoking status, LDL- and HDL-cholesterol and triglyceride concentrations;

^§n for fully adjusted models

Among the 217 cases of incident CKD occurring in participants who had undergone both retinography and urinalysis, almost one quarter developed among individuals with only retinopathy (24%, n=52), half that among those with only albuminuria (13%, n=28), and the remaining two-thirds among individuals with both (29.5%; n=64), or neither (33.6%; n=73) complication. The association of HbA1c with incident CKD, however, was similar across these subgroups. A hazard ratio of 1.27 (95% CI: 1.08-1.51) for a one percent increase in HbA1c was observed in those without either retinopathy or albuminuria, consistent with the overall observed hazards. Also consistent with overall trends, the trend for higher risk of decreased kidney function remained within each stratum of abnormalities (those developing neither albuminuria nor retinopathy, only one, or both), after adjustment for age, race and sex as shown by the graded association across the entire range of HbA1c levels (Figure 3, capping HbA1c at an upper limit of the stratum-specific 95^th percentiles).

Figure 3. Adjusted Incidence Rates (IR) of CKD by HbA1c and Microvascular Complication Status.

Incidence rates of CKD by HbA1c concentration stratified by albuminuria and retinopathy status. The curves represent minimally adjusted incidence rates based on Poisson regression models including a fourth-order polynomial for HbA1c, adjusted to the incidence rate for a 60 year old white male with a baseline eGFR of 90 mL/min/1.73 m² within each stratum. HbA1c values were capped at an upper limit equivalent to the stratum-specific 95^th percentile. The histogram represents the frequency distribution of HbA1c in the study sample.

We found no statistically significant interactions between HbA1c and any demographic characteristics. We observed higher risk associated with higher HbA1c in analyses even after stratifying by gender, race, hypertension status, history of CHD and diabetes treatment status (data not shown).

Discussion

We observed a strong association between higher HbA1c and the incidence of CKD in adults with diabetes. This association was independent of traditional CKD risk factors and was observed across the entire range of HbA1c levels examined. This is one of few prospective studies to examine the risk of incident CKD in a large biracial community-based cohort. We included all individuals with diabetes, used an HbA1c assay certified by international programs and used for over two decades in the DCCT and EDIC²³ and followed participants for an average of over 11 years. Even in the absence of both modest amounts of albuminuria and retinopathy, two hallmarks of diabetic microvascular disease, HbA1c was positively associated with incident CKD.

Diabetic nephropathy is diagnosed in the presence of persistent albuminuria (>30 mg/24 hours) equivalent to 30 mg/g (urinary albumin/creatinine), diabetic retinopathy, and no evidence of other kidney or renal tract disease.¹⁴ These results, however, demonstrate the importance of identifying the risk of developing kidney disease among individuals with diabetes even in the absence of albuminuria or retinopathy.

Sixty percent of persons with type 2 diabetes and hypertension develop nephropathy.¹² Among adults with diabetes, 13% have decreased eGFR, while 64% experience albuminuria.¹⁶ There are about 1.1 million adults over the age of 40 with both type 2 diabetes and decreased eGFR. Well over half (59%) of these adults do not have albuminuria, and an estimated 0.3 million lack both albuminuria and retinopathy.¹⁶ In this population based study, among the 217 cases of incident CKD occurring in participants who had undergone both retinography and urinary albumin measurements, one-third (n=73; 33.6%) developed among individuals without albuminuria or retinopathy, nearly one-third (n=64; 29.5%) developed among individuals with both albuminuria and retinopathy, and the remaining 37% (n=80) developed among individuals with retinopathy (24%, n=52) or albuminuria (13%, n=28).

The Framingham Heart Study offspring cohort showed that there was an increased odds of developing incident CKD associated with abnormal glycemic status,³⁵ and while we know that tight glycemic control decreases the risk of diabetes complications and CVD and CKD progression,^{17, 36, 37} kidney pathology has been underexplored in individuals with type 2 diabetes.¹⁴ Findings from the MRFIT study (a multicenter prospective cohort of men) showed that men with diabetes are at increased risk for both all-cause ESRD as well as ESRD due to causes other than diabetes.¹³ his study cannot address the specific pathophysiologic mechanisms relating elevated HbA1c levels to incident CKD, there are a number of biologically plausible explanations for observed associations, many potentially acting through damage to the glomerular basement membrane. Hemodynamic factors and advanced glycation end-products also may play significant roles in kidney disease progression among both individuals with and without diabetes.^38-41 Evidence links glucose excursions,⁴² insulin resistance,⁴³ and diabetes^{44, 45} to decreased diurnal blood pressure decline (non-dipping). Evidence also suggests that non-dippers with diabetes have poorer cardiovascular prognoses,⁴² more target organ damage⁴⁶ and sympathetic activation in diabetic nephropathy.⁴⁷ In our analysis, adjusting for blood pressure and antihypertensive medication use did not change the association. We could not, however, account for intra-individual physiologic variation over time or diurnal variations of systemic pressure. Glycemia also may affect intra-renal pressure. Intra-glomerular hypertension can contribute to progression of diabetic nephropathy even in the absence of systemic hypertension.³⁸

Unfortunately, the ARIC Study did not collect information on type of diabetes of participants. The age at first diabetes diagnosis was asked of ARIC participants at the third visit (3 years after Visit 2, the baseline of these analyses). Among those participants diagnosed prior to Visit 2 (n=773), the mean time from diagnosis to Visit 2 was 10 years (sd = 9). Only 43 (3.8% of those asked, n=1134) reported being diagnosed at age 30 or younger, suggesting that very few had Type 1 diabetes.

The current study is also limited by the lack of a direct measure of kidney function. Direct measurement of kidney function is impractical in large cohorts, and most studies have relied on serum creatinine-based estimates of GFR. Estimated GFR was based on single measures of creatinine at three different visits (measures at visits 1 and 2 to exclude prevalent cases, and at visit 4 to define incident cases). The association of higher HbA1c and CKD was also observed in analyses limited to hospitalizations involving a kidney diagnosis.

Approximately 20% of individuals classified as diabetic according to our definition did not meet the American Diabetes Association criteria for diabetes in place at the time (fasting glucose of ≥ 140 mg/dL), and only approximately 40% of our sample was prescribed medications for diabetes. Because of these “early” cases of diabetes, there are a number of individuals with HbA1c values in the normal range. Risks across HbA1c were consistent across all population subgroups and did not differ by diabetes treatment status.

Because measures for albuminuria were only available at visit 4, we could only exclude prevalent cases of CKD Stage 3 or greater, and therefore our sample may include individuals with prevalent CKD Stage 1 or 2 at baseline. Measurements of HbA1c, retinography and urinary albumin excretion were performed only once, and at three different time points from one another (retinography at visit 3 and urinalysis at visit 4). By relying on a single measure taken to detect either retinopathy or albuminuria, some cases may be missed. Those without albuminuria at visit 4 are unlikely to have had albuminuria 6 years earlier.⁴⁸ Likewise, if damage was not detected on retinal imaging taken at the third visit, it is unlikely that significant damage was present at the time of the second visit. Though specific findings of retinal damage may not be consistently observed over time, previous data from the ARIC study found regression of identified damage to be uncommon among individuals with diabetes.⁴⁹ As in any study such as this, there is still potential for residual confounding due to unmeasured or mismeasured variables.

In summary, we observed a positive association between HbA1c and incident CKD that was strong, graded, independent of traditional risk factors, and present even at mildly elevated levels of HbA1c. In this population based setting, approximately one third of CKD incidence occurred in the presence of both albuminuria and retinopathy, and one third occurred in the absence of both conditions. These data suggest that glycemic control is a significant modifiable risk factor in the pathology of kidney disease among individuals with diabetes, both in the presence and absence of other microvascular damage. These results also suggest that urinary albumin screening alone may not be adequate for CKD detection among individuals with type 2 diabetes.