Retinopathy and CKD as Predictors of All-Cause and Cardiovascular Mortality

National Health and Nutrition Examination Survey (NHANES) 1988-1994

Ana C. Ricardo, MD, MPH; Juan E. Grunwald, MD; Sharmila Parvathaneni, MD; Sean Goodin, BS; Alice Ching, MD; James P. Lash, MD

Disclosures

Am J Kidney Dis. 2014;64(2):198-203.

Abstract and Introduction

Abstract

Background: Retinopathy is associated with increased mortality risk in general populations. We evaluated the joint effect of retinopathy and chronic kidney disease (CKD) on mortality in a representative sample of US adults.

Study Design: Prospective cohort study.

Setting & Participants: 7,640 adults from NHANES (National Health and Nutrition Examination Survey) 1988–1994 with mortality linkage through December 31, 2006.

Predictors: CKD, defined as low estimated glomerular filtration rate (<60 mL/min/1.73 m²) or albuminuria (urine protein-creatinine ratio ≥30 mg/g), and retinopathy, defined as the presence of microaneurysms, hemorrhages, exudates, microvascular abnormalities, or other evidence of diabetic retinopathy by fundus photograph.

Outcomes: All-cause and cardiovascular mortality.

Measurements: Multivariable-adjusted Cox proportional hazards.

Results: Overall, 4.6% of participants had retinopathy and 15% had CKD. Mean age was 56 years, 53% were women, and 81% were non-Hispanic whites. The prevalence of retinopathy in patients with CKD was 11%. We identified 2,634 deaths during 14.5 years' follow-up. In multivariable analyses, compared with individuals with neither CKD nor retinopathy, HRs for all-cause mortality were 1.02 (95% CI, 0.75–1.38), 1.52 (95% CI, 1.35–1.72), and 2.39 (95% CI, 1.77–3.22) for individuals with retinopathy only, those with CKD only, and those with both CKD and retinopathy, respectively. Corresponding HRs for cardiovascular mortality were 0.96 (95% CI, 0.50–1.84), 1.72 (95% CI, 1.47–2.00), and 2.96 (95% CI, 2.11–4.15), respectively. There was a significant synergistic interaction between retinopathy and CKD on all-cause mortality (P = 0.04).

Limitations: The presence of retinopathy was evaluated only once. Small sample size of some of the subpopulations studied.

Conclusions: In the presence of CKD, retinopathy is a strong predictor of mortality in this adult population.

Introduction

It is estimated that more than 26 million individuals in the United States have chronic kidney disease (CKD).^[1] CKD is an independent risk factor for cardiovascular disease (CVD) and it is well known that individuals with CKD are at increased risk of cardiovascular morbidity and mortality.^[2,3] The mechanism of increased cardiovascular risk in CKD is not fully understood, but likely is due to increased burden of traditional and nontraditional CVD risk factors.^[4]

In non-CKD populations, retinopathy has been associated with increased risk of death in persons with and without diabetes.^[5–7] Retinopathy has not been well characterized in the CKD population. Recently it has become apparent that fundus pathology is prevalent in individuals with CKD^[8–10] and has been associated with prevalent CVD and cognitive dysfunction.^[8,11,12] A funduscopic examination offers a noninvasive evaluation of systemic microvascular disease. Several studies have reported correlations between retinopathy and kidney disease in individuals with and without diabetes.^[13–15] However, the association between retinopathy and mortality has not been evaluated in this particular population. A funduscopic examination may prove to be a helpful tool in predicting mortality in persons with CKD.

In this study, we used data from the Third National Health and Nutrition Examination Survey (NHANES III), 1998–1994, a nationally representative sample of the US population, to examine the joint effect of retinopathy and CKD on cardiovascular and all-cause mortality. We hypothesized that individuals with either retinopathy or CKD will have increased mortality compared with participants with neither condition and that individuals with both retinopathy and CKD will have the highest mortality risk.

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The National Kidney Foundation

Published by Elsevier

Abstract and Introduction
Methods
Results
Discussion
References

Table 1. Characteristics of NHANES III Participants by Presence of CKD and Retinopathy
Variable	Overall (N = 7,640)	CKD			No CKD
Variable	Overall (N = 7,640)	Retinopathy (n = 220)	No Retinopathy (n = 1,370)	P	Retinopathy (n = 274)	No Retinopathy (n = 5,776)	P
Age (y)	56.1 ± 0.4	65.1 ± 1.3	65.5 ± 0.8	0.8	56.3 ± 0.9	54.3 ± 0.4	0.04
Female sex	3,960 (53.2)	136 (62.8)	701 (55.6)	0.2	118 (46.6)	3,005 (52.8)	0.2
Race/ethnicity				0.004			0.2
Non-Hispanic white	3,799 (81.3)	80 (71.1)	749 (80.3)		118 (79.9)	2,852 (81.7)
Non-Hispanic black	1,792 (8.6)	68 (17.8)	329 (10.6)		73 (10.7)	1,322 (8.0)
Mexican American	1,747 (3.4)	66 (6.4)	249 (2.8)		77 (5.0)	1,355 (3.4)
Other	302 (6.6)	6 (4.7)	43 (6.3)		6 (4.4)	247 (6.8)
Annual family income < $20,000	3,481 (30.3)	138 (48.1)	806 (48.4)	0.9	134 (34.9)	2,403 (26.7)	0.03
<High school education	3,400 (27.7)	134 (45.1)	744 (40.0)	0.3	134 (33.0)	2,388 (25.1)	0.03
eGFR (mL/min/1.73 m²)	88.7 ± 0.4	72.4 ± 2.1	71.3 ± 1.2	0.7	88.7 ± 1.1	91.9 ± 0.4	0.008
Urine ACR				0.03
<30 mg/g	6,536 (89.5)	38 (27.4)	448 (32.7)		274 (100)	5,776 (100)
30-<300 mg/g	908 (9.1)	119 (57.5)	789 (58.9)
≥300 mg/g	196 (1.4)	63 (15.1)	133 (8.4)
Current smoker	1,742 (23.1)	35 (20.1)	260 (19.2)	0.9	67 (23.9)	1,380 (23.8)	0.9
Hypertension	3,608 (39.7)	178 (75.8)	989 (68.9)	0.2	143 (49.1)	2,298 (33.7)	<0.001
CVD^a	898 (9.0)	51 (21.5)	317 (18.7)	0.5	33 (9.3)	497 (7.1)	0.3
Diabetes mellitus	1,142 (10.3)	149 (58.9)	343 (22.6)	<0.001	105 (30.6)	545 (6.5)	<0.001
Family history of premature CHD	717 (11.4)	25 (16.6)	137 (12.2)	0.3	21 (6.4)	534 (11.3)	0.06
Systolic BP (mm Hg)	128.8 ± 0.4	147.1 ± 2.5	141.0 ± 0.8	0.01	132.1 ± 1.4	126.2 ± 0.4	<0.001
Diastolic BP (mm Hg)	76.3 ± 0.2	76.5 ± 1.2	77.8 ± 0.5	0.3	77.8 ± 1.0	76.0 ± 0.2	0.08
Body mass index (kg/m²)	27.3 ± 0.1	29.4 ± 0.6	28.2 ± 0.3	0.05	28.2 ± 0.4	27.1 ± 0.1	0.03
Glycated hemoglobin (%)	5.6 ± 0.03	7.4 ± 0.3	6.1 ± 0.1	<0.001	6.1 ± 0.1	5.4 ± 0.02	<0.001
Fasting total cholesterol (mg/dL)	217.8 ± 0.9	221.8 ± 4.4	227.6 ± 2.0	0.1	221.3 ± 4.5	215.6 ± 0.9	0.07
Use of ACEi/ARB	535 (6.0)	46 (17.9)	171 (13.3)	0.2	24 (7.2)	294 (4.5)	0.09

Note: Values for categorical variables are given as number (weighted percentage); values for continuous variables, as weighted mean ± standard error. Conversion factor for total cholesterol in mg/dL to mmol/L, ×0.02586.
Abbreviations: ACEi, angiotensin-converting enzyme inhibitor; ACR, albumin-creatinine ratio; ARB, angiotensin receptor blocker; BP, blood pressure; CHD, coronary heart disease; CKD, chronic kidney disease; CVD, cardiovascular disease; eGFR, estimated glomerular filtration rate; NHANES III, Third National Health and Nutrition Examination Survey.
^aIncludes a history of myocardial infarction, heart failure, or stroke.

Table 2. Cox Proportional Hazards Models for All-Cause and Cardiovascular Mortality
	No. of Events	Weighted Mortality Rate^a	Model 1^b	Model 2^c	P for Interaction^d
All-Cause Mortality
Retinopathy and CKD status					0.04
Neither retinopathy nor CKD	1,519	14.5	1.00 (reference)	1.00 (reference)
Retinopathy only	89	19.1	1.13 (0.84–1.51)	1.02 (0.75–1.38)
CKD only	865	52.3	1.73 (1.54–1.96)	1.52 (1.35–1.72)
Both CKD and retinopathy	161	69.2	3.22 (2.36–4.40)	2.39 (1.77–3.22)
Retinopathy and eGFR status					0.6
Neither retinopathy nor low eGFR	1,884	16.1	1.00 (reference)	1.00 (reference)
Retinopathy only	173	25.9	1.32 (1.07–1.64)	1.21 (0.96–1.53)
Low eGFR only	500	77.6	1.41 (1.19–1.67)	1.39 (1.17–1.65)
Both retinopathy and low eGFR	77	93.2	2.15 (1.41–3.27)	1.92 (1.27–2.89)
Retinopathy and albuminuria status					0.009
Neither retinopathy nor albuminuria	1,858	16.5	1.00 (reference)	1.00 (reference)
Retinopathy only	118	23.7	1.22 (0.93–1.61)	1.07 (0.80–1.44)
Albuminuria only	526	46.1	1.83 (1.58–2.11)	1.47 (1.30–1.67)
Both retinopathy and albuminuria	132	71.3	3.78 (2.82–5.07)	2.65 (1.93–3.64)
Cardiovascular Mortality
Retinopathy and CKD status					0.06
Neither retinopathy nor CKD	610	5.5	1.00 (reference)	1.00 (reference)
Retinopathy only	30	7.4	1.11 (0.60–2.05)	0.96 (0.50–1.84)
CKD only	439	26.4	2.05 (1.16–2.39)	1.72 (1.47–2.00)
Both CKD and retinopathy	86	35.9	4.08 (2.83–5.87)	2.96 (2.11–4.15)
Retinopathy and eGFR status					0.4
Neither retinopathy nor low eGFR	770	6.3	1.00 (reference)	1.00 (reference)
Retinopathy only	67	10.5	1.33 (0.88–2.02)	1.21 (0.77–1.89)
Low eGFR only	279	42.8	1.71 (1.34–2.17)	1.61 (1.27–2.03)
Both retinopathy and low eGFR	49	55.8	2.88 (1.83–4.54)	2.52 (1.60–3.98)
Retinopathy and albuminuria status					0.04
Neither retinopathy nor albuminuria	796	6.8	1.00 (reference)	1.00 (reference)
Retinopathy only	46	9.7	1.16 (0.62–2.17)	0.99 (0.50–1.94)
Albuminuria only	253	21.4	1.84 (1.53–2.22)	1.41 (1.20–1.67)
Both retinopathy and albuminuria	70	38.2	4.54 (3.23–6.36)	3.16 (2.28–4.37)

Note: Unless otherwise indicated, values are given as hazard ratio (95% confidence interval).
Abbreviations: CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate.
^aWeighted mortality rates per 1,000 person-years.
^bModel 1: adjusted for age, sex, race/ethnicity, education, and annual family income.
^cModel 2: adjusted for variables in model 1 plus smoking status, hypertension, hemoglobin A_1c level, diabetes, cardiovascular disease, family history of coronary heart disease, body mass index, and total cholesterol level. In addition, analyses of microalbuminuria and retinopathy were adjusted for eGFR; and analyses of eGFR and retinopathy were adjusted for natural log of urine albumin-creatinine ratio.
^dInteraction between retinopathy and either CKD, low eGFR, or microalbuminuria.