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Hypertension. 2007;49:48-54
Published online before print November 27, 2006, doi: 10.1161/01.HYP.0000252431.75154.3a
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(Hypertension. 2007;49:48.)
© 2007 American Heart Association, Inc.

Original Articles

Relationship Between Low-Normal Blood Pressure and Kidney Disease in Type 1 Diabetes

Anoop Shankar; Ronald Klein; Barbara E.K. Klein; F. Javier Nieto; Scot E. Moss

From the Department of Community, Occupational, and Family Medicine (A.S.), National University of Singapore, Singapore; and the Departments of Ophthalmology and Visual Sciences (R.K., B.E.K.K., S.E.M.) and Population Health Sciences (F.J.N.), University of Wisconsin, School of Medicine and Public Health, Madison.

Correspondence to Anoop Shankar, Department of Community, Occupational, and Family Medicine, National University of Singapore, 16 Medical Dr, Singapore 117597. E-mail ashankar{at}nus.edu.sg


*    Abstract
up arrowTop
 *Abstract
down arrowIntroduction
 down arrowMethods
 down arrowResults
 down arrowDiscussion
 down arrowReferences
 
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 m2 (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 m2 (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 m2 (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.


Key Words: type 1 diabetes • blood pressure • chronic kidney disease • GFR • proteinuria • WESDR


*    Introduction
up arrowTop
 up arrowAbstract
 *Introduction
down arrowMethods
 down arrowResults
 down arrowDiscussion
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Diabetes is the single largest contributor of end-stage renal disease patients in the United States, followed by hypertension.1 Our current knowledge of the pathophysiology of renal disease in diabetes supports the hypothesis of a protective role for blood pressure (BP) lowering, independent of glycemic control.2–10 Recent recommendations have placed lower target BPs (<130/80 mm Hg) for subjects with diabetes than for the general population3,4,11; however, these recommendations are predominantly based on studies in type 2 diabetes.5–10 In type 1 diabetes, where hyperglycemia has been shown to have an important role in the development of vascular12–14 complications, it is uncertain whether BP lowering, per se, has a significant protective effect against renal disease, independent of near-normal glycemic control.15,16

To address the hypothesis that lower BPs are protective against kidney disease in type 1 diabetes, we examined the association between BP and 16-year incidence of proteinuria and estimated glomerular filtration rate (GFR) <60 mL/min/1.73 m2 in a population-based cohort of type 1 diabetes patients in Wisconsin. This early middle-aged (age range: 18 to 70 years; mean age: 33.1 years at the 1984 to 1986 examination) cohort of type 1 diabetes patients was ideal for our objective, because its distribution of BP was predominantly in the low-normal range, thus enabling us to explore the risk of renal disease at BP values well below the recommended target of 130/80 mm Hg.4,11


*    Methods
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 up arrowAbstract
 up arrowIntroduction
 *Methods
down arrowResults
 down arrowDiscussion
 down arrowReferences
 
The Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR) has been described previously.17–21 In brief, a total of 10 135 diabetic patients receiving primary care in an 11-county area of southwestern Wisconsin were identified by chart review during 1979–1980. The subject of this study is the younger-onset diabetes subjects (all patients diagnosed <30 years of age and taking insulin [n=1210]), all of whom were later confirmed to have type 1 diabetes mellitus based on C-peptide measurements.22 A total of 99% of the cohort was white. The first examination of our cohort (1980–1982) was followed by evaluations 4 years (1984–1986), 10 years (1990–1992), 14 years (1995–1996), and 20 years (2000–2001) later. Because serum creatinine was first determined at the 1984–1986 follow-up, this is the baseline for the present analysis. This study was approved by the University of Wisconsin-Madison Human Subjects Committee.

Exposure Ascertainment
At the 1980–1982 and 1984–1986 examinations, BP was measured by trained personnel using a Hawksley random 0 sphygmomanometer. Phases I and V of the Korotkoff sounds were used to determine systolic and diastolic BP, respectively. Three readings were taken; the mean of the last 2 readings was the BP measurement that we used in our analyses.

Other pertinent procedures in the 1984–1986 examinations included collecting information on demographics, details of smoking, alcohol intake, physical activity, measurement of height and weight, taking stereoscopic color fundus photographs of 7 standard fields for determining diabetic retinopathy,23 taking urine analysis for semiquantitative determination of protein, and determining glycosylated hemoglobin levels24 from a venous blood sample using the Isolab resin microcolumn technique.

Outcome Measures
We were interested in 2 kidney disease-related outcomes: 16-year incident proteinuria and incident reduced GFR, estimated from serum creatinine. Semiquantitative determination of urinary protein excretion in a casual urine sample was performed using a reagent strip test (Labstix; Ames) at the 1984–1986, 1990–1992, 1995–1996, and 2000–2001 examinations. The presence of ≥0.3g/L of protein excretion in a casual urine specimen was defined as proteinuria. Serum creatinine was measured at the 1984–1986, 1990–1992, and 1995–1996 examinations by a method based on a modification of the Jaffe reaction.19 The coefficient of variation for creatinine determination was 2.73% at 1.1 mg/dL and 1.45% at 6.2 mg/dL on the basis of repeated (n=140) measurement controls. The method was linear up to values >20 mg/dL. Serum creatinine at the 2000–2001 examination was measured using an enzymatic rate reflectance spectrophotometric method on the Vitros Chemistry Analyzer (Ortho-Clinical Diagnostics, Johnson & Johnson Company). This method was linear to >14 mg/dL. The Vitros enzymatic method gave similar readings to the rate-blanked Jaffe method (regression equation: Vitros=[0.0208+ (0.9954xJaffe)]; R2=0.9391). GFR was estimated using the Modification of Diet in Renal Disease (MDRD) Study equation.25

Reduced GFR was defined as an estimated GFR <60 mL/min/1.73 m2 or a positive history of dialysis or renal transplantation.25 Incident proteinuria was defined as the development of new proteinuria detected at the 1990–1992, 1995–1996, or 2000–2001 cohort examination among type 1 diabetes individuals free of proteinuria at baseline (1984–1986). Similarly, incident estimated GFR <60 mL/min/1.73 m2 was defined as the development of this outcome at the 1990–1992, 1995–1996, or 2000–2001 cohort examination among type 1 diabetes individuals free of this outcome at baseline (1984–1986).

Of the 903 participants in the 1984–1986 examination, 788 individuals participated in ≥1 follow-up examination and contributed follow-up person time. We excluded those with history of dialysis (n=17), renal transplantation (n=17), missing information on baseline glycosylated hemoglobin (n=30), serum creatinine (n=44), body mass index (n=14), or BP (n=18), subjects <18 years (n=85) because the validity of the MDRD equation in diabetes is not known in younger ages, and those with estimated GFR <60 mL/min/1.73 m2 at the baseline (n=65). This resulted in 547 type 1 diabetes individuals with estimated GFR ≥60 mL/min/1.73 m2 at baseline; over the average 16-year follow-up period, 158 developed incident-estimated GFR <60 mL/min/1.73 m2, including 37 subjects with end-stage renal disease defined as positive history of dialysis or renal transplantation. Similarly, for the analysis on incident proteinuria, there were 604 subjects free of proteinuria and with relevant multivariable information at the baseline; over the 16-year follow-up period, 232 developed incident proteinuria.

Data Analysis
We calculated the 16-year cumulative incidence of proteinuria and estimated GFR <60 mL/min/1.73 m2 across each BP category by the product limit method. Multivariable proportional hazards models, with discrete handling of ties, were used to estimate the relative risk (RR) and 95% CI of incident proteinuria, and GFR <60 mL/min/1.73 m2 across each BP category. First, BP was categorized according to the classification suggested by the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure.11 Stages 1 and 2 hypertension were combined because of the paucity of individuals with higher BPs at the 1984–1986 examination. Second, systolic blood and diastolic BP were analyzed as quartiles in separate models as the main exposure. Third, based on our initial findings, we created ad hoc categories of BP using cutoffs at 120 mm Hg systolic BP and 70 mm Hg diastolic BP. We performed several sets of supplementary analyses. Although none of the study subjects at the baseline examination (1984–1986) were taking angiotensin-converting enzyme (ACE) inhibitors, a class of drugs shown to have independent renoprotective effects,26 some subjects (n=113) reported taking ACE inhibitors at the 1990–1992, 1995–1996, or 2000–2001 follow-up examinations. To specifically examine the effect of intervening ACE inhibitor intake on our results, we repeated the main analysis after additionally adjusting for any ACE inhibitor intake (yes or no) in the multivariable model. In a related analysis, we also examined the confounding effect of any use of other antihypertensive drugs, including thiazides, loop diuretics, or ß-blockers, in the association between BP and incident kidney disease; the multivariable RRs were similar to the results presented. In a second supplementary analysis, we repeated the main multivariable model with additional adjustment for ACE inhibitor intake, in a time-varying covariate analysis, incorporating updated information from each follow-up examination. In a third analysis, we examined the association between baseline BP and "any regression" in proteinuria over 16 years; of 140 baseline (1984–1986) subjects with proteinuria, 23 showed "any regression" in proteinuria (tested negative for proteinuria in ≥1 of the follow-up examinations in 1990–1992, 1995–1996, or 2000–2001). We could not perform a similar analysis for estimated GFR <60 mL/min/1.73 m2, because only 4 of 65 showed similar "any regression" with this outcome. Finally, we calculated the population-attributable risk of kidney disease associated with selected BP categories using a standard formula.27 All of the analyses were done in SAS version 8.0 (SAS Institute, Inc).


*    Results
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
 *Results
down arrowDiscussion
 down arrowReferences
 
The baseline characteristics of study participants at the 1984–1986 examination are presented in Table 1. Prevalence of hypertension at baseline was 26.6% among the 604 subjects included in the incident proteinuria analysis and 22.6% among the 547 subjects included in the incident estimated GFR <60 mL/min/1.73 m2 analysis. Corresponding prevalence of stage 2 hypertension was 1.5% (n=9 subjects) and 0.9% (n=5 subjects).


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  		TABLE 1. Baseline Characteristics of Individuals With Type 1 Diabetes Included in the Analysis of Incident Proteinuria and Estimated GFR <60 mL/min/1.73 m2

In Table 2, lower Seventh Report of the Joint National Committee BP categories were associated with lower incidence of both proteinuria (Table 3) and estimated GFR <60 mL/min/1.73 m.2 To further elucidate this relationship, we analyzed the 16-year incidence of proteinuria (Table 3) and estimated GFR <60 mL/min/1.73 m2 (Table 4) according to decreasing quartiles of systolic and diastolic BP in separate multivariable models. In general, lower quartiles of both systolic and diastolic BP were inversely associated with incidence of proteinuria (Table 3) and estimated GFR <60 mL/min/1.73 m2 (Table 4), compared with the highest quartile. For both of these outcomes, the lowest RR was consistently observed at the second-to-lowest quartile of systolic BP (range: 111 to 119 mm Hg; mean value: 115.8 mm Hg) and the lowest quartile of diastolic BP (range: 50 to 69 mm Hg; mean value: 64.7 mm Hg).


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  		TABLE 2. Association Between JNC 7 BP Categories and Incident Kidney Disease in Type 1 Diabetes


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  		TABLE 3. Association Between BP Quartiles and Incident Proteinuria in Type 1 Diabetes


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  		TABLE 4. Association Between BP Quartiles and Incident Estimated GFR <60 mL/min/1.73 m2 in Type 1 Diabetes

Next, in Table 5, we categorized our cohort at the observed maximum protective levels of systolic (<120 and ≥120 mm Hg) and diastolic (<70 and ≥70 mm Hg) BP. Compared with the rest of the cohort, the magnitude of protective association between decreasing BP and incident kidney disease–related outcomes was essentially similar for subjects with both systolic BP <120 mm Hg and diastolic BP <70 mm Hg (Table 5, analysis 2) and for subjects with either systolic BP <120 mm Hg or diastolic BP <70 mm Hg (Table 5, analysis 3). Although only 18.2% of the cohort had both systolic and diastolic BP in the observed maximum protective BP level, 57% of cohort subjects had either systolic or diastolic BP in the observed maximum protective BP level. The population-attributable risk associated with having either systolic or diastolic BP in the observed maximum protective BP level (systolic BP <120 mm Hg or diastolic BP <70 mm Hg) was 26.7% for incident proteinuria and 29.5% for incident estimated GFR <60 mL/min/1.73 m2; corresponding population-attributable risk for having both systolic and diastolic BP in the observed maximum protective BP level (systolic BP <120 mm Hg and diastolic BP <70 mm Hg) was 8.3% and 11.1%, respectively.


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  		TABLE 5. Association Between Selected BP Categories and Incident Kidney Disease in Type 1 Diabetes

We performed several sets of supplementary analyses. We repeated the analyses presented in Tables 3–5UpUp additionally adjusting for any ACE inhibitor intake during the follow-up period (n=113). The results were essentially similar. For example, compared with individuals with baseline systolic BP in quartile 4 (referent), the multivariable RR (95% CI) of incident estimated GFR <60 mL/min/1.73 m2 was 0.81 (0.53 to 1.22) in quartile 3, 0.60 (0.38 to 0.94) in quartile 2, and 0.62 (0.39 to 0.99) in quartile 1 (P for trend=0.02). In a second supplementary analysis, we repeated the main analyses in a time-varying covariate model. In general, the protective association with decreasing BP categories observed in analyses using only the baseline data was attenuated in time-varying models. For example, compared with individuals with baseline systolic BP in quartile 4 (referent), the multivariable RR (95% CI) of incident estimated GFR <60 mL/min/1.73 m2 was 0.88 (0.58 to 1.33) in quartile 3, 0.63 (0.41 to 0.97) in quartile 2, and 0.77 (0.51 to 1.16) in quartile 1 (P for trend=0.05). In a third analysis, we examined the 16-year incidence of "any regression" in proteinuria (n=23) among baseline subjects with proteinuria (n=140) by decreasing systolic and diastolic BP categories. For systolic BP, the 16-year cumulative incidence of "any regression" in proteinuria was 9.2% (n=6 of 65) in quartile 4, 19.4% (n=6 of 31) in quartile 3, 32% (n=8 of 25) in quartile 2, and 15.8% (n=3 of 19) in quartile 1 (P for trend=0.06). For diastolic BP, the 16-year cumulative incidence of "any regression" in proteinuria was 13.9% (n=9 of 65) in quartile 4, 10% (n=3 of 30) in quartile 3, 21.4% (n=6 of 28) in quartile 2, and 29.4% (n=5 of 17) in quartile 1 (P for trend=0.05). Furthermore, among type 1 diabetes individuals with baseline proteinuria, the multivariable RR (95% CI) of any regression in proteinuria during the 16-year follow-up period was 2.36 (1.00 to 5.57) among individuals with systolic or diastolic BP in the observed maximum protective BP level (systolic BP <120 mm Hg or diastolic BP <70 mm Hg; n=49 of 140). Finally, we additionally adjusted for microalbuminuria (absent or present) in the multivariable analyses presented in Tables 2–5UpUpUp; the results were essentially similar.


*    Discussion
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
 up arrowResults
 *Discussion
down arrowReferences
 
In a population-based sample of adults with type 1 diabetes, we found that lower BPs, both systolic and diastolic, were protective against incident proteinuria and incident estimated GFR <60 mL/min/1.73 m2. Results from our observational study suggest that the maximum protective effect for both of these kidney disease-related outcomes was seen at systolic BPs <120 mm Hg and diastolic BPs <70 mm Hg. Having either systolic BP <120 mm Hg or diastolic BP <70 mm Hg seemed to be protectively associated with {approx}50% of these kidney disease–related outcomes at the population level. We also found that, among individuals with proteinuria at baseline, lower systolic and diastolic BPs predicted regression of proteinuria during the 16-year follow-up period.

Although accelerated and malignant hypertension have long been known to be important risk factors for kidney disease,28 recent studies among those with less severe hypertension, both in the general population29–33 and among those with diabetes,6,7,34–36 have demonstrated that lowering BP and intraglomerular pressure also preserves kidney function in these individuals.33,36 In type 1 diabetes, clinical trial data suggest the regression and even long-term remission of nephropathy with hypertension control.37,38 Also, animal models have suggested synergistic effects between hypertension and hyperglycemia in inducing structural and functional changes39,40 supporting the plausibility2,3 of additional renal protection by further lowering BP among those with diabetes than the general population. Recent recommendations have placed lower target BPs for subjects with diabetes than for the general population3,4,11; however, these recommendations are predominantly based on studies in type 2 diabetes.5–10 A recent observational analysis6 of the United Kingdom Prospective Diabetes Study (UKPDS) validated the risk-reduction of diabetes complications, including fatal and nonfatal renal failure, attributable to lower BPs in type 2 diabetes, and suggested a target systolic BP of <120 mm Hg. However, in type 1 diabetes where hyperglycemia has been shown to have an important role in the development of vascular12–14 complications, it is uncertain whether BP lowering, per se, has a significant protective effect against renal disease, independent of near-normal glycemic control.15,16 Alternatively, in younger-onset type 1 diabetes subjects with relatively fewer comorbidities at the time of disease diagnosis, it is possible that even lower BP levels may be tolerated and protective against kidney disease.

Results from our study suggest that lower systolic and diastolic BPs, even below the current normal ranges used in clinical practice, are protectively associated with incident chronic kidney disease in persons with type 1 diabetes. This effect seemed to be independent of glycemic control. The fact that our findings were consistent in different multivariable models, in separate analyses for systolic and diastolic BP as the main risk factor, and in separate analyses for incident proteinuria and incident estimated GFR <60 mL/min/1.73 m2 as the outcome of interest, suggests that these results are less likely to be because of chance. Furthermore, indirect support for our findings could be inferred from recent clinical trials, which demonstrated the renoprotective effect of ACE inhibitors on diabetic patients with normal clinically measured BP.41–46 For example, in one such study, Viberti et al41 reported that among normotensive type 1 diabetes patients, treatment with captopril reduced albuminuria but was also accompanied by a significant reduction in mean BP. It is possible that at least part of this reduction in albumin excretion among normotensive patients was mediated through the effect of captopril on BP.

The strengths of this study include its prospective nature, long follow-up period, high participation rate, and standardized measurement of exposure and covariates. Furthermore, the possible confounding of the relationship between BP and renal disease by renoprotective antihypertensive drugs, like ACE, inhibitors is comparatively less likely in our study, because none of our cohort members were taking ACE inhibitors at the baseline examination; also, a supplementary analysis accounting for the effect of intervening ACE inhibitor intake during the follow-up period showed essentially similar results.

However, because of the observational nature of the current study, results should be interpreted with caution. Although our longitudinal results suggest that type 1 subjects with lower BPs, even below the currently accepted normal range, have lower 16-year cumulative incidence of kidney disease, it may not be directly inferred from our study that actively lowering BP below the current normal range prevents kidney disease.47 Randomized, controlled intervention trials are necessary to address this question. Also, the extent to which BP should be lowered in people with diabetes is uncertain, especially given the reports48,49 of a J-shaped relationship between BP and other disease end points in people with compromised circulation, a situation common to diabetes. In diabetes, it is possible that lowering the BP beyond a point could compromise an already damaged microvasculature, thus aggravating nephropathy and kidney disease.50

Several additional study limitations need to be considered. First, our study results may not be generalizable, because 99% of this cohort was white. However, the racial homogeneity of the study population offers advantages for the study of BP–renal disease association, because potential biases from confounding variables correlated with race are minimized. Second, issues related to creatinine calibration and GFR cutoff used in the study are important. Our serum creatinine values were not calibrated to Cleveland Clinic standards; calibration differences can account for differences in GFR, particularly at higher values, and introduce nondifferential misclassification. Small changes in GFR, especially in the "near-chronic kidney disease" ranges of 50 to 70 mL/min/1.73 m2, could also misclassify chronic kidney disease status. However, the results were similar when we examined an alternative kidney disease definition (GFR decline ≥50% during the 16-year period). We used a different creatinine measurement method at the 2000–2001 examination compared with the 3 previous examinations; this could cause nondifferential misclassification. However, in a direct comparison, the 2 methods correlated well in our collaborating laboratory. Third, selection bias because of nonparticipation at the second cohort examination, our baseline, is possible. Living nonparticipants were similar to participants, whereas nonparticipants who died before the second cohort examination had significantly higher glycosylated hemoglobin levels and higher prevalence of proteinuria and proliferative diabetic retinopathy at the 1980–1982 examination. Death and selective survival may have attenuated our results.

Perspectives
In conclusion, results from our observational study suggest that low-normal BPs, early in the course of type 1 diabetes, are protectively associated against subsequent risk of incident proteinuria and incident estimated GFR <60 mL/min/1.73 m2. These results were independent of glycemic control. As these results show the prospect of substantially reducing the burden of kidney disease in diabetes, further evidence from interventional trials is desirable.


*    Acknowledgments
 
Sources of Funding

This research is supported by a National Institutes of Health grant EY03083 (R.K., B.E.K.), an American Diabetes Association training grant (R.K., A.S.), and Research to Prevent Blindness (R.K., B.E.K.).

Disclosures

R.K. is on the advisory board of the Diabetic Retinopathy Candesartan Trials program, a randomized, controlled clinical trial sponsored by AstraZeneca. The remaining authors report no conflicts.

Received August 17, 2006; first decision September 4, 2006; accepted November 2, 2006.


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 up arrowResults
 up arrowDiscussion
 *References
 

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