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(Stroke. 1996;27:2033-2039.)
© 1996 American Heart Association, Inc.

Articles

Proteinuria Predicts Stroke and Other Atherosclerotic Vascular Disease Events in Nondiabetic and Non–Insulin-Dependent Diabetic Subjects

Heikki Miettinen, MD; Steven M. Haffner, MD; Seppo Lehto, MD; Tapani Ronnemaa, MD; Kalevi Pyorala, MD Markku Laakso, MD

the Department of Medicine, University of Kuopio (H.M., S.L., K.P., M.L.), the Department of Medicine, University of Turku (T.R.), and the Research and Development Centre, Social Insurance Institution, Turku (T.R.), Finland; and the Department of Medicine, Division of Clinical Epidemiology, University of Texas Health Science Center (San Antonio) (H.M., S.M.H.).

Correspondence to Heikki Miettinen, MD, University of Texas Health Science Center at San Antonio, Department of Medicine, Division of Clinical Epidemiology, 7703 Floyd Curl Dr, San Antonio, TX 78284-7873. E-mail miettine@messi.uku.fi. Reprint requests to Markku Laakso, MD, University of Kuopio, Department of Medicine, PO Box 1627, 70211 Kuopio, Finland.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Background and Purpose Increased urinary albumin and protein excretion is associated with cardiovascular disease mortality independent of other cardiovascular risk factors in subjects with non–insulin-dependent diabetes mellitus (NIDDM). We assessed the relationship between the different degrees of proteinuria at baseline and the incidence of stroke, as well as other atherosclerotic vascular disease events, in a prospective study of nondiabetic and NIDDM subjects.

Methods Our study was based on the 7-year follow-up of cohorts of nondiabetic (n=1375) and NIDDM (n=1056) subjects in Finland. The urinary protein concentration at baseline was stratified into three categories: no proteinuria (<150 mg/L), borderline (150 to 300 mg/L), and clinical proteinuria (>300 mg/L).

Results The association between the different degrees of proteinuria and the atherosclerotic vascular events was similar in nondiabetic and NIDDM subjects. Cardiovascular disease mortality was higher both in nondiabetic and NIDDM subjects with clinical proteinuria than in those without proteinuria. The incidence of stroke was 1.6% in nondiabetic subjects without proteinuria, 3.2% in subjects with borderline proteinuria, and 8.5% in subjects with clinical proteinuria (P<.001 for trend). In NIDDM patients, the corresponding rates were 7.2%, 11.1%, and 23.0%, respectively (P<.001 for trend). The association between clinical proteinuria and the incidence of stroke remained significant both in nondiabetic and in NIDDM subjects after adjustment for other cardiovascular risk factors. Clinical proteinuria was also associated with the incidence of coronary heart disease events and that of lower-extremity amputation. NIDDM independently increased the risk of atherosclerotic vascular disease events regardless of the proteinuria status.

Conclusions Clinical proteinuria significantly predicted stroke and other atherosclerotic vascular disease events independent of other cardiovascular risk factors. This finding is compatible with the view that increased urinary protein excretion rate may be associated with widespread vascular damage.

Key Words: atherosclerosis • coronary heart disease • diabetes mellitus • mortality • proteinuria

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
It is well established that the incidences of atherosclerotic vascular diseases such as CHD, stroke, and arterial disease of lower extremities are higher in patients with NIDDM than in nondiabetic subjects,¹ which is only in part explained by the adverse effects of diabetes on the classic cardiovascular risk factors.¹ The risk of CVD death has been found to be associated with an increased urinary albumin and protein excretion rate independent of classic cardiovascular risk factors in patients with NIDDM^{2 3 4 5 6 7 8 9 10} and nondiabetic subjects.^{5 11 12} The mechanisms of the association between albuminuria and increased CVD risk are poorly understood, and several explanations have been proposed. Increased urinary albumin excretion may be associated with adverse changes in cardiovascular risk factors,^{4 13 14 15 16} or alternatively, it may be a marker of widespread vascular damage,¹⁷ endothelial dysfunction enhancing atherogenesis,^{18 19} or a marker of CVD itself.¹⁶

Although the relationship between microalbuminuria and CVD mortality is well established in patients with NIDDM, less is known about the association between clinical proteinuria and the incidence of atherosclerotic vascular disease events, particularly in nondiabetic subjects. In particular, very few data are available regarding the relationship between proteinuria and stroke or peripheral arterial disease.^{20 21} The purpose of our study was to assess the relationship between different degrees of proteinuria at baseline and atherosclerotic vascular disease events during the 7-year follow-up of population-based cohorts of nondiabetic and NIDDM subjects. If the relationship between proteinuria and atherosclerotic vascular disease events is independent of conventional cardiovascular risk factors, the hypothesis that proteinuria is an indicator of underlying vascular damage is strengthened. We also analyzed the association between increased urinary protein concentration and non-CVD mortality because recently published observations suggest that proteinuria may also be related to non-CVD mortality in NIDDM patients.^{8 10}

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Patients With NIDDM
All diabetic patients in Finland who need drug therapy receive it free of charge according to the Sickness Insurance Act. These subjects are registered in a computerized central registry maintained by the Social Insurance Institution. On the basis of information from this registry, we identified all diabetic patients aged 45 to 64 years who were born and living in the Kuopio University Hospital district in East Finland or in the Turku University Central Hospital district in West Finland. The formation of this patient population consisting of 510 diabetic patients in East Finland (participation rate, 89%) and 549 patients in West Finland (participation rate, 79%) has been described in detail previously.^{22 23} Insulin-dependent diabetes was excluded in all patients treated with insulin by C-peptide measurements as previously described.²⁴ None of the diabetic patients in the final study population classified as having NIDDM according to the WHO criteria²⁵ had a history of ketoacidosis. For the purposes of this article, three NIDDM patients with serum creatinine higher than 200 mmol/L were excluded. The final study group included 252 diabetic men and 257 women in East Finland and 328 diabetic men and 219 women in West Finland.

Nondiabetic Subjects
A random control population sample of subjects whose place of birth was in the Kuopio University Hospital district or in the Turku University Central Hospital district and who were living in these areas was taken from the population registry containing all subjects aged 45 to 64 years. The study population consisted of 651 (participation rate, 79%) East Finland and 730 (participation rate, 85%) West Finland nondiabetic control subjects. After the exclusion of 10 nondiabetic subjects with serum creatinine higher than 200 mmol/L, the final nondiabetic study group included 312 nondiabetic men and 336 nondiabetic women in East Finland and 328 nondiabetic men and 399 nondiabetic women in West Finland.

Study Methods
The baseline examination of nondiabetic and NIDDM subjects was carried out from 1982 through 1984. The examination included an interview on previous medical history, history of smoking, and use of drugs, as well as the drawing of blood samples for laboratory examinations and measurements of height, weight, and blood pressure.

All medical records of subjects who reported in the interview that they had been admitted to the hospital because of symptoms suggestive of stroke or MI were reviewed by two experienced internists (M.L. in Kuopio and T.R. in Turku). The WHO criteria for verified definite or possible stroke were used in the ascertainment of the diagnosis of previous stroke, which was defined as a clinical syndrome consisting of definite neurological symptoms persisting for more than 24 hours.²⁶ Thromboembolic and hemorrhagic stroke, but not subarachnoid hemorrhage, were included in the diagnosis of stroke. The modified WHO MONICA criteria for verified definite or possible MI based on chest pain symptoms, electrocardiographic changes, and enzyme determinations were used in the ascertainment of the diagnosis of previous MI.²⁷ Subjects were classified as having hypertension if they were receiving drug treatment for hypertension or if systolic blood pressure was 160 mm Hg or diastolic blood pressure was 95 mm Hg measured in the sitting position after a 5-minute rest.

Serum lipids were determined from fresh serum samples drawn after a 12-hour overnight fast. Serum total cholesterol and triglyceride levels were determined enzymatically (Boehringer Mannheim GmbH). Serum HDL cholesterol was determined directly after precipitation of apolipoprotein B–containing lipoproteins with dextran sulfate and magnesium chloride. Apolipoproteins A₁ and B were determined by radioimmunoassay. HbA₁ was estimated by ion exchange affinity chromatography (Isolab Inc; reference range, 5.5% to 8.5%). Plasma glucose was determined with the glucose oxidase method (Boehringer).

Total urinary protein concentration was measured from the morning spot urine specimen with the Coomassie brilliant blue method (Bio-Rad Laboratories). For the purposes of this study, the subjects were classified into three categories according to the degree of proteinuria: no proteinuria (<150 mg/L), borderline proteinuria (150 to 299 mg/L), and clinical proteinuria (300 mg/L).

Collection of Follow-up Data
In 1990, a postal questionnaire containing questions about the hospitalization due to stroke, acute chest pain, or lower-extremity amputation was sent to every surviving patient of the original study. All medical records of the subjects who reported in the questionnaire that they had been admitted to the hospital because of stroke, chest pain symptoms, or amputation were reviewed. To complete the end point data collection and review of medical records, we used computerized hospital discharge registers to identify the hospitalizations due to stroke, CHD, and amputation for those participants who did not respond to the questionnaire, as well as the hospitalizations of those participants who had died between the baseline examination and December 31, 1989. Copies of death certificates of subjects who had died were obtained from the Central Statistical Office of Finland. In the final classification of the causes of death, hospital and autopsy records were also used if available. In the ascertainment of the diagnosis of stroke we used the WHO MONICA criteria for verified definite or possible stroke.²⁶ Thromboembolic and hemorrhagic stroke, but not subarachnoid hemorrhage, were included in the diagnosis of stroke. In the ascertainment of the diagnosis of MI, the modified WHO MONICA criteria for verified definite or possible MI were used.²⁷ Lower-extremity amputations due to trauma and other nonvascular causes were excluded.

Statistical Methods
Statistical analyses were conducted with the SAS program, version 6.10.²⁸ Differences between the groups were assessed by ² test or ANCOVA by using age, sex, and area as covariates. Because of skewed distribution, triglyceride values were log transformed for statistical analyses. Stratified analyses by using the median split for different variables were performed by ² test. For these analyses, subjects with borderline and clinical proteinuria were combined into one class. Interaction between urinary protein and each stratification variable was tested with the test of homogeneity. The associations between the different stages of proteinuria and stroke, serious CHD events (CHD death or nonfatal MI), and amputation were studied with multiple logistic regression analysis. Kaplan-Meier estimates for the survival curves for each level of the urinary protein concentration were obtained and compared using the log-rank test. Kaplan-Meier estimates for serious CHD events were not analyzed because the dates of the first nonfatal CHD events were not available. We also performed Cox regression analysis for fatal events. The results, however, were similar to those obtained by multiple logistic regression, and only the results of logistic regression analyses are presented.

This study was approved by the ethics committees of Kuopio University Hospital and Turku University Central Hospital.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Baseline Characteristics
Elevated urinary protein excretion (borderline and clinical proteinuria together) was found in East Finland in 25% of nondiabetic and 58% of NIDDM subjects and in West Finland in 16% of nondiabetic and 46% of NIDDM subjects. Borderline and clinical proteinuria were more common in East Finland than in West Finland and also in men than in women. NIDDM patients with borderline or clinical proteinuria were slightly older than NIDDM patients without proteinuria (mean±SEM, 58.6±0.2 versus 57.6±0.2 years, P<.01).

Table 1 presents clinical characteristics of nondiabetic and NIDDM subjects by the degree of proteinuria at baseline adjusted for age, sex, and area. The prevalence of hypertension was higher both in nondiabetic and NIDDM subjects with borderline or clinical proteinuria than in subjects without proteinuria. Previous MI at baseline was more common in NIDDM patients with clinical proteinuria than in those without proteinuria or with borderline proteinuria. In nondiabetic subjects, the prevalence of previous MI was similar regardless of the degree of proteinuria. The lipid profile in NIDDM patients with borderline or clinical proteinuria tended to be worse than in patients without proteinuria. Total cholesterol and triglyceride levels in NIDDM patients with proteinuria were higher, and HDL cholesterol levels lower, than in patients without proteinuria. In nondiabetic subjects, we found no difference in total or HDL cholesterol levels between different categories of proteinuria. The degree of proteinuria was not significantly associated with the duration of diabetes, but it was highly significantly related to poor metabolic control of diabetes measured either as fasting plasma glucose level or glycosylated hemoglobin.

View this table: [in this window] [in a new window]   Table 1. Characteristics of Nondiabetic and Diabetic Subjects by Different Degrees of Proteinuria at Baseline Adjusted for Study Area, Age, and Sex

Proteinuria and Mortality
Fig 1 shows the survival curves for all-cause mortality in three proteinuria categories in nondiabetic and NIDDM subjects. All-cause mortality was higher both in nondiabetic and NIDDM subjects with borderline or clinical proteinuria than in those without proteinuria.

View larger version (17K): [in this window] [in a new window]   Figure 1. Survival curves for all-cause mortality by urinary protein concentration (U-Prot) in NIDDM and nondiabetic patients.

The mortality from CVD in NIDDM patients with clinical proteinuria was significantly higher than in patients with borderline proteinuria or without proteinuria (Fig 2). The CVD mortality of NIDDM patients with borderline proteinuria was also significantly higher than in NIDDM patients without proteinuria. CVD mortality tended also to be higher in nondiabetic subjects with borderline or clinical proteinuria than in those without proteinuria. However, the differences between the groups were smaller than in NIDDM patients. The results of the survival analysis for CHD mortality were similar to those for total CVD mortality (data not shown).

View larger version (18K): [in this window] [in a new window]   Figure 2. Survival curves for CVD mortality by urinary protein concentration (U-Prot) in NIDDM and nondiabetic patients.

In NIDDM patients with borderline or clinical proteinuria, the non-CVD mortality was higher than in those without proteinuria (data not shown). In nondiabetic subjects, we found no statistically significant differences in mortality from non-CVD among different proteinuria groups. The most important causes for non-CVD deaths (n=97) in NIDDM patients were neoplasms (41%), diabetes and its complications (25%), gastrointestinal and liver diseases (15%), and traumas (6%). In nondiabetic subjects, the most important reasons for non-CVD deaths (n=43) were neoplasms (56%), traumas (23%), and gastrointestinal and liver diseases (12%).

Proteinuria and Incidence of Stroke and Other Atherosclerotic Vascular Disease Events
During the 7-year follow-up, 376 NIDDM patients (36%) and 84 nondiabetic subjects (6.1%) developed an atherosclerotic vascular disease event. The corresponding numbers for stroke were 125 (12%) and 30 (2%) and for serious CHD events 255 (24%) and 57 (4%), respectively. There were no amputations in nondiabetic subjects, but in 58 of the NIDDM patients (10%) a lower-extremity amputation was performed during the 7-year follow-up. The incidence of atherosclerotic vascular disease events during the follow-up was almost two times higher in NIDDM patients with clinical proteinuria than in those without proteinuria (Fig 3). The incidence of atherosclerotic vascular disease events increased stepwise with the degree of proteinuria in both nondiabetic and NIDDM subjects. A similar stepwise trend was found between proteinuria and stroke and CHD events both in NIDDM and nondiabetic subjects, as well as between proteinuria and amputation in NIDDM patients.

View larger version (40K): [in this window] [in a new window]   Figure 3. Incidence of CHD events (CHD death or nonfatal MI), stroke, lower-extremity amputation, and all atherosclerotic vascular disease (ASVD) events (any one of the three previous categories of events) in nondiabetic or NIDDM subjects by urinary protein concentration (U-Prot), both areas and sexes combined (probability values for trends as shown).

Table 2 shows the results of multivariate logistic regression analyses for the association between proteinuria and stroke, CHD events, and lower-extremity amputation comparing borderline or clinical proteinuria separately with the group without proteinuria. The strength of the association between borderline proteinuria and stroke as indicated by the odds ratios was similar in nondiabetic and NIDDM subjects. However, this association was not statistically significant. The association of clinical proteinuria with stroke was stronger than that of borderline proteinuria with stroke, and the strength of the association did not differ in nondiabetic and NIDDM subjects.

View this table: [in this window] [in a new window]   Table 2. Adjusted Odds Ratios and 95% Confidence Intervals for Borderline (150-300 mg/L) or Clinical (>300 mg/L) Proteinuria With Regard to CHD Events, Stroke, Amputation, and All Atherosclerotic Vascular Events Obtained Using Different Models in Logistic Regression Analysis in Nondiabetic and NIDDM Subjects

The association between borderline proteinuria and CHD events both in nondiabetic and NIDDM subjects was similar to that between borderline proteinuria and stroke (Table 2). However, the association between clinical proteinuria and stroke was even stronger than that between clinical proteinuria and CHD events. When analyses were restricted only to subjects without a previous history of MI at baseline, the strength of the association between proteinuria and CHD events did not change (odds ratios for clinical proteinuria versus group without proteinuria were 2.04 to 2.61 in nondiabetic subjects and 1.92 to 2.27 in NIDDM patients). Further adjustment for apolipoproteins A₁ and B did not change the results of multivariate logistic regression analysis (data not shown).

Furthermore, we found an association between proteinuria and lower-extremity amputation in NIDDM patients similar to the associations between proteinuria and stroke or proteinuria and CHD events (Table 2).

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
We have shown for the first time in the same prospective study that clinical proteinuria predicts the incidence of stroke, as well as serious CHD events (CHD death or nonfatal MI), both in nondiabetic and NIDDM subjects and the incidence of lower-extremity amputation in NIDDM patients. Furthermore, both the all-cause and CVD mortality were higher in nondiabetic and NIDDM subjects with clinical proteinuria (>300 mg/L) than in those without proteinuria. NIDDM independently increased the risk of atherosclerotic vascular disease events regardless of proteinuria status. Nevertheless, the association between the different degrees of proteinuria and the risk of stroke, CHD events, or lower-extremity amputation was stepwise and basically similar in nondiabetic and NIDDM subjects. The association of clinical proteinuria with the risk of stroke, as well as with the risk of CHD events or amputation, was independent of other cardiovascular risk factors in NIDDM patients.

The risk of ischemic stroke is undoubtedly higher in diabetic patients than in nondiabetic subjects.^{1 23 29 30 31 32 33} Hypertension is the strongest risk factor for stroke both in nondiabetic and diabetic subjects.^{31 34} Only a few studies have been published previously regarding the association between proteinuria and the risk of stroke. In Japanese and European prospective studies on diabetic patients, proteinuria predicted cerebrovascular diseases during the follow-up.^{20 21} On the other hand, Gall et al,⁸ in their study based on 5-year follow-up of NIDDM patients, found no significant relationship between baseline albuminuria and the mortality from stroke. However, their study included only very few subjects who developed stroke.

Our findings showing that clinical proteinuria predicts all-cause and CVD mortality are compatible with those of previous studies suggesting that increased urinary albumin^{2 3 4 7 8 35 36} or protein^{9 10} excretion is associated with increased mortality. Several studies have shown that the mortality risk is 2.3 to 4 times higher in NIDDM patients with microalbuminuria than in those without microalbuminuria.^{2 3 35 36} However, Mattock et al⁴ reported recently that the mortality risk in NIDDM patients with microalbuminuria was almost 10 times higher than in NIDDM patients without albuminuria. In these studies, CVD has been the most important cause of death.^{3 4 36} Gall et al⁸ reported recently the results of a prospective 5-year follow-up study in which the risk of cardiovascular death was 2.5-fold in NIDDM patients with macroalbuminuria (300 mg/24 h) but not in those with microalbuminuria (30 to 299 mg/24 h).

Less is known about the association of albuminuria or proteinuria and all-cause or CVD mortality in nondiabetic subjects. In prospective studies, microalbuminuria has predicted both total and CVD mortality,^{3 5 11 12} in some studies independent of other cardiovascular risk factors.^{5 12} Our results also showed that adjustment for other cardiovascular risk factors and apolipoproteins does not markedly alter the odds ratios for proteinuria with regard to different manifestations of atherosclerotic vascular disease. The implication of these findings in nondiabetic subjects and NIDDM patients is that increased urinary protein excretion rate may be the reflection of widespread vascular damage, as suggested by the Steno hypothesis (Deckert et al¹⁷ ).

Damsgaard et al³⁷ showed in nondiabetic subjects that the increase in all-cause mortality during the 8- to 9-year follow-up associated with albuminuria was mostly due to an increased mortality of albuminuric nondiabetic subjects during the first years after the baseline examination. No difference in mortality between subjects with and without albuminuria was found among those who survived the first 5 years of the follow-up. Contrary to the findings of Damsgaard et al,³⁷ in our study the mortality of both nondiabetic subjects and NIDDM patients with clinical proteinuria continued to be higher than that in corresponding subjects without proteinuria during the last years of follow-up also. Similar results have been published by other investigators.^{7 36} The implication of these findings is that proteinuria is not solely the complication of any preclinical serious disease but the reflection of underlying disorder itself.

Although the etiology of lower-extremity amputation is multifactorial, including combinations of ischemia, neuropathy, trauma, and infection, the ischemia often plays a major role in pathways leading to amputation.³⁸ As far as we know, no studies regarding the association between proteinuria and the risk of amputation have been published previously. The prevalence of peripheral arterial disease has been shown to be higher in NIDDM patients with albuminuria,^{39 40} but no association between proteinuria and the incidence of peripheral arterial disease was found in a prospective study.²¹ In our study, the association between clinical proteinuria and incidence of lower-extremity amputation in NIDDM patients was significant even though slightly weaker than that between proteinuria and incidence of stroke.

Instead of the measurement of urinary albumin excretion rate, we determined the total urinary protein concentration from the morning spot urine. In patients with increased urinary protein excretion rate due to diabetic glomerular injury, the proportion of albumin to total urinary protein is higher than in subjects without diabetic nephropathy. The commonly used cutoff point for urinary albumin excretion rate of 200 to 300 mg/24 h has been estimated to correspond to a total urinary protein excretion rate of 500 mg/24 h.⁴¹ Our cutoff point for clinical proteinuria (300 mg/L) is close to this, assuming that the mean daily volume of urine is approximately 1.5 L. Urinary protein concentration measured from spot urine has been shown to correlate very well with 24-hour urinary protein excretion.^{42 43} In our study, measurement of urinary protein concentration from spot urine instead of 24-hour urine may increase random variation and decrease the strength of the association between proteinuria and atherosclerotic vascular events. Furthermore, if we had measured urinary albumin, which is more specific to diabetic nephropathy than total urinary protein, our findings concerning associations between proteinuria and atherosclerotic vascular disease events might have been even stronger than those we now report.

The mechanisms of the association between proteinuria and CVD are poorly understood, and several explanations have been proposed. Albuminuria has been proposed to be associated with adverse changes in other known cardiovascular risk factors,^{4 13 14 15 16} a marker of established CVD itself,¹⁶ widespread vascular damage,¹⁷ or endothelial dysfunction.^{18 19} Furthermore, albuminuria has been shown to be related to the abnormalities in thrombogenic factors favoring the development of cardiovascular complications in patients with NIDDM.^{16 18} In our study, proteinuria in NIDDM patients was associated with adverse changes in most of the classic cardiovascular risk factors except smoking. Statistically significant associations were found between proteinuria and history of hypertension and elevated levels of triglycerides and total and decreased levels of HDL cholesterol. Furthermore, in NIDDM patients the metabolic control of diabetes was worse in the subjects with borderline or clinical proteinuria. However, after we controlled for all these variables, clinical proteinuria still significantly predicted the risk of stroke, as well as the risk of serious CHD events and amputation in NIDDM patients.

In conclusion, increased urinary protein concentration predicted both all-cause and CVD mortality, as well as the incidence of stroke and other atherosclerotic vascular disease events, during the 7-year follow-up both in nondiabetic and NIDDM subjects. The association between clinical proteinuria and the risk of atherosclerotic vascular disease events remained statistically significant in NIDDM subjects even after controlling for other cardiovascular risk factors. Our findings are compatible with the hypothesis that increased urinary protein excretion may be associated with widespread vascular damage.

	Selected Abbreviations and Acronyms

 

CHD = coronary heart disease CVD = cardiovascular disease MI = myocardial infarction NIDDM = non–insulin-dependent diabetes mellitus WHO = World Health Organization

	Acknowledgments

 
This study was supported by grants from the Academy of Finland, the Aarne and Aili Turunen Foundation, and the Finnish Heart Research Foundation.

Received July 2, 1996; revision received August 7, 1996; accepted August 15, 1996.

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