Plasma aldosterone concentration in the patient with diabetes mellitus Rapid Communication

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1 Kidney International, Vol. 65 (2004), pp Plasma aldosterone concentration in the patient with diabetes mellitus Rapid Communication NORMAN K. HOLLENBERG, RADOMIR STEVANOVIC, ANUPAM AGARWAL, M. CECILIA LANSANG, DEBORAH A. PRICE,LORI M.B. LAFFEL,GORDON H. WILLIAMS, and NAOMI D.L. FISHER Department of Medicine and Department of Radiology, Brigham & Women s Hospital and Harvard Medical School, Boston, Massachusetts Plasma aldosterone concentration in the patient with diabetes mellitus. Background. Vascular injury at the microvascular and macrovascular levels plays a crucial role in the patient with diabetes mellitus. Evidence for renin-system activation in many patients with type 1 diabetes mellitus has raised the possibility that aldosterone widely recognized as a contributor to vascular injury could play a role. Methods. We examined the state of the renin-angiotensinaldosterone system (RAAS) in 58 subjects with type 1 diabetes mellitus and 64 age-matched normal control subjects. All studies were performed on a fixed sodium (200 mmol/day) and potassium (100 mmol/day intake), and samples were drawn at 8:00 a.m. to avoid the influence of circadian rhythms. Results. The patient with diabetes mellitus showed an increase in plasma renin activity (PRA) (P < 0.01), plasma angiotensin II concentration (P < 0.01), and plasma aldosterone concentration (P < 0.001). A striking influence of the angiotensin receptor blocker, candesartan, on plasma aldosterone concentration in the patients with diabetes mellitus suggested strongly that renin-system activation is responsible for the elevated plasma aldosterone concentration. Conclusion. Pharmacologic interruption of the effects of aldosterone at the tissue level could be especially useful in patients with diabetes mellitus. The dose of agents that block the renin-angiotensin system (RAS) should be adjusted to maximize the fall in plasma aldosterone concentration. Vascular injury at the macrovascular and microvascular level is a pivotal complication of diabetes mellitus. A remarkable range of suggestions has been made on the factors contributing to vascular injury [1 5]. Among these possibilities, the contribution of renin-angiotensinsystem (RAS) activation is supported strongly by the Key words: plasma renin activity, plasma angiotensin II concentration, vascular injury, sodium, potassium. Received for publication September 23, 2003 and in revised form November 18, 2003 Accepted for publication December 1, 2003 C 2004 by the International Society of Nephrology clear efficacy of angiotensin-converting-enzyme (ACE) inhibitors and angiotensin receptor blocking agents in modifying vascular injury in such patients [6 11]. Moreover, a number of observations suggest that the RAS is activated in many such patients [12]. There has been growing interest in the possibility that aldosterone contributes to tissue injury through mechanisms beyond its influence on blood pressure [1 3]. Recent reviews have suggested that plasma aldosterone concentration is normal in patients with diabetes mellitus [1, 12], but the literature referred to is ambiguous for a number of reasons. Plasma aldosterone concentration is influenced not only by sodium and potassium intake, and posture, but also by the time of day at which the sample is collected: There are powerful circadian rhythms in the control of aldosterone release. In few studies has sodium or potassium intake been controlled and careful attention paid to the time of day at which the blood sample was drawn for measurement of plasma aldosterone concentration. In this study we dealt prospectively with these issues. A number of observations suggest that the renin system is often activated in patients with type 1 diabetes mellitus and in relevant animal models, through mechanisms that remain somewhat obscure [12]. This study was designed to test the hypothesis that activation of the renin system led to an increase in plasma aldosterone concentration, identifying yet another pathway that could contribute to tissue injury. Evidence that an increased aldosterone level contributes to tissue injury in diabetes, and that this is reversed by the addition of an aldosterone antagonist to ACE inhibition therapy is immediately relevant [13]. METHODS Subjects and protocols We studied 58 men and women with type 1 diabetes mellitus ranging in age from 18 to 62 years (28.2 ± 1435

2 1436 Hollenberg et al: Diabetes and aldosterone 1.5 years) and 64 normal subjects who ranged in age from 17 to 50 years (31.3 ± 4.0 years). The duration of diabetes ranged from 2 to 40 years (mean 15.4 ± 1.4 years). Type 1 diabetes mellitus was diagnosed according to accepted guidelines [14]. All were free of overt nephropathy, but were otherwise unselected, and represent sequential admissions to the study. The subjects were studied during admission to a metabolic ward, the General Clinical Research Center (GCRC) at the Brigham and Women s Hospital, where balance was achieved on a controlled diet. The protocol was approved by the Human Subjects Committee at Brigham and Women s Hospital, and written-informed consent was obtained from each subject. All of the patients and normal subjects were Caucasian. Of the diabetic patients, 29 had no other past medical history and were taking no medications aside from insulin. Of the remaining 29, each had one or more complications linked to diabetes. Specifically, there were nine cases of mild-to-moderate retinopathy, eight of proteinuria, microalbuminuric levels in seven, and near-nephrotic range in eight, five with neuropathy, four with hypertension, and 14 with hyperlipidemia. The hypertensive patients were being treated with an ACE inhibitor, an angiotensin receptor blocker, or a calcium channel blocking agent. The drugs were discontinued 10 to 14 days before admission for study. All participants were placed on a high-salt isocaloric diet starting 2 days prior to admission and continuing throughout the hospitalization, with a daily sodium intake of 200 mmol. Daily dietary potassium (100 mmol) and fluid intake (2500 ml) were constant. Twenty-four hour urine samples were collected daily and analyzed for sodium, potassium, creatinine, and protein. On the morning of the study day, an intravenous catheter was placed in both arms of each subject. In the subjects with diabetes, this was for continuous infusion of insulin that was started at units/kg/hour at 6:00 a.m. Blood glucose was measured every 30 minutes (Precision PCX; Abbott Laboratories, Chicago, IL, USA). The insulin infusion was adjusted to maintain blood glucose at levels of about 100 mg/dl. The subjects were supine and had been fasting for at least 8 hours. Hormonal measurements were made on blood samples obtained within minutes of 8:00 a.m. and at intervals after candesartan (25 mg orally) administration in a subset while the subjects were lying supine. Blood pressure was recorded during each study by an automatic recording device (Dinamap; Critikon, Tampa, FL, USA) at 5-minute intervals. Laboratory procedures Blood samples were collected on ice, spun immediately, and the plasma was frozen, and stored at 70 C until as- Table 1. Demographics Type 1 diabetes mellitus Normal Number Age years 28.3 ± ± 4.0 Duration of diabetes mellitus years 15.4 ± 1.4 Gender male/female 32/26 39/25 Body mass index kg/m ± ± 0.5 Systolic blood pressure mm Hg 123 ± ± 3 Diastolic blood pressure mm Hg 76 ± 6 65 ± 2 Hemoglobin A 1C % 7.9 ± 0.2 Fasting blood sugar mg/dl 170 ± ± 14 Serum creatinine mg/dl 1.0 ± ± 0.03 Serum sodium meq/l 140 ± ± 0.3 Serum potassium meq/l 4.3 ± ± hour urine sodium meq 251 ± ± hour urine potassium meq 57 ± 3 49 ± 6 say. Urinary sodium and serum potassium levels were measured using the ion selective electrode. Plasma renin activity (PRA) and aldosterone were determined by radioimmunoassay [15, 16]. Hemoglobin A 1C (HbA 1C ) was measured by high-performance liquid chromatography (HPLC). The normal range is 4.4% to 6.3%. Analyses Group means were calculated with the standard error of the mean (SEM) as the index of dispersion. Pearson s correlation was used to test the association of PRA to plasma aldosterone concentration. Paired t test was used to assess the adrenal response to candesartan. Fisher exact test, t test, and the Wilcoxon rank sum test were used to compare the normals and patients. Analysis of covariance (ANCOVA) was performed to account for possible confounding effects of baseline characteristics on responses to candesartan. RESULTS The demographic and relevant clinical information is summarized in Table 1. The normal subjects and patients with type 1 diabetes were well matched for age, gender distribution, body mass index (BMI), and 24-hour urine sodium and potassium excretion. Although hypertension was uncommon, both systolic and diastolic blood pressures were significantly higher in the patients with type 1 diabetes (P <.05). Out of the 58 diabetics, there were five in whom BMI exceeded 30. Systolic blood pressure exceeded 140 mm Hg in four, but diastolic blood pressure was less than 90 mm Hg in all but two. HbA 1C concentration exceeded 9.0 in nine. The baseline hormonal status of the normal subjects and the patients with type 1 diabetes mellitus in blood samples drawn at 8:00 a.m. is shown in Figure 1. As anticipated, PRA was significantly higher in the patients

3 Hollenberg et al: Diabetes and aldosterone 1437 RAAS status in type 1 diabetes mellitus 0.60 Normal (N=64) Diabetic (N=56) PRA (ng AI/mL/n) 40 Ang II (pg/ml) 6.0 Aldosterone (ng/dl) 20 Cortisol (mg/dl) P < Hollenberg P < 0.01 P < P > 0.6 Fig. 1. Renin-angiotensin-aldosterone status in patients with type 1 diabetes mellitus. Note the parallel increase in plasma renin activity (PRA), plasma-angiotensin II concentration (Ang II), and plasma aldosterone concentration in patients with type 1 diabetes mellitus. Body position, time of day, and intake of sodium and potassium were standardized. Table 2. Response of plasma aldosterone to the angiotensin receptor blocker, candesartan Normal Diabetic Baseline 4.9 ± ± minutes 3.9 ± ± 0.5 a a P < with diabetes (0.58 ± 0.06) than in the normal subjects (0.38 ± 0.06 ng/angiotensin I/mL/hour; P < 0.001). The increase in PRA was paralleled by an increase in plasma angiotenin II concentration, 23.3 ± 1.9 ng/ml in the normal subjects versus 34.7 ± 3.8 ng/ml in the patients with diabetes (P < 0.01). Similarly, plasma aldosterone concentration was increased in the patients with type 1 diabetes mellitus (5.1 ± 0.8 ng/ml) in comparison with the normal subjects (2.6 ± 0.26 ng/ml; P < 0.01). The 63% increase in PRA was associated with an 89% increase in plasma aldosterone concentration, and the correlation between the two was statistically significant (r = 0.48; P < 0.001). As anticipated in the patients with type 1 diabetes, candesartan led to a sharp, statistically significant fall in plasma aldosterone concentration from 6.2 ± 1.5 ng/ml to 3.1 ± 0.5 ng/ml (Table 2). The fall in plasma aldosterone concentration in the normal subjects did not achieve statistical significance. There was no difference in plasma aldosterone concentration in the type 1 diabetics who were free of complications and those who had microalbuminuria, retinopathy, hypertension, or hyperlipidemia. DISCUSSION Evidence of RAS activation in patients with type 1 diabetes mellitus led to several linked hypotheses tested in this study. The first hypothesis was that plasma aldosterone concentration would be elevated in patients with type 1 diabetes mellitus. Two additional hypotheses involved the mechanism responsible for the increase in plasma aldosterone concentration. Our second hypothesis was that an increase in PRA would parallel the increase in plasma aldosterone concentration. Our third hypothesis was that blockade of the RAS would lead to a fall in plasma aldosterone concentration in patients with diabetes mellitus. The results of this study confirm these hypotheses. Type 1 diabetes was associated with a highly significant and correlated increase in PRA and plasma aldosterone concentration. Plasma aldosterone concentration fell sharply in response to the angiotensin receptor blocker, providing compelling evidence for activation of the renin system as a major contributor in accord with our second hypothesis. One potential confounder in such studies involves the powerful circadian rhythms that govern plasma aldosterone concentration. Over the several hours of this study, from 8:00 a.m. to early afternoon, there is normally a sharp fall in plasma aldosterone concentration in the absence of any external force leading to a reduction [17, 18]. In the absence of a placebo group, not employed in this study, it is impossible to assess the contribution of that normal circadian rhythm to changes in plasma aldosterone concentration. In an earlier study in normal subjects on a low-salt diet we documented that agents that block the RAS led to a fall in plasma aldosterone concentration that exceeded the fall in an internal placebo-treated group [18]. It is likely that both factors contributed to the fall of plasma aldosterone concentration in the diabetics in this study. The failure of plasma aldosterone concentration to fall significantly in response to candesartan in the normal subjects probably reflects

4 1438 Hollenberg et al: Diabetes and aldosterone the fact that the study was performed on a high-salt diet, which induced the anticipated suppression of the RAS, and thus reduced the contribution of angiotensin II to aldosterone release. The rationale for performing this study on a high-salt diet involves two factors. Virtually every one of our subjects with diabetes mellitus had continued glycosuria. The resultant osmotic diuresis would lead to loss of sodium in the urine. As a consequence, the depletion of sodium would be greater in the patients with diabetes than in the normal subjects on a low-salt diet. Second, inappropriate activation of a system is typically most easily documented when the system is normally suppressed as with a highsalt diet. Two other factors that stimulate aldosterone release, serum potassium concentration and adrenocorticoid hormone, as reflected in plasma cortisol concentration, were noncontributory in this study. The potential influence of glucose movement across cell membranes with a parallel shift of potassium makes potassium homeostasis an attractive contributor to plasma aldosterone concentration. Plasma cortisol concentration did not differ between normal subjects and diabetics. Similarly, serum potassium concentration could not account for the differences in plasma aldosterone concentration. More frequent measurements of serum potassium concentration over time might uncover an influence that was missed in this study, as serum potassium concentration was measured only at baseline at 8:00 a.m. Hyperglycemia is a clear candidate for the activation of the RAS in many patients with type 1 diabetes in this study, in confirmation of Miller et al [19, 20]. Activation of the RAS was associated with an influence on the renal blood supply that rendered the kidney more responsive to the angiotensin receptor blocker, losartan. In our studies, a similar influence was shown on the renal hemodynamic response to the ACE inhibitor, captopril, and the angiotensin receptor blocker, candesartan [21]. This study extends the influence of activation of the reninangiotensin-aldosterone system (RAAS) to adrenal aldosterone release with additional implications for the pathogenesis of vascular injury. Unfortunately, neither ACE inhibition nor angiotensin receptor blockers lead to a sustained, predictable fall in plasma aldosterone [13]. What of type 2 diabetes mellitus? The state of the RAS is much more variable in type 2 diabetes, PRA often being suppressed [12]. At the extreme in patients with type 2 diabetes mellitus is a syndrome known as hyporeninemic hypoaldosteronism in which a suppressed renin system is associated with a striking reduction in aldosterone release and plasma aldosterone concentration the opposite of the findings in this study. In an earlier report from this laboratory, we described an increase in plasma aldosterone concentration in patients with type 2 diabetes compared to normal as large as that described in the study [22]. We did not draw attention to the finding because there had been no prior hypothesis. It was that observation that led to the specific hypothesis underlying this study. Moreover, in that study [22], we showed that a reduction in PRA could be misleading, masking an increase in the activity of the system at the tissue level, at least within the kidney. It is not clear whether the adrenal participates in the process at the tissue level from these data. PRA was clearly increased in the patients in this study. The available data suggests that aldosterone is playing a role in renal injury [13, 23]. Vascular injury at the level of large conduit arteries and at the arteriolar level is important in the pathogenesis of complications of diabetes mellitus. An array of plausible mechanisms is under active investigation [1 5]. Identification of new pathogenetic pathways creates an opportunity for new therapeutic approaches. In view of growing evidence that aldosterone can contribute to vascular injury the possibility that observations in this study are relevant to therapy cannot be ignored. ACKNOWLEDGMENTS This work was supported in part by the National Institutes of Health grants (NCRR GCRC M01RR02635, Hypertension SCOR 5P50HL55000, Hypertension Training T32HL07609, and 1R01DK ). We are also grateful for the pharmaceutical support of AstraZeneca Pharmaceuticals, Molndal, Sweden. We thank Charlene Malarick, R.N., Caroline Coletti, B.S., M.S., and Ms. Diana Capone for their assistance in various aspects of this study. This research study was performed at Brigham & Women s Hospital in the General Clinical Research Center. Reprint requests to Norman K. 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