Patients with primary aldosteronism (PA) are at a higher

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1 ORIGINAL ARTICLE Endocrine Care Predictors of Decreasing Glomerular Filtration Rate and Prevalence of Chronic Kidney Disease After Treatment of Primary Aldosteronism: Renal Outcome of 213 Cases Yoshitsugu Iwakura, Ryo Morimoto, Masataka Kudo, Yoshikiyo Ono, Kei Takase, Kazumasa Seiji, Yoichi Arai, Yasuhiro Nakamura, Hironobu Sasano, Sadayoshi Ito, and Fumitoshi Satoh Division of Nephrology, Endocrinology, and Vascular Medicine (Y.I., R.M., M.K., Y.O., S.I., F.S.) and Departments of Radiology (K.T., K.S.), Urology (Y.A.), and Pathology (Y.N., H.S.), Tohoku University Hospital, Sendai , Japan Context: In primary aldosteronism (PA), glomerular hyperfiltration due to excessive aldosterone is considered to underestimate actual renal damage. Objective: Our objectives were to determine the prevalence of chronic kidney disease (CKD) in PA and identify the predictors of decreasing estimated glomerular filtration rate (egfr) after treatment. Design and Setting: This was a 12-month prospective study of patients with PA treated at Tohoku University Hospital. Patients and Interventions: All patients were treated according to the results of adrenal venous sampling; 102 patients with aldosterone-producing adenoma underwent adrenalectomy, and 111 with bilateral hyperaldosteronism were treated with mineralocorticoid receptor antagonists. Main Outcome Measures: Electrolytes, blood pressure, and indicators of renal function were determined at 1 and 12 months after intervention. Results: Blood pressure, urinary albumin excretion (UAE), and egfr, which significantly decreased at 1 month after treatment of PA, did not further decrease at 12 months. Prevalence of CKD, which was 15.7% in aldosterone-producing adenoma and 8.1% in bilateral hyperaldosteronism at the first visit, increased to 37.1% and 28.3%, respectively, at the end of study (P.0001). Multivariate regression analysis revealed that higher UAE and lower serum potassium levels were found to be independent predictors of decreasing egfr after intervention. Conclusions: This large cohort study shows that the prevalence of CKD in PA was increased after treatment and that higher UAE and lower serum potassium levels at the first visit were predictors of decreasing egfr after treatment of PA. To prevent a large decrease of egfr after intervention, PA patients should be diagnosed before evolution to severe albuminuria and hypokalemia. (J Clin Endocrinol Metab 99: , 2014) Patients with primary aldosteronism (PA) are at a higher risk for cardiovascular morbidity than patients with essential hypertension (1, 2), but the risk can be reduced in ISSN Print X ISSN Online Printed in U.S.A. Copyright 2014 by the Endocrine Society Received May 9, Accepted November 19, First Published Online November 27, 2013 the long term after treatment (3). Recent studies demonstrated higher morbidity of renal damage in PA patients compared with primary hypertension (4 6). In the Pri- Abbreviations: APA, aldosterone-producing adenoma; ARR, aldosterone to renin ratio; BHA, bilateral hyperaldosteronism; BP, blood pressure; CKD, chronic kidney disease; DBP, diastolic BP; egfr, estimated GFR; GFR, glomerular filtration rate; MR, mineralocorticoid receptor; PA, primary aldosteronism; PAC, plasma aldosterone concentration; PRA, plasma renin activity; SBP, systolic BP; UAE, urinary albumin excretion. doi: /jc J Clin Endocrinol Metab, May 2014, 99(5): jcem.endojournals.org 1593

2 1594 Iwakura et al CKD in Primary Aldosteronism J Clin Endocrinol Metab, May 2014, 99(5): mary Aldosteronism Prevalence in Italy (PAPY) study, 24- hour urinary albumin excretion (UAE) was significantly greater in patients with PA than in hypertensive controls (4). Sechi et al (5) demonstrated that increased UAE and relative glomerular hyperfiltration were rapidly reversed after removal of excessive aldosterone. They also reported that, in the patients with essential hypertension, blood pressure (BP) and UAE were significantly reduced by antihypertensive agents, but creatinine clearance was not. Moreover, their UAE reduction was significantly smaller than that in PA patients (5). These results suggested that hyperaldosteronism could cause greater glomerular hyperfiltration and albuminuria as compared with essential hypertension, which was also supported by another report (6). Reincke et al (7) showed that plasma aldosterone concentration and serum potassium were independent risk factors of low glomerular filtration rate (GFR) in untreated PA patients and that specific interventions were associated with a further decrease in GFR. Thus, a clinically critical problem is the decrement of egfr after treatment of PA. Actually, we sometimes deal with patients with aldosterone-producing adenoma (APA) who develop chronic kidney disease (CKD) after adrenalectomy because of a large decrease of estimated GFR (egfr). However, there have been few reports investigating the predictive factors of renal function after treatment of PA. Therefore, we conducted a large prospective cohort study including over 200 PA subjects. Our main goal was to determine the prevalence of CKD in PA patients after treatment and to identify predictors of decreasing egfr after treatment for PA. Patients and Methods Study population and follow-up The study group comprised patients diagnosed with PA who were treated at Tohoku University Hospital between April 2007 and December Written consent was obtained from the patients after giving them sufficient information about the study; the study protocol was approved by the ethics committee of Tohoku University School of Medicine and adhered to the principles of the Declaration of Helsinki and Title 45, U.S. Code of Federal Regulations, part 46, Protection of Human Subjects, revised November 13, 2001, effective December 13, PA was diagnosed using previously reported procedures (8). At the first visit, tests for plasma aldosterone concentration (PAC) (nanograms per deciliter), plasma renin activity (PRA) (nanograms per milliliter per hour), serum creatinine, serum sodium, serum potassium, urinary sodium, urinary potassium, and UAE were performed in the morning after a 10-minute rest in the sitting position. PAC and PRA were measured by RIA; the former was measured using the SPAC-S aldosterone kit (TFB Inc), and the latter was measured using the renin Riabead kit for PRA (Dainabot Co Ltd). The diagnosis of PA was confirmed when the aldosterone to renin ratio (ARR) exceeded 20 after loading 50 mg captopril. Upon diagnosis of PA, antihypertensive agents were limited to calcium channel blockers and/or 1 -blockers according to clinical practice guidelines of The Endocrine Society (8). Patients who had other endocrine diseases were excluded from this study. We also excluded the patients with primary renal diseases, diabetes with evident proteinuria, renal artery stenosis, renal cell carcinoma, or other urinary findings such as hematuria and urinary tract infection. All patients were treated according to the results of adrenal venous sampling as previously reported (9, 10). The patients with unilateral disease diagnosed by adrenal venous sampling underwent laparoscopic adrenalectomy, whereas those with bilateral hyperaldosteronism (BHA) were treated with a pharmacological regimen that included mineralocorticoid receptor (MR) antagonists (spironolactone or eplerenone). In all patients who underwent adrenalectomy, APA was confirmed by histopathological and immunohistochemical analysis including immunohistochemistry of 3 -hydroxysteroid dehydrogenase and C17 (11). In particular, the absence of 3 hydroxysteroid dehydrogenase in the hyperplastic zona glomerulosa in the nonneoplastic adrenal with APA ruled out the possibility of bilateral or idiopathic hyperaldosteronism (11). Clinical assessments and laboratory tests were done at 1 and 12 months after a specific treatment for PA. At each visit, BP was measured using the Omron Hem-907 (Omron Healthcare Co Ltd) to verify whether the patient had achieved the target BP value of 140/90 mm Hg. In both groups, no angiotensin converting enzyme inhibitors, angiotensin II receptor blockers, or diuretics not including MR antagonists were used during the first month after treatment of PA. During follow-up and until the end of study, all classes of antihypertensive agents were allowed to achieve the target BP recommended by the guidelines (12). The egfr was calculated using the following equation established for the Japanese population by the Japanese Society of Nephrology: egfr (ml/min/1.73 m 2 ) 194 serum creatinine age ( in the case of females) (13). The UAE values are expressed as a ratio of urinary albumin concentration to urinary creatinine concentration (milligrams per gram creatinine). In this study, CKD was defined by an egfr 60 ml/min/ 1.73 m 2. Albuminuria was defined as 30 mg/g creatinine, respectively. Statistical analysis The results are presented as mean SEM values. The UAE values were log-transformed for statistical analysis due to their skewed distribution. Univariate comparisons between APA and BHA were performed using unpaired t test, as appropriate. Comparisons between before and after treatment in each group were performed by paired t test. One-way ANOVA followed by Bonferroni s correction was used to compare normally distributed quantitative variables at each time point. Univariate correlations were evaluated as Pearson s correlation coefficients. Independent correlates of egfr decline were investigated using multivariate linear regression analysis with the backward stepwise procedure. Significance was set at P.05. StatFlex version 6.0 software (Artech Co Ltd) was used for all the statistical analyses. Results Clinical characteristics of the study population A total of 213 patients with PA participated in this study. Their clinical features at the first visit are shown in

3 doi: /jc jcem.endojournals.org 1595 Table 1. Clinical Characteristics of Patients With PA at the First Visit a Variables Total (n 213) Table 1. Among these, 102 patients had APA and 111 had BHA. There were significant differences in systolic BP (SBP) and diastolic BP (DBP) between the APA and BHA groups (SBP, vs mm Hg, P.05; DBP, vs mm Hg, P.01, respectively). Duration of hypertension and family history of hypertension were comparable. PAC, PRA, ARR, and serum sodium and potassium levels also significantly differed. Serum creatinine levels and egfr were similar between the APA and BHA groups, although there were significant differences in age and number of male patients. The prevalence of CKD was 11.7% in all patients at the first visit, with no significant difference between the APA and BHA groups. The prevalence of albuminuria was 47.4% with a significant difference between groups (61.8% in APA group vs 34.2% in BHA group, P.0001). Aldosterone and BP decreased after treatment of PA The average duration of follow-up was 11.5 and 8.3 months in the APA and BHA groups, respectively. In the APA group, PAC significantly decreased and serum potassium was corrected to levels within the normal range by the first month after adrenalectomy (PAC, from 26.2 to 8.5 ng/dl, P.05; serum potassium, from 3.5 to 4.5 mmol/l, P.05) (Table 2). BP significantly decreased at 1 month after treatment, with mean values of 126/79 and 124/74 mm Hg in the APA and BHA groups, respectively. APA (n 102) BHA (n 111) P Age, y Males/females, n 89/124 52/50 37/74.01 Duration of hypertension, y NS Family history of hypertension, % NS Body mass index, kg/m SBP, mm Hg DBP, mm Hg Serum creatinine, mg/dl NS egfr, ml/min/1.73 m NS CKD, n (%) 25 (11.7) 16 (15.7) 9 (8.1) NS UAE, mg/g creatinine NS Albuminuria, n (%) 101 (47.4) 63 (61.8) 38 (34.2).0001 Serum sodium, mmol/l Serum potassium, mmol/l Urinary sodium, mmol/g creatinine NS Urinary potassium, mmol/g creatinine Plasma aldosterone, ng/dl PRA, ng/ml/h ARR, ng/dl per ng/ml/h HbA1c (NGSP), % NS Diabetes mellitus, n (%) 33 (15.5) 14 (13.7) 19 (17.1) NS Abbreviations: HbA1c, hemoglobin A1c; NGSP, National Glycohemoglobin Standardization Program; NS, not significant. a The data represent the mean SEM Unpaired t test was used for comparison between APA and BHA. CKD was defined as 60 ml/min/1.73 m 2 in egfr. BP remained stable during the 12-month follow-up period in BHA (Table 2), but SBP was significantly decreased in APA (from 126 at 1 month to 120 at 12 months, P.05). Use of antihypertensive agents At the first visit, the number of patients who took no antihypertensive medication was 18 (17.6%) and 30 (27%) in APA and BHA, respectively. The number of patients who took 1 agent was 22 (21.6%) and 30 (27%), respectively. The number of patients on multi-agent therapy was 62 (60.8%) and 51 (46%), respectively. There was significant difference only in the number of patients on multi-agent therapy between the APA and BHA group (P.05). At the end of the study, the number of patients with no agents was 20 (19.6%) in APA. APA patients on mono- and multi-therapy were 43 (42.2%) and 39 (38.2%), respectively. In BHA, all 111 patients in this group took MR antagonists during the follow-up. However, 15 patients discontinued their spironolactone prescription due to adverse effects and changed to eplerenone. At the end of the study, BHA patients on mono- and multitherapy were 12 (10.8%) and 99 (89.2%), respectively. There were significant differences in the number of patients on mono- (P.0001) and multi-agent therapy (P.0001) between the APA and BHA group (P.05). There was no difference in the therapeutic classes at the end of the study between APA and BHA groups except for MR antagonists (angiotensin converting enzyme inhibitor, 1% vs

4 1596 Iwakura et al CKD in Primary Aldosteronism J Clin Endocrinol Metab, May 2014, 99(5): Table 2. Changes in Parameters Before and After Treatment for PA a APA BHA At First Visit 1 Month After Treatment 5%; angiotensin II receptor blocker, 38% vs 44%; diuretics, 6% vs 10% in APA vs BHA, respectively). During the first month after specific treatment, angiotensin converting enzyme inhibitors, angiotensin II receptor blockers, and diuretics were not used in either group. Estimated GFR and prevalence of CKD after treatment of PA At 1 month after treatment, egfr immediately decreased in both groups (APA, from 81 to 68 ml/min/1.73 m 2, P.05; BHA, from 79 to 73 ml/min/1.73 m 2, P.05), but it showed no further significant decreases at 12 months after treatment (Table 2). The initial decrement was significantly different (APA, 13 ml/min/1.73 m 2 ; BHA, 6 ml/min/1.73 m 2, P.005). The prevalence of CKD (defined by egfr 60 ml/min/1.73 m 2 ), which was 15.7% in the APA group and 8.1% in the BHA group at 12 Months After Treatment At First Visit 1 Month After Treatment 12 Months After Treatment SBP, mm Hg b,d b,d,e b,d b,d,e DBP, mm Hg b,c,f b,c b,d,f b,d PAC, ng/dl b,d b,d PRA, ng/ml/h c b,c Serum potassium, mmol/l b,g b,d,f b,g b,d,f egfr, ml/min/1.73 m b,e 65 2 b,d b,e 69 2 b,d UAE, mg/g creatinine b 23 5 b,d b 25 7 b,d a One-way ANOVA followed by Bonferroni correction was performed for each time point. Unpaired t test was used for comparison between APA and BHA groups at each time point after treatment. Comparisons at the first visit between groups are shown in Table 1. b P.05 vs first visit in each group. c P.05, 1 vs 12 months after treatment in each group. d No significance, 1 vs 12 months after treatment in each group. e P.05, APA vs BHA groups at each time point after treatment. f P.005, APA vs BHA groups at each time point after treatment. g P.0005, APA vs BHA groups at each time point after treatment. the first visit, significantly increased to 37.1% and 28.3%, respectively, at 12 months after treatment (Figure 1). UAE and prevalence of albuminuria after treatment of PA UAE showed a significant decrease at 1 month after intervention in both groups (APA, from 80 to 21 mg/g creatinine, P.05; BHA, from 100 to 21 mg/g creatinine, P.05) (Table 2). In both groups, UAE at 12 months after treatment was not significantly changed compared with that at the first month. The prevalence of albuminuria significantly decreased at the end of the study in both the groups (from 61.8% to 14.7% in APA, P.0001; and from 34.2% to 16.2% in BHA, P.0001). The predictors of treatment-induced egfr decrease In univariate analysis, albuminuria, PAC, PRA, SBP, body mass index, and serum potassium correlated with the decrease in egfr. Backward stepwise regression analysis showed that UAE (log 10 UAE), serum potassium, and PRA at the first visit were significant predictors of the decrease in egfr at 1 month after intervention (Table 3). Table 3. Potential Predictors of the Decrement of egfr at 1 Month After Treatment a Figure 1. Prevalence of CKD. Paired t test was used for comparison between before and after treatment in each group. CKD was defined as an egfr of 60 ml/min/1.73 m 2. Compared with the first visit, the prevalence of CKD increased significantly after treatment in APA and BHA patients. Variables P UAE (log 10 ).0029 Serum potassium.0092 PRA.0144 a Backward stepwise regression analysis was performed. Adjusted R 2.178, F 12.13, and P.0001.

5 doi: /jc jcem.endojournals.org 1597 Discussion In the present study, we found similar BP and renal alterations throughout the follow-up of 12 months after treatment to those of other previous studies (5 7). Based on these findings, we provided new information about the prevalence of CKD, which increased at 12 months after treatment. In addition, we identified the predictors of decreasing egfr after treatment of PA. Prevalence of CKD and albuminuria In this study, we first observed that the prevalence of CKD was lower before treating PA than after treatment. However, it significantly increased approximately 20% after treatment in both APA and BHA groups because of decreasing egfr. This means that renal damage was initially masked in 20% of our patients and that glomerular hyperfiltration can lead to underestimation of CKD at baseline in PA patients. In 1977, Danforth et al (14) demonstrated that the histological renal changes in APA patients were more severe than expected from the preoperative hypertensive and renal evaluation. This phenomenon might be explained as glomerular hyperfiltration even in patients with a damaged kidney. Second, in the present study, both UAE and egfr were significantly decreased after treatment of PA. Sechi et al (5) demonstrated the same alteration in PA patients with a more accurate method in which urine is collected over a 24-hour period. Thus, albuminuria might also indicate hyperfiltration. Moreover, it is known to be a significant risk factor not only for cardiovascular events but also for end-stage renal disease (15). In this respect, from the results of the present study, we emphasize that renal outcome was not deteriorated but rather normalized or ameliorated instead of increasing in CKD patients after treatment of PA. Third, in the present study, there were 11.7% of PA patients who already had CKD before treatment of PA. In the German Conn registry of a multicenter study, Born- Frontsberg et al (2) reported the complications associated with chronic renal failure in untreated PA patients. Experimental studies previously demonstrated that high levels of aldosterone lead to renal damage (16, 17). Furthermore, in our study, albuminuria persisted in some patients even after the treatment. This suggests that in PA, renal impairment starts with reversible glomerular hyperfiltration associated with increasing losses of urinary albumin, followed by coexistence of irreversible structural and functional renal damage due to longstanding hypertension and persistent albuminuria. It might also arise due to other reasons such as metabolic syndrome, including obesity or diabetes without nephropathy in our patients, especially in BHA patients. Finally, we should repeatedly emphasize that the patients with urinary disorders due to other diseases or conditions such as diabetes nephropathy, urinary tract infection, and hematuria were strictly excluded in this study. Therefore, we could fairly analyze and consider our results in PA patients without such these potential causes of albuminuria. Predictors of decreasing egfr after treatment Our data demonstrated and provided new information on the predictors of decreasing egfr after treatment of PA. The strongest factor was the level of urinary albumin excretion at the first visit. This result indicated that higher urinary albumin might reflect glomerular hyperfiltration. It did not contradict previous reports that hyperaldosteronism could cause greater glomerular hyperfiltration and albuminuria in comparison with essential hypertension (5, 6). Serum potassium was also a predictor in our multivariate analysis; that is, the initial hypokalemia independently led to a lower decrease of egfr after treatment. Ribstein et al (6) showed that baseline serum potassium correlated with the change in GFR by univariate analysis. Rossi et al (4) provided evidence in the PAPY study with 64 PA patients that low serum potassium at baseline predicts albuminuria. Reincke et al (7) provided evidence in the German Conn registry with more than 400 patients that hypokalemic PA patients tended to complicate renal impairment. From these results, we suggest that hypokalemia should be considered as not only a hallmark of hyperaldosteronism but also an indication of causality with hyperfiltration or renal damage. PRA was also one of the factors; that is, the state of suppressed renin activity due to hyperaldosteronism and hypervolemia can predict the decrement of egfr after treatment. Study limitations There are some method- and participant-related limitations in this study. First, renal function might have been underestimated because of the method used to evaluate GFR. The equation we used in the present study was developed based on data from the Japanese population of patients with CKD (13). This formula is considered more suitable for the Japanese population than other formulas (eg, the Cockcroft-Gault formula). However, egfr tends to be underestimated in patients with normal renal function, more so than in PA patients with glomerular hyperfiltration. Hence, egfr of patients with glomerular hyperfiltration or without CKD might be lower than their actual GFR. Patients with diabetes generally tend to show hyporeninemic hypoaldosteronism, because of hypervolemia, especially due to the retention of sodium (18). In addition, it is reported that hyperglycemia itself can cause glomerular hyperfiltration as well as PA (19). This point

6 1598 Iwakura et al CKD in Primary Aldosteronism J Clin Endocrinol Metab, May 2014, 99(5): might also be assumed to influence the renal outcomes. Moreover, treatment with antihypertensive agents might influence the renal outcomes at the end of the study. However, none of the patients took angiotensin converting enzyme inhibitors or angiotensin II receptor blockers during the first month after adrenalectomy in APA patients and after treatment of MR blockers in BHA. Therefore, the predictive parameters identified for decreasing egfr at this time were considered as mainly depending on the effect of adrenalectomy or aldosterone antagonism. Conclusions In summary, treatment of PA resulted in increased prevalence of CKD due to decreasing egfr. Higher UAE and lower serum potassium levels at the first visit were strong predictors of a decrement in egfr. From our results, to prevent a large decrease of egfr after treatment of PA, patients should be diagnosed as early as possible before presentation with evident albuminuria and hypokalemia. Acknowledgments We thank Ms Akane Sugawara and Ms Yasuko Tsukada for secretarial assistance. Address all correspondence and requests for reprints to: Fumitoshi Satoh, MD, PhD, Division of Nephrology, Endocrinology, and Vascular Medicine, Department of Medicine, Tohoku University Graduate School of Medicine, 1-1, Seiryomachi, Aoba-ku, Sendai , Japan. fsatoh@med. tohoku.ac.jp. Disclosure Summary: The authors have nothing to disclose. References 1. Milliez P, Girerd X, Plouin PF, Blacher J, Safar ME, Mourad JJ. Evidence for an increased rate of cardiovascular events in patients with primary aldosteronism. J Am Coll Cardiol. 2005;45: Born-Frontsberg E, Reincke M, Rump LC, et al; Participants of the German Conn s Registry. Cardiovascular and cerebrovascular comorbidities of hypokalemic and normokalemic primary aldosteronism: results of the German Conn s Registry. J Clin Endocrinol Metab. 2009;94: Catena C, Colussi G, Nadalini E, et al. Cardiovascular outcomes in patients with primary aldosteronism after treatment. Arch Intern Med. 2008;168: Rossi GP, Bernini G, Desideri G, et al; PAPY Study Participants. Renal damage in primary aldosteronism: results of the PAPY Study. Hypertension. 2006;48: Sechi LA, Novello M, Lapenna R, et al. Long-term renal outcomes in patients with primary aldosteronism. JAMA. 2006;295: Ribstein J, Du Cailar G, Fesler P, Mimran A. Relative glomerular hyperfiltration in primary aldosteronism. J Am Soc Nephrol. 2005; 16: Reincke M, Rump LC, Quinkler M, et al; Participants of German Conn s Registry. Risk factors associated with a low glomerular filtration rate in primary aldosteronism. J Clin Endocrinol Metab. 2009;94: Funder JW, Carey RM, Fardella C, et al; Endocrine Society. Case detection, diagnosis, and treatment of patients with primary aldosteronism: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2008;93: Nishikawa T, Omura M, Satoh F, et al; Task Force Committee on Primary Aldosteronism, The Japan Endocrine Society. Guidelines for the diagnosis and treatment of primary aldosteronism the Japan Endocrine Society Endocr J. 2011;58: Satoh F, Abe T, Tanemoto M, et al. Localization of aldosteroneproducing adrenocortical adenomas: significance of adrenal venous sampling. Hypertens Res. 2007;30: Sasano H. Localization of steroidogenic enzymes in adrenal cortex and its disorders. Endocr J. 1994;41: Japanese Society of Hypertension. Japanese Society of Hypertension guidelines for the management of hypertension (JSH 2004). Hypertens Res. 2006;29(Suppl):S1 S Matsuo S, Imai E, Horio M, et al; Collaborators developing the Japanese equation for estimated GFR Revised equations for estimated GFR from serum creatinine in Japan. Am J Kidney Dis. 53: Danforth DN Jr, Orlando MM, Bartter FC, Javadpour N. Renal changes in primary aldosteronism. J Urol. 1977;117: Iseki K, Ikemiya Y, Iseki C, Takishita S. Proteinuria and the risk of developing end-stage renal disease. Kidney Int. 2003;63: Arima S, Kohagura K, Xu HL, et al. Nongenomic vascular action of aldosterone in the glomerular microcirculation. J Am Soc Nephrol. 2003;14: Hall JE, Granger JP, Smith MJ Jr., Premen AJ. Role of renal hemodynamics and arterial pressure in aldosterone escape. Hypertension. 1984;6:I183 I Perez GO, Lespier L, Jacobi J, et al. Hyporeninemia and hypoaldosteronism in diabetes mellitus. Arch Intern Med. 1977;137: Magee GM, Bilous RW, Cardwell CR, Hunter SJ, Kee F, Fogarty DG. Is hyperfiltration associated with the future risk of developing diabetic nephropathy? A meta-analysis. Diabetologia. 2009;52: