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Early detection of diabetic kidney disease by urinary proteomics and subsequent intervention with spironolactone to delay progression (PRIORITY): a prospective observational study and embedded randomised placebo-controlled trial.
Tofte, N, Lindhardt, M, Adamova, K, Bakker, SJL, Beige, J, Beulens, JWJ, Birkenfeld, AL, Currie, G, Delles, C, Dimos, I, et al
The lancet. Diabetes & endocrinology. 2020;(4):301-312
Abstract
BACKGROUND Microalbuminuria is an early sign of kidney disease in people with diabetes and indicates increased risk of cardiovascular disease. We tested whether a urinary proteomic risk classifier (CKD273) score was associated with development of microalbuminuria and whether progression to microalbuminuria could be prevented with the mineralocorticoid receptor antagonist spironolactone. METHODS In this multicentre, prospective, observational study with embedded randomised controlled trial (PRIORITY), we recruited people with type 2 diabetes, normal urinary albumin excretion, and preserved renal function from 15 specialist centres in ten European countries. All participants (observational cohort) were tested with the CKD273 classifier and classified as high risk (CKD273 classifier score >0·154) or low risk (≤0·154). Participants who were classified as high risk were entered into a randomised controlled trial and randomly assigned (1:1), by use of an interactive web-response system, to receive spironolactone 25 mg once daily or matched placebo (trial cohort). The primary endpoint was development of confirmed microalbuminuria in all individuals with available data (observational cohort). Secondary endpoints included reduction in incidence of microalbuminuria with spironolactone (trial cohort, intention-to-treat population) and association between CKD273 risk score and measures of impaired renal function based on estimated glomerular filtration rate (eGFR; observational cohort). Adverse events (particularly gynaecomastia and hyperkalaemia) and serious adverse events were recorded for the intention-to-treat population (trial cohort). This study is registered with the EU Clinical Trials Register (EudraCT 20120-004523-4) and ClinicalTrials.gov (NCT02040441) and is completed. FINDINGS Between March 25, 2014, and Sept 30, 2018, we enrolled and followed-up 1775 participants (observational cohort), 1559 (88%) of 1775 participants had a low-risk urinary proteomic pattern and 216 (12%) had a high-risk pattern, of whom 209 were included in the trial cohort and assigned to spironolactone (n=102) or placebo (n=107). The overall median follow-up time was 2·51 years (IQR 2·0-3·0). Progression to microalbuminuria was seen in 61 (28%) of 216 high-risk participants and 139 (9%) of 1559 low-risk participants (hazard ratio [HR] 2·48, 95% CI 1·80-3·42; p<0·0001, after adjustment for baseline variables of age, sex, HbA1c, systolic blood pressure, retinopathy, urine albumin-to-creatinine ratio [UACR], and eGFR). Development of impaired renal function (eGFR <60 mL/min per 1·73 m2) was seen in 48 (26%) of 184 high-risk participants and 119 (8%) of 1423 low-risk participants (HR 3·50; 95% CI 2·50-4·90, after adjustment for baseline variables). A 30% decrease in eGFR from baseline (post-hoc endpoint) was seen in 42 (19%) of 216 high-risk participants and 62 (4%) of 1559 low-risk participants (HR 5·15, 95% CI 3·41-7·76; p<0·0001, after adjustment for basline eGFR and UACR). In the intention-to-treat trial cohort, development of microalbuminuria was seen in 35 (33%) of 107 in the placebo group and 26 (25%) of 102 in the spironolactone group (HR 0·81, 95% CI 0·49-1·34; p=0·41). In the safety analysis (intention-to-treat trial cohort), events of plasma potassium concentrations of more than 5·5 mmol/L were seen in 13 (13%) of 102 participants in the spironolactone group and four (4%) of 107 participants in the placebo group, and gynaecomastia was seen in three (3%) participants in the spironolactone group and none in the placebo group. One patient died in the placebo group due to a cardiac event (considered possibly related to study drug) and one patient died in the spironolactone group due to cancer, deemed unrelated to study drug. INTERPRETATION In people with type 2 diabetes and normoalbuminuria, a high-risk score from the urinary proteomic classifier CKD273 was associated with an increased risk of progression to microalbuminuria over a median of 2·5 years, independent of clinical characteristics. However, spironolactone did not prevent progression to microalbuminuria in high-risk patients. FUNDING European Union Seventh Framework Programme.
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Chronic kidney disease progression in patients with resistant hypertension subject to 2 therapeutic strategies: Intensification with loop diuretics vs aldosterone antagonists.
Verdalles, U, Goicoechea, M, García de Vinuesa, S, Torres, E, Hernández, A, Verde, E, Pérez de José, A, Luño, J
Nefrologia. 2020;(1):65-73
Abstract
INTRODUCTION Actualy, there are few data about glomerular filtration rate (eGFR) drop in patients with resistant hypertension and how diferent therapies can modify chronic kidney disease progression (CKD). OBJECTIVE To evaluate CKD progression in patients with resistant hypertension undergoing 2diferent therapies: treatment with spironolactone or furosemide. METHODS We included 30 patients (21M, 9W) with a mean age of 66.3±9.1 years, eGFR 55.8±16.5ml/min/1.73 m2, SBP 162.8±8.2 and DBP 90.2±6.2mmHg: 15 patients received spironolactone and 15 furosemide and we followed up them a median of 32 months (28-41). RESULTS The mean annual eGFR decrease was -2.8±5.4ml/min/1.73 m2. In spironolactone group was -2.1±4.8ml/min/1.73 m2 and in furosemide group was -3.2±5.6ml/min/1.73 m2, P<0.01. In patients received spironolactone, SBP decreased 23±9mmHg and in furosemide group decreased 16±3mmHg, P<.01. DBP decreased 10±8mmHg and 6±2mmHg, respectively (P<.01). Treatment with spironolactone reduced albuminuria from a serum albumin/creatine ratio of 210 (121-385) mg/g to 65 (45-120) mg/g at the end of follow-up, P<.01. There were no significant changes in the albumin/creatinine ratio in the furosemide group. The slower drop in kidney function was associated with lower SBP (P=.04), higher GFR (P=.01), lower albuminuria (P=.01), not diabetes mellitus (P=.01) and treatment with spironolactone (P=.02). Treatment with spironolactone (OR 2.13, IC 1.89-2.29) and lower albuminuria (OR 0.98, CI 0.97-0.99) maintain their independent predictive power in a multivariate model. CONCLUSION Treatment with spironolactone is more effective reducing BP and albuminuria in patients with resistant hypertension compared with furosemide and it is associated with a slower progression of CKD in the long term follow up.
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Spironolactone use and higher hospital readmission for Medicare beneficiaries with heart failure, left ventricular ejection fraction <45%, and estimated glomerular filtration rate <45 ml/min/1.73 m(2.).
Inampudi, C, Parvataneni, S, Morgan, CJ, Deedwania, P, Fonarow, GC, Sanders, PW, Prabhu, SD, Butler, J, Forman, DE, Aronow, WS, et al
The American journal of cardiology. 2014;(1):79-82
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Abstract
Although randomized controlled trials have demonstrated benefits of aldosterone antagonists for patients with heart failure and reduced ejection fraction (HFrEF), they excluded patients with serum creatinine >2.5 mg/dl, and their use is contraindicated in those with advanced chronic kidney disease (CKD). In the present analysis, we examined the association of spironolactone use with readmission in hospitalized Medicare beneficiaries with HFrEF and advanced CKD. Of the 1,140 patients with HFrEF (EF <45%) and advanced CKD (estimated glomerular filtration rate [eGFR] <45 ml/min/1.73 m(2)), 207 received discharge prescriptions for spironolactone. Using propensity scores (PSs) for the receipt of discharge prescriptions for spironolactone, we estimated PS-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for spironolactone-associated outcomes. Patients (mean age 76 years, 49% women, 25% African-American) had mean EF 28%, mean eGFR 31 ml/min/1.73 m(2), and mean potassium 4.5 mEq/L. Spironolactone use had significant PS-adjusted association with higher risk of 30-day (HR 1.41, 95% CI 1.04 to 1.90) and 1-year (HR 1.36, 95% CI 1.13 to 1.63) all-cause readmissions. The risk of 1-year all-cause readmission was higher among 106 patients with eGFR <15 ml/min/1.73 m(2) (HR 4.75, 95% CI 1.84 to 12.28) than among those with eGFR 15 to 45 ml/min/1.73 m(2) (HR 1.34, 95% CI 1.11 to 1.61, p for interaction 0.003). Spironolactone use had no association with HF readmission and all-cause mortality. In conclusion, among hospitalized patients with HFrEF and advanced CKD, spironolactone use was associated with higher all-cause readmission but had no association with all-cause mortality or HF readmission.