Spironolactone Ameliorates Focal Glomerulosclerosis and Transplant Arteriopathy in Experimental Chronic Allograft Nephropathy in Rats (original) (raw)
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Spironolactone ameliorates transplant vasculopathy in renal chronic transplant dysfunction in rats
AJP: Renal Physiology, 2009
Chronic transplant dysfunction (CTD) is the leading cause of long-term renal allograft loss and is characterized by specific histological lesions including transplant vasculopathy, interstitial fibrosis, and focal glomerulosclerosis. Increasing evidence indicates that aldosterone is a direct mediator of renal damage via the mineralocorticoid receptor (MR). The MR antagonist spironolactone is renoprotective in native chronic kidney disease, but its effects on CTD are unknown. We studied the effects of spironolactone treatment on CTD development in the Dark Agouti-to-Wistar-Furth renal allograft transplant model, by treatment with 20 mg/kg spironolactone or vehicle daily by oral gavage from 2 days before transplantation (donors and recipients) throughout the experiment (12 wk, recipients). Dark Agouti-to-Dark Agouti isografts served as negative controls. Spironolactone significantly ameliorated the development of transplant vasculopathy in allografts by reducing the number of affected...
Spironolactone prevents chronic kidney disease caused by ischemic acute kidney injury
Kidney International, 2013
Acute kidney injury (AKI) has been recognized as a risk factor for the development of chronic kidney disease (CKD). Aldosterone has a critical role in promoting renal injury induced by ischemia. Here, we evaluated whether spironolactone administered before or after AKI caused by ischemia protects against CKD. In the first set of experiments, Wistar rats underwent a sham operation without or with prior spironolactone treatment, or underwent 45 minutes of bilateral renal ischemia without or with spironolactone treatment before ischemia and assessed over 270 days. The second set of rats received low (20 mg/kg) or high (80 mg/kg) doses of spironolactone at three different times after the sham operation or bilateral renal ischemia and were assessed after 90 days. Untreated animals developed CKD following ischemia-induced AKI as characterized by a progressive increase in proteinuria, renal dysfunction, podocyte injury, glomerular hypertrophy, and focal sclerosis. This was associated with increased oxidative stress, an upregulation of tumor growth factor (TGF)-b, followed by upregulation of the TGF-b downstream effectors phospho-Smad3, collagen I, fibronectin, and proinflammatory cytokines. Treatment with spironolactone either before or after ischemia prevented subsequent CKD by avoiding the activation of fibrotic and inflammatory pathways. Thus, spironolactone may be a promising treatment for the prevention of AKI-induced CKD.
BMC Nephrology
Background: Calcineurin inhibitor induced nephrotoxicity contributes to late allograft failure in kidney transplant patients. Evidence points towards aldosterone to play a role in the development of fibrosis in multiple organs. Animal studies have indicated a beneficial effect of mineralocorticoid receptor antagonists preventing calcineurin inhibitor induced nephrotoxicity. Only few studies have explored this effect in humans. The objective of this study is to evaluate the effect of spironolactone on glomerular filtration rate and fibrosis in kidney transplant patients. Method: Prospective, double-blind, randomized, clinical trial including 170 prevalent kidney transplant patients. Patients are randomized to spironolactone 25-50 mg/day or placebo for three years. Primary outcome is glomerular filtration rate evaluated by chrome-EDTA clearance. Secondary outcomes are 24-h protein excretion, amount of interstitial fibrosis in renal allograft biopsies, and cardiovascular events. As an exploratory outcome, we aim to identify markers of fibrosis in blood and urine. Discussion: Long term allograft survival remains a key issue in renal transplantation, partly due to calcineurin inhibitor induced nephrotoxicity. Evidence from animal-and small human studies indicate a beneficial effect of mineralocorticoid receptor antagonism on renal function and fibrosis. This study aims to test this hypothesis in a sufficiently powered randomized clinical trial. Results might influence the future management of long term allograft survival in renal transplantation.
Effects of Spironolactone in an Experimental Model of Chronic Cyclosporine Nephrotoxicity
Transplantation Proceedings, 2008
Background. Cyclosporine (CsA)-associated nephrotoxicity is a long-term complication in transplant patients. Chronic CsA nephrotoxicity is associated with renal fibrosis and hyaline arteriolopathy. The aim of this study was to investigate the effect of spironolactone on functional and structural alterations as well as on platelet-derived growth factor B (PDGF-B) and transforming growth factor (TGF)  expression induced by CsA in a rat model of chronic CsA nephrotoxicity. Materials and Methods. Twenty-four rats were divided into 3 groups. Group 1 (G1) received vehicle only (V); G2, CsA (15 mg/kg/d; CsA) by intraperitoneal (IP) injection; and G3, a similar CsA dosage ϩ spironolactone (20 mg/kg/d; CsA ϩ Ald.) by the oral route. At the end of 28 days, glomerular filtration rate (GFR) and blood CsA levels were measured as well as histopathological and immunohistochemical analyses performed on renal tissue. Results. Mean CsA trough levels in G2 and G3 were both above 2000 ng/mL. In G2, GFR was lower than G1 and G3 (0.35 Ϯ 0.05, 1.64 Ϯ 0.24, and 1.20 Ϯ 0.25 mL/min, respectively; P Ͻ .001). There was a significantly increased number of arteriolopathic changes in G2 and G3 vs G1 (16% Ϯ 3.7%, 15% Ϯ 6.8%, 3% Ϯ 1.2%, respectively; P Ͻ .001). Interstitial fibrosis was significantly increased in G2 vs G1 and G3 (52%, 0%, 27%, respectively; P Ͻ .05). Marked by up-regulated PDGF-B and TGF  expressions were observed in G2 vs G1 or G3: 100%, 0%, 37.5%, respectively, for PDGF-B (P Ͻ .001) and 87.5%, 0%, 12.5%, respectively, for TGF  (P Ͻ .001). Conclusion. Our results suggested that chronic CsA nephrotoxicity may be mitigated by aldosterone receptor blockade which seemed to be associated with down-regulation of PDGF-B and TGF  expression.
Experimental and therapeutic medicine, 2013
The aim of the present study was to observe the effects of spironolactone on urine protein level and kidney function in patients with chronic glomerular disease receiving angiotensin-converting enzyme inhibitors (ACEIs) and/or angiotensin II receptor blockers (ARBs). A total of 221 patients with chronic glomerular disease were divided into spironolactone and control groups. The spironolactone group was treated with spironolactone at a dose of 20 mg/day, in addition to the original treatment regime and doses of ACEIs and/or ARBs. The control group continuously received the original doses of ACEIs and/or ARBs alone. Twenty-four-hour urine protein levels, serum creatinine and potassium, plasma aldosterone (ALD) and blood pressure were monitored at 0, 4, 8, 12 and 16 weeks. The estimated glomerular filtration rates (eGFRs) were calculated based on the obtained serum creatinine results. Following treatment, the urine protein level in the spironolactone group was notably decreased compare...
American Journal of Physiology-Renal Physiology, 2019
Mineralocorticoid receptor antagonism prevents acute kidney injury induced by ischemia/reperfusion in rodent and pig preclinical models. In a pilot study, we showed that spironolactone (25 mg) reduced oxidative stress after 5 days of kidney transplant (KT). In this study, we investigated the effects of higher doses (50 and 100 mg) of spironolactone on kidney function, tubular injury markers and oxidative stress in living-donor KT recipients. We included KT recipients aged 18 years or older, who received immunosuppression therapy with interleukin-2 receptor antagonist, mycophenolate mofetil, corticosteroids and tacrolimus, with negative cross-match, and compatible blood group. Patients were randomized to receive placebo (n=27), spironolactone 50 mg (n=25) or spironolactone 100 mg (n=25). Treatment was given from three days before and up to 5 days after kidney transplant. Serum creatinine, potassium, urine neutrophil gelatinase associated lipocalin-2 (NGAL), heat shock protein 72 (Hsp...