Mineralocorticoid receptor blockade confers renoprotection in preexisting chronic cyclosporine nephrotoxicity

Pérez‐Rojas, Jazmin M.; Blanco, José; Cruz, Cristino; Trujillo, Joyce; Vaidya, Vishal S.; Uribe, Norma; Bonventre, Joseph V.; Gamba, Gerardo; Bobadilla, Norma A.

doi:10.1152/ajprenal.00147.2006

Cited by 99 publications

(93 citation statements)

References 49 publications

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“…Some strategies, like antifibrotic agents, were able to improve renal structural damage but had no beneficial effect on renal function. In contrast, strategies such as L-arginine (5,57) and spironolactone (20,43,44), which improved renal function probably due to an effect on vascular resistances, had an additional beneficial effect on structural injury, suggesting that the increase in vascular resistances, with consequent renal ischemia, seems to be a major pathophysiological mechanism involved in the development of structural injury. In this regard, we propose that aldosterone plays a central role in the establishment of renal dysfunction and structural injury observed in chronic CsA nephrotoxicity (Fig.…”

Section: A New Scheme Of Csa-induced Nephrotoxicitymentioning

confidence: 97%

“…Thus our findings in acute and chronic models of CsA nephrotoxicity indicated that spironolactone is an effective prophylactic agent to prevent the development of CsA nephrotoxicity. Finally, Perez-Rojas et al (43) analyzed whether spironolactone blockade can contribute to prevent the progression of existing tubulointerstitial injury and renal dysfunction in the model of chronic CsA nephropathy. As shown in Fig.…”

Section: Role Of Aldosterone In Csa Nephrotoxicitymentioning

confidence: 99%

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New insights into the pathophysiology of cyclosporine nephrotoxicity: a role of aldosterone

Bobadilla¹,

Gamba²

2007

American Journal of Physiology-Renal Physiology

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117

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Cyclosporine A (CsA), a calcineurin inhibitor, has improved allograft survival in solid organ transplantation and has been increasingly applied in the management of autoimmune diseases. While marked progress has been made in patient and allograft survival rates, clinical use of CsA is often limited by its nephrotoxic effect, which can be presented as two distinct and well-characterized forms: acute and chronic nephrotoxicity. The acute form is characterized by renal vasoconstriction, induced by an imbalance of vasoactive substances release, which leads to renal dysfunction. This form is reversible. The chronic toxicity, in contrast, is characterized by the vasoconstriction plus the development of structural damage that includes arteriolopathy and tubulointerstitial fibrosis that are often not reversible. The exact mechanisms of these deleterious effects are not fully understood, but major advances have occurred over the last few years. Here we review the current literature regarding the pathogenesis and strategies that have been used to ameliorate renal injury in chronic CsA nephrotoxicity. Recent observations suggest that aldosterone plays a central role in the pathogenesis of CsA nephrotoxicity and that spironolactone could be a useful agent to prevent it. These studies and the use of mineralocorticoid receptor blockade are discussed.

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Section: A New Scheme Of Csa-induced Nephrotoxicitymentioning

confidence: 97%

Section: Role Of Aldosterone In Csa Nephrotoxicitymentioning

confidence: 99%

New insights into the pathophysiology of cyclosporine nephrotoxicity: a role of aldosterone

Bobadilla¹,

Gamba²

2007

American Journal of Physiology-Renal Physiology

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117

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“…The validation studies showed a significant correlation (92%) between the ELISA and microbead-based assay. This assay has been used to determine urinary levels of Kim-1 in several recent studies using rat models (de Borst et al, 2007;Perez-Rojas et al, 2007;van Timmeren et al, 2006). …”

mentioning

confidence: 99%

Comparison of Kidney Injury Molecule-1 and Other Nephrotoxicity Biomarkers in Urine and Kidney Following Acute Exposure to Gentamicin, Mercury, and Chromium

Zhou

Vaidya

Brown

et al. 2007

Toxicological Sciences

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263

159

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Sensitive biomarkers are needed to detect kidney injury at the earliest stages. The objective of this study was to determine whether the appearance of kidney injury molecule-1 (Kim-1) protein ectodomain in urine and kidney injury molecule-1/hepatitis A viral cellular receptor-1 (Kim-1/ Havcr1) gene expression in kidney tissue may be more predictive of renal injury after exposure to nephrotoxicants when compared to traditionally used biomarkers. Male Sprague-Dawley rats were injected with a range of doses of gentamicin, mercury (Hg; HgCl 2 ), or chromium (Cr; K 2 Cr 2 O 7 ). The results showed that increases in urinary Kim-1 and kidney Kim-1/Havcr1 gene expression paralleled the degree of severity of renal histopathology and were detected at lower doses of nephrotoxicants when compared to blood urea nitrogen (BUN), serum creatinine, and urinary Nacetyl-β-D-glucosaminidase (NAG). In a time course study, urinary Kim-1 was elevated within 24 h after exposure to gentamicin (100 mg/kg), Hg (0.25 mg/kg), or Cr (5 mg/kg) and remained elevated through 72 h. NAG responses were nephrotoxicant dependent with elevations occurring early (gentamicin), late (Cr), or no change (Hg). At 72 h, after treatment with any of the three nephrotoxicants, there was increased Kim-1 immunoreactivity and necrosis involving ∼50% of the proximal tubules; however, only urinary Kim-1 was significantly increased, while BUN, serum creatinine, and NAG were not different from controls. In rats treated with the hepatotoxicant galactosamine (1.1 mg/kg), serum alanine aminotransferase was increased, but no increase in urinary Kim-1 was observed. Urinary Kim-1 and kidney Kim-1/Havcr1 expression appear to be sensitive and tissue-specific biomarkers that will improve detection of early acute kidney injury following exposure to nephrotoxic chemicals and drugs. Keywordsacute kidney injury; nephrotoxicity biomarkers; kidney injury molecule-1; mercury; chromium; gentamicin 1To whom correspondence should be addressed at Center for Devices and Radiological Health, U.S. Food and Drug Administration, White Oak Life Sciences Laboratory, WO64-4064, 10903 New Hampshire Avenue, Silver Spring, MD 20993-0002. Fax: 301-796-9826. E-mail: peter.goering@fda.hhs.gov.. NIH Public Access NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptRenal insufficiency, in some form, has been reported to occur in ∼11% of the U.S. population (Nally, 2002). Acute kidney injury (AKI) or acute renal failure (ARF) occurs in 2-5% of patients admitted to general hospitals in the United States, and AKI is associated with a high rate (up to 50%) of mortality (Chertow et al., 2005;Nally, 2002). The annual health care expenditures attributable to hospital-acquired AKI based on conservative assumptions are estimated to exceed $10 billion (Chertow et al., 2005). Patients with subclinical renal injury may be more sensitive to AKI following exposure to potentially nephrotoxic drugs and/or compounds released unintentionally from medical device materials (e.g., residues, le...

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“…The renoprotective effects of spironolactone or epleronone had been seen in many other animal models of renal injury not limited to diabetic nephropathy, as noted in a recent review by Nishiyama et al (46) These models included streptozotocin-induced and other forms of diabetic rats and mice, obese SHR rats, murine lupus nephritis, unilateral ureteral obstruction, ischemia reperfusion injury, 5/6 th nephrectomised rats and rats treated with AngII infusion, NO synthase inhibitor or cyclosporine (53)(54)(55)(56)(57)(58)(59)(60)(61)(62)(63)(64)(65)(66). In these animal models, treatment with aldosterone blockers had no effect on systemic blood pressure.…”

Section: Aldosterone Biology and Lessons Learnt From Animal Modelsmentioning

confidence: 95%

Diabetic Nephropathy: Role of Aldosterone and Benefits of Therapy with Aldosterone Receptor Blocker

Yap¹,

Saklayen²

2012

Diabetic Nephropathy

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Mineralocorticoid receptor blockade confers renoprotection in preexisting chronic cyclosporine nephrotoxicity

Cited by 99 publications

References 49 publications

New insights into the pathophysiology of cyclosporine nephrotoxicity: a role of aldosterone

New insights into the pathophysiology of cyclosporine nephrotoxicity: a role of aldosterone

Comparison of Kidney Injury Molecule-1 and Other Nephrotoxicity Biomarkers in Urine and Kidney Following Acute Exposure to Gentamicin, Mercury, and Chromium

Diabetic Nephropathy: Role of Aldosterone and Benefits of Therapy with Aldosterone Receptor Blocker

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