Losartan decreases plasma levels of TGF-β1 in transplant patients with chronic allograft nephropathy

Campistol, Josep M.; Íñigo, Pablo; Jiménez, Wladimiro; Lario, Sergio; Clesca, Paul; Oppenheimer, Federico; Rivera, Francisca

doi:10.1046/j.1523-1755.1999.00597.x

Cited by 142 publications

(79 citation statements)

References 27 publications

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“…For instance, Campistol et al 32 have reported that the circulating levels of TGF-␤ 1 decreased progressively and significantly in 14 transplant patients with chronic allograft nephropathy treated with losartan (50 mg) for 8 weeks. Since data exist that angiotensin II regulates the production of TGF-␤ 1 at different levels, 8,33 it is likely that the mechanism by which losartan decreases serum levels of this factor is through interrupting the interaction of the octapeptide with AT 1 receptors.…”

Section: Discussionmentioning

confidence: 99%

Transforming Growth Factor β in Hypertensives With Cardiorenal Damage

2000

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Abstract-We investigated whether a relationship exists between circulating transforming growth factor ␤ -1 (TGF-␤ 1 ), collagen type I metabolism, microalbuminuria, and left ventricular hypertrophy in essential hypertension and whether the ability of the angiotensin II type 1 receptor antagonist losartan to correct microalbuminuria and regress left ventricular hypertrophy in hypertensives is related to changes in TGF-␤ 1 and collagen type I metabolism. The study was performed in 30 normotensive healthy controls and 30 patients with never-treated essential hypertension classified into 2 groups: those with microalbuminuria (urinary albumin excretion Ͼ30 and Ͻ300 mg/24 h) associated with left ventricular hypertrophy (left ventricular mass index Ͼ116 g/m 2 for men and Ͼ104 g/m 2 for women) (group B; nϭ17) and those without microalbuminuria or left ventricular hypertrophy (group A; nϭ13). The measurements were repeated in all patients after 6 months of treatment with losartan (50 mg once daily). The serum concentration of TGF-␤ 1 was measured by a 2-site ELISA method, and the serum concentrations of carboxy-terminal propeptide of procollagen type I (a marker of collagen type I synthesis) and carboxy-terminal telopeptide of collagen type I (a marker of collagen type I degradation) were measured by specific radioimmunoassays. The duration of hypertension and baseline values of blood pressure were similar in the 2 groups of patients. No differences in serum TGF-␤ 1 , carboxy-terminal propeptide of procollagen type I, and carboxy-terminal telopeptide of collagen type I were found between normotensives and group A of hypertensives. Serum TGF-␤ 1 , carboxy-terminal propeptide of procollagen type I, and the ratio of carboxy-terminal propeptide of procollagen type I to carboxy-terminal telopeptide of collagen type I were increased (PϽ0.05) in group B of hypertensives compared with group A of hypertensives and normotensives. No differences in carboxy-terminal telopeptide of collagen type I were found among the 3 groups of subjects. After treatment with losartan, microalbuminuria and left ventricular hypertrophy persisted in 6 patients (then considered nonresponders) and disappeared in 11 patients (then considered responders) from group B. Compared with nonresponders, responders exhibited similar control of blood pressure and higher (PϽ0.05) blockade of angiotensin II type 1 receptors (as assessed by a higher increase in plasma levels of angiotensin II). Whereas TGF-␤ 1 , carboxy-terminal propeptide of procollagen type I, and the ratio of carboxy-terminal propeptide of procollagen type I to carboxy-terminal telopeptide of collagen type I decreased (PϽ0.05) in responders, no changes in these parameters were observed in nonresponders. These findings show that an association exists between an excess of TGF-␤ 1 , stimulation of collagen type I synthesis, inhibition of collagen type I degradation, and cardiorenal damage in a group of patients with essential hypertension. In addition, our results suggest that the ability of losartan...

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Section: Discussionmentioning

confidence: 99%

Transforming Growth Factor β in Hypertensives With Cardiorenal Damage

2000

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“…Also, in humans, ACE inhibition reduced CNI nephrotoxicity associated with cyclosporine use (360) and improved alterations of the cardiovascular system generally observed in renal transplant patients (361). Again in humans, the ARB losartan was shown to significantly decrease the plasma levels of TGF-␤ and endothelin (362,363). Creatinine clearance, however, tended to be lower with the addition of losartan, likely through the hemodynamic effects of angiotensin II receptor blockade (362,363).…”

Section: Other Approachesmentioning

confidence: 99%

“…Again in humans, the ARB losartan was shown to significantly decrease the plasma levels of TGF-␤ and endothelin (362,363). Creatinine clearance, however, tended to be lower with the addition of losartan, likely through the hemodynamic effects of angiotensin II receptor blockade (362,363). It is, therefore, not clear whether cotreatment with ARBs is able to slow the progression of CNI nephrotoxicity in a human setting.…”

Section: Other Approachesmentioning

confidence: 99%

Calcineurin Inhibitor Nephrotoxicity

Naesens

Kuypers²,

Sarwal³

2009

Clinical Journal of the American Society of Nephrology

1,216

1,000

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The use of the calcineurin inhibitors cyclosporine and tacrolimus led to major advances in the field of transplantation, with excellent short-term outcome. However, the chronic nephrotoxicity of these drugs is the Achilles' heel of current immunosuppressive regimens. In this review, the authors summarize the clinical features and histologic appearance of both acute and chronic calcineurin inhibitor nephrotoxicity in renal and nonrenal transplantation, together with the pitfalls in its diagnosis. The authors also review the available literature on the physiologic and molecular mechanisms underlying acute and chronic calcineurin inhibitor nephrotoxicity, and demonstrate that its development is related to both reversible alterations and irreversible damage to all compartments of the kidneys, including glomeruli, arterioles, and tubulo-interstitium. The main question-whether nephrotoxicity is secondary to the actions of cyclosporine and tacrolimus on the calcineurin-NFAT pathway-remains largely unanswered. The authors critically review the current evidence relating systemic blood levels of cyclosporine and tacrolimus to calcineurin inhibitor nephrotoxicity, and summarize the data suggesting that local exposure to cyclosporine or tacrolimus could be more important than systemic exposure. Finally, other local susceptibility factors for calcineurin inhibitor nephrotoxicity are reviewed, including variability in P-glycoprotein and CYP3A4/5 expression or activity, older kidney age, salt depletion, the use of nonsteroidal anti-inflammatory drugs, and genetic polymorphisms in genes like TGF-␤ and ACE. Better insight into the mechanisms underlying calcineurin inhibitor nephrotoxicity might pave the way toward more targeted therapy or prevention of calcineurin inhibitor nephrotoxicity.Clin J Am Soc Nephrol 4: 481-508, 2009. doi: 10.2215/CJN.04800908 T he introduction of the calcineurin inhibitor (CNI) cyclosporine in human kidney transplantation in the late 1970s revolutionized transplantation medicine, and made transplantation a preferable therapeutic intervention for end-stage renal diseases (1,2). In 1984, the potent immunosuppressive properties of another CNI, tacrolimus, were discovered, and tacrolimus was used successfully in human liver, kidney, and heart allograft recipients (3,4). Currently, 94% of kidney transplant recipients are discharged after transplantation with a CNI-based immunosuppressive regimen (5).The immunosuppressive properties of cyclosporine and tacrolimus result from inhibition of calcineurin, a calcium-and calmodulin-dependent phosphatase (protein phosphatase 3 [PPP3C], formerly PP2B). Intracellularly, these completely different molecules bind to cyclophylin and FKBP12 for cyclosporine and tacrolimus, respectively (6 -9). The competitive binding of cyclosporine-cyclophylin and tacrolimus-FKBP12 complexes to calcineurin inhibits phosphatase activity of calcineurin. This inhibition then suppresses the transcription of IL-2 via inhibition of the dephosphorylation and impaired translocation of the nucl...

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“…Beneficial effects of calcium antagonists on preservation of plasma flow and glomerular filtration rate in transplanted kidneys were demonstrated for nitredipine, lacidipine 121,122 and nifedipine 123 . In a single study, inhibition of RAS by ACE inhibitors has limited development of cyclosporine nephrotoxicity 124 and administration of angiotensin II blockers led to a significant reduction in plasma levels of TGF-β and endothelin 125,126 . In an experiment, application of spironolactone eliminated many of the RAS-and aldosterone-induced effects occurring during CI therapy 11 ; studies confirming these finding in humans are however not available.…”

Section: Alternative Optionsmentioning

confidence: 99%

Calcineurin Inhibitor-Induced Renal Allograft Nephrotoxicity

Krejčí¹,

Tichý²,

Bachleda³

et al. 2010

BIOMED PAP

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Background. The introduction of the calcineurin inhibitors (CI) cyclosporine and tacrolimus into immunosuppressive protocols initiated a new era in organ transplantation with excellent short-term graft survival. Nevertheless, the chronic nephrotoxicity of these drugs represents a significant adverse factor limiting their long-term use. Patients treated with a CI can be at risk for developing renal failure and this problem is especially pronounced in patients after renal transplantation.Methods and Results. In a review paper we summarize the clinical aspects, histological manifestations and pitfalls of diagnostics of acute and chronic CI nephrotoxicity in patients after kidney transplantation. We look in detail at the disputed relationship between blood concentrations of cyclosporine and tacrolimus and histological manifestation of toxicity and summarize data showing that for toxic effects, local renal exposure to CI and their metabolites can play a more significant role than systemic exposure. We also include recent views on the pathophysiologic and molecular mechanisms underlying these changes; factors influencing local susceptibility to CI nephrotoxicity are discussed, including variability of expression and activity of P-glycoprotein and cytochrome P450. Last but not least we summarize our own experience with clinically manifest and subclinical forms of nephrotoxicity and their impact on the progression of chronic graft changes.Conclusions. Owing to their unique effects, CI remain the cornerstone of most immunosuppressive protocols for renal transplantation. Together with optimization of local kidney exposure to CI and their metabolites, efforts to reduce systemic levels as much as possible are the most important preventive measure for reducing toxic renal graft damage.

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Losartan decreases plasma levels of TGF-β1 in transplant patients with chronic allograft nephropathy

Cited by 142 publications

References 27 publications

Transforming Growth Factor β in Hypertensives With Cardiorenal Damage

Transforming Growth Factor β in Hypertensives With Cardiorenal Damage

Calcineurin Inhibitor Nephrotoxicity

Calcineurin Inhibitor-Induced Renal Allograft Nephrotoxicity

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