Expression of TGF-β and fibrogenic genes in transplant recipients with tacrolimus and cyclosporine nephrotoxicity

Khanna, Ashwani; Plummer, Matthew; Bromberek, Cathy; Bresnahan, Barbara A.; Hariharan, Sundaram

doi:10.1046/j.1523-1755.2002.00668.x

Cited by 134 publications

(98 citation statements)

References 32 publications

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“…Although the present results are directed at an understanding of cyclosporine nephrotoxicity, our previous studies 15,[25][26][27][28][29] also demonstrate that TGF-␤ participates in both the immunosuppressive and nephrotoxic effects of tacrolimus and sirolimus. It is not known whether adjunctive therapy with a TGF-␤-neutralizing agent would also reduce the nephrotoxic effects of these 2 immunosuppressants.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, by in vitro, in vivo, and clinical studies, we have demonstrated induction of TGF-␤ with other immunosuppressive agents such as tacrolimus and sirolimus. [25][26][27][28][29] Therefore, it is attractive to hypothesize that anti-TGF-␤ antibody may provide similar benefits to counteract adverse nephrotoxic effects observed with long-term use of these drugs as well.…”

Section: Discussionmentioning

confidence: 99%

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Anti–Transforming Growth Factor Antibody at Low but Not High Doses Limits Cyclosporine-Mediated Nephrotoxicity Without Altering Rat Cardiac Allograft Survival

et al. 2004

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Background-Long-term treatment of cardiac transplant recipients with cyclosporine results in a progressive decline in kidney function in a large number of patients. This complication is one of the most important prognostic parameters that determine the outcome of cardiac transplantation. Transforming growth factor-␤ (TGF-␤) is one of the most potent mediators of the fibrogenic effects of cyclosporine. Methods and Results-With the use of an experimental rodent model, heterotopic heart transplantation was performed, creating histocompatibility-disparate allografts. Because TGF-␤ in part mediates both the immunosuppressive and nephrotoxic effects of cyclosporine, recipients were treated with cyclosporine with and without anti-TGF-␤ antibody to determine whether anti-TGF-␤ antibody could reduce the nephrotoxic effects of cyclosporine. Intrarenal expression of TGF-␤, collagen, fibronectin, matrix metalloproteinase-2, and tissue inhibitor of metalloproteinase-2 was studied with the use of reverse transcription-polymerase chain reaction. Intrarenal expression of TGF-␤ protein was studied by immunohistochemistry and with the use of ELISA to quantify circulating levels of TGF-␤ protein in plasma. Cyclosporine-induced graft survival (immunosuppressive effect) was abrogated with a higher concentration (2.5 mg/kg) of anti-TGF-␤ antibody, whereas a lower concentration (1 mg/kg) inhibited both cyclosporine-induced expression of fibrogenic molecules and renal toxicity. Conclusions-These results provide credence to the pivotal role of TGF-␤ in immunosuppression-associated renal toxicity in recipients of cardiac transplantation. Furthermore, these findings support a potentially significant therapeutic use of optimal concentration of anti-TGF-␤ antibody to ameliorate cyclosporine-associated nephrotoxicity in cardiac transplant recipients.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Anti–Transforming Growth Factor Antibody at Low but Not High Doses Limits Cyclosporine-Mediated Nephrotoxicity Without Altering Rat Cardiac Allograft Survival

et al. 2004

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“…A possible explanation is the profibrotic property of calcineurin inhibitors (CNIs). Cyclosporin and especially tacrolimus have been shown to upregulate transforming growth factor β in transplanted patients (38). Transforming growth factor β is thought to be of major importance in the development of peritoneal fibrosis (39).…”

Section: Discussionmentioning

confidence: 99%

Risk Factors Associated with Encapsulating Peritoneal Sclerosis in Dutch Eps Study

et al. 2011

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ORIGINAL ARTICLES♦ Objective: Encapsulating peritoneal sclerosis (EPS) is a serious complication of peritoneal dialysis (PD) with a multifactorial pathophysiology and possible increasing incidence. The aim of the present study was to evaluate the independent associations of PD duration, age, dialysis fluids, and kidney transplantation with EPS. ♦ Methods: A multicenter case-control study was performed in the Netherlands from 1 January 1996 until 1 July 2007. The population comprised 63 patients with EPS and 126 control patients. Control patients were selected from the national registry and were matched for date of PD start. Associations were analyzed using a log linear regression model. Primary outcome was appearance of EPS. ♦ Results: Compared with control patients, patients with EPS were younger at the start of PD (34.7 ± 15.4 years vs. 51.5 ± 14.7 years, p < 0.0001). The cumulative period on PD was longer in EPS patients than in control patients (78.7 ± 37.8 months vs. 32.8 ± 24 months, p < 0.0001), and the cumulative period on icodextrin was also longer in EPS patients (32.7 ± 23.3 months vs. 18.1 ± 15.7 months, p = 0.006). Compared with control patients, more EPS patients underwent kidney transplantation (47 vs. 59, p < 0.0001). With regard to the period after transplantation, the yearly probability of EPS increased in the year after transplantation to 7.5% from 1.75%. In multivariate regression analysis, cumulative PD duration, age at PD start, transplantation, time from last transplantation to EPS, calendar time, time on icodextrin, and ultrafiltration failure were independently associated with EPS. Transfer from PD to hemodialysis for reasons other than suspected EPS could not be identified as a risk factor for EPS. ♦ Conclusions: Duration of PD, age at PD start, kidney transplantation, time since last transplantation, ultrafiltration failure, and time on icodextrin were associated with a higher risk of EPS. Perit Dial Int

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“…Implicated fibrogenic cytokines include TGF-␤, matrix metalloproteinase-9, and PDGF. [41][42][43] Other investigators have focused on the pathogenic role of dysregulation of the RAAS. For example, CsA has been shown to increase transcription of angiotensin II receptors.…”

Section: Chronic Nephrotoxicitymentioning

confidence: 99%

Chronic Kidney Disease after Nonrenal Solid-Organ Transplantation

Bloom

Reese

2007

Journal of the American Society of Nephrology

163

138

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Expression of TGF-β and fibrogenic genes in transplant recipients with tacrolimus and cyclosporine nephrotoxicity

Abstract: This study compares the intrarenal expression of TGF-beta and profibrogenic genes in renal transplant recipients treated with Tac and CsA. The results show that patients diagnosed with Tac nephrotoxicity exhibit increased expression of profibrogenic genes compared to CsA nephrotoxicity.

Cited by 134 publications

References 32 publications

Anti–Transforming Growth Factor Antibody at Low but Not High Doses Limits Cyclosporine-Mediated Nephrotoxicity Without Altering Rat Cardiac Allograft Survival

Anti–Transforming Growth Factor Antibody at Low but Not High Doses Limits Cyclosporine-Mediated Nephrotoxicity Without Altering Rat Cardiac Allograft Survival

Risk Factors Associated with Encapsulating Peritoneal Sclerosis in Dutch Eps Study

Chronic Kidney Disease after Nonrenal Solid-Organ Transplantation

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