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Uwe Heemann - One of the best experts on this subject based on the ideXlab platform.
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Conversion to sirolimus of patients with Chronic Allograft Nephropathy—a retrospective analysis of outcome and influencing factors
Langenbeck's archives of surgery, 2008Co-Authors: Oliver Witzke, Ondřej Viklický, Stefan Vitko, Jens Lutz, Tobias R. Türk, Benjamin Wilde, Isabel Willenberg, Uwe HeemannAbstract:Purpose The purpose of this study was to analyse the outcome and its influencing factors in patients whose therapy was converted from calcineurin inhibitors (CNI) to sirolimus (SRL) due to Chronic Allograft Nephropathy (CAN).
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Protective effects of FTY720 on Chronic Allograft Nephropathy by reducing late lymphocytic infiltration
Kidney international, 2004Co-Authors: Minghui Wang, Shanying Liu, Erwei Song, Jens Lutz, Nengtai Ouyang, Uwe HeemannAbstract:Protective effects of FTY720 on Chronic Allograft Nephropathy by reducing late lymphocytic infiltration. Background Lymphocytic infiltration is obvious throughout early and late stages of Chronic Allograft Nephropathy. Early infiltrating lymphocytes are involved in initial insults to kidney Allografts, but the contribution of late infiltration to long-term Allograft attrition is still controversial. Early application of FTY720 reduced the number of graft infiltrating lymphocytes, and inhibited acute rejection. The present study investigated the potential of FTY720 to reduce the number of infiltrating lymphocytes even at a late stage, and, thus, slow the pace of Chronic Allograft Nephropathy. Methods Fisher (F344) rat kidneys were orthotopically transplanted into Lewis recipients with an initial 10-day course of cyclosporine A (1.5 mg/kg/day). FTY720, at a dose of 0.5 mg/kg/day, or vehicle was administered to recipients either from weeks 12 to 24 or from 20 to 24 after transplantation. Animals were harvested 24 weeks after transplantation for histologic, immunohistologic, and molecular analysis. Results FTY720, either initiated at 12 or 20 weeks after transplantation, reduced urinary protein excretion, and significantly ameliorated glomerulosclerosis, interstitial fibrosis, tubular atrophy, and intimal proliferation of graft arteries at 24 weeks after transplantation. Furthermore FTY720 markedly suppressed lymphocyte infiltration and decreased mRNA levels of interleukin-10 (IL-10), transforming growth factor-β (TGF-β), and platelet-derived growth factor-B (PDGF-B) but enhanced the number of apoptotic cells in grafts. Conclusions FTY720 ameliorated Chronic Allograft Nephropathy even at advanced stages. Furthermore, our data suggest that this effect was achieved by a reduction of graft infiltrating lymphocytes.
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Apoptosis and treatment of Chronic Allograft Nephropathy with everolimus.
Transplantation, 2003Co-Authors: Jens Lutz, Balazs Antus, Shanying Liu, Hequn Zou, Uwe HeemannAbstract:Background. Chronic Allograft Nephropathy (CAN) is responsible for most cases of late kidney Allograft loss. However, no effective treatment is available so far. Everolimus (RAD) (40-O [2-hydroxyethyl] rapamycin) is a new immunosuppressive agent with antiproliferative and apoptosis-enhancing effects. We asked whether everolimus can ameliorate CAN even at advanced stages, whether everolimus treatment affects the level of growth factor mRNA, and whether everolimus treatment affects the number of apoptotic cells in the graft. Methods. We transplanted kidneys from Fisher rats into Lewis rats and treated recipients with everolimus over different time periods. Grafts were analyzed 20 or 28 weeks after transplantation. Results. Everolimus delayed the progression of CAN when started at an early stage. Surprisingly, everolimus even ameliorated CAN when initiated at an advanced stage. Interestingly, apoptosis was more prevalent in treated animals, particularly in those with delayed treatment as compared with controls. Conclusions. Everolimus ameliorates CAN as a result of antiproliferative or apoptosis-enhancing effects.
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Opposite effects of testosterone and estrogens on Chronic Allograft Nephropathy.
Transplant International, 2002Co-Authors: Balazs Antus, Yousheng Yao, Shanying Liu, Erwei Song, Jens Lutz, Uwe HeemannAbstract:In the present study we investigated whether donor gender or the effects of sex hormones play the greater role in the development of Chronic Allograft Nephropathy. Kidneys of male and female Fisher rats were orthotopically transplanted into castrated male Lewis recipients. Animals were treated with testosterone, estradiol, or vehicle and the kidneys were harvested 20 weeks after transplantation for histological, immunohistological, and molecular analysis. Testosterone treatment resulted in increased proteinuria and profound glomerulosclerosis, irrespective of donor gender. In addition, mRNA levels of transforming growth factor-β1 (TGF-β1) and platelet-derived growth factor-A and B (PDGF-A and B) chains were enhanced in these Allografts. Estradiol reduced glomerulosclerosis and mononuclear cell infiltration in Allografts of both genders that paralleled a decreased mRNA expression of TGF-β1, PDGF-A and B. No donor gender-related differences were noted in vehicle-treated animals. Our findings demonstrate that sex hormones rather than donor gender have a significant impact on Chronic Allograft Nephropathy.
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Opposite effects of testosterone and estrogens on Chronic Allograft Nephropathy.
Transplant international : official journal of the European Society for Organ Transplantation, 2002Co-Authors: Balazs Antus, Yousheng Yao, Shanying Liu, Erwei Song, Jens Lutz, Uwe HeemannAbstract:In the present study we investigated whether donor gender or the effects of sex hormones play the greater role in the development of Chronic Allograft Nephropathy. Kidneys of male and female Fisher rats were orthotopically transplanted into castrated male Lewis recipients. Animals were treated with testosterone, estradiol, or vehicle and the kidneys were harvested 20 weeks after transplantation for histological, immunohistological, and molecular analysis. Testosterone treatment resulted in increased proteinuria and profound glomerulosclerosis, irrespective of donor gender. In addition, mRNA levels of transforming growth factor-beta1 (TGF-beta1) and platelet-derived growth factor-A and B (PDGF-A and B) chains were enhanced in these Allografts. Estradiol reduced glomerulosclerosis and mononuclear cell infiltration in Allografts of both genders that paralleled a decreased mRNA expression of TGF-beta1, PDGF-A and B. No donor gender-related differences were noted in vehicle-treated animals. Our findings demonstrate that sex hormones rather than donor gender have a significant impact on Chronic Allograft Nephropathy.
Edmond Oriordan - One of the best experts on this subject based on the ideXlab platform.
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urinary proteomic analysis of Chronic Allograft Nephropathy
Proteomics Clinical Applications, 2008Co-Authors: Edmond Oriordan, Tatyana N Orlova, Natalia Mendelev, Daniel Patschan, Rowena Kemp, Praveen N Chander, Gang Hao, Steven S Gross, Renato V IozzoAbstract:The pathogenesis of progressive renal Allograft injury, which is termed Chronic Allograft Nephropathy (CAN), remains obscure and is currently defined by histology. Prospective protocol-biopsy trials have demonstrated that clinical and standard laboratory tests are insufficiently sensitive indicators of the development and progression of CAN. The study aim was to determine if CAN could be characterized by urinary proteomic data and identify the proteins associated with disease. The urinary proteome of 75 renal transplant recipients and 20 healthy volunteers was analyzed using surface enhanced laser desorption and ionization MS. Patients could be classified into subgroups with normal histology and Banff CAN grades 2-3 with a sensitivity of 86% and a specificity of 92% by applying the classification algorithm Adaboost to urinary proteomic data. Several urinary proteins associated with advanced CAN were identified including α1-microglobulin, β2-microglobulin, prealbumin, and endorepellin, the antiangiogenic C-terminal fragment of perlecan. Increased urinary endorepellin was confirmed by ELISA and increased tissue expression of the endorepellin/perlecan ratio by immunofluoresence analysis of renal biopsies. In conclusion, analysis of urinary proteomic data has further characterized the more severe CAN grades and identified urinary endorepellin, as a potential biomarker of advanced CAN.
Shanying Liu - One of the best experts on this subject based on the ideXlab platform.
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Protective effects of FTY720 on Chronic Allograft Nephropathy by reducing late lymphocytic infiltration
Kidney international, 2004Co-Authors: Minghui Wang, Shanying Liu, Erwei Song, Jens Lutz, Nengtai Ouyang, Uwe HeemannAbstract:Protective effects of FTY720 on Chronic Allograft Nephropathy by reducing late lymphocytic infiltration. Background Lymphocytic infiltration is obvious throughout early and late stages of Chronic Allograft Nephropathy. Early infiltrating lymphocytes are involved in initial insults to kidney Allografts, but the contribution of late infiltration to long-term Allograft attrition is still controversial. Early application of FTY720 reduced the number of graft infiltrating lymphocytes, and inhibited acute rejection. The present study investigated the potential of FTY720 to reduce the number of infiltrating lymphocytes even at a late stage, and, thus, slow the pace of Chronic Allograft Nephropathy. Methods Fisher (F344) rat kidneys were orthotopically transplanted into Lewis recipients with an initial 10-day course of cyclosporine A (1.5 mg/kg/day). FTY720, at a dose of 0.5 mg/kg/day, or vehicle was administered to recipients either from weeks 12 to 24 or from 20 to 24 after transplantation. Animals were harvested 24 weeks after transplantation for histologic, immunohistologic, and molecular analysis. Results FTY720, either initiated at 12 or 20 weeks after transplantation, reduced urinary protein excretion, and significantly ameliorated glomerulosclerosis, interstitial fibrosis, tubular atrophy, and intimal proliferation of graft arteries at 24 weeks after transplantation. Furthermore FTY720 markedly suppressed lymphocyte infiltration and decreased mRNA levels of interleukin-10 (IL-10), transforming growth factor-β (TGF-β), and platelet-derived growth factor-B (PDGF-B) but enhanced the number of apoptotic cells in grafts. Conclusions FTY720 ameliorated Chronic Allograft Nephropathy even at advanced stages. Furthermore, our data suggest that this effect was achieved by a reduction of graft infiltrating lymphocytes.
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Apoptosis and treatment of Chronic Allograft Nephropathy with everolimus.
Transplantation, 2003Co-Authors: Jens Lutz, Balazs Antus, Shanying Liu, Hequn Zou, Uwe HeemannAbstract:Background. Chronic Allograft Nephropathy (CAN) is responsible for most cases of late kidney Allograft loss. However, no effective treatment is available so far. Everolimus (RAD) (40-O [2-hydroxyethyl] rapamycin) is a new immunosuppressive agent with antiproliferative and apoptosis-enhancing effects. We asked whether everolimus can ameliorate CAN even at advanced stages, whether everolimus treatment affects the level of growth factor mRNA, and whether everolimus treatment affects the number of apoptotic cells in the graft. Methods. We transplanted kidneys from Fisher rats into Lewis rats and treated recipients with everolimus over different time periods. Grafts were analyzed 20 or 28 weeks after transplantation. Results. Everolimus delayed the progression of CAN when started at an early stage. Surprisingly, everolimus even ameliorated CAN when initiated at an advanced stage. Interestingly, apoptosis was more prevalent in treated animals, particularly in those with delayed treatment as compared with controls. Conclusions. Everolimus ameliorates CAN as a result of antiproliferative or apoptosis-enhancing effects.
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Opposite effects of testosterone and estrogens on Chronic Allograft Nephropathy.
Transplant International, 2002Co-Authors: Balazs Antus, Yousheng Yao, Shanying Liu, Erwei Song, Jens Lutz, Uwe HeemannAbstract:In the present study we investigated whether donor gender or the effects of sex hormones play the greater role in the development of Chronic Allograft Nephropathy. Kidneys of male and female Fisher rats were orthotopically transplanted into castrated male Lewis recipients. Animals were treated with testosterone, estradiol, or vehicle and the kidneys were harvested 20 weeks after transplantation for histological, immunohistological, and molecular analysis. Testosterone treatment resulted in increased proteinuria and profound glomerulosclerosis, irrespective of donor gender. In addition, mRNA levels of transforming growth factor-β1 (TGF-β1) and platelet-derived growth factor-A and B (PDGF-A and B) chains were enhanced in these Allografts. Estradiol reduced glomerulosclerosis and mononuclear cell infiltration in Allografts of both genders that paralleled a decreased mRNA expression of TGF-β1, PDGF-A and B. No donor gender-related differences were noted in vehicle-treated animals. Our findings demonstrate that sex hormones rather than donor gender have a significant impact on Chronic Allograft Nephropathy.
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Opposite effects of testosterone and estrogens on Chronic Allograft Nephropathy.
Transplant international : official journal of the European Society for Organ Transplantation, 2002Co-Authors: Balazs Antus, Yousheng Yao, Shanying Liu, Erwei Song, Jens Lutz, Uwe HeemannAbstract:In the present study we investigated whether donor gender or the effects of sex hormones play the greater role in the development of Chronic Allograft Nephropathy. Kidneys of male and female Fisher rats were orthotopically transplanted into castrated male Lewis recipients. Animals were treated with testosterone, estradiol, or vehicle and the kidneys were harvested 20 weeks after transplantation for histological, immunohistological, and molecular analysis. Testosterone treatment resulted in increased proteinuria and profound glomerulosclerosis, irrespective of donor gender. In addition, mRNA levels of transforming growth factor-beta1 (TGF-beta1) and platelet-derived growth factor-A and B (PDGF-A and B) chains were enhanced in these Allografts. Estradiol reduced glomerulosclerosis and mononuclear cell infiltration in Allografts of both genders that paralleled a decreased mRNA expression of TGF-beta1, PDGF-A and B. No donor gender-related differences were noted in vehicle-treated animals. Our findings demonstrate that sex hormones rather than donor gender have a significant impact on Chronic Allograft Nephropathy.
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Recipient age and weight affect Chronic Allograft Nephropathy in rats
2002Co-Authors: Shanying LiuAbstract:In summary, our results demonstrate that recipient age and body weight profoundly influence the long-term renal Allograft outcome in our rat model. Increased recipient age and body weights are detrimental to the graft, implicating the importance of recipient functional demand in the development of Chronic Allograft Nephropathy. By contrast, donor kidney weight did not significantly affect the late Allograft injury. Only in old recipients groups, increase in donor age is associated with the progression of Chronic Allograft Nephropathy, suggesting that increased recipient functional demand may also augment the influence of donor- aging-related nephron loss in late Allograft failure. Nephron dose and immune response change with age. Thus, age is a potential risk factor for graft survival after kidney transplantation. The aim of the current study was to determine whether age-related differences are of importance for the long-term outcome after renal transplantation. Kidneys of Fisher (F344) rats were orthotopically transplanted into nephrectomized Lewis (LEW) rats. Kidneys were transplanted in donors and recipients of three age levels: young (Y: 8 weeks old), adult (A: 16 weeks old), and old (O: 40 weeks old). Rats were harvested 24 weeks after transplantation and functional, morphological, and molecular evaluations were performed. Recipient rather than donor age determined graft survival. No significant correlation was found between donor kidney weight at the day of transplantation and morphological results. Advanced recipient age was associated with reduced creatinine clearance, more severe histological injuries including extended glomerular sclerosis, interstitial fibrosis, vascular lesions, more pronounced cellular infiltration, as well as a higher expression of TGF-b, and PDGF A and B chain. However, while we observed no significant correlation between donor age or kidney weight at the day of transplantation and morphological results, there was a significant correlation between recipient body weight at the day of transplantation and Allograft injury. Therefore, recipient age and weight affect Chronic Allograft Nephropathy. Renal Allografts may benefit from young recipient age but may deteriorate in old recipients, suggesting effects of recipient functional demand on long-term outcome.
Balazs Antus - One of the best experts on this subject based on the ideXlab platform.
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Apoptosis and treatment of Chronic Allograft Nephropathy with everolimus.
Transplantation, 2003Co-Authors: Jens Lutz, Balazs Antus, Shanying Liu, Hequn Zou, Uwe HeemannAbstract:Background. Chronic Allograft Nephropathy (CAN) is responsible for most cases of late kidney Allograft loss. However, no effective treatment is available so far. Everolimus (RAD) (40-O [2-hydroxyethyl] rapamycin) is a new immunosuppressive agent with antiproliferative and apoptosis-enhancing effects. We asked whether everolimus can ameliorate CAN even at advanced stages, whether everolimus treatment affects the level of growth factor mRNA, and whether everolimus treatment affects the number of apoptotic cells in the graft. Methods. We transplanted kidneys from Fisher rats into Lewis rats and treated recipients with everolimus over different time periods. Grafts were analyzed 20 or 28 weeks after transplantation. Results. Everolimus delayed the progression of CAN when started at an early stage. Surprisingly, everolimus even ameliorated CAN when initiated at an advanced stage. Interestingly, apoptosis was more prevalent in treated animals, particularly in those with delayed treatment as compared with controls. Conclusions. Everolimus ameliorates CAN as a result of antiproliferative or apoptosis-enhancing effects.
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Opposite effects of testosterone and estrogens on Chronic Allograft Nephropathy.
Transplant International, 2002Co-Authors: Balazs Antus, Yousheng Yao, Shanying Liu, Erwei Song, Jens Lutz, Uwe HeemannAbstract:In the present study we investigated whether donor gender or the effects of sex hormones play the greater role in the development of Chronic Allograft Nephropathy. Kidneys of male and female Fisher rats were orthotopically transplanted into castrated male Lewis recipients. Animals were treated with testosterone, estradiol, or vehicle and the kidneys were harvested 20 weeks after transplantation for histological, immunohistological, and molecular analysis. Testosterone treatment resulted in increased proteinuria and profound glomerulosclerosis, irrespective of donor gender. In addition, mRNA levels of transforming growth factor-β1 (TGF-β1) and platelet-derived growth factor-A and B (PDGF-A and B) chains were enhanced in these Allografts. Estradiol reduced glomerulosclerosis and mononuclear cell infiltration in Allografts of both genders that paralleled a decreased mRNA expression of TGF-β1, PDGF-A and B. No donor gender-related differences were noted in vehicle-treated animals. Our findings demonstrate that sex hormones rather than donor gender have a significant impact on Chronic Allograft Nephropathy.
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Opposite effects of testosterone and estrogens on Chronic Allograft Nephropathy.
Transplant international : official journal of the European Society for Organ Transplantation, 2002Co-Authors: Balazs Antus, Yousheng Yao, Shanying Liu, Erwei Song, Jens Lutz, Uwe HeemannAbstract:In the present study we investigated whether donor gender or the effects of sex hormones play the greater role in the development of Chronic Allograft Nephropathy. Kidneys of male and female Fisher rats were orthotopically transplanted into castrated male Lewis recipients. Animals were treated with testosterone, estradiol, or vehicle and the kidneys were harvested 20 weeks after transplantation for histological, immunohistological, and molecular analysis. Testosterone treatment resulted in increased proteinuria and profound glomerulosclerosis, irrespective of donor gender. In addition, mRNA levels of transforming growth factor-beta1 (TGF-beta1) and platelet-derived growth factor-A and B (PDGF-A and B) chains were enhanced in these Allografts. Estradiol reduced glomerulosclerosis and mononuclear cell infiltration in Allografts of both genders that paralleled a decreased mRNA expression of TGF-beta1, PDGF-A and B. No donor gender-related differences were noted in vehicle-treated animals. Our findings demonstrate that sex hormones rather than donor gender have a significant impact on Chronic Allograft Nephropathy.
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Early application of Met-RANTES ameliorates Chronic Allograft Nephropathy
Kidney international, 2002Co-Authors: Erwei Song, Balazs Antus, Yousheng Yao, Shanying Liu, Hequn Zou, Amanda E.i. Proudfoot, Lutz Jens, Uwe HeemannAbstract:Early application of Met-RANTES ameliorates Chronic Allograft Nephropathy. Background Initial insults to kidney Allografts, characterized by infiltration of mononuclear inflammatory cells, contribute to Chronic Allograft Nephropathy. Chemokines such as RANTES (regulated upon activation, normal T cell expressed) are thought to be responsible for the recruitment and activation of infiltrating cells. The present study investigated whether early application of Met-RANTES, a chemokine receptor antagonist that blocks the effects of RANTES, can protect renal Allografts from long-term deterioration. Methods Fisher (F344) rat kidneys were orthotopically transplanted into Lewis recipients and treated with cyclosporine A (1.5 mg/kg/day) for the first 10 days following transplantation, together with either Met-RANTES at 40 μg/day, 200 μg/day or vehicle for the first 7 days. Animals were harvested at 2 and 28 weeks after transplantation for histologic, immunohistologic and molecular analysis. Results Met-RANTES treatment reduced the infiltration of lymphocytes and macrophages in Allografts at 2 weeks after transplantation, accompanied by decreased mRNA expression of interleukin (IL)-2, IL-1β, tumor necrosis factor-α (TNF-α) and RANTES. At post-transplantation week 28, Met-RANTES treatment at high and low doses reduced urinary protein excretion and significantly ameliorated glomerulosclerosis, interstitial fibrosis, tubular atrophy, intimal proliferation of graft arteries and mononuclear cell infiltration. However, creatinine clearance was not influenced by Met-RANTES. Furthermore, Met-RANTES suppressed the mRNA expression of transforming growth factor-β (TGF-β) and platelet-derived growth factor-B (PDGF-B). Conclusions Blockade of chemokine receptors by Met-RANTES diminishes early infiltration and activation of mononuclear cells in the grafts, and thus reduces the pace of Chronic Allograft Nephropathy.
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Contribution of androgens to Chronic Allograft Nephropathy is mediated by dihydrotestosterone
Kidney international, 2001Co-Authors: Balazs Antus, Yousheng Yao, Shanying Liu, Erwei Song, Jens Lutz, Uwe HeemannAbstract:Contribution of androgens to Chronic Allograft Nephropathy is mediated by dihydrotestosterone. Background Donor and recipient gender influence long-term Allograft outcome after kidney transplantation. Sex hormones are likely to contribute to these gender-related differences. The present study investigated the role of androgens and their inhibition on the development of Chronic Allograft Nephropathy. Methods Male or female Fisher (F344) kidneys were orthotopically transplanted into intact male Lewis recipients. Animals were treated either with testosterone, the antiandrogen flutamide, the 5α-reductase inhibitor finasteride, or vehicle. Twenty weeks after transplantation animals were harvested for histology, immunohistology, and molecular analysis. Results Testosterone treatment resulted in an increased proteinuria as well as profound glomerulosclerosis, tubulointerstitial fibrosis, and mononuclear cell infiltration that paralleled enhanced intragraft mRNA levels of transforming growth factor-Β (TGF-Β) and platelet-derived growth factor-A and -B chain (PDGF-A and -B). In contrast, flutamide and finasteride reduced glomerulosclerosis as well as the inflammatory cell infiltration associated with decreased TGF-Β, PDGF-A, and -B chain mRNA expression. No gender-related donor differences were noted between the groups. Conclusions Our data suggest that dihydrotestosterone mediates the adverse effects of androgens on Chronic Allograft Nephropathy. The inhibition of androgens improves long-term Allograft outcome after kidney transplantation.
Matthew R. Weir - One of the best experts on this subject based on the ideXlab platform.
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Minimizing the risk of Chronic Allograft Nephropathy.
Transplantation, 2009Co-Authors: Matthew R. Weir, Ravinder K. WaliAbstract:Chronic Allograft Nephropathy, now defined as interstital fibrosis and tubular atrophy not otherwise specified, is a near universal finding in transplant kidney biopsies by the end of the first decade posttransplantation. After excluding death with functioning graft, caused by cardiovascular disease or malignancy, Chronic Allograft Nephropathy is the leading cause of graft failure. Original assumptions were that this was not a modifiable process but inexorable, likely due to past kidney injuries. However, newer understandings suggest that acute or subacute processes are involved, and with proper diagnosis, appropriate interventions can be instituted. Our method involved a review of the primary and secondary prevention trials in calcineurin inhibitor withdrawal. Some of the more important causes of progressive graft deterioration include subclinical cellular or humoral rejection, and Chronic calcineurin inhibitor toxicity. Early graft biopsy, assessment of histology, and changes in immunosuppression may be some of the most important measures available to protect graft function. The avoidance of clinical inertia in pursuing subtle changes in graft function is critical. Modification in maintenance immunosuppression may benefit many patients with early evidence of graft deterioration.
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The role of angiotensin II and TGF-beta on the progression of Chronic Allograft Nephropathy.
Journal of the renin-angiotensin-aldosterone system : JRAAS, 2001Co-Authors: Matthew R. Weir, Chiming WeiAbstract:Chronic Allograft Nephropathy is the most prevalent cause of graft dysfunction and failure. Its pathogenesis and treatment remains poorly defined. The calcineurin inhibitors, cyclosporine and tacrolimus, may play a role in the progressive loss of renal function in patients with Chronic Allograft Nephropathy. This effect may be either related to the direct stimulation of profibrogenic cytokines such as transforming growth factor (TGF-β) or indirect mechanisms, through increases in blood pressure or alterations in either carbohydrate or lipid metabolism. Experimental studies have demonstrated that angiotensin-converting enzyme inhibitors (ACE-I) and angiotensin II receptor blockers (ARBs) can attenuate cyclosporine-mediated increases in TGF-β production in renal tissue. Clinical studies have demonstrated that either cyclosporine or tacrolimus dose reduction may help reduce the rate of loss of renal function in patients with Chronic Allograft Nephropathy. Moreover, other studies have demonstrated that a Chronic reduction in the dose of cyclosporine in transplant patients can reduce serum TGF-β levels. Treatment with an ARB can normalise the plasma levels of TGF-β in renal transplant patients receiving cyclosporine. All these observations suggest that there may be a role of cyclosporine, and possibly tacrolimus, in worsening Chronic Allograft Nephropathy through their effects on the renin-angiotensinaldosterone system (RAAS) and TGF-β production.
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Long-term impact of discontinued or reduced calcineurin inhibitor in patients with Chronic Allograft Nephropathy.
Kidney international, 2001Co-Authors: Matthew R. Weir, Mary Traver Ward, Steven A. Blahut, David K. Klassen, Charles B. Cangro, Stephen T. Bartlett, Jeffrey C. FinkAbstract:Long-term impact of discontinued or reduced calcineurin inhibitor in patients with Chronic Allograft Nephropathy. Background Chronic Allograft Nephropathy is the major cause of progressive renal failure in renal transplant recipients. It has no definitive treatment. Methods One hundred eighteen renal transplant recipients with declining kidney function and biopsy-proven Chronic Allograft Nephropathy had their cyclosporine or tacrolimus dose reduced or discontinued with either the addition or continuation of mycophenolate mofetil and low-dose steroids at a mean of 853.3 days post-transplantation. Their renal function was modeled before and after this intervention by two methods: A least-square regression was used to assess the decay of renal function after the intervention and to compare that with the slope pre-intervention, whereas a hinge regression line method was used to assess the correlation of the intervention with the inflection point and the impact of the intervention on the decay of renal function. Mean follow-up was 651.0 days after the intervention. Serum creatinine at the time of intervention was 2.8 ± 0.9 mg/dL in the reduced dose cyclosporine ( N = 67) and reduced dose tacrolimus ( N = 33) groups, and was 2.7 ± 0.7 mg/dL in the group with discontinued calcineurin inhibitor ( N = 18). Results Using the least-square method, 91.7% of the no calcineurin inhibitor group, 51.6% of the reduced dose cyclosporine group, and 59.3% of the reduced dose tacrolimus group had improved or lack of deterioration in slope after the intervention. Using the hinge regression line method, there was a statistically significant correlation of the inflection point with the intervention ( P = 0.001). Moreover, there was a similar relationship with stabilized or improved graft function observed with the hinge regression line method and the least-square method, as 72.2% of the calcineurin inhibitor withdrawal group, 54.4% of reduced-dose cyclosporine group, and 40% of the reduced-dose tacrolimus group had improved the slope of decay of renal function or lack of deterioration after the inflection point. The difference between the calcineurin inhibitor withdrawal group and the reduced-dose cyclosporine/tacrolimus groups on the decay in renal function was significant ( P = 0.038) with the least-square method and nearly significant ( P = 0.056) using the hinge regression line method. Conclusion This intervention was safe, well tolerated, and associated with a minimal risk of acute rejection. We conclude that the reduction and possible withdrawal of calcineurin inhibitors may be necessary to slow the rate of loss of renal function in patients with Chronic Allograft Nephropathy and deteriorating renal function.