Mycophenolate Mofetil Is Associated with Altered Expression of Chronic Renal Transplant Histology

Nankivell, Brian J.; Wavamunno, Moses; Borrows, Richard; Vitalone, Matthew J.; Fung, Caroline; Allen, Richard D.; Chapman, Jeremy R.; O’Connell, Philip J.

doi:10.1111/j.1600-6143.2006.01633.x

Cited by 44 publications

(33 citation statements)

References 44 publications

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“…Both of these findings, however, accompany the clinical observation of less immunologic insult (i.e., fewer rejection episodes and less subclinical rejection) with tacrolimus-based therapies (42). Subsequently, the Westmeade group documented the addition of mycophenolate to cyclosporinebased immunosuppression not only to reduce adverse immunologic events but also to diminish the lesions thought to be the sine qua non of CNI nephrotoxicity: arteriolar hyalinosis and striped interstitial fibrosis (43). Indeed, several series have documented much greater stability of renal function, despite ongoing use of CNI-based therapy, in the current era (35,44).…”

Section: Alternatives To An Incomplete Paradigmmentioning

confidence: 99%

Chronic Calcineurin Inhibitor Nephrotoxicity

Gaston

2009

Clinical Journal of the American Society of Nephrology

113

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Use of the calcineurin inhibitors (CNI) cyclosporine and tacrolimus has revolutionized solid organ transplantation. For more than 30 yr, the transplant community has dealt with nephrotoxicity attributed to these agents. Acute renal vasoconstriction (as described by many investigators, including John Curtis and colleagues) is the unequivocal consequence of their use; chronic CNI nephropathy, although indistinct in terms of histology and pathophysiology, has become accepted as a major cause of late kidney allograft failure. This article examines clinical, laboratory, and histologic findings that evolved into a paradigm that was never fully consistent with observed outcomes and new evidence that may offer an alternative interpretation for adverse events that are attributed to CNI nephrotoxicity in kidney transplant recipients.

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Section: Alternatives To An Incomplete Paradigmmentioning

confidence: 99%

Chronic Calcineurin Inhibitor Nephrotoxicity

Gaston

2009

Clinical Journal of the American Society of Nephrology

113

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“…[13][14][15][16] Several in vivo studies reported that MPA significantly reduces mesangial matrix deposition, interstitial fibrosis, myofibroblast infiltration, and glomerular sclerosis in patients with chronic graft rejection, CNI nephrotoxicity, and glomerulonephritides. [17][18][19][20] Even in different models of non-immune-mediated renal diseases, including unilateral ureteric obstruction and the 5/6-remnant kidney, MPA was shown to reduce glomerular sclerosis and interstitial fibrosis. 21,22 These results suggest that MPA may exert an anti-fibrotic action, although the molecular mechanisms underlying this effect are still largely unknown.…”

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confidence: 99%

The Anti-Fibrotic Effect of Mycophenolic Acid–Induced Neutral Endopeptidase

Dell'Oglio

Zaza

Rossini

et al. 2010

Journal of the American Society of Nephrology

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Mycophenolic acid (MPA) appears to have anti-fibrotic effects, but the molecular mechanisms underlying this are unknown. We prospectively studied 35 stable kidney transplant recipients maintained on cyclosporine and azathioprine. We converted 20 patients from azathioprine to enteric-coated mycophenolate sodium (EC-MPS) and continued the remaining 15 patients on azathioprine. Exploratory mRNA expression profiling, performed on five randomly selected EC-MPS patients, revealed significant upregulation of neutral endopeptidase (NEP), which is an enzyme that degrades angiotensin II. We confirmed these microarray data by measuring levels of NEP expression in all subjects; in addition, we found that NEP gene expression correlated inversely with proteinuria. In an additional 33 patients, glomerular and tubular NEP protein levels from renal graft biopsies were significantly higher among the 13 patients receiving cyclosporine ϩ EC-MPS than among the 12 patients receiving cyclosporine ϩ azathioprine or 8 patients receiving cyclosporine alone. Glomerular NEP expression inversely correlated with glomerulosclerosis and proteinuria, and tubular NEP expression inversely correlated with interstitial fibrosis. Incubation of human proximal tubular cells with MPA increased NEP gene expression in a doseand time-dependent manner. Moreover, MPA reduced angiotensin II-induced expression of the profibrotic factor plasminogen activator inhibitor-1, and a specific NEP inhibitor completely reversed this effect. Taken together, our data suggest that MPA directly induces expression of neutral endopeptidase, which may reduce proteinuria and slow the progression of renal damage in kidney transplant recipients. 21: 215721: -216821: , 201021: . doi: 10.1681 Over the last decade, the continuous progress in the development of immunosuppressive agents has enhanced both the efficacy and safety of antirejection regimens after renal transplantation, leading to a dramatic reduction in the incidence of acute rejection. 1 This significant improvement in short-term graft outcome was not followed by a similar advance in preventing graft loss caused by chronic graft injury. 2,3 The addition of mycophenolic acid (MPA) into contemporary immunosuppressive regimens represented an important step forward in the development of new therapeutic protocols in kidney transplantation. J Am Soc NephrolMPA exerts its immunosuppressive effect by inhibiting the inosine 5Ј monophosphate dehydro-

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“…Whereas hypertension, hyperlipidemia, and cosmetic side effects such as hirsutism are more common with CsA, impaired glucose tolerance, neurotoxicity, and alopecia are more common with TAC. Some clinicians also feel that TAC may exhibit less nephrotoxicity; supporting this opinion are studies where pathological evidence of decreased fibrogenicity were noted with TAC (8,9). However, such evidence remains controversial as other studies have not reported any differences in profibrogenic effects of CsA and TAC at either the renal or molecular level, and the effects of adjunctive therapies cannot be separated easily from the primary effects of CsA or TAC (8,10).…”

Section: Achieving Balance Between Efficacy and Toxicitymentioning

confidence: 82%

“…These lesions increased in prevalence over time in the lifespan of an allograft (6). However, lesions of vascular sclerosis, interstitial fibrosis, and importantly in this observational series, the cumulative incidence of subclinical rejection were significantly greater in patients on CsA and azathioprine (AZA) compared with those on TAC and mycophenolate mofetil (MMF) (8). The fact that immunological factors remain important in the pathogenesis of the attrition of renal allograft function over time is illustrated in a recent study of protocol biopsies in TAC-and MMF-treated renal transplant recipients in whom the occurrence of rejection and low TAC exposure were independent risk factors for the development of chronic pathological lesions in allografts (11).…”

Section: Achieving Balance Between Efficacy and Toxicitymentioning

confidence: 87%

Minimizing Immunosuppression, an Alternative Approach to Reducing Side Effects

Srinivas¹,

Meier‐Kriesche²

2008

Clinical Journal of the American Society of Nephrology

122

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Exceptionally low acute rejection rates and excellent graft survival can be achieved with cyclosporine and tacrolimus (CNI)-based immunosuppressive protocols that incorporate antiproliferative immunosuppressants and corticosteroids. However, despite short-term success, long-term attrition of graft function and side effects of immunosuppressive agents continue to be significant problems, leaving clinicians looking for possible interventions. CNI nephrotoxicity is but one of numerous factors that may contribute to long-term damage in transplant kidneys. Metabolic, cosmetic, and neuropsychiatric complications of steroids affect quality of life after transplantation. Newer immunosuppressive agents such as mycophenolate mofetil and sirolimus (Rapa) have raised the possibility of withdrawing or avoiding CNIs or steroids altogether. In this report we review studies that address either CNI or steroid minimization strategies and discuss their risks versus benefits. Given the accumulated experience to date, in our opinion the use of CNIs and steroids as part of immunosuppressive regimens remains the proven standard of care for renal transplant patients. The long-term safety and efficacy of CNI and steroid minimization strategies needs to be further validated in controlled clinical trials with adequate long-term follow-up.

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Mycophenolate Mofetil Is Associated with Altered Expression of Chronic Renal Transplant Histology

Cited by 44 publications

References 44 publications

Chronic Calcineurin Inhibitor Nephrotoxicity

Chronic Calcineurin Inhibitor Nephrotoxicity

The Anti-Fibrotic Effect of Mycophenolic Acid–Induced Neutral Endopeptidase

Minimizing Immunosuppression, an Alternative Approach to Reducing Side Effects

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