Mycophenolate Mofetil Substitution for Cyclosporine A in Renal Transplant Recipients with Chronic Progressive Allograft Dysfunction: The ???Creeping Creatinine??? Study1

Dudley, Christopher; Pohanka, E; Riad, Hany; Dedochova, Jarmila; Wijngaard, Peter; Sutter, Carolyn; Silva, Hélio Tedesco

doi:10.1097/01.tp.0000151632.21551.00

Cited by 153 publications

(116 citation statements)

References 24 publications

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“…All renal transplant recipients followed up in our out-patient clinic were screened for graft dysfunction based on serial serum creatinine and proteinuria assessments. Patients with proteinuria of .0.5g/ d assessed by urine protein creatinine ratio on three consecutive random urine samples and/or deteriorating function as assessed by change in 1/ creatinine over a year 39 were offered a transplant biopsy. On the basis of the histology, they were grouped into patients with a histologic phenotype of rejection (GD-R, n=25) or patients with no evidence of rejection (GD-NR, n=22).…”

Section: Study Participantsmentioning

confidence: 99%

Immunologic Human Renal Allograft Injury Associates with an Altered IL-10/TNF-α Expression Ratio in Regulatory B Cells

Cherukuri

Rothstein²,

Clark

et al. 2014

Journal of the American Society of Nephrology

127

130

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Human B cells with immunoregulatory properties in vitro (Bregs) have been defined by the expression of IL-10 and are enriched in various B-cell subsets. However, proinflammatory cytokine expression in B-cell subsets is largely unexplored. We examined the cytokine profiles of human PBMCs and found that subsets of CD24 hi CD38 hi transitional B cells (TrBs), CD24 hi CD27 + memory B cells, and naïve B cells express IL-10 and the proinflammatory cytokine TNF-a simultaneously. TrBs had the highest IL-10/TNF-a ratio and suppressed proinflammatory helper T cell 1 (Th1) cytokine expression by autologous T cells in vitro more potently than memory B cells did, despite similar IL-10 expression. Whereas neutralization of IL-10 significantly inhibited TrB-mediated suppression of autologous Th1 cytokine expression, blocking TNF-a increased the suppressive capacity of both memory and naïve B-cell subsets. Thus, the ratio of IL-10/TNF-a expression, a measure of cytokine polarization, may be a better indicator of regulatory function than IL-10 expression alone. Indeed, compared with TrB cells from patients with stable kidney graft function, TrBs from patients with graft rejection displayed similar IL-10 expression levels but increased TNF-a expression (i.e., reduced IL-10/TNF-a ratio), did not inhibit in vitro expression of Th1 cytokines by T cells, and abnormally suppressed expression of Th2 cytokines. In patients with graft dysfunction, a low IL-10/TNF-a ratio in TrBs associated with poor graft outcomes after 3 years of follow-up. In summary, these results indicate that B cell-mediated immune regulation is best characterized by the cytokine polarization profile, a finding that was confirmed in renal transplant patients.

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Section: Study Participantsmentioning

confidence: 99%

Immunologic Human Renal Allograft Injury Associates with an Altered IL-10/TNF-α Expression Ratio in Regulatory B Cells

Cherukuri

Rothstein²,

Clark

et al. 2014

Journal of the American Society of Nephrology

127

130

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“…Nine studies included patients with deteriorating renal function and biopsy-proven CAN, and three studies included patients with CAD (no biopsy) (11)(12)(13). Studies enrolled patients Ͼ 6 mo post-transplant.…”

Section: Patient Characteristicsmentioning

confidence: 99%

“…Most studies excluded patients with an alternate cause of deteriorating renal function and pregnant patients. Several studies excluded patients with active infection or malignancy (11,12,16,19,20). Some studies also excluded patients who were diabetic (19), who began angiotensin converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) within 3 mo before recruitment (16), or who had known medication allergies (11,19).…”

Section: Patient Characteristicsmentioning

confidence: 99%

Management of Chronic Allograft Nephropathy

Birnbaum

Lipman²,

Paraskevas³

et al. 2009

Clinical Journal of the American Society of Nephrology

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Despite improving immunosuppressive protocols in renal transplantation, chronic allograft nephropathy (CAN) remains a major impediment to long-term graft survival. The optimal immunosuppressive regimen for a patient with CAN is unknown. The aim of this study is to evaluate the various immunosuppressive management strategies of biopsy-proven CAN and of chronic allograft dysfunction (CAD) (no biopsy). A systematic review of randomized trials (n ‫؍‬ 12 trials with 635 patients) was conducted. Studies included patients who were >6 mo post-transplant. All patients were on a calcineurin inhibitor (CNI), most often cyclosporine, and were randomized to convert to mycophenolate mofetil (MMF), tacrolimus, or sirolimus (Rapa) or to add azathioprine, MMF or Rapa to their current regimen. Follow-up time was 6 to 36 mo. The outcome measures evaluated were renal function in 11 of 12 studies and repeat renal biopsy results in one study. The methodological quality scores of the trials were generally low, using the Jadad scale (median value 2/5). Results varied between studies but suggested that CNI withdrawal is safe and that conversion to MMF or Rapa may be beneficial. The incidence of adverse effects ranged from 0% to 68% between the studies, and medication withdrawal occurred in 0% to 24% of patients. The review did not result in a consensus regarding the management of CAN and CAD. Further studies are required to determine the best therapeutic option for patients with CAD and CAN.

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“…Significant improvement in renal function occurred in patients maintained only on MMF and prednisone compared with those continued on CsA. Most remarkably, acute rejection did not increase after withdrawal of CsA (84). This study suggests that, in renal transplant patients with worsening renal function, CsA withdrawal with the addition of MMF confers significantly better renal function and possibly improved graft survival compared with CsA maintenance therapy.…”

Section: Csa Withdrawal In Patients With Deteriorating Graft Functionmentioning

confidence: 54%

“…In a randomized clinical trial reported by Dudley et al (MMF Creeping Creatinine Study Group), 143 patients who had significant deterioration in renal function (by serial reciprocal values of serum creatinine) Ͼ6 mo posttransplantation were either maintained on their CsA-based immunosuppressive regimen or withdrawn from CsA and maintained on only MMF and corticosteroids (84). Significant improvement in renal function occurred in patients maintained only on MMF and prednisone compared with those continued on CsA.…”

Section: Csa Withdrawal In Patients With Deteriorating Graft Functionmentioning

confidence: 99%

Minimizing Immunosuppression, an Alternative Approach to Reducing Side Effects

Srinivas¹,

Meier‐Kriesche²

2008

Clinical Journal of the American Society of Nephrology

120

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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 Substitution for Cyclosporine A in Renal Transplant Recipients with Chronic Progressive Allograft Dysfunction: The ???Creeping Creatinine??? Study1

Abstract: In patients with progressively deteriorating renal function secondary to CAN, addition of MMF followed by withdrawal of CsA results in a significant improvement in transplant function without the risk of acute rejection.

Cited by 153 publications

References 24 publications

Immunologic Human Renal Allograft Injury Associates with an Altered IL-10/TNF-α Expression Ratio in Regulatory B Cells

Immunologic Human Renal Allograft Injury Associates with an Altered IL-10/TNF-α Expression Ratio in Regulatory B Cells

Management of Chronic Allograft Nephropathy

Minimizing Immunosuppression, an Alternative Approach to Reducing Side Effects

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