Cyclosporine-Associated Chronic Nephropathy

Myers, Bryan D.; Ross, John; Newton, Lynn; Luetscher, John A.; Perlroth, Mark G.

doi:10.1056/nejm198409133111103

Cited by 1,109 publications

(407 citation statements)

References 26 publications

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“…CsA or CnABP expression resulted in 60% (P < 0.01) and 50% (P < 0.01) reduction of luciferase, respectively. *, P < 0.05; **, P < 0.01. in kidney development (49) and homeostasis (50). Interestingly, a number of calcineurin pathway components, including calcineurin A, were recently identified as specifically up-regulated in relapsing WTs (9).…”

Section: Regulation Of Calcineurin Signaling By Cnabpmentioning

confidence: 99%

Calcineurin A–Binding Protein, a Novel Modulator of the Calcineurin-Nuclear Factor of Activated T-Cell Signaling Pathway, Is Overexpressed in Wilms' Tumors and Promotes Cell Migration

Nguyen

Béland²,

Gaitan³

et al. 2009

Molecular Cancer Research

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Current therapeutic strategies against Wilms' tumor (WT) reach 80% to 85% success rate. In spite of this, a remaining 15% to 20% of tumors relapse and are associated with increased metastasis and poor prognosis. To identify new regulators of WT progression, we screened for developmental target genes of Pax2, a key regulator of kidney development and a WT signature gene. We show that one of these target genes, calcineurin A-binding protein (CnABP), is coexpressed with Pax2 during kidney development and is overexpressed in >70% of WT samples analyzed. The CnABP gene encodes a novel protein product conserved in higher vertebrates. We show that CnABP promotes cell proliferation and migration in cell culture experiments. Biochemical analyses additionally identified an interaction between CnABP and calcineurin Aβ, the catalytic subunit of the calcium-responsive serine/ threonine phosphatase calcineurin. We show that this interaction leads to the inhibition of calcineurin phosphatase activity and prevents nuclear factor of activated T-cell (NFAT) nuclear translocation. Inhibition of NFAT nuclear localization results in decreased NFAT transcriptional response. Together, these data identify a new modulator of calcineurin signaling up-regulated in WTs. (Mol Cancer Res 2009;7(6):821-31)

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Section: Regulation Of Calcineurin Signaling By Cnabpmentioning

confidence: 99%

Calcineurin A–Binding Protein, a Novel Modulator of the Calcineurin-Nuclear Factor of Activated T-Cell Signaling Pathway, Is Overexpressed in Wilms' Tumors and Promotes Cell Migration

Nguyen

Béland²,

Gaitan³

et al. 2009

Molecular Cancer Research

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“…The activation of NFAT requires calcineurin phosphatase, which in turn is inhibited by immunosuppressants such as Cyclosporine (CsA) (20 -22); it is therefore conceivable that immunosuppressive agents could also interfere with the regulated expression of COX-2 in vivo, particularly in the kidney. It is well known that the kidney is vulnerable toward adverse effects of CsA, including decrease of GFR, tubular dysfunction, glomerulosclerosis, and renal interstitial fibrosis (23,24). In view of the involving role of COX-2 for normal kidney function (25) and the demonstration of NFAT binding sites on its promotor, it appeared of interest to us to determine the effects of calcineurin inhibitors on renal COX-2 expression as well as on the presumably COX-2-dependent regulation of renin synthesis and renin secretion (25).…”

mentioning

confidence: 99%

Cyclosporine A Suppresses Cyclooxygenase-2 Expression in the Rat Kidney

Höcherl¹,

Dreher²,

Vitzthum

et al. 2002

Journal of the American Society of Nephrology

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Abstract. On the basis of recent evidence that the cyclooxygenase-2 (COX-2) gene promoter contains functional binding sites for the nuclear factor of activated T cells (NFAT) and that COX-2 is expressed in a regulated fashion in the kidney, this study aimed to assess the effect of immunosuppressants on COX-2 expression in the kidney. Therefore, Wistar-Kyoto rats were treated with cyclosporine A (CsA; 15 mg/kg per day) or tacrolimus (5 mg/kg per day) for 7 d each. Both drugs markedly lowered COX-2 expression while COX-1 expression remained unaltered. Furthermore, CsA blunted the increase of renocortical COX-2 expression in response to low salt intake or a combination of low-salt diet with the ACE inhibitor ramipril (10 mg/kg per day), which strongly stimulates renocortical COX-2 expression. At the same time, calcineurin inhibitors moderately enhanced basal as well as stimulated renin secretion and renin gene expression. These findings suggest that inhibition of calcineurin could be a crucial determinant for the regulated expression of COX-2 in the kidney. Inhibition of COX-2 expression may therefore at least in part account for the well-known adverse effects of immunosuppressants in the kidney. Moreover, our data suggest that the stimulation of the renin system by low salt and by ACE inhibitors is not essentially mediated by COX-2 activity.The family of cyclooxygenases (COX)

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“…Grafts American were implanted within 18 to 30 hours after harvesting using a conventional method. 6 …”

Section: Operationmentioning

confidence: 99%

Cyclosporine-Steroid Combination Therapy in 84 Cadaveric Renal Transplants

Gordon

Iwatsuki

Shaw

et al. 1985

American Journal of Kidney Diseases

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Sixty-three primary and 21 retransplant cadaver kidney allografts were placed in 77 patients over a one-year period with three-to six-month follow-up. Eight primary grafts (12.7%) and six retransplants (28.6%) were lost to rejection. Patient mortality was 3.9%. There were no grafts lost and no deaths due to opportunistic infections. Renal function at 6 months after transplantation was similar in all primary transplant recipients regardless of risk factors, including advanced age, diabetes, or the need for postoperative dialysis. Keywords Cyclosporine; kidney transplantResults previously reported from this center for cadaver renal transplants performed during 1981 demonstrated the superiority of combination cyclosporine-prednisone therapy over conventional immunosuppression with azathioprine and steroids. [1][2][3] Encouraged by these results, the resources of the general surgery division concentrated on expansion of the liver transplant program with similar success during 1982 and 1983. 4 In November 1983, we resumed a program in cadaveric renal transplantation on the general surgery service at this center. We report here the results of the first 84 consecutive renal transplants performed using cyclosporine-steroid therapy between November 15, 1983 and November 15, 1984 with three-to six-month follow-up. MATERIALS AND METHODS Case MaterialPrimary cadaveric renal transplants were performed in 63 patients with a mean age of 45.6 ± 11.4 (SD) years (range 9 to 68 years). Twenty-one retransplantations were performed, including seven patients from the primary series who lost their first grafts within six months. There were 13 patients in the series with type I insulin-dependent diabetes mellitus. Additional demographic features of the patients are given in Tables 1 and 2. Patients were selected for transplantation based only on the results of the preoperative screen for preformed antidonor cytotoxic antibodies. OperationRenal allografts from heart beating cadavers were harvested using the in-situ flush technique recently described for multiple organ procurements. 5 All grafts were separated immediately after harvesting and stored in iced Collins' solution. Grafts American were implanted within 18 to 30 hours after harvesting using a conventional method. 6 ImmunosuppressionThe rationale for combined cyclosporine-prednisone therapy has been previously described. 1-3 Whenever possible, patients received a 17.5 mg/kg oral loading dose of CsA 4 to 6 hours prior to surgery. No further CsA was given until after surgery. If oral loading was not possible, 2 mg/kg intravenous CsA was administered over one hour intraoperatively after revascularization of the graft was completed.Renal recipients usually resumed oral intake within 12 to 24 hours after surgery and could be maintained on oral CsA 17.5 mg/kg per day in two divided doses. If needed, this was supplemented or replaced by intravenous CsA, 2 mg/kg given two or three times per day. Whole blood CsA trough levels were monitored daily using radioimmune assay tec...

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Cyclosporine-Associated Chronic Nephropathy

Cited by 1,109 publications

References 26 publications

Calcineurin A–Binding Protein, a Novel Modulator of the Calcineurin-Nuclear Factor of Activated T-Cell Signaling Pathway, Is Overexpressed in Wilms' Tumors and Promotes Cell Migration

Calcineurin A–Binding Protein, a Novel Modulator of the Calcineurin-Nuclear Factor of Activated T-Cell Signaling Pathway, Is Overexpressed in Wilms' Tumors and Promotes Cell Migration

Cyclosporine A Suppresses Cyclooxygenase-2 Expression in the Rat Kidney

Cyclosporine-Steroid Combination Therapy in 84 Cadaveric Renal Transplants

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