Chronic Injury of Human Renal Microvessels With Low-Dose Cyclosporine Therapy

Myers, Bryan D.; Newton, Lynne; Boshkos, C; Macoviak, John A.; Frist, William H.; Derby, Geraldine C.; Perlroth, Mark G.; Sibley, Richard K.

doi:10.1097/00007890-198811000-00014

Cited by 151 publications

(51 citation statements)

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“…However, because no routine kidney biopsies are performed in nonrenal transplant recipients, not much data are available on the evolution of histologic CNI nephrotoxicity. In a study in cardiac transplant recipients, patients treated with low doses of cyclosporine had slightly lower mean serum creatinine concentrations, but similar pathologic changes were seen on the renal biopsies when compared with biopsies from patients treated with higher cyclosporine doses (265). This again suggests that low versus high dosage of cyclosporine confers only marginal protection against CNI-mediated injury.…”

Section: Systemic Levels Of Cyclosporine and Tacrolimusmentioning

confidence: 85%

Calcineurin Inhibitor Nephrotoxicity

Naesens

Kuypers²,

Sarwal³

2009

Clinical Journal of the American Society of Nephrology

1,241

1,000

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The use of the calcineurin inhibitors cyclosporine and tacrolimus led to major advances in the field of transplantation, with excellent short-term outcome. However, the chronic nephrotoxicity of these drugs is the Achilles' heel of current immunosuppressive regimens. In this review, the authors summarize the clinical features and histologic appearance of both acute and chronic calcineurin inhibitor nephrotoxicity in renal and nonrenal transplantation, together with the pitfalls in its diagnosis. The authors also review the available literature on the physiologic and molecular mechanisms underlying acute and chronic calcineurin inhibitor nephrotoxicity, and demonstrate that its development is related to both reversible alterations and irreversible damage to all compartments of the kidneys, including glomeruli, arterioles, and tubulo-interstitium. The main question-whether nephrotoxicity is secondary to the actions of cyclosporine and tacrolimus on the calcineurin-NFAT pathway-remains largely unanswered. The authors critically review the current evidence relating systemic blood levels of cyclosporine and tacrolimus to calcineurin inhibitor nephrotoxicity, and summarize the data suggesting that local exposure to cyclosporine or tacrolimus could be more important than systemic exposure. Finally, other local susceptibility factors for calcineurin inhibitor nephrotoxicity are reviewed, including variability in P-glycoprotein and CYP3A4/5 expression or activity, older kidney age, salt depletion, the use of nonsteroidal anti-inflammatory drugs, and genetic polymorphisms in genes like TGF-␤ and ACE. Better insight into the mechanisms underlying calcineurin inhibitor nephrotoxicity might pave the way toward more targeted therapy or prevention of calcineurin inhibitor nephrotoxicity.Clin J Am Soc Nephrol 4: 481-508, 2009. doi: 10.2215/CJN.04800908 T he introduction of the calcineurin inhibitor (CNI) cyclosporine in human kidney transplantation in the late 1970s revolutionized transplantation medicine, and made transplantation a preferable therapeutic intervention for end-stage renal diseases (1,2). In 1984, the potent immunosuppressive properties of another CNI, tacrolimus, were discovered, and tacrolimus was used successfully in human liver, kidney, and heart allograft recipients (3,4). Currently, 94% of kidney transplant recipients are discharged after transplantation with a CNI-based immunosuppressive regimen (5).The immunosuppressive properties of cyclosporine and tacrolimus result from inhibition of calcineurin, a calcium-and calmodulin-dependent phosphatase (protein phosphatase 3 [PPP3C], formerly PP2B). Intracellularly, these completely different molecules bind to cyclophylin and FKBP12 for cyclosporine and tacrolimus, respectively (6 -9). The competitive binding of cyclosporine-cyclophylin and tacrolimus-FKBP12 complexes to calcineurin inhibits phosphatase activity of calcineurin. This inhibition then suppresses the transcription of IL-2 via inhibition of the dephosphorylation and impaired translocation of the nucl...

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Section: Systemic Levels Of Cyclosporine and Tacrolimusmentioning

confidence: 85%

Calcineurin Inhibitor Nephrotoxicity

Naesens

Kuypers²,

Sarwal³

2009

Clinical Journal of the American Society of Nephrology

1,241

1,000

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“…3 and 7) within the arterioles (57,61,101). Immunofluorescence examination shows these deposits to contain several proteins including fibrin, immunoglobulin M, C3, and Clq.…”

Section: Arteriolar Hyalinosismentioning

confidence: 99%

“…It should be kept in mind, however, that focal segmental sclerosis is also a nonspecific lesion that may be observed in many diseases, including chronic rejection, renal artery stenosis, recurrent glomerulonephritis, and reflux nephropathy. The pathogenesis in cases of drug-induced injury may reflect segmental ischemic collapse of the glomerular capillary loops secondary to the lesion of arteriolar hyalinosis (57,61,101). Resolution of intraglomerular capillary thrombosis could account for some cases (76,82).…”

Section: Glomerular Pathologymentioning

confidence: 99%

Tacrolimus (FK506)-Associated Renal Pathology

Randhawa¹,

Starzl

Demetris³

1997

Advances in Anatomic Pathology

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“…Because CsA is known to induce intense afferent arteriolar vasoconstriction (3,4), it has been presumed that the above tubulointerstitial changes are the result of chronic low grade ischemia. However recent studies showed that CsA could be directly toxic to renal tubular cells with site selective action on proximal tubule (5,6).…”

Section: Introductionmentioning

confidence: 99%

α-Melanocyte Stimulating Hormone (MSH) decreases cyclosporine A induced apoptosis in cultured human proximal tubular cells

Lee

Han

et al. 2001

J Korean Med Sci

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The pathogenesis of chronic cyclosporine A (CsA) nephrotoxicity has not been elucidated, but apoptosis is thought to play an important role in CsA induced tubular atrophy. Recently Fas-Fas ligand system mediated apoptosis has been frequently reported in many epithelial cells as well as in T lymphocytes. We investigated the ability of CsA to induce apoptosis in cultured human proximal tubular epithelial cells and also the effect of alpha-MSH on them. Fas, Fas ligand, and an intracellular adaptor protein, Fas-associating protein with death domain (FADD) expression, and poly-ADP ribose polymerase (PARP) cleavage were also studied. CsA induced apoptosis in cultured tubular epithelial cells demonstrated by increased number of TUNEL positive cells and it was accompanied by a significant increase in Fas mRNA and Fas ligand protein expressions. FADD and the cleavage product of PARP also increased, indicating the activation of caspase. In alpha-MSH co-treated cells, apoptosis markedly decreased with downregulation of Fas, Fas ligand and FADD expressions and also the cleavage product of PARP. In conclusion, these data suggest that tubular cell apoptosis mediated by Fas system may play a role in tubular atrophy in chronic CsA nephrotoxicity and pretreatment of alpha-MSH may have a some inhibitory effect on CsA induced tubular cell apoptosis.

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Chronic Injury of Human Renal Microvessels With Low-Dose Cyclosporine Therapy

Cited by 151 publications

References 0 publications

Calcineurin Inhibitor Nephrotoxicity

Calcineurin Inhibitor Nephrotoxicity

Tacrolimus (FK506)-Associated Renal Pathology

α-Melanocyte Stimulating Hormone (MSH) decreases cyclosporine A induced apoptosis in cultured human proximal tubular cells

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