Calcineurin inhibitor-induced nephrotoxicity and renal expression of P-glycoprotein

Pharmacotherapy. 2005 Jun;25(6):779-89. doi: 10.1592/phco.2005.25.6.779.

Abstract

Study objective: To evaluate immunohistochemistry staining patterns for P-glycoprotein (P-gp) and a marker of early apoptosis (active caspase-3) in renal biopsy specimens obtained from solid organ transplant recipients with nephrotoxicity and those from a control group.

Design: Retrospective analysis of pathology specimens and medical records.

Setting: Medical university.

Subjects: Twenty-nine solid organ transplant recipients with nephrotoxicity and 32 control patients.

Measurements and main results: Medical records were reviewed for patient demographics, clinical laboratory results, and prescribed drugs. Immunohistochemistry techniques using primary antibodies to P-gp and active caspase-3 were performed to evaluate staining patterns of these proteins in the kidney specimens. Differences in measures of interest between groups were compared with the Fisher exact test for categoric data and Wilcoxon rank sum test for continuous data. Logistic and linear modeling were used to evaluate difference in measures of P-gp and active caspase-3 between groups while controlling for confounders. Immunohistochemistry confirmed the presence of P-gp in the renal tubules (apical and basal membranes and cytoplasm). Intensity of P-gp staining (score range 0-4) was reduced in renal specimens of transplant recipients with nephrotoxicity compared with the control specimens (mean +/- SD intensity scores 3.2 +/- 0.7 vs 3.8 +/- 0.4, p=0.0002). Neither P-gp-inducing nor P-gp-inhibiting drugs predicted expression of P-gp in the renal specimens of either group. The extent of tubular staining (score range 1-4) for the apoptosis marker, active caspase-3, was less in the nephrotoxicity group than in the control group (mean +/- SD extent scores 1.7 +/- 0.6 vs 2.8 +/- 0.5, p=0.0003).

Conclusion: P-glycoprotein expression was less pronounced in renal biopsy specimens with calcineurin inhibitor-induced nephrotoxicity compared with the nonnephrotoxic control specimens. Reduced P-gp expression was evident even when the analysis controlled for factors such as renal function, age, sex, race, diabetes mellitus, level of proteinuria, or prescribed therapy with P-gp inducers or inhibitors. Interpretation of the results from active caspase-3 staining requires further study.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / isolation & purification
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism*
  • Adult
  • Calcineurin Inhibitors*
  • Case-Control Studies
  • Coloring Agents
  • Cyclosporine / adverse effects*
  • Cyclosporine / therapeutic use
  • Female
  • Humans
  • Immunosuppressive Agents / adverse effects*
  • Immunosuppressive Agents / therapeutic use
  • Kidney Diseases / chemically induced
  • Kidney Diseases / pathology*
  • Kidney Transplantation*
  • Logistic Models
  • Male
  • Tacrolimus / adverse effects*
  • Tacrolimus / therapeutic use

Substances

  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Calcineurin Inhibitors
  • Coloring Agents
  • Immunosuppressive Agents
  • Cyclosporine
  • Tacrolimus