Calcineurin Inhibitor-Induced Nephrotoxicity and Renal Expression of P-Glycoprotein

Melanie S. Joy, Pharm.D., FCCP; Volker Nickeleit, M.D.; Susan L. Hogan, Ph.D.; Bawana D. Thompson, B.S.; William F. Finn, M.D.


Pharmacotherapy. 2005;25(6):779-789. 

In This Article

Abstract and Introduction

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 B1 SD intensity scores 3.2 B1 0.7 vs 3.8 B1 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 B1 SD extent scores 1.7 B1 0.6 vs 2.8 B1 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.

The transplant drug protocols that use the calcineurin inhibitors cyclosporine and tacrolimus have greatly improved organ and patient survival. Recent reports suggest 5-year cadaveric kidney and liver graft survival rates, respectively, are 65.7% and 64.1%.[1] The risk associated with this improved immunosuppression with cyclosporine and tacrolimus is often drug-induced nephrotoxicity. Nephrotoxicity secondary to calcineurin inhibitors is thought to occur in 52% and 75% of liver and heart organ transplant recipients, respectively.[2,3] Histologic evidence of calcineurin inhibitor-induced nephrotoxicity in kidney transplant recipients may be as high as 76.4% and 93.5% in patients at 1 and 5 years after transplantation, respectively.[4] The clinical manifestations accompanying calcineurin inhibitor-induced nephrotoxicity are elevations in serum creatinine and blood urea nitrogen levels, abnormalities in acid-base and electrolyte regulation, and renal endocrine abnormalities with deficiencies in erythropoietin and 1,25 dihydroxyvitamin D.

The mechanisms of renal damage induced by cyclosporine and tacrolimus are thought to occur by either hemodynamically mediated changes in renal blood flow or direct anatomic injury to blood vessels, glomeruli, tubular epithelial cells, or renal interstitium.[5,6,7] Renal biopsy findings consistent with calcineurin inhibitor-induced nephrotoxicity are well described and include arteriolopathy, microthrombi, and tubular vacuolization.[5,6,8,9] Several risk factors for nephrotoxicity have been suggested, including advanced age, preexistent renal disease, and intravascular volume depletion. One confounding problem with the identification of risk factors for nephrotoxicity from calcineurin inhibitors is the widespread variability in the occurrence and severity of nephrotoxic injury across these patients. The identification of specific risk factors, perhaps at the cellular level, may greatly reduce the rates of nephrotoxicity by allowing drug therapy modifications at the start of the nephrotoxic event or even before the presentation of the toxic response.

The role of drug transporters such as P-glycoprotein (P-gp) in modulating risks of nephro-toxicity is intriguing. Transporters, especially those located on the apical membranes of renal cell structures, have the ability to move toxic substances from the interior to the exterior of cells, resulting in a detoxification type of reaction. Recent research has suggested that P-gp is located on the apical membranes of human renal structures, with predominance in the tubules.[10,11,12,13] Since P-gp has been associated with regulation of toxicity and efficacy to cancer chemotherapy, it is inter-esting to ponder the association of this transporter with cellular toxicity (e.g., nephrotoxicity associated with cyclosporine and tacrolimus, as both of these compounds are transported by P-gp).[14,15] P-glycoprotein may also play a role in the apoptotic response to nephrotoxicity, with recent data suggesting that P-gp may regulate the apoptotic cascade.[16,17] Thus, not only could the cellular expression of P-gp affect the ability to exhibit nephrotoxicity, but also P-gp could modulate the process of apoptosis that can be associated with the toxicity.

The purpose of this study was to evaluate P-gp and active caspase-3 (as a marker of early stages of apoptosis) localization and staining intensity patterns in renal biopsy specimens from solid organ transplant recipients who exhibited calcineurin inhibitor-induced nephrotoxicity. These were compared with a control group of renal biopsy specimens from patients with various renal diagnoses, but without nephrotoxicity. The main hypothesis for this study was that solid organ transplant recipients with nephrotoxicity would exhibit reduced expression and/or intensity of staining for P-gp. We also hypothesized that the nephrotoxicity group would have increased expression and/or intensity of staining for active caspase-3 since the reduced P-gp expression would limit the ability of P-gp to modulate the apoptotic cascade.


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