Treatment of acute kidney injury associated with cyclosporine overdose in a dog using hemodialysis and charcoal hemoperfusion.

OBJECTIVE: To describe the management of cyclosporine overdose using hemodialysis and hemoperfusion in a dog. CASE SUMMARY: A 6-year-old, spayed female Australian Shepherd was presented for treatment of cyclosporine overdose and acute kidney injury. Five days prior to presentation, the dog had been diagnosed by its referring veterinarian with immune-mediated thrombocytopenia. Treatment was initiated with prednisone, but since no response was noted, azathioprine (50 mg PO q 24 h) and cyclosporine (6 mg/kg IV q 24 h) were added. On day 4, an overdose of cyclosporine (33 mg/kg IV) was administered accidentally. Upon presentation, serum biochemistry panel revealed azotemia [creatinine, 521.6 µmol/L (5.9 mg/dL); BUN, 59.3 mmol/L (166 mg/dL)], increased activities of liver enzymes, and hyperbilirubinemia. Due to the presumed diagnosis cyclosporine overdose and acute kidney injury, a combined hemodialysis and charcoal hemoperfusion treatment was planned. Hemosorba CH-350 charcoal hemoperfusion cartridge was placed in series upstream in the extracorporeal circuit from the hemodialyzer. A 3-hour treatment was performed and a total of 0.74 L/kg of blood was processed. Pretreatment blood cyclosporine concentration was 960 nmol/L (1154 ng/mL) and decreased to 440 nmol/L (529 ng/mL) posttreatment (54% fractional reduction, 18% per hour). Thirty-one hours following treatment, blood cyclosporine concentration was 220 nmol/L (265 ng/mL; 1.5% decrease per hour). Twelve days following presentation to our hospital, the dog was euthanized due to lack of response to medical management. NEW OR UNIQUE INFORMATION PROVIDED: Combined hemodialysis and charcoal hemoperfusion treatment can significantly reduce blood cyclosporine concentrations following acute intoxication or overdosage, and should be considered as an option for decontamination in such cases.

Acute calcineurin inhibitor overdose: analysis of cases reported to a national poison center between 1995 and 2011.

Transplant recipients and other patients requiring immunosuppression with calcineurin inhibitors or their household contacts may be exposed to overdose. This study investigated the circumstances, pharmacokinetics and outcomes of overdose with cyclosporine and tacrolimus reported to the Swiss Toxicological Information Centre between 1995 and 2011. Of 145,396 reports by healthcare professionals, 28 (0.02%) concerned enteral or parenteral overdose with these calcineurin inhibitors. Thirteen (46%) were iatrogenic errors, 12 (43%) were with suicidal intent and 3 (11%) were accidental. Iatrogenic overdoses usually involved noncapsule drug formulations. Acute enteral overdoses caused symptoms in a dose-dependent fashion but were generally well tolerated; the mean multiple of patient's usual dose was 20.8 ± 28.8 for symptomatic versus 4.4 ± 3.4 for asymptomatic cases (p = 0.037). The most common symptoms were nausea, headache, somnolence, confusion, hypertension and renal impairment. In contrast, acute intravenous overdoses were often poorly tolerated and resulted in one fatality due to cerebral edema after a cyclosporine overdose. Enteral decontamination measures were performed in six cases involving oral ingestion and appeared to reduce drug absorption, as shown by pharmacokinetic calculations. In the one case where it was used, pharmacoenhancement appeared to accelerate tacrolimus clearance after intravenous overdose.

Management of cyclosporine overdose in a hematopoietic stem cell transplant patient with sequential plasma exchange and red blood cell exchange.

Cyclosporine is commonly used as an immunosuppressive agent in both solid organ and bone marrow transplant. While used for graft rejection in organ transplantation, cyclosporine has been used to enable tolerance and for prevention of acute graft-versus-host disease in bone marrow transplant [Ratanatharathorn et al., Blood 1998;92:2303-2314]. Cyclosporine has a narrow therapeutic window, and many patients develop some level of toxicity even within the therapeutic range. Common toxicities include hypertension, nephrotoxicity, electrolyte abnormalities, hyperglycemia, and neurotoxicity [Woo et al., Bone Marrow Transplant 1997;20:1095-1098]. Management of cyclosporine toxicity is not clearly defined and is primarily supportive in nature. In cases of significant elevations of cyclosporine levels, limited data are available but suggest that whole blood exchange may be effective [Kwon et al., J Heart Lung Transplant 2006;25:483-485; Leitner et al., Transplantation 2003;75:1764-1765]. We present a case of successful rapid clearance of cyclosporine utilizing a combined approach of red cell exchange and plasma exchange.

Dose switch to another dosage form of Neoral increase the risk of medication error?

BACKGROUND: One of the most significant ways to avoid medication errors is to study the errors that have occurred in other institutions and to use the information to prevent similar accidents at other practice sites. CASE REPORT: We report a cyclosporine overdose that was caused, in part, by misinterpretation of the medication order of a transplanted patient. In transplantation regimen, a 15 mg BID dose of cyclosporine was supposed to be given as part of the immunosuppressive therapy. Unfortunately the patient received a total of 1500 mg but survived the overdose. CONCLUSIONS: This case should be considered in the development of strategies to prevent unfavorable outcomes resulting from such errors.

Successful whole blood exchange by apheresis in a patient with acute cyclosporine intoxication without long-term sequelae.

Acute cyclosporine A (CsA) intoxication after organ transplantation may occur during the changeover from one form of drug to another, or from miscalculation of dosage. Sometimes, it may cause severe hepatotoxicity, nephrotoxicity and neurotoxicity. However, the therapeutic plasma exchange for the CsA intoxication was not established. Here, we present a case of very severe CsA intoxication after cardiac transplantation who recovered from intoxication without long-term sequelae via whole blood exchange; therapeutic erythrocytapheresis followed by total plasma exchange.

The effect of alpha-melanocyte-stimulating hormone on renal tubular cell apoptosis and tubulointerstitial fibrosis in cyclosporine A nephrotoxicity.

BACKGROUND: The pathogenesis of cyclosporine A (CsA)-induced nephrotoxicity has been known to be secondary to hemodynamic changes, but increasing evidence indicates that CsA has a direct toxicity to renal tubular cells, leading to their apoptosis and tubulointerstitial fibrosis. This study evaluated the mechanism for CsA-induced tubular cell apoptosis, tubulointerstitial fibrosis and its associated proteins, and the therapeutic effects of alpha-melanocyte-stimulating hormone (MSH) on them. METHODS: Male Sprague-Dawley rats fed with a low-sodium diet were divided into three treatment groups: group A (vehicle-injected group), group B (CsA 15 mg/kg-injected group), and group C(CsA+alpha-MSH-injected group). After 42 days, creatinine clearance; blood CsA level; apoptosis; inflammation and tubulointerstitial fibrosis in renal tissue; and the expression of Bax, Bcl2, Fas, FasL, and transforming growth factor (TGF)-beta protein were determined. RESULTS: CsA-induced tubular cell apoptosis; cellular infiltration; and increase of Fas, Bax, TGF-beta protein expression with significant tubulointerstitial fibrosis, and reduced Bcl2 protein expression. alpha-MSH treatment prevented the Bax and TGF-beta protein increase and induced Bcl2 protein increase, together with reduction of apoptosis, inflammation, and tubulointerstitial fibrosis. CONCLUSIONS: These findings suggest that chronic CsA nephrotoxicity is related to Bax and Bcl2-related apoptosis pathways, and that alpha-MSH can attenuate the CsA-induced tubulointerstitial fibrosis as well as tubular cell apoptosis.

Differentiation between chronic rejection and chronic cyclosporine toxicity by analysis of renal cortical mRNA.

BACKGROUND: In kidney transplantation, chronic allograft nephropathy (CAN) is the major cause of graft loss. Causes of CAN include chronic rejection and chronic cyclosporine A (CsA) nephrotoxicity. It is necessary to differentiate between these two entities in order to apply the appropriate therapeutic regimen for the individual patient, but this is hampered by the lack of discriminating functional and morphologic parameters. We investigated whether renal cortical mRNA levels for several matrix proteins can serve as discriminating parameters. METHODS: Patients with chronic rejection (N= 19) and chronic CsA toxicity (N= 17) were selected by clinical and histologic criteria. Protocol biopsies without histologic abnormalities, taken at 6 months after transplantation from patients receiving CsA, were used as controls (N= 6). Total RNA was extracted from the renal biopsy tissue, and mRNA levels of transforming growth factor-beta (TGF-beta) and the extracellular matrix (ECM) molecules collagen Ialpha1, IIIalpha1, IValpha3, decorin, fibronectin, and laminin beta2 were measured by real-time polymerase chain reaction (PCR). RESULTS: In both patient groups, the mean collagen IValpha3 and fibronectin mRNA levels were significantly elevated compared to those in controls, whereas only in CsA toxicity were the laminin beta2 and TGF-beta mRNA levels significantly increased. The increase of laminin beta2 and TGF-beta mRNA levels was significantly higher in the CsA toxicity group than in the chronic rejection group (P < 0.001 and P= 0.004, respectively). Receiver-operating characteristic (ROC) curve analysis showed that with a 15.6-fold increase in laminin beta2 mRNA expression as cut-off point, the presence of CsA toxicity could be predicted with an 87% sensitivity and an 88% specificity. CONCLUSION: Renal laminin beta2 and TGF-beta mRNA levels can be used to differentiate between chronic rejection and chronic CsA toxicity in renal transplants. The method of mRNA quantification might be applicable as an additional diagnostic tool in clinical practice.

Sirolimus increases transforming growth factor-beta1 expression and potentiates chronic cyclosporine nephrotoxicity.

BACKGROUND: Sirolimus (SRL) is increasingly being used to decrease cyclosporine (CsA) exposure. SRL is not known to be nephrotoxic and has a mechanism of action distinct from CsA. We investigated the effect of combining CsA and SRL on renal structure and function and on transforming growth factor-beta1 (TGF-beta1) and extracellular matrix (ECM) proteins in a model of chronic CsA nephrotoxicity. METHODS: Rats treated with vehicle, SRL 0.3 mg/kg/day, CsA 5 or 10 mg/kg/day, or CsA5+SRL were sacrificed at 7 or 28 days. Physiologic and histologic changes were studied in addition to TGF-beta1 mRNA and protein expressions, and mRNA expression of plasminogen activator inhibitor-1 (PAI-1) and ECM proteins biglycan and types I and IV collagen. RESULTS: While SRL alone did not alter renal function and structure, it potentiated the nephrotoxic actions of CsA when used in combination with low-dose CsA5 and resulted in significant changes similar to high-dose CsA10. In addition, SRL alone increased TGF-beta1 by 44% to 49% (P < 0.05 vs. VH). When used in combination with low-dose CsA5, SRL potentiated TGF-beta1 mRNA and protein by 121% and 176%, respectively (P < 0.05 vs. VH and CsA5), to levels achieved with high-dose CsA10. The expression of the ECM proteins followed that of TGF-beta1; a similar effect was observed with PAI-1, suggesting a decrease in ECM degradation. CONCLUSION: Because SRL augments nephrotoxicity, caution should be exercised when it is used in combination with CsA. More studies are needed to determine the long-term clinical impact of SRL on nephrotoxicity and allograft function.

Chronic cyclosporine nephrotoxicity: new insights and preventive strategies.

Cyclosporine (CsA) has improved patient and graft survival rates following solid-organ transplantation and has been increasingly applied with significant clinical benefits in the management of autoimmune diseases. However, the clinical use of CsA is often limited by acute and chronic nephrotoxicity, which remains a major problem. Acute nephrotoxicity depends on the dosage of CsA and seems to be caused by a reduction in renal blood flow related to afferent arteriolar vasoconstriction. However, the mechanisms underlying chronic CsA nephrotoxicity are not fully understood. Activation of the intrarenal renin-angiotensin system, increased release of endothelin-1, dysregulation of nitric oxide (NO) and NO synthase, upregulation of transforming growth factor-beta1, inappropriate apoptosis, stimulation of inflammatory mediators, and enhanced immunogenecity have all been implicated in the pathogenesis of chronic CsA nephrotoxicity. Reducing the CsA dose or withdrawing it and using combined nephroprotective drugs (mycophenolate mofetil, losartan, and pravastatin) may ameliorate chronic CsA-induced renal injury. This review discusses new insights and preventive strategies for this clinical dilemma.

Chronic Cyclosporine Nephrotoxicity: New Insights and Preventive Strategies

Cyclosporine (CsA) has improved patient and graft survival rates following solid-organ transplantation and has been increasingly applied with significant clinical benefits in the management of autoimmune diseases. However, the clinical use of CsA is often limited by acute and chronic nephrotoxicity, which remains a major problem. Acute nephrotoxicity depends on the dosage of CsA and seems to be caused by a reduction in renal blood flow related to afferent arteriolar vasoconstriction. However, the mechanisms underlying chronic CsA nephrotoxicity are not fully understood. Activation of the intrarenal renin-angiotensin system, increased release of endothelin-1, dysregulation of nitric oxide (NO) and NO synthase, upregulation of transforming growth factor-beta1, inappropriate apoptosis, stimulation of inflammatory mediators, and enhanced immunogenecity have all been implicated in the pathogenesis of chronic CsA nephrotoxicity. Reducing the CsA dose or withdrawing it and using combined nephroprotective drugs (mycophenolate mofetil, losartan, and pravastatin) may ameliorate chronic CsA-induced renal injury. This review discusses new insights and preventive strategies for this clinical dilemma.

Amelioration of cyclosporin A effect on microvasculature by endothelin inhibitor.

BACKGROUND: We have previously shown that endothelial injury by cyclosporin A (CyA) is associated with an increased endothelin-1 (ET-1) release. We now sought to determine, in an animal model of angiogenesis, if inhibiting the effect of ET-1 on endothelial cells (ECs) would reverse the CyA-mediated endothelial injury in an animal model of angiogenesis. METHODS: An angiogenic mixture of Matrigel (0.5 ml), fibroblast growth factor (1 ng/ml), vascular endothelial growth factor (100 ng/ml), and heparin (64 unit/ml) was injected as a subcutaneous plug in the flank of C3H mice (n = 5). In experimental groups CyA (20 mg/ml), CyA, and BQ 123 (ET-A receptor antagonist), CyA and PD 142893 (ET-A and ET-B receptor antagonist), or CyA and ET-1 antibody were added to the angiogenic mixture. Angiogenesis in the mixture was quantified by modified planimetric point counting method in skin/Matrigel cross-sections stained with factor VIII to highlight endothelial neocapillaries. Mean +/- SD of angiogenic area was analyzed with analysis of variance and Bonferroni test. The survival curves obtained by Kaplan-Meier analysis were compared between the groups, and the statistical significance of survival and mortality rates was computed by log rank's and Fisher's exact test, respectively. RESULTS: The mean +/- SD of angiogenic area in control animals (without CyA in the angiogenic mixture) was 56.76 +/- 4.2. CyA inhibited angiogenesis in the subcutaneous angiogenic plug. Adding CyA to the angiogenic mixture significantly reduced angiogenic area (5.33 +/- 1.4, P <.001) while vehicle for CyA had no such effect (56.33 +/- 3.8, P =.10). Polyclonal ET-1 antibody or PD 142893 ameliorated the effect of CyA, whereas BQ 123 did not. The mean angiogenic areas in animals with ET-1 antibody, PD 142893, or BQ 123 in the angiogenic mixture were 57.20 +/- 7.5 (P =.06), 46.00 +/- 11.5 (P = 1.0), 8.60 +/- 2.9 (P <.001), respectively. CONCLUSIONS: Our data show that blocking ET-B receptors specifically ameliorates the microvascular injury to the neocapillaries in angiogenesis caused by CyA. Antiendothelin-1 antibody and ETR antagonist (PD 142893) could, therefore, reduce the ill effects of CyA on microvascular endothelium.

Activation of transcription factors AP-1 and NF-kappaB in chronic cyclosporine A nephrotoxicity: role in beneficial effects of magnesium supplementation.

BACKGROUND: It has been shown that the transcription factors activator protein (AP)-1 and nuclear factor (NF)-kappaB play a pivotal role in various renal diseases. We aimed to study their activations in chronic cyclosporine A (CsA) nephrotoxicity and evaluate the effect of magnesium (Mg) supplementation and blockade of the renin-angiotensin system (RAS), which are known to ameliorate CsA nephrotoxicity, on these transcription factors. METHODS: CsA (15 mg/kg/day) was administered subcutaneously daily to rats maintained on a low-sodium diet for 7, 14, and 28 days. DNA-binding activities of AP-1 and NF-kappaB in renal cortex were determined by electrophoretic mobility shift assay. RESULTS: DNA-binding activity of AP-1 and NF-kappaB started to increase at day 14 and further elevated at day 28 by CsA treatment. These activations were markedly attenuated when rats were maintained on a high-Mg diet. In contrast, angiotensin-converting enzyme inhibitor (ACEI) had no effect on CsA-induced AP-1 activation. CsA-induced activation of NF-kappaB was suppressed by ACEI at day 14, whereas such effect could not be observed at day 28. CONCLUSIONS: Renal cortical AP-1 and NF-kappaB DNA binding were activated in chronic CsA nephrotoxicity. These activations were induced largely by means of RAS-independent mechanisms. It is suggested that prevention of CsA-induced DNA-binding activation of these transcription factors is at least in part responsible for the beneficial effects of Mg supplementation on CsA nephrotoxicity.

Nitric oxide modulates vascular endothelial growth factor and receptors in chronic cyclosporine nephrotoxicity.

BACKGROUND: Vascular endothelial growth factor (VEGF) is involved in angiogenesis, wound healing, and inflammation and exerts its effect via tyrosine kinase receptors, fms-like tyrosine kinase (Flt-1) and fetal liver kinase (Flk-1 or KDR). We have previously shown that VEGF is up-regulated in a model of chronic cyclosporine (CsA) nephrotoxicity and that l-arginine (l-Arg) improved while N-nitro-l-arginine-methyl ester (L-NAME) worsened fibrosis. We examined the role of nitric oxide modulation on VEGF in this model. METHODS: Pair-fed salt-depleted rats were administered CsA, CsA + L-NAME, CsA +l-Arg, vehicle (VH), VH + L-NAME or VH +l-Arg and were sacrificed at 7 or 28 days. Physiologic and histologic changes were studied in addition to the mRNA expression of VEGF and its receptors Flt-1 and KDR/Flk-1 by Northern blot and the protein expression of VEGF by Western blot and immunohistochemical staining. RESULTS: While L-NAME worsened renal function and histology, l-Arg had the opposite beneficial effect in CsA-treated rats. VEGF mRNA and protein expressions increased with CsA, further increased with L-NAME and became significantly reduced with L-Arg. Flt-1 expression was similar in all groups. On the other hand, KDR/Flk-1 mRNA expression was modulated in a fashion similar to VEGF. Also, nitric oxide modulation did not have an effect on VH-treated rats. CONCLUSIONS: VEGF expression in chronic CsA nephrotoxicity is increased by nitric oxide blockade and decreased by nitric oxide enhancement. Moreover, VEGF probably exerted its effect via the KDR/Flk-1 receptor. The actions of VEGF in this model remain speculative, but it is probable that VEGF plays a role, either independently or through nitric oxide, in CsA-induced fibrosis.

Role of endogenous vascular endothelial growth factor in tubular cell protection against acute cyclosporine toxicity.

BACKGROUND: Recent studies have shown that exogenous administration of vascular endothelial growth factor (VEGF) is protective against cyclosporine A (CsA) renal toxicity. No data are available, however, on the possible role of endogenous VEGF. Our objective was to examine whether endogenous VEGF has a significant role in the renal response against CsA toxicity. METHODS: In vivo, we used high-dose (50-150 mg/kg/day) CsA +/- specific goat anti-mouse VEGF blocking monoclonal antibody (alpha-VEGF) in mice. In vitro, we exposed mouse tubular cells (MCT) to CsA +/- alpha-VEGF. RESULTS: alpha-VEGF markedly enhanced CsA renal toxicity, inducing severe tubular damage and increased blood urea nitrogen. In animals treated with CsA + alpha-VEGF, damage progressed to generalized tubular injury (histology) and apoptosis (terminal deoxynucleotide transferase-mediated dUTP nick-end labeling) with associated anemia and reticulocytosis (18 days of treatment). CsA + alpha-VEGF treatments strikingly increased tubular VEGF and Bcl-xL proteins. In vitro, autocrine production of VEGF by MCT was identified by Western blot. Of specific interest, CsA toxicity in MCT increased significantly in the presence of alpha-VEGF. CONCLUSIONS: Endogenous VEGF has a relevant role in the renal tubular defense against CsA toxicity. Blockade of the VEGF effect by alpha-VEGF results in clear-cut intensification of the tubular injury and appearance of regenerative anemia in the CsA + alpha-VEGF-treated animals. The occurrence of both in vivo and in vitro effects of VEGF blockade provides evidence of a direct protective effect of VEGF on the tubular cell.

Disparate effects of chronic and acute theophylline on cyclosporine A nephrotoxicity.

We previously developed a model of acute cyclosporine A (CsA)-induced vasomotor nephrotoxicity in rabbits. As exogenous adenosine infusion mimics the haemodynamic changes that characterize acute renal failure (ARF), we wanted to know whether adenosine was a mediator in this model and whether an adenosine receptor blocker could prevent the CsA-induced ARF. Group 1 were untreated controls. Group 2 received CsA (25 mg/kg per day) for 5 days. Renal function parameters were measured, showing ARF in all animals compared to controls. Theophylline (1 mg/kg i.v. bolus) was then administered and renal function was reassessed. Theophylline significantly reduced renal vascular resistance (-8%) and increased renal blood flow (RBF) (+20%), glomerular filtration rate (GFR) (+50%), filtration fraction (+24%) and diuresis (+73%), suggesting that adenosine was involved in the CsA-induced ARF. In group 3, theophylline (30 mg/kg per day) was given concomitantly with CsA for 5 days. GFR was normalized, but theophylline did not hinder the drop in RBF seen with CsA alone in group 2. Microscopy observation of the kidneys showed that chronic theophylline administration aggravated the morphological changes induced by CsA alone. We conclude that CsA administration for 5 days induced a vasomotor nephropathy with an adenosine-mediated afferent arteriolar constriction which cannot be prevented by concomitant theophylline administration.

Conversion from cyclosporine to FK506 in adult liver transplant recipients: a combined North American and European experience.

BACKGROUND: Although cyclosporine (CsA) made clinical liver transplantation possible, side effects and development of rejection have limited its use. In some patients, conversion to tacrolimus has been necessary to abrogate side effects and to preserve allograft function. METHODS: The results of conversion from CsA to tacrolimus were studied retrospectively in 94 liver allograft recipients from a North American and a European transplant center (Duke University Medical Center, Durham, NC, and Hopital Beaujon, Clichy, France). RESULTS: Forty-seven of 94 patients (50%) were converted for steroid-resistant acute rejection. Conversion was successful in 91% of these patients, whereas 9% of patients developed chronic rejection. A further nine patients were converted for chronic allograft rejection with positive results in eight of nine grafts. Mean serum bilirubin in these nine patients was 8.7 mg/dl before conversion and 2.1 mg/dl 6 months after conversion (P=0.02). Nine patients were converted due to inability to wean steroid. Of these, six patients remains steroid free 1 year after conversion. Twenty-three patients (24%) were converted for nephrotoxicity with a reduction in serum creatinine from 167+/-36 mmol/L to 119+/-28 mmol/L 1 year after conversion (P=0.006). Eight of 11 patients converted for neurotoxicity improved after conversion. Conversion to tacrolimus had no effect on seizure frequency or memory loss. CONCLUSIONS: These results suggest that conversion to tacrolimus from CsA is an appropriate paradigm for graft rescue and treatment of a variety of side effects after liver transplant. However, some situations such as memory loss and hypertension may require other strategies.

Effect of low dose cyclosporine and sirolimus on hepatic drug metabolism in the rat1.

BACKGROUND: We examined the effect cyclosporine (CsA) and sirolimus (SRL) alone and in combination on hepatic cytochrome P450-mediated metabolism in rats. METHODS: Rats were given 1 mg/kg of CsA or 0.4 mg/kg of SRL alone or in combination via constant intravenous infusion. Renal function was evaluated at the end of treatment. Blood samples were obtained to estimate CsA and SRL concentrations. Hepatic microsomes were prepared for immunoblotting and catalytic assays. RESULTS: CsA alone did not alter serum creatinine levels. SRL given alone or in combination with CsA produced a significant increase in urine output without changes in fluid balance. Although CsA and SRL administered alone caused damage to renal proximal tubules, the two-drug combination dramatically increased the renal structural damage. CsA alone suppressed cytochrome P450 (CYP) 3A2 protein levels by 39% (P=0.012) and catalytic activity by 30% (P=0.042). SRL alone reduced catalytic activity by 38% (P=0.012). Combination therapy reduced both CYP3A2 levels by 55% (P<0.001) and catalytic activity by 55% (P=0.001). CYP2C11 protein expression or catalytic activity were not changed in any group. CYP2A1 protein expression and catalytic activity were both significantly reduced in rats given CsA or/and SRL. Steady-state CsA levels were increased during concurrent SRL dosing, however, SRL concentrations were not changed by CsA coadministration. CONCLUSIONS: Concurrent SRL dosing increases CsA concentrations due to inhibition of hepatic CYP3A2 protein expression. Nephrotoxicity caused by combination therapy is due to CsA elevating levels of SRL or by SRL itself. Concurrent administration of CsA and SRL in transplant patients should be performed with caution.