Long-term Cyclosporin A Treatment Research Articles

Cyclosporine A-induced systemic metabolic perturbations in rats: A comprehensive metabolome analysis

A better understanding of cyclosporine A (CsA)-induced nephro- and hepatotoxicity at the molecular level is necessary for safe and effective use. Utilizing a sophisticated study design, this study explored metabolic alterations after long-term CsA treatment in vivo. Rats were exposed to CsA with 4, 10, and 25 mg/kg for 4 weeks and then sacrificed to obtain liver, kidney, urine, and serum for untargeted metabolomics analysis. Differential network analysis was conducted to explore the biological relevance of metabolites significantly altered by toxicity-induced disturbance. Dose-dependent toxicity was observed in all biospecimens. The toxic effects were characterized by alterations of metabolites related to energy metabolism and cellular membrane composition, which could lead to the cholestasis-induced accumulation of bile acids in the tissues. The unfavorable impacts were also demonstrated in the serum and urine. Intriguingly, phenylacetylglycine was increased in the kidney, urine, and serum treated with high doses versus controls. Differential correlation network analysis revealed the strong correlations of deoxycytidine and guanosine with other metabolites in the network, which highlighted the influence of repeated CsA exposure on DNA synthesis. Overall, prolonged CsA administration had system-level dose-dependent effects on the metabolome in treated rats, suggesting the need for careful usage and dose adjustment.

Low dose of cyclosporine A disrupts sperm parameters and testosterone levels reversibly in mice

The prevalence of autoimmune diseases has increased worldwide, including in men of reproductive age. Cyclosporine A (CsA) is an immunosuppressive drug commonly used for long periods in the prophylaxis and treatment of autoimmune dysfunction and transplant rejection. Owing to CsA toxicity, most clinical settings use lower CsA doses. Therefore, we evaluated whether a low dose (10 mg/kg) of CsA affects sperm parameters (daily sperm production, motility, morphology, mitochondrial activity, and acrosomal integrity), plasma testosterone levels, and fertility after short-term (10 days) and long-term (50 days) treatments in mice. Short-term CsA treatment partially affected sperm parameters and fertility, as shown by the reduction in sperm hyperactivation and gestational rate 10 days after the interruption of short-term CsA treatment. Long-term CsA treatment impairs sperm count, hyperactivated motility, and acrosomal integrity. This treatment regimen further decreased plasma testosterone concentrations but did not affect reproductive outcomes in mating trials. These outcomes were reversed 50 days after the interruption of long-term CsA treatment. We conclude that a low CsA dose differentially impairs sperm parameters and testicular steroidogenesis in a time-dependent and mostly reversible manner but does not affect male fertility.

Long-term cyclosporine A treatment promotes anxiety-like behavior: Possible relation with glutamate signaling in rat hippocampus

• Long-term CsA treatment induces anxiety-like behavior; • Hippocampus of CsA-treated rats presents increased GluN2 levels, NOS and CREB activities; • Chronic CsA administration affects hippocampal adaptive responses that can induce anxiogenic behavior. Chronic immunosuppressive treatment with cyclosporine A (CsA) leads to multiple side effects, including some that occur in the central nervous system (CNS). This study aims to investigate the impact of long-term CsA treatment on anxiety behavior and verify the alterations related to glutamate signaling in the rat hippocampus. Adult male Wistar rats were intraperitoneally injected with 15 mg/kg/day CsA for eight weeks, subjected to anxiety tests, and had their brains collected for biochemistry and Western blot analysis. Herein, we reported that eight weeks of CsA treatment promoted an anxiety-like effect and increased N-methyl-D-aspartate receptor (NMDAR) GluN2 subunit levels, nitric oxide synthase, and cAMP-response element binding protein (CREB) activities. Future work should consider the impact of long-term CsA treatment on NMDAR function, as well as on other neurotransmitter signaling pathways. Peripheral side effects should also be considered a factor that could lead to CsA-induced neuropsychiatric effects. In conclusion, this work reports modifications to CNS adaptive responses following chronic CsA treatment, which can influence anxiogenic behavior and other associated neurotoxic events. Understanding the mechanisms underlying CsA-induced neuropsychiatric side effects is an important step toward better symptom management in patients submitted to immunosuppression in the clinical setting.

Metformin and silymarin afford protection in cyclosporine A induced hepatorenal toxicity in rat by modulating redox status and inflammation.

The use of cyclosporine A (CsA) as an immunosuppressive agent is often limited owing to its hepatotoxic and nephrotoxic properties. The present study was designed to evaluate the protective effect of metformin and silymarin in a rat model of CsA induced hepatorenal toxicity. The study included seven groups of Wistar albino rats (n = 6 per group): normal control, experimental control (CsA alone, 25 mg/kg), CsA + metformin (50 and 500 mg/kg), CsA + silymarin (50 and 200 mg/kg) and CsA + vitamin E (100 mg/kg). All the drugs were given daily for a period of 21 days by oral gavage and their effect was evaluated on serum levels of organ function markers (serum glutamate pyruvate transaminase, serum glutamate oxaloacetate transaminase, bilirubin, urea/blood urea nitrogen, creatinine), markers of oxidative stress (thiobarbituric acid reactive substances, glutathione, superoxide dismutase), inflammation (nitrite, myeloperoxidase, tumour necrosis factor-alpha, prostaglandin E2 ), apoptosis (terminal deoxynucleotidyl transferase dUTP nick end labelling positivity) in addition to tissue histology, cyclooxygenase (COX)-2 and inducible nitric oxide synthase (iNOS) immunoreactivity. Administration of metformin and silymarin along with CsA ameliorated functional damage to liver and kidneys in a dose-dependent manner. Significant and comparable improvement in the tissue levels of oxidative stress, inflammation, apoptotic markers was also observed following treatment with both the test drugs. Normalization of histology scores, as well as COX-2 and iNOS immunoreactivity scores, further strengthened these findings. The hepatoprotective and nephroprotective effects of metformin and silymarin were comparable and matched with that of reference drug, vitamin E. The findings of the present study suggest that both metformin and silymarin have a potential for clinical use in patients receiving long-term CsA treatment to maintain their liver and kidney functions.

Differential expression of cyclosporine A-Induced calcineurin isoform-specific matrix metalloproteinase 9 (MMP-9) in renal fibroblasts

Long-term treatment with the potent immunosuppressive drug cyclosporine A (CsA) results in chronic nephrotoxicity. Its immunosuppressive properties are due to the inhibition of the calcium- and calmodulin-dependent phosphatase protein calcineurin A (CnA) which has three catalytic isoforms. Of those, the CnAα and β isoforms are ubiquitously expressed, particularly in the kidney. Additionally, chronic nephrotoxicity has been associated with an imbalance of extracellular matrix (ECM) synthesis and degradation resulting in an accumulation of ECM molecules. This study evaluates whether the expressions of matrix metalloproteinases (MMP-2 and MMP-9) induced by CsA are calcineurin isoform specific. Wild-type (WT), CnAα knockout (CnAα−/−) and CnAβ knockout (CnAβ−/−) kidney fibroblast cell lines (an in vitro innovative tool that was previously created in our lab) were treated with CsA at 10 ng/ml for 48 h. ELISA analysis demonstrated that the CsA-induced secretion profile of MMP-9 was highest in CnAα−/− cells and lowest in CnAβ−/− cells vs. WT cells. In contrast, CsA did not induce an increase in MMP-2 protein levels in WT, CnAα−/− nor CnAβ−/− renal fibroblasts. These results indicate that MMP-9 secretion is CnA-isoform specific, i.e. the CnAβ isoform contributes to the CsA-induced upregulation of MMP-9 while the CnAα does not. As such, understanding the role of calcineurin A isoforms in the regulation of the homeostasis of ECM degradation in the kidney after long-term CsA treatment needs to be further investigated.

Abstract A11: Cyclosporin A promotes tumor angiogenesis in a calcineurin-independent manner by increasing mitochondrial reactive oxygen species

Abstract The commonly used immunosuppressant cyclosporin A (CsA), a potent calcineurin inhibitor, significantly increases the incidence of cancer in organ transplant patients. Calcineurin signaling is an important mediator of VEGF signaling in endothelial cells. Negative regulation of calcineurin by its endogenous inhibitor, Down Syndrome Candidate Region-1 (DSCR1), suppresses tumor growth and angiogenesis, in contrast to the effect observed after long-term CsA treatment. Despite the significance of calcineurin signaling in endothelial cells, the consequences of CsA on tumor angiogenesis has not been investigated. Using an in vivo model of skin carcinogenesis, we show that long-term CsA treatment promotes tumor growth and angiogenesis. Treatment of endothelial cells in vitro with CsA increases proliferation and migration in a calcineurin-independent manner and is associated with increased mitochondrial reactive oxygen species. Co-treatment with antioxidants significantly abrogated CsA-induced endothelial cell activation. Furthermore, mice treated with antioxidants were protected against CsA-mediated tumor progression. Taken together, these findings show that CsA functions independent of calcineurin to potentiate tumor growth by promoting tumor angiogenesis via mitochondrial reactive oxygen species production. This work identifies a previously undescribed mechanism underlying a significantly adverse off-target effect of CsA and suggests that co-treatment with antioxidants may inhibit the tumor promoting effects of CsA. Citation Format: Alice Yao Zhou, Sandra W. Ryeom. Cyclosporin A promotes tumor angiogenesis in a calcineurin-independent manner by increasing mitochondrial reactive oxygen species. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr A11. doi:10.1158/1538-7445.CHTME14-A11

Excessive microglial activation aggravates olfactory dysfunction by impeding the survival of newborn neurons in the olfactory bulb of Niemann–Pick disease type C1 mice

Progressive olfactory impairment is one of the earliest markers of neurodegeneration. However, the underlying mechanism for this dysfunction remains unclear. The present study investigated the possible role of microgliosis in olfactory deficits using a mouse model of Niemann–Pick disease type C1 (NPC1), which is an incurable neurodegenerative disorder with disrupted lipid trafficking. At 7weeks of age, NPC1 mutants showed a distinct olfactory impairment in an olfactory test compared with age-matched wild-type controls (WT). The marked loss of olfactory sensory neurons within the NPC1 affected olfactory bulb (NPC1-OB) suggests that NPC1 dysfunction impairs olfactory structure. Furthermore, the pool of neuroblasts in the OB was diminished in NPC1 mice despite the intact proliferative capacity of neural stem/progenitor cells in the subventricular zone. Instead, pro-inflammatory proliferating microglia accumulated extensively in the NPC1-OB as the disease progressed. To evaluate the impact of abnormal microglial activation on olfaction in NPC1 mice, a microglial inhibition study was performed using the anti-inflammatory agent Cyclosporin A (CsA). Importantly, long-term CsA treatment in NPC1 mice reduced reactive microgliosis, restored the survival of newly generated neurons in the OB and improved overall performance on the olfactory test. Therefore, our study highlights the possible role of microglia in the regulation of neuronal turnover in the OB and provides insight into the possible therapeutic applications of microglial inhibition in the attenuation or reversal of olfactory impairment.

Clinical evaluation of chronic nephrotoxicity of long‐term cyclosporine A treatment in adult patients with steroid‐dependent nephrotic syndrome

Chronic nephrotoxicity of long-term cyclosporine A (CsA) treatment is a matter of concern in patients with steroid-dependent nephrotic syndrome (SDNS). Twenty-eight adult NS patients (25, minimal-change nephrotic syndrome (NS); three, focal-segmental glomerulosclerosis) were divided into three groups. Group A was continuously treated with CsA for more than 5 years (143 ± 40 months, 1.3 ± 0.4 mg/kg per day at final analysis, n = 12); group B had been previously treated with CsA (70 ± 27 months, n = 6); and group C had been treated with corticosteroids alone (n = 10). The clinical variables related to chronic CsA nephrotoxicity were examined. In groups A and B, estimated glomerular filtration rate decreased from 86 ± 22 and 107 ± 17 to 83 ± 23 and 88 ± 13 mL/min per 1.73 m(2) , respectively, at final analysis (both P < 0.05). Serum magnesium levels in group A were significantly lower than those in group B or C (A, 1.78 ± 0.16 mg/dL; B, 2.00 ± 0.14 mg/dL; C, 2.03 ± 0.10 mg/dL; A vs B, C, P < 0.01), and a significant correlation between these and the duration of CsA treatment was found (r = -0.68, P < 0.001). There was a trend towards a correlation between the duration of CsA administration and urinary α1-microglobulin (r = 0.38, P = 0.07). Mild decrease in renal function and hypomagnesemia were found in adult SDNS patients with long-term CsA treatment. Careful monitoring of renal function, blood pressure and serum magnesium levels is necessary.

Serum indoxyl sulfate as an early marker for detecting chronic cyclosporine nephrotoxicity

Cyclosporine A (CsA) is an effective agent for frequently relapsing steroid-dependent nephrotic syndrome (FR-SDNS), but its use can also be complicated by renal toxicity. Because no biochemical markers from urine or blood samples have yet been established for detecting CsA-induced renal injury to date, repeated renal biopsies are therefore required for all patients with long-term CsA treatment. The purpose of the present study was therefore to detect early change of CsA nephropathy (CsAN) using blood samples. Several biochemical markers were analyzed in an attempt to examine the renal function in 24 patients with FR-SDNS who had been treated with CsA. Those included serum cystatin C and indoxyl sulfate, as well as creatinine and beta2-microglobulin. Renal biopsy findings indicated chronic CsAN in 13 of the 24 patients. Among those markers, only serum indoxyl sulfate was significantly elevated in patients with CsAN. It may be possible for measurement of serum indoxyl sulfate level to replace repeated renal biopsies in evaluation of chronic CsAN in pediatric patients with FR-SDNS.

Long-Term Topical Cyclosporine Treatment Improves Tear Production and Reduces Keratoconjunctivitis in Rabbits With Induced Autoimmune Dacryoadenitis

To use a rabbit model of induced autoimmune dacryoadenitis to evaluate the efficacy of topical ophthalmic cyclosporine A (CsA). Autoimmune dacryoadenitis was induced by injecting autologous peripheral blood lymphocytes, which had been activated in a mixed cell reaction with acinar cells isolated from one inferior lacrimal gland (LG), back into the donor animal's remaining inferior LG. Schirmer's test, tear breakup time, and rose Bengal staining were assessed. Animals with established disease were treated topically with either CsA or Endura twice daily for 5 months. Without treatment tear production and tear stability were abnormal for 6 months, and clear signs of ocular surface defects were evident. Severe immune cell infiltration was observed in the LG. Long-term CsA treatment increased tear production only slightly, but the severity of LG histopathology decreased noticeably. CD4(+) T-cell infiltration of the LG was decreased and infiltration by MHC class II-expressing cells was also decreased. For the Endura-treated group tear production did not improve, rose Bengal scores remained high, and histopathology showed infiltration comparable to the untreated group, but by the end of the study the tear breakup time did improve. The rabbit model of autoimmune dacryoadenitis had signs of chronic dry eye disease 6 months after induction of disease. Tear production improved slightly with CsA treatment and CD4(+) T-cell infiltration decreased significantly in the LG. This suggests that some Sjögren's patients may benefit from long-term CsA treatment.

The actin cytoskeleton of kidney podocytes is a direct target of the antiproteinuric effect of cyclosporine A

The immunosuppressive action of the calcineurin inhibitor cyclosporine A (CsA) stems from the inhibition of nuclear factor of activated T cells (NFAT) signaling in T cells. CsA is also used for the treatment of proteinuric kidney diseases. As it stands, the antiproteinuric effect of CsA is attributed to its immunosuppressive action. Here we show that the beneficial effect of CsA on proteinuria is not dependent on NFAT inhibition in T cells, but rather results from the stabilization of the actin cytoskeleton in kidney podocytes. CsA blocks the calcineurin-mediated dephosphorylation of synaptopodin, a regulator of Rho GTPases in podocytes, thereby preserving the phosphorylation-dependent synaptopodin-14-3-3 beta interaction. Preservation of this interaction, in turn, protects synaptopodin from cathepsin L-mediated degradation. These results represent a new view of calcineurin signaling and shed further light on the treatment of proteinuric kidney diseases. Novel calcineurin substrates such as synaptopodin may provide promising starting points for antiproteinuric drugs that avoid the serious side effects of long-term CsA treatment.

Downregulation of Renal Sodium Transporters and Tonicity-Responsive Enhancer Binding Protein by Long-Term Treatment with Cyclosporin A

Tonicity-responsive enhancer binding protein (TonEBP) is a transcriptional activator that is regulated by ambient tonicity. TonEBP protects the renal medulla from the deleterious effects of hyperosmolality and regulates the urinary concentration by stimulating aquaporin-2 and urea transporters. The therapeutic use of cyclosporin A (CsA) is limited by nephrotoxicity that is manifested by reduced GFR, fibrosis, and tubular defects, including reduced urinary concentration. It was reported recently that long-term CsA treatment was associated with decreased renal expression of TonEBP target genes, including aquaporin-2, urea transporter, and aldose reductase. This study tested the hypothesis that long-term CsA treatment reduces the salinity/tonicity of the renal medullary interstitium as a result of inhibition of active sodium transporters, leading to downregulation of TonEBP. CsA treatment for 7 d did not affect TonEBP or renal function. Whereas expression of sodium transporters was altered, the medullary tonicity seemed unchanged. Conversely, 28 d of CsA treatment led to downregulation of TonEBP and overt nephrotoxicity. The downregulation of TonEBP involved reduced expression, cytoplasmic shift, and reduced transcription of its target genes. This was associated with reduced expression of active sodium transporters-sodium/potassium/chloride transporter type 2 (NKCC2), sodium/chloride transporter, and Na(+),K(+)-ATPase-along with increased sodium excretion and reduced urinary concentration. Infusion of vasopressin restored the expression of NKCC2 in the outer medulla as well as the expression and the activity of TonEBP. It is concluded that the downregulation of TonEBP in the setting of long-term CsA administration is secondary to the reduced tonicity of the renal medullary interstitium.

TGF-β1 mRNA upregulation influences chronic renal allograft dysfunction

Acute rejection (AR) is a dominant risk factor for developing chronic allograft nephropathy (CAN) after kidney transplantation. CAN is characterized by progressive interstitial fibrosis. It has been associated with increased transforming growth factor (TGF)-beta1 expression, however, kinetic studies are absent. We investigated whether intragraft TGF-beta1 expression in various causes of early graft dysfunction may influence late renal allograft dysfunction. A total of 174 human renal biopsies were quantified for TGF-beta1 mRNA expression using real-time reverse transcriptase-polymerase chain reaction. Expression levels were correlated with the Banff histopathological grades, TGF-beta1 immunohistology, and clinical follow-up. TGF-beta1 was most markedly upregulated in AR, CAN, and acute tubular necrosis - delayed graft function compared to non-rejecting controls (P < 0.001). TGF-beta1 expression was heightened in borderline changes (P < 0.01), recurrence of glomerulonephritis, and cyclosporine toxicity (P < 0.05). There was no correlation between intragraft TGF-beta1 expression during AR and short-term outcome of a rejection episode. TGF-beta1 gene overexpression during CAN has been shown to be associated with the increased risk for renal allograft dysfunction 18 months after biopsy (odds ratios 9.9 vs 3.2, respectively). Intragraft TGF-beta1 mRNA expression is significantly upregulated in both AR and CAN. Thus, our results support the hypothesis that TGF-beta1 might play a key role in chronic allograft dysfunction.

Renal Biopsy Findings in Children Receiving Long-Term Treatment with Cyclosporine A Given as a Single Daily Dose

Long-term treatment of childhood nephrotic syndrome (NS) and rheumatic diseases with cyclosporine A (CsA) given as a single daily dose may yield better results and allow safer use of the drug than the conventional twice-daily dosing. However, the safety of such long-term treatment from the histological standpoint remains to be established. Posttreatment renal biopsy was conducted in a total of eight children (5 with minimal change NS, 2 with focal segmental glomerulosclerosis and 1 with X-linked immune dysregulation, polyendocrinopathy and enteropathy) receiving CsA as a single daily dose, after a mean treatment duration of 20 months (9-36 months). The initial daily dose of CsA (Neoral) was 2.0 mg/kg, given as a single daily dose before breakfast. The dose was subsequently adjusted to achieve a peak (between 1 and 2 hrs post-dosing, C1-C2) blood level of around 800 ng/ml. The mean daily CsA dose, mean C1-C2 blood level, and mean trough blood level in the subjects were 1.9 +/- 0.6 mg/kg, 803.8 +/- 117.2 ng/ml and 36.1 +/- 12.7 ng/ml, respectively. The result revealed no evidence of CsA-related nephrotoxicity, including arteriopathy, striped interstitial fibrosis or tubular atrophy, in any of the study participants. Also, no significant changes were observed in the mean estimated glomerular filtration rate as compared to the pretreatment values (127.6 +/- 14.9 ml/min/1.73 m(2) vs 115.6 +/- 22.8 ml/min/1.73 m(2), and except for mild hypertrichosis, no significant adverse effects of CsA were observed. These findings lend further support to the safety of long-term low-dose CsA treatment (median treatment duration in this study, 20 months), with the drug administered as a single daily dose while maintaining a peak (C1-C2) blood level of around 800 ng/ml.

Cyclosporine therapy monitored with abbreviated area under curve in nephrotic syndrome

Cyclosporin A (CsA) is an effective therapy for children with long-lasting nephrotic syndrome (NS). Long-term treatment can result in chronic CsA nephropathy (CsAN) and there is controversy concerning its incidence and severity. Trough levels are commonly used to monitor the drug concentration. We report a retrospective clinical and histological analysis of 18 children (12 males, 6 females) with steroid-dependent nephrotic syndrome (15 patients) and partially steroid-sensitive nephrotic syndrome (3 patients) treated with CsA for a long-term period (mean 4.9 years, range 2.2-6.9). Before CsA treatment all patients had normal creatinine clearance. CsA was started at a dose of 5 mg/kg per day administered orally in two divided doses and adjusted to maintain the mean CsA blood concentration between 250 and 350 ng/ml obtained from abbreviated area under the curve (AUC). A renal biopsy was performed after a mean period of 3.9 years (range 2.2-6.2) from the start of CsA treatment. Tubular, interstitial, and arteriolar lesions were evaluated in order to assess CsAN. The mean CsA dose and the mean CsA blood concentration were 4.4 mg/kg per day (range 3.6-5.8) and 276.6 ng/ml (range 162-346), respectively. No child had a worsening creatinine clearance during CsA treatment and follow-up after CsA discontinuation. If compared with the year before the start of CsA treatment, NS relapses and prednisone (PDN) dose significantly decreased during CsA treatment, 4/year versus 0.8/year (P <0.0001) and 0.9 mg/kg per day versus 0.2 mg/kg per day (P <0.0001), respectively. Histological analysis showed 15 patients with minimal change disease and 3 with focal segmental glomerulosclerosis. Clear-cut lesions diagnostic of CsAN were never found and only mild lesions were observed in 5 children (suggestive of CsAN in 2 patients and consistent with CsAN in 3 patients). Long-term CsA treatment is confirmed to be effective in preventing NS relapses and reducing PDN dose. Renal function is not a reliable indicator of CsAN. With the mean CsA blood concentrations used in our patients CsAN presented a low incidence (28%) and was generally mild. Renal biopsy should be performed 2-3 years from the start of long-term CsA treatment, especially if the mean CsA blood concentrations are not regularly monitored.

Progressive bilateral sensorineural hearing loss probably induced by chronic cyclosporin a treatment after renal transplantation for focal glomerulosclerosis

ObjectiveThe immunosuppressive agent cyclosporin A (CsA) has contributed to the success of organ and bone marrow transplantation. CsA-related neurotoxicity is a well-known occurrence. Sensorineural hearing loss (SNHL) due to initiation of CsA treatment is an extremely rare finding.Material and MethodsA 32-year-old man who had undergone technically uneventful cadaveric renal transplantation for focal glomerulosclerosis when 25 years old was evaluated as the result of a 10-month history of bilateral hearing loss. The patient had been taking only CsA (150 mg twice daily) and methylprednisolone.ResultsProgressive bilateral SNHL was confirmed by an audiological examination. Eight months after dose reduction of CsA, pure-tone audiometry excluded progression of hearing loss.ConclusionsTo the best of our knowledge, only rare cases of CsA-related hearing loss have been reported, and none after long-term CsA treatment. Audiological findings confirmed the cochlear origin of SNHL in our patient. The action of CsA on the blood–inner ear barrier has recently been demonstrated but the mechanism of cochlear damage is still unknown. A prospective study to determine the incidence of CsA-induced hearing loss has been instituted in our department.

Adverse effects with long-term cyclosporin for severe psoriasis.

The use of cyclosporin A (CSA) for the treatment of severe psoriasis is well established. However its use is limited by its adverse effects, especially nephrotoxicity. We reviewed 28 patients treated with CSA for severe psoriasis over an 11-year period. All patients were on long-term CSA treatment (median duration 55.5 months). Twenty patients developed renal impairment which required discontinuation of treatment in seven. Twelve patients' renal function stabilized on dose reduction and one improved. Sixteen patients developed hypertension. For this small group of patients with severe psoriasis, recalcitrant to other treatments, CSA afforded better quality of life which they otherwise could not enjoy. Although this comes at a cost with the development of renal impairment we feel that such patients can be continued on CSA provided that they are under the combined care of a dermatologist and a nephrologist.

Imbalance in endothelial vasoactive factors as a possible cause of cyclosporin toxicity: A role for endothelin-converting enzyme

Cyclosporin A (CsA) is a powerful, widely used immunosuppresant, but it is not devoid of serious clinical side effects such as hypertension and nephrotoxicity. To clarify the mechanisms involved in the genesis of these side effects, we studied the effects of chronic CsA administration on the expression of some endothelial vasoactive factors in the aorta and kidney. For this purpose rats were treated for 30 days with 50 mg/kg/day CsA, and hypertension and renal insufficiency developed. In rats receiving CsA, the mRNA expression of pre-pro-endothelin-1 increased, whereas that of endothelial nitric oxide (NO) synthase decreased, both in the aorta and in the renal cortex (increases in pre-pro-endothelin-1 mRNA in aorta and renal cortex, respectively: 275% ± 18%, 300% ± 27%; decreases in endothelial NO synthase mRNA in aorta and renal cortex respectively: 40% ± 8%, 42% ± 6%). Moreover, long-term CsA treatment also induced an up-regulation of the endothelin-converting enzyme 1 mRNA expression (156% vs control rats) in the renal cortex, with a significantly increased protein content and enzyme activity. In contrast, no changes were detected in endothelin-converting enzyme 1 mRNA expression in aortas from rats receiving the drug. This imbalance between endothelin-1 and NO systems could explain the hypertension and the deranged kidney function observed after long-term CsA treatment in rats. (J Lab Clin Med 2000;136:395-401)

Renal hemodynamic effects of l-arginine and sodium nitroprusside in heart transplant recipients

Long-term treatment with cyclosporine A (CsA) induces vasoconstriction in the kidney and causes renal impairment. An altered L-arginine (L-Arg)/nitric oxide (NO) pathway may play a key role in CsA nephrotoxicity. We studied the effect of L-Arg (dosage, 17 mg/kg/min over 30 min), the precursor of NO synthesis, and sodium nitroprusside (SNP; dosage, 1.0 microgram/kg/min over 30 min) on renal hemodynamics in a double-blind, placebo-controlled, randomized, three-way cross-over study comprising 12 stable cardiac transplant recipients on long-term CsA treatment, 10 patients with chronic nephropathy not receiving CsA, and 13 healthy controls. Renal plasma flow (RPF) and glomerular filtration rate (GFR) were measured by paraaminohippurate (PAH) and the inulin clearance method, respectively. In healthy subjects, L-Arg induced an increase in RPF (P = 0.009) and GFR (P = 0.001). By contrast, L-Arg did not induce renal hemodynamic effects in heart transplant patients or patients with chronic nephropathy. SNP reduced RPF (P = 0.050) and GFR (P = 0.005) in patients with chronic nephropathy but did not affect renal hemodynamics in heart transplant recipients or in healthy subjects. These data indicate that L-Arg cannot be used to reverse CsA-induced renal vasoconstriction in heart transplant recipients under long-term CsA treatment, although these patients have a normal renal response to SNP.

RENAL HEMODYNAMIC EFFECTS OF L-ARGININE AND SODIUM-NITROPRUSSIDE IN HEART TRANSPLANT RECIPIENTS

406 Background: Long-term treatment with Cyclosporine A (CsA) induces renal vasoconstriction with subsequent end-organ damage. An altered L-arginine (L-arg)/nitric oxide (NO) pathway may play a key role in CsA induced nephrotoxicity. The aim of the present study was to study the effect of L-arg (dosage: 17 mg/kg/min over 30 minutes), the precursor of NO-synthesis and sodium-nitroprusside (SNP; dosage: 1.0 μg/kg/min over 30 minutes), an endothelium-independent vasodilator, on renal plasma flow (RPF) and glomerular filtration rate (GFR) in 12 stable cardiac transplant recipients on long-term CsA treatment (mean age: 60.2±9.4 years, time after cardiac transplant: 55.8±21.2 months, creatinine clearance: 60.5±9.1 ml/min), 10 patients with chronic nephropathy (mean age : 64.2±9.3 years, creatinine clearance: 52.7±3.8 ml/min) and 13 healthy, age matched controls (mean age: 59.5±8.5 years, creatinine clearance: 112.6±15.8 ml/min) in a double-blind, placebo-controlled, randomized, 3-way cross over study. Results: In healthy subjects L-arg induced an increase in RPF (p=0.009) and GFR (p=0.001). By contrast, in heart transplant recipients and patients with chronic nephropathy L-arg did not induce an increase in renal hemodynamics. SNP reduced RPF (p=0.050) and GFR (p=0.005) in patients with chronic nephropathy, but did not affect renal hemodynamics in healthy controls and heart transplant recipients. Conclusion: Our data indicate that the renal hemodynamic response to L-arg is different in heart transplant recipients under chronic CsA treatment and healthy subjects. By contrast no evidence for an altered renal reactivity to exogenous NO was apparent in cardiac transplant patients. This likewise supports the hypothesis, that patients under long-term CsA treatment have an altered L-arg-NO pathway.