Endothelin-1 receptor antagonists protect the kidney against the nephrotoxicity induced by cyclosporine-A in normotensive and hypertensive rats

Cyclosporin-A (CsA) is an immunosuppressant associated with acute kidney injury and chronic kidney disease. Nephrotoxicity associated with CsA involves the increase in afferent and efferent arteriole resistance, decreased renal blood flow (RBF) and glomerular filtration. The aim of this study was to evaluate the effect of Endothelin-1 (ET-1) receptor blockade with bosentan (BOS) and macitentan (MAC) antagonists on altered renal function induced by CsA in normotensive and hypertensive animals. Wistar and genetically hypertensive rats (SHR) were separated into control group, CsA group that received intraperitoneal injections of CsA (40 mg/kg) for 15 days, CsA+BOS and CsA+MAC that received CsA and BOS (5 mg/kg) or MAC (25 mg/kg) by gavage for 15 days. Plasma creatinine and urea, mean arterial pressure (MAP), RBF and renal vascular resistance (RVR), and immunohistochemistry for ET-1 in the kidney cortex were measured. CsA decreased renal function, as shown by increased creatinine and urea. There was a decrease in RBF and an increase in MAP and RVR in normotensive and hypertensive animals. These effects were partially reversed by ET-1 antagonists, especially in SHR where increased ET-1 production was observed in the kidney. Most MAC effects were similar to BOS, but BOS seemed to be better at reversing cyclosporine-induced changes in renal function in hypertensive animals. The results of this work suggested the direct participation of ET-1 in renal hemodynamics changes induced by cyclosporin in normotensive and hypertensive rats. The antagonists of ET-1 MAC and BOS reversed part of these effects.

Influence of cyclosporine on the occurrence of nephrotoxicity after allogeneic hematopoietic stem cell transplantation: a systematic review

Cyclosporine, a drug used in immunosuppression protocols for hematopoietic stem cell transplantation that has a narrow therapeutic index, may cause various adverse reactions, including nephrotoxicity. This has a direct clinical impact on the patient. This study aims to summarize available evidence in the scientific literature on the use of cyclosporine in respect to its risk factor for the development of nephrotoxicity in patients submitted to hematopoietic stem cell transplantation. A systematic review was made with the following electronic databases: PubMed, Web of Science, Embase, Scopus, CINAHL, LILACS, SciELO and Cochrane BVS. The keywords used were: "bone marrow transplantation" OR "stem cell transplantation" OR "grafting, bone marrow" AND cyclosporine OR cyclosporin OR "risk factors" AND "acute kidney injury" OR "acute kidney injuries" OR "acute renal failure" OR "acute renal failures" OR "nephrotoxicity". The level of scientific evidence of the studies was classified according to the Oxford Centre for Evidence Based Medicine. The final sample was composed of 19 studies, most of which (89.5%) had an observational design, evidence level 2B and pointed to an incidence of nephrotoxicity above 30%. The available evidence, considered as good quality and appropriate for the analyzed event, indicates that cyclosporine represents a risk factor for the occurrence of nephrotoxicity, particularly when combined with amphotericin B or aminoglycosides, agents commonly used in hematopoietic stem cell transplantation recipients...

Prophylactic effect of vitamin C on cyclosporine A-induced liver toxicity

Cyclosporine A [CsA] is an important immunosuppressive agent; however, its clinical use is limited by several side effects such as hepatotoxicity. Vitamin C [ascorbic acid] is a very important and powerful antioxidant and protects membranes against oxidation. The aim of this study was to study protective role of vitamin C against CSA-induced hepatotoxicity. Thirty male Wister strain rats weighting 230-260g were randomly divided into 3 groups [n = 10]: group A was the control group and received placebo [Normal Saline], group B was the CSA-treated group and received 15mg/kg/day CsA for 21 days, group C was the CsA + vitamin C group and was received 200mg/kg/day vitamin C orally 3 hours before receiving 15mg/kg/day CsA. On 22[th] day rats serum obtained for measuring biochemical factors including bilirubin, alanine aminotransferase [ALT], aspartate aminotransferase [AST], triglyceride, alkaline phosphatase [ALP] and lactate dehydrogenase [LDH], total protein, and albumin. Bilirubin, ALT, AST, triglyceride, ALP, and LDH levels were lower in CsA + ascorbic acid group than that of CsA group [P < 0.05] while plasma total protein and albumin were significantly higher in CsA + ascorbic acid group than that of CsA group [P < 0.05]. In conclusion, we have shown that vitamin C administration provides protection against CSA-induced injury in rat liver function and may have hepatoprotective role in the patients experiencing CSA treatment

Comparison of Early and Late Conversion of Sirolimus in Experimental Model of Chronic Cyclosporine Nephropathy

Sirolimus (SRL) is a promising drug for replacing calcineurin inhibitors. We performed this study to determine the optimal time of conversion from cyclosporine (CsA) to SRL in an experimental model of chronic CsA nephropathy. Three separate studies were performed. In the first study, SRL was given to rats with or without CsA for 4 weeks. In the second study, rats were treated initially with CsA for 1 week, and then switched to SRL (early conversion). In the third study, CsA was given for 4 weeks and then replaced by SRL for 4 weeks treatment of CsA (late conversion). The influence of SRL on CsA-induced renal injury was evaluated by assessing renal function, histopathology (interstitial inflammation and fibrosis), and apoptotic cell death. Combined CsA and SRL treatment significantly impaired renal function, increased apoptosis, and interstitial fibrosis and inflammation compared with CsA or SRL treatment alone. Early conversion to SRL did not change renal function, histopathology, or apoptosis compared with early CsA withdrawal. By contrast, late conversion to SRL significantly aggravated these parameters compared with late CsA withdrawal. In conclusion, early conversion from CsA to SRL is effective in preventing CsA-induced renal injury in a setting of CsA-induced renal injury.

Inmunosupresíón en niños con trasplante hepático / Immunosuppression in children with liver transplantation

La inmunosupresión en niños con trasplante hepático, ha evolucionado con dos momentos clave: la disponibilidad de los inhibidores de calcineurina ciclosporina y tacrolimus. La inmunosupresión primaria se diseña sobre la base de un inhibidor de calcineurina como fármaco principal. Los esteroides se incluyen en la pauta de inmunosupresión primaria en la mayoría de los centros. Las pautas habituales a largo plazo consisten en ciclosporina o tacrolimus, en monoterapia a niveles inferiores a los deseados en el periodo precoz postrasplante, o en combinación con dosis bajas de esteroide. Los inhibidor e s de c a l c ineur ina induc en vasoconstricción arterial aguda y crónica que causa nefrotoxicidad, con disminución del filtrado glomerular y tubulopatía. Los niveles ensangre de ciclosporina o de tacrolimus se determinan para evaluar el estado de inmunosupresión. La edad de adolescente y adulto joven es una etapa de riesgo para el injerto por ser frecuente la omisión accidental de dosis de medicación inmunosupresora, una irregularidad que es difícil de evaluar en su extensión a pesar de una buena relación médicopaciente y frecuentes chequeos. El rechazo tiene una incidencia entre el 30 y 50% de los pacientes, entre los días 5 y 30 postrasplante.

Immunosuppression in children with liver transplantation has evolved with two key moments: the availability of calcineurin inhibitors, cyclosporine and tacrolimus. The primary immunosuppression is designed on the basis of a calcineurin inhibitor as primary drug. Steroids are included in the pr imary immunosuppression regimen in most schools. The long-term normal patterns consist of cyclosporine or tacrolimus as monotherapy to lower than desired levels in the early period aftertransplantation, or in combination with low dose steroid. Calcineurin inhibitors induce arterial vasoconstriction causing acute and chronic nephrotoxicity, with reduced glomerular filtration and tubular. Blood levels of cyclosporine or tacrolimus are determined to assess the state of immunosuppression. The age of adolescence and young adulthood is a time of risk to the graft by the accidental omission to be frequent doses ofimmunosuppressive medication, an irregularitywhich is difficult to assess its extent in spite of a good doctor-patient relationship and frequentcheckups. The rejection has an incidence between 30 and 50% of patients, between 5 and 30 aftertransplantation.

Melatonin prevents cyclosporine- induced hepatotoxicity in rats

Cyclosporine A [CsA] is a widely used immuno-suppressive agent that is implicated in the formation of free oxygen radicals. Melatonin is known to be a free radical scavenger and an antioxidant agent. This study was designed to investigate the effects of melatonin on CsA-induced liver damage by histopathological examination. Thirty-two male rats of Sprague-Dawley origin were divided into 4 groups of 8 and treated for 28 days as follows: group 1 received daily doses of 0.1 ml/kg olive oil s.c.; group 2 received 4mg/kg of melatonin; group 3 received 10mg/kg CsA diluted in 0.1 ml/kg olive oil; group 4 was treated with 4 mg/kg melatonin i.p. and 10 mg/kg CsA s.c. Finally, the rats were sacrificed by terminal anesthesia, and liver tissue specimens were processed for light microscopy, stained with HE and examined under a light microscope. Specimens of the control group showed normal liver histology, whereas group 3 showed major histopathological changes, such as cytoplasmic vacuolization, dilatation of the sinusoids, apoptosis and many mitotic figures. In group 4, the normal histology of the liver was preserved, although apoptosis, mitotic figures and cytoplasmic vacuolization were still infrequently observed. Nevertheless, there were significant differences between group 2 [melatonin] and group 3 [CsA] and between group 3 [CsA] and group 4 [CsA + melatonin] concerning these 3 parameters [vacuolization, sinusoidal dilatation and apoptosis]. The results of this study suggest that CsA-related liver toxicity in rats could be significantly reduced by melatonin adminstration

Una nueva percepción del papel de la aldosterona en la fisiopatología de la nefrotoxicidad crónica inducida por la ciclosporina / A new perception of aldosterone role in the pathophysiology of cyclosporin induced chronic nephrotoxicity

La ciclosporina A (CsA), un inhibidor de la calcineurina, ha mejorado la supervivencia de injertos del transplante de órganos sólidos y su uso para manejar las enfermedades autoinmunitarias es cada vez más común. Si bien las tasas de supervivencia de pacientes y de injertos han aumentado, el uso clínico de la CsA es limitado ya que frecuentemente tiene efectos nefrotóxicos que se pueden presentar en dos formas distintas y bien caracterizadas: nefrotoxicidad aguda y crónica. La forma aguda se caracteriza por vasoconstricción renal inducida por un desequilibrio en la liberación de sustancias vasoactivas, lo que conduce a una disfunción renal. Esta forma de nefrotoxicidad es reversible. La toxicidad crónica, por su parte, se caracteriza por vasoconstricción y daño estructural que incluye patologías de las arteriolas y fibrosis tubulointersticial, las cuales, por lo general, no son reversibles. Los mecanismos de estos efectos perjudiciales no se conocen con exactitud aunque, en los últimos años, se han hecho grandes avances. En este artículo revisamos la literatura actual sobre la patogenia y las estrategias de tratamiento que se han utilizado para mejorar el daño renal causado por la nefrotoxicidad crónica por CsA. Recientemente se ha sugerido que la aldosterona juega un papel central en la patogenia de la nefrotoxicidad causada por CsA y que la espironolactona puede ser útil para prevenirla. Se discuten estos resultados y el uso del bloqueo de los receptores de mineralocorticoides.

Cyclosporine A (CsA) is a calcineurin inhibitor widely use to prevent organ transplant rejection and for treating autoimmune diseases. Since CsA introduction, organ transplant and patient survival significantly increased and this outcome has not been modified by the new immunosuppressive agents. The long use of CsA, however has been limited because its nephrotoxic side effect. Two forms of renal toxicity have been described, the acute and the chronic toxicity

Induction of PPAR Gamma mRNA and Protein Expression by Rosiglitazone in Chronic Cyclosporine Nephropathy in the Rat

PURPOSE: We recently reported that rosiglitazone (RGTZ), a peroxisome proliferator-activated receptor gamma (PPARgamma) agonist, has a protective effect against cyclosporine (CsA)- induced renal injury. Here we report the effect of RGTZ on peroxisome proliferator-activated receptor gamma (PPARgamma) expression in an experimental model of chronic cyclosporine (CsA) nephropathy. MATERIALS AND METHODS: Chronic CsA nephropathy was induced in Sprague-Dawley rats by administering CsA (15mg/kg per day) for 28 days, and control rats were treated with vehicle (VH group, olive oil 1mL/kg per day) for 28 days. RGTZ (3mg/kg) was concurrently administered via gavage to the CsA and VH groups. Expression of PPARgamma mRNA and protein was evaluated with RT-PCR, immunohistochemistry, and immunoblotting. RESULTS: PPARgamma mRNA expression was similar to the level of PPARgamma protein constitutively expressed in the kidneys of the VH treated rats, with expression in the glomerular epithelial, distal tubular cells, and collecting tubular cells. PPARgamma protein expression in CsA-treated rat kidneys was significantly less than in the VH group. However, concomitant administration of RGTZ restored PPARgamma protein expression in the kidneys of the CsA- reated rats. CONCLUSION: Exogenous administration of RGTZ treatment upregulates PPARgamma expression and that this mechanism may play a role in protecting against CsA-induced renal injury.

Activation of Intrarenal Complement System in Mouse Model for Chronic Cyclosporine Nephrotoxicity

PURPOSE: Local activation of the complement system plays a role in target organ damage. The aim of our study was to investigate the influence of cyclosporine (CsA)- induced renal injury on the complement system in the kidney. MATERIALS AND METHODS: Mice fed a low salt (0.01%) diet were treated with vehicle (VH, olive oil, 1mL/kg/day) or CsA (30mg/kg/day) for one or four weeks. Induction of chronic CsA nephrotoxicity was evaluated with renal function and histomorphology. Activation of the complement system was assessed through analysis of the expression of C3, C4d, and membrane attack complex (MAC), and the regulatory proteins, CD46 and CD55. CsA treatment induced renal dysfunction and typical morphology (tubulointerstitial inflammation and fibrosis) at four weeks. RESULTS: CsA-induced renal injury was associated with increased the expression of C3, C4d, and MAC (C9 and upregulation of complement regulatory proteins (CD 46 and CD55). Immunohistochemistry revealed that the activated complement components were mainly confined to the injured tubulointerstitium. CONCLUSION: CsA-induced renal injury is associated with activation of the intrarenal complement system.

Role of imaging in renal transplant complications - a hospital based study

Thirty five thousands patients receive renal transplants every year world wide. This study was conducted to determine and evaluate the diagnostic role and accuracy of Ultrasonography including Doppler analysis and Radionuclide Scanning in patients with renal transplant complications. It was an observational study. Cases were collected from AFIU, MH and Jinnah Memorial Hospital Rawalpindi. Ultrasound and Doppler analyses were done in the Radiology Department of CMH Rawalpindi. Renal isotope scans were performed at NMC Rawalpindi. A total number of 52 patients were studied. Male female ratio was 42 to 10 [80.8% to 19.2%]. The post-transplant duration was 02 days to 06 years. The most frequent complications were peri-transplant fluid collection [27%], followed by rejection of transplant [25%] and cyclosporine nephrotoxicity [11.54%]. Other complications which were also observed were Acute Tubular Necrosis [7.69%] and hydronephrosis [15.4%]. Ultrasound is excellent modality to evaluate location, volume and change in volume of Perinephric fluid collection. Radionuclide imaging detects altered or diminished renal function due to acute tubular necrosis, rejection of transplant and toxicity from medications. Radionuclide imaging is most useful modality for assessing renal function. Standard for evaluating vascular complications is angiography, however duplex Doppler ultrasound is an excellent non invasive method for screening. Other transplant complications like abnormalities of collecting system and renal parenchyma are well evaluated by both ultrasound and radionuclide imaging

Ftalato de di-(2-etilexila) (DEHP) em bolsas de PVC para soluções parenterais de grandes volumes / Di-(2-ethylhexyl) phthalate (DEHP) in PVC bags used to pack large volume parental solutions

Soluções parenterais de grandes volumes (SPGV) têm sido amplamente utilizadas como veículos para a administração de fármacos por via intravenosa e as bolsas flexíveis de policloreto de vinila (PVC) são, atualmente, os recipientes plásticos mais usados no acondicionamento das SPGV, apresentando vantagens relacionadas à sua colapsação e à redução de contaminações e de embolias gasosas. Este artigo apresenta uma revisão sobre aspectos relevantes das embalagens de PVC contendo o plastificante ftalato de di-(2-etilexila) (DEHP), que são usadas para acondicionamento de SPGV. São abordadas as interações entre fármacos e a embalagem, com ênfase no fenômeno da migração do DEHP presente em bolsas plásticas de PVC para SPGV contendo ciclosporina, um fármaco com atividade imunossupressora, e os aspectos toxicológicos inerentes

Estudo experimental da nefotoxicidade aguda do sirolimus: estudos in vitro e in vivo / Sirolimus acute nephrotoxicity: in vitro and in vivo studies

Avaliou-se os efeitos do Sirolimus (SIRO 3mg/kg/diaVO) isoladamente e associado a Ciclosporina A (CsA 3mg/kg/dia SC) em túbulos renais proximais isolados (TP) e sobre a função renal de ratos Wistar normais e submetidos à isquemia renal (30 min). SIRO não apresentou efeito tóxico em TP e nem potencializou a toxicidade da CsA. SIRO não afetou a recuperação da filtração glomerular (FG) após isquemia e foi capaz de prevenir a diminuição da FG induzida pela CsA, a despeito da persistência da vasoconstrição e maior infiltrado inflamatório /The effects of sirolimus (SIRO 3 mg/kg/day PO) alone or associated with ciclosporine (CsA 3 mg/kg/day SC) were evaluated in isolated proximal tubules suspensions (PT) and in control and ischemic (30 min) Wistar rats. SIRO was neither toxic to PT nor affected CsA toxicity. SIRO did not affect glomerular filtration rate (GFR) recovery after ischemia and it prevented CsA induced aggravation despite persistence of vasoconstriction and greater inflammatory infiltrate...

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

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 -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 -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 -MSH may have a some inhibitory effect on CsA induced tubular cell apoptosis.

Tratamiento con dosis bajas de ciclosporina A en pacientes con enfermedad ocular inflamatoria de etiología no infecciosa / Treatment of non infectious ocular inflammatory disease with low doses of cyclosporin A

Background: Cyclosporin A has an adequate immunosuppressive capacity and can be useful in the treatment of non infectious ocular inflammatory diseases. Aim: To describe the clinical effect of cyclosporin A treatment in low doses, along with corticosteroids, in the treatment of refractory ocular inflammatory diseases. Patients and methods: Twenty patients (13 female), aged 17 to 74 years old with severe and refractory ocular inflammatory diseases were studied. All except one, received variable doses of prednisone (10 to 60 mg/kg/day) and all received cyclosporin in doses that started in 2.5 mg/day and were increased to 5 mg/kg/day, according to clinical response. Patients were followed from 8 to 24 months, with monthly assessments of ocular inflammation (using a four point score), visual acuity and adverse effects of treatment. Results: A two points or more reduction in the ocular inflammation score was observed in 52 percent of patients. Visual acuity improved in 10 subjects, stabilized in 8 and worsened in 2. Prednisone doses were reduced in most patients. Observed adverse effects were hypertension in 2 patients, creatinine elevation in 2, gastrointestinal disturbances in 3 and hypertrichosis in 12. A reduction of cyclosporin dose was required in these cases, but it was discontinued only in one patient with a vascular purpura. Conclusions: Low cyclosporin doses, associated to prednisone, are useful to reduce inflammation and improve visual acuity in patients with non infectious ocular inflammatory diseases, refractory to other treatment methods

Using cyclosporin A in the rheumatology practice

The treatment of connective tissue diseases with cyclosporin-A is discussed with emphasis in nowadays literature and discuss some aspects like mechanism of

Investigaçäo de neuropatia periférica durante o período recente do transplante de medula óssea / Peripheral neuropathy investigation in the early stage of bone marrow transplantation

Investigamos prospectivamente a incidência de neuropatia periférica em 43 pacientes através do estudo da velocidade de conduçao nervosa e do teste de limiar de sensibilidade vibratória (palestesiômetro) realizados antes e após o transplante de medula óssea. Nesse período as principais drogas utilizadas para o condicionamento e imunossupressao foram o bussulfan, ciclofosfamida, ciclosporina A, methotrexate e corticoesteróides. Foram estudadas as velocidades de conduçao nervosa nos nervos mediano motor, fibular, tibial, mediano sensitivo e sural. Obtivemos alteraçoes estatisticamente significativas na duraçao do potencial composto proximal do nervo mediano motor, na amplitude distal do nervo tibial posterior e na amplitude proximal do nervo sural. As diferenças observadas nao se correlacionaram com alteraçoes clínicas, e nao foram suficientes para o diagnóstico de neuropatia periférica. Acreditamos que o esquema terapêutico utilizado nao provoca toxicidade neurológica periférica no período recente do transplante de medula óssea.

Avaliaçäo da funçäo tubular proximal utilizando o clearance de lítio no tratamento pela ciclosporina A em ratos / Evaluation of the proximal tubular function using the clearance of the lithium in the treatment by cyclosporine A in rats

Estudamos as alteraçöes renais como o uso da CSA (12,5 mg/kg/d/6 semanas), em ratos Wistar Nx à direita (G1 = controle, n = 12) (G2 = CSA, n = 12). Foram realizados clearances de creatinina (Ccr), lítio (CLi) e estudo histopatológico do rim E. Os resultados näo mostraram alteraçao significativa no Ccr. O CLi caiu significativamente (p < 0,01) no G2. A fraçäo de excreçäo de lítio (FELi) também foi menor neste grupo. A carga filtrada de sódio (CF) näo diferiu entre os grupos. A reabsorçäo fracional proximal de sódio (RFrPNa) foi maior no G2 (p < 0,01), conseqüentemente o aporte distal (AD) caiu (p < 0,01). A RFrD-I e II (distal) foram menores no G2. Estes achados demonstraram alteraçöes funcionais tubulares renais artribuídas à CSA, que näo correspondem às alteraçöes de filtraçäo glomerular ou às alteraçöes morfológicas nestas condiçöes experimentais.

Light microscopic and electron microscopic features of cyclosporine nephrotoxicity in rats

In order to clarify morphologic changes associated with cyclosporine (CS) nephrotoxicity, CS in ethyl alcohol at 25 mg/kg/day i.p. was administered to male Sprague-Dawley rats for periods of 1 to 8 weeks. Mean systolic BP was slightly increased in the CS group at 4 weeks (p < 0.05), but there was no difference compared to a control group at 8 weeks. Blood urea nitrogen was significantly elevated at 4 weeks and continued to rise (p < 0.005), whereas serum creatinine was elevated at 8 weeks. Microscopic examination of the kidneys from CS-treated rats at one week revealed cytoplasmic vacuolization in all segments of the proximal tubules, tubular inclusion bodies, and peritubular capillary congestion. Ultrastructurally, some vacuoles were neutral fat droplets, while others appeared as single membrane-bound structures due to dilatation of the endoplasmic reticulum. The tubular inclusion bodies were enlarged autolysosomes filled with distorted mitochondrial fragments. At two weeks, tubular regeneration was prominent, in addition to the above mentioned toxic tubulopathy. At four weeks, focal areas of interstitial fibrosis and tubular atrophy associated with cystic dilatation were seen. At 8 weeks, interstitial and intratubular microcalcification were present, in addition to patchy foci of interstitial fibrosis, but vascular lesions were not demonstrated. Although renal tubular changes characterized by vacuolization, inclusion bodies, and microcalcification and interstitial fibrosis are not specific for CS toxicity, these changes are commonly found in both humans and rats at high doses of CS.