Toward an Integrated View of Operational Tolerance in Human Renal Transplantation: A Systems Biology Perspective.

Operational tolerance (OT) is the phenomenon occurring in human renal and liver transplantation in which the body does not reject the organ after discontinuing immunosuppression for at least a year. We revisited the data generated by The Brazilian Multicenter Study on Operational Tolerance involving different conceptual fields - antigen-specific cytokine response, immune cell numbers and repertoire, signaling pathways, and epigenetics. We integrated our data to pave the way to systems biology thinking and harness debate on potential mechanisms in OT. We present original data on systems biology in OT, connecting potential mechanistic players. Using bioinformatics, we identified three dominant features that discriminate OT from its opposing clinical outcome, chronic rejection (CR). The OT-CR discriminative molecules were FOXP3, GATA3 and STAT6, each corresponding to a differential profile: (1) In FOXP3, OT presents preserved regulatory T cell (Treg) numbers but decreased numbers in CR; (2) in GATA3, increased expression is seen in OT; and (3) in STAT6, decreased monocyte activation is seen in OT. With these variables, we built molecular networks to identify interactions related to OT versus CR. Our first systems biology endeavor gave rise to novel potentially relevant interconnected players in OT mechanisms: FOXP3 connecting to interleukin-9 (IL-9) and IL-35 signaling, suggesting their immunoregulatory involvement in OT. Likewise, GATA3/FOXP3 interactions incrementing/stabilizing FOXP3 transcription suggest participation in keeping healthy FOXP3+ Tregs in OT. We envision that systems biology thinking will greatly contribute to advancing knowledge in human transplantation tolerance in an interactive perspective.

Regulatory/inflammatory cellular response discrimination in operational tolerance.

BACKGROUND: Antigen-specific cellular response is essential in immune tolerance. We tested whether antigen-specific cellular response is differentially modulated in operational tolerance (OT) in renal transplantation with respect to critical antigenic challenges in allotransplantation-donor antigens, pathogenic antigens and self-antigens. METHODS: We analysed the profile of immunoregulatory (REG) and pro-inflammatory (INFLAMMA) cytokines for the antigen-specific response directed to these three antigen groups, by Luminex. RESULTS: We showed that, in contrast to chronic rejection and healthy individuals, OT gives rise to an immunoregulatory deviation in the cellular response to donor human leucocyte antigen DR isotype peptides, while preserving the pro-inflammatory response to pathogenic peptides. Cellular autoreactivity to the N6 heat shock protein 60 (Hsp60) peptide also showed a REG profile in OT, increasing IL4, IL-5, IL-10 and IL-13. CONCLUSIONS: The REG shift of donor indirect alloreactivity in OT, with inhibition of interleukin (IL)-1B, IL-8, IL-12, IL-17, granulocyte colony-stimulating factor, Interferon-γ and monocyte chemoattractant protein-1, indicates that this may be an important mechanism in OT. In addition, the differential REG profile of cellular response to the Hsp60 peptide in OT suggests that REG autoimmunity may also play a role in human transplantation tolerance. Despite cross-reactivity of antigen-specific T cell responses, a systemic functional antigen-specific discrimination takes place in OT.

Pharmacokinetics of polymyxin B in patients on continuous venovenous haemodialysis.

OBJECTIVES: To evaluate the pharmacokinetics of polymyxin B in patients on continuous venovenous haemodialysis (CVVHD) after intravenous administration of unadjusted dosage regimens. PATIENTS AND METHODS: Two critically ill patients had eight blood samples collected during a 12 h interval on days 8 and 10 of polymyxin B therapy. Dialysate was collected every hour during the 12 h dosing interval. Polymyxin B binding in plasma was determined by rapid equilibrium dialysis. Concentrations of polymyxin B in plasma and dialysate samples were quantified using a validated ultra-performance liquid chromatography-tandem mass spectrometry assay. RESULTS: Respective maximum plasma concentrations in patients 1 and 2 were 8.62 and 4.38 mg/L; total body clearances (scaled linearly by body weight) were 0.043 and 0.027 L/h/kg, respectively, of which 12.2% and 5.62% were dialysis clearance, respectively. The corresponding volumes of distribution of polymyxin B at steady state were 0.50 and 0.34 L/kg, respectively, and protein binding in pooled plasma samples was 74.1% and 48.8%, respectively. CONCLUSIONS: Our findings indicate that the recommended polymyxin B doses should not be reduced for patients on CVVHD.

Rethinking the multiple roles of B cells in organ transplantation.

PURPOSE OF REVIEW: To discuss the B-cell diverse functions in organ transplantation, highlighting the emerging debate on the role of regulatory B cells (Bregs). We underscore the need to re-examine and integrate data on B-cell functional activities, aiming to discriminate their regulatory (REG) and inflammatory (INFLAMMA) functions and to translate this knowledge for the development of novel immunomodulatory therapeutic strategies and to rethink the current ones. RECENT FINDINGS: Data from both experimental models and clinical trials point that B cells of various phenotypes have immunoregulatory activity and play an important role in controlling graft inflammation. Data on the state of operational tolerance, in kidney transplantation, suggest the relevance of preserving a healthy B-cell compartment - in numbers and in the Breg capacity to activate the CD40/STAT3 signalling pathway - for achieving and maintaining homeostasis. Moreover, autoantibodies also comprise transplant immunobiology and it seems that not all alloantibodies are deleterious. SUMMARY: The role of B cells, in organ transplantation, can no longer be taken as mere generators of plasma cells, which produce alloantibodies deleterious to the graft. B cells also seem to integrate a complex immunoregulatory network in organ transplantation, with Bregs of various phenotypes and possibly also antibodies. The functional discrimination of REG/INFLAMMA B-cell roles needs to be considered in the clinical setting.

GATA3 and a dominant regulatory gene expression profile discriminate operational tolerance in human transplantation.

Some organ-transplanted patients achieve a state of "operational tolerance" (OT) in which graft function is maintained after the complete withdrawal of immunosuppressive drugs. We used a gene panel of regulatory/inflammatory molecules (FOXP3, GATA3, IL10, TGFB1, TGFBR1/ TBX21, TNF and IFNG) to investigate the gene expression profile in peripheral blood mononuclear cells of renal-transplanted individuals experiencing OT compared to transplanted individuals not displaying OT and healthy individuals (HI). OT subjects showed a predominant regulatory (REG) profile with higher gene expression of GATA3, FOXP3, TGFB1 and TGFB receptor 1 compared to the other groups. This predominant REG gene expression profile displayed stability over time. The significant GATA3 gene and protein expressions in OT individuals suggest that a Th2 deviation may be a relevant pathway to OT. Moreover, the capacity of the REG/INFLAMMA gene panel to discriminate OT by peripheral blood analysis indicates that this state has systemic repercussions.

Preserving the B-cell compartment favors operational tolerance in human renal transplantation.

Transplanted individuals in operational tolerance (OT) maintain long-term stable graft function after completely stopping immunosuppression. Understanding the mechanisms involved in OT can provide valuable information about pathways to human transplantation tolerance. Here we report that operationally tolerant individuals display quantitative and functional preservation of the B-cell compartment in renal transplantation. OT exhibited normal numbers of circulating total B cells, naive, memory and regulatory B cells (Bregs) as well as preserved B-cell receptor repertoire, similar to healthy individuals. In addition, OT also displayed conserved capacity to activate the cluster of differentiation 40 (CD40)/signal transducer and activator of transcription 3 (STAT3) signaling pathway in Bregs, in contrast, with chronic rejection. Rather than expansion or higher activation, we show that the preservation of the B-cell compartment favors OT.

Differential microRNA Profile in Operational Tolerance: A Potential Role in Favoring Cell Survival.

Background: Operational tolerance (OT) is a state of graft functional stability that occurs after at least 1 year of immunosuppressant withdrawal. MicroRNAs (microRNA) are small non-coding RNAs that downregulate messenger RNA/protein expression of innumerous molecules and are critical for homeostasis. We investigated whether OT in kidney transplantation displays a differential microRNA profile, which would suggest that microRNAs participate in Operational Tolerance mechanisms, and may reveal potential molecular pathways. Methods: We first compared serum microRNA in OT (n = 8) with chronic rejection (CR) (n = 5) and healthy individuals (HI) (n = 5), using a 768-microRNA qPCR-panel. We used the Thermo Fisher Cloud computing platform to compare the levels of microRNAs in the OT group in relation to the other study groups. We performed validation experiments for miR-885-5p, by q-PCR, in a larger number of study subjects (OT = 8, CR = 12, HI = 12), as individual samples. Results: We detected a differential microRNA profile in OT vs. its opposing clinical outcome-CR-suggesting that microRNAs may integrate transplantation tolerance mechanisms. Some miRNAs were detected at higher levels in OT: miR-885-5p, miR-331-3p, miR-27a-5p vs. CR; others, we found at lower levels: miR-1233-3p, miR-572, miR-638, miR-1260a. Considering highly predicted/experimentally demonstrated targets of these miRNAs, bioinformatics analysis revealed that the granzyme B, and death receptor pathways are dominant, suggesting that cell death regulation integrates transplantation tolerance mechanisms. We confirmed higher miR-885-5p levels in OT vs. CR, and vs. HI, in a larger number of subjects. Conclusions: We propose that epigenetics mechanisms involving microRNAs may integrate human transplantation tolerance mechanisms, and regulate key members of the cell death/survival signaling. miR-885-5p could favor cell survival in OT by diminishing the levels of CRADD/RAIDD and CASP3. Nonetheless, given the nature of any complex phenomenon in humans, only cumulative data will help to determine whether this microRNA differential profile may be related to the cause or consequence of operational tolerance.

Is depression a risk factor for mortality in chronic hemodialysis patients?

OBJECTIVE: The present study was conducted to assess the association between depressive symptomatology and mortality in chronic hemodialysis. METHOD: A cohort of 40 patients was followed for a median period of 10.5 months. The Beck Depression Inventory was used to classify patients as exposed to depression (Beck Depression Inventory score > 14) or not (Beck Depression Inventory < or = 14). Kaplan-Meier survival curves were used to compare the mortality rate between the two groups. The effects of potential confounding factors were adjusted using Cox proportional hazards model. RESULTS: After 24 months of follow-up, survival rates were 39% for exposed and 95% for non-exposed patients (p = 0.029). The Cox proportional hazards model showed results similar to those of the bivariate analysis, indicating that depressive symptomatology tended to be associated with mortality (HR = 6.5, 95%CI: 0.8-55.6; p = 0.085). Other study variables, including age, concurrent systemic diseases, and biochemical markers, were not significantly associated with mortality. Exposed patients remained on dialysis longer and received kidney transplants less frequently (9% vs. 50% for non-exposed patients). When kidney transplantation was included in the Cox regression model, the hazard ratio of mortality for exposed as compared to non-exposed patients lost statistical significance (HR = 4.5; 95%CI: 0.5-40.0; p = 0.17). CONCLUSIONS: Our study suggests that the presence of depressive symptoms may act as an independent risk factor for mortality in chronic hemodialysis patients. However, this finding needs further investigations.

Contrast-induced nephropathy after computed tomography.

INTRODUCTION: Contrast induced nephropathy is the third most prevalent preventable cause of acute kidney injury in hospitalized patients. It defined as an absolute increase in serum creatinine ≥ 0.5 mg/dL and relative ≥ 25% increase. OBJECTIVE: We studied the risk factors to intravenous injection contrast nephropathy after computed tomography. METHODS: We studied 400 patients prospectively. RESULTS: The incidence of contrast induced nephropathy, with an absolute or a relative increase were 4.0% and 13.9%, respectively. Diabetes and cardiac failure were independent risk factors for CIN a relative increase de serum creatinine (O.R.: 3.5 [95% CI: 1.92-6.36], p < 0.01, 2.61 [95% CI: 1.14-6.03%], p < 0.05, respectively). CONCLUSIONS: We showed association between uses of intravenous injection contrast after computed tomography with acute injury renal, notably with diabetes and heart failure.

Use of Thymoglobulin® (antithymocyte immunoglobulin) in renal transplantation: practical guide.

The combination of immunosuppressive drugs is part of the treatment regimen of patients undergoing kidney transplantation (RT). Thymoglobulin®, a rabbit immunoglobulin directed against human thymocytes, is the most commonly agent used for induction therapy in RT in the US. In Brazil, Thymoglobulin® is approved by ANVISA for the use in patients who underwent kidney transplantation and despite being widely used, there are controversies regarding the drug administration. We prepared a systematic review of the literature, evaluating studies that used Thymoglobulin® for induction and for acute rejection treatment in patients undergoing RT. The review used the computadorized databases of EMBASE, LILACS and MedLine. Data were extracted from the studies concerning general features, methodological characteristics and variables analyzed in each study. From the results, a practical guide was prepared analyzing various aspects on the use of Thymoglobulin® in patients submitted to RT.

Nephrotoxic acute renal failure in a renal transplant patient with recurrent lymphocele treated with povidone-iodine irrigation.

Povidone-iodine sclerosis has been suggested in the literature as a safe and effective treatment for post-renal transplant lymphoceles. No significant complications of this method have been described. We report on a kidney allograft recipient with recurrent lymphoceles treated with povidone-iodine instillations who developed acute renal failure secondary to iodine intoxication. Four days after the beginning of the povidone-iodine irrigations, metabolic acidosis was present, and renal function started to deteriorate. After a few days, despite the suspension of irrigations, the patient developed oliguria, and dialysis was needed. A renal biopsy was performed, and intense acute tubular necrosis was the only relevant finding. The lymphocele was corrected surgically, and the patient eventually recovered. As has been described in other settings, povidone-iodine instillation for the treatment of post-renal transplant lymphoceles may lead to iodine kidney toxicity and acute renal failure.

Modified location of the major histocompatibility protein Kb by co-delivery with VP22 protein.

We report the construction of an expression vector pVP22::Kb that encodes a chimeric protein composed of VP22 and murine major histocompatibility complex class I molecule, Kb. Flow cytometry assays show that VP22 modifies normal cell surface localization of Kb protein.

Contrast-induced nephropathy after computed tomography / Nefropatia induzida por contraste após tomografia computadorizada / Nefropatia induzida por contraste após tomografia computadorizada

Introduction: Contrast induced nephropathy is the third most prevalent preventable cause of acute kidney injury in hospitalized patients. It defined as an absolute increase in serum creatinine ≥ 0.5 mg/dL and relative ≥ 25% increase. Objective: We studied the risk factors to intravenous injection contrast nephropathy after computed tomography. Methods: We studied 400 patients prospectively. Results: The incidence of contrast induced nephropathy, with an absolute or a relative increase were 4.0% and 13.9%, respectively. Diabetes and cardiac failure were independent risk factors for CIN a relative increase de serum creatinine (O.R.: 3.5 [95% CI: 1.92-6.36], p < 0.01, 2.61 [95% CI: 1.14-6.03%], p < 0.05, respectively). Conclusions: We showed association between uses of intravenous injection contrast after computed tomography with acute injury renal, notably with diabetes and heart failure. .

Introdução: Nefropatia induzida por contraste é a terceira causa de lesão renal aguda em pacientes hospitalizados. Ela é definida como: um aumento absoluto da creatinina sérica ≥ 0,5 mg/dL e relativo em ≥ 25%. Objetivo: Nós estudamos os fatores de risco associados à nefropatia do contraste após tomografia computadorizada. Métodos: Analisamos prospectivamente 400 pacientes submetidos ao contraste endovenoso na tomografia computadorizada. Resultados: A incidência de nefropatia por contraste variou de 4 a 13,9%, conforme o critério de aumento da creatinina sérica. Diabetes e insuficiência cardíaca foram associados significativamente no aumento absoluto da creatinina sérica (O.R.: 3,5 [95% CI: 1,92-6,36], p < 0,01, 2,61 [95% CI: 1,14-6,03%], p < 0,05, respectivamente). Conclusão: Encontramos uma relação direta da infusão de contraste endovenoso na tomografia computadorizada e injúria renal, notadamente com diabetes e insuficiência cardíaca. .

Is there an association between non-steroidal anti-inflammatory drugs and contrast nephropathy?

BACKGROUND: The association between the use of nonsteroidal anti-inflammatory drugs (NSAIDs) and acute or chronic renal failure is well documented, but evidence of such association between NSAIDs and Contrast-Induced Nephropathies (CIN) is not found in the indexed literature. OBJECTIVE: To evaluate the possible association between NSAIDs and CIN. METHODS: In a cohort study, through clinical interviews of patients that underwent cardiac catheterization, we analyzed the use of NSAIDs and its association with the development of CIN, through alterations in serum creatinine or glomerular filtration rate in 48 or 72 hours. RESULTS: From July 2005 to July 2006, 236 patients were enrolled in the study, of which 29 were later excluded. The incidence of CIN was 10.37% (20 of 207) and 42% of the patients were using NSAIDs until the moment of the evaluation. There was no association between the use of NSAIDs and the development of CIN with OR of 1.293 95% CI (0.46-4.2). The study detected known risk factors for the development of CIN, such as diabetes with OR of 2.77 95%CI (1.05-7.47) and chronic renal failure with OR 3.48 95%CI (1.1-11.07). A protective action of saline solution hydration is also suggested, with OR of 0.166 95%CI (0.03-0.92). CONCLUSION: Based on the data obtained, we conclude that there was no association between CIN and previous use of NSAIDs, at least with an OR higher then 2.85, which our sample detected.

Differential monocyte STAT6 activation and CD4(+)CD25(+)Foxp3(+) T cells in kidney operational tolerance transplanted individuals.

In organ transplantation, the immunosuppression withdrawal leads, in most cases, to rejection. Nonetheless, a special group of patients maintain stable graft function after complete withdrawal of immunosuppression, achieving a state called "operational tolerance." The study of such patients may be important to understand the mechanisms involved in human transplantation tolerance. We compared the profile of CD4(+)CD25(+)Foxp3(+) T cells and the signaling pathways IL-6/STAT3 (signal transducers and activators of transcription) and IL-4/STAT6 in peripheral blood mononuclear cells of four kidney transplant groups: (i) operational tolerance (OT), (ii) chronic allograft nephropathy (CR), (iii) stable graft function under standard immunosuppression (Sta), (iv) stable graft function under low immunosuppression, and (v) healthy individuals. Both CR and Sta displayed lower numbers and percentages of CD4(+)CD25(+)Foxp3(+) T cells compared with all other groups (p < 0.05). The OT patients displayed a reduced activation of the IL-4/STAT6 pathway in monocytes, compared with all other groups (p < 0.05). The lower numbers of CD4(+)CD25(+)Foxp3(+) T cells observed in CR individuals may be a feature of chronic allograft nephropathy. The differential OT signaling profile, with reduced phosphorylation of STAT6, in monocytes' region, suggests that some altered function of STAT6 signaling may be important for the operational tolerance state.

Guia prático para usar Thymoglobuline® (globulina antitimócito) em transplante renal / Use of Thymoglobulin® (antithymocyte immunoglobulin) in renal transplantation: practical guide

Resumo A combinação de imunossupressores faz parte do protocolo de tratamento de pacientes submetidos a um transplante renal (TR). A Thymoglobuline®, imunoglobulina policlonal de coelho dirigida contra timócitos humanos, é o agente mais usado como terapia de indução no TR nos Estados Unidos. No Brasil, a Thymoglobuline® está aprovada para uso em pacientes que foram submetidos a transplante e, apesar de ser amplamente utilizada, ainda existem controvérsias em relação ao seu modo de uso. Realizamos uma revisão sistemática da literatura avaliando os estudos que utilizaram a Thymoglobuline® na indução e no tratamento de rejeição em pacientes submetidos ao TR. A revisão utilizou os bancos de dados computadorizados da EMBASE, LILACS e MedLine e dos trabalhos selecionados foram extraídas informações sobre os dados gerais dos pacientes, as características metodológicas e as variáveis analisadas em cada estudo. Dos resultados obtidos, desenvolvemos um guia prático sobre o uso de Thymoglobuline® em pacientes transplantados renais.

Abstract The combination of immunosuppressive drugs is part of the treatment regimen of patients undergoing kidney transplantation (RT). Thymoglobulin®, a rabbit immunoglobulin directed against human thymocytes, is the most commonly agent used for induction therapy in RT in the US. In Brazil, Thymoglobulin® is approved by ANVISA for the use in patients who underwent kidney transplantation and despite being widely used, there are controversies regarding the drug administration. We prepared a systematic review of the literature, evaluating studies that used Thymoglobulin® for induction and for acute rejection treatment in patients undergoing RT. The review used the computadorized databases of EMBASE, LILACS and MedLine. Data were extracted from the studies concerning general features, methodological characteristics and variables analyzed in each study. From the results, a practical guide was prepared analyzing various aspects on the use of Thymoglobulin® in patients submitted to RT.

Serum homocysteine levels in renal transplant recipients with and without hypercholesterolemia.

BACKGROUND: Hyperhomocysteinemia seems to be frequent after renal transplantation. No study so far has assessed the role of homocysteine (Hcy) associated with dyslipidemia in Brazil. OBJECTIVE: To determine the prevalence of hyperhomocysteinemia (serum Hcy >15 mmol/l) in stable renal transplant recipients and to evaluate the role of serum lipids and graft function in serum Hcy levels. METHODS: One hundred and five stable renal transplant recipients were evaluated, considering age, post-transplant time, cholesterol levels, graft function, proteinuria, and cyclosporine (analyzed using multiple linear regression). The prevalence of hyperhomocysteinemia was 74.3%. Patients were further divided into two groups, hyper (total cholesterol >200 mg/dl, LDL-cholesterol >130 mg/dl) and normocholesterolemic. RESULTS: Hypercholesterolemic recipients were older, had shorter post-transplant time, lower endogenous creatinine clearance, and higher proteinuria and Hcy serum levels. Patients with hyperhomocysteinemia had statistically significantly higher serum triglycerides and poorer graft function, and their LDL-cholesterol also tended to be higher. A positive correlation was found between serum creatinine and Hcy levels (r = 0.32, P = 0.01). Multiple regression analysis revealed that both dyslipidemia and renal function independently affect Hcy values. CONCLUSION: We observed a high prevalence of hyperhomocysteinemia in renal transplant recipients, especially in hypercholesterolemic, suggesting that worse graft function may influence serum Hcy and cholesterol levels negatively. Further studies should investigate if this adverse metabolic profile is associated with higher cardiovascular mortality in the long term.

First case report of Neisseria lactamica causing cavitary lung disease in an adult organ transplant recipient.

We describe a case of an adult organ recipient patient with a pulmonary cavitary lesion due to Neisseria lactamica, a harmless commensal organism that rarely causes human infection. To our knowledge, this is the first report of pulmonary disease caused by this organism and the second case of N. lactamica infection in an adult patient.

Modelos experimentais parao estudo do diabetes tipo 1: [revisão] / Animal models for type 1 diabetes studies: [review]

Os modelos animais de diabetes têm sido usados extensivamente na obtenção do esclarecimento sobre esta doença. O objetivo deste estudo foi realizar uma revisão bibliográfica sobre os principais modelos experimentais para o estudo do diabetes mellitus. Dentre os modelos experimentais para o estudo do diabetes, existem os modelos induzidos quimicamente por aloxana e streptozotocina, sendo que a dose utilizada depende da espécie do animal e do seu peso. Além disso, existem dois excelentes modelos de diabetes espontâneo: os ratos BB (Biobreading) e os camundongos NOD (Non ObeseDiabetic). Os camundongos NOD são o modelo mais estudado de doença espontânea auto-imune órgão-específico em todo o mundo. As razões para a preferência deste modelo incluem um genoma bem definido, maior quantidade de reagentes monoclonais para a análise de componentes do sistema imune e um custo razoavelmente baixo, comparado com a utilização de ratos. Estes camundongos exibem autoimunidade espontânea com destruição das ilhotas pancreáticas, de forma semelhante à observada em humanos. A destruição auto-imune é caracterizada por insulite e infiltrado leucocitárionas ilhotas pancreáticas. Esta infiltração é composta predominantemente por células dendríticas, macrófagos, por células TCD4, TCD8 e células B. Os fatores ambientais em conjunto com a genética, claramente modificam a incidência do diabetes tipo 1 nos modelos experimentais espontâneos. A suscetibilidade destes camundongos é poligênica e ambiental, enfatizando condições de habitação, sanitárias, dietéticas e de gênero. A incidência de diabetes em camundongos NOD é aproximadamente quatro vezes maior em fêmeas do que em machos. As informações obtidas através deste excelente modelo animal podem ser relevantes para O entendimento do processo da doença nos humanos.

The animal models of diabetes have been used extensively in obtaining the information on this disease. The objective of this study was a literature review on the main experimental models for the study of diabetes mellitus. Among the experimental models for the study of diabetes, the models are chemically induced by aloxan and streptozotocin, and the dose used depends on the species of the animal and its weight. Also, there are two excellent models of spontaneous diabetes: the BB rats (Biobreading) and NOD mice (Non Obese Diabetic). The NOD mice are the most studied model of spontaneous self immune disease-specific body in the world. The reasons for the preference genome of this model include a well-defined, greater quantity of monoclonal reagents for the analysis of components of the immune system and a reasonably low cost, compared with the use of rats. These mice exhibit spontaneous autoimmunity with destruction of pancreatic is lets, in a manner similar to that seen in humans. The auto-immune destruction is characterized by insulite in pancreatic is lets. This infiltration is composed predominantly of dendritic cells, macrophages, CD4 T cells, CD8 cells and B. The environmental factors together with the genetics, clearly alter the incidence of type 1 diabetes in experimental models spontaneous. The susceptibility of these mice is genetics and environment, emphasizing adequate housing, health, diet and gender. The incidence of diabetes in NOD mice is about four times higher in females than in males. Information obtained through this excellent animal model may be relevant to the understanding of the process of the disease in humans.

Há uma associação entre anti-inflamatórios não-esteroides e nefropatia induzida por contraste? / Is there an association between non-steroidal anti-inflammatory drugs and contrast nephropathy? / ¿Hay una asociación entre antiinflamatorios no esteroides y nefropatía inducida por contraste?

FUNDAMENTO: A associação entre o uso de anti-inflamatórios não-esteroides (AINEs) e insuficiência renal aguda ou crônica é bem documentada, mas evidências sobre a associação entre AINEs e nefropatia induzida por contraste (NIC) não são encontradas na literatura. OBJETIVO: Avaliar uma possível associação entre AINEs e NIC. MÉTODOS: Em um estudo de coorte, através da entrevista clínica de pacientes que foram submetidos à cateterização cardíaca, analisamos o uso de AINEs e sua associação com desenvolvimento de NIC, através da alteração dos níveis de creatinina sérica ou taxa de filtração glomerular em 48 ou 72 horas. RESULTADOS: No período de julho de 2005 a julho de 2006, 236 pacientes foram incluídos no estudo, dos quais 29 foram posteriormente excluídos. A incidência de NIC foi 10,37 por cento (20 de 207) e 42 por cento dos pacientes estavam recebendo AINEs até o momento da avaliação. Não houve associação entre o uso de AINEs e o desenvolvimento de NIC com OR de 1,293; IC95 por cento (0,46-4,2). O estudo detectou fatores de risco conhecidos para o desenvolvimento de NIC, tais como diabete, com OR de 2,77; IC95 por cento (1,05-7,47) e insuficiência renal crônica com OR de 3,48; IC95 por cento (1,1-11,07) e também sugeriu uma ação protetora da hidratação com solução salina com OR de 0,166; IC95 por cento (0,03-0,92). CONCLUSÃO: Com base nos dados obtidos, concluímos que não houve associação entre NIC e uso prévio de AINEs, pelo menos com um OR > 2,85, o qual nossa amostra detectou.

BACKGROUND: The association between the use of nonsteroidal anti-inflammatory drugs (NSAIDs) and acute or chronic renal failure is well documented, but evidence of such association between NSAIDs and Contrast-Induced Nephropathies (CIN) is not found in the indexed literature. OBJECTIVE: To evaluate the possible association between NSAIDs and CIN. METHODS: In a cohort study, through clinical interviews of patients that underwent cardiac catheterization, we analyzed the use of NSAIDs and its association with the development of CIN, through alterations in serum creatinine or glomerular filtration rate in 48 or 72 hours. RESULTS: From July 2005 to July 2006, 236 patients were enrolled in the study, of which 29 were later excluded. The incidence of CIN was 10.37 percent (20 of 207) and 42 percent of the patients were using NSAIDs until the moment of the evaluation. There was no association between the use of NSAIDs and the development of CIN with OR of 1.293 95 percent CI (0.46-4.2). The study detected known risk factors for the development of CIN, such as diabetes with OR of 2.77 95 percentCI (1.05-7.47) and chronic renal failure with OR 3.48 95 percentCI (1.1-11.07). A protective action of saline solution hydrationis also suggested, with OR of 0.166 95 percentCI (0.03-0.92). CONCLUSION: Based on the data obtained, we conclude that there was no association between CIN and previous use of NSAIDs, at least with an OR higher then 2.85, which our sample detected.

FUNDAMENTO: La asociación entre el uso de antiinflamatorios no esteroides (AINEs) e insuficiencia renal aguda o crónica está bien documentada, pero evidencias sobre la asociación entre AINEs y nefropatía inducida por contraste (NIC) no son encontradas en la literatura. OBJETIVO: Evaluar una posible asociación entre AINEs y NIC. MÉTODOS: En un estudio de cohorte, a través de la entrevista clínica de pacientes que fueron sometidos a cateterismo cardíaco, analizamos el uso de AINEs y su asociación con desarrollo de NIC, a través de la alteración de los niveles de creatinina sérica o tasa de filtrado glomerular en 48 o 72 horas. RESULTADOS: En el período de julio de 2005 a julio de 2006, 236 pacientes fueron incluidos en el estudio, de los cuales 29 fueron posteriormente excluidos. La incidencia de NIC fue 10,37 por ciento (20 de 207) y 42 por ciento de los pacientes estaban recibiendo AINEs hasta el momento de la evaluación. No hubo asociación entre el uso de AINEs y el desarrollo de NIC con OR de 1,293; IC95 por ciento (0,46-4,2). El estudio detectó factores de riesgo conocidos para el desarrollo de NIC, tales como diabetes, con OR de 2,77; IC95 por ciento (1,05-7,47) e insuficiencia renal crónica con OR de 3,48; IC95 por ciento (1,1-11,07) y también sugirió una acción protectora de la hidratación con solución salina con OR de 0,166; IC95 por ciento (0,03-0,92). CONCLUSIÓN: Con base en los datos obtenidos, concluimos que no hubo asociación entre NIC y uso previo de AINEs, por lo menos con un OR > 2,85, el cual nuestra muestra detectó.