Membranous nephropathy / Nefropatia membranosa

ABSTRACT Membranous nephropathy is a glomerulopathy, which main affected target is the podocyte, and has consequences on the glomerular basement membrane. It is more common in adults, especially over 50 years of age. The clinical presentation is nephrotic syndrome, but many cases can evolve with asymptomatic non-nephrotic proteinuria. The mechanism consists of the deposition of immune complexes in the subepithelial space of the glomerular capillary loop with subsequent activation of the complement system. Great advances in the identification of potential target antigens have occurred in the last twenty years, and the main one is the protein "M-type phospholipase-A2 receptor" (PLA2R) with the circulating anti-PLA2R antibody, which makes it possible to evaluate the activity and prognosis of this nephropathy. This route of injury corresponds to approximately 70% to 80% of cases of membranous nephropathy characterized as primary. In the last 10 years, several other potential target antigens have been identified. This review proposes to present clinical, etiopathogenic and therapeutic aspects of membranous nephropathy in a didactic manner, including cases that occur during kidney transplantation.

RESUMO A nefropatia membranosa é uma glomerulopatia, cujo principal alvo acometido é o podócito, e acarreta consequências na membrana basal glomerular. Tem maior frequência em adultos, principalmente acima dos 50 anos. A apresentação clínica é a síndrome nefrótica, mas muitos casos podem evoluir com proteinúria não nefrótica assintomática. O mecanismo consiste na deposição de complexos imunes no espaço subepitelial da alça capilar glomerular com subsequente ativação do sistema do complemento. Grandes avanços na identificação de potenciais antígenos alvo têm ocorrido nos últimos vinte anos, e o principal é a proteína "M-type phospholipase-A2 receptor" (PLA2R) com o anticorpo anti-PLA2R circulante, o que possibilita avaliar a atividade e o prognóstico dessa nefropatia. Essa via de lesão corresponde aproximadamente a 70% a 80% dos casos da nefropatia membranosa caracterizada como primária. Nos últimos 10 anos vários outros antígenos alvo potenciais têm sido identificados. Esta revisão se propõe a apresentar de modo didático aspectos clínicos, etiopatogênicos e terapêuticos da nefropatia membranosa, incluídos os casos com ocorrência no transplante renal.

Dermatite atópica grave: guia prático de tratamento da Associação Brasileira de Alergia e Imunologia e Sociedade Brasileira de Pediatria / Severe atopic dermatitis: a practical treatment guide from the Brazilian Association of Allergy and Immunology and the Brazilian Society of Pediatrics

A dermatite atópica (DA) é uma doença cutânea inflamatória, crônica, comum, complexa e de etiologia multifatorial, que se manifesta clinicamente com prurido muitas vezes incapacitante, lesões recorrentes do tipo eczema, xerose e que pode evoluir para liquenificação. Embora o conhecimento sobre a sua fisiopatologia venham crescendo nos últimos anos, ainda as formas graves são frequentes e representam um desafio para o clínico. Para o presente guia realizou-se revisão não sistemática da literatura relacionada à DA grave refratária aos tratamentos habituais com o objetivo de elaborar um documento prático e que auxilie na compreensão dos mecanismos envolvidos na DA, assim como dos possíveis fatores de risco associados à sua apresentação. A integridade da barreira cutânea é um dos pontos fundamentais para a manutenção da homeostase da pele. Além dos cuidados gerais: evitação dos agentes desencadeantes e/ou irritantes, o uso de hidratantes, suporte emocional, entre outros, o uso de agentes anti-inflamatórios/imunossupressores de uso tópico e/ou sistêmico também foi revisado. A aquisição de novos agentes, os imunobiológicos e as pequenas moléculas, melhorou a terapêutica para os pacientes com formas graves de DA, sobretudo as refratárias aos tratamentos convencionais.

Atopic dermatitis is a chronic, common, and complex inflammatory skin disease with a multifactorial etiology. It manifests clinically with often disabling pruritus, recurrent eczema-like lesions, and xerosis, and can progress to lichenification. Although understanding of the disease's pathophysiology has been growing in recent years, severe forms are still frequent and represent a challenge for clinicians. A non-systematic review of the literature on severe atopic dermatitis refractory to conventional treatment was conducted to develop the present guide, whose purpose is to help clarify the mechanisms involved in the disease and possible risk factors. The integrity of the skin barrier is fundamental for maintaining skin homeostasis. In addition to general care, patients should avoid triggering and/or irritating agents and moisturizers and seek emotional support, etc.; the use of topical and/or systemic anti-inflammatory/immunosuppressive agents was also reviewed. New agents, immunobiologicals, and small molecules have led to a broader range of therapies for patients with severe forms of the disease, especially cases refractory to conventional treatment.

Incidência de reações adversas associadas ao uso de inibidores de calcineurina em pacientes submetidos ao transplante pulmonar / Incidence of adverse reactions associated with the use of calcineurin inhibitors in patients undergoing lung transplantation

Introdução: O uso de terapia imunossupressora é de extrema importância no transplante pulmonar, entretanto existem diversas reações adversas (RAMs) associadas ao seu uso. Neste trabalho buscamos descrever a incidência de perda de função renal (FR), diabetes mellitus (DM), hipertensão arterial sistêmica (HAS) e hipercolesterolemia associadas ao uso de ICN na população de transplantados pulmonares do Hospital de Clínicas de Porto Alegre após 1 ano de transplante.Metodologia: Estudo de coorte retrospectivo, conduzido no Hospital de Clínicas de Porto Alegre. Foram incluídos os pacientes transplantados de pulmão no período de 2016 a 2018.Resultados: Após um ano do transplante 56,5% (13/23) tiveram uma perda de FR em comparação ao basal, mas com valores ainda dentro da normalidade e 30,4% (7/23) perderam FR. A diferença de FR antes e após o transplante foi estatisticamente significativa com p < 0,001, no entanto não foi observado diferença entre os ICN (p = 0,499). Entre as variáveis: DM, HAS e Hipercolesterolemia, apenas o desenvolvimento de HAS foi estaticamente significativo quando comparado ao período pré-transplante (p < 0,001).Conclusão: Nossos dados demonstraram importante perda de FR após uso de imunossupressores ICN, corroborando com dados já publicados, no entanto, não foi possível identificar associação com ICN específico, sugerindo que benefícios na intercambialidade de terapias entre os ICN na tentativa de preservação da FR devem ser melhor estudados. Diante da possibilidade de desenvolvimento de RAMs associadas ao uso de imunossupressores, destacamos a importância da inserção do farmacêutico clínico nas equipes de transplante.

Introduction: Immunosuppressive therapy is extremely important in lung transplantation, but there are several adverse drug reactions (ADRs) associated with its use.Objective: To report the incidence of loss of renal function (RF), diabetes mellitus (DM), systemic arterial hypertension (SAH), and hypercholesterolemia associated with the use of calcineurin inhibitors (CNIs) in the population of lung transplant recipients at Hospital de Clínicas de Porto Alegre at 1 year after transplant. Methods: We conducted a retrospective cohort study of patients undergoing a lung transplant at Hospital de Clínicas de Porto Alegre from 2016 to 2018.Results: At 1 year after transplant, 56.5% (13/23) had loss of RF compared with baseline, but the values remained within the normal range, whereas 30.4% (7/23) had complete loss of RF. There was a statistically significant difference in RF before and after transplant (p < 0.001), but not in CNIs (p = 0.499). Among the variables DM, SAH, and hypercholesterolemia, only the development of SAH was statistically significant compared with the pre-transplant period (p < 0.001).Conclusion: Our data demonstrated an important loss of RF after the use of CNI immunosuppressants, which is consistent with published data. However, no association was identified with the type of CNI, suggesting that the benefits of the interchangeability of CNI therapies aimed at preserving RF should be further studied. Given the potential occurrence of ADRs associated with the use of immunosuppressants, we highlight the importance of the presence of a clinical pharmacist in the transplant team.

Clinical features and treatment of calcineurin inhibitor-induced pain syndrome in renal transplant recipients / 药学实践杂志

Objective To understand the clinical features and therapeutic methods for calcineurin inhibitor-induced pain syndrome (CIPS) in kidney transplant recipients. Methods The related articles or abstracts from January 1991 to December 2020 were obtained by searching PubMed, Google Scholar, CNKI, Wanfang and VIP databases. The reviews, duplicate literatures and the articles involved in non-kidney transplant recipients were excluded. 11 full papers were included with 15 case reports. Results The average age of patients at the time of diagnosis of CIPS was (44.6±8.31) years, and the 53.3% of the patients was male. The average appearance time of CIPS was (2.42±3.07) months after kidney transplantation. CIPS mainly affected bilateral hands, elbows, wrists, knees, ankles, feet and back. The patients had normal or elevated trough concentrations of calcineurin inhibitors (CNIs) when CIPS occurred. Some patients had elevated alkaline phosphatase, parathyroid hormone, blood calcium, C-reactive protein levels, and abnormal phosphorus levels, while rheumatoid factor and uric acid levels were normal. CIPS symptoms in most patients disappeared with dose reduction of CNIs, change to different class of CNIs, pamidronate IV injection, pregabalin, calcium channel antagonists, etc. The average recovery time was (4.43±3.31) months. Conclusion The most effective treatment for CIPS is to reduce the dose of CNIs and replace immunosuppressants. Other treatments include GABA analogs, intravenous pamidronate, calcium channel blockers and conservative therapy.

Alternative Oral Mucous Membrane Pemphigoid Therapy Using Tacrolimus: A Case Report

ABSTRACT: Mucous membrane pemphigoid (MMP) is a blistering disease that predominantly involves the mucous membranes and that can lead to major negative impacts on patient quality of life. The first-line MMP treatment is based on the use of topical and systemic corticosteroids. In this report, we presented a 45-year-old female patient presented blisters in the inferior gingiva for over 8-months. The patient reported being allergic to corticosteroids. Under the clinical hypothesi s of oral lichen planus and MMP, an incisional biopsy was performed, and the histopathological diagnosis of MMP was established. Thus, it was instituted an alternative therapy with tacrolimus 0.03 %. The patient showed an excellent clinical outcome with no recurrence five months after the end of therapy. Tacrolimus 0.03 % may represent an effective therapeutic alternative in MMP treatment and may be used in cases of hypersensitivity to standard therapy.

RESUMEN: El penfigoide de la membrana mucosa (PMM) es una enfermedad ampollosa que afecta predominantemente a las membranas mucosas y que puede provocar importantes impactos negativos en la calidad de vida del paciente. El tratamiento de primera línea de PMM se basa en el uso de corticosteroides tópicos y sistémicos. En este informe, presentamos un caso de una paciente femenina de 45 años que presentó ampollas en la encía inferior durante más de 8 meses. La paciente informó ser alérgica a los corticosteroides. Bajo la hipótesis clínica de liquen plano oral y PMM, se realizó una biopsia incisional y se estableció el diagnóstico histopatológico de PMM. Por lo tanto, se instituyó una terapia alternativa con tacrolimus tópico al 0,03 %. La paciente mostró un excelente resultado clínico sin recurrencia después de 5 meses de la terapia final. Tacrolimus 0,03 % puede representar una alternativa terapéutica efectiva en el tratamiento de PMM y se puede usar en casos de hipersensibilidad a la terapia estándar.

Regulatory control of the Na-Cl co-transporter NCC and its therapeutic potential for hypertension

Hypertension is the largest risk factor for cardiovascular disease, the leading cause of mortality worldwide. As blood pressure regulation is influenced by multiple physiological systems, hypertension cannot be attributed to a single identifiable etiology. Three decades of research into Mendelian forms of hypertension implicated alterations in the renal tubular sodium handling, particularly the distal convoluted tubule (DCT)-native, thiazide-sensitive Na-Cl cotransporter (NCC). Altered functions of the NCC have shown to have profound effects on blood pressure regulation as illustrated by the over activation and inactivation of the NCC in Gordon's and Gitelman syndromes respectively. Substantial progress has uncovered multiple factors that affect the expression and activity of the NCC. In particular, NCC activity is controlled by phosphorylation/dephosphorylation, and NCC expression is facilitated by glycosylation and negatively regulated by ubiquitination. Studies have even found parvalbumin to be an unexpected regulator of the NCC. In recent years, there have been considerable advances in our understanding of NCC control mechanisms, particularly

Etiology of graft dysfunction in renal transplant recipients

Background: Kidney transplantation is the preferred mode of renal replacement therapy for the endstage renal disease, with dramatic improvements in patient and graft survival over the last 50 years. In the modern era of immunosuppression, 1-year patient survival is close to 98%, and 1-year allograft survival rates have improved to 90% for deceased donor kidney transplants and 95 % for living donor kidney transplants with some inter-center variability. The aim of the study: To elucidate the etiology of graft dysfunction among renal transplant recipients. Materials and methods: A retrospective study was conducted among 155 patients who underwent both cadavers and live donor transplant from October 2009 to March 2011 at a tertiary care center in Chennai, South India. All the transplant recipients were regularly followed with serum urea and creatinine, urine routine, calcineurin inhibitor drug levels in the serum, USG Abdomen, urine culture depending on the graft status. Graft dysfunction defined by a rise in the creatinine more than 25% or 0.3 to 0.5 mg per dl from the baseline. Those who developed graft dysfunction were presented for graft biopsy and managed based on the report accordingly. S. Thirumavalavan, Krishna Kumar, S. A. K. Noor Mohamed, R Vijaya Kumar. Etiology of graft dysfunction in renal transplant recipients. IAIM, 2019; 6(3): 313-318. Page 314 Results: Among the 155 transplant recipient patients, 66 (44%) patients developed graft dysfunction and underwent renal biopsy. The graft dysfunction was due to chronic allograft dysfunction (interstitial fibrosis and tubular atrophy) in 24 (15.4%) patients, acute cellular rejection in 13 (8.4%) patients, acute antibody-mediated rejection in 2 (1.3%) patients, acute tubular necrosis in 9 (5.8%) patients, calcineurin toxicity in 6 (3.9%) patients, thrombotic microangiopathy in 6 (3.9%) patients, IgA nephropathy in 3 (1.9%) patients and transplant renal artery stenosis in 1(0.6%) patient. Conclusion: Among the various causes, acute cellular, acute antibody rejection and chronic allograft nephropathy holds nearly 25% of the incidence of graft dysfunction. It indicates appropriate immunological evaluation, appropriate immunosuppression, use of induction agents in high-risk patients and protocol renal biopsy to identify early rejection in high-risk patient and appropriate early intervention is important to improve long-term term graft and patient survival.

Predictive factors analysis of the efficacy of cyclophosphamide combined with glucocorticoids in the treatment of idiopathic membranous nephropathy / 中华肾脏病杂志

Objective To investigate the predictive factors affecting the efficacy of cyclophosphamide (CTX) combined with glucocorticoids in the treatment of idiopathic membranous nephropathy (IMN),and to evaluate the efficacy of calcineurin inhibitor (CNI) adjustment due to poor treatment.Methods A retrospective cohort study was conducted.Two hundreds and twenty-eight patients with IMN diagnosed by renal biopsy in the People's Hospital of Guangxi Zhuang Autonomous Region from January 1,2007 to December 1,2016 were enrolled.All subjects were treated with CTX in combination with glucocorticoids.The patients were divided into two groups:remission group and no remission group.Multivariable logistic regression analysis was used to determine the baseline clinical-pathological influencing factors for the remission of IMN in the enrolled patients.Results The number of total remission (including complete and partial remission) of the first CTX combined with glucocorticoid treatment in 228 patients with IMN was 188(82.5％).Among them,141 patients (61.8％) had complete remission (CR),the median time for CR was 8(6,12) months,and the median time for partial remission (PR) was 3(1,4) months.The median follow-up time for this study was 25(13,43) months.Compared with the remission group,the serum albumin level was lower in the non-remission group,the 24-hour urine protein content,the blood complement C3 and C4 levels were higher,and the pathological stage was milder (all P ＜ 0.05).Multivariate logistic regression analysis suggested that the levels of baseline serum albumin,complement C4,and pathological stage were independent predictors of clinical remission in IMN patients.Twenty-four non-remission patients were treated with CNI.The overall response rate was 66.7％(16/24) at 6 months and 77.3％(17/22) at 12 months.Conclusions The levels of baseline albumin,blood complement C4,and pathological stage were independent predictors of clinical remission in IMN patients treated with CTX plus glucocorticoids.The non-remission patients with CTX combined with glucocorticoid therapy can still achieve a higher response rate after adjusting for CNI.

Immutol induces immune tolerance of cardiac grafts in rat models / 器官移植

Objective To investigate the effect of Immutol on inducing the immune tolerance of cardiac grafts in rat models. Methods A rat model of heterotopic abdominal heart transplantation was established. The recipient rats were divided into 5 groups: blank control group (n=6); dimethyl sulfoxide (DMSO) group (n=6), in which DMSO was administered until the cardiac graft arrest; Immutol group (n=6), in which Immutol was administered until the cardiac graft arrest; ciclosporin (CsA) group (n=10), in which CsA was administered for 20 d; combined group (n=13), in which Immutol was given for 60 d combined with CsA for 20 d. The survival time and pathological changes of cardiac grafts in each group were observed. The contents of serum interleukin (IL)-10 and interferon (IFN)-γ were detected. The expression levels of indoleamine 2, 3-dioxygenase (IDO) and fibrinogen-like protein 2(Fgl2) messenger RNA(mRNA) in heart tissues of rats in each group were measured. Results In the combined group, the cardiac grafts survived for >180 d and immune tolerance was induced. The pathological score of cardiac grafts in the combined group was significantly lower than that in the CsA group at postoperative 39 d (P < 0.05). The levels of serum IL-10 and IFN-γ in the combined group were significantly higher than those in the CsA group at 9 d and 39 d after operation (both P < 0.05). The content of serum IL-10 and IFN-γ in the combined group were gradually increased over time. At postoperative 39 d, the expression levels of IDO and Fgl2 mRNA in the combined group were significantly higher than those in the CsA group (both P < 0.05). The expression level of IDO mRNA in the combined group tended to gradually elevate after operation. In the combined group, the expression level of Fgl2 mRNA at postoperative 180 d was significantly higher than those at 9 d and 39 d after operation (both P < 0.05). Conclusions Combined administration of Immutol and CsA can effectively inhibit the incidence of acute rejection, and maintain the long-term survival of the cardiac grafts and induce immune tolerance after drug withdrawal.

Impact of calcineurin inhibitors on rat glioma cells viability / 영남의대학술지

BACKGROUND: Although kidney transplantation outcomes have improved dramatically after using calcineurin inhibitors (CNIs), CNI toxicity continues to be reported and the mechanism remains uncertain. Here, we investigated the neurotoxicity of CNIs by focusing on the viability of glioma cells.METHODS: Glioma cells were treated with several concentrations of CNIs for 24 hours at 37℃ and their cell viability was evaluated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay.RESULTS: Exposure to 0, 0.25, 0.5, 2.5, 5.0, and 10.0 mM concentrations respectively showed 100%, 64.3%, 61.3%, 68.1%, 62.4%, and 68.6% cell viability for cyclosporine and 100%, 38.6%, 40.8%, 43.7%, 37.8%, and 43.0% for tacrolimus. The direct toxic effect of tacrolimus on glioma cell viability was stronger than that of cyclosporine at the same concentration.CONCLUSION: CNIs can cause neurological side effects by directly exerting cytotoxic effects on brain cells. Therefore, we should carefully monitor the neurologic symptoms and level of CNIs in kidney transplant patients.

Risk factors for new-onset diabetes mellitus after kidney transplantation (NODAT): a Brazilian single center study

ABSTRACT Objectives: This study aims to verify the new-onset diabetes after kidney transplant (NODAT) incidence in recipients within 1 year after kidney transplantation from a single center in Southern Brazil and to assess the associated conditions. Subjects and methods: A retrospective study of 258 post-renal transplant patients was performed. Demographic (gender, age, ethnic background) and clinical (origin of graft, associated infections, body mass index (BMI) at transplant time and 6 and 12 months after, causes of renal failure, and comorbidities) data were analyzed. All patients were on tacrolimus, mycophenolate mofetil, and prednisone treatment. Patients with and without NODAT were compared. Results: A NODAT incidence of 31.2% was noted 1 year post transplantation. In the univariate analysis, patients with NODAT were older (p = 0.001), mostly had African-American ethnic background (p = 0.02), and had renal failure secondary to high blood pressure (HBP) (p = 0.001). The group of patients with NODAT also had more incidence of post-transplant HBP (p = 0.01), heart failure (p = 0.02), and dyslipidemia (p = 0.001). Logistic regression showed that African-American ethnic background, post-transplant HBP, and dyslipidemia were independently associated with NODAT. Conclusion: This study shows a NODAT incidence that is greater in patients with African-American ethnic background and that is associated with HBP and dyslipidemia.

Guia prático de atualização em dermatite atópica - Parte II: abordagem terapêutica. Posicionamento conjunto da Associação Brasileira de Alergia e Imunologia e da Sociedade Brasileira de Pediatria / Updated practical guide on atopic dermatitis - Part II: treatment approach. Joint position paper of the Brazilian Association of Allergy and Immunology and the Brazilian Society of Pediatrics

Nas últimas décadas o conhecimento sobre a etiopatogenia da dermatite atópica (DA) avançou muito. Além da identificação dos principais agentes desencadeantes e/ou agravantes envolvidos na expressão clínica da DA, verificou-se ser a integridade da barreira cutânea um dos pontos fundamentais para a manutenção da homeostase da pele. Assim, no tratamento do paciente com DA, além da evitação dos agentes desencadeantes e/ou irritantes, o uso de hidratantes é parte fundamental, e acredita-se que tenha ação preventiva de surtos agudos. Além disso, a aquisição de agentes anti-inflamatórios de uso tópico tem permitido o controle de pacientes com formas leves a moderadas da DA. Embora tenham uso mais restrito, os agentes imunossupressores sistêmicos também têm sido empregados no tratamento de pacientes com DA grave ou refratária aos procedimentos habituais. Comenta-se também a imunoterapia alérgeno-específica como tratamento adjuvante da DA para alguns pacientes, sobretudo alérgicos aos ácaros e com manifestações respiratórias associadas. A aquisição de novos agentes, os imunobiológicos, também são apresentados à luz das evidências científicas e clínicas atuais. O presente guia prático de atualização em dermatite atópica ­ abordagem terapêutica teve por objetivo rever os esquemas de tratamento disponíveis e empregados no acompanhamento de pacientes com DA, além de apresentar terapêuticas futuras, como os agentes imunobiológicos que em breve estarão à disposição para o tratamento de formas mais graves e/ou refratárias da DA.

Over the last few decades, knowledge of the etiopathogenesis of atopic dermatitis (AD) advanced greatly. The main triggering and/or aggravating factors involved in the clinical expression of AD have been identified, and cutaneous barrier integrity has been found to be key for the maintenance of skin homeostasis. Thus, when treating patients with AD, in addition to avoiding triggering and/ or irritating agents, recommending the use of skin moisturizers is paramount ­ and believed to have a preventive action against acute outbreaks. Moreover, topical anti-inflammatory agents have allowed AD control in patients with mild to moderate forms of the disease. Although more restricted, systemic immunosuppressive agents have also been used in the treatment of patients with severe or refractory AD. Specific allergen immunotherapy is presented as a possible adjunctive treatment for AD in some patients, especially those allergic to mites and presenting associated respiratory manifestations. Finally, the use of new immunobiological agents is discussed in the light of the scientific and clinical evidence currently available. The objectives of this updated practical guide on atopic dermatitis ­ treatment approach were to review the treatment regimens available and used in the follow-up of patients with AD and to present new therapies (e.g., immunobiological agents) that will soon be available for the treatment of more severe and/ or refractory forms of AD.

Efficacy of tacrolimus for induction of remission in patients with moderate-to-severe ulcerative colitis: a systematic review and meta-analysis / Eficácia do tacrolimus para indução de remissão em pacientes com colite ulcerosa moderada a grave: uma revisão sistemática e meta-análise

ABSTRACT BACKGROUND There is evidence that shows that calcineurin inhibitors may be useful for the treatment of severe ulcerative colitis. However, evidence regarding the efficacy of tacrolimus for remission induction in this setting is scarce. OBJECTIVE To develop a systematic review on the existing evidence regarding the clinical efficacy of tacrolimus for the induction of remission in patients with moderate-to-severe ulcerative colitis. METHODS A literature search was undertaken from 1966 to August 2016 using MEDLINE, Embase, LILACS and the Cochrane Library. The following MeSH terms were used: “Inflammatory Bowel Diseases” or “Ulcerative Colitis” and “Calcineurin Inhibitors” or “Tacrolimus” or “FK506”. Studies performed in adult ulcerative colitis patients that evaluated the clinical efficacy of tacrolimus for the induction of remission were considered for revision. A meta-analysis was performed with those included studies that were also placebo-controlled and randomized. Clinical response as well as clinical remission and mucosal healing were evaluated. RESULTS Overall, 755 references were identified, from which 22 studies were finally included. Only two of them were randomized, placebo-controlled trials. A total of 172 patients were evaluated. A significantly lower risk of failure in clinical response was found for tacrolimus versus placebo [RR 0.58 (0.45-0.73)]; moreover, a lower risk of failure in the induction of remission was also found versus placebo [RR 0.91 (0.82-1)]. CONCLUSION Tacrolimus seems to be a valid therapeutic alternative for the induction of remission in patients with moderate-to-severe ulcerative colitis.

RESUMO CONTEXTO Há evidências que mostram que os inibidores de calcineurina podem ser úteis para o tratamento da colite ulcerativa severa. No entanto, há poucos dados sobre a eficácia do tacrolimus para indução de remissão neste cenário. OBJETIVO Desenvolver uma revisão sistemática sobre evidências existentes sobre a eficácia clínica do tacrolimus para a indução de remissão em pacientes com colite ulcerosa de moderada a grave. MÉTODOS Realizada pesquisa bibliográfica de 1966 a agosto de 2016 usando MEDLINE, Embase, LILACS e Biblioteca Cochrane. Foram utilizados os seguintes termos MeSH: “doenças inflamatórias intestinais” ou “colite ulcerativa “ e “inibidores da calcineurina” ou “tacrolimo” ou “FK506”. Foram considerados para revisão estudos que avaliaram a eficácia clínica do tacrolimus para a indução de remissão em pacientes adultos com colite ulcerosa. Uma meta-análise foi realizada com esses estudos incluídos que também fossem controlados por placebo e randomizados. Avaliou-se a resposta clínica, bem como remissão clínica e a cicatrização da mucosa. RESULTADOS No total, 755 referências foram identificadas, dos quais 22 estudos foram finalmente incluídos. Apenas dois deles eram experimentações randomizadas e, placebo-controlada. Um total de 172 pacientes foram avaliados. Verificou-se um risco significativamente menor de falha na resposta clínica para tacrolimus versus placebo [RR 0.58 (0.45-0,73)]; Além disso, um menor risco de falha na indução da remissão também foi encontrado versus placebo [RR 0,91 (0,82-1)]. CONCLUSÃO Tacrolimus parece ser uma alternativa terapêutica válida para a indução de remissão em pacientes com colite ulcerosa moderada a grave.

Interaction of Gender and Hepatitis C in Risk of Chronic Renal Failure After Liver Transplantation

ABSTRACT Background. Chronic renal failure (CRF) is a significant cause of morbidity and mortality in post-liver transplantation (LT) recipients. The risk factors associated with the development of renal dysfunction are not clearly elucidated. Objectives. To examine the risk factors in the development of CRF in these patients. Material and methods. Retrospective case-cohort of liver transplant patients without baseline kidney dysfunction who developed chronic renal failure during their follow-up. Results. Of 370 patients, 254 met the inclusion criteria. 30% (76) of these patients had CRF of which 57% (43) were male. Age, estimated glomerular filtration rate (eGFR) at discharge, and HCV infection were found to be risk factors for CRF post-LT. The odds ratio of developing CRF was 1.4 (0.6-3.3) in males with HCV, 1.6 (0.7-3.9) in females without HCV and 4.4 (1.5-13.2) among females with HCV when compared to men without HCV. Conclusions. In this cohort of LT receipients of a major Canadian city, age, eGFR, and HCV infection were risk factors for CRF. Female gender and HCV increased this odds by a factor of more than 4.

Conversion to Mycophenolate Mofetil Monotherapy in Liver Recipients: Calcineurin Inhibitor Levels are Key

Abstract: The use of calcineurin inhibitors (CNI) after liver transplantation is associated with post-transplant nephrotoxicity. Conversion to mycophenolate mofetil (MMF) monotherapy improves renal function, but is related to graft rejection in some recipients. Our aim was to identify variables associated with rejection after conversion to MMF monotherapy. Conversion was attempted in 40 liver transplant recipients. Clinical variables were determined and peripheral mononuclear blood cells were immunophenotyped during a 12-month follow- up. Conversion was classified as successful (SC) if rejection did not occur during the follow-up. MMF conversion was successful with 28 patients (70%) and was associated with higher glomerular filtration rates at the end of study. It also correlated with increased time elapsed since transplantation, low baseline CNI levels (Tacrolimus ≤ 6.5 ng/mL or Cyclosporine ≤ 635 ng/mL) and lower frequency of tacrolimus use. The only clinical variable independently related to SC in multivariate analysis was low baseline CNI levels (p = 0.02, OR: 6.93, 95%, CI: 1.3-29.7). Mean baseline fluorescent intensity of FOXP3+ T cells was significantly higher among recipients with SC. In conclusion, this study suggests that baseline CNI levels can be used to identify recipients with higher probability of SC to MMF monotherapy. Clinicaltrials.gov identification: NCT01321112.

Significance of acute kidney injury biomarkers in the treatment of refractory nephrotic syndrome with calcineurin inhibitors / 中华实用儿科临床杂志

Objective To investigate the significance of acute kidney injury biomarkers with calcineurin inhibitors (CNI) related nephrotoxicity in the treatment of refractory nephritic syndrome.Methods Ninety-two patients were included with 59 males and 33 females with average age of (5.67 ± 3.65) years old,who were diagnosed with nephrotic syndrome at Shanghai Children's Hospital from March 2014 to December 2015.66 patients including 44 males and 22 females with mean age of (4.97 ± 3.52) were treated by steroid as the control group and 26 patients including 15 males and 11 females with mean age of (6.59 ± 3.95) were treated by steroid combined with CsA and FK506 as the observation group.The blood,urine samples were collected before drug treatment (0 d) and very early stage of treatment (3 d),early stage (1 month),middle and late stage (3 months and 6 months) as the different observation time points.The change level of neutrophil gelatinase associated lipocalin(NGAL),kidney injury molecular-1 (KIM-1),fibronectin(FN) and tumor necrosis factor-alpha(TNF-α) in serum and urine were detected at different time points to compare with biomarkers such as retinol-binding protein(RBP),N-acetyl-β-D-glucosamccharase(NAG) in urine.Results The serum NGAL(sNAGL) level was more obvious after 6 months of CNI treatment in the observation group than in the control group[(138.00 ±32.49) μg/L vs.(46.54± 11.41) μg/L,t =2.115,P ＜0.05];the level of urine TNF-oα(uTNF-α) was higher obviously after 6 months of CNI treatment in the observation group than in the control group with significant differences [(2.35 ± 0.78) pg/μmol vs.(0.75 ± 0.36) pg/μmol,t =1.840,P ＜ 0.05];the level of urine KIM-1 (uKIM-1) was lower in the observation group than the control group after 3 months treatment of the CNI [(0.15 ± 0.03) ng/μmol vs.(0.33 ± 0.07) ng/μmol,t =-2.077,P ＜ 0.05);the level of urine NGAL (uNGAL) was lower in the observation group than the control group after 3 months treatment of the CNI [(0.09 ±0.03) ng/μmol vs.(0.23 ± 0.04) ng/μmol,t =-2.959,P ＜ 0.05].But the serum TNF-α (sTNF-α),urine FN (uFN),urine RBP(uRBP) and urine NAG (uNAG)did not show any significant change before and after the C NI treatment.Conclusions Compared with other acute kidney injury biomarkers (uNGAL,KIM-1,FN,RBP,and NAG),sNAGL and uTNF-α may be more sensitive to the early evaluation of CNI related nephrotoxicity.The occurrence of CNI related kidney injury shall be watched out at the beginning of 6-month of CNI treatment.

Significance of acute kidney injury biomarkers in the treatment of refractory nephrotic syndrome with calcineurin inhibitors / 中华实用儿科临床杂志

Objective To investigate the significance of acute kidney injury biomarkers with calcineurin inhibitors (CNI) related nephrotoxicity in the treatment of refractory nephritic syndrome.Methods Ninety-two patients were included with 59 males and 33 females with average age of (5.67 ± 3.65) years old,who were diagnosed with nephrotic syndrome at Shanghai Children's Hospital from March 2014 to December 2015.66 patients including 44 males and 22 females with mean age of (4.97 ± 3.52) were treated by steroid as the control group and 26 patients including 15 males and 11 females with mean age of (6.59 ± 3.95) were treated by steroid combined with CsA and FK506 as the observation group.The blood,urine samples were collected before drug treatment (0 d) and very early stage of treatment (3 d),early stage (1 month),middle and late stage (3 months and 6 months) as the different observation time points.The change level of neutrophil gelatinase associated lipocalin(NGAL),kidney injury molecular-1 (KIM-1),fibronectin(FN) and tumor necrosis factor-alpha(TNF-α) in serum and urine were detected at different time points to compare with biomarkers such as retinol-binding protein(RBP),N-acetyl-β-D-glucosamccharase(NAG) in urine.Results The serum NGAL(sNAGL) level was more obvious after 6 months of CNI treatment in the observation group than in the control group[(138.00 ±32.49) μg/L vs.(46.54± 11.41) μg/L,t =2.115,P ＜0.05];the level of urine TNF-oα(uTNF-α) was higher obviously after 6 months of CNI treatment in the observation group than in the control group with significant differences [(2.35 ± 0.78) pg/μmol vs.(0.75 ± 0.36) pg/μmol,t =1.840,P ＜ 0.05];the level of urine KIM-1 (uKIM-1) was lower in the observation group than the control group after 3 months treatment of the CNI [(0.15 ± 0.03) ng/μmol vs.(0.33 ± 0.07) ng/μmol,t =-2.077,P ＜ 0.05);the level of urine NGAL (uNGAL) was lower in the observation group than the control group after 3 months treatment of the CNI [(0.09 ±0.03) ng/μmol vs.(0.23 ± 0.04) ng/μmol,t =-2.959,P ＜ 0.05].But the serum TNF-α (sTNF-α),urine FN (uFN),urine RBP(uRBP) and urine NAG (uNAG)did not show any significant change before and after the C NI treatment.Conclusions Compared with other acute kidney injury biomarkers (uNGAL,KIM-1,FN,RBP,and NAG),sNAGL and uTNF-α may be more sensitive to the early evaluation of CNI related nephrotoxicity.The occurrence of CNI related kidney injury shall be watched out at the beginning of 6-month of CNI treatment.

Síndrome nefrótico resistente a corticoides en pediatría, actualización / Steroid-resistant nephrotic syndrome in pediatrics, an update

El síndrome nefrótico (SN) constituye la glomerulopatía más frecuente en pediatría. El pilar del tratamiento con-tinúa siendo la terapia con corticoides. Dependiendo de la respuesta se clasifica en síndrome nefrótico corti-coresistente (SNCR) y corticosensible. La mayoría de los pacientes con SNCR tienen glomeruloesclerosis focal y segmentaria, asociada con 50% de riesgo de enfermedad renal terminal, por lo que se recomienda biopsia renal. Es importante realizar pruebas genéticas, ya que ciertas mutaciones resultan en corticorresistencia, siendo la mutación del gen NPHS2 (podocina) la más relacionada. Este artículo es una revisión de la literatura mundial y nacional acerca del SNCR en pediatría, enfatizando en nuevos enfoques de diagnóstico y tratamiento

Nephrotic syndrome (NS) is the most frequent glomerulopathy in pediatrics. The mainstay of treatment continues to be corticosteroid therapy. Depending on the response, it is classified as corticosteroid nephrotic syndrome (SNCR) and corticosensitive syndrome. Most patients with SNCR have focal and segmental glomerulosclerosis, associated with a 50% risk of end-stage renal disease, and renal biopsy is recommended. It is important to perform genetic tests, since certain mutations result in corticoresistance, with the mutation of NPHS2 gene (podocin) being the most related. This article is a review of the global and national literature on SNCR in pediatrics, emphasizing new approaches to diagnosis and treatment.

Implications of Calcineurin/NFAT Inhibitors' Regulation of Dendritic Cells and Innate Immune Cells in Islet Xenotransplantation

Calcineurin inhibitors, such as cyclosporine and tacrolimus (FK506) are broadly used in organ transplantations as immune suppressants. As the calcineurin/NFAT signaling pathway has been identified as critical pathway in the interleukin-2 (IL-2) production of T cells, inhibition of T-cell derived IL-2 has been considered the major mechanism of calcineurin inhibitors. However, there is increasing evidence that NFAT transcription factor is involved in multiple functions of dendritic cells and innate immune cells as well. NFAT expression is not restricted to T cells, and IL-2 can be produced in dendritic cells and macrophages through the calcineurin/NFAT pathway. Furthermore, it has been discovered that NFAT regulates expressions of several inflammatory mediators, including TNF-α and cyclooxygenase-2 in innate immune cells. Therefore, calcineurin inhibitors may have much broader effects in the transplant recipients than previously being considered. In this review, we reviewed recently discovered roles of NFAT pathway in dendritic cells and innate immune cells, and discussed positive and negative implications of calcineurin inhibitors' broader effects with a focus on islet xenotransplantation.

Everolimus after liver transplantation: a Meta-analysis / 中华肝胆外科杂志

Objective To compare everolimus (EVR) with calcineurin inhibitor (CNI) minimization or withdrawal on renal function of liver transplant patients with standard CNI therapy.Methods A search was conducted on databases which included the PubMed,Embase and Cochrane library for randomized controlled trials (RCTs) comparing EVR with CNI with minimization or withdrawal (the EVR group) with standard CNI therapy (the standard CNIs group) on renal function of liver transplant patients.A metaanalysis was performed using RevMan 5.3 software.Results Five RCTs which included 1 264 patients were selected into this study.There were 790 patients in the EVR group and 474 patients in the standard CNIs group.On meta-analysis,the EVR group had significantly better renal function (SMD =0.36,95％ CI 0.09 ～ 0.64,P ＜ 0.05),but higher rates of infection (RR =1.37,95％ CI 1.08 ～ 1.74,P ＜ 0.05),dyslipidemia (RR =2.46,95％ CI 1.79 ～ 3.38) and leukopenia (RR =2.37,95％ CI 1.32 ～ 4.26).No significant differences were found on the mortality and the acute rejection rates between the two groups (all P ＜ 0.05).Conclusions EVR with CNI minimization or withdrawal after liver transplantation provided effective immunosuppression and improved patients' renal function.The treatment increased the rates of infection,dyslipidemia and leukopenia.