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.

Comparison of effects of m-TOR inhibitors and calcineurin inhibitor on SUPAR and ox-LDL levels in renal transplant recipients / Comparación de los efectos de los inhibidores de m-TOR y el inhibidor de calcineurina sobre los niveles de SUPAR y ox-LDL en receptores de trasplante renal

ABSTRACT Introduction: We aimed to investigate the effect of different immunosuppressive regimens on SUPAR and ox-LDL levels which are early markers of inflammation in renal transplant recipients. Methods: A total number of 83 patients were enrolled in our study. While fourty- eight of those were received mTORi, thirty five patients were been receiving CNI. According to the immunosuppressive regimen patients were divided into CNI and m-TORi receving groups and serum SUPAR and ox-LDL levels were measured. Results: Log-SUPAR values were lower in the group receiving m-TORi (3.40 ± 0.1 vs 3.48 ± 0.4, p=0.010). OxLDL / LDL levels were higher (0.0168± 005 vs 0.0132 ±004, p=0.009) in the CNI group. In linear regression analysis, a statistically significant relationship was detected between the use of m-TORi and log-SUPAR (β = -0.052, 95% CI [-0.224, -0.012], p = 0.041) . A negative and independent relationship was found between HT and log-SUPAR (β = -0.60, 95% CI--0.112, -0.018], p=0.0024) and ox-LDL (β = -0.169 [-0.330, -0.008], p=0.040). Very strong correlation (r=1.0, p=<0.001) and independent relationship (β=0.321 [0.313,0.330], p=<0.001) was detected between ox-LDL and SUPAR. Conclusion: As a result, when compared immunsuppression between m-TORi and CNI, the former was associated with lower SUPAR and oxLDL levels.

RESUMEN Introducción: Nuestro objetivo fue investigar el efecto de diferentes regímenes inmunosupresores sobre los niveles de SUPAR y ox-LDL, que son marcadores tempranos de inflamación en receptores de trasplante renal. Material y métodos: Un total de 83 pacientes se inscribieron en nuestro estudio. Mientras que cuarenta y ocho de ellos recibieron mTORi, treinta y cinco pacientes recibieron CNI. De acuerdo con el régimen inmunosupresor, los pacientes se dividieron en grupos receptores de CNI y m-TORi y se midieron los niveles séricos de SUPAR y ox-LDL. Resultados: Los valores de Log-SUPAR fueron menores en el grupo que recibió m-TORi (3,40 ± 0,1 vs 3,48 ± 0,4, p = 0,010). Los niveles de OxLDL/LDL fueron mayores (0,0168± 005 vs 0,0132 ±004, p=0,009) en el grupo CNI. En el análisis de regresión lineal, se detectó una relación estadísticamente significativa entre el uso de m-TORi y log-SUPAR (β = -0,052, IC del 95% [-0,224, -0,012], p = 0,041). Se encontró una relación negativa e independiente entre HT y log-SUPAR (β = -0.60, 95% IC--0.112, -0.018], p = 0.0024) y ox-LDL (β = -0.169 [-0.330, -0.008], p = 0,040). Se detectó una correlación muy fuerte (r = 1,0, p <0,001) y una relación independiente (β = 0,321 [0,313, 0,330], p <0,001) entre ox-LDL y SUPAR. Conclusión: Como resultado, cuando se comparó la inmunosupresión entre m-TORi y CNI, la primera se asoció con niveles más bajos de SUPAR y oxLDL.

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.

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.

Retrospective analysis of clinical data and treatment of primary focal segmental glomerulosclerosis patients / Análisis retrospectivo de datos clínicos y tratamiento de pacientes con glomeruloesclerosis segmentaria focalprimaria

Abstract Introduction: The aim of the study is to compare clinical data of primary focal segmental glomerulosclerosis patients with other data in the literature. In addition, initial immunosuppressive therapy (steroid, calcineurin inhibitors) responses are aimed to be compared with the results in the literature. Methods: Forty seven patients, who were followed up for at least 12 months with primary focal segmental glomerulosclerosis as a result of kidney biopsy. Results of biochemical tests and treatment modalities were evaluated. Results: The mean age of the 47 patients with primary focal segmental glomerulosclerosis was 45.68 (± 13.92). Twenty-one (44.6 %) of 47 patients had anangiotensin converting enzyme inhibitor / angiotensin receptor blocker, 7 (14.8 %) had only corticosteroids, and 6 (12. 7%) had calcineurin inhibitor + low-dose corticosteroids treatment. Thirteen patients (27.6 %) used calcineurin inhibitor + low-dose corticosteroids after receiving corticosteroids treatment. The patients who received corticosteroids or calcineurin inhibitor + low-dose corticosteroids treatment as the initial treatment were compared at the 0, 6 and 12 months of treatment in terms of laboratory and clinical features. At the end of the first year, 4 out of 6 (66 %) patients with low-dose corticosteroids and calcineurin inhibitor and 6 out of (86 %) of 7 patients with corticosteroids had remission (p>0.05). Conclusion: We found the initial steroid treatment and calcineurin inhibitor treatment to be equally effective. We thought that patients with steroid intolerance could be given calcineurin inhibitor in the first step, but if the cost is considered, the first option, such as The Kidney Disease Improving Global Outcomes recommendation, was again steroid.

Resumen Introducción:El objetivo del estudio es comparar los datos clínicos de pacientes con glomeruloesclerosis segmentaria focal primaria con otros datos de la bibliografía. Asimismo, se busca comparar las respuestas de la terapia inmunosupresora inicial (esteroides, inhibidores de la calcineurina) con los resultados en las publicaciones citadas. Material y métodos: Se incluyeron 47 pacientes con glomeruloesclerosis segmentaria focal primaria como resultado de una biopsia renal, y cuyo seguimiento duró, al menos, 12 meses. Se evaluaron los resultados de las pruebas bioquímicas y las modalidades de tratamiento. Resultados: La edad media de los 47 pacientes con glomeruloesclerosis segmentaria focal primaria fue de 45,68 (± 13,92). 21 (44,6 %) del total de los pacientes tenían un inhibidor de la enzima convertidora de la angiotensina / bloqueante del receptor de la angiotensina. Siete pacientes (14,8 %) solo tenían corticosteroides y 6 (12,7 %) tenían un inhibidor de la calcineurina + un tratamiento con esteroides en dosis bajas. Se aplicóinhibidores de la calcineurina + dosis bajas de corticoesteroides en13 pacientes (27,6 %) después de recibir tratamiento con ciclosporina. Los pacientes que recibieron ciclosporina o inhibidores de la calcineurina+ dosis bajas de esteroides como tratamiento inicial se compararon al inicio del tratamiento, a los 6 y 12 meses en sus parámetros de laboratorio y características clínicas. Al final del primer año, 4 de 6 pacientes (66,7 %) con dosis bajas de ciclosporina e inhibidores de la calcineurina y 6 de 7 pacientes (85,7 %) con ciclosporina presentaron remisión (p>0,05). Conclusión: Se encontró que el tratamiento inicial con esteroides y el tratamiento con inhibidores de la calcineurinason igualmente efectivos. Pensamos que, a los pacientes con intolerancia a los esteroides, se les podría administrarinhibidores de la calcineurinaen el primer paso, pero si se considera el costo, la primera opción son nuevamente los esteroides, como lo recomienda el consorcio Kidney Disease Improving Global Outcomes.

Sarcoma de Kaposi intestinal en paciente trasplantado renal / Intestinal KaposiÆs Sarcoma in renal transplant patient

El sarcoma de Kaposi (SK) es una neoplasia vascular, en la cual podemos distinguir cuatro formas clínicas: la clásica o mediterránea, endémica o africana, asociada al VIH y la iatrogénica. Sus manifestaciones clínicas más frecuentes son las lesiones mucocutáneas y afectación de ganglios linfáticos si bien puede cursar con afectación a nivel visceral. Presentamos a continuación el caso de un paciente trasplantado renal que fue diagnosticado de un sarcoma de Kaposi intestinal, sin lesiones cutáneas asociadas

Kaposi's sarcoma (KS) is a vascular neoplasm, in which we can distinguish four clinical forms: the classic or Mediterranean, endemic or African, associated with HIV and iatrogenic. Its most frequent clinical manifestations are mucocutaneous lesions and lymph node involvement, although it may manifest with involvement at the visceral level. We present the case of a renal transplant patient who was diagnosed with an intestinal Kaposi's sarcoma, with no associated cutaneous lesions

A physiology-based approach to a patient with hyperkalemic renal tubular acidosis / Abordagem diagnóstica de um paciente com acidose tubular renal hipercalêmica

ABSTRACT Hyperkalemic renal tubular acidosis is a non-anion gap metabolic acidosis that invariably indicates an abnormality in potassium, ammonium, and hydrogen ion secretion. In clinical practice, it is usually attributed to real or apparent hypoaldosteronism caused by diseases or drug toxicity. We describe a 54-year-old liver transplant patient that was admitted with flaccid muscle weakness associated with plasma potassium level of 9.25 mEq/L. Additional investigation revealed type 4 renal tubular acidosis and marked hypomagnesemia with high fractional excretion of magnesium. Relevant past medical history included a recent diagnosis of Paracoccidioidomycosis, a systemic fungal infection that is endemic in some parts of South America, and his outpatient medications contained trimethoprim-sulfamethoxazole, tacrolimus, and propranolol. In the present acid-base and electrolyte case study, we discuss a clinical approach for the diagnosis of hyperkalemic renal tubular acidosis and review the pathophysiology of this disorder.

RESUMO A acidose tubular renal hipercalêmica é uma acidose metabólica de ânion gap normal que invariavelmente indica anormalidade na secreção de íons potássio, amônio e hidrogênio. Na prática clínica, está geralmente atribuída a um estado de hipoaldosteronismo real ou aparente, causado por doenças ou toxicidade por drogas. Descrevemos um paciente de 54 anos, transplantado hepático, que foi admitido com fraqueza muscular associada à hipercalemia, potássio plasmático de 9,25 mEq/L. A investigação adicional revelou acidose tubular renal tipo 4 e importante hipomagnesemia com elevada fração de excreção de magnésio. A história patológica pregressa incluía um diagnóstico recente de Paracoccidioidomicose - uma infecção sistêmica fúngica endêmica que ocorre em algumas partes da América do Sul -, e as medicações de uso habitual continham sulfametoxazol-trimetoprim, tacrolimus e propranolol. No presente relato de caso, discutiremos uma abordagem clínico-laboratorial para o diagnóstico da acidose tubular renal hipercalêmica, assim como da hipomagnesemia, revisando a fisiopatologia desses transtornos.

Síndrome doloroso por inhibidores de la calcineurina: reporte de 4 casos en pacientes con retrasplante renal / Calcineurin-inhibitor induced pain syndrome: a 4-case report on patients with kidney retransplantation

INTRODUCCIÓN: El trasplante renal es el tratamiento de elección para pacientes con insuficiencia renal crónica. Los inmunosupresores como los inhibidores de la calcineurina pueden estar asociados a efectos adversos. El Síndrome Doloroso por Inhibidores de la Calcineurina (SDIC) se caracteriza por dolores óseos simétricos, agudos e incapacitantes de miembros inferiores, e imágenes características en la resonancia magnética. Se presentan 4 casos de SDIC con retrasplante renal, uso de tacrolimus como inmunosupresor y diagnóstico por resonancia magnética. MATERIAL Y MÉTODOS: Cuatro pacientes (3 mujeres y 1 varón) que se retrasplantaron con riñones cadavéricos, entre marzo de 2014 y septiembre de 2015, presentaron fuertes dolores en miembros inferiores. Tacrolimus fue el principal agente inmunosupresor. Se realizaron resonancias magnéticas de miembros inferiores, se indicó tratamiento y ajuste en la dosis de tacrolimus. RESULTADOS: El SDIC comenzó a los 2 meses del trasplante y 2 semanas de la detección de niveles tóxicos de tacrolimus. El cuadro doloroso permaneció aproximadamente 2 semanas y fue cediendo. La localización fue exclusiva de miembros inferiores (rodillas, tobillos y pies). El dolor fue referido por los pacientes como agudo, punzante, incapacitante y empeoraba de pie. La resonancia magnética confirmó el diagnóstico, revelando un patrón de edema de médula ósea en meseta tibial y astrágalos. Todos los casos fueron reversibles con el tratamiento indicado. CONCLUSIONES: Reportamos la aparición de SDIC en 4 pacientes con retrasplante renal, uso de tacrolimus y buena evolución. El diagnóstico se basó en sospecha clínica, forma de presentación e imágenes típicas en las resonancias magnéticas

INTRODUCTION: Kidney transplant is the first-line therapy for chronic kidney disease. Immunosuppressants such as calcineurin-inhibitors may be associated with side effects. Calcineurin-inhibitor induced pain syndrome (CIPS) is characterized by symmetrical, severe and disabling bone pain in the lower limbs and can be easily identified by magnetic resonance imaging due to its typical patterns. Four CIPS cases after kidney retransplantation are presented, confirmed by MRI and with immunosuppressive therapy consisting of tacrolimus. METHODS: Four patients (3 females and 1 male) with cadaveric kidney retransplantation, performed between March 2014 and September 2015 showed intense pains in their lower limbs. Tacrolimus was the main immunosuppressive agent. MRI scans of the lower limbs were performed; tacrolimus treatment and dosage adjustment were indicated. RESULTS: CIPS started 2 months after transplantation and 2 weeks after detection of tacrolimus toxic levels. Pain lasted around 2 weeks and it gradually became less severe. Symptoms were exclusively located in the lower limbs (knees, ankles and feet). Patients described the pain as sharp, throbbing, disabling, and becoming worse when standing. MRI confirmed the diagnosis, revealing a pattern of bone marrow edema in tibial plateau and tali. All cases were reversible with the indicated treatment. CONCLUSIONS: This study registers 4 cases of CIPS in patients who had undergone kidney retransplantation and had taken tacrolimus with good response. Diagnosis was reached by clinical suspicion, form and location of pain, and characteristic patterns in the MRI scans

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.

Belatacept in kidney transplantation - past and future perspectives / Belatacept no transplante renal - perspectivas passadas e futuras

Abstract Calcineurin inhibitors (CNIs) are used widely for maintenance immunosuppression in renal transplant recipients. However, their side effect profile has led researchers to attempt to find safer alternatives that can maintain effective long-term immunosuppression with less toxicity. Belatacept is a CTLA4-Ig molecule designed to block the costimulatory B7-CD28 signal needed for activation of effector T cells. While it has shown great promise in clinical trials, it has made halting progress towards replacing CNIs in actual clinical practice. The BENEFIT trial revealed some of the advantages of belatacept in terms of maintaining renal function after transplant and reducing some of the metabolic side effects of CNIs related to hypertension and dyslipidemia. Despite that, some cautionary signals have emerged as well, in that belatacept-treated patients experience higher acute rejection rates and greater risk for PTLD. Furthermore, the requirement for monthly intravenous infusions has presented logistical and cost challenges for widespread adoption.

Resumo Os inibidores da calcineurina (INC) são amplamente utilizados para a imunossupressão de manutenção em pacientes receptores de transplante renal. No entanto, o seu perfil de efeitos colaterais tem levado os pesquisadores a tentar encontrar alternativas mais seguras, que possam manter efetiva imunossupressão de longo prazo com menos toxicidade. O Belatacept é uma molécula de CTLA4-IgG concebida para bloquear o sinal co-estimulador B7-CD28, necessário para a ativação de linfócitos T efetores. Embora tenha demonstrado grande promessa em ensaios clínicos, não tem tido progresso na substituição de INCs na prática clínica. O estudo BENEFIT revelou algumas das vantagens do belatacept em termos da manutenção da função renal após o transplante, e da redução de alguns dos efeitos secundários metabólicos dos INCs, relacionados à hipertensão e dislipidemia. Apesar disso, alguns sinais de precaução também têm surgido, quando doentes tratados com belatacept tem maiores taxas de rejeição aguda e maior risco de DLPT. Além disso, a necessidade de perfusões intravenosas mensais apresenta desafios logísticos e de custo para sua adoção generalizada.

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.

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.

Atypical haemolytic uraemic syndrome. Two cases / Síndrome hemolítico-urêmica atípica. Relato de dois casos

Haemolytic uraemic syndrome is a disfunction known as thrombotic microangiopathy. When it is not caused by Shiga toxin, produced by Escherichia coli, the disease is called atypical, which is classified in primary and secondary. This paper aims to study two case reports diagnosed as atypical haemolytic uraemic syndrome secondary to calcineurin inhibitors. Both are patients that had undergone kidney transplantation, but lost their graft due to atypical haemolytic uraemic syndrome. Their presentations were pancytopenia for one and anaemia of difficult management for the other, the first one was taking the medication called tacrolimus and the second one was taking cyclosporine. Nephrotoxicity related to the usage of calcineurin inhibitors was already known since it was introduced in the medical practice, however its efficacy in the control of graft rejection may exceed the problems regarding side effects. Nevertheless, it was observed that in long terms, the morbidity related to these side effects are indeed relevant. Therefore, new medicines and therapeutic schemes capable of lowering exposure to calcineurin inhibitors are being studied. There are two options of treatment established to atypical haemolytic uraemic syndrome and both of them were used in the case reports presented in this paper: plasmapheresis or plasma infusion and eculizumab, an antibody that blocks the complement system pro inflammation, pro thrombotic and lytic functions. There is great discussion regarding which one of these treatments are the most suitable for atypical haemolytic uraemic syndrome. However, the choice of the therapy depends of each patient, individually, as was seen in the cases presented in this article.

A síndrome hemolítico-urêmica (SHU) é uma disfunção caracterizada por microangiopatia trombótica (MTA). Quando sua causa não é devido à toxina Shiga, produzida por Escherichia coli, ela é dita atípica, que se classifica em primária e secundária. Este artigo visou relatar dois casos clínicos de síndrome hemolítico-urêmica atípica secundária ao uso de inibidores da calcineurina, para os quais foram feitos os seguintes diagnósticos diferenciais: púrpura trombocitopênica trombótica, síndrome hemolítico-urêmica atípica primária, anemia hemolítica autoimune e hemoglobinúria paroxística noturna. Ambos os casos eram pacientes transplantados renais que sofreram perda do enxerto devido à síndrome hemolítico-urêmica atípica; um estava em uso de tacrolimo, enquanto a outra paciente estava em uso de ciclosporina. A nefrotoxicidade relacionada com o uso de inibidores da calcineurina já era conhecida desde sua introdução na prática clínica, entretanto sua eficácia no controle da rejeição do enxerto superava as preocupações em relação às reações adversas. Porém observou-se que, a longo prazo, a morbidade relacionada a essas reações é significativa e, hoje, os estudos buscam novos medicamentos e esquemas terapêuticos capazes de diminuir a exposição aos inibidores da calcineurina. O tratamento estabelecido para síndrome hemolítico-urêmica atípica era de plasmaferese e/ou infusão de plasma, mas, em 2011, foi aprovado o uso de eculizumabe, um anticorpo que bloqueia as funções pró-inflamatórias, pró-trombóticas e líticas do complemento. O uso de eculizumabe para tratamento dessa enfermidade é ainda recente, mas já demonstra benefícios em relação ao tratamento de plasmaferese e infusão de plasma.

Imnunosupresión tras el trasplante hepático: más nefrones, menos hepatocarcinoma / Immunosupression after liver transplant: more nephrons, less hepatocellular carcinoma

Following liver transplantation, immunosuppressive drugs are responsible for a significant proportion of the morbidity and mortality. Thus, renal failure and hepatocellular carcinoma recurrence are critically related to the use of immunosuppressive drugs. In this article, the immunosuppressive strategies that allow preservation of the renal function and minimization of the recurrence rate of hepatocellular carcinoma are detailed.

Tras el trasplante hepático, la inmunosupresión es responsable de buena parte de la morbi-mortalidad asociada. El deterioro de la función renal y la recurrencia del hepatocarcinoma son ámbitos donde la inmunosupresión tiene un impacto significativo. En el presente artículo se abordan las estrategias inmunosupresoras que permiten preservar la función renal y minimizar la recurrencia del hepatocarcinoma tras el trasplante hepático.

Efectos de la introducción progresiva de los inhibidores de la calcineurina en la función renal de una cohorte de pacientes que recibieron trasplante de hígado / Effects of progressive introduction of calcineurin inhibitors on the renal function of a cohort of liver transplant recipients

Introducción: la enfermedad renal aguda (ERA) se presenta en el postrasplante de hígado con una incidencia que varía de 12-64%, con una mortalidad intrahospitalaria asociada de 40-67%. Este estudio utiliza los criterios RIFLE para analizar el efecto del esquema inmunosupresor con inhibidores de la calcineurina en la aparición de ERA en los primeros quince días postrasplante de hígado. También evalúa el protocolo de introducción tardía y progresiva de los medicamentos inhibidores de la calcineurina (CNi) como estrategia para disminuir la incidencia de ERA postrasplante. Métodos: estudio analítico de cohortes de 163 pacientes con trasplante de hígado. Resultados: ciento sesenta y tres pacientes cumplieron con los criterios de inclusión del estudio con un promedio de edad de 51 (46-56) años. De éstos, sólo 11 (6.74%) presentaron ERA postrasplante. Ciclosporina fue administrada a 126 (77.3%) de los pacientes trasplantados y tacrolimus a 21 (12.88%). Inmediatamente después del trasplante los pacientes fueron clasificados en dos grupos: pacientes con riesgo alto de desarrollar ERA y pacientes sin problemas renales. A los primeros se les inició el CNi a partir del tercer día postrasplante y a los últimos entre seis y 18 horas después del trasplante, a una dosis que se aumentó gradualmente Conclusiones: la introducción tardía y progresiva de los CNi podría ser una estrategia efectiva para disminuir la incidencia de ERA en el postrasplante de hígado (Acta Med Colomb 2011; 36: 130-134).

Background: acute renal disease (ARD) occurs in liver transplantation with an incidence ranging from 12 to 64%, with an associated hospital mortality of 40 to 67%.This study used the RIFLE criteria to analyze the effect of an immunosuppressive regime including calcineurin inhibitors (CNi) in the development of ARD in patients with liver transplantation. It also assesses the protocol and progressive late introduction of CNi as a strategy to reduce the incidence of posttransplant ARD Methods: cohort analytic study of 163 patients with liver transplantation Results: 163 patients met the study inclusion criteria with an average age of 51 (46-56) years. Of these patients, only 11 (6.74%) had ARD transplantation. Cyclosporine was administered to 126 (77.3%) of tacrolimus in transplant patients and 21 (12.88%). Immediately after the transplant, patients were classified into two groups: patients with high risk of developing ERA and patients without kidney problems. At first they were introduced to the CNi from the third day after transplantation and the last six to 18 hours after the transplant, a dose that was gradually increased Conclusions: late and gradual introduction of CNi could be an effective strategy to reduce the incidence of acute renal disease in liver transplantation (Acta Med Colomb 2011; 36: 130-134).

Incidencia de enfermedad renal crónica y factores de riesgo para su desarrollo en pacientes postrasplante hepático en el Hospital Universitario Fundación Santa Fe de Bogotá 2004-2008 / Incidence of chronic kidney disease and risk factors for patients who underwent liver transplantation at Fundación Santa Fe University Hospital from 2004 to 2008

Antecedentes: La enfermedad renal crónica (ERC) se desarrolla frecuentemente después de someter a pacientes a trasplante de órganos sólidos como hepático, cardíaco, pulmonar, intestino delgado, y se asocia con un aumento en la morbimortalidad, costos y deterioro de la calidad de vida del paciente. El desarrollo de enfermedad renal crónica es una complicación común en pacientes postrasplante hepático. Es definida como una tasa de filtración glomerular entre 60 y 29 ml/min/1,73 m² de área de superficie corporal en el postoperatorio. Múltiples factores contribuyen al riesgo de desarrollar ERC en este grupo de pacientes. Entre los más importantes se encuentran la función renal previa al trasplante, medida por la fórmula MDRD (Modification of Diet in Renal Disease), injuria renal aguda durante el perioperatorio, inmunosupresores como los inhibidores de calcineurina. Durante los primeros seis meses del trasplante es cuando ocurre el deterioro mas rápido de la función renal y en meses posteriores esta declina lentamente. Es importante determinar nuestra incidencia de falla renal crónica, el grado de severidad de esta según la clasificación y los factores de riesgo en pacientes de trasplante hepático. El objetivo de este estudio es determinar la incidencia de enfermedad renal crónica y los factores de riesgo para su desarrollo en pacientes postrasplante hepático en el Hospital Universitario Fundación Santa Fe de Bogotá en el periodo comprendido entre enero del 2004 y noviembre de 2008. Materiales y métodos: Es un estudio descriptivo, retrospectivo. La población, fueron los pacientes llevados a trasplante hepático en el Hospital Universitario Fundación Santa Fe de Bogotá entre enero 1 del 2004 y noviembre 11 del 2008, que tuvieran previo al trasplante una función renal normal, calculada por MDRD, excluyendo insuficiencia renal previa al trasplante y aquellos que requirieron trasplante combinado hígado-riñón. Resultados: De 79 pacientes incluidos en el estudio, 27 (34,2% IC 95% 23,9-45,7) presentaron falla renal al sexto mes de seguimiento con un MDRD de estadio 2. De los 27 pacientes que desarrollaron falla renal crónica postrasplante a los seis meses de seguimiento, 6 (22,2%) tenían diagnóstico de cirrosis por NASH; 5 (18,5%) tenían diagnóstico de hepatitis C. Los 27 pacientes que desarrollaron falla renal crónica al sexto mes de seguimiento, tenían un MDRD pretrasplante en promedio de 89,4 ml/min/m²/SC. La falla renal crónica postrasplante es una complicación que viene en ascenso y que se asocia a factores de riesgo pretrasplante y postrasplante, como son hipertensión arterial, diabetes mellitus, hepatitis C e inmunosupresión. Conclusiones: Podemos decir que existe una tendencia a que los pacientes con diagnóstico pretrasplante de cirrosis por NASH y hepatitis C desarrollen más falla renal crónica. La inmunosupresión en el postrasplante inmediato influye en el desarrollo de falla renal crónica; en nuestro trabajo se observa como ciclosporina A, en un gran porcentaje presente en los pacientes que desarrollaron falla renal crónica. Se necesitarán nuevos estudios para determinar asociación entre estos factores de riesgo y el desarrollo de falla renal crónica.

Background: Chronic Renal Failure (CRF) frequently develops in patients who undergo transplantation of solid organs such as livers, hearts, lungs, and small intestines. CRF increases morbidity and mortality rates, increases costs and results in deterioration in the quality of patients' lives. The development of CRF is a common complication in post-liver transplant patients. It is defined as a glomerular filtration rate between 29 and 60 ml/min/1.73 m² of body surface area during post-surgical procedures. Multiple factors contribute to the risk of developing CRF in this group of patients. The most important among these factors are renal function prior to transplantation as measured by MDRD formula (Modification of Diet in Renal Disease), acute perioperative renal failure, and immune-suppressors such as calcineurin inhibitors. During the first six months after transplantation renal function deteriorates rapidly, but declines slowly thereafter. It is important to determine our incidence of chronic renal failure, the degree of severity according to the classification and the risk factors in patients who underwent liver transplantation. The aim of this study is to determine the incidence of chronic renal disease and the risk factors affecting post-liver transplant patients in the Fundación Santa Fe de Bogota University Hospital from January 2004 to November 2008. Materials and methods: This was a descriptive and retrospective study of a population of patients who had undergone liver transplantation in the Fundación Santa Fe de Bogota University Hospital between January 1, 2004 and November 11, 2008. These patients presented normal renal functions as measured by the MDRD formula. We excluded patients with previous renal insufficiency and combined liver-kidney transplantation patients. Results: 79 patients were included in the study. 27 (34.2% CI 95% 23.9 - 45.7) had developed Stage 2 MDRD renal failure by the 6th month of surveillance. 6 of the 27 patients (22.2%) presented cirrhosis resulting from NASH. 5 of the 27 (18.5%) presented hepatitis C. The 27 patients who developed chronic renal failure by the 6th month of surveillance presented an average MDRD score of 89.4 ml/min/m²/SC prior to transplantation. Chronic renal failure following transplantation is an increasingly common complication, associated with risk factors prior to and following transplantation. These factors include arterial hypertension, diabetes mellitus, hepatitis C and immunosuppression. Conclusions: Patients with pre-transplantation diagnoses of cirrhosis resulting from NASH or of hepatitis have a tendency to develop chronic renal failure. Immunosuppression immediately after transplantation influences the development of chronic renal failure. In our study we observed high percentages of cyclosporine A in patients who developed chronic renal failure. New studies are needed to determine the association between these risk factors and the development of chronic renal failure.

Balanite plasmocitária de Zoon: relato de dois casos tratados com pimecrolimo / Zoon's plasma cell balanitis: a report of two cases treated with pimecrolimus

Inicialmente, denominada "Balanoposthite chronique circonscrite benigne a plasmocytes", a balanite plasmocitária de Zoon é uma dermatose inflamatória crônica da glande e prepúcio afetando homens não circuncisados. As diferentes opções de tratamento para esta afecção apresentam frequentemente resultados parciais. Relatos têm demonstrado sucesso terapêutico, com o uso de tacrolimo tópico. Relatamos o uso de pimecrolimus, um homólogo de tacrolimo, com boa resposta. Dois doentes do sexo masculino, com diagnóstico de Balanite de Zoon confirmado através de biópsia, foram submetidos a um tratamento diário com pimecrolimus tópico a 1 por cento, com importante melhora da doença após 6 semanas para o paciente, 1 e 8 semanas para o 2. Conclusão: O pimecrolimus em creme pode ser uma opção para o tratamento da doença.

Initially called (in French) "Balanoposthite chronique circonscrite benigne a plasmocytes", Zoon's plasma cell balanitis is a chronic inflammatory dermatosis affecting the glans and foreskin of uncircumcised men. The different treatment options for this condition often present partial results. Reports have shown therapeutic success using topical tacrolimus. We report the use of pimecrolimus, a homologue of tacrolimus, with good response. Two male patients diagnosed with Zoon's plasma cell balanitis, confirmed by biopsy, were subjected to daily treatment with topical pimecrolimus1 percent. Significant improvement was noted in patient 1 after 6 weeks and after 8 weeks in patient 2. Conclusion: Pimecrolimus cream may be an option for the treatment of this disease.