Rituximab use in adult glomerulopathies and its rationale / Uso do rituximabe em glomerulopatias em adultos e justificativas

Abstract Glomerulopathies are one of the leading causes of end-stage renal disease. In the last years, clinical research has made significant contributions to the understanding of such conditions. Recently, rituximab (RTX) has appeared as a reasonably safe treatment. The Kidney Disease: Improving Global Outcomes guidelines (KDIGO) recommended RTX only as initial treatment in antineutrophil cytoplasm antibody associated vasculitis (AAV) and in non-responders patients with lupus nephritis (LN), but these guidelines have not been updated since 2012. Nowadays, RTX seems to be at least as effective as other immunosuppressive regimens in idiopathic membranous nephropathy (IMN). In minimal-change disease, (MCD) this drug might allow a long-lasting remission period in steroid-dependent or frequently relapsing patients. Preliminary results support the use of RTX in patients with pure membranous LN and immunoglobulin-mediated membranoproliferative glomerulonephritis (MPGN), but not in patients with class III/IV LN or complement-mediated MPGN. No conclusion can be drawn in idiopathic focal segmental glomerulosclerosis (FSGS) and anti-glomerular basement membrane antibody glomerulonephritis (anti-GBM GN) because studies are small, heterogeneous, and scarce. Lastly, immunosuppression including RTX is not particularly useful in IgA nephropathy. This review presents the general background, outcomes, and safety for RTX treatment in different glomerulopathies. In this regard, we describe randomized controlled trials (RCTs) performed in adults, whenever possible. A literature search was performed using clinicaltrials.gov and PubMed.

Resumo As glomerulopatias figuram entre as principais causas de doença renal terminal. Nos últimos anos, a pesquisa clínica efetuou contribuições significativas para a compreensão desse grupo de patologias. Recentemente, o rituximabe (RTX) surgiu como um tratamento razoavelmente seguro. As diretrizes do Kidney Disease: Improving Global Outcomes (KDIGO) recomendam o RTX apenas como tratamento inicial na vasculite associada ao ANCA (VAA) e em pacientes não respondedores com nefrite lúpica (NL), embora não sejam atualizadas desde 2012. Atualmente, o RTX parece ser pelo menos tão eficaz quanto outros esquemas imunossupressores na nefropatia membranosa idiopática (NMI). Na doença por lesão mínima (DLM), o medicamento pode proporcionar um período de remissão duradouro em pacientes córtico-dependentes ou com recidivas frequentes. Resultados preliminares corroboram o uso de RTX em pacientes com NL membranosa pura e glomerulonefrite membranoproliferativa (GNMP) mediada por imunoglobulina, mas não em pacientes com NL classe III/IV ou GNMP mediada por complemento. Os achados a respeito de glomeruloesclerose segmentar e focal (GESF) idiopática e doença por anticorpo antimembrana basal glomerular (anti-MBG) não são conclusivos em função do pequeno número, porte e heterogeneidade dos estudos publicados até o presente momento. Por fim, a imunossupressão com RTX não é particularmente útil na nefropatia por IgA. A presente revisão apresenta o racional da prescrição de RTX nas diferentes glomerulopatias, desfechos e segurança. Nesse sentido, foram incluídos ensaios clínicos randomizados (ECRs) realizados em adultos, sempre que possível. Pesquisas bibliográficas foram realizadas nas bases de dados do clinictrials.gov e no PubMed.

Doença de lesões mínimas e glomeruloesclerose segmentar e focal em adultos: resposta a corticoide e risco de insuficiência renal / Minimal change disease and focal segmental glomerulosclerosis in adults: response to steroids and risk of renal failure

Resumo Introdução: O perfil clínico de pacientes brasileiros adultos com síndrome nefrótica por doença de lesões mínimas (LM) e glomeruloesclerose segmentar e focal (GESF) é pouco conhecido. Objetivo: Avaliamos as características clínico-laboratoriais e resposta a tratamento em pacientes adultos com síndrome nefrótica e diagnósticos histológicos de LM ou GESF. Métodos: Fez-se a análise retrospectiva de 50 pacientes adultos com LM e 120 com GESF. Todos os pacientes foram inicialmente tratados com corticosteroide. Os desfechos do estudo foram: resposta a corticosteroide, prevalência de remissão total, progressão para doença renal crônica estágio 5 (DRC5) e necessidade de terapia de substituição renal por DRC5. Resultados: Níveis iniciais de creatinina sérica foram 24% mais elevados entre pacientes com GESF (p = 0,02) e os de proteinúria foram 36% mais altos em LM (p < 0,001). Pacientes com LM foram córtico-sensíveis em 80% dos casos, com remissão total em 74%, e os pacientes com GESF em 58% (p = 0,01), com remissão total em 30% (p = 0,002). A prevalência de insuficiência renal aguda em pacientes com GESF foi de 39% (vs. 12%, p = 0,013) e DRC5 de 10% (vs. 0%, p < 0,001). Remissão completa ou parcial com o uso de corticosteroide reduziu em 83% o risco de DRC5 (p < 0,001) e remissão total associou-se a redução no risco de DRC5 de 89% (p < 0,001). Conclusão: A resposta positiva à corticoterapia foi o fator mais importante relacionado à preservação da função renal ao longo de mais de uma década de seguimento, e GESF relacionou-se a menor índice de resposta a corticosteroide.

Abstract Introduction: There is scarce data on the clinical profile of adult Brazilian patients with nephrotic syndrome caused by minimal change disease (MCD) and focal segmental glomerulosclerosis. Objective: We evaluated the clinical characteristics and response to treatment in adult patients with nephrotic syndrome having a histological diagnosis of MCD or FSGS. Methods: This is a retrospective analysis of 50 patients with MCD and 120 with FSGS. All patients were initially treated with steroids. The study outcomes were: steroid responsiveness, prevalence of total remission, progression to chronic renal failure and need of renal replacement therapy due to end-stage renal disease (ESRD). Results: Initial serum creatinine level was 24% higher among patients with FSGS (p = 0.02), and proteinuria levels were 36% higher in MCD (p < 0.001). Patients with MCD were sensitive to steroid therapy in 80% of the cases, with total remission in 74%, while patients with FSGS were sensitive in 58% (p = 0.01), with total remission in 30% (p = 0.002). Patients with FSGS had an acute renal failure prevalence of 39% (vs. 12%, p = 0.013) and ESRD of 10% (vs. 0%, p < 0.001). Steroid responsiveness reduced in 83% the risk of ESRD (p < 0.001), while total remission was associated to a reduction in risk of 89% (p < 0.001). Conclusion: A positive response to steroid therapy was the most important factor related with preservation of renal function and FSGS was related with less steroid responsiveness.

Proteinuria predicts relapse in adolescent and adult minimal change disease

OBJECTIVE: This study sought to outline the clinical and laboratory characteristics of minimal change disease in adolescents and adults and establish the clinical and laboratory characteristics of relapsing and non-relapsing patients. METHODS: We retrospectively evaluated patients with confirmed diagnoses of minimal change disease by renal biopsy from 1979 to 2009; the patients were aged >13 years and had minimum 1-year follow-ups. RESULTS: Sixty-three patients with a median age (at diagnosis) of 34 (23-49) years were studied, including 23 males and 40 females. At diagnosis, eight (12.7%) patients presented with microscopic hematuria, 17 (27%) with hypertension and 17 (27%) with acute kidney injury. After the initial treatment, 55 (87.3%) patients showed complete remission, six (9.5%) showed partial remission and two (3.1%) were nonresponders. Disease relapse was observed in 34 (54%) patients who were initial responders (n = 61). In a comparison between the relapsing patients (n = 34) and the non-relapsing patients (n = 27), only proteinuria at diagnosis showed any significant difference (8.8 (7.1-12.0) vs. 6.0 (3.6-7.3) g/day, respectively, p = 0.001). Proteinuria greater than 7 g/day at the initial screening was associated with relapsing disease. CONCLUSIONS: In conclusion, minimal change disease in adults may sometimes present concurrently with hematuria, hypertension, and acute kidney injury. The relapsing pattern in our patients was associated with basal proteinuria over 7 g/day.

Minimal change disease associated with type 1 and type 2 diabetes mellitus / Glomerulopatia de lesões mínimas associada ao diabetes melito do tipo 1 e do tipo 2

A 19-year-old female with type 1 diabetes for four years, and a 73-year-old female with type 2 diabetes for twenty years developed sudden-onset nephrotic syndrome. Examination by light microscopy, immunofluorescence, and electron microscopy (in one case) identified minimal change disease (MCD) in both cases. There was a potential causative drug (meloxicam) for the 73-year-old patient. Both patients were treated with prednisone and responded with complete remission. The patient with type 1 diabetes showed complete remission without relapse, and the patient with type 2 diabetes had two relapses; complete remission was sustained after associated treatment with cyclophosphamide and prednisone. Both patients had two years of follow-up evaluation after remission. We discuss the outcomes of both patients and emphasize the role of kidney biopsy in diabetic patients with an atypical proteinuric clinical course, because patients with MCD clearly respond to corticotherapy alone or in conjunction with other immunosuppressive agents.

Uma paciente de 19 anos de idade com diabetes tipo 1 durante quatro anos e uma paciente de 73 anos de idade com diabetes tipo 2 durante vinte anos desenvolveram quadro súbito de síndrome nefrótica. O exame histológico à microscopia de luz, imunofluorescência e microscopia eletrônica (em um caso) diagnosticou glomerulopatia de lesões mínimas (GLM) em ambos os casos. Na paciente de 73 anos de idade, houve uma associação com o uso de meloxicam. As duas pacientes foram tratadas com corticosteroides e responderam com remissão completa do quadro. A paciente de 19 anos com diabetes tipo 1 apresentou remissão completa sem recidivas, e a paciente de 73 anos com diabetes tipo 2 apresentou dois episódios de recidiva; a remissão completa foi conseguida após associação ao tratamento com ciclofosfamida. As duas pacientes foram seguidas dois anos após a remissão completa. Os casos descritos enfatizam o papel da biópsia renal em pacientes diabéticos com evolução atípica do aparecimento de proteinúria, pois pacientes com GLM respondem bem à corticoterapia como único tratamento ou associado a outro agente imunossupressor.

A Case of Minimal Change Disease Treated Successfully with Mycophenolate Mofetil in a Patient with Systemic Lupus Erythematosus

The World Health Organization classifies lupus nephritis as class I to V or VI. However, a few cases of minimal change glomerulopathy have been reported in association with systemic lupus erythematosus (SLE). Mycophenolate mofetil has been shown to be effective for treatment of minimal change disease and lupus nephritis. A 24-year-old woman diagnosed with SLE five years prior to presentation complained of a mild generalized edema. The urinalysis showed microscopic hematuria and proteinuria. The assessed amount of total proteinuria was 1,618 mg/24 hours. A renal biopsy demonstrated diffuse fusion of the foot processes of podocytes on electron microscopy. Mycophenolate mofetil was started in addition to the maintenance medications of prednisolone 10 mg/day and hydroxychloroquine 400 mg/day. After six months of treatment, the microscopic hematuria and proteinuria resolved, and the total urine protein decreased to 100 mg/24 hours.

Single-center experience with cyclosporine for treatment of idiopathic minimal change nephrotic syndrome in children

Cyclosporine A is used in the treatment of idiopathic nephrotic syndrome. We conducted this study to evaluate the effect of cyclosporine and its combination with ketoconazole in Egyptian nephrotic children with steroid-resistant and steroid-dependant minimal change. Forty-eight children with minimal change lesions who received cyclosporine with or without ketoconazole were studied. Their mean age was 5.17 +/- 1.59 years, and they were 31 boys and 17 girls. The mean duration of the disease was 6.22 +/- 3.16 years. Thirty-one of the children were steroid dependent and 17 were steroid resistant. Cyclosporine treatment was commenced after remission was attained and adjusted to a target trough level of 100 nanogram/mL. The mean cyclosporine therapy at a dose of 2.07 +/- 0.91 mg/kg was administered for a mean of 25.75 +/- 1.95 months. Thirty-three patients received adjunctive ketoconazole therapy. Thirty-eight patients [79.2%] responded well to cyclosporine. Steroid therapy could be discontinued in 43 patients [89.6%], but 9 experienced relapse. Ten patients [20.8%] were resistant to cyclosporine therapy. Fifteen patients received cyclosporine alone, while 33 received concomitant cyclosporine and ketoconazole. The response to cyclosporine was significantly better in those on ketoconazole. The economic effect of ketoconazole therapy was a reduction in the costs of cyclosporine treatment by 47.4% at 1 year of treatment. Cyclosporine treatment in children with minimal change nephrotic syndrome is effective in preventing relapse and decreasing steroid toxicity. Its combination with low-dose ketoconazole is safe, reduces treatment costs, and improves the response to cyclosporine

Pneumatosis Intestinalis Associated with Immune-suppressive Agents in a Case of Minimal Change Disease

We report treatment of a 38-year-old man with minimal change disease (MCD) who developed pneumatosis intestinalis (PI) during administration of immune-suppressive agents. His immunosuppressive medication had been tapered to 15 mg/day of prednisolone. MCD was steroid-resistant type. Abdominal examination and laboratory studies were not clinically remarkable. Radiologic findings were consistent with PI. Abnormal air accumulation was noted in the bowel, peritoneum, mediastinum and retroperitoneum. Conservative therapy with oxygen and metronidazole improved the PI symptoms. In 1993, a case of PI with nephrotic syndrome following steroid treatment was reported in Japan. However this is only the second case reported in the literature, and the first in English.

Natural history and response to treatment of minimal change nephrotic syndrome.

This study is a retrospective analysis of 177 patients of minimal change nephrotic syndrome seen between 1985 and 1989. Fifty nine of these had renal biopsy done and the others were diagnosed on clinical grounds. Short courses of prednisolone were used for three episodes in one year. If a fourth episode occurred in any 12 month period, cyclophosphamide was started. This was needed in 26 patients and was also used in 9 patients who did not respond to 8 weeks of prednisolone. Follow up ranged from 4 months to 5 years (mean 1.4 years). Thirty nine percent of patients sustained remission after the first course of steroids. Histological variations (presence or absence of diffuse mesangial proliferation or IgM deposits) and age made no difference to the response to treatment and subsequent relapses.

Glomerulonefrite em pediatria / Gomerulonephritis in children

Os autores apresentam uma apreciaçäo clínico-patológica das glomerulonefrites na infância, relatando sua experiência no HUPE-UERJ). 1) GN com lesäo mínima: 128 casos (54,7% pré-escolares e 67,9% do sexo masculino): com prognóstico muito bom. 2) Esclerose focal e segmentar: 37 casos, quatro em remissäo, 11 com SN em atividade, 16 evoluíram para IRC (sete óbitos) e seis näo foram acompanhados. 3) GN membranosa: 10 casos, quatro em remissäo, quatro com SN em atividade e dois foram perdidos do acompanhamento. 4) GN endoteliomesangial: 257 casos, todos evoluíram para cura embora 15,3% apresentassem complicaçöes graves. 5) GN mesangial: oito casos, dois em remissäo, três com SBN em atividade, um em IRC e dois óbitos. 6) GN crescêntica: 11 pacientes, sete estäo bem, um em IRC e três morreram. 7) GN membranoproliferativa: seis pacientes: um em remissäo, dois em IRC, dois com SN em atividade e um faleceu

Lesión glomerular mínima / Minimal glomerular lesion

Se consideran la presentación clínica, la evolución, el tratamiento y el pronóstico de la lesión glomerular mínima (LGM) en el adulto y se analizan 43 pacientes con sindrome nefrótico idiopático por LGM. Se describen las alteraciones histológicas que la caracterizan; glomérulos normales en microscopía óptica y fusión de los pedicelios de las células epiteliales en microscopía electrónica. Se discute la etiopatogenia y se refiere como probable mecanismo patogénico una disfunción de las células T, con producción de linfokinas, que disminuiría la carga negativa de la membrana basal glomerular, con producción de proteinuria. Se refiere que clinicamente se presenta como un sindrome nefrótico con excelente respuesta al tratamiento corticoideo, que en 80 por ciento de los casos evoluciona con empujes y recaídas y sin deterioro de la función renal. Se discuten los resultados del tratamiento, la iatrogenia corticoidea en los pacientes recaedores frecuentes y corticodependientes y los beneficios de la asociación de drogas citotóxicas

Nefrosis lipoidea en la infancia: evolución y correlación anatomoclínica / Lipoid nephrosis in children. Development and anatomoclinical correlation

Se presentan 34 pacientes; 23 hombres, con diagnóstico de nefrosis lipoidea (NL) confirmado con biopsia renal. El promedio de seguimiento fue 6,8 años (rango 2,2 a 14 años); 97% de pacientes respondieron satisfactoriamente a los esteroides, a los inmunosupresores o ambos. Durante la actividad de la enfermedad 4,7% de los episodios se complicaron con infecciones graves; 94% de los pacientes estaban en remisión a los 5 años de iniciada la enfermedad. Las lesiones morfológicas renales varían con el tiempo de evolución (x 39 días en casos con desaparición completa de los pedicelos, 11 meses en 14 casos con desaparición parcelar y 20 meses en 15 casos con zonas de desaparición segmentaria alternando con otras con pedicelos normales). No se observaron diferencias significativas entre 2 biopsias en cinco pacientes dependientes (n = 4) o resistentes (n = 1) a los corticosteroides a quienes se practicaron biopsias renales. No hubo mortalidad en esta serie ni deterioro de la función renal

Nephrotic syndrome with minimal charge

On 230 cases of nephrotic syndrome treated between 1982 and 1988, 40 nephrotic syndromes were with minimal charge. The average of age was 22 years with a light male predominance [56%]. Oedema was the first motive of consultation, no case of arterial hypertension was seen. While hematuria was noted in 16% of the cases, proteinuria was between 3 g/24h and 22g/24h, protidemia average was 42.5 g/l, albuminemia was 17g/l. Corticosensibility was observed in 95.5% of cases. Relapse were frequent, the infection was the principal reason