Subject(s)
Antibodies, Monoclonal, Humanized , Glomerulonephritis, Membranous , Receptors, Phospholipase A2 , Humans , Antibodies, Monoclonal, Humanized/therapeutic use , Glomerulonephritis, Membranous/drug therapy , Receptors, Phospholipase A2/immunology , Drug Resistance , Male , Female , Middle AgedSubject(s)
Humans , Glomerulonephritis, Membranous , Autoantibodies , Cyclophosphamide , Nephrotic Syndrome , Proteins , Creatinine , BiopsyABSTRACT
Background: Genetic causes are increasingly recognized in patients with focal segmental glomerulosclerosis (FSGS), but it remains unclear which patients should undergo genetic study. Our objective was to determine the frequency and distribution of genetic variants in steroid-resistant nephrotic syndrome FSGS (SRNS-FSGS) and in FSGS of undetermined cause (FSGS-UC). Methods: We performed targeted exome sequencing of 84 genes associated with glomerulopathy in patients with adult-onset SRNS-FSGS or FSGS-UC after ruling out secondary causes. Results: Seventy-six patients met the study criteria; 24 presented with SRNS-FSGS and 52 with FSGS-UC. We detected FSGS-related disease-causing variants in 27/76 patients (35.5%). There were no differences between genetic and non-genetic causes in age, proteinuria, glomerular filtration rate, serum albumin, body mass index, hypertension, diabetes or family history. Hematuria was more prevalent among patients with genetic causes. We found 19 pathogenic variants in COL4A3-5 genes in 16 (29.3%) patients. NPHS2 mutations were identified in 6 (16.2%) patients. The remaining cases had variants affecting INF2, OCRL, ACTN4 genes or APOL1 high-risk alleles. FSGS-related genetic variants were more common in SRNS-FSGS than in FSGS-UC (41.7% vs 32.7%). Four SRNS-FSGS patients presented with NPHS2 disease-causing variants. COL4A variants were the most prevalent finding in FSGS-UC patients, with 12 patients carrying disease-causing variants in these genes. Conclusions: FSGS-related variants were detected in a substantial number of patients with SRNS-FSGS or FSGS-UC, regardless of age of onset of disease or the patient's family history. In our experience, genetic testing should be performed in routine clinical practice for the diagnosis of this group of patients.
ABSTRACT
Introducción: La amiloidosis secundaria (AA) es una complicación grave asociada a enfermedades inflamatorias. Se caracteriza por el depósito sistémico de proteína fibrilar AA, con especial repercusión renal. La participación de la interleucina 6 en su mecanismo patogénico ha supuesto que tocilizumab (TCZ) sea considerado una opción terapéutica en estos pacientes. Varias series publicadas muestran su eficacia en el tratamiento de la amiloidosis AA, permitiendo incluso la regresión de depósitos renales ya presentes.Material y métodoRevisión retrospectiva que incluyó pacientes con diagnóstico histológico de amiloidosis renal AA en tratamiento con TCZ durante los años 2018-2019 en nuestro centro. Registramos variables clínicas y demográficas; evaluamos la función renal mediante filtrado glomerular (FG) calculado por CKD-EPI e índice proteína/creatinina a los 3, 6 y 12 meses de seguimiento. Definimos «respuesta renal» como la disminución >30% de la proteinuria y/o estabilización o mejoría del FG. Consideramos «respuesta antiinflamatoria» la disminución >50% de las cifras de proteína sérica amiloide (PSA) y/o proteína C reactiva (PCR).ResultadosPresentamos una serie de 3 pacientes (2 varones y una mujer; 55, 74 y 75 años, respectivamente), con un tiempo de seguimiento de 13, 14 y 75 meses, respectivamente. Con la terapia con TCZ, el FG se estabilizó en 2 pacientes; el tercero permaneció en hemodiálisis durante el seguimiento, aunque con excelente control de su enfermedad inflamatoria de base; a los 12 meses recibió un trasplante renal. En los 3 casos se objetivó reducción de proteína PSA y PCR. No se han producido eventos adversos. (AU)
Introduction: AA (secondary) amyloidosis is a severe complication of chronic inflammatory disorders. It is characterized by the systemic deposition of an abnormal protein called amyloid, affecting mainly renal function. IL-6 is a cytokine with a relevant role in this disease development. Interleukin-receptor antagonists, like Tocilizumab (TCZ), have become possible treatment choice for AA amyloidosis. In published reports, TCZ has shown good efficacy for AA amyloidosis, being associated with regression of renal amyloid deposits.MethodsRetrospective review that included patients with histological diagnosis of AA renal amyloidosis under treatment with TCZ during the years 2018-2019 in our center. We have registered clinical and demographic variables. Renal function was measured by means of CKD-EPI equation to estimate the glomerular filtration rate (FG) and protein/creatinine ratio (IPC) at 3, 6 and 12 months. We define renal response as a decrease by at least 30% of proteinuria and/or stabilization or improvement of FG. We consider that an anti-inflammatory response is a decrease of more than 50% in serum amyloid protein (PSA) and/or C-reactive protein (CRP).ResultsWe collected 3 cases of patients with histologically proven AA amyloidosis treated with TCZ (2 men; 1 woman; aged 55, 74 and 75 years). The follow-up was 13, 14 and 75 months. FG was stabilized in two patients. The third patient remained on hemodialysis during follow-up, although with excellent control of her underlying inflammatory disease. In all three cases, reduced PSA and CRP were observed. There have been no adverse events.ConclusionsThe TCZ may be an effective and safe option in treatment of AA amyloidosis with renal involvement. Our results position it as an interesting therapeutic option to consider in these cases, although prospective studies would be necessary to evaluate the global role of TCZ in AA amyloidosis. (AU)
Subject(s)
Humans , Nephrology , Interleukin-6/therapeutic use , AmyloidosisABSTRACT
INTRODUCTION: AA (secondary) amyloidosis is a severe complication of chronic inflammatory disorders. It is characterized by the systemic deposition of an abnormal protein called amyloid, affecting mainly renal function. IL-6 is a cytokine with a relevant role in this disease development. Interleukin-receptor antagonists, like Tocilizumab (TCZ), have become possible treatment choice for AA amyloidosis. In published reports, TCZ has shown good efficacy for AA amyloidosis, being associated with regression of renal amyloid deposits. METHODS: Retrospective review that included patients with histological diagnosis of AA renal amyloidosis under treatment with TCZ during the years 2018-2019 in our center. We have registered clinical and demographic variables. Renal function was measured by means of CKD-EPI equation to estimate the glomerular filtration rate (FG) and protein/creatinine ratio (IPC) at 3, 6 and 12 months. We define renal response as a decrease by at least 30% of proteinuria and/or stabilization or improvement of FG. We consider that an anti-inflammatory response is a decrease of more than 50% in serum amyloid protein (PSA) and/or C-reactive protein (CRP). RESULTS: We collected 3 cases of patients with histologically proven AA amyloidosis treated with TCZ (2 men; 1 woman; aged 55, 74 and 75 years). The follow-up was 13, 14 and 75 months. FG was stabilized in two patients. The third patient remained on hemodialysis during follow-up, although with excellent control of her underlying inflammatory disease. In all three cases, reduced PSA and CRP were observed. There have been no adverse events. CONCLUSIONS: The TCZ may be an effective and safe option in treatment of AA amyloidosis with renal involvement. Our results position it as an interesting therapeutic option to consider in these cases, although prospective studies would be necessary to evaluate the global role of TCZ in AA amyloidosis.
