RESUMEN
BACKGROUND: The reason why mesangial C4d deposits are detected in only certain biopsies of immunoglobulin A nephropathy (IGAN) remains unclear. We analyse the association between IgA glycosylation patterns, mesangial C4 deposition and clinical phenotypes in IgAN. METHODS: This cross-sectional study included 145 patients with idiopathic IgAN. We measured the serum levels of three different IgA1 lectin-binding specificities using enzyme-linked immunosorbent assays with and without treatment with neuraminidase and we analysed the relationship between these glycoforms, C4d mesangial deposits and clinical phenotypes. RESULTS: C4d-positive versus Cd4-negative patients had higher proteinuria [median 3.1 g/g (0.9-4.2) versus 1.8 (1-2.2); P = 0.000], haematuria [223 cells/µL (32-278) versus 99 (25-186); P = 0.000] and higher levels of IgA binding to neuraminidase untreated Helix aspersa (HA IgA1 neu-; 150.6 ± 52 U versus 96.2 ± 64.1; P = 0.000), neuraminidase untreated Helix pomatia (HPA IgA1 neu-; 0.34 ± 0.15 U versus 0.27 ± 0.13; P = 0.04), Triticum vulgaris (TV IgA1; 85.1 ± 31.7 U versus 42.2 ± 26.9; P = 0.000) and Canavalia ensiformis (ConA IgA1; 32.5 ± 18 U versus 16.7 ± 9.38; P = 0.000). The levels of HA IgA1 neu-, HPA IgA1 neu-, TV IgA1 and ConA IgA1 were all associated with the mesangial deposition of C4d, extracapillary proliferation and acute kidney injury. In receiver operating characteristics curves, HA IgA1 neu-, HPA IgA1 neu-, TV IgA1 and ConA IgA1 significantly discriminated between C4d-positive ad C4d-negative biopsies. In logistics models, TV IgA1 and ConA IgA1 were the only independent predictors of mesangial C4d deposits. CONCLUSIONS: In IgAN, the severity of the disease is associated with the level of IgA exposing N-acetyl-d-galactosamine, N-acetyl-d-glucosamine or mannose, whereas C4d deposits are only associated with elevated levels of IgA1 glycoforms exhibiting glycan residues with specificity for mannose and N-acetyl-d-glucosamine binding lectins.
Asunto(s)
Glomerulonefritis por IGA , Complemento C4b , Estudios Transversales , Glomerulonefritis por IGA/patología , Humanos , Inmunoglobulina A , Lectinas/metabolismo , Fragmentos de Péptidos , FenotipoRESUMEN
Donor-specific antibodies (DSA) cause antibody-mediated rejection (AMR); however, their pathogenic role has not yet been adequately investigated after liver transplantation. The aim of our study was to analyse the clinical significance of DSA and complement-binding DSA for the prediction of AMR after liver transplantation. Our cohort included 120 liver recipients with assessed protocol biopsies one year post-transplant. All patients had defined HLA-specific and complement-binding (C1q + and C3d+) antibodies before and in regular intervals after transplantation. The incidence of DSA was evaluated in relation with clinical and histopathological data in the liver allografts. A higher occurrence of acute AMR was observed in recipients with preformed complement-binding DSA to HLA Class I antigens. Patients who developed chronic AMR had more frequently de novo-produced antibodies against HLA Class II antigens (P = 0.0002). A correlation was also found between de novo-formed C1q + and C3d+-binding antibodies to HLA Class II antigens and the development of chronic AMR (P = 0.043). Our study implies that preformed complement-binding DSA to HLA Class I antigens are related to increased risk of acute antibody-mediated rejection, while chronic AMR is more frequent in patients with de novo-produced antibodies to HLA Class II antigens after liver transplantation.
Asunto(s)
Trasplante de Riñón , Trasplante de Hígado , Complemento C1q , Rechazo de Injerto , Supervivencia de Injerto , Antígenos HLA , Humanos , Isoanticuerpos , Trasplante de Hígado/efectos adversos , Estudios Retrospectivos , Donantes de TejidosRESUMEN
BACKGROUND AND OBJECTIVES: The prognostic value of mesangial C4d deposits in IgA nephropathy has been analyzed in patients with reduced GFR but has not been analyzed in those with normal kidney function. The main objective of the study was to analyze the prognostic value of C4d deposits and association with response to treatment in patients with IgA nephropathy and normal GFR. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This retrospective cohort study included 190 patients with idiopathic IgA nephropathy diagnosed by kidney biopsy between 1988 and 2005. The patients had GFR≥80 ml/min per 1.73 m2 at the time of diagnosis, and they had a paraffin-embedded kidney biopsy with eight glomeruli available. RESULTS: In total, 170 (89%) and 20 (11%) patients were >18 and <18 years old, respectively; median (interquartile range) follow-up was 15 (12-22) years. Mesangial C4d deposit prevalence was 20% (38 of 190). At diagnosis, C4d-positive versus -negative patients had higher protein-to-creatinine ratio (median [interquartile range]: 1.94 g/g [0.9-3.1] versus 1.45 g/g [0.9-2.2]; P=0.04). During follow-up, C4d-positive patients showed a higher number of nephritic flares (median [range]: 1.4 [0-5] versus 0.9 [0-2]; P=0.04), had a higher protein-to-creatinine ratio (median [interquartile range]: 1.32 g/g [0.7-1.7] versus 0.89 g/g [0.1-1.3]; P<0.01), were more prone to receive repeated treatment with corticosteroids (45% versus 24%; P<0.01), and showed a larger reduction in eGFR (-1.6 versus -0.8 ml/min per 1.73 m2 per year; P=0.04). Furthermore, the presence of mesangial C4d deposits was an independent predictor of long-term kidney survival. CONCLUSIONS: C4d deposits may be one of the earliest poor prognostic variables available for patients with idiopathic IgA nephropathy and normal kidney function at the time of diagnosis. However, Cd4 deposits alone are not associated with the response to angiotensin blockers or corticosteroid treatment.
Asunto(s)
Complemento C4b/análisis , Mesangio Glomerular/inmunología , Glomerulonefritis por IGA/inmunología , Fragmentos de Péptidos/análisis , Adolescente , Adulto , Biomarcadores/análisis , Biopsia , Progresión de la Enfermedad , Femenino , Tasa de Filtración Glomerular , Mesangio Glomerular/efectos de los fármacos , Mesangio Glomerular/patología , Mesangio Glomerular/fisiopatología , Glomerulonefritis por IGA/tratamiento farmacológico , Glomerulonefritis por IGA/patología , Glomerulonefritis por IGA/fisiopatología , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Factores de Tiempo , Resultado del Tratamiento , Adulto JovenRESUMEN
IgA nephropathy (IgAN) is one of the leading causes of glomerulonephritis characterized by the findings of IgA and IgG immune deposits in the mesangium of kidney biopsies from patients with persistent microscopic haematuria. IgAN is frequently detected among adolescents and young adults. IgAN presents a highly variable course that includes a spectrum from a very mild disease to end-stage renal disease (ESRD). There are several clinical and histological factors that strongly determined the final outcome of patients with IgAN. Pathological variables associated with unfavorable outcomes are mesangial hypercellularity, segmental glomerulosclerosis, endocapillary hypercellularity and interstitial fibrosis/tubular atrophy, according to the Oxford classification. Moreover, some studies also suggest a role for complement activation in the pathogenesis of IgAN. In this regard, staining for C4d may be an independent risk factor for the development of ESRD in IgAN. Despite the growing number of studies assessing IgAN risk factors, this kind of investigation in paediatric patients is still very limited. The aim of this article is to revise pathological markers related to deterioration of renal function in paediatric patients with IgAN, particularly those that can independently affect renal survival.