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C3 glomerulonephritis: clinicopathological findings, complement abnormalities, glomerular proteomic profile, treatment, and follow-up.

ABSTRACT: C3 glomerulonephritis (C3GN) is a recently described disorder that typically results from abnormalities in the alternative pathway (AP) of complement. Here, we describe the clinical features, kidney biopsy findings, AP abnormalities, glomerular proteomic profile, and follow-up in 12 cases of C3GN. This disorder equally affected all ages, both genders, and typically presented with hematuria and proteinuria. In both the short and long term, renal function remained stable in the majority of patients with native kidney disease. In two patients, C3GN recurred within 1 year of transplantation and resulted in a decline in allograft function. Kidney biopsy mainly showed a membranoproliferative pattern, although both mesangial proliferative and diffuse endocapillary proliferative glomerulonephritis were noted. AP abnormalities were heterogeneous, both acquired and genetic. The most common acquired abnormality was the presence of C3 nephritic factors, while the most common genetic finding was the presence of H402 and V62 alleles of Factor H. In addition to these risk factors, other abnormalities included Factor H autoantibodies and mutations in CFH, CFI, and CFHR genes. Laser dissection and mass spectrometry of glomeruli from patients with C3GN showed accumulation of AP and terminal complement complex proteins. Thus, C3GN results from diverse abnormalities of the alternative complement pathway leading to subsequent glomerular injury.

SUBMITTER: Sethi S

PROVIDER: S-EPMC4438675 | biostudies-literature | 2012 Aug

REPOSITORIES: biostudies-literature

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C3 glomerulonephritis: clinicopathological findings, complement abnormalities, glomerular proteomic profile, treatment, and follow-up.

Sethi Sanjeev S Fervenza Fernando C FC Zhang Yuzhou Y Zand Ladan L Vrana Julie A JA Nasr Samih H SH Theis Jason D JD Dogan Ahmet A Smith Richard J H RJ

Kidney international 20120801 4

C3 glomerulonephritis (C3GN) is a recently described disorder that typically results from abnormalities in the alternative pathway (AP) of complement. Here, we describe the clinical features, kidney biopsy findings, AP abnormalities, glomerular proteomic profile, and follow-up in 12 cases of C3GN. This disorder equally affected all ages, both genders, and typically presented with hematuria and proteinuria. In both the short and long term, renal function remained stable in the majority of patient ...[more]

PMID: 22673887

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Project description:C3 glomerulopathy (C3G) applies to a group of renal diseases defined by a specific renal biopsy finding: a dominant pattern of C3 fragment deposition on immunofluorescence. The primary pathogenic mechanism involves abnormal control of the alternative complement pathway, although a full description of the disease spectrum remains to be determined. This study sought to validate and define the association of complement dysregulation with C3G and to determine whether specific complement pathway abnormalities could inform disease definition.This study included 34 patients with C3G (17 with C3 glomerulonephritis [C3GN] and 17 with dense deposit disease [DDD]) diagnosed between 2008 and 2013 selected from the C3G Registry. Control samples (n=100) were recruited from regional blood drives. Nineteen complement biomarkers were assayed on all samples. Results were compared between C3G disease categories and with normal controls.Assessment of the alternative complement pathway showed that compared with controls, patients with C3G had lower levels of serum C3 (P<0.001 for both DDD and C3GN) and factor B (P<0.001 for both DDD and C3GN) as well as higher levels of complement breakdown products including C3d (P<0.001 for both DDD and C3GN) and Bb (P<0.001 for both DDD and C3GN). A comparison of terminal complement pathway proteins showed that although C5 levels were significantly suppressed (P<0.001 for both DDD and C3GN) its breakdown product C5a was significantly higher only in patients with C3GN (P<0.05). Of the other terminal pathway components (C6-C9), the only significant difference was in C7 levels between patients with C3GN and controls (P<0.01). Soluble C5b-9 was elevated in both diseases but only the difference between patients with C3GN and controls reached statistical significance (P<0.001). Levels of C3 nephritic factor activity were qualitatively higher in patients with DDD compared with patients with C3GN.Complement biomarkers are significantly abnormal in patients with C3G compared with controls. These data substantiate the link between complement dysregulation and C3G and identify C3G interdisease differences.

Project description:BACKGROUND:Uromodulin (UMOD), also known as Tamm-Horsfall protein, is a kidney-specific protein expressed by epithelial cells lining the thick ascending limb of the loop of Henle. In the current study, we aimed to clarify the clinical significance of UMOD in ANCA-associated glomerulonephritis (AAG). MATERIALS AND METHODS:Sixty-one biopsy-proven AAG patients were included in this study. UMOD was measured using ELISA. The relationships between serum UMOD (sUMOD) levels and various clinicopathological findings were evaluated. RESULTS:AAG was classified into four categories (focal, crescentic, mixed, and sclerotic). In addition, tubulointerstitial lesions were classified as mild, moderate, and severe. The levels of sUMOD and urinary UMOD (uUMOD) were correlated with each other. A negative correlation between sUMOD levels and serum Cr levels, and positive correlation between sUMOD levels and eGFR were found. Patients in the high sUMOD group were associated with low serum Cr levels, focal classification, and mild tubulointerstitial injury compared to the low sUMOD group. Comparing the characteristics among histopathological classes, patients in the focal class had the best renal function and the highest levels of uUMOD/Cr and sUMOD. The focal class had significantly better renal survival compared with the severe histopathological classes (crescentic, mixed, and sclerotic). In univariate logistic regression analyses, prognostic factors for severe histopathological classes were low uUMOD/Cr, high serum Cr, and low sUMOD. Multivariate analyses revealed that low sUMOD predicted severe histopathological classes independent of serum Cr. The mean levels of sUMOD were significantly different between the focal class and severe histopathological classes, with a sensitivity of 70.6% and specificity of 90.0% (cut-off 143 ng/ml, AUC 0.80) by ROC curves. CONCLUSION:Low sUMOD levels were associated with severe clinicopathological findings and might be considered as a risk factor for end stage renal disease in AAG.

Dataset Information

C3 glomerulonephritis: clinicopathological findings, complement abnormalities, glomerular proteomic profile, treatment, and follow-up.

Publications

C3 glomerulonephritis: clinicopathological findings, complement abnormalities, glomerular proteomic profile, treatment, and follow-up.

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