Activated complement C3: A potentially novel predictor of progressive IgA nephropathy

IgA nephropathy (IgAN) is one of the most common forms of glomerular disease. It is diagnosed by the dominant or co-dominant IgA deposition in the mesangial region by histopathological examination of kidney biopsy. Kidney biopsy has its own complication and not performed frequently. microRNA (miRNA) is a small RNA, which plays an important role at the post transcriptional level by downregulating mRNAs. We have tried to establish a miRNA based biomarker for IgAN. We quantified miR-148b and let-7b from plasma in IgAN patients and healthy controls. Logistic regression models and receiver operating curve analysis used to analyze the miRNAs quantity and Oxford MEST-C scoring parameters (M- Mesangial hypercellularity, E- Endocapillary hypercellularity, S- Segmental glomerulosclerosis, T- Tubular atrophy/Interstitial fibrosis, C- Crescents). miR-148b and let-7b levels in IgAN were found to be higher by 2.9 and 5.48 times than the healthy controls, respectively. let-7b was positively correlated with complement C3 levels. Similarly, miR-148b was positively correlated with estimated glomerular filtration rate (eGFR) and negatively correlated with S, T, and blood pressure (BP). The sensitivity, specificity, and area under the curve (AUC) of receiver operating characteristic (ROC) for miR-148b against T were 0.87, 0.77, and 0.85, respectively. The threshold value of miR-148b concentration was found to be 8479 to differentiate the severe condition of IgAN. Furthermore, the decrease in miR-148b concentration at a threshold point indicated the progression of the severity of the IgAN. It can also be used to predict the IgAN at an earlier stage.

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Serum uric acid level is correlated with the clinical, pathological progression and prognosis of IgA nephropathy: an observational retrospective pilot-study

PeerJ ◽

10.7717/peerj.10130 ◽

2020 ◽

Vol 8 ◽

pp. e10130

Author(s):

Pingfan Lu ◽

Xiaoqing Li ◽

Na Zhu ◽

Yuanjun Deng ◽

Yang Cai ◽

...

Keyword(s):

Uric Acid ◽

Iga Nephropathy ◽

Serum Uric Acid ◽

Interstitial Fibrosis ◽

Serum Uric Acid Level ◽

Immunoglobulin M ◽

Complement C3 ◽

Renal Outcome ◽

Glomerular Sclerosis ◽

Significant Difference

Objectives This study was aimed to assess the relationship between serum uric acid (SUA) level and the clinical, pathological phenotype of IgA nephropathy (IgAN), and to determine the role of SUA level in the progression and prognosis of IgAN. Methods A total of 208 patients with IgAN were included in this study, and were classified into the normo-uricemia group and hyperuricemia group according to the SUA level. The clinical data at baseline, IgAN Oxford classification scores (MEST-C scoring system), and other pathological features were collected and further analyzed. All patients were followed up and the prognosis was assessed using Kaplan-Meier survival curves. GraphPad Prism 7.0 and SPSS 23.0 were used for statistical analyses. Results In clinical indicators, patients with hyperuricemia had the significantly higher proportion of males to females, mean arterial pressure, the levels of total cholesterol, triglyceride, Scr, BUN, 24 hour-urine protein, C3, and C4, the lower levels of high-density lipoprotein cholesterol and eGFR than those without (p < 0.05). In terms of pathological characteristics, the tubular atrophy/interstitial fibrosis scores, vascular injury scores, and glomerular sclerosis percentage were significantly higher in patients with hyperuricemia compared with those without (p < 0.01). There was no significant difference in the scores of mesangial hypercellularity, endocapillary hypercellularity, focal segmental glomerulosclerosis, as well as crescents between the two groups (p > 0.05). As for the depositions of immune complexes deposition in IgAN, the hyperuricemia group had less deposition of immunoglobulin G and FRA than the normo-uricemia group (p < 0.05), while the deposition of immunoglobulin A, immunoglobulin M, and complement C3 in the two groups showed no statistical difference. The survival curve suggested that patients in the hyperuricemia group have significantly poorer renal outcome than those in the normo-uricemia group (p = 0.0147). Results also revealed that the SUA level is a valuable predictor of renal outcome in patients with IgAN. The optimal cutoff value was 361.1 µmol/L (AUC = 0.76 ± 0.08167) and 614 µmol/L (AUC = 0.5728 ± 0.2029) for female and male, respectively. Conclusions The level of SUA is associated with renal function level and pathological severity of IgAN, and maybe a prognostic indicator of IgAN.

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Renal cortical complement C3 gene expression in IgA nephropathy.

Journal of the American Society of Nephrology ◽

10.1681/asn.v83415 ◽

1997 ◽

Vol 8 (3) ◽

pp. 415-425

Author(s):

V Montinaro ◽

L Gesualdo ◽

E Ranieri ◽

R Monno ◽

G Grandaliano ◽

...

Keyword(s):

Gene Expression ◽

In Situ Hybridization ◽

Iga Nephropathy ◽

Immunoglobulin A ◽

Complement C3 ◽

Tubular Atrophy ◽

Complement Components ◽

Tubular Cells ◽

C3 Gene

Glomerular C3 deposits are commonly found in immunoglobulin A (IgA) nephropathy. Renal gene expression and protein synthesis of complement components have been shown in settings of tissue inflammation. In this study, the pathogenetic involvement of locally produced C3 in IgA nephropathy was analyzed. C3 gene expression was analyzed by reverse transcription, polymerase chain reaction, and in situ hybridization techniques. C3 mRNA was detected in 56% of cases, with a significantly higher percentage in patients with moderate-to-severe lesions than in those with mild lesions (P < 0.01). By in situ hybridization, C3 transcript was predominantly expressed by tubular cells and some interstitial cells. C3 mRNA was also observed on glomerular parietal epithelial cells. Immunoreactive native C3 was detected on cortical tubuli by an anti-C3c immunoalkaline-phosphatase technique. A significant correlation was found between renal C3 transcription and glomerulosclerosis, intracapillary proliferation (both P < 0.005) and markers of interstitial damage, including tubular atrophy (P < 0.05), interstitial infiltration (P < 0.05), and fibrosis (P < 0.005). Proteinuria (P < 0.05), but not serum creatinine, at the time of renal biopsy correlated with C3 mRNA. In conclusion, it was demonstrated that the C3 gene was expressed primarily in proximal tubular cells and occasionally in glomerular crescents, and that its expression correlated with clinical and histologic markers of severity and poor outcome of IgA nephropathy. Thus, a pathogenetic involvement of the local transcription and translation of the C3 gene in IgA nephropathy was suggested.

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Clinicopathological and prognostic study of IgA-dominant postinfectious glomerulonephritis

BMC Nephrology ◽

10.1186/s12882-021-02462-3 ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Ziyuan Huang ◽

Bo Chen ◽

Ying Zhou ◽

Yan Liang ◽

Wenxian Qiu ◽

...

Keyword(s):

Electron Microscopy ◽

Iga Nephropathy ◽

Deposition Rate ◽

Selection Criteria ◽

Proliferative Glomerulonephritis ◽

Complement C3 ◽

Mesangial Area ◽

Postinfectious Glomerulonephritis ◽

Endocapillary Proliferative Glomerulonephritis ◽

Area Deposition

Abstract Background The clinicopathological and prognostic features of IgA-dominant postinfectious glomerulonephritis and its difference from the primary IgA nephropathy remains to be investigated. Methods The clinical and pathological data of 6542 patients who underwent renal biopsy from 2009 to 2020 in our hospital were reviewed and 50 patients who met the selection criteria of IgA-dominant postinfectious glomerulonephritis were enrolled to conduct a retrospective and observational single-center study. The selection criteria were: meet the characteristics of IgA dominance or codominance in immunofluorescence, and conform to 3 of the following 5 criteria: 1.Clinical or laboratory evidence show that there is infection before or at the onset of glomerulonephritis; 2.The level of serum complement decreased; 3.Renal pathology is consistent with endocapillary proliferative glomerulonephritis; 4. Glomerular immunofluorescence staining showed complement C3 dominance or codominance; 5. Hump-like subepithelial immune complex deposition was observed under electron microscopy. According to age, sex, renal function (estimated glomerular filtration rate, eGFR) and follow-up time, the control group was constructed with 1:3 matched cases of primary IgA nephropathy. The clinicopathological and prognostic differences between the two groups were analyzed. Results The most common histological pattern of IgA-dominant postinfectious glomerulonephritis was acute endocapillary proliferative glomerulonephritis and exudative glomerulonephritis. Immunofluorescence showed mainly IgA deposition or IgA deposition only, mainly deposited in the mesangial area (deposition rate 100 %), with typical C3 high-intensity staining (intensity++~+++), mainly deposited in the mesangial area (deposition rate 92.0 %). The fluorescence intensity of kappa is usually not weaker than lambda. The probability of the appearance of typical hump-like electron deposition under electron microscopy is low. Compared to primary IgA nephropathy, patients with IgA-dominant postinfectious glomerulonephritis had higher proportion of crescents (p = 0. 005) and endocapillary hypercellularity (p < 0.001) in pathological manifestations. Using serum creatinine level doubled of the baseline or reached end-stage renal disease as the endpoint, the prognosis of IgA-dominant postinfectious glomerulonephritis patients was worse than that of primary IgA nephropathy patients (p = 0.013). Conclusions The clinicopathological features of patients with IgA-dominant postinfectious glomerulonephritis was different from that of primary IgA nephropathy, and the prognosis was worse.

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