Circulating complement factor H–related protein 5 levels contribute to development and progression of IgA nephropathy
2018; Elsevier BV; Volume: 94; Issue: 1 Linguagem: Inglês
10.1016/j.kint.2018.02.023
ISSN1523-1755
AutoresLi Zhu, Weiyi Guo, Sufang Shi, Lijun Liu, Jicheng Lv, Nicholas Medjeral‐Thomas, Hannah J. Lomax-Browne, Matthew C. Pickering, Hong Zhang,
Tópico(s)Chronic Kidney Disease and Diabetes
ResumoIgA nephropathy (IgAN) is a disease associated with activation of the complement system. But the factors influencing complement activation in IgAN are not fully understood. Complement factor H (FH) is an essential negative regulator of complement C3 activation. Complement factor H–related protein (FHR)-5 shares high sequence similarity with factor H. However, unlike factor H, on binding to activated C3 it enables further activation to proceed. Previously, we reported the contribution of rare variants of the CFHR5 gene to IgAN susceptibility. Here we compared circulating levels of FHR-5 in 1126 patients with IgAN and regular follow-up with those of 153 unrelated healthy individuals to explore the relationship of FHR-5 levels with IgAN development and progression. Circulating FHR-5 levels were significantly elevated in patients with IgAN compared to healthy individuals (median 4.55 [interquartile range 3.58 to 5.85] μg/ml vs 3.19 [interquartile range 2.55 to 3.92] μg/ml). Higher circulating FHR-5 levels were associated with a lower estimated glomerular filtration rate, hypertension, and severe Oxford-T and Oxford-C scores. High FHR-5 levels were independently and significantly associated with a risk of developing either a 30% decline in the estimated glomerular filtration rate or end-stage renal disease (hazard ratio, per standard deviation increment of natural square root transformed FHR-5 of 1.226; 95% confidence interval: 1.106-1.359). Thus, the circulating FHR-5 level is an independent risk factor for IgAN progression. IgA nephropathy (IgAN) is a disease associated with activation of the complement system. But the factors influencing complement activation in IgAN are not fully understood. Complement factor H (FH) is an essential negative regulator of complement C3 activation. Complement factor H–related protein (FHR)-5 shares high sequence similarity with factor H. However, unlike factor H, on binding to activated C3 it enables further activation to proceed. Previously, we reported the contribution of rare variants of the CFHR5 gene to IgAN susceptibility. Here we compared circulating levels of FHR-5 in 1126 patients with IgAN and regular follow-up with those of 153 unrelated healthy individuals to explore the relationship of FHR-5 levels with IgAN development and progression. Circulating FHR-5 levels were significantly elevated in patients with IgAN compared to healthy individuals (median 4.55 [interquartile range 3.58 to 5.85] μg/ml vs 3.19 [interquartile range 2.55 to 3.92] μg/ml). Higher circulating FHR-5 levels were associated with a lower estimated glomerular filtration rate, hypertension, and severe Oxford-T and Oxford-C scores. High FHR-5 levels were independently and significantly associated with a risk of developing either a 30% decline in the estimated glomerular filtration rate or end-stage renal disease (hazard ratio, per standard deviation increment of natural square root transformed FHR-5 of 1.226; 95% confidence interval: 1.106-1.359). Thus, the circulating FHR-5 level is an independent risk factor for IgAN progression. IgA nephropathy (IgAN) is the commonest pattern of primary glomerulonephritis around the world.1D'Amico G. The commonest glomerulonephritis in the world: IgA nephropathy.Q J Med. 1987; 64: 709-727Google Scholar Although the precise pathogenesis of IgAN is still unclear, the multi-hit model is currently the most widely accepted mechanism for IgAN. The model implicates the binding of galactose-deficient IgA1 molecules and anti-glycan antibody to form circulating immune complexes that accumulate in the glomerular mesangium and induce renal injury.2Suzuki H. Kiryluk K. Novak J. et al.The pathophysiology of IgA nephropathy.J Am Soc Nephrol. 2011; 22: 1795-1803Google Scholar Complement component C3 is observed in both circulating immune complexes and glomerular deposits accompanied with IgA in IgAN,3Czerkinsky C. Koopman W.J. Jackson S. et al.Circulating immune complexes and immunoglobulin A rheumatoid factor in patients with mesangial immunoglobulin A nephropathies.J Clin Invest. 1986; 77: 1931-1938Scopus (148) Google Scholar, 4Onda K. Ohi H. Tamano M. et al.Hypercomplementemia in adult patients with IgA nephropathy.J Clin Lab Anal. 2007; 21: 77-84Google Scholar, 5Zhang J.J. Jiang L. Liu G. et al.Levels of urinary complement factor H in patients with IgA nephropathy are closely associated with disease activity.Scand J Immunol. 2009; 69: 457-464Google Scholar suggesting a role for complement activation in IgAN. Moreover, the degree of mesangial C3 deposits was reported to predict renal outcome in patients with IgAN, which suggested a role for complement activation in IgAN progression.6Kim S.J. Koo H.M. Lim B.J. et al.Decreased circulating C3 levels and mesangial C3 deposition predict renal outcome in patients with IgA nephropathy.PloS One. 2012; 7e40495Google Scholar However, the regulatory factors for complement activation in IgAN remain incompletely understood. Complement factor H (FH) is an essential negative regulator of complement C3 activation through the alternative pathway and the C3b amplification loop.7Rodríguez de Córdoba S. Esparza-Gordillo J. Goicoechea de Jorge E. et al.The human complement factor H: functional roles, genetic variations and disease associations.Mol Immunol. 2004; 41: 355-367Google Scholar In addition, 5 complement factor H–related proteins (FHR-1, FHR-2, FHR-3, FHR-4, FHR-5), which share high sequence similarity to FH exist.8Skerka C. Chen Q. Fremeaux-Bacchi V. et al.Complement factor H related proteins (CFHRs).Mol Immunol. 2013; 56: 170-180Google Scholar, 9Medjeral-Thomas N. Pickering M.C. The complement factor H-related proteins.Immunol Rev. 2016; 274: 191-201Google Scholar Unlike FH, the FHR proteins do not contain complement regulatory domains. However, both FH and the FHR proteins contain C3b binding domains. In vitro studies have demonstrated that FHR-1, FHR-2, and FHR-5 could function as competitive antagonists of FH for the binding to C3b. This process, termed FH deregulation, could impair the ability of FH to negatively regulate C3 on surfaces such as the mesangium, and potentially enhance C3 deposition.10Goicoechea de Jorge E. Caesar J.J. Malik T.H. et al.Dimerization of complement factor H-related proteins modulates complement activation in vivo.Proc Natl Acad Sci U S A. 2013; 110: 4685-4690Google Scholar, 11Tortajada A. Yébenes H. Abarrategui-Garrido C. et al.C3 glomerulopathy-associated CFHR1 mutation alters FHR oligomerization and complement regulation.J Clin Invest. 2013; 123: 2434-2446Google Scholar The contribution of FH and FHRs to IgAN aroused considerable interest after chromosome location 1q32, which contains the CFH, CFHR3, CFHR1, CFHR4, CFHR2, and CFHR5 genes, was identified as an IgAN-susceptible locus in a genome-wide association study.12Gharavi A.G. Kiryluk K. Choi M. et al.Genome-wide association study identifies susceptibility loci for IgA nephropathy.Nat Genet. 2011; 43: 321-327Google Scholar, 13Kiryluk K. Li Y. Sanna-Cherchi S. et al.Geographic differences in genetic susceptibility to IgA nephropathy: GWAS replication study and geospatial risk analysis.PLoS Genet. 2012; 8: e1002765Google Scholar In addition, the high clinical similarity between IgAN and CFHR5 nephropathy, which is caused by internal duplication of the CFHR5 gene, implicated a specific role for FHR-5 in IgAN pathogenesis.14Gale D.P. de Jorge E.G. Cook H.T. et al.Identification of a mutation in complement factor H-related protein 5 in patients of Cypriot origin with glomerulonephritis.Lancet. 2010; 376: 794-801Google Scholar, 15Athanasiou Y. Voskarides K. Gale D.P. et al.Familial C3 glomerulopathy associated with CFHR5 mutations: clinical characteristics of 91 patients in 16 pedigrees.Clin J Am Soc Nephrol. 2011; 6: 1436-1446Google Scholar We previously screened the coding sequence of the CFHR5 gene in IgAN patients and demonstrated the contribution of rare variants of the CFHR5 gene in IgAN susceptibility.16Zhai Y.L. Meng S.J. Zhu L. et al.Rare variants in the complement factor H-related protein 5 gene contribute to genetic susceptibility to IgA nephropathy.J Am Soc Nephrol. 2016; 27: 2894-2905Crossref Scopus (46) Google Scholar Additionally, Medjeral-Thomas et al. recently observed elevated circulating FHR-5 levels in IgAN, and an association between elevated FHR-5 levels and progressive IgAN.17Medjeral-Thomas N.R. Lomax-Browne H.J. Beckwith H. et al.Circulating complement factor H-related proteins 1 and 5 correlate with disease activity in IgA nephropathy.Kidney Int. 2017; 92: 942-952Google Scholar These data suggested that FHR-5 could influence both susceptibility to IgAN and its severity. In order to elucidate the contribution of FHR-5 levels to IgAN, we measured circulating FHR-5 levels in a large cohort of IgAN patients with regular follow-up, and we explored the relationship of FHR-5 levels with IgAN phenotypes and progression. We defined the time of renal biopsy as baseline for our recruited patients with IgAN. Among the 1126 recruited patients with IgAN, 569 (50.5%) were male and 557 (49.5%) female, with a median age of 33 (interquartile range [IQR] 26–42) years (Table 1). At the time of renal biopsy, the median proteinuria was 1.30 (IQR 0.69–2.52) g/24 hours, and average estimated glomerular filtration rate (eGFR) was 82.73 ± 30.56 ml/min per 1.73 m2. In total, 551 (49.0%) IgAN patients presented with hypertension, defined as blood pressure over 140/90 or taking antihypertensive medications to prevent hypertension. Except for 21 patients with less than 8 glomeruli in biopsy specimens, the pathological lesions of 1105 patients were graded using the Oxford classification (MESTC scores). Mesangial hypercellularity (M1), endocapillary hypercellularity (E1), and segmental glomerulosclerosis (S1) were found in 739 (66.9%), 498 (45.1%), and 759 (68.7%) patients, respectively. For tubular atrophy and interstitial fibrosis (Oxford-T) and crescent (Oxford-C) lesions, T0, T1, and T2 were found in 715 (64.7%), 278 (25.2%), and 112 (10.1%) patients, while C0, C1, and C2 were found in 494 (44.7%), 491 (44.4%), and 120 (10.9%) patients. All patients were regularly followed up, with a median follow-up time of 43.5 (IQR, 24.0–79.0) months. During follow-up, 511 (45.4%) of 1126 patients received corticosteroids and/or immunosuppressive agents, and 373 (33.1%) reached the composite end point, defined as 30% eGFR decline or end-stage renal disease (ESRD).Table 1Demographic, clinical, and histological characteristics of patients with IgANCharacteristicMean ± SD or median (IQR)n = 1126Group 11st quartern = 281Group 22nd quartern = 282Group 33rd quartern = 282Group 44th quartern = 281P valueaP value was used to indicate the differences among the 4 groups.P valuebP value was used to indicate the differences between group 1 and group 4.FHR-5 levels (μg/ml)4.55 (3.58, 5.85) 5.850<0.001<0.001Baseline Age (yr)33 (26, 42)32 (25, 40)33 (26, 42)33 (26, 42)34 (27, 44)0.1310.023 Sex (male)569 (50.5%)98 (34.9%)133 (47.2%)153 (54.3%)185 (65.8%)<0.001<0.001 Initial proteinuria (g/d)1.30 (0.69, 2.52)1.17 (0.64, 2.52)1.24 (0.65, 2.43)1.15 (0.68, 2.37)1.58 (0.80, 2.67)0.0320.012 eGFR (ml/min per 1.73 m2)82.73 ± 30.5687.63 ± 28.7384.78 ± 29.4184.30 ± 31.2374.19 ± 31.26<0.001<0.001 HBP (with, %)551 (49.0%)114 (40.6%)137 (48.6%)137 (48.8%)163 (58.0%)<0.001 0.5), the presence of endocapillary proliferation (E1: present), segmental glomerulosclerosis/adhesion (S1: present), severity of tubular atrophy/interstitial fibrosis (T1: 26%–50%, T2 >50%), and presence of crescent (C1: 1%–25%, C2: 26%–100%). Oxford classification was developed by the Working Group of the International IgA Nephropathy Network and the Renal Pathology Society. Oxford scores of 21 patients were unavailable because each of them had fewer than 8 glomeruli.M1739 (66.9%)180 (65.2%)190 (68.3%)185 (67.0%)184 (66.9%)0.7670.675E1498 (45.1%)131 (47.5%)143 (51.4%)117 (42.4%)107 (38.9%)0.0100.043S1759 (68.7%)184 (66.7%)188 (67.6%)184 (66.7%)203 (73.8%)0.1010.066T1/T2278 (25.2%)/112 (10.1%)49 (17.8%)/26 (9.4%)60 (21.6%)/27 (9.7%)76 (27.5%)/24 (8.7%)93 (33.8%)/35 (12.7%)<0.001<0.001C1/C2491 (44.4%)/120 (10.9%)114 (41.3%)/16 (5.8%)122 (43.9%)/21 (7.6%)141 (51.1%)/32 (11.6%)114 (41.5%)/51 (18.5%)<0.001<0.001Follow-up Follow-up interval (mo)43.5 (24.0, 79.0)61.0 (32.0, 99.0)48.0 (26.0, 84.0)36.0 (20.0, 64.0)38.0 (24.0, 62.5)<0.001<0.001 Treated with prednisone or other immunosuppressive agents (%)511 (45.4%)134 (47.7%)116 (41.1%)121 (42.9%)140 (49.8%)0.5380.613Outcome Composite end point (%)dComposite outcome included 30% eGFR decline or ESRD, whichever occurred first.373 (33.1%)92 (32.7%)101 (35.8%)83 (29.4%)97 (34.5%)0.9320.655 Composite end point–free time (mo)39.0 (22.0, 69.0)51.0 (27.5, 88.5)43.5 (22.0, 75.3)32.5 (18.8, 56.0)34.0 (22.0, 56.0)<0.001<0.001 30% decline in eGFR (%)370 (32.9%)92 (32.7%)98 (34.8%)83 (29.4%)97 (34.5%)1.0000.655 30% eGFR decline–free time (mo)39.0 (22.0, 69.0)51.0 (27.5, 88.5)43.5 (22.0, 75.3)32.5 (18.8, 56.0)34.0 (22.0, 56.0)<0.001<0.001 ESRD (%)108 (9.6%)32 (11.4%)28 (9.9%)17 (6.0%)31 (11.0%)0.5260.894 ESRD-free time (mo)43.0 (24.0, 78.0)61.0 (31.5, 98.0)48.0 (26.0, 82.5)36.0 (20.0, 64.0)38.0 (23.0, 62.5)<0.001 0.5), the presence of endocapillary proliferation (E1: present), segmental glomerulosclerosis/adhesion (S1: present), severity of tubular atrophy/interstitial fibrosis (T1: 26%–50%, T2 >50%), and presence of crescent (C1: 1%–25%, C2: 26%–100%). Oxford classification was developed by the Working Group of the International IgA Nephropathy Network and the Renal Pathology Society. Oxford scores of 21 patients were unavailable because each of them had fewer than 8 glomeruli.d Composite outcome included 30% eGFR decline or ESRD, whichever occurred first. Open table in a new tab eGFR, estimated glomerular filtration rate; ESRD, end-stage renal disease; FHR-5, complement factor H–related protein 5; HBP, high blood pressure; IgAN, IgA nephropathy; IQR, interquartile range; Circulating FHR-5 levels in patients with IgAN (median 4.55 μg/ml, IQR 3.58–5.85) were significantly higher compared with healthy controls (median 3.19 μg/ml, IQR 2.55–3.92, P < 0.001, Figure 1a). Next, we investigated the correlation of FHR-5 levels with clinical and pathological manifestations in patients with IgAN. In the whole IgAN cohort, the FHR-5 levels showed weak but significant negative correlation with eGFR (correlation coefficient –0.159, P < 0.001, Figure 1b). However, firstly, when we compared IgAN patients with normal renal function (chronic kidney disease stage 1 and eGFR > 90 ml/min per 1.73 m2) with healthy controls, circulating FHR-5 levels remained significantly elevated in the IgAN cohort (Figure 1c). Secondly, no correlation was found between circulating FHR-5 levels and eGFR in our diabetic nephropathy cohort, who presented with highly variable levels of eGFR (Figure 1d). This indicated that the raised FHR-5 levels in IgAN were not due to changes in eGFR. FHR-5 levels in patients with IgAN also showed significant but weak correlation with proteinuria (correlation coefficient 0.074, P = 0.014, Figure 1e) and were higher in IgAN patients with hypertension (Figure 1f). We also noted differences in FHR-5 levels when we compared IgAN patients based on the Oxford classification (MESTC scores) (Figure 2). FHR-5 levels differed between patients when stratified according to Oxford-E, Oxford-T, and Oxford-C lesions (Figure 2b, d, and e), but not when stratified according to either Oxford-M (Figure 2a) or Oxford-S lesions (Figure 2c). FHR-5 levels were higher in patients with Oxford E0 (4.75 μg/ml, IQR 3.64–5.96, P = 0.020) compared with Oxford E1 (median 4.34 μg/ml, IQR 3.55–5.57). Patients with severe Oxford T2 (4.86 μg/ml, IQR 3.65–6.20) and T1 (4.96 μg/ml, IQR 3.96–6.29) lesions showed higher FHR-5 levels than those with Oxford T0 (4.38 μg/ml, IQR 3.46–5.53). FHR-5 levels showed a step-wise correlation with glomerular crescents. FHR-5 levels were higher in patients with Oxford-C2 (median 5.42 μg/ml, IQR 4.09–6.90) than Oxford-C1 (median 4.65 μg/ml, IQR 3.65–5.75), and lowest in patients with Oxford-C0 (median 4.29 μg/ml, IQR 3.35–5.65). Circulating FHR-5 levels were significantly higher in male IgAN patients (median 4.98 μg/ml, IQR 3.93–6.18) compared with female IgAN patients (median 4.15 μg/ml, IQR 3.25–5.33, P < 0.001, Figure 3a). Because FHR-5 levels did not differ between male and female healthy controls (Figure 3b), the higher level in the male IgAN patients may reflect more severe disease (Table 1). Considering the highly variable clinical and pathological manifestations in patients with IgAN, and in order to explore the association of circulating FHR-5 levels with IgAN phenotypes, we divided patients into 4 equal groups according to the quartiles of the FHR-5 distribution (Table 1). Group 1 to group 4 were defined as IgAN patients with circulating FHR-5 levels of 5.850 μg/ml, respectively. We found that IgAN patients in groups with high FHR-5 levels showed more severe clinical and pathological manifestations than those with lower FHR-5 levels. From group 1 to group 4, patients had gradually decreased eGFR (87.63 ± 28.73 ml/min per 1.73 m2 vs. 84.78 ± 29.41 ml/min per 1.73 m2 vs. 84.30 ± 31.23 ml/min per 1.73 m2 vs. 74.19 ± 31.26 ml/min per 1.73m2; P < 0.001), increased incidence of hypertension (40.6% vs. 48.6% vs. 48.8% vs. 50.6%; P < 0.001), and increased proportion of higher Oxford T-scores (T1/T2: 49 [17.8%]/26 [9.4%] vs. 60 [21.6%]/27 [9.7%] vs. 76 [27.5%]/24 [8.7%] vs. 93 [33.8%]/35 [12.7%]; P < 0.001) and Oxford C-scores (C1/C2: 114 [41.3%]/16 [5.8%] vs. 122 [43.9%]/21 [7.6%] vs. 141 [51.1%]/32 [11.6%] vs. 114 [41.5%]/51 [18.5%]; P < 0.001). With regard to proteinuria and Oxford-E scores, differences were observed between the 4 groups (group 1–4: proteinuria: 1.17 g/d [0.64, 2.52] vs. 1.24 [0.65, 2.43] vs. 1.15 [0.68, 2.37] vs. 1.58 [0.80, 2.67]; P = 0.032; Oxford-E scores: 131 [47.5%] vs. 143 [51.4%] vs. 117 [42.4%] vs. 107 [38.9%]; P = 0.010). Only patients in group 4 showed higher proteinuria and lower Oxford-E scores than the other 3 groups. No significant differences were found between groups 1, 2, and 3. Both the IgAN associated markers, circulating IgA levels and renal IgA deposits, and the complement-related markers, circulating C3 levels, and renal C3 deposits showed no significant differences among the 4 groups (Table 1). Our IgAN patient cohort had a median renal survival time to composite end point (30% eGFR decline or ESRD) of 95 months. In total, 373 of 1126 patients (33.1%) reached the composite end point. Among them, 370 reached the end point of 30% eGFR decline, 108 reached the end point of ESRD, and 105 reached both end points during follow-up. Kaplan-Meier survival analysis revealed that renal survivals for the composite end point were significantly different among these 4 groups (P < 0.001, Figure 4a). Group 1 had the best renal outcome, whereas group 4 had the worst, as represented by the gradually shortened median renal survival times of 113, 95, 85, and 73 months for groups 1, 2, 3, and 4, respectively. Moreover, we also compared the survival curves among these 4 groups using either 30% eGFR decline (Figure 4b) or ESRD (Figure 4c) as end points. Using 30% eGFR decline as an end point, IgAN patients in these 4 groups also showed significant difference regarding disease progression (P < 0.001, Figure 4b). When the ESRD end point was used, we observed a similar trend (patients in group 4 showed worst renal survival rate, whereas patients in group 1 showed the best), although IgAN patients in these 4 groups only showed a suggestive significance in Kaplan-Meier survival analysis (P = 0.083, Figure 4c). Because circulating FHR-5 levels in our patients with IgAN were associated with multiple clinical and pathological manifestations, which were widely accepted as risk factors for IgAN progression, we next used the Cox proportional hazards model to explore the adjusted hazard ratio of FHR-5 levels for poor renal outcome in IgAN. In univariate survival analysis, circulating FHR-5 levels were significantly associated with IgAN progression, both when expressed as a continuous variable (hazard ratio [HR] per SD increment of natural square root–transformed FHR-5: 1.267; 95% confidence interval [CI]: 1.150–1.396; P < 0.001) or in quartiles (group 2: 1.384 [1.042–1.838], P = 0.025; group 3: 1.452 [1.077–1.958], P = 0.014; group 4: 1.845 [1.379–2.469], P < 0.001; compared with group 1). Moreover, after adjusting for multiple risk factors associated with IgAN severity (including baseline proteinuria, eGFR, hypertension, Oxford scores, and steroid or other immunosuppressive therapy), circulating FHR-5 levels remained an independent risk factor for IgAN progression (HR per SD increment of natural square root–transformed FHR-5: 1.226; 95% CI: 1.106–1.359; P < 0.001; Table 2 and Supplementary Table S1). Similarly, after adjusting for multiple clinical and pathological risk factors, as well as immunosuppressive therapy use, compared with group 1, groups 2 and 4 showed significant risk for poor renal outcome (group 2 HR: 1.420 [95% CI 1.057–1.907], P = 0.020; group 4 HR: 1.756 [95% CI 1.283–2.403], P < 0.001; Table 2 and Supplementary Table S2). Group 3 retained significant association with IgAN progression after adjusting for clinical manifestations (model 2 HR: 1.462 [1.078–1.983], P = 0.015, Table 2). However, the statistical significance of this association was lost after additional adjustment for pathological lesions and steroid or other immunosuppressive therapy (model 4 HR: 1.338 [0.974–1.836], P = 0.072; Table 2).Table 2Risks of composite end point of circulating FHR-5 levelsFHR-5 (μg/ml)median (IQR)UnadjustedHazard ratio (95% confidence interval) and P valueModel 1aModel 1 adjusted for sex (female and male) and age. Sex was analyzed as dichotomous data.Model 2bModel 2 adjusted for covariates in model 1 plus estimate glomerular filtration rate, proteinuria, and hypertension (with or without). Hypertension was analyzed as categorical data.Model 3cModel 3 adjusted for covariates in model 2 plus Oxford classification scores. Oxford classification: mesangial hypercellularity score (M1 > 0.5), the presence of endocapillary proliferation (E1: present), segmental glomerulosclerosis/adhesion (S1: present), severity of tubular atrophy/interstitial fibrosis (T1: 26%–50%, T2 > 50%), and presence of crescent (C1: 1%–25%, C2: 26%–100%).Model 4dModel 4 adjusted for covariates in model 3 plus steroid or other immunosuppressants use (yes or no). The latter variable was analyzed as dichotomous data.Composite end pointeComposite outcome included 30% estimate glomerular filtration rate decline or end-stage renal disease, whichever occurred first.4.55 (3.58, 5.85)1.267 (1.150–1.396)1.291 (1.169–1.425)1.265 (1.144–1.398)1.223 (1.103–1.356)1.226 (1.106–1.359) Per 1 SD of natural square root–transformed FHR-5<0.001<0.001<0.001<0.001<0.001FHR-5 subgroup Group 1: 1st quarter2.89 (2.38, 3.27)1 (reference)1 (reference)1 (reference)1 (reference)1 (reference) Group 2: 2nd quarter4.06 (3.83, 4.27)1.384 (1.042–1.838)1.447 (1.086–1.927)1.457 (1.093–1.943)1.386 (1.032–1.861)1.420 (1.057–1.907)0.0250.0120.0100.0300.020 Group 3: 3rd quarter5.12 (4.85, 5.46)1.452 (1.077–1.958)1.507 (1.116–2.034)1.462 (1.078–1.983)1.328 (0.967–1.822)1.338 (0.974–1.836)0.0140.0070.0150.0790.072 Group 4: 4th quarter6.88 (6.24, 7.87)1.845 (1.379–2.469)1.991 (1.475–2.689)1.930 (1.424–2.617)1.737 (1.269–2.379)1.756 (1.283–2.403)<0.001<0.001<0.0010.001 0.5), the presence of endocapillary proliferation (E1: present), segmental glomerulosclerosis/adhesion (S1: present), severity of tubular atrophy/interstitial fibrosis (T1: 26%–50%, T2 > 50%), and presence of crescent (C1: 1%–25%, C2: 26%–100%).d Model 4 adjusted for covariates in model 3 plus steroid or other immunosuppressants use (yes or no). The latter variable was analyzed as dichotomous data.e Composite outcome included 30% estimate glomerular filtration rate decline or end-stage renal disease, whichever occurred first. Open table in a new tab FHR-5, complement factor H–related protein 5; IQR, interquartile range. The highly phenotypic similarity between CFHR5 nephropathy and IgA nephropathy15Athanasiou Y. Voskarides K. Gale D.P. et al.Familial C3 glomerulopathy associated with CFHR5 mutations: clinical characteristics of 91 patients in 16 pedigrees.Clin J Am Soc Nephrol. 2011; 6: 1436-1446Google Scholar attracted our attention to the role of FHR-5 in IgAN. In addition to our previous finding that rare variants caused functional changes of FHR-5 and contributed to IgAN,16Zhai Y.L. Meng S.J. Zhu L. et al.Rare variants in the complement factor H-related protein 5 gene contribute to genetic susceptibility to IgA nephropathy.J Am Soc Nephrol. 2016; 27: 2894-2905Crossref Scopus (46) Google Scholar here we detected circulating FHR-5 levels in a large IgAN cohort with regular follow-up and observed a deleterious effect of high FHR-5 levels on IgAN progression. This further supports the involvement of FHR-5 in the development and progression of IgAN. Prior to the present study, Medjeral-Thomas et al. investigated circulating FHR-5 levels in patients with IgAN and reported elevated FHR-5 levels in IgAN for the first time.17Medjeral-Thomas N.R. Lomax-Browne H.J. Beckwith H. et al.Circulating complement factor H-related proteins 1 and 5 correlate with disease activity in IgA nephropathy.Kidney Int. 2017; 92: 942-952Google Scholar Consistent with that report, we also observed significant higher FHR-5 levels in our Peking University IgAN cohort. Moreover, we found significant sex difference in FHR-5 levels in IgAN patients, but not in healthy controls. FHR-5 is synthesized in the liver,18McRae J.L. Duthy T.G. Griggs K.M. et al.Human factor H-related protein 5 has cofactor activity, inhibits C3 convertase activity, binds heparin and C-reactive protein, and associates with lipoprotein.J Immunol. 2005; 174: 6250-6256Scopus (98) Google Scholar as supported by high liver expression of FHR-5 in microarray expression data and RNA-Seq expression data using the UCSC Genome Browser (http://www.genome.ucsc.edu). Although binding sites for transcription factors PPAR-gamma1, PPAR-gamma2, Zic1, and POU3F1 were found in the CFHR5 gene promoter, as predicted by SABiosciences’ text mining application and the UCSC Genome Browser, no sex-associated factor was reported to influence FHR-5 expression. In North American and European cohorts, IgA nephropathy is more common in males by a ratio of about 2:1.19Roberts I.S. Pathology of IgA nephropathy.Nat Rev Nephrol. 2014; 10: 445-454Google Scholar For CFHR5 nephropathy, a disease caused by CFHR5 gene internal duplication, the number of men reaching ESRD is significantly larger than that of women.15Athanasiou Y. Voskarides K. Gale D.P. et al.Familial C3 glomerulopathy associated with CFHR5 mutations: clinical characteristics of 91 patients in 16 pedigrees.Clin J Am Soc Nephrol. 2011; 6: 1436-1446Google Scholar It seems that male sex accelerated the deterioration of both IgAN and CFHR5 nephropathy, but the underlying mechanism is still unclear. Another finding in our present study was the association between FHR-5 levels and both IgAN severity and progression. In our IgAN cohort, associations were observed for higher FHR-5 levels and several clinical and pathological features associated with IgAN severity, including eGFR, proportion of patients with hypertension, and Oxford T- and C-scores. Notably, when we compared FHR-5 levels between healthy controls and IgAN patients with normal renal function (CKD stage 1 and eGFR > 90 ml/min per 1.73 m2), we still found significant elevated FHR-5 in IgAN patients. Moreover, no correlation was found in circulating CFHR5 levels and eGFR in diabetic nephropathy patients. This indicates that patients with IgAN have elevated FHR-5 expression, independent of impaired renal clearance. In another European IgAN cohort, Medjeral-Thomas et al. also reported the association of FHR5 levels with higher overall Oxford classification
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