CD71 mesangial IgA1 receptor and the progression of IgA nephropathy

The transferrin receptor (CD71) is known as a for IgA1 on mesangial cells, but the role of CD71 in IgA nephropathy (IgAN) unknown. We studied clinical implication 282 patients with biopsy-proven IgAN (2005–2018). transcript and protein expression glomerular was determined by real-time polymerase chain reaction immunohistochemistry. Ten subjects microscopic hematuria only no evidence histologic abnormalities kidney biopsy were considered controls. Human cells (HMCs) treated sera from levels inflammatory cytokine markers compared according to disease status. Disease progression defined ?30% decline estimated filtration rate baseline value. During mean follow up 53.5 (18.3–75.9) months, 80 (28.4%) developed progression. mRNA significantly higher progressors than nonprogressors (P = 0.001). Among Oxford classification scores, M1 had those M0. In multivariable Cox model, elevated associated 4.32-fold risk 0.009). Furthermore, independently predicted increase proteinuria ?50% 0.03). Finally, HMCs score (M1E1S1T0) more increased negative (M0E0S0T0). However, silencing reduced genes. Our results show that may play biologic IgAN. AT A GLANCE COMMENTARYJhee JH, et al.BackgroundThis study demonstrated level Glomerular adverse renal outcomes such nephropathy. human resulted genes, which attenuated CD71.Translational SignificanceThese findings suggest substantial prognostic triggering factor injury Jhee al. This CD71. These most prevalent primary worldwide.1Wyatt RJ Julian BA nephropathy.N Engl J Med. 2013; 368: 2402-2414Crossref PubMed Scopus (703) Google Scholar, 2Donadio JV Grande JP 2002; 347: 738-748Crossref (666) 3Yim T Kim S-U Park S al.Patterns diseases diagnosed biopsy: single-center experience.Kidney Res Clin Pract. 2020; 39: 60-69Crossref (14) Scholar Most are asymptomatic less aggressive feature other rapidly progressive glomerulonephritis usually benign course. can progress failure approximately 30% eventually require dialysis or transplantation end within 20 years after diagnosis.4Li PK Ho KK Szeto CC Yu L Lai FM Prognostic indicators Chinese–clinical pathological perspectives.Nephrol Dial Transplant. 17: 64-69Crossref (140) 5Donadio Jr., Immunoglobulin nephropathy: perspective.J Am Soc Nephrol. 1997; 8: 1324-1332PubMed 6Coppo R D'Amico G Factors predicting nephropathies.J 2005; 18: 503-512PubMed pathogenesis complicated multistep process.7Floege Moura IC Daha MR New insights into nephropathy.Semin Immunopathol. 2014; 36: 431-442Crossref (41) First, poorly galactosylated hinge region produced circulation. Then, IgG antibodies generated against this misglycated drive formation large immune-complex. Subsequently, pathogenic immune-complexes deposited mesangium via interaction receptors Upon binding receptors, complement pathway activated along sequential cascades damage structures, lead terminal fibrotic process. To date, several IgA-binding molecules have been identified.8Lechner SM Papista C Chemouny JM Berthelot Monteiro RC Role nephropathy.J 2016; 29: 5-11Crossref (23) include Fc (Fc?RI; CD89),9Launay P Grossetete B Arcos-Fajardo M al.Fc alpha (CD89) mediates development immunoglobulin (IgA) (Berger's disease). Evidence soluble receptor-IgA complexes CD89 transgenic mice.J Exp 2000; 191: 1999-2009Crossref (202) polymeric-Ig (pIgR),10Yanagihara Kumagai Y Norose al.Age-dependent decrease polymeric Ig elevation ddY mice: possible cause nephropathy.Lab Invest. 2004; 84: 63-70Crossref (11) Fc?/?R,11McDonald KJ Cameron AJ Allen Jardine AG Expression alpha/mu cells: candidate immune complex deposition nephropathy.Biochem Biophys Commun. 290: 438-442Crossref (69) asialoglycoprotein receptor,12Gomez-Guerrero Duque N Egido Mesangial possess an affinity A.J 1998; 9: 568-576PubMed ?1,4-galactosyltransferase 1,13Molyneux K Wimbury D Pawluczyk I al.Beta1,4-galactosyltransferase 1 novel cells.Kidney Int. 2017; 92: 1458-1468Abstract Full Text PDF (35) (CD71).14Moura Centelles MN al.Identification (Ig)A1 its enhanced 2001; 194: 417-425Crossref (225) these, found has regarded pathologic fact, multiligand binds transferrin, hemochromatosis protein, arenavirus.15Coulon Dussiot Grapton al.Polymeric controls erythroblast proliferation accelerates erythropoiesis recovery anemia.Nat 2011; 1456-1465Crossref (56) Moreover, expressed functions receptor. Its undergalactosylated immune-complex containing induce activation ignite process glomeruli IgAN.14Moura Scholar,16Haddad E al.Enhanced Berger Henoch-Schonlein nephritis: association between deposits.J 2003; 14: 327-337Crossref (84) spite potential CD71, little about outcomes. there one study, colocalized strongly proliferative lesion.16Haddad Notably, relationship degree findings. cross-sectional 16 patients. With background, we aimed investigate longitudinal observation cohort. also whether plays total 344 2005 2018 eligible study. Demographic laboratory data obtained Glomerulonephritis Registry Yonsei University Health System (YUHS). flow diagram depicting participant selection presented Supplementary Figure 1. excluded 62 who met following criteria: (1) aged <18 years, (2) inadequate sample number <7, (3) previous history transplantation, (4) stage at time diagnosis, (5) (eGFR) <15 mL/min/1.73 m2, 6) Secondary conditions infection-associated combined autoimmune including Henoch–Schönlein purpura, systemic lupus nephritis, rheumatoid arthritis, Sjogren's syndrome, IgG4-related disease, ankylosing spondylitis. Thus, included analysis. All enrolled voluntarily, informed consent all cases. carried out accordance Declaration Helsinki approved institutional review board YUHS Clinical Trial Center (4-2019-0548). Using database YUHS, demographic, clinical, biochemical age, sex, blood pressure (BP), body mass index (BMI), past medical history, medication retrieved data. eGFR using CKD Epidemiologic Collaboration equation.17Levey AS Stevens LA Schmid CH al.A new equation estimate rate.Ann Intern 2009; 150: 604-612Crossref (14803) Spot urine test creatinine performed AU680 analyzer (Beckman Coulter Inc., CA, USA) quantified ratio (UPCR). Follow-up BP, UPCR, recorded 3-month interval visits. specimens reassessed pathologist blinded patients’ classification. For detailed methods, see Supplemental Material. Immortalized purchased Applied Biological Materials Inc. (Richmond, BC, Canada). cultured RPMI 1640 medium 10% FBS (Gibco), 100 U/mL penicillin (Sigma-Aldrich, UK), 2.5 ?g/mL amphotericin ng/mL EGF UK). Sera control (n 3) lower (M0M0S0T0) 3). Serum samples prepared µg/mL methods previously described then given HMCs.18Schmitt Stahl AL Olin AI al.The galactose-deficient streptococcal Protein inducing IL-6 C3 secretion implications Immunol. 193: 317-326Crossref (39) harvested 24 hours incubation. (PCR) compare fibronectin, IL-6, tumor necrosis factor-alpha (TNF-?), monocyte chemoattractant protein-1 (MCP-1). sequences primers used Table short interfering RNA (siRNA) (ON_TARGETplus SMARTpool, Dharmacon, CO, further exam changes profibrotic marker genes knockdown gene. transfected Lipofectamine 2000 (Invitrogen Co., Carlsbad, hours. incubated media harvested. endpoint onset during follow-up. sustained least 2 consecutive measurements. first these measurements retrospectively designated endpoint. Accordingly, reached progressor group. secondary baseline. statistical analyses IBM SPSS software Windows version 23.0 (IBM Corporation, Armonk, NY, 3.3.1 (http://www.R-project.org). Continuous variables ± standard deviation median (interquartile range), categorical absolute numbers percentages. Each variable tested normality before Comparisons groups made analysis variance Student's t continuous variables, chi-square Fisher's exact variables. Kolmogorov–Smirnov determine distribution parameters. If resulting did not normal distribution, geometric reported; Mann–Whitney U-test Kruskal–Wallis multiple comparisons. gene nonprogressor examined group vs nonincreased assess utility model conducted evaluate reduction levels. Proportional hazards assumptions confirmed Schoenfeld residuals. Variables value <0.10 univariable clinically important adjustment. Patients lost follow-up censored date last examination. hazard ratios (HRs) developing increment >50% assessed variable. Because BP highly follow-up, modeled time-varying exposures. analyses, <0.05 statistically significant. IgAN, age 40.4 13.3 55.7% male, 89.9 26.9 m2. Baseline characteristics 80, 28.4%) 202, 71.6%) (Table 1). At biopsy, older, likely be male hypertension nonprogressors. components, M, E, scores addition, (73.7 26.0 96.4 24.5 <0.001). UPCR (2.0 1.7 1.0 1.9 g/g Cr, <0 .001), hemoglobin (12.1 1.6 g/dL, <0.001) serum albumin (3.8 0.5 4.1 0.6 take medications RAS blockades, statin, diuretics, corticosteroids significant differences BMI, systolic diastolic BPs (SBP DBP), uric acid, fasting plasma glucose, cholesterol, hs-CRP, groups.Table 1Baseline characteristicsTotal (N 282)Nonprogressors 202)Progressors 80)PDemographic Age, years40.4 13.338.8 13.444.7 12.20.01 Male157 (55.7)105 (52.0)52 (65.0)0.03 kg/m223.1 3.222.9 3.323.5 3.20.26 SBP, mm Hg125.7 16.5124.8 16.5127.8 16.30.16 DBP, Hg79.8 11.879.4 11.981.0 11.50.31 Hypertension, n (%)169 (59.9)111 (55.0)58 (72.5)0.01Oxford M135 (16.1)13 (8.3)22 (35.5)<0.001 E165 (29.7)42 (26.9)23 (36.5)0.11 S1146 (66.7)97 (62.2)49 (77.8)0.02 T114 (6.4)7 (4.5)7 (11.1)<0.001 T25 (2.3)0 (0.0)5 (7.9)Laboratory eGFR, m289.9 26.996.4 24.573.7 26.0<0.001 categories<0.001 ?90 m2160 (56.7)135 (66.8)25 (31.3) 60–90 m273 (25.9)45 (22.3)28 (35.0) 30–60 m245 (16.0)22 (10.9)23 (28.7) <30 m24 (1.4)0 (0.0)4 (5.0) g/gCr1.3 1.91.0 1.92.0 1.7<0.001 Hemoglobin, g/dL13.0 1.713.3 1.612.1 Albumin, g/dL4.0 0.64.1 0.63.8 0.5<0.001 Uric mg/dL5.5 1.65.3 1.55.8 1.90.06 Fasting mg/dL96.4 14.995.5 13.898.8 17.50.09 Total mg/dL189.7 46.8189.5 50.5190.2 36.20.90 mg/dL0.71 (0.34–1.37)0.53 (0.23–0.96)1.32 (0.71–3.14)0.87 IgA, mg/dL327.5 125.0323.3 121.1131.8 80.10.47Medication usage, (%) blockades216 (77.4)141 (70.9)75 (93.8)<0.001 Statin100 (35.8)52 (26.1)48 (60.0)<0.001 Diuretics30 (10.8)11 (5.5)19 (23.8)<0.001 Corticosteroids45 (16.1)16 (8.0)29 (36.3)<0.001Note: Data deviation, range) (%)Abbreviations: index; pressure; rate; high sensitivity C-reactive protein; RAS, renin-angiotensin system; ratio. Open table tab Note: Abbreviations: Next, comparison, measured 10 Alport syndrome thin basement membrane Real-time PCR revealed Interestingly, without 0.01) (Fig level. Immunohistochemical staining showed similar pattern observed quantitative mainly cytoplasm cells. intensity stronger 2, A–C). different among 4 Oxford-MEST lesions. M0 (0.34 0.07 0.20 0.03, 0.03) (Supplementary 2). S, lesions, presence absence each lesion. evaluated disease. eGFR. Unadjusted HR reaching 5.00 (95% confidence [CI], 1.94–12.83; adjusted hemoglobin, albumin, usage blockade, corticosteroid, (HR per log (CD71/18S) increase, 4.32; 95% CI, 1.43–13.02; 0.009) 2).Table 2Multivariable models levelsModel 1Model 2Model 3Model 4HR CI)PHR CI)PCD71, increase5.10 (1.94–13.42)0.0015.00 (1.94–12.83)0.0014.61 (1.64–12.90)0.0044.32 (1.43–13.02)0.009Note: represents log-transformed normalized 18S variable.Model 1: model.Model 2: Adjusted Model + sex.Model 3: cholesterol.Model 4: 3 corticosteroid.Abbreviations: interval; HR, ratio; model. sex. cholesterol. corticosteroid. our reported lesion persistent lesions IgAN.19Yoon CY Chang TI Kang EW al.Clinical usefulness determining immunosuppressive treatment nephropathy.Ann 49: 217-229Crossref (7) Given above, proteinuria. categorized groups, depending Based cut-off value, 46 (16.3%) period. non-increased (0.47 0.26 0.19 0.02, 0.02) substantiated regression 3.99 1.75–9.13, 0.01). 3.04; 1.07–8.60; could HMCs. As shown Fig 3, inflammation (M0E0S0T0) 3A). TNF-?, MCP-1 concomitantly response B–E). siRNA 4, A–E).Fig 4Silencing (A) (B) (C, D, E) (*P Abbreviation: nephropathy; siRNA, RNA; FN,fibronectin; factor-alpha; MCP-1, protein-1View Large Image ViewerDownload Hi-res image Download (PPT) components classification, expression. featured processes. Misglycated IgA1-containing formed circulation deposits mesangium. sequentially induces cell proliferation, matrix expansion, infiltration intraglomerular interstitial cells.20Barratt Smith AC Molyneux Feehally Immunopathogenesis IgAN.Semin 2007; 427-443Crossref (60) Several studies tried stop processes experimental IgAN.21Moldoveanu Z Wyatt Lee JY al.Patients levels.Kidney 71: 1148-1154Abstract (274) 22Novak Tomana Matousovic al.IgA1-containing differentially affect 67: 504-513Abstract (170) 23Gomez-Guerrero Lopez-Armada MJ Gonzalez Soluble aggregates catabolized rat production TNF-alpha proliferation.J 1994; 153: 5247-5255PubMed available drugs specifically targ