Clinical Use of Complement, Inflammation, and Fibrosis Biomarkers in Autoimmune Glomerulonephritis.
Khalili Myriam,Bonnefoy Arnaud,Genest Dominique S,Quadri Jérémy,Rioux Jean-Philippe,Troyanov Stéphan
Kidney international reports
Introduction:Complement activation, inflammation, and fibrosis play central roles in the mechanisms of injury in autoimmune glomerulonephritis (GN) but they are seldom assessed in epidemiologic studies. The measurement of urinary biomarkers of these pathways of injury could parallel disease activity and add clinical value beyond proteinuria. Methods:We performed a prospective cohort study of 100 patients with focal and segmental glomerulosclerosis (FSGS), membranous nephropathy (MN), IgA nephropathy (IgAN), lupus nephritis (LN), anti-neutrophil cytoplasmic autoantibody-associated vasculitis (AAV), and membranoproliferative GN (MPGN) followed for 33 (18-54) months. Repeated urinary samples were collected throughout their follow-up to determine proteinuria, urinary sC5b-9, monocyte chemoattractant protein-1 (MCP-1), and transforming growth factor-beta 1 (TGF-β1), expressed as creatinine ratios. We identified 177 periods of active and inactive disease based on current remission definitions for each disease. Results:Urinary sC5b-9, MCP-1, and TGF-β1 were present in each disease. In periods leading to a remission, the reduction of urinary sC5b-9 was 91%, greater than for proteinuria with 76%. During inactive periods, those who did not experience a relapse maintained lower levels of biomarkers compared with those who relapsed. At that time, the increase in urinary sC5b-9 was significantly greater than the rise in proteinuria (8.5-fold increase compared with 3.2-fold) and urinary MCP-1 and TGF-β1. Using current remission definitions for each disease, thresholds for each biomarker were determined using receiver operating characteristic curves. Individuals who averaged levels below these cutoffs during their follow-up had better renal outcomes. Conclusion:In autoimmune glomerular diseases, urinary sC5b-9, MCP-1, and TGF-β1 are present and parallel disease activity and outcomes. Urinary sC5b-9 appears to be a more discerning marker of immunologic remissions and relapses.
Early proteinuria response: a valid real-life situation predictor of long-term lupus renal outcome in an ethnically diverse group with severe biopsy-proven nephritis?
Ugolini-Lopes Michelle R,Seguro Luciana Parente C,Castro Maitê Xavier F,Daffre Danielle,Lopes Alex C,Borba Eduardo F,Bonfá Eloisa
Lupus science & medicine
Objective:Two recent important lupus nephritis trials reported that proteinuria was a good predictor of renal outcome in Caucasians, but data on real-life situation, other races and severe nephritis are lacking to substantiate this finding as a simple test to guide clinical practice. The aim of this study was to validate proteinuria as a predictor of long-term renal outcome in real-life situation in a racially diverse group of patients with severe nephritis. Methods:Proteinuria, serum creatinine (SCr) and urine red blood cells were assessed at baseline and after 3, 6 and 12 months, as early predictors of long-term renal outcome (SCr <1.5 mg/dL at 7 years), in 94 patients with biopsy-proven lupus nephritis. The parameter performance and cut-off values were computed by receiver operating characteristic curves. Kaplan-Meier curves were used to validate the parameter. Results:A proteinuria <0.8 g/24 hours at 12 months was the best single predictor of long-term renal outcome (sensitivity 90%, specificity 78%, positive predictive value 67%, negative predictive value (NPV) 94% and area under the curve 0.86; p<0.001). Addition of other variables to proteinuria such as SCr and haematuria at 12 months did not improve its performance. The proteinuria cut-off value of 0.8 g/24 hours at 12 months was a good predictor of 7-year renal survival (years free of dialysis) for patients with pure membranous (p=0.005) and proliferative nephritis (p=0.043), as well as black (p=0.002) and white race (p=0.001), anti-dsDNA positive (p=0.001) and anti-dsDNA negative (p=0.04) and male (p=0.028) and female (p=0.003) patients. Conclusion:We provided novel evidence that, in a real-life situation, proteinuria at 12 months of follow-up was the single best predictor of renal outcome at 7 years for an ethnically diverse group of patients with severe nephritis and a valid parameter for distinct histological classes, races, genders and anti-dsDNA profiles. The remarkably high NPV obtained reinforces its recommendation as the ideal predictor for clinical practice, since it is of low cost, easy to interpret, non-invasive and widely available.
Predictors of Good Long-Term Renal Outcomes in Lupus Nephritis: Results from a Single Lupus Cohort.
Fung William A,Su Jiandong,Touma Zahi
BioMed research international
This study aims to elucidate the predictive capabilities of proteinuria, serum creatinine (Cr), and urine RBCs (uRBCs) with respect to long-term renal outcomes in lupus nephritis (LN) in patients followed in clinic. . A retrospective analysis was performed on patients with LN. We evaluated the ability of proteinuria, serum Cr, and uRBCs at 12 months to predict good long-term renal outcomes defined as serum Cr ≤ 100 mmol/L and kidney transplant/dialysis-free at the 7th year. Receiver operator characteristic curves were generated for proteinuria, serum Cr, and uRBCs to study their ability to predict good long-term outcomes and to identify their best cut-off. Descriptive statistics studied the pattern of change of proteinuria and serum Cr. . Proteinuria of 0.6 g/d and Cr of 83 mmol/L performed independently moderately well in predicting good long-term renal outcomes while uRBC was less accurate. Combining serum Cr to proteinuria gave a small increase in positive predictive value with a trade-off in sensitivity. Proteinuria changed within the first year whereas serum Cr changed until the 7th year. . Both proteinuria and Cr predict good long-term renal outcomes in LN. Proteinuria's ability to change faster at 12 months makes it a favorable endpoint for clinical trials and research studies.
The Impact of Baseline Serum Creatinine on Complete Remission Rate and Long-Term Outcome in Patients with Severe Lupus Nephritis.
,Korbet Stephen M,Whittier William L,Lewis Edmund J
BACKGROUND/AIM:We assess the impact of serum creatinine at baseline on complete remission rate and long-term outcome in severe lupus nephritis (SLN). METHODS:A total of 86 adult patients with SLN [International Society of Nephrology/Renal Pathology Society (ISN/RPS) class IV lesions] were evaluated based on baseline serum creatinine levels (≤1.0, 1.01-1.5, 1.51-2.0, 2.01-3.0, and >3.0 mg/dl; n = 22, 23, 16, 12, and 13, respectively). The complete remission rates (serum creatinine level of ≤1.4 mg/dl and proteinuria of ≤0.33 g/day) and long-term outcomes (stable renal function, dialysis, and death) were compared. The patients were followed for 121 ± 64 months. RESULTS:The baseline clinical features were similar, but the chronicity index was significantly higher with increasing levels of serum creatinine. Complete remission rates were significantly higher in patients with lower levels of serum creatinine (86 vs. 52 vs. 19 vs. 25 vs. 0%, p < 0.0001). Patients with a baseline serum creatinine level of ≤1.0 mg/dl were >16 times as likely (OR 16.2; 95% CI: 4.2-61.5) to attain a complete remission and >6 times as likely (OR 6.1; 95% CI: 1.9-18.6) to have stable renal function at the last follow-up as compared to patients with a serum creatinine level of >1.0 mg/dl. The 15-year renal survival rate was greatest among those patients with a baseline serum creatinine level of ≤1.0 mg/dl (76 vs. 57 vs. 48 vs. 25 vs. 10%, p < 0.0001). CONCLUSION:The prognosis of SLN is significantly affected by the serum creatinine level at baseline. The complete remission rate is highest, and the long-term prognosis most favorable, in patients with a baseline serum creatinine level of ≤1.0 mg/dl. This emphasizes the importance of early diagnosis and treatment.
Podocyte foot process width is a prediction marker for complete renal response at 6 and 12 months after induction therapy in lupus nephritis.
Ichinose Kunihiro,Kitamura Mineaki,Sato Shuntaro,Fujikawa Keita,Horai Yoshiro,Matsuoka Naoki,Tsuboi Masahiko,Nonaka Fumiaki,Shimizu Toshimasa,Fukui Shoichi,Umeda Masataka,Koga Tomohiro,Kawashiri Shin-Ya,Iwamoto Naoki,Igawa Takashi,Tamai Mami,Nakamura Hideki,Origuchi Tomoki,Nishino Tomoya,Kawakami Atsushi
Clinical immunology (Orlando, Fla.)
Morphological change that includes diffuse effacement of podocyte foot processes is correlated with proteinuria in patients with lupus nephritis (LN). We collected the data of clinico-pathological parameters and assessed foot process width (FPW) as an index of podocyte effacement in 73 patients with LN who had undergone renal biopsy. The multivariate analysis revealed that female gender (OR: 5.288; 95%CI: 1.197-37.29; p = .0267) and FPW (OR = 0.999, 95%CI = 0.997-0.999, p = .0150) were significantly predictive of a complete renal response (CR) at 6 months, while lymphocyte counts (OR = 1.002; 95%CI = 1.001-1.003, p = .0028) and FPW (OR = 0.998, 95%CI = 0.996-0.999, p = .0027) were significantly predictive of CR at 12 months. The cut-off point determined by the Classification and Regression Trees algorithm showed that FPW <908.3 nm provides the best performance for predicting patients who achieve CR at 12 months. A smaller FPW appears to be a predictive factor for CR at 6 and 12 months after induction therapy.
Chronicity index, especially glomerular sclerosis, is the most powerful predictor of renal response following immunosuppressive treatment in patients with lupus nephritis.
Park Dong-Jin,Choi Sung-Eun,Xu Haimuzi,Kang Ji-Hyoun,Lee Kyung-Eun,Lee Ji Shin,Choi Yoo-Duk,Lee Shin-Seok
International journal of rheumatic diseases
AIM:Renal responses to immunosuppressive agents in patients with lupus nephritis (LN) differ depending on ethnicity, follow-up duration, disease severity and treatment. Thus, we evaluated predictors of complete remission during the first year following immunosuppressive treatment in patients with LN. METHODS:We retrospectively reviewed 79 patients who underwent kidney biopsy prior to the start of induction treatment and who were subsequently treated with immunosuppressive drugs for at least 6 months and followed-up for more than a year. Complete remission (CR) was defined as inactive urinary sediment, a decrease in urinary protein to a creatinine ratio < 0.2, and normal or stable renal function. Multivariate analyses were performed using the logistic regression model to identify independent predictors of CR in LN patients. RESULTS:After 1 year, renal response was achieved in 39 of 79 patients (49.4%) treated with immunosuppressive drugs. Intravenous cyclophosphamide was most commonly used as a treatment, followed in descending order of frequency by mycophenolate mofetil, azathioprine and cyclosporine. CR was associated with disease duration at the onset of LN, serum erythrocyte sedimentation rate, chronicity index on renal histology, glomerular sclerosis, tubular atrophy, interstitial fibrosis, and the use of hydroxychloroquine at the onset of LN. In multivariable regression analysis, glomerular sclerosis in the chronicity index was a significant predictor of complete remission in LN patients. CONCLUSION:Our findings suggest that glomerular sclerosis in the chronicity index is an independent predictor of CR after the start of therapy in LN patients.
Histologic versus clinical remission in proliferative lupus nephritis.
Malvar Ana,Pirruccio Paola,Alberton Valeria,Lococo Bruno,Recalde Cecilia,Fazini Bernanda,Nagaraja Haikady,Indrakanti Divya,Rovin Brad H
Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association
Background:Treatment response in lupus nephritis (LN) is defined clinically, without consideration of renal histology. Few studies have systematically examined histologic responses to induction therapy. In LN patients who underwent protocol kidney biopsies after induction immunosuppression, we describe the renal histology of the second biopsy and correlate histologic activity and damage with short- and long-term kidney outcomes. Methods:Patients with suspected LN were biopsied for diagnosis (Biopsy 1), and those with proliferative LN were rebiopsied after induction (Biopsy 2). Histologic activity and damage at each biopsy were calculated as the National Institutes of Health activity and chronicity indices. Complete and partial renal responses after induction and after long-term follow-up were determined clinically. Results:One-third of patients who achieved a complete clinical response after induction had persistently high histologic activity, and 62% of patients who had complete histologic remission on rebiopsy were still clinically active. Chronic renal damage increased after induction even in complete clinical responders. Chronicity at Biopsy 2 associated with long-term kidney function and development of chronic kidney disease. Conclusions:Early clinical and histologic outcomes are discordant in proliferative LN, and neither correlates with long-term renal outcome. The kidney accrues chronic damage rapidly and despite clinical response in LN. Preservation of kidney function may require therapeutic targeting of both chronic damage and inflammation during LN induction treatment.
What is damaging the kidney in lupus nephritis?
Nature reviews. Rheumatology
Despite marked improvements in the survival of patients with severe lupus nephritis over the past 50 years, the rate of complete clinical remission after immune suppression therapy is <50% and renal impairment still occurs in 40% of affected patients. An appreciation of the factors that lead to the development of chronic kidney disease following acute or subacute renal injury in patients with systemic lupus erythematosus is beginning to emerge. Processes that contribute to end-stage renal injury include continuing inflammation, activation of intrinsic renal cells, cell stress and hypoxia, metabolic abnormalities, aberrant tissue repair and tissue fibrosis. A deeper understanding of these processes is leading to the development of novel or adjunctive therapies that could protect the kidney from the secondary non-immune consequences of acute injury. Approaches based on a molecular-proteomic-lipidomic classification of disease should yield new information about the functional basis of disease heterogeneity so that the most effective and least toxic treatment regimens can be formulated for individual patients.
Long-term follow-up of the MAINTAIN Nephritis Trial, comparing azathioprine and mycophenolate mofetil as maintenance therapy of lupus nephritis.
Tamirou Farah,D'Cruz David,Sangle Shirish,Remy Philippe,Vasconcelos Carlos,Fiehn Christoph,Ayala Guttierez Maria del Mar,Gilboe Inge-Magrethe,Tektonidou Maria,Blockmans Daniel,Ravelingien Isabelle,le Guern Véronique,Depresseux Geneviève,Guillevin Loïc,Cervera Ricard,Houssiau Frédéric A,
Annals of the rheumatic diseases
OBJECTIVE:To report the 10-year follow-up of the MAINTAIN Nephritis Trial comparing azathioprine (AZA) and mycophenolate mofetil (MMF) as maintenance therapy of proliferative lupus nephritis, and to test different definitions of early response as predictors of long-term renal outcome. METHODS:In 2014, data on survival, kidney function, 24 h proteinuria, renal flares and other outcomes were collected for the 105 patients randomised between 2002 and 2006, except in 13 lost to follow-up. RESULTS:Death (2 and 3 in the AZA and MMF groups, respectively) and end-stage renal disease (1 and 3, respectively) were rare events. Time to renal flare (22 and 19 flares in AZA and MMF groups, respectively) did not differ between AZA and MMF patients. Patients with good long-term renal outcome had a much more stringent early decrease of 24 h proteinuria compared with patients with poor outcome. The positive predictive value of a 24 h proteinuria <0.5 g/day at 3 months, 6 months and 12 months for a good long-term renal outcome was excellent (between 89% and 92%). Inclusion of renal function and urinalysis in the early response criteria did not impact the value of early proteinuria decrease as long-term prognostic marker. CONCLUSIONS:The long-term follow-up data of the MAINTAIN Nephritis Trial do not indicate that MMF is superior to AZA as maintenance therapy in a Caucasian population suffering from proliferative lupus nephritis. Moreover, we confirm the excellent positive predictive value of an early proteinuria decrease for long-term renal outcome. TRIAL REGISTRATION NUMBER:NCT00204022.
Definition and initial validation of a Lupus Low Disease Activity State (LLDAS).
Franklyn Kate,Lau Chak Sing,Navarra Sandra V,Louthrenoo Worawit,Lateef Aisha,Hamijoyo Laniyati,Wahono C Singgih,Chen Shun Le,Jin Ou,Morton Susan,Hoi Alberta,Huq Molla,Nikpour Mandana,Morand Eric F,
Annals of the rheumatic diseases
AIMS:Treating to low disease activity is routine in rheumatoid arthritis, but no comparable goal has been defined for systemic lupus erythematosus (SLE). We sought to define and validate a Lupus Low Disease Activity State (LLDAS). METHODS:A consensus definition of LLDAS was generated using Delphi and nominal group techniques. Criterion validity was determined by measuring the ability of LLDAS attainment, in a single-centre SLE cohort, to predict non-accrual of irreversible organ damage, measured using the Systemic Lupus International Collaborating Clinics Damage Index (SDI). RESULTS:Consensus methodology led to the following definition of LLDAS: (1) SLE Disease Activity Index (SLEDAI)-2K ≤4, with no activity in major organ systems (renal, central nervous system (CNS), cardiopulmonary, vasculitis, fever) and no haemolytic anaemia or gastrointestinal activity; (2) no new lupus disease activity compared with the previous assessment; (3) a Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA)-SLEDAI physician global assessment (scale 0-3) ≤1; (4) a current prednisolone (or equivalent) dose ≤7.5 mg daily; and (5) well tolerated standard maintenance doses of immunosuppressive drugs and approved biological agents. Achievement of LLDAS was determined in 191 patients followed for a mean of 3.9 years. Patients who spent greater than 50% of their observed time in LLDAS had significantly reduced organ damage accrual compared with patients who spent less than 50% of their time in LLDAS (p=0.0007) and were significantly less likely to have an increase in SDI of ≥1 (relative risk 0.47, 95% CI 0.28 to 0.79, p=0.005). CONCLUSIONS:A definition of LLDAS has been generated, and preliminary validation demonstrates its attainment to be associated with improved outcomes in SLE.
Clinical characteristics and renal prognosis associated with interstitial fibrosis and tubular atrophy (IFTA) and vascular injury in lupus nephritis biopsies.
Leatherwood Cianna,Speyer Cameron B,Feldman Candace H,D'Silva Kristin,Gómez-Puerta José A,Hoover Paul J,Waikar Sushrut S,McMahon Gearoid M,Rennke Helmut G,Costenbader Karen H
Seminars in arthritis and rheumatism
BACKGROUND:Interstitial fibrosis and tubular atrophy (IFTA) and vascular injury are frequent histologic features of lupus nephritis renal biopsies, but their clinical correlates and prognostic value are not well understood. This cohort study investigated demographic, clinical and laboratory characteristics, and outcomes, associated with IFTA and vascular injury in lupus nephritis. METHODS:Reports of all renal biopsies performed at an academic medical center (1990-2017) with WHO/ISN/RPS Class II-V lupus nephritis were reviewed. Demographics, clinical variables and labs at biopsy, treatment, and date of death were collected. Additional data from the U.S. Renal Data System (USRDS) provided dates of ESRD and death after ESRD. Multivariable regression analyses identified demographic and clinical factors associated with each histologic finding. Cumulative incidence functions and multivariable Cox proportional hazard models estimated the risk of progression to ESRD and death. RESULTS:Within 202 initial biopsies, IFTA was associated with the patient's SLICC/ACR damage index (without renal domain) and serum creatinine, and vascular injury was associated with serum creatinine in multivariable models. In Cox regression models adjusting for age, sex, race, serum creatinine, calendar year, and biopsy class, moderate/severe IFTA was associated with elevated ESRD (HR 5.18, 95% CI 2.53, 10.59) and death (HR 4.19, 95%CI 1.27, 13.81). After adjustment for age, sex and race, moderate/severe vascular injury was associated with ESRD (HR 2.13, 95% CI 1.21, 3.75) and but this relationship was not significant after adjustment for serum creatinine and calendar year. CONCLUSIONS:IFTA is a strong predictor of ESRD and death, even in proliferative nephritis, and a risk factor for poor outcomes independent of class. Vascular injury is a strong predictor of prognosis, but not independent of serum creatinine and class. The prognostic value of these lesions calls for consideration when determining treatment for lupus nephritis.
Comparison of the 2018 and 2003 International Society of Nephrology/Renal Pathology Society classification in terms of renal prognosis in patients of lupus nephritis: a retrospective cohort study.
Umeda Ryosuke,Ogata Soshiro,Hara Shigeo,Takahashi Kazuo,Inaguma Daijo,Hasegawa Midori,Yasuoka Hidetaka,Yuzawa Yukio,Hayashi Hiroki,Tsuboi Naotake
Arthritis research & therapy
BACKGROUND:Although the 2018 revised International Society of Nephrology/Renal Pathology Society (ISN/RPS) classification was proposed recently, until now, no reports have been made comparing the association of renal prognosis between the 2018 revised ISN/RPS classification and the 2003 ISN/RPS classification. The present study aimed to assess the usefulness, especially of activity and chronicity assessment, of the 2018 revised ISN/RPS classification for lupus nephritis (LN) in terms of renal prognosis compared to the classification in 2003. METHODS:We retrospectively collected medical records of 170 LN patients from the database of renal biopsy at Fujita Health University from January 2003 to April 2019. Each renal biopsy specimen was reevaluated according to both the 2003 ISN/RPS classification and the 2018 revised ISN/RPS classification. Renal endpoint was defined as a 30% decline of estimated glomerular filtration rate (eGFR). RESULTS:A total of 129 patients were class III/IV±V (class III, 44 patients; class IV, 35 patients; class III/IV+V, 50 patients). The mean age was 42 years, 88% were female, and the median observation period was 50.5 months. Renal prognosis was significantly different among the classes and significantly poor in the patients with higher modified National Institute of Health (mNIH) chronicity index (C index, ≥ 4) by a log-rank test (p = 0.05 and p = 0.02, respectively). By Cox proportional hazard models, only the C index was significantly associated with renal outcome (hazard ratio 1.32, 95% CI 1.11-1.56, p ≤ 0.01), while the classes, the 2003 activity and chronicity subdivision, and the mNIH activity index had no significant association with renal outcome. Each component of the C index was significantly associated with renal outcome in different models. CONCLUSION:This study demonstrates that the 2018 revised ISN/RPS classification was more useful in terms of association with renal prognosis compared to the 2003 ISN/RPS classification.
Sensitivity and Specificity of Pathologic Findings to Diagnose Lupus Nephritis.
Kudose Satoru,Santoriello Dominick,Bomback Andrew S,Stokes M Barry,D'Agati Vivette D,Markowitz Glen S
Clinical journal of the American Society of Nephrology : CJASN
BACKGROUND AND OBJECTIVES:In 2012, the Systemic Lupus International Collaborating Clinics proposed that lupus nephritis, in the presence of positive ANA or anti-dsDNA antibody, is sufficient to diagnose SLE. However, this "stand-alone" kidney biopsy criterion is problematic because the ISN/RPS classification does not specifically define lupus nephritis. We investigated the combination of pathologic features with optimal sensitivity and specificity for the diagnosis of lupus nephritis. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS:Three hundred consecutive biopsies with lupus nephritis and 560 contemporaneous biopsies with nonlupus glomerulopathies were compared. Lupus nephritis was diagnosed if there was a clinical diagnosis of SLE and kidney biopsy revealed findings compatible with lupus nephritis. The control group consisted of consecutives biopsies showing diverse glomerulopathies from patients without SLE, including IgA nephropathy, membranous glomerulopathy, pauci-immune glomerulonephritis, membranoproliferative glomerulonephritis (excluding C3 GN), and infection-related glomerulonephritis. Sensitivity and specificity of individual pathologic features and combinations of features were computed. RESULTS:Five characteristic features of lupus nephritis were identified: "full-house" staining by immunofluorescence, intense C1q staining, extraglomerular deposits, combined subendothelial and subepithelial deposits, and endothelial tubuloreticular inclusions, each with sensitivity ranging from 0.68 to 0.80 and specificity from 0.8 to 0.96. The presence of at least two, three, or four of the five criteria had a sensitivity of 0.92, 0.8, and 0.66 for the diagnosis of lupus nephritis, and a specificity of 0.89, 0.95, and 0.98. CONCLUSIONS:In conclusion, combinations of pathologic features can distinguish lupus nephritis from nonlupus glomerulopathies with high specificity and varying sensitivity. Even with stringent criteria, however, rare examples of nonlupus glomerulopathies may exhibit characteristic features of lupus nephritis.
Autoantibodies against C-Reactive Protein Influence Complement Activation and Clinical Course in Lupus Nephritis.
Li Qiu-Yu,Li Hai-Yun,Fu Ge,Yu Feng,Wu Yi,Zhao Ming-Hui
Journal of the American Society of Nephrology : JASN
Autoantibodies against the major acute-phase reactant C-reactive protein (CRP) are frequently found in patients with lupus nephritis. Further defining the autoimmune epitopes on CRP may not only improve patient stratification but also, hint at mechanisms of CRP action. Herein, we show that amino acids 35-47 constitute the major epitope recognized by anti-CRP autoantibodies in patients with lupus nephritis. Notably, the presence of autoantibodies against amino acids 35-47 associated with more severe renal damage and predicted worse outcome. This epitope is exposed on CRP only after irreversible structure changes, yielding a conformationally altered form termed modified or monomeric CRP (mCRP). ELISA and surface plasmon resonance assays showed that amino acids 35-47 mediate the interaction of mCRP with complement factor H, an inhibitor of alternative pathway activation, and this interaction greatly enhanced the cofactor activity of complement factor H. In contrast, autoantibodies against amino acids 35-47 inhibited these actions of mCRP. Our results thus provide evidence for the generation of mCRP in a human disease and suggest that mCRP actively controls the pathogenesis of lupus nephritis by regulating complement activation. Therefore, amino acids 35-47 constitute a functional autoimmune epitope on CRP that can be targeted therapeutically and diagnostically.
Changing patterns in clinical-histological presentation and renal outcome over the last five decades in a cohort of 499 patients with lupus nephritis.
Moroni Gabriella,Vercelloni Paolo Gilles,Quaglini Silvana,Gatto Mariele,Gianfreda Davide,Sacchi Lucia,Raffiotta Francesca,Zen Margherita,Costantini Gloria,Urban Maria Letizia,Pieruzzi Federico,Messa Piergiorgio,Vaglio Augusto,Sinico Renato Alberto,Doria Andrea
Annals of the rheumatic diseases
OBJECTIVES:To evaluate changes in demographic, clinical and histological presentation, and prognosis of lupus nephritis (LN) over time. PATIENTS AND METHODS:We studied a multicentre cohort of 499 patients diagnosed with LN from 1970 to 2016. The 46-year follow-up was subdivided into three periods (P): P1 1970-1985, P2 1986-2001 and P3 2002-2016, and patients accordingly grouped based on the year of LN diagnosis. Predictors of patient and renal survival were investigated by univariate and multivariate proportional hazards Cox regression analyses. Survival curves were compared using the log-rank test. RESULTS:A progressive increase in patient age at the time of LN diagnosis (p<0.0001) and a longer time between systemic lupus erythematosus onset and LN occurrence (p<0.0001) was observed from 1970 to 2016. During the same period, the frequency of renal insufficiency at the time of LN presentation progressively decreased (p<0.0001) and that of isolated urinary abnormalities increased (p<0.0001). No changes in histological class and activity index were observed, while chronicity index significantly decreased from 1970 to 2016 (p=0.023). Survival without end-stage renal disease (ESRD) was 87% in P1, 94% in P2% and 99% in P3 at 10 years, 80% in P1 and 90% in P2 at 20 years (p=0.0019). At multivariate analysis, male gender, arterial hypertension, absence of maintenance immunosuppressive therapy, increased serum creatinine, and high activity and chronicity index were independent predictors of ESRD. CONCLUSIONS:Clinical presentation of LN has become less severe in the last years, leading to a better long-term renal survival.
Proteinuria selectivity index as a prognostic biomarker in lupus nephritis.
Hasegawa T,Suzuki K,Kaneko Y,Takeuchi T
Objectives The selectivity index has been proposed in predicting the response to immunosuppressive therapy in nephrotic syndrome and other primary kidney disorders. The aim of this study was to elucidate the predictive value of the selectivity index for the treatment response and renal outcome in patients with lupus nephritis. Methods Forty-four patients with lupus nephritis with selectivity index available at the time of renal biopsy were divided into two groups according to the cut-off value of the selectivity index determined by a receiver operating characteristics curve to differentiate treatment responders from non-responders. The baseline characteristics, overall response rate and renal functional outcome were studied retrospectively, and compared between the two groups. Prognostic factors for achieving remission were identified. Results The cut-off value of the selectivity index was 0.167. The low selectivity index (<0.167) and the high selectivity index (≥0.167) group included 24 and 20 patients, respectively. The overall response rate was significantly higher (88% vs. 50%, P = 0.007) and the rate of progression to end-stage renal disease was lower in the low selectivity index group (0% vs. 15%, P = 0.049). More patients in the high selectivity index group had chronic lesions on renal biopsy ( P = 0.002). The selectivity index was the prognostic factor for achieving overall response based on a multivariate analysis ( P = 0.020). Conclusions A selectivity index ≥0.167 was a strong predictor for a poor treatment response and the presence of chronic lesions on renal biopsy. Further exploration with a larger cohort and longer follow-up period is warranted.
Redefining lupus nephritis: clinical implications of pathophysiologic subtypes.
Yu Feng,Haas Mark,Glassock Richard,Zhao Ming-Hui
Nature reviews. Nephrology
Systemic lupus erythematosus (SLE) is associated with a broad spectrum of clinical and immunologic manifestations, of which lupus nephritis is the most common cause of morbidity and mortality. The development of nephritis in patients with SLE involves multiple pathogenic pathways including aberrant apoptosis, autoantibody production, immune complex deposition and complement activation. The 2003 International Society of Nephrology/Renal Pathology Society (ISN/RPS) classification system for lupus nephritis was widely accepted with high intraobserver and interobserver concordance to guide therapeutic strategy and provide prognostic information. However, this classification system is not based on the underlying disease pathophysiology. Some additional lesions that contribute to disease presentation, including glomerular crescents, podocyte injury, tubulointerstitial lesions and vascular injury, should be recognized. Although outcomes for patients with lupus nephritis have improved over the past 30 years, treatment of this disease remains challenging and is best approached on the basis of the underlying pathogenesis, which is only partially represented by the various pathological phenotypes defined by the ISN/RPS classification. Here, we discuss the heterogeneous mechanisms involved in the pathogenesis of lupus nephritis and how improved understanding of underlying disease mechanisms might help guide therapeutic strategies.
Two-Parametric Immunological Score Development for Assessing Renal Involvement and Disease Activity in Systemic Lupus Erythematosus.
Sjöwall Christopher,Bentow Chelsea,Aure Mary Ann,Mahler Michael
Journal of immunology research
Objective:Anti-double-stranded (ds) DNA and anti-C1q autoantibodies are useful tools in the assessment of disease activity and nephritis in systemic lupus erythematosus (SLE) patients. This study aimed to explore the utility of these antibodies along with anti-Ku antibodies in an oligoparametric model approach for the assessment of disease activity and lupus nephritis. Methods:Samples from 261 well-characterized SLE patients were tested using chemiluminescent immunoassays (CIA) for anti-dsDNA and anti-Ku antibodies as well as by anti-C1q antibody ELISA (Inova Diagnostics, USA). Of these SLE patients, 26.4% had lupus nephritis (LN) at the time of blood draw or had a history of LN, and modified SLE disease activity index-2K (SLEDAI) scores were used to assess disease activity. Results:All three antibodies demonstrated higher prevalence and higher antibody levels in active versus inactive SLE patients and in LN versus non-LN patients. When oligoparametric analysis was performed, the likelihood of LN and patients with active disease increased with dual and triple positivity. Conclusions:Anti-dsDNA and anti-C1q antibodies are useful tools to identify disease activity and/or renal involvement in SLE patients. In addition, the combination of those antibodies in a two-parametric score might improve the clinical utility of those markers.
2019 European League Against Rheumatism/American College of Rheumatology classification criteria for systemic lupus erythematosus.
Aringer Martin,Costenbader Karen,Daikh David,Brinks Ralph,Mosca Marta,Ramsey-Goldman Rosalind,Smolen Josef S,Wofsy David,Boumpas Dimitrios T,Kamen Diane L,Jayne David,Cervera Ricard,Costedoat-Chalumeau Nathalie,Diamond Betty,Gladman Dafna D,Hahn Bevra,Hiepe Falk,Jacobsen Søren,Khanna Dinesh,Lerstrøm Kirsten,Massarotti Elena,McCune Joseph,Ruiz-Irastorza Guillermo,Sanchez-Guerrero Jorge,Schneider Matthias,Urowitz Murray,Bertsias George,Hoyer Bimba F,Leuchten Nicolai,Tani Chiara,Tedeschi Sara K,Touma Zahi,Schmajuk Gabriela,Anic Branimir,Assan Florence,Chan Tak Mao,Clarke Ann Elaine,Crow Mary K,Czirják László,Doria Andrea,Graninger Winfried,Halda-Kiss Bernadett,Hasni Sarfaraz,Izmirly Peter M,Jung Michelle,Kumánovics Gábor,Mariette Xavier,Padjen Ivan,Pego-Reigosa José M,Romero-Diaz Juanita,Rúa-Figueroa Fernández Íñigo,Seror Raphaèle,Stummvoll Georg H,Tanaka Yoshiya,Tektonidou Maria G,Vasconcelos Carlos,Vital Edward M,Wallace Daniel J,Yavuz Sule,Meroni Pier Luigi,Fritzler Marvin J,Naden Ray,Dörner Thomas,Johnson Sindhu R
Annals of the rheumatic diseases
OBJECTIVE:To develop new classification criteria for systemic lupus erythematosus (SLE) jointly supported by the European League Against Rheumatism (EULAR) and the American College of Rheumatology (ACR). METHODS:This international initiative had four phases. (1) Evaluation of antinuclear antibody (ANA) as an entry criterion through systematic review and meta-regression of the literature and criteria generation through an international Delphi exercise, an early patient cohort and a patient survey. (2) Criteria reduction by Delphi and nominal group technique exercises. (3) Criteria definition and weighting based on criterion performance and on results of a multi-criteria decision analysis. (4) Refinement of weights and threshold scores in a new derivation cohort of 1001 subjects and validation compared with previous criteria in a new validation cohort of 1270 subjects. RESULTS:The 2019 EULAR/ACR classification criteria for SLE include positive ANA at least once as obligatory entry criterion; followed by additive weighted criteria grouped in seven clinical (constitutional, haematological, neuropsychiatric, mucocutaneous, serosal, musculoskeletal, renal) and three immunological (antiphospholipid antibodies, complement proteins, SLE-specific antibodies) domains, and weighted from 2 to 10. Patients accumulating ≥10 points are classified. In the validation cohort, the new criteria had a sensitivity of 96.1% and specificity of 93.4%, compared with 82.8% sensitivity and 93.4% specificity of the ACR 1997 and 96.7% sensitivity and 83.7% specificity of the Systemic Lupus International Collaborating Clinics 2012 criteria. CONCLUSION:These new classification criteria were developed using rigorous methodology with multidisciplinary and international input, and have excellent sensitivity and specificity. Use of ANA entry criterion, hierarchically clustered and weighted criteria reflect current thinking about SLE and provide an improved foundation for SLE research.
Analysis of clinical and laboratory characteristics and pathology of lupus nephritis-based on 710 renal biopsies in China.
Song Kangkang,Liu Xiaomin,Liu Jiaona,Yin Zhong,Chen Pu,Cai Guangyan,Chen Xiangmei
OBJECTIVES:This study aimed to analyse the clinical and laboratory characteristics of different pathologic classifications of lupus nephritis (LN) patients in terms of age at systemic lupus erythematosus (SLE) diagnosis and nephritis onset. METHOD:Clinical, laboratory, and pathological data of 710 LN patients diagnosed by renal biopsy at our institution between 2000 and 2018 were retrospectively analysed. Patients were divided into the different pathological classification groups; childhood-, adult- and elderly-onset SLE groups and early- and late-onset LN groups. RESULTS:Class IV occurred most frequently and had the lowest complement C3 level. There was an obvious increase in active index in class IV and class V + IV. Patients with class VI showed some clinical characteristics similar to end-stage renal disease. Patients with proliferative nephritis were younger at SLE diagnosis and had higher blood pressure, higher frequency of proteinuria and urinary erythrocyte and lower haemoglobin and complement C3. Pathologic classification between childhood-, adult- and elderly-onset SLE patients or between early- and late-onset LN patients was not significantly different. Elderly-onset SLE patients had the highest chronic index (CI), IgA, IgG and Sjögren's syndrome A antibodies and Sjögren's syndrome B antibodies rates, whereas late-onset LN patients showed significantly higher CI, haemoglobin, complement C3 and C4 but lower uric acid, IgM and IgG. CONCLUSIONS:LN patients present with different clinical and laboratory characteristics according to pathological classification, age at SLE diagnosis and nephritis onset. These results might be valuable for estimating the pathology and guiding treatment and prognosis. Key Points • Patients with proliferative nephritis have more severe immune disorders, worse renal function and stronger inflammatory state. • The elderly-onset SLE patients showed a poorer condition. • The late-onset LN patients might have a more stable status.
A Validation of the 2018 Revision of International Society of Nephrology/Renal Pathology Society Classification for Lupus Nephritis: A Cohort Study from China.
Tao Juan,Wang Hui,Yu Xiao-Juan,Tan Ying,Yu Feng,Wang Su-Xia,Haas Mark,Glassock Richard J,Zhao Ming-Hui
American journal of nephrology
BACKGROUND:A revision of the International Society of Nephrology/Renal Pathology Society (ISN/RPS) classification for lupus nephritis has been published in 2018. The current study aimed to verify the utility of this system. MATERIALS AND METHODS:A total of 101 lupus nephritis patients from a large Chinese cohort who underwent renal biopsy in Peking University First Hospital were reevaluated by 2 renal pathologists, who had no knowledge of the clinical findings. The association between clinical data at the time of initial renal biopsy and follow-up and pathological features were further analyzed on all patients selected. RESULTS:The mean age of the cohort was 33 years with a male/female ratio of 1:9, and a median follow-up period of 128 months. The presence and extent of mesangial hypercellularity, endocapillary hypercellularity, global and segmental glomerulosclerosis, neutrophil exudation/karyorrhexis, glomerular hyaline deposits, extracapillary proliferation (crescents), tubular atrophy/interstitial fibrosis, and interstitial inflammation were significantly correlated with several clinical renal injury indices (systemic lupus erythematosus disease activity index, serum creatinine value, proteinuria, and C3 level) at the time of biopsy. By multivariable Cox hazard analysis, fibrous crescents, tubular atrophy/interstitial fibrosis, and the modified National Institutes of Health chronicity index were independent risk factors for patients' composite renal outcomes (hazard ratio [HR] 4.100 [95% CI 1.544-10.890], p = 0.005; HR 8.584 [95% CI 2.509-29.367], p = 0.001; and HR 3.218 [95% CI 1.138-9.099], p = 0.028; respectively). CONCLUSIONS:The 2018 revision of the ISN/RPS classification for lupus nephritis has utility for prediction of clinical renal outcomes.
The ISN/RPS 2016 classification predicts renal prognosis in patients with first-onset class III/IV lupus nephritis.
Hachiya Asaka,Karasawa Munetoshi,Imaizumi Takahiro,Kato Noritoshi,Katsuno Takayuki,Ishimoto Takuji,Kosugi Tomoki,Tsuboi Naotake,Maruyama Shoichi
Lupus nephritis (LN) is a life-threatening complication of systemic lupus erythematosus. The 2003 pathological classification of LN was revised in 2016; it quantitatively evaluates the interstitium in addition to the glomeruli. We performed a retrospective multi-centre cohort study and investigated the utility of the 2016 classification-including the activity index (AI), chronicity index (CI), and each pathological component to predict complete remission or renal function decline, defined as 1.5-fold increase in serum creatinine levels-and compare with that of the 2003 classification. Ninety-one consecutive adult patients with first-onset class III/IV LN who were newly prescribed any immunosuppressants were enrolled and followed up for a median of 51 months from January 2004. Cox regression analysis demonstrated the subclasses based on the 2003 classification, which mainly evaluate glomerular lesions, were not associated with clinical outcomes. After adjustments for estimated glomerular filtration rate and urinary protein levels, higher CI and higher interstitial fibrosis and lower hyaline deposit scores were associated with renal functional decline. Similarly, higher CI and interstitial inflammation scores were associated with failure to achieve complete remission. Therefore, the 2016 classification can predict the clinical outcomes more precisely than the 2003 classification.
Brief Report: Tubulointerstitial Damage in Lupus Nephritis: A Comparison of the Factors Associated With Tubulointerstitial Inflammation and Renal Scarring.
Londoño Jimenez Alejandra,Mowrey Wenzhu B,Putterman Chaim,Buyon Jill,Goilav Beatrice,Broder Anna
Arthritis & rheumatology (Hoboken, N.J.)
OBJECTIVE:To characterize and compare the factors associated with tubulointerstitial inflammation (TII) and tubulointerstitial scarring, defined as interstitial fibrosis and/or tubular atrophy (IF/TA), in patients with lupus nephritis (LN). METHODS:We identified systemic lupus erythematosus patients who had renal biopsy results consistent with LN between 2005 and 2017. Clinical data were collected from medical records. Multivariable logistic regression models were fitted to assess factors associated with TII and with IF/TA (moderate-to-severe versus none/mild). RESULTS:Of 203 LN patients included, 41 (20%) had moderate-to-severe TII, 45 (22%) had moderate-to-severe IF/TA, and 21 (10%) had both. Multivariable logistic regression models showed that moderate-to-severe TII was associated with a shorter disease duration, African American race, proliferative LN, and an estimated glomerular filtration rate (eGFR) of <60 ml/minute/1.73 m at the time of biopsy. Hydroxychloroquine use was associated with significantly lower odds of moderate-to-severe TII (odds ratio 0.27 [95% confidence interval 0.10-0.70], P = 0.008). Similar to TII, factors associated with moderate-to-severe IF/TA included proliferative LN and eGFR <60 ml/minute/1.73 m at the time of biopsy. In addition, the presence of moderate-to-severe TII and older age was associated with moderate-to-severe IF/TA. None of the routinely available serologic markers-including anti-double-stranded DNA antibodies, anti-Ro/La antibodies, and low complement-were associated with tubulointerstitial damage. CONCLUSION:The use of hydroxychloroquine was strongly associated with less inflammation, while the presence of TII, proliferative LN, and low eGFR were major determinants of tubulointerstitial scarring. Identifying modifiable factors is critical for the development of better preventive and therapeutic strategies with the goal of improving survival in patients with lupus-related kidney disease.