Interstitial inflammation and interstitial fibrosis and tubular atrophy predict renal survival in lupus nephritis

BackgroundIn patients with secondary (autoimmune) membranous nephropathy, two novel proteins, Exostosin 1 and Exostosin 2 (EXT1/EXT2), are potential disease antigens, biomarkers, or both. In this study, we validate the EXT1/EXT2 findings in a large cohort of membranous lupus nephritis.MethodsWe conducted a retrospective cohort study of patients with membranous lupus nephritis, and performed immunohistochemistry studies on the kidney biopsy specimens against EXT1 and EXT2. Clinicopathologic features and outcomes of EXT1/EXT2-positive versus EXT1/EXT2-negative patients were compared.ResultsOur study cohort included 374 biopsy-proven membranous lupus nephritis cases, of which 122 (32.6%) were EXT1/EXT2-positive and 252 (67.4%) were EXT1/EXT2-negative. EXT1/EXT2-positive patients were significantly younger (P=0.01), had significantly lower serum creatinine levels (P=0.02), were significantly more likely to present with proteinuria ≥3.5 g/24 h (P=0.009), and had significantly less chronicity features (glomerulosclerosis, P=0.001 or interstitial fibrosis and tubular atrophy, P<0.001) on kidney biopsy. Clinical follow-up data were available for 160 patients, of which 64 (40%) biopsy results were EXT1/EXT2-positive and 96 (60%) were EXT1/EXT2-negative. The proportion of patients with class 3/4 lupus nephritis coexisting with membranous lupus nephritis was not different between the EXT1/EXT2-positive and EXT1/EXT2-negative groups (25.0% versus 32.3%; P=0.32). The patients who were EXT1/EXT2-negative evolved to ESKD faster and more frequently compared with EXT1/EXT2-positive patients (18.8% versus 3.1%; P=0.003).ConclusionsThe prevalence of EXT1/EXT2 positivity was 32.6% in our cohort of membranous lupus nephritis. Compared with EXT1/EXT2-negative membranous lupus nephritis, EXT1/EXT2-positive disease appears to represent a subgroup with favorable kidney biopsy findings with respect to chronicity indices. Cases of membranous lupus nephritis that are EXT1/EXT2-negative are more likely to progress to ESKD compared with those that are EXT1/EXT2-positive.

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Clinical characteristics and renal prognosis associated with interstitial fibrosis and tubular atrophy (IFTA) and vascular injury in lupus nephritis biopsies

Seminars in Arthritis and Rheumatism ◽

10.1016/j.semarthrit.2019.06.002 ◽

2019 ◽

Vol 49 (3) ◽

pp. 396-404 ◽

Cited By ~ 8

Author(s):

Cianna Leatherwood ◽

Cameron B. Speyer ◽

Candace H. Feldman ◽

Kristin D'Silva ◽

José A. Gómez-Puerta ◽

...

Keyword(s):

Lupus Nephritis ◽

Vascular Injury ◽

Clinical Characteristics ◽

Interstitial Fibrosis ◽

Tubular Atrophy ◽

Renal Prognosis

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The Crescentic Implication of Renal Outcomes in Proliferative Lupus Nephritis

The Journal of Rheumatology ◽

10.3899/jrheum.170553 ◽

2018 ◽

Vol 45 (4) ◽

pp. 513-520 ◽

Cited By ~ 7

Author(s):

Fanghao Cai ◽

Fei Han ◽

Hongya Wang ◽

Haidongqin Han ◽

Jingyun Le ◽

...

Keyword(s):

Risk Factors ◽

Lupus Nephritis ◽

Renal Survival ◽

Endstage Renal Disease ◽

Tubular Atrophy ◽

Renal Outcomes ◽

Proliferative Lupus Nephritis ◽

Independent Risk Factors ◽

Cox Proportional Hazard Regression ◽

Renal Tubular

Objective.To determine the association between crescents and renal outcomes, and the implications on therapeutic choices.Methods.There were 231 patients with biopsy-proven proliferative lupus nephritis (PLN) who were divided into 4 groups: 59 patients were in the noncrescent group (NC); 59 patients exclusively with segmental crescents were in the segmental crescent group (SC); patients with circumferential crescents were categorized into 2 groups according to the crescentic ratio (C1 had 64 patients with ≤ 25%, and C2 had 49 patients with > 25%). Their baseline laboratory tests, histopathological manifestations, and outcomes were compared.Results.Remission rates in NC, SC, C1, and C2 groups were 92.1%, 85.4%, 95.0%, and 76.1%, respectively. Fewer patients in the C2 group achieved complete remission than the other 3 groups. For longterm outcomes evaluated by serum creatinine (SCr) doubling or endstage renal disease (ESRD), the renal survival rate was lowest in the C2 group (p = 0.003). Including clinical and pathological variables in the Cox proportional hazard regression model separately, the multivariate analysis revealed that these were independent risk factors for SCr doubling or ESRD: baseline SCr (with every 1 mg/dl increase: HR = 1.834, 95% CI 1.465–2.296; p < 0.001), hemoglobin (with every 1 g/l increase: HR = 0.970, 95% CI 0.947–0.992; p = 0.009), the proportions of cellular crescents (with every 1% increase: HR = 1.040, 95% CI 1.015–1.066; p = 0.002) and fibrocellular crescents (with every 1% increase: HR = 1.085, 95% CI 1.013–1.163; p = 0.020), and severe renal tubular atrophy (HR = 5.348, 95% CI 1.278–22.373; p = 0.022).Conclusion.PLN with crescents > 25% had worse renal outcomes both in short and long terms. Proportions of cellular and fibrocellular crescents were independent risk factors for poor renal survival.

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Propylthiouracil-induced Antineutrophil Cytoplasmic Antibody (ANCA)-associated Renal Vasculitis Versus Primary ANCA-associated Renal Vasculitis: A Comparative Study

The Journal of Rheumatology ◽

10.3899/jrheum.110931 ◽

2012 ◽

Vol 39 (3) ◽

pp. 558-563 ◽

Cited By ~ 18

Author(s):

YONG-XI CHEN ◽

WEN ZHANG ◽

XIAO-NONG CHEN ◽

HAI-JIN YU ◽

LI-YAN NI ◽

...

Keyword(s):

Estimated Glomerular Filtration Rate ◽

Interstitial Fibrosis ◽

Renal Involvement ◽

Antineutrophil Cytoplasmic Antibody ◽

Good Prognosis ◽

Small Vessel Vasculitis ◽

Renal Survival ◽

Tubular Atrophy ◽

Renal Vasculitis ◽

Immunological Abnormalities

Objective.Renal involvement is frequently present in primary antineutrophil cytoplasmic antibody-associated small-vessel vasculitis (AAV) as well as propylthiouracil (PTU)-induced AAV. We analyzed the characteristics of patients with PTU-induced AAV with renal involvement and investigated the differences of the 2 diseases.Methods.Thirty-six patients with PTU-induced AAV, diagnosed from 1997 to 2010, were enrolled for study. Their data were compared with those of 174 patients with primary AAV diagnosed at the same time. Renal involvement was present in all patients.Results.There was a prominent proportion of young women with PTU-induced AAV (p < 0.01). They had lower levels of proteinuria and serum creatinine and higher estimated glomerular filtration rate (p < 0.01, p < 0.01, and p < 0.01, respectively). Clinical immunological abnormalities were less severe in patients with PTU-induced AAV. Patients with PTU-induced AAV had less organ involvement and lower Birmingham Vasculitis Assessment Score than patients with primary AAV (p < 0.01). Renal biopsies showed a lower proportion of glomeruli with crescents (p < 0.01). Interstitial inflammation was less severe in patients with PTU-induced AAV (p < 0.05). Similarly, interstitial fibrosis and tubular atrophy were less severe in patients with PTU-induced AAV (p < 0.01, p < 0.05, respectively). Renal survival and total survival were better in patients with PTU-associated vasculitis (p < 0.05, p = 0.01).Conclusion.Clinical and histopathological abnormalities were less severe in patients with PTU-induced AAV and most of them had a good prognosis.

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Electron microscopy study of 496 cases of lupus nephritis: A single-center experience

Lupus ◽

10.1177/0961203320984539 ◽

2021 ◽

pp. 096120332098453

Author(s):

Bahar Bagheri ◽

Seyed Mohammad Owji ◽

Simin Torabinezhad ◽

Hadi Raeisi Shahraki ◽

Amirhossein Kamalinia ◽

...

Keyword(s):

Electron Microscopy ◽

Lupus Nephritis ◽

Light Microscopy ◽

Lupus Erythematosus ◽

Interstitial Fibrosis ◽

Renal Involvement ◽

Correct Classification ◽

Tubular Atrophy ◽

Diagnosis And Classification

Introduction Renal involvement is seen in about 40-82% of systemic lupus erythematosus (SLE) Asian patients. The exact diagnosis and classification of lupus nephritis are important for treatment and prognosis. This study aimed to investigate the value of electron microscopy (EM) in the diagnosis and classification of lupus nephritis compared with light microscopy. Method In this cross-sectional referral-center 16-year study of lupus nephritis, the final diagnosis was based on the EM study. Primary light microscopy findings were compared with EM diagnosis. Moreover, Immunofluorescence patterns distribution was assessed. Results From 496 patients diagnosed with lupus nephritis based on EM, 225(45.4%) of patients were categorized in class IV, followed by 98(19.7%), 93(18.8%), 46(9.3%), and 14(2.8%) who were categorized into classes of II, III, V, and VI respectively. Only 1(0.2%) patient belonged to class I, and 19(3.8%) cases were diagnosed with mixed two classes. Using EM was essential for diagnosing 25.6% of cases taking the correct classification by light microscopy into account; however, disregarding correct classification, this could change to a 7.4% contribution rate of EM. The most common cause of misdiagnosis, disregarding incorrect classification, was inadequate or wrong tissue. Positive associations were detected between tubular atrophy and interstitial fibrosis of both electron and light microscopy with different classes (P < 0.001). Conclusion While light microscopy is highly accurate for diagnosing lupus nephritis regardless of correct classification, EM contributes substantially to the correct classification of lupus nephritis types.

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Comparative Histological Subtyping of Immune Cell Infiltrates in MPO-ANCA and PR3-ANCA Glomerulonephritis

Frontiers in Immunology ◽

10.3389/fimmu.2021.737708 ◽

2021 ◽

Vol 12 ◽

Author(s):

Samy Hakroush ◽

Désirée Tampe ◽

Philipp Ströbel ◽

Peter Korsten ◽

Björn Tampe

Keyword(s):

Mononuclear Cell ◽

Plasma Cells ◽

Immune Cell ◽

Interstitial Fibrosis ◽

Kidney Injury ◽

Tubular Atrophy ◽

Interstitial Inflammation ◽

Tubulointerstitial Lesions ◽

Mononuclear Cell Infiltrates ◽

Immune Cell Infiltrates

BackgroundAcute kidney injury (AKI) is a common and severe complication of anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV), potentially leading to chronic kidney disease (CKD), end-stage renal disease (ESRD), or death. Pathogenic ANCAs, in particular proteinase 3 (PR3) and myeloperoxidase (MPO), trigger a deleterious immune response with intrarenal immune cell infiltration resulting in a pauci-immune necrotizing and crescentic glomerulonephritis (GN). However, a systematic analysis of intrarenal immune cell subtypes concerning neutrophils, eosinophils, plasma cells, and mononuclear cell infiltrates (macrophages, lymphocytes) in ANCA GN remains elusive. Therefore, we aimed to compare distinct immune cell infiltrates in association with clinicopathological findings in ANCA GN.MethodsA total of 53 kidney biopsies with ANCA GN at the University Medical Center Göttingen were retrospectively analyzed. Histological infiltrates of neutrophils, eosinophils, plasma cells, and mononucleated cells (macrophages, lymphocytes) were quantified as a fraction of the total area of inflammation.ResultsNeutrophilic infiltrates were associated with glomerular necrosis and severe kidney injury in ANCA GN. Among tubulointerstitial lesions, intrarenal neutrophils correlated with interstitial inflammation, tubulitis, and inflammation in areas of interstitial fibrosis/tubular atrophy (IFTA), representing active inflammatory lesions. Concerning eosinophils, infiltrates were associated with severe kidney injury, interstitial inflammation, and cellular casts independent of glomerular lesions, implicating a distinct role in inflammation and damage in ANCA GN. Plasma cell infiltrates correlated with tubulitis and interstitial fibrosis and were associated with renal replacement therapy during the short-term disease course. Finally, mononuclear cell infiltrates correlated with severe kidney injury and active histopathological lesions (glomerular crescents, interstitial inflammation, tubulitis, inflammation, and tubulitis in areas of IFTA) besides chronic lesions (interstitial fibrosis and tubular atrophy) in ANCA GN. Interestingly, intrarenal subtypes of immune cell infiltrates differed in MPO-ANCA versus PR3-ANCA GN and were associated with distinct glomerular and tubulointerstitial lesions, implicating different pathogenic mechanisms of kidney injury in ANCA subtypes.ConclusionOur observations imply distinct pathomechanisms contributing to inflammation and renal injury in MPO vs. PR3-associated ANCA GN and potentially contribute to new therapeutic targets in specific ANCA subtypes.

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A Validation of the 2018 Revision of International Society of Nephrology/Renal Pathology Society Classification for Lupus Nephritis: A Cohort Study from China

American Journal of Nephrology ◽

10.1159/000507213 ◽

2020 ◽

Vol 51 (6) ◽

pp. 483-492 ◽

Cited By ~ 2

Author(s):

Juan Tao ◽

Hui Wang ◽

Xiao-Juan Yu ◽

Ying Tan ◽

Feng Yu ◽

...

Keyword(s):

Lupus Nephritis ◽

Renal Biopsy ◽

International Society ◽

Interstitial Fibrosis ◽

Activity Index ◽

Renal Pathology ◽

Tubular Atrophy ◽

Female Ratio ◽

Renal Outcomes

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.

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What is the value of repeat kidney biopsies in patients with lupus nephritis?

Lupus ◽

10.1177/0961203320965703 ◽

2020 ◽

Vol 30 (1) ◽

pp. 25-34

Author(s):

Enrique Morales ◽

Hernando Trujillo ◽

Teresa Bada ◽

Marina Alonso ◽

Eduardo Gutiérrez ◽

...

Keyword(s):

Kidney Disease ◽

Lupus Nephritis ◽

Disease Progression ◽

Kidney Biopsy ◽

Interstitial Fibrosis ◽

Repeat Biopsy ◽

Vascular Lesions ◽

Clinical Indication ◽

Tubular Atrophy ◽

Kidney Disease Progression

Introduction Recent studies with protocol biopsies have shown a mismatch between clinical and histological remission in lupus nephritis (LN). We aimed to evaluate histological changes in repeat kidney biopsies by clinical indication in patients with LN. Methods We analyzed 107 patients with LN in which a kidney biopsy was performed between 2008 and 2018. Of those, we included 26 (24.2%) who had ≥2 kidney biopsies. Classification was done according to the International Society of Nephrology/Renal Pathology Society. Results Mean time between biopsies was 71.5 ± 10.7 months. 73.1% of patients presented a change of class at repeat biopsy; 38.4% to a higher class and 34.6% to a lower class. A significant increase in glomerulosclerosis (% GS) (3.8% vs 18.7%, p = 0.006), interstitial fibrosis (3.8% vs 26.9%, p = 0.021), tubular atrophy (15.4% vs 57.7%, p = 0.001) and chronicity index (CI) (1 vs 3, p < 0.001) was observed at repeat biopsy. Subjects who developed chronic kidney disease progression had a lower rate of complete remission at 12 months (0% vs 37.5%, p = 0.02), higher % GS at first biopsy (7.9% vs 1.2%, p = 0.02) and higher CI (4 vs 2, p = 0.006), tubular atrophy (90% vs 37.6%, p = 0.008), interstitial fibrosis (50% vs 12.5%, p = 0.036) and vascular lesions (60% vs 18.8%, p = 0.031) at second biopsy. Conclusions Our major finding was that patients with LN showed a significant increase in % GS, interstitial fibrosis, tubular atrophy and vascular lesions in repeat biopsies performed by clinical indication. This suggest that a second kidney biopsy may provide valuable and useful information regarding kidney disease progression.

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P0426HISTOLOGICAL PREDICTORS OF RENAL PROGNOSIS IN LUPUS NEPHRITIS: WHICH COMPARTMENT MAKES THE DIFFERENCE?

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfaa142.p0426 ◽

2020 ◽

Vol 35 (Supplement_3) ◽

Author(s):

Gabriel Stefan ◽

Simona Stancu ◽

Carmen Georgescu ◽

Adrian Dorin Zugravu ◽

Nicoleta Petre ◽

...

Keyword(s):

Lupus Nephritis ◽

Composite Endpoint ◽

Vascular Lesions ◽

Renal Outcome ◽

Renal Survival ◽

Tubular Atrophy ◽

Entire Cohort ◽

Renal Replacement Therapy Initiation ◽

Lower Egfr ◽

The Difference

Abstract Background and Aims Lupus nephritis (LN) encompasses a spectrum of glomerular, tubulointerstitial, and vascular lesions; we aimed to evaluate which compartment injury has renal prognostic value. Method We retrospectively examined the renal outcome at 31 December 2015 of 66 patients (age 36 [28-52] years; 76% female; eGFR at baseline 60.8 [24.4-78.1] mL/min) who were diagnosed with lupus nephritis by kidney biopsy during 2010-2015. Data regarding the clinical presentation, renal function, histology (presence/absence of lesions - Table 1; ISN/RPS classification) and treatment were retrieved from the electronic patients’ files. We used a composite endpoint in the survival analysis (Cox proportional hazard models, CPH): renal replacement therapy initiation, doubling of serum creatinine and death, whichever came first. Results Nephrotic syndrome was the most frequent form of presentation (42%), followed by nephritic (24%) and nephrotic-nephritic (15%). Most of the patients received immunosuppression treatment (97%, 70% cyclophosphamide regimen). Twenty-five patients (38%) reached the composite endpoint. They were older, male more often, had higher mean arterial pressure (MAP), lower serum albumin, decreased eGFR and higher proteinuria. Moreover, they were in class IV LN and had glomerulosclerosis more frequently. Median renal survival for the entire cohort was 4.4 (95%CI, 2.3-6.5) years. In the multivariatle CPH for the histological predictors, only ISN/RPS classification and tubular atrophy were associated with renal survival (Table 1). In a CPH that included clinical, histological and treatment variables, only lower eGFR (0.97 (95%CI, 0.95-0.99)), MAP (1.03 (95%CI, 1.00-1.06)) and tubular atrophy (4.52 (95%CI, 1.50-13.55)) remained as independent predictors of renal survival. Conclusion Tubular atrophy seems to be an important prognostic sign in LN; therefore, greater importance should be given to the tubulointerstitial compartment evaluation.

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Identification, Confirmation, and Replication of Novel Urinary MicroRNA Biomarkers in Lupus Nephritis and Diabetic Nephropathy

Clinical Chemistry ◽

10.1373/clinchem.2017.274175 ◽

2017 ◽

Vol 63 (9) ◽

pp. 1515-1526 ◽

Cited By ~ 40

Author(s):

Mariana Cardenas-Gonzalez ◽

Anand Srivastava ◽

Mira Pavkovic ◽

Vanesa Bijol ◽

Helmut G Rennke ◽

...

Keyword(s):

Diabetic Nephropathy ◽

Lupus Nephritis ◽

Kidney Function ◽

Lupus Erythematosus ◽

Interstitial Fibrosis ◽

Functional Markers ◽

Tubular Atrophy ◽

Patients With Diabetes ◽

Noninvasive Biomarkers ◽

N 93

Abstract BACKGROUND The prevalence of chronic kidney disease (CKD) is increasing, leading to significant morbidity and mortality. Kidney biopsy remains the gold standard for diagnosing the underlying etiology of CKD, but the procedure carries complication risks. The aim of this study was to identify novel noninvasive biomarkers correlating with kidney function and histopathology in biopsy-proven CKD patients. METHODS We profiled 2402 urinary microRNAs (miRNAs) to identify and confirm differentially expressed miRNAs associated with kidney function and histopathology in patients with diabetic nephropathy (n = 58) or lupus nephritis (n = 89), important etiologies of CKD, compared with healthy controls (n = 93 and 119, respectively). Top performing miRNAs were then measured in 2 independent multi-institutional cohorts of patients with diabetes mellitus with (n = 74) or without nephropathy (n = 71) and systemic lupus erythematosus with (n = 86) or without (n = 37) nephritis. RESULTS In patients with diabetic nephropathy, miR-2861, miR-1915-3p, and miR-4532 were down-regulated (>10-fold, P < 0.0001) and were associated with estimated glomerular filtration rate (P < 0.01) and interstitial fibrosis/tubular atrophy (P < 0.05). The c-statistics for miR-2861, miR-1915-3p, and miR-4532 were 0.91, 0.86, and 0.85, respectively. In lupus nephritis patients, miR-3201 and miR-1273e were down-regulated (>3-fold, P < 0.0001) and associated with endocapillary glomerular inflammation (P < 0.01), with c-statistics of 0.97 and 0.91, respectively. CONCLUSIONS We have identified novel miRNAs that correlate with histopathological lesions and functional markers of kidney damage to facilitate sensitive, specific, and noninvasive detection of diabetic nephropathy and lupus nephritis.

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