Effect of a Single Apolipoprotein L1 Gene Nephropathy Variant on the Risk of Advanced Lupus Nephritis in Brazilians

Objective.Apolipoprotein L1 gene (APOL1) G1 and G2 renal risk alleles (RRA) are associated with endstage renal disease in blacks with lupus nephritis (LN). The present study determined frequencies of APOL1 RRA in nonwhite Brazilian patients with LN and controls to assess association with renal outcomes.Methods.APOL1 RRA were genotyped in 222 healthy blood donors (controls) and 201 cases with LN from 3 outpatient clinics. Two single-nucleotide polymorphisms in the G1 (rs73885319 and rs60910145) and an indel for the G2 (rs71785313) variant were genotyped.Results.The frequency of APOL1 RRA in nonwhite Brazilian LN cases did not differ significantly from healthy controls, and few participants had 2 RRA. In the sample, 84.6% of LN cases and 84.2% of controls had 0 RRA, 13.4% and 15.3% had 1 RRA, and 2.0% and 0.4% had 2 RRA, respectively. LN cases with ≥ 1 APOL1 RRA had similar baseline characteristics and renal responses to treatment, yet faced higher risk for progressive chronic kidney disease (CKD) to an estimated glomerular filtration rate < 30 ml/min/1.73 m2 compared to those with 0 RRA (11.2% with 0, 29.6% with 1; 50% with 2 RRA, p = 0.005). Although glomerular lesions and activity scores on initial kidney biopsy did not differ significantly between individuals based on APOL1 genotype, chronicity scores, tubular atrophy, and interstitial fibrosis were more severe in those with ≥ 1 RRA (p = 0.011, p = 0.002, p = 0.018, respectively).Conclusion.Although initial kidney lesions and treatment responses were similar, a single APOL1 RRA in nonwhite Brazilians with LN was associated with increased risk of advanced CKD and possibly more tubulointerstitial damage.

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Polymorphisms inHSD17B1: Early Onset and Increased Risk of Alzheimer’s Disease in Women with Down Syndrome

Current Gerontology and Geriatrics Research ◽

10.1155/2012/361218 ◽

2012 ◽

Vol 2012 ◽

pp. 1-8 ◽

Cited By ~ 8

Author(s):

Joseph H. Lee ◽

Susan Gurney ◽

Deborah Pang ◽

Alexis Temkin ◽

Naeun Park ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Down Syndrome ◽

Age At Onset ◽

Nucleotide Polymorphisms ◽

Risk Alleles ◽

Increased Risk ◽

Estrogen Activity ◽

Intron 4

Background/Aims. Genetic variants that affect estrogen activity may influence the risk of Alzheimer's disease (AD). In women with Down syndrome, we examined the relation of polymorphisms in hydroxysteroid-17beta-dehydrogenase (HSD17B1) to age at onset and risk of AD.HSD17B1encodes the enzyme 17β-hydroxysteroid dehydrogenase (HSD1), which catalyzes the conversion of estrone to estradiol.Methods. Two hundred and thirty-eight women with DS, nondemented at baseline, 31–78 years of age, were followed at 14–18-month intervals for 4.5 years. Women were genotyped for 5 haplotype-tagging single-nucleotide polymorphisms (SNPs) in theHSD17B1gene region, and their association with incident AD was examined.Results. Age at onset was earlier, and risk of AD was elevated from two- to threefold among women homozygous for the minor allele at 3 SNPs in intron 4 (rs676387), exon 6 (rs605059), and exon 4 inCOASY(rs598126). Carriers of the haplotype TCC, based on the risk alleles for these three SNPs, had an almost twofold increased risk of developing AD (hazard ratio = 1.8, 95% CI, 1.1–3.1).Conclusion. These findings support experimental and clinical studies of the neuroprotective role of estrogen.

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In Patients with Membranous Lupus Nephritis, Exostosin-Positivity and Exostosin-Negativity Represent Two Different Phenotypes

Journal of the American Society of Nephrology ◽

10.1681/asn.2020081181 ◽

2021 ◽

pp. ASN.2020081181 ◽

Cited By ~ 1

Author(s):

Aishwarya Ravindran ◽

Marta Casal Moura ◽

Fernando C. Fervenza ◽

Samih H. Nasr ◽

Mariam P. Alexander ◽

...

Keyword(s):

Lupus Nephritis ◽

Kidney Biopsy ◽

Interstitial Fibrosis ◽

Study Cohort ◽

Lower Serum ◽

Tubular Atrophy ◽

Novel Proteins ◽

Biopsy Specimens ◽

Membranous 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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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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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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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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Differences in clinico-pathological characteristics and outcomes between proteinase 3-ANCA positivity and myeloperoxidase-ANCA positivity in lupus nephritis

Lupus ◽

10.1177/0961203319861680 ◽

2019 ◽

Vol 28 (9) ◽

pp. 1111-1119 ◽

Cited By ~ 2

Author(s):

C Li ◽

J -J Wang ◽

M -L Zhou ◽

D -D Liang ◽

J Yang ◽

...

Keyword(s):

Lupus Nephritis ◽

Interstitial Fibrosis ◽

Survival Rates ◽

Proteinase 3 ◽

Tubular Atrophy ◽

Positive Group ◽

Renal Outcomes ◽

Pathological Characteristics ◽

Chronicity Index ◽

Low Prevalence

Background Owing to the low prevalence of anti-neutrophil cytoplasmic antibodies (ANCA) in lupus nephritis (LN), there is no study about the differences between proteinase 3 (PR3)-ANCA positivity and myeloperoxidase (MPO)-ANCA positivity in LN until now. Methods Here we perform a retrospective study to determine whether there are differences in clinic-pathological characteristics and renal outcomes between PR3-ANCA-positive LN patients and MPO-ANCA-positive LN patients. Results A total of 26 (27.4%) PR3-ANCA-positive LN patients and 69 (72.6%) MPO-ANCA-positive LN patients ( p < 0.001) were eligible for this study. Compared with PR3-ANCA-positive LN patients, MPO-ANCA-positive LN patients had significantly higher levels of serum creatinine (109.6 µmol/l vs. 74.3 µmol/l, p = 0.02), lower titers of antinuclear antibodies (ANA) (128 vs. 256, p = 0.01), and higher serum concentrations of C3 and C4 (0.54 g/l vs. 0.36 g/l, p = 0.002; 0.12 g/l vs. 0.06 g/l, p < 0.001; respectively). Furthermore, the MPO-ANCA-positive group had higher scores for chronicity index ( p = 0.007), including interstitial fibrosis ( p = 0.001) and tubular atrophy ( p = 0.03) on biopsy specimens. The renal survival rates for MPO-ANCA-positive LN patients were 94.1% at 1 year, 83.2% at 5 years and 79.6% at 10 years; these values were worse when compared with those of the PR3-ANCA-positive group, which were 100%, 100% and 100%, respectively. Conclusion MPO-ANCA-positive LN patients had more severely impaired baseline renal function and less active lupus serology. More severely chronic pathological changes, including interstitial fibrosis and tubular atrophy on renal specimens, occurred in MPO-ANCA-positive LN patients. We found that MPO-ANCA-positive LN patients had worse renal outcomes.

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Genetic Variants in pre-miR-146a, pre-miR-499, pre-miR-125a, pre-miR-605, and pri-miR-182 Are Associated with Breast Cancer Susceptibility in a South American Population

Genes ◽

10.3390/genes9090427 ◽

2018 ◽

Vol 9 (9) ◽

pp. 427 ◽

Cited By ~ 14

Author(s):

Sebastián Morales ◽

Tomas De Mayo ◽

Felipe Gulppi ◽

Patricio Gonzalez-Hormazabal ◽

Valentina Carrasco ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Susceptibility ◽

Breast Cancer Susceptibility ◽

South American ◽

Dependent Manner ◽

Nucleotide Polymorphisms ◽

American Population ◽

South American Population ◽

Risk Alleles ◽

Increased Risk

Breast cancer (BC) is one of the most frequent tumors affecting women worldwide. microRNAs (miRNAs) single-nucleotide polymorphisms (SNPs) likely contribute to BC susceptibility. We evaluated the association of five SNPs with BC risk in non-carriers of the BRCA1/2-mutation from a South American population. The SNPs were genotyped in 440 Chilean BRCA1/2-negative BC cases and 1048 controls. Our data do not support an association between rs2910164:G>C or rs3746444:A>G and BC risk. The rs12975333:G>T is monomorphic in the Chilean population. The pre-miR-605 rs2043556-C allele was associated with a decreased risk of BC, both in patients with a strong family history of BC and in early-onset non-familial BC (Odds ratio (OR) = 0.5 [95% confidence interval (CI) 0.4–0.9] p = 0.006 and OR = 0.6 [95% CI 0.5–0.9] p = 0.02, respectively). The rs4541843-T allele is associated with increased risk of familial BC. This is the first association study on rs4541843 and BC risk. Previously, we showed that the TOX3-rs3803662:C>T was significantly associated with increased risk of familial BC. Given that TOX3 mRNA is a target of miR-182, and that both the TOX3 rs3803662-T and pri-miR-182 rs4541843-T alleles are associated with increased BC risk, we evaluated their combined effect. Risk of familial BC increased in a dose-dependent manner with the number of risk alleles (p-trend = 0.0005), indicating an additive effect.

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