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Zoshima T, Baba T, Nakatani K, Nagata M, Mukaida N, Kawano M. The CCL2-CCR2 axis determines whether glomerular endocapillary hypercellularity or wire-loop lesions develop through glomerular macrophage and neutrophil infiltration in lupus nephritis. J Pathol 2024; 264:174-185. [PMID: 39056146 DOI: 10.1002/path.6331] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2024] [Revised: 05/14/2024] [Accepted: 06/18/2024] [Indexed: 07/28/2024]
Abstract
The CCL2-CCR2 axis is involved in lupus nephritis, however the precise roles in the mechanisms by which different pathological lesions develop after glomerular immune complex deposition remain elusive. Previously, we demonstrated that genetic CCR2 inhibition induced a histological switch from glomerular endocapillary hypercellularity to wire-loop lesions in murine lupus nephritis. This study aimed to clarify the CCL2-CCR2 axis-mediated cellular mechanism in the formation of these different pathological lesions. We injected MRL/lpr mouse-derived monoclonal IgG3 antibody-producing hybridomas, 2B11.3 or B1, into wild-type (WT) mice to selectively induce glomerular endocapillary hypercellularity or wire-loop lesions. The expression of chemokine and chemokine receptors was analyzed using RT-quantitative PCR and/or immunofluorescence. We found 2B11.3 caused glomerular endocapillary hypercellularity in WT mice with glomerular infiltration of larger numbers of CCR2-expressing macrophages and neutrophils phagocyting immune complex, whereas B1 induced wire-loop lesions. In glomerular endocapillary hypercellularity, CCL2 was identified as the ligand involved in the CCR2-positive cell infiltration; it was expressed by glomerular endothelial cells and macrophages. Notably, 2B11.3-induced glomerular endocapillary hypercellularity converted to wire-loop lesions with reduced glomerular macrophage and neutrophil infiltration in CCL2-deficient (Ccl2-/-) mice similarly observed in Ccr2-/- mice. Moreover, this histological conversion was also observed when both glomerular macrophage and neutrophil infiltration were inhibited in anti-Ly6G antibody-treated Ccr5-/- mice but not when only glomerular macrophage infiltration was inhibited in Ccr5-/- mice or when only glomerular neutrophil infiltration was inhibited in anti-Ly6G antibody-treated WT mice. In contrast, B1 injection caused wire-loop lesions in Ccl2-/- and Ccr2-/- mice, as observed in WT mice. Moreover, 2B11.3 induced CCL2 from glomerular endothelial cells to a larger extent than B1 when injected into Ccr2-/- mice. In conclusion, the CCL2-CCR2 axis determines whether glomerular endocapillary hypercellularity or wire-loop lesions develop by regulating glomerular infiltration of phagocytic cells: macrophages and neutrophils. © 2024 The Pathological Society of Great Britain and Ireland.
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Affiliation(s)
- Takeshi Zoshima
- Department of Nephrology and Rheumatology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
| | - Tomohisa Baba
- Division of Cancer and Senescent Biology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan
| | - Kimihiko Nakatani
- Department of Nephrology, Kyoto Yamashiro General Medical Center, Kizugawa, Japan
| | - Michio Nagata
- Kidney and Vascular Pathology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
| | - Naofumi Mukaida
- Cancer Research Institute, Kanazawa University, Kanazawa, Japan
| | - Mitsuhiro Kawano
- Department of Nephrology and Rheumatology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
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Jiang K, Greenberg JH, Abraham A, Xu Y, Schelling JR, Feldman HI, Schrauben SJ, Waikar SS, Shlipak MG, Wettersten N, Coca SG, Vasan RS, Gutierrez OM, Ix JH, Warady BA, Kimmel PL, Bonventre JV, Parikh CR, Mitsnefes MM, Denburg MR, Furth S. Associations of Biomarkers of Kidney Tubule Health, Injury, and Inflammation with Left Ventricular Hypertrophy in Children with CKD. KIDNEY360 2023; 4:1039-1047. [PMID: 37303083 PMCID: PMC10476681 DOI: 10.34067/kid.0000000000000183] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/21/2022] [Accepted: 05/23/2023] [Indexed: 06/13/2023]
Abstract
Key Points Higher plasma and urine kidney injury molecule-1, urine monocyte chemoattractant protein-1, and lower urine alpha-1-microglobulin were associated with left ventricular hypertrophy, even after adjustment for confounders. Biomarkers of tubular injury, dysfunction, and inflammation may indicate the severity of kidney pathology and are associated with left ventricular hypertrophy. Background Left ventricular hypertrophy (LVH) is common in children with CKD and is associated with an increased risk of cardiovascular disease and mortality. We have shown that several plasma and urine biomarkers are associated with increased risk of CKD progression. As CKD is associated with LVH, we sought to investigate the association between the biomarkers and LVH. Methods In the CKD in Children Cohort Study, children aged 6 months to 16 years with an eGFR of 30–90 ml/min per 1.73 m2 were enrolled at 54 centers in the United States and Canada. We measured plasma biomarkers kidney injury molecule-1 (KIM-1), tumor necrosis factor receptor-1, tumor necrosis factor receptor-2, soluble urokinase-type plasminogen activator receptor and urine KIM-1, monocyte chemoattractant protein-1 (MCP-1), YKL-40, alpha-1-microglobulin (alpha-1m), and epidermal growth factor in stored plasma and urine collected 5 months after enrollment. Echocardiograms were performed 1 year after enrollment. We assessed the cross-sectional association between the log2 biomarker levels and LVH (left ventricular mass index greater than or equal to the 95th percentile) using a Poisson regression model, adjusted for age, sex, race, body mass index, hypertension, glomerular diagnosis, urine protein-to-creatinine ratio, and eGFR at study entry. Results Among the 504 children, LVH prevalence was 12% (n =59) 1 year after enrollment. In a multivariable-adjusted model, higher plasma and urine KIM-1 and urine MCP-1 concentrations were associated with a higher prevalence of LVH (plasma KIM-1 prevalence ratio [PR] per log2: 1.27, 95% confidence interval [CI], 1.02 to 1.58; urine KIM-1 PR: 1.21, 95% CI, 1.11 to 1.48; and urine MCP-1 PR: 1.18, 95% CI, 1.04 to 1.34). After multivariable adjustment for covariates, lower urine alpha-1m was also associated with a higher prevalence of LVH (PR: 0.90, 95% CI, 0.82 to 0.99). Conclusions Higher plasma and urine KIM-1, urine MCP-1, and lower urine alpha-1m were each associated with LVH prevalence in children with CKD. These biomarkers may better inform risk and help elucidate the pathophysiology of LVH in pediatric CKD.
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Affiliation(s)
- Kuan Jiang
- Yale School of Medicine, New Haven, Connecticut
| | | | - Alison Abraham
- University of Colorado, Anschutz Medical Campus, Denver, Colorado
- Johns Hopkins University, Baltimore, Maryland
| | - Yunwen Xu
- Johns Hopkins University, Baltimore, Maryland
| | | | - Harold I. Feldman
- Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
| | - Sarah J. Schrauben
- Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
| | | | | | | | - Steven G. Coca
- Icahn School of Medicine at Mount Sinai, New York, New York
| | | | | | - Joachim H. Ix
- University of California San Diego, San Diego, California
| | | | | | | | | | | | | | - Susan Furth
- Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
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Pérez-Arias AA, Méndez-Pérez RA, Cruz C, Zavala-Miranda MF, Romero-Diaz J, Márquez-Macedo SE, Comunidad-Bonilla RA, García-Rueda CC, Mejía-Vilet JM. The first-year course of urine MCP-1 and its association with response to treatment and long-term kidney prognosis in lupus nephritis. Clin Rheumatol 2023; 42:83-92. [PMID: 36107264 DOI: 10.1007/s10067-022-06373-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Revised: 09/05/2022] [Accepted: 09/08/2022] [Indexed: 01/27/2023]
Abstract
OBJECTIVES The present study aims to assess the course of uMCP-1 and its association with response to therapy and long-term kidney function in a prospective cohort of adults who received a kidney biopsy for suspicion of active lupus nephritis (LN). METHODS Subjects were segregated into a histologically active LN group and a histologically chronic LN group. Both groups were followed for > = 36 months and urine were collected at flare, 3, 6, and 12 months of follow-up. The association between the course of uMCP-1, response to treatment, and progression to 30% loss of the eGFR was evaluated by linear mixed models for repeated measures. RESULTS A kidney biopsy was performed on 125 subjects. In 114, the report was consistent with histologically active LN; in 11, with histologically chronic LN. Urine MCP-1 levels were significantly higher in the active LN than in the chronic LN group. Urine MCP-1 levels correlated with the histological findings of cellular crescents, endocapillary hypercellularity, interstitial inflammation, glomerular sclerosis, interstitial fibrosis, and tubular atrophy. The mean estimates of uMCP-1 at flare were higher in the non-response group than in the complete response group, and decreased in the complete/partial response groups by the third month, while they remained elevated in the non-response group. The mean estimates for uMCP-1 were higher at LN flare and remained elevated in patients who progressed to loss of 30% of the eGFR, while they decreased in patients with stable kidney function. CONCLUSION The first-year course of uMCP-1 is associated with response to therapy and kidney survival in LN. Key Points •Urine MCP-1 levels differentiate histologically-active lupus nephritis from histologically-chronic lupus nephritis •Urine MCP-1 levels decrease by 3 months of therapy in subjects with a favorable response whose kidney function remains stable long-term •Urine MCP-1 levels remain elevated during the first year of therapy in subjects the will later lose kidney function.
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Affiliation(s)
- Abril A Pérez-Arias
- Department of Nephrology and Mineral Metabolism, Instituto Nacional de Ciencias Médicas Y Nutrición Salvador Zubirán, Belisario Dominguez Sección XVI, 15 Vasco de Quiroga, Tlalpan, Mexico City, Mexico
| | - R Angélica Méndez-Pérez
- Department of Nephrology and Mineral Metabolism, Instituto Nacional de Ciencias Médicas Y Nutrición Salvador Zubirán, Belisario Dominguez Sección XVI, 15 Vasco de Quiroga, Tlalpan, Mexico City, Mexico
| | - Cristino Cruz
- Department of Nephrology and Mineral Metabolism, Instituto Nacional de Ciencias Médicas Y Nutrición Salvador Zubirán, Belisario Dominguez Sección XVI, 15 Vasco de Quiroga, Tlalpan, Mexico City, Mexico
| | - María Fernanda Zavala-Miranda
- Department of Nephrology and Mineral Metabolism, Instituto Nacional de Ciencias Médicas Y Nutrición Salvador Zubirán, Belisario Dominguez Sección XVI, 15 Vasco de Quiroga, Tlalpan, Mexico City, Mexico
| | - Juanita Romero-Diaz
- Department of Immunology and Rheumatology, Instituto Nacional de Ciencias Médicas Y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - Sofía E Márquez-Macedo
- Department of Nephrology and Mineral Metabolism, Instituto Nacional de Ciencias Médicas Y Nutrición Salvador Zubirán, Belisario Dominguez Sección XVI, 15 Vasco de Quiroga, Tlalpan, Mexico City, Mexico
| | - Roque A Comunidad-Bonilla
- Department of Nephrology and Mineral Metabolism, Instituto Nacional de Ciencias Médicas Y Nutrición Salvador Zubirán, Belisario Dominguez Sección XVI, 15 Vasco de Quiroga, Tlalpan, Mexico City, Mexico
| | - C Carolina García-Rueda
- Department of Immunology and Rheumatology, Instituto Nacional de Ciencias Médicas Y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - Juan M Mejía-Vilet
- Department of Nephrology and Mineral Metabolism, Instituto Nacional de Ciencias Médicas Y Nutrición Salvador Zubirán, Belisario Dominguez Sección XVI, 15 Vasco de Quiroga, Tlalpan, Mexico City, Mexico.
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Macrophages in Lupus Nephritis: Exploring a potential new therapeutic avenue. Clin Exp Rheumatol 2022; 21:103211. [PMID: 36252930 DOI: 10.1016/j.autrev.2022.103211] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Accepted: 10/11/2022] [Indexed: 12/14/2022]
Abstract
Lupus nephritis (LN) is a serious complication of systemic lupus erythematosus (SLE) that occurs in about half of patients. LN is characterized by glomerular deposition of immune complexes, leading to subendothelial, mesangial and subepithelial electron dense deposits, triggering immune cell infiltration and glomerular as well as tubulointerstitial injury. Monocytes and macrophages are abundantly present in inflammatory lesions, both in glomeruli and the tubulointerstitium. Here we discuss how monocytes and macrophages are involved in this process and how monocytes and macrophages may represent specific therapeutic targets to control LN.
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Ruacho G, Lira-Junior R, Gunnarsson I, Svenungsson E, Boström EA. Inflammatory markers in saliva and urine reflect disease activity in patients with systemic lupus erythematosus. Lupus Sci Med 2022; 9:9/1/e000607. [PMID: 35246487 PMCID: PMC8900065 DOI: 10.1136/lupus-2021-000607] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Accepted: 02/21/2022] [Indexed: 12/17/2022]
Abstract
BACKGROUND Laboratory tests of blood and sometimes urine are used to diagnose and to monitor disease activity (DA) in SLE. Clinical practice would be simplified if non-invasive urine and salivary tests could be introduced as alternatives to blood samples. We therefore explored the levels of innate immunity-related biomarkers in matched serum, urine and saliva samples from patients with SLE. METHODS A total of 84 patients with SLE selected to represent high and low general DA, and 21 controls were included. All participants underwent a thorough clinical examination. General DA and renal DA were measured. The levels of colony-stimulating factor (CSF)-1, interleukin (IL)-34, tumour necrosis factor (TNF)-α, interferon-γ-induced protein (IP)-10, monocyte chemoattractant protein (MCP)-1, calprotectin, macrophage inflammatory protein (MIP)-1α and MIP-1β were analysed by immunoassays and related to DA. RESULTS CSF-1, TNF-α, IP-10 and MCP-1 in saliva, serum and urine, as well as calprotectin in saliva and urine were increased in patients with SLE as compared with controls (p<0.05). TNF-α, IP-10 and MCP-1 in saliva, serum and urine, and CSF-1 in saliva and serum distinguished patients with SLE from controls (area under the curve >0.659; p<0.05 for all). CSF-1 in serum and urine, and calprotectin in saliva and urine, as well as TNF- α, IP-10 and MCP-1 in urine correlated positively with measures of general DA (p<0.05). Patients with SLE with active renal disease presented elevated levels of TNF-α, IP-10 and MCP-1 in urine and CSF-1 and IP-10 in serum as compared with patients with SLE with non-active renal disease. CONCLUSIONS Our investigation demonstrates that saliva is a novel alternative body fluid, with potential for surveillance of general DA in patients with SLE, but urine is more informative in patients with SLE with predominantly renal DA.
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Affiliation(s)
- Guillermo Ruacho
- Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.,Centre for Clinical Research Sörmland, Uppsala University, Eskilstuna, Sweden.,Public Dental Services, Folktandvården Stockholms Län AB, Stockholm, Sweden
| | - Ronaldo Lira-Junior
- Division of Oral diagnostics & Rehabilitation, Department of Dental Medicine, Karolinska Institutet, Huddinge, Sweden
| | - Iva Gunnarsson
- Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Elisabet Svenungsson
- Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Elisabeth A Boström
- Division of Oral diagnostics & Rehabilitation, Department of Dental Medicine, Karolinska Institutet, Huddinge, Sweden .,Department of Orofacial Medicine, Folktandvården Stockholms Län AB, Stockholm, Sweden
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Zoshima T, Baba T, Tanabe Y, Ishida Y, Nakatani K, Nagata M, Mukaida N, Kawano M. CCR2- and CCR5-mediated macrophage infiltration contributes to glomerular endocapillary hypercellularity in antibody-induced lupus nephritis. Rheumatology (Oxford) 2021; 61:3033-3048. [PMID: 34747459 DOI: 10.1093/rheumatology/keab825] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2021] [Revised: 10/24/2021] [Indexed: 11/14/2022] Open
Abstract
OBJECTIVES Lupus nephritis comprises various glomerular lesions, including endocapillary hypercellularity with macrophage infiltration. In this study, we aimed to clarify the involvement of macrophage-tropic chemokine receptors in the pathogenesis of these glomerular lesions. METHODS MRL/lpr mouse-derived monoclonal IgG3 antibody-producing hybridomas, 2B11.3 and B1, were injected intraperitoneally into BALB/c mice (WT) to induce endocapillary hypercellularity and wire-loop lesions, respectively. The expression of chemokine and chemokine receptors was analyzed by quantitative real time PCR and immunofluorescence. The roles of chemokine receptors in these lesions were evaluated using chemokine receptor-deficient mice or a selective CCR5 antagonist, maraviroc. RESULTS 2B11.3 caused glomerular endocapillary hypercellularity with a significant number of glomerular CD68-positive macrophages. Further, enhanced expression of CCL2, CCL3, CCR2, CCR5, and CX3CR1 was observed in the renal cortex, compared with B1 injection, which induced wire-loop lesions. In 2B11.3-induced glomerular lesions, CD68-positive glomerular macrophages expressed CCL2, CCL3, CCR2, CCR5, and CX3CR1, while glomerular endothelial cells expressed CCL2, CCL3, CX3CL1, and CCR2. When 2B11.3 was injected, CCR2-/- and CCR5-/-, but not CX3CR1-/-, mice exhibited reduced endocapillary hypercellularity, attenuated glomerular macrophage infiltration, and improved serum blood urea nitrogen (BUN) levels. Only CCR2-/- mice developed wire-loop lesions. B1 injection caused wire-loop lesions in these chemokine receptor-deficient mice to a similar extent as WT. Maraviroc treatment reduced 2B11.3-induced endocapillary hypercellularity and improved serum BUN levels. CONCLUSION CCR2 and CCR5 regulate glomerular macrophage infiltration and contribute to the development of glomerular endocapillary hypercellularity in lupus nephritis. CCR5 inhibition can be a specific therapy for endocapillary hypercellularity without inducing wire-loop lesions.
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Affiliation(s)
- Takeshi Zoshima
- Department of Rheumatology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan
| | - Tomohisa Baba
- Division of Molecular Bioregulation, Cancer Research Institute, Kanazawa University, Kanazawa, Japan
| | - Yamato Tanabe
- Division of Molecular Bioregulation, Cancer Research Institute, Kanazawa University, Kanazawa, Japan
| | - Yuko Ishida
- Department of Forensic Medicine, Wakayama Medical University, Wakayama, Japan
| | - Kimihiko Nakatani
- Department of Nephrology, Kyoto Yamashiro General Medical Center, Kizugawa, Japan
| | - Michio Nagata
- Kidney and Vascular Pathology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
| | - Naofumi Mukaida
- Division of Molecular Bioregulation, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.,Department of Forensic Medicine, Wakayama Medical University, Wakayama, Japan
| | - Mitsuhiro Kawano
- Department of Rheumatology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan
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Lai CF, Wang JJ, Tu YC, Hsu CY, Wu HY, Fang CC, Chen YM, Wu MS, Tsai TJ. Associations between urinary cysteine-rich protein 61 excretion and kidney function decline in outpatients with chronic kidney disease: a prospective cohort study in Taiwan. BMJ Open 2021; 11:e051165. [PMID: 34615677 PMCID: PMC8496378 DOI: 10.1136/bmjopen-2021-051165] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/03/2022] Open
Abstract
OBJECTIVES To examine whether urinary excretion of cysteine-rich protein 61 (Cyr61), an acknowledged proinflammatory factor in kidney pathologies, increases in chronic kidney disease (CKD) and is associated with subsequent rapid kidney function decline. DESIGN An observational cohort study. SETTING In the nephrology outpatient clinics of a tertiary hospital in Taiwan. PARTICIPANTS We enrolled 138 adult CKD outpatients (n=12, 32, 18, 18, 29 and 29 in stages 1, 2, 3a, 3b, 4 and 5 CKD, respectively) between February and October 2014 and followed them for 1 year. Their mean age was 60.46±13.16 years, and 51 (37%) of them were women. PRIMARY OUTCOME MEASURES Urinary Cyr61 levels were measured by ELISA. Rapid kidney function decline was defined as an estimated glomerular filtration rate (eGFR) decline rate ≥ 4 mL/min/1.73 m2/year or developing end-stage renal disease during subsequent 3-month or 1-year follow-up period. Models were adjusted for demographic and clinical variables. RESULTS The urine Cyr61-to-creatinine ratio (UCyr61CR) increased significantly in patients with stage 4 or 5 CKD. Multivariable linear regression analysis showed that log(UCyr61CR) was positively correlated with log(urine protein-to-creatinine ratio) (p<0.001) but negatively correlated with baseline eGFR (p<0.001) and hypertension (p=0.007). Complete serum creatinine data during the follow-up were available for 112 patients (81.2%). Among them, multivariable logistic regression identified log(UCyr61CR) was independently associated with rapid kidney function decline (adjusted OR 2.29, 95% CI 1.27 to 4.15) during the subsequent 3 months. UCyr61CR improved the discriminative performance of clinical models to predict 3-month rapid kidney function decline. In contrast, log(UCyr61CR) was not associated with rapid eGFR decline during the entire 1-year follow-up. CONCLUSIONS Elevated urinary Cyr61 excretion is associated with rapid short-term kidney function deterioration in patients with CKD. Measuring urinary Cyr61 excretion is clinically valuable for monitoring disease trajectory and may guide treatment planning.
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Affiliation(s)
- Chun-Fu Lai
- Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
| | | | - Ya-Chun Tu
- Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
| | - Chia-Yu Hsu
- Department of Family Medicine, Mackay Memorial Hospital, Taipei, Taiwan
| | - Hon-Yen Wu
- Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
- Department of Internal Medicine, Far Eastern Memorial Hospital, New Taipei City, Taiwan
- School of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan
| | - Cheng-Chung Fang
- Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
- Department of Emergency Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
| | - Yung-Ming Chen
- Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
- Department of Geriatrics and Gerontology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
| | - Ming-Shiou Wu
- Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
| | - Tun-Jun Tsai
- Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
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Mejia-Vilet JM, Malvar A, Arazi A, Rovin BH. The lupus nephritis management renaissance. Kidney Int 2021; 101:242-255. [PMID: 34619230 DOI: 10.1016/j.kint.2021.09.012] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2021] [Revised: 09/01/2021] [Accepted: 09/02/2021] [Indexed: 12/12/2022]
Abstract
Over the past year, and for the first time ever, the US Food and Drug Administration approved 2 drugs specifically for the treatment of lupus nephritis (LN). As the lupus community works toward understanding how to best use these new therapies, it is also an ideal time to begin to rethink the overall management strategy of LN. In addition to new drugs, this must include how to use kidney biopsies for management and not just diagnosis, how molecular technologies can be applied to interrogate biopsies and how such data can impact management, and how to incorporate LN biomarkers into management paradigms. Herein, we will review new developments in these areas of LN and put them into perspective for disease management now and in the future.
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Affiliation(s)
- Juan M Mejia-Vilet
- Department of Nephrology, Instituto Nacional de Ciencas Medicas y Nutricion Salvador Zubiran, Mexico City, Mexico
| | - Ana Malvar
- Department of Nephrology, Hospital Fernandez, Buenos Aires, Argentina
| | - Arnon Arazi
- Institute of Molecular Medicine, Feinstein Institutes for Medical Research, Manhasset, New York, USA
| | - Brad H Rovin
- Department of Medicine and Division of Nephrology, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA.
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Janssens P, Decuypere JP, De Rechter S, Breysem L, Van Giel D, Billen J, Hindryckx A, De Catte L, Baldewijns M, Claes KBM, Wissing KM, Devriendt K, Bammens B, Meyts I, Torres VE, Vennekens R, Mekahli D. Enhanced MCP-1 Release in Early Autosomal Dominant Polycystic Kidney Disease. Kidney Int Rep 2021; 6:1687-1698. [PMID: 34169210 PMCID: PMC8207325 DOI: 10.1016/j.ekir.2021.03.893] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2021] [Revised: 03/07/2021] [Accepted: 03/22/2021] [Indexed: 01/09/2023] Open
Abstract
Introduction Autosomal dominant polycystic kidney disease (ADPKD) causes kidney failure typically in adulthood, but the disease starts in utero. Copeptin, epidermal growth factor (EGF), and monocyte chemoattractant protein-1 (MCP-1) are associated with severity and hold prognostic value in adults but remain unstudied in the early disease stage. Kidneys from adults with ADPKD exhibit macrophage infiltration, and a prominent role of MCP-1 secretion by tubular epithelial cells is suggested from rodent models. Methods In a cross-sectional study, plasma copeptin, urinary EGF, and urinary MCP-1 were evaluated in a pediatric ADPKD cohort and compared with age-, sex-, and body mass index (BMI)-matched healthy controls. MCP-1 was studied in mouse collecting duct cells, human proximal tubular cells, and fetal kidney tissue. Results Fifty-three genotyped ADPKD patients and 53 controls were included. The mean (SD) age was 10.4 (5.9) versus 10.5 (6.1) years (P = 0.543), and the estimated glomerular filtration rate (eGFR) was 122.7 (39.8) versus 114.5 (23.1) ml/min per 1.73 m2 (P = 0.177) in patients versus controls, respectively. Plasma copeptin and EGF secretion were comparable between groups. The median (interquartile range) urinary MCP-1 (pg/mg creatinine) was significantly higher in ADPKD patients (185.4 [213.8]) compared with controls (154.7 [98.0], P = 0.010). Human proximal tubular cells with a heterozygous PKD1 mutation and mouse collecting duct cells with a PKD1 knockout exhibited increased MCP-1 secretion. Human fetal ADPKD kidneys displayed prominent MCP-1 immunoreactivity and M2 macrophage infiltration. Conclusion An increase in tubular MCP-1 secretion is an early event in ADPKD. MCP-1 is an early disease severity marker and a potential treatment target.
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Affiliation(s)
- Peter Janssens
- PKD Research Group, Laboratory of Pediatrics, Department of Development and Regeneration, KU Leuven, Leuven, Belgium.,Department of Nephrology, University Hospitals Brussels, Brussels, Belgium
| | - Jean-Paul Decuypere
- PKD Research Group, Laboratory of Pediatrics, Department of Development and Regeneration, KU Leuven, Leuven, Belgium
| | - Stéphanie De Rechter
- PKD Research Group, Laboratory of Pediatrics, Department of Development and Regeneration, KU Leuven, Leuven, Belgium
| | - Luc Breysem
- Department of Radiology, University Hospitals Leuven, Leuven, Belgium
| | - Dorien Van Giel
- PKD Research Group, Laboratory of Pediatrics, Department of Development and Regeneration, KU Leuven, Leuven, Belgium.,Laboratory of Ion Channel Research, Department of Cellular and Molecular Medicine, Biomedical Sciences Group, KU Leuven, Leuven, Belgium
| | - Jaak Billen
- Department of Laboratory Medicine, University Hospitals Leuven, Belgium
| | - An Hindryckx
- Department of Obstetrics and Gynecology, KU Leuven, Belgium
| | - Luc De Catte
- Department of Obstetrics and Gynecology, KU Leuven, Belgium
| | | | | | - Karl M Wissing
- Department of Nephrology, University Hospitals Brussels, Brussels, Belgium
| | - Koen Devriendt
- Department of Human Genetics, KU Leuven, Leuven, Belgium
| | - Bert Bammens
- Department of Nephrology, Dialysis and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium
| | - Isabelle Meyts
- Laboratory for Inborn Errors of Immunity, Department of Microbiology, Immunology and Transplantation, University Hospitals Leuven, Leuven, Belgium.,Laboratory for Inborn Errors of Immunity, Department of Pediatrics, University Hospitals Leuven, Leuven, Belgium
| | - Vicente E Torres
- Division of Nephrology and Hypertension, Mayo Clinic College of Medicine, Rochester, Minnesota, USA
| | - Rudi Vennekens
- Laboratory of Ion Channel Research, Department of Cellular and Molecular Medicine, Biomedical Sciences Group, KU Leuven, Leuven, Belgium
| | - Djalila Mekahli
- PKD Research Group, Laboratory of Pediatrics, Department of Development and Regeneration, KU Leuven, Leuven, Belgium.,Department of Pediatric Nephrology and Organ Transplantation, University Hospitals Leuven, Leuven, Belgium
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10
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Liu C, Mor MK, Palevsky PM, Kaufman JS, Thiessen Philbrook H, Weisbord SD, Parikh CR. Postangiography Increases in Serum Creatinine and Biomarkers of Injury and Repair. Clin J Am Soc Nephrol 2020; 15:1240-1250. [PMID: 32839195 PMCID: PMC7480551 DOI: 10.2215/cjn.15931219] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2019] [Accepted: 07/02/2020] [Indexed: 12/20/2022]
Abstract
BACKGROUND AND OBJECTIVES It is unknown whether iodinated contrast causes kidney parenchymal damage. Biomarkers that are more specific to nephron injury than serum creatinine may provide insight into whether contrast-associated AKI reflects tubular damage. We assessed the association between biomarker changes after contrast angiography with contrast-associated AKI and 90-day major adverse kidney events and death. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS We conducted a longitudinal analysis of participants from the biomarker substudy of the Prevention of Serious Adverse Events following Angiography trial. We measured injury (kidney injury molecule-1, neutrophil gelatinase-associated lipocalin, IL-18) and repair (monocyte chemoattractant protein-1, uromodulin, YKL-40) proteins from plasma and urine samples at baseline and 2-4 hours postangiography. We assessed the associations between absolute changes and relative ratios of biomarkers with contrast-associated AKI and 90-day major adverse kidney events and death. RESULTS Participants (n=922) were predominately men (97%) with diabetes (82%). Mean age was 70±8 years, and eGFR was 48±13 ml/min per 1.73 m2; 73 (8%) and 60 (7%) participants experienced contrast-associated AKI and 90-day major adverse kidney events and death, respectively. No postangiography urine biomarkers were associated with contrast-associated AKI. Postangiography plasma kidney injury molecule-1 and IL-18 were significantly higher in participants with contrast-associated AKI compared with those who did not develop contrast-associated AKI: 428 (248, 745) versus 306 (179, 567) mg/dl; P=0.04 and 325 (247, 422) versus 280 (212, 366) mg/dl; P=0.009, respectively. The majority of patients did not experience an increase in urine or plasma biomarkers. Absolute changes in plasma IL-18 were comparable in participants with contrast-associated AKI (-30 [-71, -9] mg/dl) and those without contrast-associated AKI (-27 [-53, -10] mg/dl; P=0.62). Relative ratios of plasma IL-18 were also comparable in participants with contrast-associated AKI (0.91; 0.86, 0.97) and those without contrast-associated AKI (0.91; 0.85, 0.96; P=0.54). CONCLUSIONS The lack of significant differences in the absolute changes and relative ratios of injury and repair biomarkers by contrast-associated AKI status suggests that the majority of mild contrast-associated AKI cases may be driven by hemodynamic changes at the kidney.
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Affiliation(s)
- Caroline Liu
- Division of Nephrology, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Maria K Mor
- Center for Health Equity Research and Promotion, Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, Pennsylvania .,Department of Biostatistics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania
| | - Paul M Palevsky
- Renal Section, Medical Service, Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, Pennsylvania.,University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - James S Kaufman
- Division of Nephrology, Veterans Affairs New York Harbor Healthcare System and New York University School of Medicine, New York, New York
| | | | - Steven D Weisbord
- Renal Section, Medical Service, Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, Pennsylvania.,Renal Section, Medical Service and Center for Health Equity Research and Promotion, Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, Pennsylvania
| | - Chirag R Parikh
- Division of Nephrology, Johns Hopkins University School of Medicine, Baltimore, Maryland
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11
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Abstract
The current unidimensional paradigm of kidney disease detection is incompatible with the complexity and heterogeneity of renal pathology. The diagnosis of kidney disease has largely focused on glomerular filtration, while assessment of kidney tubular health has notably been absent. Following insult, the kidney tubular cells undergo a cascade of cellular responses that result in the production and accumulation of low-molecular-weight proteins in the urine and systemic circulation. Modern advancements in molecular analysis and proteomics have allowed the identification and quantification of these proteins as biomarkers for assessing and characterizing kidney diseases. In this review, we highlight promising biomarkers of kidney tubular health that have strong underpinnings in the pathophysiology of kidney disease. These biomarkers have been applied to various specific clinical settings from the spectrum of acute to chronic kidney diseases, demonstrating the potential to improve patient care.
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Affiliation(s)
- William R Zhang
- Kidney Health Research Collaborative, University of California San Francisco School of Medicine, San Francisco, California 94121, USA
| | - Chirag R Parikh
- Division of Nephrology, Johns Hopkins School of Medicine, Baltimore, Maryland 21287, USA;
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12
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Fasano S, Pierro L, Borgia A, Coscia MA, Formica R, Bucci L, Riccardi A, Ciccia F. Biomarker panels may be superior over single molecules in prediction of renal flares in systemic lupus erythematosus: an exploratory study. Rheumatology (Oxford) 2020; 59:3193-3200. [DOI: 10.1093/rheumatology/keaa074] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2019] [Revised: 01/27/2020] [Indexed: 01/30/2023] Open
Abstract
Abstract
Objective
Recent evidence suggests that some urinary biomarkers, namely Vascular Cell Adhesion Molecule-1 (VCAM-1), Intercellular Adhesion Molecule-1 (ICAM-1), Monocyte Chemoattractant Protein 1 (MCP-1), Neutrophil Gelatinase Associated Lipocalcin and Lipocalin-type Prostaglandin D-Synthetase (L-PGDS), might discriminate SLE patients with ongoing renal activity from those with stable disease. The objective of this study was to assess the role of these markers in predicting renal flares in comparison with conventional biomarkers and to derive a biomarker panel which may improve diagnostic accuracy.
Methods
Eligible participants were SLE patients prospectively followed at our clinic. Urinary biomarker levels were measured in urinary sample by ELISA assay and were compared by the unpaired Student’s t test or the Mann–Whitney U test as appropriate. Receiver operating characteristic analysis was used to calculate the area under the curve. Cox regression was used to identify independent factors associated with disease flares.
Results
Urine was collected from 61 patients. During 8 months’ follow-up, eight patients experienced a renal flare. Urinary L-PGDS, ICAM-1 and VCAM-1 levels were significantly increased in the patients who subsequently experienced a renal flare with respect to the remaining 53. At Cox regression analysis, L-PGDS, ICAM-1, VCAM-1, hypocomplementemia and anti-dsDNA antibodies were factors associated with renal flares. Based on receiver operating characteristic analysis, a combination of novel and conventional biomarkers demonstrated an excellent ability for accurately identifying a flare.
Conclusion
This study might suggest the usefulness of a novel biomarker panel in predicting a renal flare in SLE.
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Affiliation(s)
- Serena Fasano
- Rheumatology Section, Department of Precision Medicine, University of Campania L. Vanvitelli, Naples, Italy
| | - Luciana Pierro
- Rheumatology Section, Department of Precision Medicine, University of Campania L. Vanvitelli, Naples, Italy
| | - Alessia Borgia
- Rheumatology Section, Department of Precision Medicine, University of Campania L. Vanvitelli, Naples, Italy
| | - Melania Alessia Coscia
- Rheumatology Section, Department of Precision Medicine, University of Campania L. Vanvitelli, Naples, Italy
| | - Ranieri Formica
- Rheumatology Section, Department of Precision Medicine, University of Campania L. Vanvitelli, Naples, Italy
| | - Laura Bucci
- Rheumatology Section, Department of Precision Medicine, University of Campania L. Vanvitelli, Naples, Italy
| | - Antonella Riccardi
- Rheumatology Section, Department of Precision Medicine, University of Campania L. Vanvitelli, Naples, Italy
| | - Francesco Ciccia
- Rheumatology Section, Department of Precision Medicine, University of Campania L. Vanvitelli, Naples, Italy
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13
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Gembillo G, Cernaro V, Siligato R, Curreri F, Catalano A, Santoro D. Protective Role of Vitamin D in Renal Tubulopathies. Metabolites 2020; 10:115. [PMID: 32204545 PMCID: PMC7142711 DOI: 10.3390/metabo10030115] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2020] [Revised: 03/13/2020] [Accepted: 03/17/2020] [Indexed: 02/06/2023] Open
Abstract
Vitamin D is tightly linked with renal tubular homeostasis: the mitochondria of proximal convoluted tubule cells are the production site of 1α,25-dihydroxyvitamin D3. Patients with renal impairment or tubular injury often suffer from chronic inflammation. This alteration comes from oxidative stress, acidosis, decreased clearance of inflammatory cytokines and stimulation of inflammatory factors. The challenge is to find the right formula for each patient to correctly modulate the landscape of treatment and preserve the essential functions of the organism without perturbating its homeostasis. The complexity of the counter-regulation mechanisms and the different axis involved in the Vitamin D equilibrium pose a major issue on Vitamin D as a potential effective anti-inflammatory drug. The therapeutic use of this compound should be able to inhibit the development of inflammation without interfering with normal homeostasis. Megalin-Cubilin-Amnionless and the FGF23-Klotho axis represent two Vitamin D-linked mechanisms that could modulate and ameliorate the damage response at the renal tubular level, balancing Vitamin D therapy with an effect potent enough to contrast the inflammatory cascades, but which avoids potential severe side effects.
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Affiliation(s)
- Guido Gembillo
- Unit of Nephrology and Dialysis, Department of Clinical and Experimental Medicine, University of Messina, Via Consolare Valeria, 98125 Messina, Italy; (V.C.); (R.S.)
| | - Valeria Cernaro
- Unit of Nephrology and Dialysis, Department of Clinical and Experimental Medicine, University of Messina, Via Consolare Valeria, 98125 Messina, Italy; (V.C.); (R.S.)
| | - Rossella Siligato
- Unit of Nephrology and Dialysis, Department of Clinical and Experimental Medicine, University of Messina, Via Consolare Valeria, 98125 Messina, Italy; (V.C.); (R.S.)
| | | | - Antonino Catalano
- Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy;
| | - Domenico Santoro
- Unit of Nephrology and Dialysis, Department of Clinical and Experimental Medicine, University of Messina, Via Consolare Valeria, 98125 Messina, Italy; (V.C.); (R.S.)
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14
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CCR2 knockout ameliorates obesity-induced kidney injury through inhibiting oxidative stress and ER stress. PLoS One 2019; 14:e0222352. [PMID: 31498850 PMCID: PMC6733486 DOI: 10.1371/journal.pone.0222352] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2019] [Accepted: 08/27/2019] [Indexed: 12/23/2022] Open
Abstract
CCL2/CCR2 signaling is believed to play an important role in kidney diseases. Several studies have demonstrated that blocking of CCR2 has a therapeutic effect on kidney diseases. However, the effects of CCR2 knockout on obesity-induced kidney injury remain unclear. We investigated the therapeutic effects and the mechanism of CCL2/CCR2 signaling in obesity-induced kidney injury. We used C57BL/6-CCR2 wild type and C57BL/6-CCR2 knockout mice: Regular diet wild type (RD WT), RD CCR2 knockout (RD KO), High-fat diet WT (HFD WT), HFD CCR2 KO (HFD KO). Body weight of WT mice was significantly increased after HFD. However, the body weight of HFD KO mice was not decreased compared to HFD WT mice. Food intake and calorie showed no significant differences between HFD WT and HFD KO mice. Glucose, insulin, total cholesterol, and triglycerides levels increased in HFD WT mice were decreased in HFD KO mice. Insulin resistance, increased insulin secretion, and lipid accumulation showed in HFD WT mice were improved in HFD KO mice. Increased desmin expression, macrophage infiltration, and TNF-α in HFD mice were reduced in HFD KO mice. HFD-induced albuminuria, glomerular hypertrophy, glomerular basement membrane thickening, and podocyte effacement were restored by CCR2 depletion. HFD-induced elevated expressions of xBP1, Bip, and Nox4 at RNA and protein levels were significantly decreased in HFD KO. Therefore, blockade of CCL2/CCR2 signaling by CCR2 depletion might ameliorate obesity-induced albuminuria through blocking oxidative stress, ER stress, and lipid accumulation.
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15
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Adhya Z, El Anbari M, Anwar S, Mortimer A, Marr N, Karim MY. Soluble TNF-R1, VEGF and other cytokines as markers of disease activity in systemic lupus erythematosus and lupus nephritis. Lupus 2019; 28:713-721. [DOI: 10.1177/0961203319845487] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Background Current non-invasive methods of assessing disease activity in systemic lupus erythematosus (SLE) are of limited sensitivity and specificity. Testing includes acute phase markers, autoantibodies and complement levels. Although measurements of dsDNA antibodies and complement C3/C4 levels are routine, they remain of limited value. Improved blood and urine markers may help in early detection of flare, distinction between flare and chronic damage, and monitoring response to therapy. Methods A total of 87 patients with SLE were tested for the following cytokines in serum and urine: monocyte chemoattractant protein 1 (MCP-1), regulated upon activation, normal T cell expressed and secreted (RANTES), soluble tumour necrosis factor receptor 1 (sTNF-R1), interferon-inducible protein 10 (IP-10), monocyte inhibitory protein 1α (MIP-1α) and vascular endothelial growth factor (VEGF). Patients attending the Lupus Unit at St Thomas’ Hospital, London, UK were divided into active lupus nephritis (LN), inactive LN and non-renal SLE groups based on their renal pathology and SLE disease activity index (SLEDAI). Cytokine testing was performed using the FIDIS multiplex bead assay. Results The mean level of serum sTNF-R1 was higher in the active LN group compared with both inactive LN and non-renal SLE groups ( p < 0.001). For urine measurements there were significant differences between active LN and non-renal SLE for VEGF ( p = 0.016), after statistical correction for multiple testing. Both urinary and serum sTNF-R1 and IP-10 levels correlated with SLEDAI scores ( p < 0.001), while serum VEGF correlated weakly with SLEDAI ( p = 0.025). The optimum combination for differentiating active from inactive LN patients was serum VEGF, sTNF-R1, MCP-1 and glomerular filtration rate plus urinary sTNF-R1 and protein-creatinine ratio. Conclusion These results indicate that for active LN, sTNF-R1 could be a useful serum cytokine marker, with potential for VEGF in the urine. This study has confirmed the ability of the multiplex bead technique to detect cytokines in a good analytical range, including very low and high levels, in both serum and urine. Combining serum and urine markers provided additional sensitivity in distinguishing active from inactive LN.
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Affiliation(s)
- Z Adhya
- Immunology, King’s College Hospital, London, UK
- Immunology, Guy’s & St Thomas’ Hospitals, London, UK
| | - M El Anbari
- Research Branch, Sidra Medicine, Doha, Qatar
| | - S Anwar
- Section of Nephrology, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | | | - N Marr
- Research Branch, Sidra Medicine, Doha, Qatar
- College of Health and Life Sciences, Hamad Bin Khalifa University, Doha, Qatar
| | - M Y Karim
- Immunology, Guy’s & St Thomas’ Hospitals, London, UK
- Lupus Unit, Guy’s & St Thomas’ Hospitals, London, UK
- Pathology, Sidra Medicine, Doha, Qatar
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16
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Murkamilov IT, Aitbaev KA, Fomin VV, Murkamilova ZA, Bayzhigitova AA. Pentoxifylline and nephroprotection: effects on renal dysfunction and cardiovascular risks. TERAPEVT ARKH 2019; 91:95-100. [PMID: 31090379 DOI: 10.26442/00403660.2019.01.000037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Generalized data on nephroprotective efficacy of pentoxifylline in chronic kidney disease (CKD) are presented. The potential of this drug in treating people suffering from CKD and cardiovascular diseases (CVD) with a high risk of developing the terminal stage of renal dysfunction is considered. Antiproteinuric, antifibrotic and anti-inflammatory effects of pentoxifylline significantly reduce the risk of progression of CKD and joining of CVD in the future. Efficacy in preventing the onset of the uremic stage of CKD, safety andapplicability at all stages of renal dysfunction development make pentoxifylline a very appealing drug not only for nephrologists but also for physicians. Keywords: chronic kidney disease, progression, pentoxifylline, nephroprotection, cardiovascular diseases.
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Affiliation(s)
- I T Murkamilov
- Kyrgyz State Medical Academy named after I.K. Akhunbaev, Bishkek, Kyrgyzstan.,Kyrgyz Russian Slavic University named after the First President of Russia B.N. Yeltsin, Bishkek, Kyrgyzstan
| | - K A Aitbaev
- Scientific Research Institute of Molecular Biology and Medicine, Bishkek, Kyrgyzstan
| | - V V Fomin
- I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian
| | | | - A A Bayzhigitova
- National Hospital under the Ministry of Health of the Kyrgyz Republic, Bishkek, Kyrgyzstan
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17
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Gasparin AA, Pamplona Bueno de Andrade N, Hax V, Tres GL, Veronese FV, Monticielo OA. Urinary biomarkers for lupus nephritis: the role of the vascular cell adhesion molecule-1. Lupus 2019; 28:265-272. [PMID: 30712490 DOI: 10.1177/0961203319826695] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
Renal involvement is one of the main complications of systemic lupus erythematosus, causing a significant impact on patients' morbidity and mortality. Renal biopsy is still the gold standard of diagnosis, but it has many limitations. In this sense, several recent studies aim to identify biomarkers that not only predict disease activity and renal histology, but also lead to earlier treatment. In previous studies, the soluble vascular cell adhesion molecule-1 measured in urine showed a strong association with the presence of lupus nephritis, with clinical and histological activity indexes of the disease and with more severe renal lesions. This paper reviews the main urinary biomarkers of lupus nephritis that have been studied, with special emphasis on vascular cell adhesion molecule-1 results.
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Affiliation(s)
- A A Gasparin
- Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil
| | | | - V Hax
- Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil
| | - G Leví Tres
- Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil
| | - F V Veronese
- Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil
| | - O A Monticielo
- Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil
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18
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Kitagawa A, Tsuboi N, Yokoe Y, Katsuno T, Ikeuchi H, Kajiyama H, Endo N, Sawa Y, Suwa J, Sugiyama Y, Hachiya A, Mimura T, Hiromura K, Maruyama S. Urinary levels of the leukocyte surface molecule CD11b associate with glomerular inflammation in lupus nephritis. Kidney Int 2019; 95:680-692. [PMID: 30712924 DOI: 10.1016/j.kint.2018.10.025] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2018] [Revised: 10/01/2018] [Accepted: 10/18/2018] [Indexed: 12/15/2022]
Abstract
Noninvasive biomarkers of disease activity are needed to monitor response to therapy and predict disease recurrence in patients with glomerulonephritis. The leukocyte surface markers integrin Mac-1 and CD16b have been implicated in the pathogenesis of lupus nephritis (LN). Mac-1 comprises a unique α subunit (CD11b) complexed with a common β2 subunit, which are released along with CD16b from specific leukocyte subsets under inflammatory conditions including glomerulonephritis. We investigated the association of urinary CD11b and CD16b with histopathological activity in 272 patients with biopsy-proven glomerular diseases, including 118 with LN. Urine CD11b and CD16b were measured via enzyme-linked immunosorbent assay. Urinary levels of both markers were increased in LN, but only urinary CD11b was correlated with the number of glomerular leukocytes and with overall histopathological activity. In a subset of patients with samples available from the time of biopsy and subsequent clinical remission of LN, urinary levels of CD11b decreased with successful glucocorticoid treatment. Receiver-operating characteristic curve analysis demonstrated that urinary CD11b was superior to CD16b, the scavenger receptor CD163, and monocyte chemotactic protein-1 for the prediction of proliferative LN. In anti-mouse nephrotoxic serum glomerulonephritis, urinary CD11b correlated with histologic damage and decreased with corticosteroid treatment. In vitro, CD11b levels were decreased on activated mouse neutrophils displaying Fcγ receptor clustering and transendothelial migration, suggesting that leukocyte activation and transmigration are required for CD11b shedding in urine. Together, our results suggest that urinary CD11b may be a useful biomarker to estimate histopathological activity, particularly glomerular leukocyte accumulation, in LN.
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Affiliation(s)
- Akimitsu Kitagawa
- Department of Nephrology, Internal Medicine, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan
| | - Naotake Tsuboi
- Department of Nephrology, Internal Medicine, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan; Department of Nephrology, School of Medicine, Fujita Health University, Toyoake, Aichi, Japan.
| | - Yuki Yokoe
- Department of Nephrology, Internal Medicine, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan
| | - Takayuki Katsuno
- Department of Nephrology and Rheumatology, Aichi Medical University, Nagakute, Aichi, Japan
| | - Hidekazu Ikeuchi
- Department of Nephrology and Rheumatology, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan
| | - Hiroshi Kajiyama
- Department of Rheumatology and Applied Immunology, Faculty of Medicine, Saitama Medical University, Iruma, Saitama, Japan
| | - Nobuhide Endo
- Department of Nephrology, Internal Medicine, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan
| | - Yuriko Sawa
- Department of Nephrology, Internal Medicine, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan
| | - Junya Suwa
- Department of Nephrology and Rheumatology, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan
| | - Yutaka Sugiyama
- Department of Nephrology, Internal Medicine, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan
| | - Asaka Hachiya
- Department of Nephrology, Internal Medicine, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan
| | - Toshihide Mimura
- Department of Rheumatology and Applied Immunology, Faculty of Medicine, Saitama Medical University, Iruma, Saitama, Japan
| | - Keiju Hiromura
- Department of Nephrology and Rheumatology, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan
| | - Shoichi Maruyama
- Department of Nephrology, Internal Medicine, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan
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19
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Spensley KJ, Tam FWK. From Renal Biomarkers to Therapeutic Targets: The Use of Monocyte Chemoattractant Protein 1, Transforming Growth Factor-Beta, and Connective Tissue Growth Factor in Diabetic Nephropathy and Antineutrophil Cytoplasmic Antibody-Associated Vasculitis. EUROPEAN MEDICAL JOURNAL 2018. [DOI: 10.33590/emj/10310232] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
In an ideal world, every condition would have a sensitive and specific marker that could be measured in a noninvasive or minimally invasive way. Instead, the medical community depends on invasive biomarkers, which carry inherent risks, to make a diagnosis and plan treatment. In this review article, the current state of research into biomarkers for a range of kidney diseases is discussed, beginning with those biomarkers that are already in clinical use and then moving to conditions for which no validated biomarker yet exists. This review focusses on diabetic nephropathy at the proteinuric end of the spectrum and antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis at the nephritic end. An interesting feature is that the same biomarker, monocyte chemoattractant protein-1 (MCP-1, also known as CCL2), has been identified as a potential target in both conditions, which suggests a shared pathogenic process that results in two very distinct clinical presentations. One of the major limiting features of research into this area, particularly for ANCA-associated vasculitis, is the recruitment of a sufficient number of patients to generate strong enough evidence to justify the biomarker’s routine use; this overlap in biomarkers may enable research in one condition to be applied more generally. In addition to their role as biomarkers, these molecules are also therapeutic targets, and some early research has been carried out to investigate this. Overall, this review brings together research from diverse fields to focus attention on the outstanding areas and the future areas that warrant further investigation.
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Affiliation(s)
- Katrina J. Spensley
- Renal and Vascular Inflammation Section, Department of Medicine, Imperial College London, Hammersmith Hospital, London, UK
| | - Frederick W. K. Tam
- Renal and Vascular Inflammation Section, Department of Medicine, Imperial College London, Hammersmith Hospital, London, UK
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20
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Vincent FB, Slavin L, Hoi AY, Kitching AR, Mackay F, Harris J, Kandane-Rathnayake R, Morand EF. Analysis of urinary macrophage migration inhibitory factor in systemic lupus erythematosus. Lupus Sci Med 2018; 5:e000277. [PMID: 30397495 PMCID: PMC6203042 DOI: 10.1136/lupus-2018-000277] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2018] [Revised: 08/20/2018] [Accepted: 08/27/2018] [Indexed: 01/02/2023]
Abstract
Objective To characterise the clinical relevance of urinary macrophage migration inhibitory factor (uMIF) concentrations in patients with systemic lupus erythematosus (SLE). Methods MIF, adjusted for urine creatinine, was quantified by ELISA in urine samples from 64 prospectively recruited patients with SLE. Serum MIF and urinary monocyte chemoattractant protein 1 (uMCP-1) were quantified by ELISA in a subset of patients (n = 39). Disease activity was assessed using the SLE Disease Activity Index-2000 (SLEDAI-2K) score. Results uMIF was detectable in all patients with SLE. uMIF was positively correlated with overall SLEDAI-2K, was significantly higher in patients with SLE with high disease activity (SLEDAI-2K≥10) compared with those with inactive disease (SLEDAI-2K<4), and this association remained significant after adjusting for ethnicity, flare and use of immunosuppressants. uMIF was also significantly higher in SLE patients with flare of disease, although not confirmed in multivariable analysis. No significant differences in uMIF levels were observed according to the presence of renal disease activity, as assessed by renal SLEDAI-2K or biopsy-confirmed lupus nephritis. In contrast, uMCP-1 was significantly higher in SLE patients with active renal disease. uMIF expression was not associated with irreversible organ damage accrual or glucocorticoid use. Conclusions These data suggest uMIF as a potential overall but not renal-specific SLE biomarker, whereas uMCP-1 is a renal-specific SLE biomarker.
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Affiliation(s)
- Fabien B Vincent
- Centre for Inflammatory Diseases, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia
| | - Laura Slavin
- Centre for Inflammatory Diseases, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia
| | - Alberta Y Hoi
- Centre for Inflammatory Diseases, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia
| | - Arthur Richard Kitching
- Centre for Inflammatory Diseases, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia
| | - Fabienne Mackay
- Department of Microbiology and Immunology, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Melbourne, Victoria, Australia.,Department of Immunology and Pathology, Central Clinical School, Monash University, Melbourne, Victoria, Australia
| | - James Harris
- Centre for Inflammatory Diseases, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia
| | - Rangi Kandane-Rathnayake
- Centre for Inflammatory Diseases, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia
| | - Eric F Morand
- Centre for Inflammatory Diseases, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia
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21
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Vincent FB, Kandane-Rathnayake R, Hoi AY, Slavin L, Godsell JD, Kitching AR, Harris J, Nelson CL, Jenkins AJ, Chrysostomou A, Hibbs ML, Kerr PG, Rischmueller M, Mackay F, Morand EF. Urinary B-cell-activating factor of the tumour necrosis factor family (BAFF) in systemic lupus erythematosus. Lupus 2018; 27:2029-2040. [PMID: 30301439 DOI: 10.1177/0961203318804885] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
INTRODUCTION We examined the clinical relevance of urinary concentrations of B-cell-activating factor of the tumour necrosis factor family (BAFF) and a proliferation-inducing ligand (APRIL) in systemic lupus erythematosus (SLE). METHODS We quantified urinary BAFF (uBAFF) by enzyme-linked immunosorbent assay in 85 SLE, 28 primary Sjögren syndrome (pSS), 40 immunoglobulin A nephropathy (IgAN) patients and 36 healthy controls (HCs). Urinary APRIL (uAPRIL) and monocyte chemoattractant protein 1 (uMCP-1) were also quantified. Overall and renal SLE disease activity were assessed using the Systemic Lupus Erythematosus Disease Activity Index 2000. RESULTS uBAFF was detected in 12% (10/85) of SLE patients, but was undetectable in HCs, IgAN and pSS patients. uBAFF was detectable in 28% (5/18) of SLE patients with active nephritis vs 5/67 (7%) of those without ( p = 0.03), and uBAFF was significantly higher in active renal patients ( p = 0.02) and more likely to be detected in patients with persistently active renal disease. In comparison, uAPRIL and uMCP-1 were detected in 32% (25/77) and 46% (22/48) of SLE patients, respectively. While no difference in proportion of samples with detectable uAPRIL was observed between SLE, HCs and IgAN patients, both uAPRIL and uMCP-1 were significantly detectable in higher proportions of patients with active renal disease. CONCLUSIONS uBAFF was detectable in a small but a significant proportion of SLE patients but not in other groups tested, and was higher in SLE patients with active renal disease.
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Affiliation(s)
- F B Vincent
- 1 Centre for Inflammatory Diseases, Monash University School of Clinical Sciences at Monash Health, Melbourne, Victoria, Australia
| | - R Kandane-Rathnayake
- 1 Centre for Inflammatory Diseases, Monash University School of Clinical Sciences at Monash Health, Melbourne, Victoria, Australia
| | - A Y Hoi
- 1 Centre for Inflammatory Diseases, Monash University School of Clinical Sciences at Monash Health, Melbourne, Victoria, Australia
| | - L Slavin
- 1 Centre for Inflammatory Diseases, Monash University School of Clinical Sciences at Monash Health, Melbourne, Victoria, Australia
| | - J D Godsell
- 1 Centre for Inflammatory Diseases, Monash University School of Clinical Sciences at Monash Health, Melbourne, Victoria, Australia
| | - A R Kitching
- 1 Centre for Inflammatory Diseases, Monash University School of Clinical Sciences at Monash Health, Melbourne, Victoria, Australia.,2 Department of Nephrology, Monash Health, and Monash University, Clayton, Victoria, Australia
| | - J Harris
- 1 Centre for Inflammatory Diseases, Monash University School of Clinical Sciences at Monash Health, Melbourne, Victoria, Australia
| | - C L Nelson
- 3 Western Health, Department of Nephrology, St Albans, Victoria, Australia.,4 The Department of Medicine, Western Health, The University of Melbourne, St Albans, Victoria, Australia
| | - A J Jenkins
- 5 National Health and Medical Research Council (NHMRC) Clinical Trials Centre, University of Sydney, Camperdown, New South Wales, Australia
| | - A Chrysostomou
- 6 The Renal Unit, The Alfred Hospital, Prahran, Victoria, Australia
| | - M L Hibbs
- 7 Department of Immunology and Pathology, Monash University, Central Clinical School, Melbourne, Victoria, Australia
| | - P G Kerr
- 2 Department of Nephrology, Monash Health, and Monash University, Clayton, Victoria, Australia
| | - M Rischmueller
- 8 Rheumatology Department, The Queen Elizabeth Hospital, and Discipline of Medicine, University of Adelaide, Adelaide, South Australia, Australia
| | - F Mackay
- 7 Department of Immunology and Pathology, Monash University, Central Clinical School, Melbourne, Victoria, Australia.,9 Department of Microbiology and Immunology, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Melbourne, Victoria, Australia
| | - E F Morand
- 1 Centre for Inflammatory Diseases, Monash University School of Clinical Sciences at Monash Health, Melbourne, Victoria, Australia
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22
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Wu CY, Yang HY, Chien HP, Tseng MH, Huang JL. Urinary clusterin-a novel urinary biomarker associated with pediatric lupus renal histopathologic features and renal survival. Pediatr Nephrol 2018; 33:1189-1198. [PMID: 29511890 DOI: 10.1007/s00467-018-3924-4] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2017] [Revised: 01/29/2018] [Accepted: 01/30/2018] [Indexed: 12/12/2022]
Abstract
BACKGROUND Lupus nephritis (LN) is a major risk factor for systemic lupus erythematous (SLE)-related morbidity and mortality. With the aim of bypassing renal biopsy, we analyzed urinary biomarkers for their ability to predict renal histopathologic features and end-stage kidney disease (ESKD). METHODS Urinary albumin, ß2-microglobulin (B2M), cystatin C, kidney injury molecule-1 (KIM-1), monocyte chemoattractant protein 1 (MCP-1), clusterin, calbindin, interleukin-18 (IL-18), neutrophil gelatinase-associated lipocalin (NGAL), trefoil factor 3 (TFF3), osteopontin, and glutathione S-transferase π (GST-π) levels were measured at time of renal biopsy. Renal histopathologies were carefully reviewed. RESULTS Urine from 60 pediatric SLE cases with LN, 29 without and 22 healthy controls were collected. Median age at SLE diagnosis was 12.92 years (range = 4.27-17.30 years) and 10 cases progressed to ESKD during a period of 4.12 ± 2.17 years. Urinary albumin and clusterin were significantly elevated (p = 0.035 and 0.048, respectively) in patients with tubulointerstitial renal lesions. Urinary clusterin among all urinary markers, performed best at predicting ESKD with cutoff of 0.61 × 10-4 (AUC = 0.804; p = 0.002). Interestingly, elevation of urinary clusterin likely resulted from local over-expression in tubulointerstitial tissue since the level of serum clusterin was not concomitantly higher (p = 0.424). CONCLUSION Urinary biomarkers are emerging as non-invasive indicators for lupus-related renal histopathology and renal outcome prediction in pediatric SLE patients. Urinary clusterin, a newly identified biomarker, is an indicator that shows an association with tubulointerstitial renal lesions and demonstrates the best ability to predict ESKD.
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Affiliation(s)
- Chao-Yi Wu
- Division of Allergy, Asthma, and Rheumatology, Department of Pediatrics, Chang Gung Memorial Hospital Linko branch, Taoyuan, Taiwan.,Chang Gung University, College of Medicine, Taoyuan, Taiwan
| | - Huang-Yu Yang
- Chang Gung University, College of Medicine, Taoyuan, Taiwan.,Department of Nephrology, Chang Gung Memorial Hospital Linko branch, Taoyuan, Taiwan
| | - Hui-Ping Chien
- Chang Gung University, College of Medicine, Taoyuan, Taiwan.,Department of Pathology, Chang Gung Memorial Hospital Linko branch, Taoyuan, Taiwan
| | - Min-Hua Tseng
- Chang Gung University, College of Medicine, Taoyuan, Taiwan.,Division of Pediatric Nephrology, Department of Pediatrics, Chang Gung Memorial Hospital Linko branch, Taoyuan, Taiwan
| | - Jing-Long Huang
- Division of Allergy, Asthma, and Rheumatology, Department of Pediatrics, Chang Gung Memorial Hospital Linko branch, Taoyuan, Taiwan. .,Chang Gung University, College of Medicine, Taoyuan, Taiwan.
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23
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López-Mejías R, Castañeda S, Genre F, Remuzgo-Martínez S, Carmona FD, Llorca J, Blanco R, Martín J, González-Gay MA. Genetics of immunoglobulin-A vasculitis (Henoch-Schönlein purpura): An updated review. Autoimmun Rev 2018; 17:301-315. [DOI: 10.1016/j.autrev.2017.11.024] [Citation(s) in RCA: 60] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2017] [Accepted: 11/16/2017] [Indexed: 12/12/2022]
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Abstract
OBJECTIVE This study aimed to evaluate whether urinary monocyte chemoattractant protein-1 (MCP-1) could serve as a biomarker for lupus nephritis (LN). METHODS We performed a meta-analysis to examine the relationship between urinary MCP-1 level and LN in three comparisons: active LN versus inactive LN, active LN versus control, and inactive LN versus control. RESULTS Eight studies of a total of 399 patients with LN (204 with active LN, and 195 with inactive LN) and 130 controls were available for this meta-analysis. The meta-analysis revealed that the urinary MCP-1 level was significantly higher in the active-LN group than in the inactive-LN group (standard mean difference [SMD] = 1.883, 95 % confidence interval [CI] = 0.811-2.954, p = 0.001). The meta-analysis showed that the urinary MCP-1 level was significantly higher in the active-LN group than in the control group (SMD = 3.085, 95 % CI = 1.684-4.485, p = 1.6 × 10-5). Furthermore, stratification by ethnicity showed significantly elevated urinary MCP-1 levels in the active-LN group in Caucasian, Asian, and Egyptian populations (SMD = 2.408, 95 % CI = 1.711-3.105, p < 1.0 × 10-8; SMD = 1.020, 95 % CI = 0.623-2.153, p = 4.6 × 10-7; and SMD = 7.370, 95 % CI = 1.467-2.157, p = 5.9 × 10-5, respectively). The meta-analysis indicated that the urinary MCP-1 level was also significantly higher in the inactive-LN group than in the control group (SMD = 1.812, 95 % CI = 0.628-2.996, p = 0.003). CONCLUSIONS The meta-analysis demonstrated that urinary MCP-1 was significantly higher in patients with active LN than in those with inactive LN and control subjects, and the patients with inactive LN showed significantly higher urinary MCP-1 levels than the controls.
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Affiliation(s)
- Y H Lee
- Division of Rheumatology, Department of Internal Medicine, Korea University Medical Center, Korea University College of Medicine, 73 Inchon-ro, Seongbuk-gu, 02841, Seoul, Korea.
| | - G G Song
- Division of Rheumatology, Department of Internal Medicine, Korea University Medical Center, Korea University College of Medicine, 73 Inchon-ro, Seongbuk-gu, 02841, Seoul, Korea
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25
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Ikuma D, Hiromura K, Kajiyama H, Suwa J, Ikeuchi H, Sakairi T, Kaneko Y, Maeshima A, Kurosawa H, Hirayama Y, Yokota K, Araki Y, Sato K, Asanuma YF, Akiyama Y, Hara M, Nojima Y, Mimura T. The correlation of urinary podocytes and podocalyxin with histological features of lupus nephritis. Lupus 2017; 27:484-493. [PMID: 29050536 DOI: 10.1177/0961203317734918] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Objectives The objective of this study was to test the correlation of urinary podocyte number (U-Pod) and urinary podocalyxin levels (U-PCX) with histology of lupus nephritis. Methods This was an observational, cross-sectional study. Sixty-four patients were enrolled: 40 with lupus nephritis and 24 without lupus nephritis (12 lupus nephritis patients in complete remission and 12 systemic lupus erythematosus patients without lupus nephritis). Urine samples were collected before initiating treatment. U-Pod was determined by counting podocalyxin-positive cells, and U-PCX was measured by sandwich ELISA, normalized to urinary creatinine levels (U-Pod/Cr, U-PCX/Cr). Results Lupus nephritis patients showed significantly higher U-Pod/Cr and U-PCX/Cr compared with patients without lupus nephritis. U-Pod/Cr was high in proliferative lupus nephritis (class III±V/IV±V), especially in pure class IV (4.57 (2.02-16.75)), but low in pure class V (0.30 (0.00-0.71)). U-Pod/Cr showed a positive correlation with activity index ( r=0.50, P=0.0012) and was independently associated with cellular crescent formation. In contrast, U-PCX/Cr was high in both proliferative and membranous lupus nephritis. Receiver operating characteristic analysis revealed significant correlation of U-Pod/Cr with pure class IV, class IV±V and cellular crescent formation, and the combined values of U-Pod/Cr and U-PCX/Cr were shown to be associated with pure class V. Conclusions U-Pod/Cr and U-PCX/Cr correlate with histological features of lupus nephritis.
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Affiliation(s)
- D Ikuma
- 1 Department of Rheumatology and Applied Immunology, Saitama Medical University, Saitama, Japan
| | - K Hiromura
- 2 Department of Medicine and Clinical Science, Gunma University Graduate School of Medicine, Gunma, Japan
| | - H Kajiyama
- 1 Department of Rheumatology and Applied Immunology, Saitama Medical University, Saitama, Japan
| | - J Suwa
- 2 Department of Medicine and Clinical Science, Gunma University Graduate School of Medicine, Gunma, Japan
| | - H Ikeuchi
- 2 Department of Medicine and Clinical Science, Gunma University Graduate School of Medicine, Gunma, Japan
| | - T Sakairi
- 2 Department of Medicine and Clinical Science, Gunma University Graduate School of Medicine, Gunma, Japan
| | - Y Kaneko
- 2 Department of Medicine and Clinical Science, Gunma University Graduate School of Medicine, Gunma, Japan
| | - A Maeshima
- 2 Department of Medicine and Clinical Science, Gunma University Graduate School of Medicine, Gunma, Japan
| | - H Kurosawa
- 3 Diagnostics Research Department, Denka Innovation Center, Tokyo, Japan
| | - Y Hirayama
- 3 Diagnostics Research Department, Denka Innovation Center, Tokyo, Japan
| | - K Yokota
- 1 Department of Rheumatology and Applied Immunology, Saitama Medical University, Saitama, Japan
| | - Y Araki
- 1 Department of Rheumatology and Applied Immunology, Saitama Medical University, Saitama, Japan
| | - K Sato
- 1 Department of Rheumatology and Applied Immunology, Saitama Medical University, Saitama, Japan
| | - Y F Asanuma
- 1 Department of Rheumatology and Applied Immunology, Saitama Medical University, Saitama, Japan
| | - Y Akiyama
- 1 Department of Rheumatology and Applied Immunology, Saitama Medical University, Saitama, Japan.,4 Department of Rheumatology, Japanese Red Cross Ogawa Hospital, Saitama, Japan
| | - M Hara
- 5 Department of Pediatrics, Yoshida Hospital, Niigata, Japan
| | - Y Nojima
- 6 Department of Nephrology, Japanese Red Cross Maebashi Hospital, Gunma, Japan
| | - T Mimura
- 1 Department of Rheumatology and Applied Immunology, Saitama Medical University, Saitama, Japan
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26
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Arriens C, Wren JD, Munroe ME, Mohan C. Systemic lupus erythematosus biomarkers: the challenging quest. Rheumatology (Oxford) 2017; 56:i32-i45. [PMID: 28013203 DOI: 10.1093/rheumatology/kew407] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2016] [Indexed: 01/01/2023] Open
Abstract
SLE, a multisystem heterogeneous disease, is characterized by production of antibodies to cellular components, with activation of both the innate and the adaptive immune system. Decades of investigation of blood biomarkers has resulted in incremental improvements in the understanding of SLE. Owing to the heterogeneity of immune dysregulation, no single biomarker has emerged as a surrogate for disease activity or prediction of disease. Beyond identification of surrogate biomarkers, a multitude of clinical trials have sought to inhibit elevated SLE biomarkers for therapeutic benefit. Armed with new -omics technologies, the necessary yet daunting quest to identify better surrogate biomarkers and successful therapeutics for SLE continues with tenacity.
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Affiliation(s)
- Cristina Arriens
- Department of Arthritis and Clinical Immunology, Oklahoma Medical Research Foundation.,Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK
| | - Jonathan D Wren
- Department of Arthritis and Clinical Immunology, Oklahoma Medical Research Foundation
| | - Melissa E Munroe
- Department of Arthritis and Clinical Immunology, Oklahoma Medical Research Foundation
| | - Chandra Mohan
- Department of Biomedical Engineering, University of Houston, Houston, TX, USA
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27
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Abstract
PURPOSE OF REVIEW Recently, initial studies have been carried out in patients using monocyte chemoattractant protein-1 (MCP-1) inhibitors. This review summarizes the known function of MCP-1 in regulating monocytes during inflammation and its role in inflammatory disease of the kidney. RECENT FINDINGS MCP-1 is one of the first chemokines described and plays an important role in renal inflammatory disease. The function of MCP-1 has been investigated and analyzed in both animal models of renal disease and renal patients. MCP-1 mediates firstly the release of monocytes from the bone marrow, and then generates a gradient in the endothelial glycocalyx to direct monocytes to sites of inflammation, thereby alleviating the migration of blood leukocytes into the inflamed tissue. In addition, MCP-1 has direct signaling effects in monocytes and influences migration, proliferation, and differentiation of leukocytes. Blockade of MCP-1 in several models of renal disease has ameliorated the disease, suggesting that inhibition of MCP-1 is a promising and valid strategy to treat patients with renal inflammatory disease. SUMMARY Understanding the role of MCP-1 in monocyte homeostasis and the implications of MCP-1 inhibition in renal disease will help in designing better diagnostic and therapeutic strategies in patients with inflammatory renal disease.
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28
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Soliman S, Mohan C. Lupus nephritis biomarkers. Clin Immunol 2016; 185:10-20. [PMID: 27498110 DOI: 10.1016/j.clim.2016.08.001] [Citation(s) in RCA: 94] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2016] [Revised: 07/30/2016] [Accepted: 08/01/2016] [Indexed: 12/13/2022]
Abstract
Lupus nephritis (LN), a potentially destructive outcome of SLE, is a real challenge in the management of SLE because of the difficulty in diagnosing its subclinical onset and identifying relapses before serious complications set in. Conventional clinical parameters such as proteinuria, GFR, urine sediments, anti-dsDNA and complement levels are not sensitive or specific enough for detecting ongoing disease activity in lupus kidneys and early relapse of nephritis. There has long been a need for biomarkers of disease activity in LN. Such markers ideally should be capable of predicting early sub-clinical flares and could be used to gauge response to therapy, thus obviating the need for serial renal biopsies with their possible hazardous complications. Since urine can be readily obtained, it lends itself as an obvious biological substrate. In this review, the use of urine and serum as sources of lupus nephritis biomarkers is described, and the results of biomarker discovery studies using candidate and proteomic approaches are summarized.
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Affiliation(s)
- Samar Soliman
- Department of Biomedical Engineering, University of Houston, Houston, TX 77204, United States; Rheumatology & Rehabilitation Dept., Faculty of Medicine, Minya University, Egypt
| | - Chandra Mohan
- Department of Biomedical Engineering, University of Houston, Houston, TX 77204, United States.
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29
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Guo H, Leung JCK, Chan LYY, Lui SL, Tsang AWL, Lai KN. Modulation of intra-pulmonary TGF-b expression by mycophenolate mofetil in lupus prone MRL/lpr mice. Lupus 2016; 14:583-92. [PMID: 16175929 DOI: 10.1191/0961203305lu2170oa] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
We investigated the expression profile of inflammatory cytokines in the lung of lupus-prone MRL/lpr mice and evaluated the therapeutic potential of mycophenolate mofetil (MMF) in reducing pulmonary cytokines in active lupus. Eight-week old female MRL/lpr mice ( n = 20) were treated with MMF in vehicle by oral gavage. Disease control MRL/lpr mice ( n = 30) or normal control MRL mice ( n = 20) received vehicle alone. The mice were sacrificed after eight or 12 weeks of treatment. Gene expression and protein synthesis of IL-1β, MCP-1 and TGF-β1 in lung tissues were determined. We found an increase in the gene expression of IL-1β, MCP-1 and TGF-β1 in lung tissues of untreated MRL/lpr mice compared with MRL mice at either 16 weeks or 20 weeks of age. MMF treatment significantly prolonged the survival of MRL/lpr mice, down-regulated the gene expression of IL-1β, MCP-1 and TGF-β1 in lung tissues at the end of eight or 12 weeks of treatment. Protein synthesis of TGF-b1 was decreased following eight weeks of MMF treatment. We conclude that MMF treatment can reduce the TGF-b1 gene expression and protein synthesis in lung tissues of lupus-prone mice. Our findings provide experimental data suggesting a beneficial potential of MMF therapy in pulmonary involvement of lupus.
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Affiliation(s)
- H Guo
- Department of Medicine, Queen Mary Hospital, University of Hong Kong, Pokfulam, Hong Kong
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30
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Smith EMD, Beresford MW. Urinary biomarkers in childhood lupus nephritis. Clin Immunol 2016; 185:21-31. [PMID: 27373868 DOI: 10.1016/j.clim.2016.06.010] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2016] [Revised: 06/26/2016] [Accepted: 06/27/2016] [Indexed: 12/12/2022]
Abstract
Juvenile-onset systemic lupus erythematosus (JSLE) is a rare, severe multisystem autoimmune disease affecting the kidney (Lupus Nephritis, LN) in up to 80% of children. LN is more severe in children than adults, with potential for irreversible kidney damage requiring dialysis or transplant. Renal biopsy is currently the gold standard for diagnosing and monitoring LN, however, it is invasive and associated with complications. Urine biomarkers have been shown to be better than serum biomarkers in differentiating renal disease from other organ manifestations. Over the past decade, there have been an increasing number of studies investigating specific candidate biomarkers implicated in the pathogenesis of LN or screening for urinary biomarkers using hypothesis free methods. In this review, developments in urine biomarkers for LN will be reviewed, highlighting those that are of relevance to children and have gone through validation in independent international patient cohorts, bringing them close to clinical translation.
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Affiliation(s)
- Eve M D Smith
- Department of Women's & Children's Health, Institute of Translational Medicine, University of Liverpool, Institute in the Park, Alder Hey Children's NHS Foundation Trust Hospital, East Prescott Road, Liverpool L14 5AB, UK.
| | - Michael W Beresford
- Department of Women's & Children's Health, Institute of Translational Medicine, University of Liverpool, Institute in the Park, Alder Hey Children's NHS Foundation Trust Hospital, East Prescott Road, Liverpool L14 5AB, UK; Department of Paediatric Rheumatology, Alder Hey Children's NHS Foundation Trust in the Park, East Prescott Road, Liverpool, L14 5AB, Liverpool, UK.
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31
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Endo N, Tsuboi N, Furuhashi K, Shi Y, Du Q, Abe T, Hori M, Imaizumi T, Kim H, Katsuno T, Ozaki T, Kosugi T, Matsuo S, Maruyama S. Urinary soluble CD163 level reflects glomerular inflammation in human lupus nephritis. Nephrol Dial Transplant 2016; 31:2023-2033. [PMID: 27242373 DOI: 10.1093/ndt/gfw214] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2016] [Accepted: 04/17/2016] [Indexed: 11/14/2022] Open
Abstract
BACKGROUND In addition to classically activated macrophages that have effector roles in tissue injury, alternatively activated M2 macrophages are involved in the resolution of inflammation in animal models of kidney disease. To clarify the clinical relevance of macrophage phenotypes in human glomerular diseases, we evaluated the renal accumulation of macrophages and plasma and urine levels of CD163, an M2 marker, in lupus nephritis (LN) patients. METHODS Kidney biopsies and plasma and urine samples were obtained from LN patients who underwent renal biopsy between 2008 and 2012. CD163+, CD68+ and CD204+ cells were counted in paraffin-embedded and frozen sections. LN histological activity was evaluated semiquantitatively using the biopsy activity index. Plasma and urinary soluble CD163 (sCD163) concentrations were also measured and evaluated for their significance as potential LN biomarkers. RESULTS Immunohistological analysis of glomeruli from LN patients revealed that >60% of CD68+ macrophages had merged with CD163+ cells. The increased number of glomerular CD163+ macrophages was correlated with LN severity, as determined by the biopsy active index (r = 0.635). Urinary (u-) sCD163 level was strongly correlated with glomerular CD163+ cell counts and histological disease score as well as urinary monocyte chemoattractant protein 1 levels (r = 0.638 and 0.592, respectively). Furthermore, the u-sCD163 level was higher in patients with active LN than in those with other diseases. CONCLUSIONS Glomerular CD163+ macrophages are the predominant phenotype in the kidneys of lupus patients. These findings indicate that the u-sCD163 level can serve as a biomarker for macrophage-dependent glomerular inflammation in human LN.
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Affiliation(s)
- Nobuhide Endo
- Department of Nephrology, Internal Medicine, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya, Aichi, Japan
| | - Naotake Tsuboi
- Department of Nephrology, Internal Medicine, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya, Aichi, Japan
| | - Kazuhiro Furuhashi
- Department of Nephrology, Internal Medicine, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya, Aichi, Japan.,Columbia Center for Translational Immunology, Department of Medicine, Surgery and Microbiology/Immunology, College of Physicians and Surgeons, Columbia University, New York, NY, USA
| | - Yiqin Shi
- Department of Nephrology, Internal Medicine, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya, Aichi, Japan
| | - Qiuna Du
- Department of Nephrology, Internal Medicine, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya, Aichi, Japan
| | - Tomoko Abe
- Department of Nephrology, Internal Medicine, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya, Aichi, Japan
| | - Mayuko Hori
- Department of Nephrology, Internal Medicine, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya, Aichi, Japan
| | - Takahiro Imaizumi
- Department of Nephrology, Internal Medicine, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya, Aichi, Japan
| | - Hangsoo Kim
- Department of Nephrology, Internal Medicine, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya, Aichi, Japan
| | - Takayuki Katsuno
- Department of Nephrology, Internal Medicine, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya, Aichi, Japan
| | - Takenori Ozaki
- Department of Nephrology, Banbuntane Hotokukai Hospital and Fujita Health University, Nakagawa-ku, Nagoya, Aichi, Japan
| | - Tomoki Kosugi
- Department of Nephrology, Internal Medicine, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya, Aichi, Japan
| | - Seiichi Matsuo
- Department of Nephrology, Internal Medicine, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya, Aichi, Japan
| | - Shoichi Maruyama
- Department of Nephrology, Internal Medicine, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya, Aichi, Japan
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32
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Choi J, Selmi C, Leung PSC, Kenny TP, Roskams T, Gershwin ME. Chemokine and chemokine receptors in autoimmunity: the case of primary biliary cholangitis. Expert Rev Clin Immunol 2016; 12:661-72. [PMID: 26821815 DOI: 10.1586/1744666x.2016.1147956] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Chemokines represent a major mediator of innate immunity and play a key role in the selective recruitment of cells during localized inflammatory responses. Beyond critical extracellular mediators of leukocyte trafficking, chemokines and their cognate receptors are expressed by a variety of resident and infiltrating cells (monocytes, lymphocytes, NK cells, mast cells, and NKT cells). Chemokines represent ideal candidates for mechanistic studies (particularly in murine models) to better understand the pathogenesis of chronic inflammation and possibly become biomarkers of disease. Nonetheless, therapeutic approaches targeting chemokines have led to unsatisfactory results in rheumatoid arthritis, while biologics against pro-inflammatory cytokines are being used worldwide with success. In this comprehensive review we will discuss the evidence supporting the involvement of chemokines and their specific receptors in mediating the effector cell response, utilizing the autoimmune/primary biliary cholangitis setting as a paradigm.
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Affiliation(s)
- Jinjung Choi
- a Division of Rheumatology, Allergy and Clinical Immunology , University of California Davis , Davis , CA , USA.,b Division of Rheumatology , CHA University Medical Center , Bundang , Korea
| | - Carlo Selmi
- c Rheumatology and Clinical Immunology , Humanitas Research Hospital , Rozzano , Italy.,d BIOMETRA Department , University of Milan , Milano , Italy
| | - Patrick S C Leung
- a Division of Rheumatology, Allergy and Clinical Immunology , University of California Davis , Davis , CA , USA
| | - Thomas P Kenny
- a Division of Rheumatology, Allergy and Clinical Immunology , University of California Davis , Davis , CA , USA
| | - Tania Roskams
- e Translational Cell and Tissue Research , University of Leuven , Leuven , Belgium
| | - M Eric Gershwin
- a Division of Rheumatology, Allergy and Clinical Immunology , University of California Davis , Davis , CA , USA
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Lopez-Giacoman S, Madero M. Biomarkers in chronic kidney disease, from kidney function to kidney damage. World J Nephrol 2015; 4:57-73. [PMID: 25664247 PMCID: PMC4317628 DOI: 10.5527/wjn.v4.i1.57] [Citation(s) in RCA: 218] [Impact Index Per Article: 21.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2014] [Revised: 10/21/2014] [Accepted: 11/10/2014] [Indexed: 02/06/2023] Open
Abstract
Chronic kidney disease (CKD) typically evolves over many years, with a long latent period when the disease is clinically silent and therefore diagnosis, evaluation and treatment is based mainly on biomarkers that assess kidney function. Glomerular filtration rate (GFR) remains the ideal marker of kidney function. Unfortunately measuring GFR is time consuming and therefore GFR is usually estimated from equations that take into account endogenous filtration markers like serum creatinine (SCr) and cystatin C (CysC). Other biomarkers such as albuminuria may precede kidney function decline and have demonstrated to have strong associations with disease progression and outcomes. New potential biomarkers have arisen with the promise of detecting kidney damage prior to the currently used markers. The aim of this review is to discuss the utility of the GFR estimating equations and biomarkers in CKD and the different clinical settings where these should be applied. The CKD-Epidemiology Collaboration equation performs better than the modification of diet in renal disease equation, especially at GFR above 60 mL/min per 1.73 m2. Equations combining CysC and SCr perform better than the equations using either CysC or SCr alone and are recommended in situations where CKD needs to be confirmed. Combining creatinine, CysC and urine albumin to creatinine ratio improves risk stratification for kidney disease progression and mortality. Kidney injury molecule and neutrophil gelatinase-associated lipocalin are considered reasonable biomarkers in urine and plasma to determine severity and prognosis of CKD.
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Biomarkers of renal function, which and when? Clin Chim Acta 2015; 438:350-7. [DOI: 10.1016/j.cca.2014.08.039] [Citation(s) in RCA: 200] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2014] [Revised: 08/27/2014] [Accepted: 08/29/2014] [Indexed: 12/11/2022]
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Abstract
Systemic lupus erythematosus (SLE) is a relapsing autoimmune disease with clinical manifestations that affect multiple organ systems. Lupus nephritis is recognized as one of the most severe organ involvements in SLE and affects half of the lupus patients. Notably, lupus nephritis is characterized by intrarenal lymphocyte activation and inflammation. Since most of the cytokines exert their effects in a paracrine fashion, measuring their expression at the site of pathology should be of biological relevance. Although kidney biopsy is widely used to determine the histology and severity of lupus nephritis, this invasive procedure has its own risk and is not practical for serial monitoring. In the past decade, extraction and quantification of messenger RNA (mRNA) from urinary sediment has emerged as a robust laboratory technique. Quantification of mRNA expression in urinary sediment has been tested as a noninvasive means to assess the disease activity of SLE patients. Available published evidence, however, is limited to small-scale studies. Based on the result of these studies, a number of cytokine and transcript factor genes have been found to have potential for the differentiation between active and inactive SLE, between proliferative and membranous types of lupus nephritis, assessment of the systemic lupus activity or histological activity of kidney biopsy specimen, monitoring of treatment response in active lupus nephritis, or detection of lupus disease flare in clinically quiescent patients. Being a simple and noninvasive method, urinary mRNA level deserves further studies to validate its role in risk stratification and monitoring of therapeutic response in patients with lupus nephritis.
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Hartono SP, Knudsen BE, Lerman LO, Textor SC, Grande JP. Combined effect of hyperfiltration and renin angiotensin system activation on development of chronic kidney disease in diabetic db/db mice. BMC Nephrol 2014; 15:58. [PMID: 24708836 PMCID: PMC3984262 DOI: 10.1186/1471-2369-15-58] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2013] [Accepted: 03/31/2014] [Indexed: 12/17/2022] Open
Abstract
Background Hypertension is a major risk factor for renal disease progression. However, the mechanisms by which hypertension aggravates the effects of diabetes on the kidney are incompletely understood. We tested the hypothesis that renovascular hypertension accelerates angiotensin-II-dependent kidney damage and inflammation in the db/db mouse, a model of type II diabetes. Methods Renovascular hypertension was established in db/db and wild-type control mice through unilateral renal artery stenosis (RAS); the non-stenotic contralateral kidneys evaluated 2, 4 and 6 weeks later. Angiotensin-II infusion (1000 ng/kg/min), unilateral nephrectomy, or both were also performed in db/db mice to discern the contributions of hypertension versus hyperfiltration to development of chronic renal injury in db/db mice with RAS. The effect of blood pressure reduction in db/db mice with RAS was assessed using angiotensin-receptor-blocker (ARB) or hydralazine treatment. Results Db/db mice with renovascular hypertension developed greater and more prolonged elevation of renin activity than all other groups studied. Stenotic kidneys of db/db mice developed progressive interstitial fibrosis, tubular atrophy, and interstitial inflammation. Contralateral kidneys of wild type mice with RAS showed minimal histopathologic abnormalities, whereas db/db mice with RAS developed severe diffuse mesangial sclerosis, interstitial fibrosis, tubular atrophy, and interstitial inflammation. Db/db mice with Angiotensin II-induced hypertension developed interstitial lesions and albuminuria but not mesangial matrix expansion, while nephrectomized db/db mice exhibited modest mesangial expansion and interstitial fibrosis, but not significant albuminuria. The combination of unilateral nephrectomy and angiotensin II infusion reproduced all the features of the injury albeit in a less severe manner. ARB and hydralazine were equally effective in attenuating the development of mesangial expansion in the contralateral kidneys of db/db mice with RAS. However, only ARB prevented elevation of urinary albumin/creatinine in db/db mice with RAS. Conclusion Renovascular hypertension superimposed on diabetes exacerbates development of chronic renal disease in db/db mice at least in part through interaction with the renin-angiotensin system. Both ARB and hydralazine were equally effective in reducing systolic blood pressure and in preventing renal injury in the contralateral kidney of db/db mice with renal artery stenosis. ARB but not hydralazine prevented elevation of urinary albumin/creatinine in the db/db RAS model.
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Affiliation(s)
| | | | | | | | - Joseph P Grande
- Department of Laboratory Medicine & Pathology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.
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Oates JC, Mashmoushi AK, Shaftman SR, Gilkeson GS. NADPH oxidase and nitric oxide synthase-dependent superoxide production is increased in proliferative lupus nephritis. Lupus 2013; 22:1361-70. [PMID: 24106214 PMCID: PMC3839955 DOI: 10.1177/0961203313507988] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
OBJECTIVE Lupus nephritis (LN) is an immune complex-mediated glomerulonephritis. Proliferative LN (PLN, ISN/RPS classes III and IV)) often leads to renal injury or failure despite traditional induction and maintenance therapy. Successful targeted therapeutic development requires insight into mediators of inflammation in PLN. Superoxide (SO) and its metabolites are mediators of the innate immune response through their ability to mediate reduction-oxidation signaling. Endothelial nitric oxide synthase (eNOS) modulates inflammatory responses in endothelial cells. We hypothesized that markers of SO production would be increased in active PLN and that SO production would be dependent on the activity of select enzymes in the renal cortex. METHODS Patients with systemic lupus erythematosus were enrolled at the time of renal biopsy for active LN of all classes. Serum collected at baseline was analyzed by HPLC with electrochemical detection for markers of SO production (durable modifications of serum protein Tyr ultimately requiring SO as a substrate). Renal cortex from MRL/MpJ-FAS(lpr) (MRL/lpr) mice with and without functional eNOS was analyzed during active disease for superoxide (SO) production with and without inhibitors of SO-producing enzymes. RESULTS Serum protein modifications indicative of total SO production were significantly higher in patients with PLN. These markers were increased in association with more active, inflammatory PLN. Mice lacking functional eNOS had 80% higher levels of renal cortical SO during active disease, and inhibitors of nitric oxide synthase and NADPH oxidase reduced these levels by 60% and 77%, respectively. CONCLUSION These studies demonstrate that SO production is unique to active PLN in a NOS and NADPH oxidase-dependent fashion. These findings suggest the emulating or augmenting eNOS activity or inhibiting NADPH oxidase SO production may be targets of therapy in patients with PLN. The markers of SO production used in this study could rationally be used to select SO-modulating therapies and serve as pharmacodynamic indicators for dose titration.
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Affiliation(s)
- Jim C. Oates
- Department of Medicine, Division of Rheumatology, Medical University of South Carolina, Charleston, SC and Medical Service, Ralph H. Johnson VA Medical Center, Charleston, SC
| | - Ahmad K. Mashmoushi
- Department of Medicine, Division of Rheumatology, Medical University of South Carolina, Charleston, SC
| | - Stephanie R. Shaftman
- Department of Biostatistics, Bioinformatics & Epidemiology, Medical University of South Carolina, Charleston, SC
| | - Gary S. Gilkeson
- Department of Medicine, Division of Rheumatology, Medical University of South Carolina, Charleston, SC and Medical Service, Ralph H. Johnson VA Medical Center, Charleston, SC
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Liu CC, Kao AH, Manzi S, Ahearn JM. Biomarkers in systemic lupus erythematosus: challenges and prospects for the future. Ther Adv Musculoskelet Dis 2013; 5:210-33. [PMID: 23904865 DOI: 10.1177/1759720x13485503] [Citation(s) in RCA: 69] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
The search for lupus biomarkers to diagnose, monitor, stratify, and predict individual response to therapy is currently more intense than ever before. This effort is essential for several reasons. First, epidemic overdiagnosis and underdiagnosis of lupus, even by certified rheumatologists, leads to errors in therapy with concomitant side effects which may be more serious than the disease itself. Second, identification of lupus flares remains as much an art as it is a science. Third, the capacity to stratify patients so as to predict those who will develop specific patterns of organ involvement is not currently possible but would potentially lead to preventive therapeutic strategies. Fourth, only one new drug for the treatment of lupus has been approved by the US Food and Drug Administration in over 50 years. A major obstacle in this pipeline is the dearth of biomarkers available to prove a patient has responded to an experimental therapeutic intervention. This review will summarize the challenges faced in the discovery and validation of lupus biomarkers, the most promising lupus biomarkers identified to date, and the promise of future directions.
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Affiliation(s)
- Chau-Ching Liu
- Allegheny Singer Research Institute,Temple University School of Medicine,320 East North Avenue Pittsburgh, PA 15212, USA
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Lu Y, Zhou Q, Zhong F, Guo S, Hao X, Li C, Wang W, Chen N. 15-Deoxy-Δ(12,14)-prostaglandin J(2) modulates lipopolysaccharide-induced chemokine expression by blocking nuclear factor-κB activation via peroxisome proliferator activated receptor-γ-independent mechanism in renal tubular epithelial cells. Nephron Clin Pract 2013; 123:1-10. [PMID: 23887394 DOI: 10.1159/000353232] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2012] [Accepted: 07/25/2013] [Indexed: 01/29/2023] Open
Abstract
BACKGROUND/AIMS Inflammation is an unavoidable milieu for renal tubular cells during the development of renal tubulointerstitial fibrosis. It has been demonstrated that chemokines including monocyte chemoattractant protein-1 (MCP-1) and IL-8 are related to tubulointerstitial lesions. 15d-PGJ2 may modulate renal tubulointerstitial fibrosis progression via anti-inflammatory effects. However, no information is known about the effects of 15d-PGJ2 on chemokine expression in human proximal renal tubular cells (HPTECs) under inflammation. METHODS In the present study, HPTECs (HK-2 cells) were stimulated with lipopolysaccharide (LPS) only, or preincubated with 15d-PGJ2. IL-8 and MCP-1 expressions were determined by real-time PCR and ELISA. Nuclear factor-κB (NF-κB) location was detected by immunofluorescence analysis. The p-IKK, p-IκBα and p65/p50 were analyzed by immunoblotting. To investigate the mechanism of inhibitory effects of 15d-PGJ2, the PPAR-γ gene was effectively silenced in HK-2 cells using specific siRNA. RESULTS The results showed that application of LPS significantly increased IL-8 and MCP-1 production. Phosphorylation of IκBα, IKK and nucleus translocation of NF-κB significantly increased in LPS-stimulated HK-2 cells. 15d-PGJ2 downregulated LPS-induced IL-8 and MCP-1 production. Interestingly, in PPAR-γ-deficient HK-2 cells, 15d-PGJ2 was still capable of inhibiting chemokines expression and attenuating phosphorylation of IκBα and nucleus translocation of NF-κB. CONCLUSION Collectively, these results suggest that 15d-PGJ2 exerts anti-inflammatory actions on HK-2 cells by attenuating chemokines expression. 15d-PGJ2 inhibits chemokines expression via a PPAR-γ-independent way, which is related to block NF-κB pathway. Since NF-κB is an important regulator of the response of HPTECs to injury, PPAR-γ agonists may represent a key pharmacological target for ameliorating inflammation-associated tubulointerstitial fibrosis.
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Affiliation(s)
- Ying Lu
- Department of Nephrology, Ruijin Hospital, Shanghai Jiao Tong University, Shanghai, PR China
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Ramos PS, Oates JC, Kamen DL, Williams AH, Gaffney PM, Kelly JA, Kaufman KM, Kimberly RP, Niewold TB, Jacob CO, Tsao BP, Alarcón GS, Brown EE, Edberg JC, Petri MA, Ramsey-Goldman R, Reveille JD, Vilá LM, James JA, Guthridge JM, Merrill JT, Boackle SA, Freedman BI, Scofield RH, Stevens AM, Vyse TJ, Criswell LA, Moser KL, Alarcón-Riquelme ME, Langefeld CD, Harley JB, Gilkeson GS. Variable association of reactive intermediate genes with systemic lupus erythematosus in populations with different African ancestry. J Rheumatol 2013; 40:842-9. [PMID: 23637325 PMCID: PMC3735344 DOI: 10.3899/jrheum.120989] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
OBJECTIVE Little is known about the genetic etiology of systemic lupus erythematosus (SLE) in individuals of African ancestry, despite its higher prevalence and greater disease severity. Overproduction of nitric oxide (NO) and reactive oxygen species are implicated in the pathogenesis and severity of SLE, making NO synthases and other reactive intermediate-related genes biological candidates for disease susceptibility. We analyzed variation in reactive intermediate genes for association with SLE in 2 populations with African ancestry. METHODS A total of 244 single-nucleotide polymorphisms (SNP) from 53 regions were analyzed in non-Gullah African Americans (AA; 1432 cases and 1687 controls) and the genetically more homogeneous Gullah of the Sea Islands of South Carolina (133 cases and 112 controls). Single-marker, haplotype, and 2-locus interaction tests were computed for these populations. RESULTS The glutathione reductase gene GSR (rs2253409; p = 0.0014, OR 1.26, 95% CI 1.09-1.44) was the most significant single SNP association in AA. In the Gullah, the NADH dehydrogenase NDUFS4 (rs381575; p = 0.0065, OR 2.10, 95% CI 1.23-3.59) and NO synthase gene NOS1 (rs561712; p = 0.0072, OR 0.62, 95% CI 0.44-0.88) were most strongly associated with SLE. When both populations were analyzed together, GSR remained the most significant effect (rs2253409; p = 0.00072, OR 1.26, 95% CI 1.10-1.44). Haplotype and 2-locus interaction analyses also uncovered different loci in each population. CONCLUSION These results suggest distinct patterns of association with SLE in African-derived populations; specific loci may be more strongly associated within select population groups.
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Affiliation(s)
- Paula S Ramos
- Department of Medicine, Medical University of South Carolina, Charleston, SC, USA.
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Zhang W, Zhou Q, Xu W, Cai Y, Yin Z, Gao X, Xiong S. DNA-dependent activator of interferon-regulatory factors (DAI) promotes lupus nephritis by activating the calcium pathway. J Biol Chem 2013; 288:13534-50. [PMID: 23553627 DOI: 10.1074/jbc.m113.457218] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
BACKGROUND Macrophage M2b polarization conferred by self-DNA immunization initiates and propagates lupus nephritis. RESULTS Knockdown of DNA-dependent activator of interferon-regulatory factors (DAI) ameliorates SLE syndrome via blunting macrophage M2b polarization. CONCLUSION DAI functions as a DNA sensor in self-DNA-induced macrophage M2b polarization and lupus nephritis. SIGNIFICANCE We disclose the mechanism by which self-DNA induces macrophage M2b polarization and lupus nephritis DNA-dependent activator of interferon-regulatory factors (DAI) functions as a cytoplasmic DNA sensor that activates the innate immune system. We previously found that activated lymphocyte-derived self-apoptotic DNA (ALD-DNA) immunization led to pathological macrophage activation and M2b polarization, which could initiate and propagate murine lupus nephritis. However, the specific DNA sensor(s) as well as underlying molecular mechanisms involved in ALD-DNA-induced macrophage M2b polarization in systemic lupus erythematosus (SLE) disease remains unknown. In this study, we reported that DAI expression was significantly increased in SLE patients as well as in lupus mice. Gain- and loss-of-function studies revealed that DAI was involved in ALD-DNA-induced macrophage activation and M2b polarization. Moreover, ALD-DNA notably induced dimerization/oligomerization of DAI and consequently activation of nuclear factor κB (NF-κB) and interferon regulatory factor 3 (IRF3) signaling pathways via calcium signaling, resulting in macrophage activation and M2b polarization. More importantly, blockade of DAI in vivo or selective knockdown of DAI in macrophages could ameliorate SLE syndrome via blunting macrophage M2b polarization and inhibiting inflammatory response in lupus mice. Our results suggest that DAI could function as a DNA sensor and a regulator in ALD-DNA-induced macrophage M2b polarization and lupus nephritis, providing the possible molecular mechanisms involved in ALD-DNA-induced macrophage M2b polarization in SLE disease and making DAI as a potential therapeutic target for the treatment of SLE.
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Affiliation(s)
- Weijuan Zhang
- Institute for Immunobiology and Department of Immunology, Shanghai Medical College, Fudan University, Shanghai 200032, China
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Shad KF, Aghazadeh Y, Ahmad S, Kress B. Peripheral markers of Alzheimer's disease: Surveillance of white blood cells. Synapse 2013; 67:541-3. [DOI: 10.1002/syn.21651] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2012] [Accepted: 02/07/2013] [Indexed: 11/07/2022]
Affiliation(s)
- Kaneez Fatima Shad
- PAP RSB Institute of Health Sciences; Universiti Brunei Darussalam; Jalan Tungku Link; Gadong; BE 1410; Brunei Darussalam
| | - Yashar Aghazadeh
- Chefarzt des Instituts für Neuroradiologie; Krankenhaus Nordwest; Steinbacher Hohl 2-26; 60488; Frankfurt; Germany
| | - Sagheer Ahmad
- PAP RSB Institute of Health Sciences; Universiti Brunei Darussalam; Jalan Tungku Link; Gadong; BE 1410; Brunei Darussalam
| | - Bodo Kress
- Chefarzt des Instituts für Neuroradiologie; Krankenhaus Nordwest; Steinbacher Hohl 2-26; 60488; Frankfurt; Germany
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Zhang W, Cai Y, Xu W, Yin Z, Gao X, Xiong S. AIM2 Facilitates the Apoptotic DNA-induced Systemic Lupus Erythematosus via Arbitrating Macrophage Functional Maturation. J Clin Immunol 2013; 33:925-37. [DOI: 10.1007/s10875-013-9881-6] [Citation(s) in RCA: 95] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2012] [Accepted: 02/27/2013] [Indexed: 02/07/2023]
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Watson L, Beresford MW. Urine biomarkers in juvenile-onset SLE nephritis. Pediatr Nephrol 2013; 28:363-74. [PMID: 22588674 DOI: 10.1007/s00467-012-2184-y] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2011] [Revised: 03/27/2012] [Accepted: 03/27/2012] [Indexed: 01/18/2023]
Abstract
Over 80 % of patients with juvenile-onset systemic lupus erythematosus will have renal involvement compared to 40 % with adult-onset disease. Up to 44 % of children who do have lupus nephritis (LN) progress to renal failure in early adulthood. Improved methods of detecting onset of LN would allow earlier treatment, which may prevent irreversible renal scarring and a decline in renal function. Current conventional markers of disease activity fail to adequately predict renal lupus flares and include proteinuria, complement levels, anti-double-stranded DNA antibodies and serum creatinine concentrations. Standardized histological classification is currently the gold standard for diagnosing and classifying LN, but its invasive nature limits routine use for monitoring, especially in a childhood population. Novel biomarkers need to be sensitive and specific-and preferably non-invasive and cost-effective. The most promising biomarkers in juvenile-onset LN include urinary neutrophil gelatinase associated lipocalin, monocyte chemoattractant protein 1 and transforming growth factor-beta, although many others have been identified and are under investigation. No one biomarker yet discovered is unique to LN, indicating an overlap in disease pathophysiology. It is likely that a combination of biomarkers will be required for assessing disease flare detection, response to treatment and prognostic information. Potential biomarkers require longitudinal validation in large paediatric, prospective cohorts to assess their ability to act as clinically useful adjuncts.
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Affiliation(s)
- Louise Watson
- Department of Women's and Children's Health, Institute of Translational Medicine, University of Liverpool, Eaton Road, Liverpool L12 2AP, UK.
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Nishihara K, Masuda S, Shinke H, Ozawa A, Ichimura T, Yonezawa A, Nakagawa S, Inui KI, Bonventre JV, Matsubara K. Urinary chemokine (C-C motif) ligand 2 (monocyte chemotactic protein-1) as a tubular injury marker for early detection of cisplatin-induced nephrotoxicity. Biochem Pharmacol 2013; 85:570-82. [PMID: 23291264 DOI: 10.1016/j.bcp.2012.12.019] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2012] [Revised: 12/19/2012] [Accepted: 12/21/2012] [Indexed: 10/27/2022]
Abstract
Because of the difficulty in detecting segment-specific response in the kidney, we investigated the molecular events underlying acute kidney injury in the proximal tubules of rats with cisplatin (cis-diamminedichloroplatinum II)-induced nephrotoxicity. Microarray analysis revealed that mRNA levels of several cytokines and chemokines, such as interleukin-1beta, chemokine (C-C motif) ligand (CCL) 2, CCL20, chemokine (C-X-C motif) ligand (CXCL) 1, and CXCL10 were significantly increased after cisplatin treatment in both isolated proximal tubules and whole kidney. Interestingly, tubular CCL2 mRNA levels increased soon after cisplatin administration, whereas CCL2 mRNA levels in whole kidney first decreased and then increased. Levels of both CCL2 and kidney injury molecule-1 (KIM-1) in the whole kidney increased after cisplatin administration. Immunofluorescence analysis revealed CCL2 changes in the proximal tubular cells initially and then in the medullary interstitium. Urinary CCL2 excretion significantly increased approximately 3-fold compared with controls the day after cisplatin administration (5mg/kg), when no changes were observed plasma creatinine and blood urea nitrogen levels. Urinary levels of KIM-1 also increased 3-fold after cisplatin administration. In addition, urinary CCL2 rather than KIM-1 increased in chronic renal failure rats after administration of low-dose cisplatin (2mg/kg), suggesting that urinary CCL2 was selective for cisplatin-induced nephrotoxicity in renal impairment. These results indicated that the increase in cytokine and chemokine expression in renal epithelial cells might be responsible for kidney deterioration in cisplatin-induced nephrotoxicity, and that urinary CCL2 is associated with tubular injury and serves as a sensitive and noninvasive marker for the early detection of cisplatin-induced tubular injury.
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Affiliation(s)
- Kumiko Nishihara
- Department of Pharmacy, Kyoto University Hospital, Faculty of Medicine, Sakyo-ku, Kyoto 606-8507, Japan
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Sagara =A, Furuichi =K, Sakai =N, Hara =A, Iwata =Y, Matsushima =K, Kaneko =S, Wada =T. Contribution of inflammation-associated bone-marrow-derived cells to kidney fibrosis. Inflamm Regen 2013. [DOI: 10.2492/inflammregen.33.090] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
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Murea M, Register TC, Divers J, Bowden DW, Carr JJ, Hightower CR, Xu J, Smith SC, Hruska KA, Langefeld CD, Freedman BI. Relationships between serum MCP-1 and subclinical kidney disease: African American-Diabetes Heart Study. BMC Nephrol 2012; 13:148. [PMID: 23151275 PMCID: PMC3534523 DOI: 10.1186/1471-2369-13-148] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2012] [Accepted: 10/18/2012] [Indexed: 11/21/2022] Open
Abstract
Background Monocyte chemoattractant protein-1 (MCP-1) plays important roles in kidney disease susceptibility and atherogenesis in experimental models. Relationships between serum MCP-1 concentration and early nephropathy and subclinical cardiovascular disease (CVD) were assessed in African Americans (AAs) with type 2 diabetes (T2D). Methods Serum MCP-1 concentration, urine albumin:creatinine ratio (ACR), estimated glomerular filtration rate (eGFR), and atherosclerotic calcified plaque (CP) in the coronary and carotid arteries and infrarenal aorta were measured in 479 unrelated AAs with T2D. Generalized linear models were fitted to test for associations between MCP-1 and urine ACR, eGFR, and CP. Results Participants were 57% female, with mean ± SD (median) age 55.6±9.5 (55.0) years, diabetes duration 10.3±8.2 (8.0) years, urine ACR 149.7±566.7 (14.0) mg/g, CKD-EPI eGFR 92.4±23.3 (92.0) ml/min/1.73m2, MCP-1 262.9±239.1 (224.4) pg/ml, coronary artery CP 280.1±633.8 (13.5), carotid artery CP 47.1±132.9 (0), and aorta CP 1616.0±2864.0 (319.0). Adjusting for age, sex, smoking, HbA1c, BMI, and LDL, serum MCP-1 was positively associated with albuminuria (parameter estimate 0.0021, P=0.04) and negatively associated with eGFR (parameter estimate −0.0003, P=0.001). MCP-1 remained associated with eGFR after adjustment for urine ACR. MCP-1 levels did not correlate with the extent of CP in any vascular bed, HbA1c or diabetes duration, but were positively associated with BMI. No interaction between BMI and MCP-1 was detected on nephropathy outcomes. Conclusions Serum MCP-1 levels are associated with eGFR and albuminuria in AAs with T2D. MCP-1 was not associated with subclinical CVD in this population. Inflammation appears to play important roles in development and/or progression of kidney disease in AAs.
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Affiliation(s)
- Mariana Murea
- Department of Internal Medicine/Nephrology, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC, 27157-1053, USA.
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Torabinejad S, Mardani R, Habibagahi Z, Roozbeh J, Khajedehi P, Pakfetrat M, Banihashemi MA, Banihashemi SJ. Urinary monocyte chemotactic protein-1 and transforming growth factor-β in systemic lupus erythematosus. Indian J Nephrol 2012; 22:5-12. [PMID: 22279336 PMCID: PMC3263065 DOI: 10.4103/0971-4065.91179] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Abstract
The purpose of this investigation was to assess the correlation of two biomarkers with the occurrence of renal flares in systemic lupus erythematosus (SLE). Urine levels of monocyte chemotactic protein-1 (MCP-1) and transforming growth factor beta (TGF-β) were measured at baseline, and at two and four months in five groups of patients: 25 lupus nephritis patients with active disease (active LN), 10 lupus nephritis patients with SLE in remission (remission LN), 25 patients with clinical active SLE and without nephritis (active NLN), 10 patients without nephritis with SLE in remission (remission NLN) and 10 healthy controls. We used repeated measurement and ANOVA with Duncan's post hoc to analyze the data; the urine level of the two proteins could distinguish the groups based on the existence of lupus nephritis and/or activity of SLE disease. Furthermore we performed receiver operating curve analysis to identify a cutoff point with a good sensitivity and specificity to diagnose lupus nephritis with either one of the urine proteins. Finally the samples from active LN were grouped according to whether they were Class IV or other classes. Baseline urinary MCP-1, but not TGF-β, was significantly different between the classes. Further investigation into the use of these cytokines in a prospective study is needed to determine their capacity as diagnostic tools for renal flares.
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Affiliation(s)
- S Torabinejad
- Shiraz Nephrology Urology Research Center, Zand Avenue, Shiraz, Iran
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Rosa RF, Takei K, Araújo NC, Loduca SMA, Szajubok JCM, Chahade WH. Monocyte chemoattractant-1 as a urinary biomarker for the diagnosis of activity of lupus nephritis in Brazilian patients. J Rheumatol 2012; 39:1948-54. [PMID: 22942263 DOI: 10.3899/jrheum.110201] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
OBJECTIVE Monocyte chemotactic protein (MCP-1), involved in the pathogenesis of lupus nephritis (LN), has recently been indicated as a new biomarker of kidney activity in systemic lupus erythematosus (SLE). Our aim was to assess urinary MCP-1 (uMCP-1) as a biomarker of renal activity in patients with SLE and to compare it to other disease activity markers, using the ELISA. METHODS Seventy-five female Brazilian patients with SLE and a control group participated in our study. Patients with SLE were distributed among 3 groups according to kidney involvement and classified according to disease activity based on clinical and laboratory measures such as urinary sediment, proteinuria, kidney function, C3, C4, anti-dsDNA, disease activity index, and renal SLE disease activity index. The serum and uMCP-1 concentrations were measured by sandwich ELISA. RESULTS In the A-LN group (active lupus nephritis: SLE with kidney involvement), the concentration of uMCP-1 was significantly higher than in other groups. A cutoff point was established using the results of the control group to apply this test in the detection of LN. A-LN had a higher frequency of positive results for uMCP-1 in comparison to the other groups (p < 0.001). To detect disease activity in patients with LN, a new cutoff was determined based on the results of patients with SLE with kidney involvement. Setting specificity at 90%, the sensitivity of the test was 50%. CONCLUSION The high specificity makes uMCP-1 a useful test as a predictor of kidney activity in SLE, especially when associated to other measures used in clinical practice.
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Affiliation(s)
- Renata Ferreira Rosa
- Department of Rheumatology, and the Department of Immunology, Servidor Publico Estadual Hospital, São Paulo, Brazil.
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