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1.
BMC Nephrol ; 24(1): 218, 2023 07 24.
Artigo em Inglês | MEDLINE | ID: mdl-37488532

RESUMO

BACKGROUND: Recent developments in mass spectrometry (MS) have revealed target antigens for membranous nephropathy (MN), including phospholipase A2 receptor and exostosin 1/exostosin 2 (EXT1/2). EXT1/2 are known antigens of autoimmune disease-related MN, especially membranous lupus nephritis. We describe the case of an elderly man who developed nephrotic syndrome followed by progressive renal dysfunction. CASE PRESENTATION: A 78-year-old man presented with rapidly progressive renal dysfunction with proteinuria and hematuria. Three years previously, he had developed leg edema but did not receive any treatment. Laboratory tests showed elevated anti-nuclear antibody (Ab), anti-dsDNA Ab titer, and hypocomplementemia, indicating systemic lupus erythematous. Myeloperoxidase anti-neutrophil cytoplasmic Ab (ANCA) and anti-glomerular basement membrane (GBM) Ab were also detected. The renal pathologic findings were compatible with crescentic glomerulonephritis (GN), whereas non-crescentic glomeruli exhibited MN without remarkable endocapillary or mesangial proliferative change. Immunofluorescence microscopy revealed glomerular IgG, C3, and C1q deposition. All IgG subclasses were positive in glomeruli. Anti-PLA2R Ab in serum was negative. MS analysis was performed to detect the antigens of MN, and EXT1/2 was detected in glomeruli. Therefore, we reached a diagnosis of membranous lupus nephritis concurrent with both ANCA-associated vasculitis and anti-GBM-GN. The simultaneous occurrence of these three diseases is extremely rare. CONCLUSIONS: This is the first report of EXT1/2-related membranous lupus nephritis concurrent with ANCA-associated vasculitis and anti-GBM-GN. This case demonstrates the usefulness of MS in diagnosing complicated cases of MN.


Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos , Glomerulonefrite Membranoproliferativa , Glomerulonefrite Membranosa , Glomerulonefrite , Lúpus Eritematoso Sistêmico , Nefrite Lúpica , Idoso , Humanos , Masculino , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/complicações , Anticorpos Anticitoplasma de Neutrófilos , Glomerulonefrite/patologia , Glomerulonefrite Membranoproliferativa/complicações , Glomerulonefrite Membranosa/complicações , Glomerulonefrite Membranosa/diagnóstico , Imunoglobulina G , Lúpus Eritematoso Sistêmico/complicações , Nefrite Lúpica/complicações , Nefrite Lúpica/diagnóstico , Espectrometria de Massas , N-Acetilglucosaminiltransferases
2.
Int J Mol Sci ; 24(9)2023 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-37176142

RESUMO

Recently, the comprehensive concept of "infection-related glomerulonephritis (IRGN)" has replaced that of postinfectious glomerulonephritis (PIGN) because of the diverse infection patterns, epidemiology, clinical features, and pathogenesis. In addition to evidence of infection, hypocomplementemia particularly depresses serum complement 3 (C3), with endocapillary proliferative and exudative GN developing into membranoproliferative glomerulonephritis (MPGN); also, C3-dominant or co-dominant glomerular immunofluorescence staining is central for diagnosing IRGN. Moreover, nephritis-associated plasmin receptor (NAPlr), originally isolated from the cytoplasmic fraction of group A Streptococci, is vital as an essential inducer of C3-dominant glomerular injury and is a key diagnostic biomarker for IRGN. Meanwhile, "C3 glomerulopathy (C3G)", also showing a histological pattern of MPGN due to acquired or genetic dysregulation of the complement alternative pathway (AP), mimics C3-dominant IRGN. Initially, C3G was characterized by intensive "isolated C3" deposition on glomeruli. However, updated definitions allow for glomerular deposition of other complement factors or immunoglobulins if C3 positivity is dominant and at least two orders of magnitude greater than any other immunoreactant, which makes it challenging to quickly distinguish pathomorphological findings between IRGN and C3G. As for NAPlr, it was demonstrated to induce complement AP activation directly in vitro, and it aggravates glomerular injury in the development of IRGN. A recent report identified anti-factor B autoantibodies as a contributing factor for complement AP activation in pediatric patients with PIGN. Moreover, C3G with glomerular NAPlr deposition without evidence of infection was reported. Taken together, the clinico-pathogenic features of IRGN overlap considerably with those of C3G. In this review, similarities and differences between the two diseases are highlighted.


Assuntos
Glomerulonefrite Membranoproliferativa , Glomerulonefrite , Humanos , Criança , Glomerulonefrite/patologia , Glomerulonefrite Membranoproliferativa/etiologia , Glomérulos Renais/patologia , Autoanticorpos
3.
Kidney Blood Press Res ; 45(3): 391-406, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32146474

RESUMO

BACKGROUND: Recombinant human soluble thrombomodulin (rhTM) was approved in 2008 and has been used for treatment of disseminated intravascular coagulation in Japan. The antifibrotic effects of rhTM in acute exacerbation of idiopathic pulmonary fibrosis are well established, but the therapeutic potential of rhTM in renal fibrosis remains poorly understood. METHODS: Nephrotoxic serum nephritis (NTS-N) was induced in 22 female Wistar-Kyoto (WKY) rats on day 0. Rats were administered either rhTM or vehicle intraperitoneally, every day from day 4 to day 55. Rats were sacrificed on day 56 when renal fibrosis was established and renal morphological investigations were performed. In vitro, rat renal fibroblasts (NRK-49F) were pretreated with rhTM or saline, and expression levels of profibrogenic gene induced by thrombin were analyzed by real-time reverse transcription polymerase chain reaction. RESULTS: Compared to WKY-GN-vehicle rats, the body weights of WKY-GN-rhTM rats were significantly greater on day 55. By day 56, rhTM had significantly reduced serum creatinine levels in NTS-N. On the other hand, urinary protein excretion was comparable between the two treatment groups throughout the study. The percentage of Masson trichrome-positive areas in WKY-GN-rhTM rats was significantly lower compared to that in WKY-GN-vehicle rats. Glomerular fibrin deposition was significantly reduced in WKY-GN-rhTM rats. In addition, rhTM significantly reduced the renal cortical mRNA expression levels of TNF-α, Toll-like receptor 4, MYD88, TGF-ß, αSMA, collagen I, collagen III, fibronectin, and protease-activated receptor 1 (PAR1), a thrombin receptor. In vitro, thrombin stimulation of NRK-49F cells significantly enhanced the mRNA expression levels of αSMA and PAR1, and these upregulations were significantly reduced by pretreatment with rhTM. CONCLUSIONS: Administration of rhTM after establishment of crescentic glomerulonephritis (GN) attenuated the subsequent development of renal fibrosis in NTS-N, possibly in part by inhibiting thrombin-mediated fibrogenesis. Our results suggest that rhTM may offer a therapeutic option for limiting the progression of chronic kidney disease in crescentic GN.


Assuntos
Nefrite/tratamento farmacológico , Insuficiência Renal Crônica/tratamento farmacológico , Trombomodulina/uso terapêutico , Animais , Feminino , Humanos , Ratos , Ratos Endogâmicos WKY
4.
J Am Soc Nephrol ; 30(2): 244-259, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30622154

RESUMO

BACKGROUND: In people with SLE and in the MRL-Faslpr lupus mouse model, macrophages and autoantibodies are central to lupus nephritis. IL-34 mediates macrophage survival and proliferation, is expressed by tubular epithelial cells (TECs), and binds to the cFMS receptor on macrophages and to a newly identified second receptor, PTPRZ. METHODS: To investigate whether IL-34-dependent intrarenal and systemic mechanisms promote lupus nephritis, we compared lupus nephritis and systemic illness in MRL-Faslpr mice expressing IL-34 and IL-34 knockout (KO) MRL-Faslpr mice. We also assessed expression of IL-34 and the cFMS and PTPRZ receptors in patients with lupus nephritis. RESULTS: Intrarenal IL-34 and its two receptors increase during lupus nephritis in MRL-Faslpr mice. In knockout mice lacking IL-34, nephritis and systemic illness are suppressed. IL-34 fosters intrarenal macrophage accumulation via monocyte proliferation in bone marrow (which increases circulating monocytes that are recruited by chemokines into the kidney) and via intrarenal macrophage proliferation. This accumulation leads to macrophage-mediated TEC apoptosis. We also found suppression of circulating autoantibodies and glomerular antibody deposits in the knockout mice. This is consistent with fewer activated and proliferating intrarenal and splenic B cells in mice lacking IL-34, and with our novel discovery that PTPRZ is expressed by macrophages, B and T cells. These findings appear translatable to human patients with lupus nephritis, whose expression of IL-34, cFMS, and PTPRZ is similar to that seen in the MRL-Faslpr lupus mouse model. Moreover, expression of IL-34 in TECs correlates with disease activity. CONCLUSIONS: IL-34 is a promising novel therapeutic target for patients with lupus nephritis.


Assuntos
Morte Celular/genética , Sobrevivência Celular/genética , Interleucinas/genética , Nefrite Lúpica/patologia , Terapia de Alvo Molecular/métodos , Monócitos/citologia , Animais , Morte Celular/imunologia , Proliferação de Células/genética , Células Cultivadas , Quimiocinas/metabolismo , Modelos Animais de Doenças , Progressão da Doença , Regulação da Expressão Gênica , Interleucinas/imunologia , Interleucinas/metabolismo , Túbulos Renais/patologia , Túbulos Renais/fisiopatologia , Nefrite Lúpica/tratamento farmacológico , Nefrite Lúpica/imunologia , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos MRL lpr , Camundongos Knockout , Monócitos/fisiologia , Medição de Risco , Especificidade da Espécie
5.
Am J Pathol ; 188(12): 2745-2762, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30268775

RESUMO

Mutations in mitochondrial DNA as well as nuclear-encoded mitochondrial proteins have been reported to cause tubulointerstitial kidney diseases and focal segmental glomerulosclerosis (FSGS). Recently, genes and pathways affecting mitochondrial turnover and permeability have been implicated in adult-onset FSGS. Furthermore, dysfunctioning mitochondria may be capable of engaging intracellular innate immune-sensing pathways. To determine the impact of mitochondrial dysfunction in FSGS and secondary innate immune responses, we generated Cre/loxP transgenic mice to generate a loss-of-function deletion mutation of the complex IV assembly cofactor heme A:farnesyltransferase (COX10) restricted to cells of the developing nephrons. These mice develop severe, early-onset FSGS with innate immune activation and die prematurely with kidney failure. Mutant kidneys showed loss of glomerular and tubular epithelial function, epithelial apoptosis, and, in addition, a marked interferon response. In vitro modeling of Cox10 deletion in primary kidney epithelium compromises oxygen consumption, ATP generation, and induces oxidative stress. In addition, loss of Cox10 triggers a selective interferon response, which may be caused by the leak of mitochondrial DNA into the cytosol activating the intracellular DNA sensor, stimulator of interferon genes. This new animal model provides a mechanism to study mitochondrial dysfunction in vivo and demonstrates a direct link between mitochondrial dysfunction and intracellular innate immune response.


Assuntos
Alquil e Aril Transferases/fisiologia , Modelos Animais de Doenças , Glomerulosclerose Segmentar e Focal/etiologia , Fatores Reguladores de Interferon/metabolismo , Interferons/farmacologia , Proteínas de Membrana/fisiologia , Estresse Oxidativo , Deleção de Sequência , Animais , Antivirais/farmacologia , Feminino , Glomerulosclerose Segmentar e Focal/metabolismo , Glomerulosclerose Segmentar e Focal/patologia , Fatores Reguladores de Interferon/genética , Masculino , Camundongos , Camundongos Transgênicos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/imunologia , Mitocôndrias/patologia
6.
Nephrol Dial Transplant ; 34(5): 774-782, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-29982644

RESUMO

BACKGROUND: Since recombinant human soluble thrombomodulin (RH-TM) has anti-inflammatory properties through neutralizing high-mobility group box 1 protein (HMGB1), the protective effects of RH-TM were examined in anti-glomerular basement membrane (GBM) glomerulonephritis (GN) in Wistar-Kyoto rats. METHODS: Rats were injected with nephrotoxic serum (NTS) to induce anti-GBM GN on Day 0, and were given either RH-TM or vehicle from Day 0 to Day 6. Rats were sacrificed 7 days after NTS injection. RESULTS: RH-TM-treated rats had decreased proteinuria and serum creatinine level. RH-TM significantly reduced the percentage of glomeruli with crescentic features and fibrinoid necrosis. In addition, RH-TM-treated rats had significantly reduced glomerular ED1+ macrophage accumulation as well as reduced renal cortical proinflammatory cytokine expression. Furthermore, RH-TM had a potent effect in reducing intercellular adhesion molecule-1 (ICAM-1) expression in kidneys and urine. RH-TM significantly reduced renal cortical mRNA levels for toll-like receptor -2 and -4, known as receptors for HMGB1, and their downstream adopter protein, myeloid differentiation primary respond protein 88 (MyD88). CONCLUSIONS: We showed for the first time that anti-inflammatory effects, which were characterized by reduced glomerular macrophage influx concomitant with a marked reduction in proinflammatory cytokines, were involved in the mechanism of attenuating experimental anti-GBM GN by RH-TM. The observed effects might be attributable to the downregulation of ICAM-1 by reducing the HMGB1/TLR/MyD88 signaling pathway.


Assuntos
Doença Antimembrana Basal Glomerular/tratamento farmacológico , Creatinina/metabolismo , Citocinas/metabolismo , Glomérulos Renais/patologia , Trombomodulina/uso terapêutico , Animais , Doença Antimembrana Basal Glomerular/metabolismo , Doença Antimembrana Basal Glomerular/patologia , Biomarcadores/metabolismo , Modelos Animais de Doenças , Feminino , Glomérulos Renais/metabolismo , Ratos , Ratos Endogâmicos WKY , Proteínas Recombinantes
8.
Nephrol Dial Transplant ; 33(4): 598-606, 2018 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-28992288

RESUMO

Background: Increasing evidence indicates that epidermal growth factor receptor (EGFR) has a pathogenic role in renal fibrosis. Currently no effective treatment can completely halt the progression of chronic kidney disease (CKD). This study was undertaken to investigate the renoprotective effects of erlotinib, a tyrosine kinase inhibitor that can block EGFR activity in the progression of CKD and the mechanisms involved. Methods: Sprague Dawley rats with 5/6 nephrectomy were administered either erlotinib or vehicle from 2 weeks after surgery and for a period of 8 weeks. Blood pressure, proteinuria and serum creatinine were measured periodically. Renal morphological investigations were performed at sacrifice. In vitro, we used normal human mesangial cells (NHMCs) and human proximal tubular cells to investigate the inhibitory effects of erlotinib on renal fibrosis-associated signaling pathways by western blotting. Results: Erlotinib treatment significantly blunted the progression of CKD as evidenced by reduced levels of serum creatinine, proteinuria and renal cortical profibrogenic genes and scores of glomerulosclerosis and tubulointerstitial damage. Tubulointerstitial macrophage infiltration and multiple pro-inflammatory cytokine gene expression levels were also attenuated by erlotinib treatment. In vitro, heparin-binding epidermal growth factor-like growth factor-induced Akt and extracellular-regulated kinase (ERK) 1/2 activation in normal human mesangial cells and human proximal tubular cells was inhibited by pretreatment with erlotinib. Conclusions: EGFR blocking by erlotinib protected against renal fibrosis in 5/6 nephrectomized rats via inhibition of Akt and ERK 1/2 signaling pathways, which are associated with renal fibrosis. Erlotinib also has anti-inflammatory properties, which may contribute to its renoprotective effects. Erlotinib represents a potential novel therapeutic strategy for the treatment of CKD.


Assuntos
Cloridrato de Erlotinib/farmacologia , Fibrose/prevenção & controle , Inibidores de Proteínas Quinases/farmacologia , Insuficiência Renal Crônica/prevenção & controle , Transdução de Sinais/efeitos dos fármacos , Animais , Células Cultivadas , Progressão da Doença , Receptores ErbB/antagonistas & inibidores , Fibrose/etiologia , Fibrose/metabolismo , Humanos , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Nefrectomia/efeitos adversos , Ratos , Ratos Sprague-Dawley , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/patologia
10.
Am J Physiol Renal Physiol ; 310(11): F1182-91, 2016 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-27053690

RESUMO

Recent studies have demonstrated that conditioned media derived from mesenchymal stem cells (MSC-CM) have therapeutic effects in various experimental diseases. However, the therapeutic mechanism is not fully understood. In the present study, we investigated the therapeutic effects and mechanism of MSC-CM in experimental antiglomerular basement membrane glomerulonephritis. We administered either MSC-CM or vehicle from day 0 to day 10 after the induction of nephrotoxic serum nephritis in Wistar-Kyoto rats. In vitro, we analyzed the effects of MSC-CM on TNF-α-mediated cytokine production in cultured normal human mesangial cells, proximal tubular (HK-2) cells, human umbilical vein endothelial cells, and monocytes (THP-1 and peripheral blood mononuclear cells). Compared with vehicle treatment, MSC-CM treatment improved proteinuria and renal dysfunction. Histologically, MSC-CM-treated rats had reduced crescent formation and glomerular ED1(+) macrophage infiltration and increased glomerular ED2(+) macrophage infiltration. Increased serum monocyte chemoattractant protein (MCP)-1 levels were observed in MSC-CM-treated rats. Renal cortical mRNA expression levels of proinflammatory cytokines, such as TNF-α and IL-6, and of the T helper cell 1 cytokine interferon-γ were greatly decreased by MSC-CM treatment. In vitro, pretreatment with MSC-CM blocked TNF-α-mediated IL-8 release in normal human mesangial cells and HK-2 cells. TNF-α-mediated MCP-1 release was enhanced by pretreatment with MSC-CM in human umbilical vein endothelial cells and HK-2 cells and was strikingly enhanced in THP-1 cells. Stimulation of peripheral blood mononuclear cells with a combination of MCP-1 and IL-4 enhanced the expression of M2-associated genes compared with IL-4 alone. We demonstrated that MSC-CM had therapeutic effects in experimental antiglomerular basement membrane glomerulonephritis that were mediated through anti-inflammatory effects that were partly due to acceleration of M2 macrophage polarization, which might be mediated by MCP-1 enhancement.


Assuntos
Meios de Cultivo Condicionados/farmacologia , Glomerulonefrite/tratamento farmacológico , Células-Tronco Mesenquimais/metabolismo , Animais , Quimiocina CCL2/farmacologia , Meios de Cultivo Condicionados/metabolismo , Citocinas/metabolismo , Glomerulonefrite/metabolismo , Glomerulonefrite/patologia , Interleucina-4/farmacologia , Rim/metabolismo , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Ratos , Ratos Endogâmicos WKY , Fator de Necrose Tumoral alfa/metabolismo
11.
Tohoku J Exp Med ; 238(3): 205-12, 2016 03.
Artigo em Inglês | MEDLINE | ID: mdl-26947314

RESUMO

Denosumab (DMAb), a complete human type monoclonal antibody directed against the receptor activator of nuclear factor-κB ligand, has gained attention as a novel treatment for osteoporosis. However, its efficacy in patients with chronic kidney disease (CKD) remains unclear. We describe a 64-year-old man with severe bone loss and persistent secondary hyperparathyroidism (SHPT) after renal transplantation, whose condition failed to respond to conventional pharmacologic or surgical interventions. He underwent parathyroidectomy with left forearm autograft of crushed tiny parathyroid gland (PTG) particles. However, the autografted PTGs became swollen and caused persistent SHPT in spite of two additional parathyroidectomies of the left forearm. A single subcutaneous administration of DMAb induced hypocalcemia, which was corrected by calcium supplementation and high-dose calcitriol. Eventually, combination therapy with DMAb and calcitriol led to a decline in the patient's elevated serum parathyroid hormone levels, normalization of laboratory markers of bone metabolism, and improvement in bone mineral density in a short period of time. To the best of our knowledge, this is the first case report of severe bone loss with persistent SHPT in a renal transplant recipient effectively treated with the combination therapy of DMAb and vitamin D (VD). Although DMAb itself exerts no direct effects on PTGs, the DMAb treatment improved the patient's bone loss. In addition, administration of DMAb allowed for high-dose VD therapy which ultimately controlled SHPT and prevented DMAb-induced hypocalcemia. Therefore, this combination therapy might be a reasonable therapeutic strategy to reverse severe bone loss due to therapy-resistant SHPT in patients with CKD.


Assuntos
Conservadores da Densidade Óssea/uso terapêutico , Calcitriol/uso terapêutico , Denosumab/uso terapêutico , Hiperparatireoidismo Secundário , Transplante de Rim , Osteoporose/tratamento farmacológico , Combinação de Medicamentos , Humanos , Transplante de Rim/efeitos adversos , Masculino , Pessoa de Meia-Idade , Osteoporose/etiologia
12.
CEN Case Rep ; 13(5): 318-325, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-38280123

RESUMO

Recently, several target antigens of membranous nephropathy (MN), such as phospholipase A2 receptor (PLA2R) and exostosin 1/exostosin 2 (EXT1/2), have been discovered. A 30-year-old woman was referred to our hospital with nephrotic range proteinuria and microscopic hematuria. She was first noted to have proteinuria before pregnancy, and her proteinuria worsened in the postpartum period. A renal biopsy showed MN. Immunofluorescence microscopy showed IgG, IgA, IgM, C3, C4, and C1q depositions in the mesangial area and glomerular capillary walls (GCWs). Regarding the IgG subclass, IgG1 and IgG3 were detected on glomeruli. Electron microscopy showed subepithelial electron-dense deposits (EDDs). EDDs were also detected in paramesangial and subendothelial areas. The diagnosis of membranous lupus nephritis (MLN) was suspected, but she did not fulfill the criteria for systemic lupus erythematosus. Neither anti-nuclear antibody nor hypocomplementemia were detected. We further evaluated glomerular EXT1/2 expressions, which were evident on GCWs. In addition, PLA2R was also detected on GCWs, although serum antibody for PLA2R was negative. She responded to immunosuppressive therapy with decreased proteinuria. In the present case, glomerular PLA2R expression implied the possibility of primary MN. However, pathological findings with a full-house staining pattern and glomerular EXT1/2 expressions were very similar to those of lupus-associated MN. Glomerular PLA2R expression appeared not to reflect immunocomplexes of PLA2R and autoantibody when considering the results for glomerular IgG subclass and the absence of serum anti-PLA2R antibody. Collectively, it is plausible that this was a case of a relatively young postpartum female who developed latent MLN rather than primary MN.


Assuntos
Glomerulonefrite Membranosa , Glomérulos Renais , Período Pós-Parto , Receptores da Fosfolipase A2 , Humanos , Feminino , Receptores da Fosfolipase A2/imunologia , Adulto , Glomerulonefrite Membranosa/diagnóstico , Glomerulonefrite Membranosa/imunologia , Glomerulonefrite Membranosa/patologia , Glomérulos Renais/patologia , Glomérulos Renais/ultraestrutura , N-Acetilglucosaminiltransferases , Proteinúria/etiologia , Proteinúria/diagnóstico , Nefrite Lúpica/diagnóstico , Nefrite Lúpica/imunologia , Gravidez
13.
Case Rep Nephrol Dial ; 14(1): 128-137, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39118826

RESUMO

Introduction: Drug-induced tubulointerstitial injury is a common cause of renal impairment. Since the mechanisms of drug-induced tubular injury are diverse, various treatment approaches are needed according to the pathogenesis. Renal biopsy is indispensable to determine not only the pathological diagnosis, but also the underlying mechanism, and to guide appropriate treatment. Most recently, one of the red yeast supplements has been widely highlighted as a novel cause of tubular damage, mainly in Japan and Asia. However, neither detailed pathological findings nor the mechanism of renal impairment has been sufficiently reported. Case Presentation: Two cases of renal impairment after taking red yeast supplement internally are presented. Both cases showed renal dysfunction with low uric acid, potassium, and phosphorus levels, characteristic features of Fanconi syndrome. The renal biopsy findings of both cases showed severe injury to the proximal tubules with mild inflammatory cell infiltration. The proximal tubules exhibited diffuse loss of the brush border, flattening, and tubular lumen dilation. Immunofluorescence showed no deposition of immunoglobulin and complement in the glomeruli and tubules. Electron microscopic findings indicated proximal tubular damage without crystal deposition. Moreover, immunohistochemistry using the proximal tubular marker CD10 and a marker for distal tubules including the loop of Henle, E-cadherin, collectively demonstrated that the focus of renal injury in both cases was mainly the proximal tubules. Conclusions: The red yeast rice supplement itself, its metabolized product, or other unknown contaminant components might directly induce proximal tubulopathy rather than an allergic reaction-related tubulointerstitial nephritis.

14.
Nephrol Dial Transplant ; 28(3): 576-84, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23045430

RESUMO

BACKGROUND: Imatinib is a selective tyrosine kinase inhibitor that can block platelet-derived growth factor (PDGF) receptor activity. Imatinib is also known as an anti-inflammatory agent. We examined the therapeutic effects of long- or short-term imatinib treatment in Wistar-Kyoto (WKY) rats with established anti-glomerular basement membrane (GBM) nephritis. METHODS: Nephrotoxic serum (NTS) nephritis was induced in WKY rats on day 0. Groups of animals were given either imatinib or vehicle daily by intraperitoneal injection, from day 7 to day 49 in the long-term treatment study, and from day 7 to 13 in the short-term treatment study; all rats were sacrificed at day 50. RESULTS: In long-term treatment, imatinib showed marked renoprotective effects; imatinib suppressed proteinuria, improved renal function, attenuated the development of glomerulosclerosis and tubulointerstitial injury and reduced the expression levels of collagen type I and transforming growth factor-beta (TGF-ß) in renal cortex. The key finding of the present study was that short-term treatment with imatinib also significantly attenuated the development of renal injury until day 50, although the degree of renoprotection was slightly inferior to that of long-term treatment. CONCLUSIONS: These results suggest that administration of imatinib is a promising strategy for limiting the progression of glomerulonephritis (GN) to end-stage renal failure. In particular, a short period of treatment at an early stage of GN is more beneficial in terms of cost-effectiveness and reduction of adverse effects in comparison to a continuous and long period of treatment.


Assuntos
Doença Antimembrana Basal Glomerular/complicações , Benzamidas/uso terapêutico , Piperazinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/uso terapêutico , Insuficiência Renal Crônica/prevenção & controle , Animais , Doença Antimembrana Basal Glomerular/patologia , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Creatinina/metabolismo , Progressão da Doença , Feminino , Imunofluorescência , Mesilato de Imatinib , Proteinúria , RNA Mensageiro/genética , Ratos , Ratos Endogâmicos WKY , Reação em Cadeia da Polimerase em Tempo Real , Insuficiência Renal Crônica/etiologia , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/patologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Tempo , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismo
15.
Clin Exp Nephrol ; 17(1): 73-82, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22752397

RESUMO

BACKGROUND: Immunoglobulin (Ig) A nephropathy (IgAN) is characterized by mesangial deposits of IgA1 and C3, often with co-deposits of IgG. We attempted to clarify the clinical significance of mesangial IgG deposition in patients with IgAN. METHODS: We retrospectively reviewed 57 patients who were diagnosed with IgAN on the basis of pathological examination of renal biopsy specimens obtained between October 2006 and December 2010. Subjects were divided into two groups: IgA+IgG deposition (IgA-IgG) group (n = 29) and IgA deposition alone (IgA) group (n = 28). The study outcome was complete remission (CR), defined as negative proteinuria by dipstick urinalysis and urinary erythrocytes of less than 1-4/high-power field. RESULTS: Proteinuria was greater in the IgA-IgG group than the IgA group (1.1 ± 0.8 vs. 0.7 ± 0.6 g/day, Mann-Whitney U test, P = 0.042). Capillary wall IgA deposits were noted more frequently in the IgA-IgG group than the IgA group (59 vs. 11 %, Fisher's exact test, P = 0.014). During the median follow-up period of 33.3 months (range 6-55 months) in the 57 patients, we observed CR in 24 cases (42.1 %). After the start of treatment, urinary abnormalities disappeared earlier in the IgA group than in the IgA-IgG group (log rank test, P = 0.012). Cox's regression model showed that IgG deposition reduced the hazard ratio for CR (hazard ratio 0.35; 95 % confidence interval 0.14-0.82, P = 0.014). Therefore, IgG deposition is a risk factor for persistent urinary abnormalities. CONCLUSION: Mesangial IgG deposition is associated with more severe clinical features in patients with IgAN.


Assuntos
Mesângio Glomerular/imunologia , Glomerulonefrite por IGA/imunologia , Imunoglobulina A/análise , Imunoglobulina G/análise , Adolescente , Adulto , Biópsia , Feminino , Imunofluorescência , Mesângio Glomerular/patologia , Glomerulonefrite por IGA/patologia , Glomerulonefrite por IGA/terapia , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Valor Preditivo dos Testes , Modelos de Riscos Proporcionais , Proteinúria/imunologia , Proteinúria/patologia , Fitas Reagentes , Indução de Remissão , Estudos Retrospectivos , Fatores de Risco , Índice de Gravidade de Doença , Resultado do Tratamento , Urinálise/instrumentação , Urina/citologia , Adulto Jovem
16.
J Cardiol ; 82(4): 279-285, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37211246

RESUMO

BACKGROUND: Despite optimal treatment, a residual inflammatory risk often remains in patients with atherosclerotic cardiovascular disease. In a US-based phase 2 trial, ziltivekimab, a fully human monoclonal antibody targeting the interleukin-6 ligand, significantly reduced biomarkers of inflammation compared with placebo in patients at high atherosclerotic risk. Here, we report the efficacy and safety of ziltivekimab in Japanese patients. METHODS: RESCUE-2 was a randomized, double-blind, 12-week, phase 2 trial. Participants aged ≥20 years with stage 3-5 non-dialysis-dependent chronic kidney disease and high-sensitivity C-reactive protein (hsCRP) ≥2 mg/L were randomized to receive placebo (n = 13) or subcutaneous ziltivekimab 15 mg (n = 11) or 30 mg (n = 12) at Weeks 0, 4, and 8. The primary endpoint was percentage change in hsCRP levels from baseline to end of treatment (EOT; mean of Week 10 and Week 12 values). RESULTS: At EOT, median hsCRP levels were reduced by 96.2 % in the 15 mg group (p < 0.0001 versus placebo), by 93.4 % in the 30 mg group (p = 0.002 versus placebo), and by 27.0 % in the placebo group. Serum amyloid A and fibrinogen levels were also reduced significantly. Ziltivekimab was well tolerated and did not affect total cholesterol to high-density lipoprotein cholesterol ratios. There was a small, but statistically significant increase in triglyceride levels with ziltivekimab 15 mg and 30 mg compared with placebo. CONCLUSIONS: The efficacy and safety results support the development of ziltivekimab for secondary prevention and the treatment of patients at high atherosclerotic risk. CLINICALTRIALS: gov identifier, NCT04626505.


Assuntos
Aterosclerose , Interleucina-6 , Humanos , Aterosclerose/tratamento farmacológico , Aterosclerose/prevenção & controle , Proteína C-Reativa/metabolismo , HDL-Colesterol , Método Duplo-Cego , Interleucina-6/antagonistas & inibidores , Japão , Resultado do Tratamento
17.
Am J Physiol Renal Physiol ; 302(2): F244-50, 2012 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-21993883

RESUMO

We investigated the potential role of IL-17A in the induction of granulocyte colony-stimulating factor (G-CSF), a critical granulopoietic growth factor, in human renal proximal tubular epithelial cells. Human renal proximal tubular cells (HK-2, ATCC) were used to characterize the effects of IL-17A or IL-17F on G-CSF production, using ELISA, real-time RT-PCR, and immunoblotting. The cell surface expression of IL-17 receptors (IL-17Rs) was analyzed by flow cytometry. IL-17A stimulation of proximal tubular cells led to a dose- and time-dependent increase in secreted G-CSF. This effect was dependent on mRNA transcription and protein translation. Real-time RT-PCR demonstrated that G-CSF mRNA expression reached a maximum level at 6 h following IL-17A stimulation and that this increase was dose dependent. Both IL-17RA and IL-17RC were expressed on proximal tubular cells. IL-17A also enhanced TNF-α- or IL-1ß-mediated G-CSF secretion from cells. Additionally, IL-17A induced MAPK (ERK1/2 but not p38 MAPK or JNK) activation, and pharmacological inhibitors of MEK1/2 (U0126) but not of p38 MAPK (SB203580) or JNK (SP600125), significantly blocked the IL-17A-mediated G-CSF release. We demonstrated the potential ability of IL-17A to induce G-CSF in renal proximal tubular cells. It is proposed that IL-17A may play an important role in neutrophil transmigration and activation via stimulation of G-CSF in tubular injury.


Assuntos
Células Epiteliais/efeitos dos fármacos , Fator Estimulador de Colônias de Granulócitos/biossíntese , Interleucina-17/farmacologia , Túbulos Renais Proximais/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Humanos , Interleucina-1beta/farmacologia , Túbulos Renais Proximais/citologia , Túbulos Renais Proximais/metabolismo , MAP Quinase Quinase 4/metabolismo , Fosforilação/efeitos dos fármacos , Receptores de Interleucina-17/metabolismo , Fator de Necrose Tumoral alfa/farmacologia , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
18.
CEN Case Rep ; 11(4): 399-403, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-35171449

RESUMO

Polyarteritis nodosa, which is a systemic vasculitis of small- and medium-sized arteries, can cause arterial aneurysms in various organs, sometimes resulting in aneurysm rupture and hemorrhage. A kidney is one of the major targets of polyarteritis nodosa. Here, we report a 73-year-old woman who presented with sudden-onset high fever, diarrhea, and renal injury with bilateral renal subcapsular hematoma shown on contrast-enhanced computed tomography scan. She did not have trauma and significant medical history other than breast cancer in remission. Serological and immunological tests except for anti-Sjögren's syndrome-A and anti-Sjögren's syndrome-B were all negative. Digital subtraction angiography revealed bilateral intrarenal micro aneurysms, which allowed us to diagnose the patient with polyarteritis nodosa. As continuous monitoring of bilateral intrarenal hematoma by ultrasonography and computed tomography scan did not detect progression of intrarenal hemorrhage and extra renal hematoma, transcatheter arterial embolization and nephrectomy were not performed. Although hemodialysis therapy was required temporarily for acute kidney injury with anuria, her general condition and kidney function remarkably improved after receiving systemic immunosuppressive therapy with corticosteroids and cyclophosphamide. In conclusion, this is a rare case of polyarteritis nodosa manifesting as spontaneous bilateral subcapsular renal hemorrhage with deteriorated renal function, which was successfully treated with immunosuppressive therapy.


Assuntos
Injúria Renal Aguda , Aneurisma , Poliarterite Nodosa , Feminino , Humanos , Idoso , Poliarterite Nodosa/diagnóstico , Hematoma/etiologia , Rim/fisiologia , Aneurisma/etiologia , Hemorragia , Injúria Renal Aguda/complicações
19.
Virchows Arch ; 481(4): 553-563, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35809093

RESUMO

Intestinal immunity has been closely associated with the pathogenesis and progression of renal diseases, a relationship known as the "gut-kidney axis." To determine the association between immunoglobulin A nephropathy (IgAN) and Crohn's disease (CD), a clinico-pathological study was performed on patients who had IgAN with CD (CD-IgAN) and without CD (NOS-IgAN). We enrolled 29 patients diagnosed with IgAN via renal biopsy at the Tokyo Yamate Medical Center from 2009 to 2017. The patients were divided into CD-IgAN (n = 18) and NOS-IgAN (n = 11) and evaluated for clinical and pathological findings. IgA subclasses and galactose-deficient IgA1 (Gd-IgA1) were examined via immunohistochemistry using formalin-fixed paraffin-embedded sections from renal biopsy. Our results showed no significant difference in the extent of mesangial IgA subclasses or Gd-IgA1 deposition according to the presence or absence of CD. Pathologically, however, those with CD-IgAN had remarkably higher percentage of global glomerulosclerosis and extent of interstitial fibrosis and tubular atrophy (IF/TA) compared to those with NOS-IgAN. Moreover, the extent of macrophage infiltration in the glomerulus and interstitium was significantly higher in CD-IgAN than in NOS-IgAN. Clinically, the CD-IgAN group had significantly worse responsiveness to steroid treatment compared to the NOS-IgAN group. In conclusion, the similar immunological characteristics of deposited IgA molecules in the glomeruli between the CD-IgAN and NOS-IgAN groups might suggest their etiological similarity. However, a renal pathology showing advanced glomerular and tubulointerstitial sclerosis accompanying increased macrophage infiltration and highly resistant clinical features in patients with CD-IgAN suggests that some pathophysiological factors in CD, including abnormal intestinal immunity, may promote and activate the inflammatory process in IgAN via undetermined mechanisms.


Assuntos
Doença de Crohn , Glomerulonefrite por IGA , Biópsia , Estudos de Casos e Controles , Doença de Crohn/patologia , Formaldeído , Galactose , Glomerulonefrite por IGA/patologia , Humanos , Imunoglobulina A , Inflamação/patologia , Rim/patologia , Esteroides
20.
Virchows Arch ; 479(5): 997-1005, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34302213

RESUMO

Exostosin 1 and exostosin 2 (EXT1/EXT2) on glomerular basement membrane (GBM) were recently reported as novel putative antigens in secondary membranous nephropathy with autoimmune disease. However, the clinical significance of glomerular EXT1/EXT2 remains elusive in patients with lupus nephritis (LN). The immunofluorescence staining pattern of glomerular EXT1/EXT2 is also undetermined in membranous LN (MLN) or proliferative LN (PLN). We cross-sectionally analyzed patients with MLN (pure class V, n = 11) and PLN (class III, IV, and mixed class III/IV + V, n = 22) who underwent renal biopsies between 2010 and 2020 at Showa University Hospital. Glomerular EXT1/EXT2 expressions were evaluated by immunofluorescence. T-helper (Th) cell-related serum inflammatory cytokines were measured using enzyme-linked immunosorbent assay. The positivity for both EXT1/EXT2 was higher in patients with MLN than PLN (90.9% vs 63.6%, P = 0.212). MLN showed global and bright granular EXT1/EXT2 expressions along GBM, while PLN showed segmental and moderate expressions on GBM. Additionally, glomerular EXT1/EXT2 positivity was not associated with the degree of proteinuria or renal function in MLN and PLN patients, but the levels of serum anti-dsDNA antibody and circulating immune complexes were lower in patients with EXT1/EXT2-positive MLN than EXT1/EXT2-negative PLN. Moreover, serum complement levels and IL-4/IFN-γ ratios were elevated in EXT1/EXT2-positive MLN than EXT1/EXT2-negative PLN. Collectively, immunofluorescence staining for glomerular EXT1/EXT2 had characteristic patterns between MLN and PLN. Glomerular EXT1/EXT2 expressions tended to be high in Th2-dominant MLN patients without severe hypocomplementemia and elevated autoantibodies. Thus, EXT1/EXT2 might be involved in the unique developmental mechanism of MLN.


Assuntos
Imuno-Histoquímica , Glomérulos Renais/química , Nefrite Lúpica/metabolismo , N-Acetilglucosaminiltransferases/análise , Adulto , Anticorpos Antinucleares/sangue , Complexo Antígeno-Anticorpo/sangue , Biomarcadores/sangue , Biópsia , Estudos Transversais , Citocinas/sangue , Feminino , Humanos , Mediadores da Inflamação/sangue , Japão , Glomérulos Renais/patologia , Nefrite Lúpica/imunologia , Nefrite Lúpica/patologia , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Auxiliares-Indutores/metabolismo
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