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Background: In contrast to childhood minimal change disease (MCD), adult-onset MCD frequently recurs and requires prolonged immunosuppressive therapy. Accordingly, an investigation of the pathogenesis of adult MCD is required. MCD is usually accompanied by severe dyslipidaemia. Oxidized low-density lipoprotein (ox-LDL) is known to function in a damage-associated molecular pattern (DAMP) through CD36, triggering the NOD-like receptor thermal protein domain-associated protein 3 (NLRP3) inflammasome and programmed cell death called pyroptosis. However, the relationship between MCD pathogenesis and NLRP3 inflammasome/pyroptosis activation via CD36 is not fully understood. Methods: We conducted comprehensive histological and clinical evaluations by analysing renal biopsy (RBx) specimens and urine samples obtained from 26 patients with MCD. These samples were compared with control kidneys from 15 transplant donors and urine samples from 15 healthy volunteers. Results: The number of podocytes was lower in the MCD group than in the control group. Urinary ox-LDL levels were higher in the MCD group than in the control group. Immunofluorescence staining revealed that NLRP3 and CD36 were upregulated in MCD podocytes. Urinary interleukin (IL)-18 levels increased in patients with MCD. Steroid therapy performed before RBx appeared to maintain the podocyte number and reduce urinary ox-LDL and IL-18 levels. Conclusion: In MCD, the NLRP3 inflammasome and pyroptosis cascade seem to be activated via upregulation of CD36 in podocytes, associated with increased urinary ox-LDL. Elevated urinary IL-18 levels suggest that pyroptosis may occur in MCD. Further research is required to confirm the significance of the podocyte NLRP3 inflammasome/pyroptosis in MCD.
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Minimal change disease (MCD), a common cause of idiopathic nephrotic syndrome, has been postulated to exhibit an association with allergic conditions. Recent studies revealed the crucial role of interleukin (IL)-33 in type 2 innate immunity. We hypothesized that development of MCD involves an IL-33-related immune response. We examined 49 patients with biopsy-proven MCD, 6 healthy volunteers, and 29 patients in remission. In addition to clinical features, serum and urinary levels of IL-33 and soluble suppression of tumorigenicity 2 protein (sST2), a secreted form of the receptor of IL-33, were analyzed. Although IL-33 was barely detectable in either MCD or control samples, sST2 levels at diagnosis were elevated in MCD patients. Serum sST2 levels of MCD patients were correlated with serum total protein level (r = - 0.36, p = 0.010) and serum creatinine level (r = 0.34, p = 0.016). Furthermore, the elevated sST2 levels were observed to decrease following remission. Immunofluorescence revealed IL-33 expression in the podocytes among MCD patients, with a significant increase compared with controls. In vitro, mouse podocyte cells incubated with serum from a MCD patient at disease onset showed increased IL-33 secretion. These results suggest an IL-33-related immune response plays a role in MCD.
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Nefrose Lipoide , Síndrome Nefrótica , Animais , Humanos , Camundongos , Expressão Gênica , Proteína 1 Semelhante a Receptor de Interleucina-1 , Interleucina-33 , Nefrose Lipoide/urinaRESUMO
Osteoporosis is a crucial complication in patients with chronic kidney disease (CKD), similar to that in the general population. Although romosozumab, a monoclonal antibody targeting sclerostin, has been administered for patients with CKD, its clinical effectiveness in these patients, especially in patients on hemodialysis (HD), remains to be studied. Herein, we report the case of a 42-year-old man on HD who developed severe osteoporosis. Serum calcium levels were extremely high, bone metabolic markers were abnormal, and the patient had pathological fractures. The bone biopsy indicated a bone metabolism disorder and high bone turnover. We administered romosozumab once a month as an intervention for bone alteration. Through the 10-month usage, bone metabolic markers improved, and the decrease in bone mineral density was ameliorated. We hypothesized that romosozumab could be a therapeutic option for osteoporosis in patients undergoing HD, especially in those with bone mineralization disorders.
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Conservadores da Densidade Óssea , Doenças Ósseas , Osteoporose , Rim Policístico Autossômico Dominante , Insuficiência Renal Crônica , Humanos , Adulto , Rim Policístico Autossômico Dominante/tratamento farmacológico , Osteoporose/tratamento farmacológico , Osteoporose/etiologia , Osteoporose/metabolismo , Densidade Óssea , Anticorpos Monoclonais/uso terapêutico , Conservadores da Densidade Óssea/uso terapêutico , Insuficiência Renal Crônica/terapia , Insuficiência Renal Crônica/tratamento farmacológico , Diálise RenalRESUMO
INTRODUCTION: Uromodulin (UMOD), also known as Tamm-Horsfall protein, is a kidney-specific protein. Recently, low levels of urinary UMOD (uUMOD) have been reported as a risk factor for renal function decline in IgA nephropathy (IgAN). However, the clinical significance of serum UMOD (sUMOD) is not clear. In this study, we clarified the clinical significance of sUMOD in IgAN. METHODS: One hundred eight biopsy-proven IgAN patients were included in this study. The relationships between sUMOD levels and various clinicopathological findings were evaluated. RESULTS: sUMOD was positively correlated with estimated glomerular filtration rate (eGFR) (p < 0.001, r = 0.5) and negatively correlated with creatinine (Cr) (p < 0.0001, r = -0.51) and urinary protein (UP) (p = 0.005, r = -0.33). In the low sUMOD group (<145 ng/mL), Cr was significantly higher (p < 0.0001) and histopathological changes were severe. The cumulative incidence of a 30% decline in eGFR was 25.6% overall, 0% in histological grade (H-G) I, 33.3% in H-G II, 59.6% in H-G III, and 66.7% in H-G IV. In univariate analyses, prognostic factors for a 30% decline in eGFR were male, high UP, low albumin, low eGFR, and low sUMOD. When comparing the severe histopathological classes (H-G II-IV) and H-G I, low sUMOD was a risk factor for severe histopathological changes. Furthermore, in patients with eGFR > 60 (n = 74), multivariate analyses revealed that low sUMOD independently predicted a 30% decline in eGFR and having severe histopathological changes. CONCLUSION: In IgAN, sUMOD levels were associated with renal function. Low sUMOD levels may be a risk factor for worsening renal function, especially in the early stage of IgAN.
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Glomerulonefrite por IGA , Creatinina , Feminino , Taxa de Filtração Glomerular , Glomerulonefrite por IGA/patologia , Humanos , Rim/patologia , Masculino , Uromodulina/urinaRESUMO
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.
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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/metabolismoRESUMO
INTRODUCTION: Interleukin-34 (IL-34) shares a receptor (cFMS) with colony stimulating factor-1 (CSF-1), and these two ligands mediate macrophage proliferation. However, in contrast to CSF-1, the influence of IL-34 on tubular epithelial cells (TECs) injury remains unclear. We investigated the physiological effects of IL-34 on TEC damage caused by cisplatin nephrotoxicity (CP-N). METHODS: Mice were administered anti-mouse IL-34 antibody (anti-IL-34 Ab; 400 ng/kg) or vehicle from 1 day before and up to 2 days after CP-N induction. In vitro, mouse renal proximal TECs (MRPTEpiC) were cultured to analyze the inhibitory effects of IL-34 on CP-induced TEC apoptosis. RESULTS: Compared to vehicle treatment, anti-IL-34 Ab treatment significantly suppressed the intra-renal expression of IL-34 and its two receptors, cFMS and PTP-ζ, and significantly improved renal function, ameliorated tubulointerstitial injury, suppressed macrophage infiltration, and reduced apoptotic cell numbers in CP-N mice. It also significantly reduced the renal transcript levels of Kim-1, MIP-1/CCL3, TNF-α, and Bax in CP-N mice. Furthermore, anti-IL-34 Ab-treated CP-N mice showed less renal infiltration of F4/80+TNF-α+ cells. In vitro, stimulation with CP induced the expression of IL-34 and its two receptors in MRPTEpiC. Anti-IL-34 Ab treatment significantly suppressed CP-induced Bax expression with the degradation of ERK1/2 phosphorylation in damaged MRPTEpiC. CONCLUSIONS: IL-34 secreted from damaged TECs appeared to be involved in the progression of CP-N. Inhibition of IL-34 with neutralizing antibody directly prevented CP-induced TEC apoptosis by inhibiting the phosphorylation of ERK 1/2. Blocking of IL-34 appears to suppress the proliferation of cytotoxic macrophages, which indirectly attenuates CP-N. Thus, IL-34 represents a potential therapeutic target for TEC injury, and the inhibition of IL-34 might have a reno-protective effect.
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Anticorpos/uso terapêutico , Antineoplásicos/efeitos adversos , Cisplatino/efeitos adversos , Interleucinas/antagonistas & inibidores , Nefropatias/induzido quimicamente , Nefropatias/prevenção & controle , Substâncias Protetoras/uso terapêutico , Animais , Apoptose/efeitos dos fármacos , Células Cultivadas , Nefropatias/patologia , Túbulos Renais Proximais/citologia , Túbulos Renais Proximais/efeitos dos fármacos , Túbulos Renais Proximais/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BLRESUMO
We present six cases of antimelanoma differentiation-associated gene 5 antibody (anti-MDA5-Ab)-positive clinically amyopathic dermatomyositis (CADM) with rapidly progressive interstitial lung disease (RP-ILD), which is known to have a poor prognosis. The outcomes of these cases are described after treatment with therapeutic plasma exchange (TPE). Clinical and therapeutic data for patients with CADM with RP-ILD were collected retrospectively from medical records. All six patients received early intensive care including high-dose corticosteroids, intravenous cyclophosphamide, and a calcineurin inhibitor, but lung disease and hypoxia became more severe. TPE was performed over a median of 9.5 sessions (range 3-14) per patient, and the median duration from admission to TPE was 23 days. Three patients received combined direct hemoperfusion using a polymyxin B-immobilized fiber column (PMX-DHP) therapy on successive days to manage acute respiratory failure. Four patients survived and two died due to respiratory failure. In the survival cases, ferritin decreased, and ferritin and KL-6 were lower at diagnosis. The patients who died had a higher alveolar-arterial oxygen difference and more severe lung lesions at the time of initiation of TPE. These findings indicate that a combination of conventional therapy and TPE may be useful for improvement of the prognosis of CADM with RP-ILD at the early stage of onset.
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Autoanticorpos/sangue , Dermatomiosite/terapia , Helicase IFIH1 Induzida por Interferon/imunologia , Doenças Pulmonares Intersticiais/terapia , Troca Plasmática/métodos , Idoso , Dermatomiosite/diagnóstico , Dermatomiosite/imunologia , Feminino , Humanos , Doenças Pulmonares Intersticiais/imunologia , Masculino , Pessoa de Meia-IdadeRESUMO
INTRODUCTION: Recent studies noted that Henoch-Schönlein purpura nephritis (HSPN) and IgA nephropathy (IgAN) share the feature of galactose-deficient IgA1 (Gd-IgA1)-oriented pathogenesis, although there are distinct clinical differences. We aimed to clarify the clinicopathologic differences between these 2 diseases. METHODS: We cross-sectionally analyzed adult patients with HSPN (n = 24) or IgAN (n = 56) who underwent renal biopsy (RB) between 2008 and 2018 at Showa University Hospital. Serum Gd-IgA1 (s-Gd-IgA1) levels at the time of RB were compared among study groups using enzyme-linked immunosorbent assay (ELISA) with anti-human Gd-IgA1-specific monoclonal antibody (KM55). We also immunohistochemically stained paraffin-embedded sections for glomerular Gd-IgA1 (g-Gd-IgA1)-deposition using KM55. Serum inflammatory cytokines were measured using ELISA. RESULTS: Glomerular endothelial injury with subendothelial IgA deposition was significant in patients with HSPN. Serum IL-8, MCP-1, TNF-α, and IL-6 levels were significantly higher in patients with HSPN than IgAN. Levels of s-Gd-IgA1 were comparable among patients with HSPN and IgAN, and a similar degree of g-Gd-IgA1-deposition was detected in both diseases. Furthermore, g-Gd-IgA1-deposition was evident in patients with histopathologically advanced HSPN or IgAN. In HSPN, significant positive correlations between s-Gd-IgA1 levels and crescent formation or IL-6 elevation were confirmed, and g-Gd-IgA1 intensity showed a significant positive correlation with MCP-1 and a tendency to positively correlate with IL-8. Meanwhile, patients with IgAN showed no correlation between inflammatory cytokines and both-Gd-IgA1. Moreover, most g-Gd-IgA1-positive areas were not double stained with CD31 in HSPN. CONCLUSIONS: Although assessing both-Gd-IgA1 alone was insufficient to distinguish between HSPN and IgAN, patients with HSPN showed considerable glomerular capillaritis with subendothelial IgA deposition and significant elevation of serum inflammatory cytokines. Furthermore, such glomerular subendothelial IgA deposition might not contain Gd-IgA1, and factors associated with Gd-IgA1 were inconsistent among these 2 diseases. Thus, developmental mechanisms for IgAN might not apply to HSPN completely, and these 2 diseases still have different aspects.
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Glomerulonefrite por IGA/patologia , Vasculite por IgA/patologia , Imunoglobulina A/sangue , Adulto , Biomarcadores/sangue , Estudos Transversais , Citocinas/sangue , Feminino , Galactose/sangue , Glomerulonefrite por IGA/sangue , Humanos , Vasculite por IgA/sangue , Inflamação/sangue , Inflamação/patologia , Glomérulos Renais/patologia , MasculinoRESUMO
Calciphylaxis is a rare and severe disease that manifests with painful skin ulceration and necrosis. Herein, we report five patients of hemodialysis patients with skin biopsy-proven calciphylaxis at a single facility. One patient had undergone parathyroidectomy (PTx) due to severe secondary hyperparathyroidism, four had been treated with vitamin D receptor activators, and two were on warfarin therapy. All patients had hyperphosphatemia, and one had hypercalcemia. The intact parathyroid hormone level at diagnosis was 2 pg/ml in the patient after PTx, while three patients were within the target range. The average period after diagnosis of calciphylaxis was 2 months. Skin lesions were present on the thighs and lower legs in two patients, and on the dorsum of the foot in one patient. In skin biopsy, calcification was found in the arteriolar media in four patients, and calcium (Ca) was deposited in the dermal lesion in one patient. All patients received local cures, surgical debridement, antibiotics to control infectious diseases, and strict control of serum Ca and phosphate. Calcimimetics were used in all patients except one who had undergone PTx one month before, sodium thiosulfate was used in 4 patients, and low Ca dialysate was used in three patients. The average follow-up period was 7.4 months. Four patients were cured, and one died due to infection. We suggest that multidisciplinary management for infectious diseases, surgical debridement, strict control of mineral and bone markers from the early stage, and elimination of risk factors may improve the course of calciphylaxis, which is a life-threatening disease.
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Calciofilaxia/tratamento farmacológico , Calciofilaxia/cirurgia , Hiperparatireoidismo Secundário/cirurgia , Receptores de Calcitriol/agonistas , Adulto , Idoso , Calciofilaxia/etiologia , Calciofilaxia/patologia , Terapia Combinada , Feminino , Humanos , Hipercalcemia/diagnóstico , Hiperparatireoidismo Secundário/complicações , Hiperparatireoidismo Secundário/tratamento farmacológico , Hiperfosfatemia/diagnóstico , Comunicação Interdisciplinar , Masculino , Pessoa de Meia-Idade , Necrose/etiologia , Necrose/patologia , Paratireoidectomia/efeitos adversos , Diálise Renal/efeitos adversos , Úlcera Cutânea/etiologia , Úlcera Cutânea/patologia , Resultado do Tratamento , Varfarina/uso terapêuticoRESUMO
BACKGROUND: Uromodulin (UMOD), also known as Tamm-Horsfall protein, is a kidney-specific protein expressed by epithelial cells lining the thick ascending limb of the loop of Henle. In the current study, we aimed to clarify the clinical significance of UMOD in ANCA-associated glomerulonephritis (AAG). MATERIALS AND METHODS: Sixty-one biopsy-proven AAG patients were included in this study. UMOD was measured using ELISA. The relationships between serum UMOD (sUMOD) levels and various clinicopathological findings were evaluated. RESULTS: AAG was classified into four categories (focal, crescentic, mixed, and sclerotic). In addition, tubulointerstitial lesions were classified as mild, moderate, and severe. The levels of sUMOD and urinary UMOD (uUMOD) were correlated with each other. A negative correlation between sUMOD levels and serum Cr levels, and positive correlation between sUMOD levels and eGFR were found. Patients in the high sUMOD group were associated with low serum Cr levels, focal classification, and mild tubulointerstitial injury compared to the low sUMOD group. Comparing the characteristics among histopathological classes, patients in the focal class had the best renal function and the highest levels of uUMOD/Cr and sUMOD. The focal class had significantly better renal survival compared with the severe histopathological classes (crescentic, mixed, and sclerotic). In univariate logistic regression analyses, prognostic factors for severe histopathological classes were low uUMOD/Cr, high serum Cr, and low sUMOD. Multivariate analyses revealed that low sUMOD predicted severe histopathological classes independent of serum Cr. The mean levels of sUMOD were significantly different between the focal class and severe histopathological classes, with a sensitivity of 70.6% and specificity of 90.0% (cut-off 143 ng/ml, AUC 0.80) by ROC curves. CONCLUSION: Low sUMOD levels were associated with severe clinicopathological findings and might be considered as a risk factor for end stage renal disease in AAG.
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Anticorpos Anticitoplasma de Neutrófilos , Glomerulonefrite , Falência Renal Crônica , Uromodulina , Idoso , Feminino , Taxa de Filtração Glomerular , Glomerulonefrite/sangue , Glomerulonefrite/patologia , Glomerulonefrite/urina , Humanos , Rim/metabolismo , Rim/patologia , Falência Renal Crônica/sangue , Falência Renal Crônica/patologia , Falência Renal Crônica/urina , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Uromodulina/sangue , Uromodulina/urinaRESUMO
INTRODUCTION: Galactose-deficient IgA1 (Gd-IgA1) is a critical pathogenic factor for IgA nephropathy (IgAN), but its value as a disease-specific biomarker remains controversial. We aimed to clarify the clinical significance of Gd-IgA1 in patients with IgAN. METHODS: We retrospectively reviewed 111 patients who were diagnosed with IgAN based on the findings of renal biopsies (RB) at Showa University Hospital since 2007. Serum Gd-IgA1 (s-Gd-IgA1) at the time of RB was compared among 111 IgAN patients, 18 Henoch-Schönlein purpura nephritis (HSPN) patients, 29 lupus nephritis (LN) patients, 28 ANCA-associated vasculitis (AAV) patients, and 13 minimal change disease (MCD) patients using ELISA with an anti-human Gd-IgA1-specific monoclonal antibody (KM55). We also immunohistochemically stained paraffin-embedded sections for mesangial Gd-IgA1 (m-Gd-IgA1) deposition using KM55. RESULTS: Although levels of s-Gd-IgA1 were comparable among IgAN and HSPN, s-Gd-IgA1 levels were significantly elevated in patients with IgAN compared with LN, AAV and MCD (IgAN vs. HSPN, LN, AAV, and MCD: 16.2 ± 9.1 vs. 14.2 ± 10.8, p = 0.263; 12.7 ± 9.4, p = 0.008; 13.1 ± 7.3, p = 0.059; and 8.2 ± 4.8 µg/mL, p<0.001, respectively). Mesangial-Gd-IgA1 deposition was specifically detected in IgAN or HSPN. The increase in s-Gd-IgA1 significantly correlated with m-Gd-IgA1 positivity in patients with IgAN, and s-Gd-IgA1 elevation and m-Gd-IgA1 deposition were evident in patients with histopathologically advanced IgAN. Moreover, s-Gd-IgA1 levels were significantly higher in IgAN patients with glomerular sclerosis and tubulo-interstitial lesions. Mesangial-Gd-IgA1 intensity negatively correlated with eGFR in IgAN. Multivariate analysis selected s-Gd-IgA1 elevation as a significant risk factor for a 30%-reduction in eGFR in IgAN (HR, 1.37; 95% CI, 1.02-1.89; p = 0.038). CONCLUSIONS: Although IgAN and HSPN remain difficult to differentiate, s-Gd-IgA1 elevation and m-Gd-IgA1 deposition are reliable diagnostic factors that reflect IgAN severity. Serum-Gd-IgA1 could serve as a predictor of renal outcomes in IgAN. Thus, Gd-IgA1 could be significant biomarker for patients with IgAN.
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Biomarcadores/sangue , Galactose/sangue , Glomerulonefrite por IGA/sangue , Imunoglobulina A/sangue , Adolescente , Adulto , Idoso , Biópsia , Feminino , Galactose/deficiência , Galactose/genética , Mesângio Glomerular/metabolismo , Mesângio Glomerular/patologia , Glomerulonefrite por IGA/genética , Glomerulonefrite por IGA/patologia , Glicosilação , Humanos , Vasculite por IgA/sangue , Vasculite por IgA/patologia , Rim/irrigação sanguínea , Rim/patologia , Nefrite Lúpica/sangue , Nefrite Lúpica/patologia , Masculino , Pessoa de Meia-Idade , Proteinúria/sangue , Proteinúria/patologia , Vasculite/sangue , Vasculite/patologia , Adulto JovemRESUMO
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.
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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/patologiaRESUMO
The phospholipase A2 receptor (PLA2R) is the major target antigen (Ag) in idiopathic membranous nephropathy (IMN). Recently, several types of immunoassay systems for anti-PLA2R antibody (Ab) have been developed. However, the correlation of serum anti-PLA2R Abs and glomerular expression of PLA2R Ag, and their association with clinicopathological characteristics have yet to be proven in Japanese patients. We examined serum anti-PLA2R Abs by both ELISA and cell-based indirect immunofluorescence assay (CIIFA), and glomerular PLA2R expression by immunofluorescence (IF) in 59 biopsy-proven MN patients including IMN (n = 38) and secondary MN (SMN) (n = 21). In this study, anti-PLA2R Abs were present in 50% of IMN patients, but was absent in SMN patients. The concordance rate between ELISA and CIIFA was 100%. Serum IgG levels were significantly lower in anti-PLA2R Ab-positive patients. Serum albumin levels correlated inversely with serum anti-PLA2R Ab titers. The prevalence and intensity of glomerular staining for IgG4 by IF were significantly higher in anti-PLA2R Ab-positive patients than in -negative patients. Glomerular PLA2 Ag expression evaluated by IF was positive in 52.6% of IMN patients, but was absent in SMN patients. The concordance rate between the prevalence of glomerular PLA2R Ag expression and anti-PLA2R Ab was 84.2%. The prevalence of anti-PLA2R Abs measured by ELISA/CIIFA was equivalent to previous Japanese studies evaluated using Western blotting. These analyses showed an excellent specificity for the diagnosis of IMN, and anti-PLA2R positivity was associated with some clinicopathological features, especially glomerular IgG4-dominant deposition.
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Anticorpos/sangue , Glomerulonefrite Membranosa/imunologia , Receptores da Fosfolipase A2/sangue , Receptores da Fosfolipase A2/imunologia , Adulto , Idoso , Biópsia , Feminino , Glomerulonefrite Membranosa/sangue , Humanos , Imunoglobulina G/sangue , Imunossupressores , Japão , Glomérulos Renais/metabolismo , Masculino , Pessoa de Meia-Idade , RecidivaRESUMO
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/metabolismoRESUMO
Medullary cystic kidney disease (MCKD) is a progressive tubulointerstitial nephropathy, and it leads to end-stage kidney disease (ESKD). It is an autosomal dominant inherited disease, and is categorized into two types according to the localizing chromosome and timing of ESKD onset. Its pathogenesis has not been revealed clearly, thus accumulation of the cases is very valuable. We report here the first reported case of MCKD with kidney enlargement complicated by IgA nephropathy. A 70-year-old male was admitted to our hospital because of renal dysfunction and bilateral kidney enlargement. He was diagnosed as having MCKD complicated by IgA nephropathy (IgA-N) by renal biopsy. We speculated that he had MCKD type 1 on the basis of the late onset of renal failure and no significant evidence of mutation in the UMOD gene that is associated with MCKD type 2. Thereafter, his kidney function decreased progressively and he started to receive hemodialysis. This is an interesting case of MCKD1 in terms of its sporadic nature, kidney enlargement, and complication of IgA-N.
Assuntos
Glomerulonefrite por IGA/patologia , Rim/patologia , Rim Policístico Autossômico Dominante/patologia , Idoso , Diagnóstico Diferencial , Glomerulonefrite por IGA/complicações , Glomerulonefrite por IGA/diagnóstico , Humanos , Masculino , Mutação/genética , Rim Policístico Autossômico Dominante/complicações , Rim Policístico Autossômico Dominante/diagnóstico , Uromodulina/deficiência , Uromodulina/genéticaRESUMO
The effects of blocking the epidermal growth factor receptor (EGFR) in acute kidney injury (AKI) are controversial. Here we investigated the renoprotective effect of erlotinib, a selective tyrosine kinase inhibitor that can block EGFR activity, on cisplatin (CP)-induced AKI. Groups of animals were given either erlotinib or vehicle from one day before up to Day 3 following induction of CP-nephrotoxicity (CP-N). In addition, we analyzed the effects of erlotinib on signaling pathways involved in CP-N by using human renal proximal tubular cells (HK-2). Compared to controls, rats treated with erlotinib exhibited significant improvement of renal function and attenuation of tubulointerstitial injury, and reduced the number of apoptotic and proliferating cells. Erlotinib-treated rats had a significant reduction of renal cortical mRNA for profibrogenic genes. The Bax/Bcl-2 mRNA and protein ratios were significantly reduced by erlotinib treatment. In vitro, we observed that erlotinib significantly reduced the phosphorylation of MEK1 and Akt, processes that were induced by CP in HK-2. Taken together, these data indicate that erlotinib has renoprotective properties that are likely mediated through decreases in the apoptosis and proliferation of tubular cells, effects that reflect inhibition of downstream signaling pathways of EGFR. These results suggest that erlotinib may be useful for preventing AKI in patients receiving CP chemotherapy.
Assuntos
Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Cisplatino/efeitos adversos , Receptores ErbB/antagonistas & inibidores , Fígado/efeitos dos fármacos , Inibidores de Proteínas Quinases/uso terapêutico , Quinazolinas/uso terapêutico , Animais , Antineoplásicos/efeitos adversos , Apoptose , Peso Corporal , Linhagem Celular , Receptores ErbB/metabolismo , Cloridrato de Erlotinib , Humanos , Túbulos Renais Proximais/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Masculino , Fosforilação , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-DawleyRESUMO
INTRODUCTION: Multipotent mesenchymal stem cells (MSCs) have become a promising therapeutic approach in many clinical conditions. The hypothesis that MSCs can provide a potential therapy for human anti-glomerular basement membrane (GBM) glomerulonephritis (GN) was tested. METHODS: Nephrotoxic serum nephritis was induced in Wistar-Kyoto rats on day 0. Groups of animals were given either human MSCs (hMSCs, 3×10(6)) or vehicle by intravenous injection on day 4; all rats were sacrificed at either day 7 or day 13. RESULTS: Fluorescently labeled hMSCs were localized in glomeruli and tubulointerstitium 5 h after hMSC administration and persisted until 48 h, but hMSCs were barely detectable after 7 days. hMSC-treated rats had decreased kidney weight, proteinuria, and glomerular tuft area at each time point. The serum creatinine level and degree of glomerular crescent formation were decreased by hMSC treatment on day 13. ED1-positive macrophages, CD8-positive cells, and TUNEL-positive apoptotic cells in glomeruli were reduced by hMSC treatment on day 7, and this trend in apoptotic cells persisted to day 13. Renal cortical mRNA for TNF-α, IL-1ß, and IL-17, and the serum IL-17A level were decreased, whereas renal cortical mRNA for IL-4 and Foxp3 and the serum IL-10 level were increased in the MSC-treated group on day 7. Collagen types I and III and TGF-ß mRNA were decreased by hMSC treatment on day 13. CONCLUSION: The present results demonstrated that anti-inflammatory and immunomodulatory effects were involved in the mechanism of attenuating established experimental anti-GBM GN by hMSCs. These results suggest that hMSCs are a promising therapeutic candidate for the treatment of anti-GBM GN.