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1.
FASEB J ; 37(8): e23094, 2023 08.
Artículo en Inglés | MEDLINE | ID: mdl-37462513

RESUMEN

Little is known about the effect of the recently developed calcimimetic evocalcet (Evo) on parathyroid calcium-sensing receptor (CaSR) and vitamin D receptor (VDR) expression. We examined the effects of Evo and cinacalcet (Cina) on CaSR and VDR expression in 5/6 nephrectomized Sprague-Dawley rats fed a high-phosphorus diet for 4 weeks to develop secondary hyperparathyroidism (SHPT). These uremic rats were divided into 4 groups-baseline control (Nx4W) and groups with additional treatment with either the Vehicle, Evo, or Cina for 2 weeks; normal rats were used as normal controls (NC). Blood parameters and parathyroid tissue were analyzed. CaSR and VDR expression levels were determined using immunohistochemistry. The degree of kidney injury and hyperphosphatemia was similar in the uremic groups (Nx4W, Vehicle, Cina, and Evo). Serum parathyroid hormone levels were significantly higher in the Nx4W and Vehicle groups than in the NC group. This increase was significantly suppressed in the Cina and Evo groups compared with that in the Vehicle group. Serum calcium levels were significantly and equally lower in the Cina and Evo groups relative to those in the Vehicle group. CaSR expression was significantly lower in the Nx4W and Vehicle groups than in the NC group. This downregulation was of an equally lesser magnitude in the Cina and Evo groups. A similar trend was observed for VDR expression. These results indicate that Evo and Cina treatment can increase parathyroid CaSR and VDR expression in uremic rats with SHPT, which could provide better control of mineral and bone disorder markers.


Asunto(s)
Hiperparatiroidismo Secundario , Receptores de Calcitriol , Ratas , Animales , Receptores de Calcitriol/metabolismo , Receptores Sensibles al Calcio/metabolismo , Ratas Sprague-Dawley , Glándulas Paratiroides/metabolismo , Hiperparatiroidismo Secundario/tratamiento farmacológico , Hiperparatiroidismo Secundario/complicaciones , Hiperparatiroidismo Secundario/metabolismo , Hormona Paratiroidea/metabolismo , Cinacalcet/farmacología , Cinacalcet/metabolismo
2.
Cochrane Database Syst Rev ; 9: CD014820, 2024 Sep 20.
Artículo en Inglés | MEDLINE | ID: mdl-39301879

RESUMEN

BACKGROUND: Acute kidney injury (AKI) is characterised by a rapid decline in kidney function and is caused by a variety of clinical conditions. The incidence of AKI in hospitalised adults is high. In animal studies, erythropoiesis-stimulating agents (ESA) have been shown to act as a novel nephroprotective agent against ischaemic, toxic, and septic AKI by inhibiting apoptosis, promoting cell proliferation, and inducing antioxidant and anti-inflammatory responses. As a result, ESAs may reduce the incidence of AKI in humans. Randomised controlled trials (RCTs) have been conducted on the efficacy and safety of ESAs, but no prior systematic reviews exist that comprehensively examine ESAs with respect to AKI prevention, although the effectiveness of these agents has been examined for a range of other diseases and clinical situations. OBJECTIVES: This review aimed to look at the benefits and harms of ESAs for preventing AKI in the context of any health condition. SEARCH METHODS: We searched the Cochrane Kidney and Transplant Register of Studies up to 30 August 2024 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Registry Platform (ICTRP) Search Portal and ClinicalTrials.gov. SELECTION CRITERIA: We included RCTs and quasi-RCTs (in which allocation to treatment was based on alternate assignment or order of medical records, admission dates, date of birth or other non-random methods) that compared ESAs with placebo or standard care in people at risk of AKI. DATA COLLECTION AND ANALYSIS: Three authors independently extracted data and assessed the risk of bias for included studies. We used random-effects model meta-analyses to perform quantitative synthesis of the data. We used the I2 statistic to measure heterogeneity amongst the studies in each analysis. We indicated summary estimates as a risk ratio (RR) for dichotomous outcomes and mean difference (MD) for continuous outcomes with their 95% confidence interval (CI). We assessed the certainty of the evidence for each main outcome using the Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) approach. MAIN RESULTS: A total of 20 studies (36 records, 5348 participants) were included. The number of participants ranged from 10 to 1302, and most studies were carried out in single centres (13/20). All the included studies compared ESAs to placebo or usual care. Many of the studies were judged to have unclear or high risk of reporting bias, but were at low risk for other types of bias. ESAs, when compared to control interventions, may make little or no difference to the risk of AKI (18 studies, 5314 participants: RR 0.97, 95% CI 0.85 to 1.10; I² = 19%; moderate-certainty evidence), death (18 studies, 5263 participants: RR 0.92, 95% CI 0.80 to 1.06; I² = 0%; moderate-certainty evidence), or the initiation of dialysis (14 studies, 2059 participants: RR 1.16, 95% CI 0.90 to 1.51; I² = 0%; low-certainty evidence). Even with standardised measurement of AKI, the studies showed no difference in results between different routes of administration (subcutaneous or intravenous), background diseases (cardiac surgeries, children or neonates, other adults at risk of AKI), or duration or dose of ESA. ESAs may make little or no difference to the risk of thrombosis when compared to control interventions (8 studies, 3484 participants: RR 0.92, 95% CI 0.68 to 1.24; I² = 0%). Similarly, there were probably no differences in kidney function measures and adverse events such as myocardial infarction, stroke or hypertension. However, this may be due to the low incidence of these adverse events. AUTHORS' CONCLUSIONS: In patients at risk of AKI, ESAs probably do not reduce the risk of AKI or death and may not reduce the need for starting dialysis. Similarly, there were probably no differences in kidney function measures and adverse events such as thrombosis, myocardial infarction, stroke or hypertension. There are currently two ongoing studies that have either not been completed or published, and it is unclear whether they will change the results. Caution should be exercised when using ESAs to prevent AKI.


Asunto(s)
Lesión Renal Aguda , Hematínicos , Ensayos Clínicos Controlados Aleatorios como Asunto , Humanos , Lesión Renal Aguda/prevención & control , Hematínicos/uso terapéutico , Hematínicos/efectos adversos , Sesgo , Eritropoyetina/uso terapéutico , Eritropoyetina/efectos adversos , Adulto
3.
Lab Invest ; 103(9): 100199, 2023 09.
Artículo en Inglés | MEDLINE | ID: mdl-37331628

RESUMEN

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is known to play a crucial role in dyslipidemia, and an increase in serum PCSK9 levels has also been reported in patients with nephrotic syndrome (NS). However, the specific effects of PCSK9 in kidney disease and the therapeutic potential of targeting PCSK9 in NS remain elusive. We thus investigated the effects of evolocumab (EVO) in mice with adriamycin (ADR)-induced NS. Male BALB/c mice were divided into the following 4 groups: Control, N = 11; EVO (monoclonal antibody for PCSK9), N = 11; ADR, N = 11; and ADR+EVO, N = 11. We also performed in vitro experiments using immortalized murine podocyte cells to validate the direct effects of PCSK9 on podocytes. EVO decreased urinary albumin levels and ameliorated podocytopathy in mice with ADR nephropathy. Further, EVO suppressed the Nod-like receptor protein 3 (NLRP3) inflammasome pathway in podocytes. PCSK9 expression upregulated CD36, a scavenger receptor of oxidized low-density lipoprotein (Ox-LDL), which in turn stimulated the absorption of Ox-LDL in vitro. EVO downregulated CD36 expression in podocytes both in vitro and in vivo. Immunofluorescence staining analysis reveals that CD36 and PCSK9 colocalized in the glomerular tufts of mice with ADR nephropathy. In the patients with focal segmental glomerulosclerosis, the CD36+ area in glomerular tufts increased compared with those diagnosed with minor glomerular abnormalities. This study revealed that EVO ameliorated mouse ADR nephropathy through the regulation of CD36 and NLRP3 inflammasome signaling. EVO treatment represents a potential therapeutic strategy for human NS.


Asunto(s)
Síndrome Nefrótico , Podocitos , Humanos , Masculino , Animales , Ratones , Proproteína Convertasa 9/genética , Proproteína Convertasa 9/metabolismo , Síndrome Nefrótico/tratamiento farmacológico , Podocitos/metabolismo , Inflamasomas , Proteína con Dominio Pirina 3 de la Familia NLR , Doxorrubicina , Subtilisinas/uso terapéutico
4.
Calcif Tissue Int ; 112(1): 34-44, 2023 01.
Artículo en Inglés | MEDLINE | ID: mdl-36287217

RESUMEN

There is limited evidence on the use of romosozumab (ROMO) in the treatment of osteoporosis in patients on hemodialysis (HD); thus, we aimed to investigate this topic. This prospective, observational, single-center cohort study included 13 prior osteoporosis treatment-naïve patients on HD with osteoporosis. They first received ROMO once monthly for 12 months (210 mg; subcutaneously once every month). Thereafter, they received denosumab (DENO) for an additional 12 months (60 mg; subcutaneously once every 6 months). We examined the incidence of new fractures; treatment safety; and temporal changes in the bone mineral density (BMD), bone metabolism markers, and vascular calcification. No new cases of fractures were noted. The median one-year percentage changes (from the baseline) in the BMDs at the lumbar spine (LS), total hip (TH), and femoral neck (FN) were + 9.0%, + 2.5%, and + 4.7%, respectively. These changes were maintained for 24 months. The corresponding relative changes from the baseline to 24 months thereafter were + 14.9%, + 5.4%, and + 6.5%, respectively. The percentage changes in TH BMD and FN BMD were negatively correlated with baseline BMD. Coronary artery and thoracic aorta calcification scores increased slightly from baseline to 12 months thereafter. However, fatal events (cardiovascular disease-associated and all-cause deaths) did not occur during ROMO treatment. Effectiveness of ROMO was better in patients who had severe osteoporosis with low TH BMD, low FN BMD, and high tartrate-resistant acid phosphatase 5b level at ROMO initiation.


Asunto(s)
Conservadores de la Densidad Ósea , Enfermedades Óseas Metabólicas , Fracturas Óseas , Osteoporosis Posmenopáusica , Osteoporosis , Humanos , Femenino , Denosumab/farmacología , Denosumab/uso terapéutico , Estudios Prospectivos , Estudios de Cohortes , Osteoporosis/tratamiento farmacológico , Osteoporosis/inducido químicamente , Densidad Ósea , Fracturas Óseas/epidemiología , Enfermedades Óseas Metabólicas/inducido químicamente , Diálisis Renal
5.
Osteoporos Int ; 33(12): 2649-2652, 2022 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-35980440

RESUMEN

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.


Asunto(s)
Conservadores de la Densidad Ósea , Enfermedades Óseas , Osteoporosis , Riñón Poliquístico Autosómico Dominante , Insuficiencia Renal Crónica , Humanos , Adulto , Riñón Poliquístico Autosómico Dominante/tratamiento farmacológico , Osteoporosis/tratamiento farmacológico , Osteoporosis/etiología , Osteoporosis/metabolismo , Densidad Ósea , Anticuerpos Monoclonales/uso terapéutico , Conservadores de la Densidad Ósea/uso terapéutico , Insuficiencia Renal Crónica/terapia , Insuficiencia Renal Crónica/tratamiento farmacológico , Diálisis Renal
6.
Am J Nephrol ; 53(7): 575-585, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35921808

RESUMEN

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.


Asunto(s)
Glomerulonefritis por IGA , Creatinina , Femenino , Tasa de Filtración Glomerular , Glomerulonefritis por IGA/patología , Humanos , Riñón/patología , Masculino , Uromodulina/orina
7.
J Clin Apher ; 36(1): 196-205, 2021 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-32823371

RESUMEN

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.


Asunto(s)
Autoanticuerpos/sangre , Dermatomiositis/terapia , Helicasa Inducida por Interferón IFIH1/inmunología , Enfermedades Pulmonares Intersticiales/terapia , Intercambio Plasmático/métodos , Anciano , Dermatomiositis/diagnóstico , Dermatomiositis/inmunología , Femenino , Humanos , Enfermedades Pulmonares Intersticiales/inmunología , Masculino , Persona de Mediana Edad
8.
Kidney Blood Press Res ; 45(3): 391-406, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32146474

RESUMEN

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.


Asunto(s)
Nefritis/tratamiento farmacológico , Insuficiencia Renal Crónica/tratamiento farmacológico , Trombomodulina/uso terapéutico , Animales , Femenino , Humanos , Ratas , Ratas Endogámicas WKY
9.
Nephrol Dial Transplant ; 34(5): 774-782, 2019 05 01.
Artículo en Inglés | MEDLINE | ID: mdl-29982644

RESUMEN

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.


Asunto(s)
Enfermedad por Anticuerpos Antimembrana Basal Glomerular/tratamiento farmacológico , Creatinina/metabolismo , Citocinas/metabolismo , Glomérulos Renales/patología , Trombomodulina/uso terapéutico , Animales , Enfermedad por Anticuerpos Antimembrana Basal Glomerular/metabolismo , Enfermedad por Anticuerpos Antimembrana Basal Glomerular/patología , Biomarcadores/metabolismo , Modelos Animales de Enfermedad , Femenino , Glomérulos Renales/metabolismo , Ratas , Ratas Endogámicas WKY , Proteínas Recombinantes
10.
Am J Physiol Renal Physiol ; 315(5): F1449-F1464, 2018 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-30019931

RESUMEN

Under certain circumstances, podocytes can be partially replaced following their loss in disease. The inability of podocytes to proliferate suggests that replacement derives from other cell types. Because neural/glial antigen 2 (NG2)-expressing cells can serve as progenitors in other organs and because herein we showed increased NG2 staining in podocytes following their loss in experimental focal segmental glomerulosclerosis, we used lineage tracing in NG2-CreER tdTomato mice to test the hypothesis that partial podocyte replacement might derive from this cell population. The percentage of glomeruli with red fluorescence protein (RFP)-labeled NG2 cells increased following podocyte depletion, which was augmented by enalapril. However, BrdU was not detected in RFP-labeled cells, consistent with the migration of these cells to the glomerulus. Within glomeruli, RFP-labeled cells did not coexpress podocyte proteins (p57, synaptopodin, nephrin, or podocin) but did coexpress markers for mesangial (α8 integrin, PDGFß receptor) and parietal epithelial cells (PAX8, src-suppressed C-kinase substrate). These results suggest that following podocyte depletion, cells of NG2 lineage do not serve as adult podocyte progenitors but have the ability to transdifferentiate to mesangial and parietal epithelial cell fates.


Asunto(s)
Antígenos/metabolismo , Linaje de la Célula , Proliferación Celular , Transdiferenciación Celular , Glomeruloesclerosis Focal y Segmentaria/patología , Glomérulos Renales/patología , Podocitos/patología , Proteoglicanos/metabolismo , Regeneración , Proteínas de Anclaje a la Quinasa A/metabolismo , Animales , Antígenos/genética , Biomarcadores/metabolismo , Proteínas de Ciclo Celular/metabolismo , Modelos Animales de Enfermedad , Glomeruloesclerosis Focal y Segmentaria/genética , Glomeruloesclerosis Focal y Segmentaria/metabolismo , Cadenas alfa de Integrinas/metabolismo , Glomérulos Renales/metabolismo , Ratones , Ratones Transgénicos , Factor de Transcripción PAX8/metabolismo , Fenotipo , Podocitos/metabolismo , Proteoglicanos/genética , Receptor beta de Factor de Crecimiento Derivado de Plaquetas/metabolismo
11.
Nephrol Dial Transplant ; 33(4): 598-606, 2018 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-28992288

RESUMEN

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.


Asunto(s)
Clorhidrato de Erlotinib/farmacología , Fibrosis/prevención & control , Inhibidores de Proteínas Quinasas/farmacología , Insuficiencia Renal Crónica/prevención & control , Transducción de Señal/efectos de los fármacos , Animales , Células Cultivadas , Progresión de la Enfermedad , Receptores ErbB/antagonistas & inhibidores , Fibrosis/etiología , Fibrosis/metabolismo , Humanos , Macrófagos/citología , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Masculino , Nefrectomía/efectos adversos , Ratas , Ratas Sprague-Dawley , Insuficiencia Renal Crónica/metabolismo , Insuficiencia Renal Crónica/patología
12.
Am J Physiol Renal Physiol ; 310(11): F1182-91, 2016 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-27053690

RESUMEN

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.


Asunto(s)
Medios de Cultivo Condicionados/farmacología , Glomerulonefritis/tratamiento farmacológico , Células Madre Mesenquimatosas/metabolismo , Animales , Quimiocina CCL2/farmacología , Medios de Cultivo Condicionados/metabolismo , Citocinas/metabolismo , Glomerulonefritis/metabolismo , Glomerulonefritis/patología , Interleucina-4/farmacología , Riñón/metabolismo , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/metabolismo , Ratas , Ratas Endogámicas WKY , Factor de Necrosis Tumoral alfa/metabolismo
13.
Pathol Int ; 65(7): 379-82, 2015 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-25818408

RESUMEN

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.


Asunto(s)
Glomerulonefritis por IGA/patología , Riñón/patología , Riñón Poliquístico Autosómico Dominante/patología , Anciano , Diagnóstico Diferencial , Glomerulonefritis por IGA/complicaciones , Glomerulonefritis por IGA/diagnóstico , Humanos , Masculino , Mutación/genética , Riñón Poliquístico Autosómico Dominante/complicaciones , Riñón Poliquístico Autosómico Dominante/diagnóstico , Uromodulina/deficiencia , Uromodulina/genética
14.
Clin Kidney J ; 17(8): sfae216, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-39114498

RESUMEN

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.

15.
Sci Rep ; 13(1): 18776, 2023 10 31.
Artículo en Inglés | MEDLINE | ID: mdl-37907612

RESUMEN

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.


Asunto(s)
Nefrosis Lipoidea , Síndrome Nefrótico , Animales , Humanos , Ratones , Expresión Génica , Proteína 1 Similar al Receptor de Interleucina-1 , Interleucina-33 , Nefrosis Lipoidea/orina
16.
BMJ Open ; 13(5): e070345, 2023 05 03.
Artículo en Inglés | MEDLINE | ID: mdl-37137558

RESUMEN

INTRODUCTION: Renin-angiotensin system (RAS) plays a key role in various types of cardiovascular disease and many kinds of RAS inhibitors have been developed. The effect of discontinuation of RAS inhibitors on clinical outcomes is still controversial. This study aims to evaluate the effects of discontinuing RAS inhibitor medication on the clinical outcomes of patients continuously taking these agents. METHODS AND ANALYSIS: This article presents a systematic review protocol described in accordance with Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols guidelines. We will include randomised controlled trials in which the effects of RAS inhibitor withdrawal were evaluated. Initially, four authors will search for eligible studies in MEDLINE, EMBASE, the Cochrane Database Trial Register, European trial registry and ClinicalTrials.gov. Abstracts and full-text screenings will be performed by the four authors with data extraction performed by each author independently. We will include patients taking RAS inhibitors-including ACE inhibitor, angiotensin receptor blocker and angiotensin receptor neprilysin inhibitor and exclude the patients undergoing renal replacement therapy (RRT), adolescents (under 18 years of age) and patients with acute infectious diseases. Our search will be performed on 1 May 2023. Studies in which the patients discontinued RAS inhibitors due to any reason will be included. Patients who continuously took RAS inhibitors under conditions in which the intervention group discontinued these agents will be considered eligible as the comparison group. Death (any cause), Death (cardiovascular disease (CVD)) and CVD events will be set as primary outcomes. Secondary outcomes will be set as RRT, acute kidney injury, renal function (analysis of the change in estimated glomerular filtration rate), hyperkalaemia, proteinuria and blood pressure. ETHICS AND DISSEMINATION: Research ethics approval was not required in this study due to it being a systematic review, and any data belonging to individuals cannot be identified. The results of this study will be disseminated through peer-reviewed journals and conferences. TRIAL REGISTRATION NUMBER: PROSPERO CRD42022300777.


Asunto(s)
Enfermedades Cardiovasculares , Fallo Renal Crónico , Humanos , Adolescente , Sistema Renina-Angiotensina , Enfermedades Cardiovasculares/tratamiento farmacológico , Fallo Renal Crónico/prevención & control , Antihipertensivos/uso terapéutico , Inhibidores de la Enzima Convertidora de Angiotensina/efectos adversos , Metaanálisis como Asunto , Revisiones Sistemáticas como Asunto
17.
Clin Calcium ; 22(10): 1543-9, 2012 Oct.
Artículo en Japonés | MEDLINE | ID: mdl-23023635

RESUMEN

In the latter 1990s, phosphate, as well as calcium, has been shown to have a direct action on parathyroid function. Since then although many researchers have tried to detect the phosphate sensor in parathyroid gland, none has found it yet. In 2000s, the importance of FGF23 was revealed in patients with autosomal dominant hypophosphatemic rickets and then investigating the role of FGF23 in mineral metabolism has spread. FGF23 target organs comprise those that express coreceptor Klotho, such as kidney and parathyroid glands. While associations of calcium sensing receptor or vitamin D receptor with parathyroid function have been mainly investigated for parathyroid dysfunction, many efforts recently have made to study the effects of FGF23 on parathyroid glands.


Asunto(s)
Hormona Paratiroidea/metabolismo , Fosfatos/metabolismo , Animales , Calcio/metabolismo , Factor-23 de Crecimiento de Fibroblastos , Factores de Crecimiento de Fibroblastos/metabolismo , Glucuronidasa/metabolismo , Homeostasis/fisiología , Humanos , Proteínas Klotho
18.
Virchows Arch ; 479(5): 997-1005, 2021 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-34302213

RESUMEN

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.


Asunto(s)
Inmunohistoquímica , Glomérulos Renales/química , Nefritis Lúpica/metabolismo , N-Acetilglucosaminiltransferasas/análisis , Adulto , Anticuerpos Antinucleares/sangre , Complejo Antígeno-Anticuerpo/sangre , Biomarcadores/sangre , Biopsia , Estudios Transversales , Citocinas/sangre , Femenino , Humanos , Mediadores de Inflamación/sangre , Japón , Glomérulos Renales/patología , Nefritis Lúpica/inmunología , Nefritis Lúpica/patología , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Linfocitos T Colaboradores-Inductores/inmunología , Linfocitos T Colaboradores-Inductores/metabolismo
19.
PLoS One ; 16(1): e0245340, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33428678

RESUMEN

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.


Asunto(s)
Anticuerpos/uso terapéutico , Antineoplásicos/efectos adversos , Cisplatino/efectos adversos , Interleucinas/antagonistas & inhibidores , Enfermedades Renales/inducido químicamente , Enfermedades Renales/prevención & control , Sustancias Protectoras/uso terapéutico , Animales , Apoptosis/efectos de los fármacos , Células Cultivadas , Enfermedades Renales/patología , Túbulos Renales Proximales/citología , Túbulos Renales Proximales/efectos de los fármacos , Túbulos Renales Proximales/patología , Masculino , Ratones , Ratones Endogámicos C57BL
20.
PLoS One ; 15(4): e0232194, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32324811

RESUMEN

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.


Asunto(s)
Glomerulonefritis por IGA/patología , Vasculitis por IgA/patología , Inmunoglobulina A/sangre , Adulto , Biomarcadores/sangre , Estudios Transversales , Citocinas/sangre , Femenino , Galactosa/sangre , Glomerulonefritis por IGA/sangre , Humanos , Vasculitis por IgA/sangre , Inflamación/sangre , Inflamación/patología , Glomérulos Renales/patología , Masculino
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