RESUMO
ATP depletion plays a central role in the pathogenesis of kidney diseases. Recently, we reported spatiotemporal intracellular ATP dynamics during ischemia reperfusion (IR) using GO-ATeam2 mice systemically expressing an ATP biosensor. However, observation from the kidney surface did not allow visualization of deeper nephrons or accurate evaluation of ATP synthesis pathways. Here, we established a novel ATP imaging system using slice culture of GO-ATeam2 mouse kidneys, evaluated the ATP synthesis pathway, and analyzed intracellular ATP dynamics using an ex vivo IR-mimicking model and a cisplatin nephropathy model. Proximal tubules (PTs) were found to be strongly dependent on oxidative phosphorylation (OXPHOS) using the inhibitor oligomycin A, whereas podocytes relied on both OXPHOS and glycolysis using phloretin an active transport inhibitor of glucose. We also confirmed that an ex vivo IR-mimicking model could recapitulate ATP dynamics in vivo; ATP recovery in PTs after reoxygenation varied depending on anoxic time length, whereas ATP in distal tubules (DTs) recovered well even after long-term anoxia. After cisplatin administration, ATP levels in PTs decreased first, followed by a decrease in DTs. An organic cation transporter 2 inhibitor, cimetidine, suppressed cisplatin uptake in kidney slices, leading to better ATP recovery in PTs, but not in DTs. Finally, we confirmed that a mitochondria protection reagent (Mitochonic Acid 5) delayed the cisplatin-induced ATP decrease in PTs. Thus, our novel system may provide new insights into the energy dynamics and pathogenesis of kidney disease.
Assuntos
Trifosfato de Adenosina , Cisplatino , Glicólise , Túbulos Renais Proximais , Fosforilação Oxidativa , Animais , Trifosfato de Adenosina/metabolismo , Túbulos Renais Proximais/metabolismo , Camundongos , Podócitos/metabolismo , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Modelos Animais de Doenças , Cimetidina/farmacologia , Masculino , Túbulos Renais Distais/metabolismo , Técnicas de Cultura de Órgãos , Camundongos Transgênicos , Oligomicinas/farmacologia , Floretina/farmacologia , Camundongos Endogâmicos C57BLRESUMO
Immune checkpoint inhibitors (ICIs) can provide survival benefits to cancer patients; however, they sometimes result in the development of renal immune-related adverse events (irAEs). Tubulointerstitial nephritis (TIN) is the most representative pathological feature of renal irAEs. However, the clinicopathological entity and underlying pathogenesis of ICI-induced TIN are unclear. Therefore, we compared the clinical and histological features of this condition with those of non-ICI drug-induced TIN. Age and C-reactive protein levels were significantly higher in ICI-induced TIN, but there were no significant differences in renal function. Immunophenotyping of ICI-induced TIN showed massive T cell and macrophage infiltration with fewer B cells, plasma cells, neutrophils, and eosinophils. Compared with those in non-ICI drug-induced TIN, CD4+ cell numbers were significantly lower in ICI-induced TIN but CD8+ cell numbers were not significantly different. However, CD8/CD3 and CD8/CD4 ratios were higher in ICI-induced TIN. Moreover, CD25+ and FOXP3+ cells, namely regulatory T cells, were less abundant in ICI-induced TIN. In conclusion, T cell, B cell, plasma cell, neutrophil, and eosinophil numbers proved useful for differentiating ICI-induced and non-ICI drug-induced TIN. Furthermore, the predominant distribution of CD8+ cells and low accumulation of regulatory T cells might be associated with ICI-induced TIN development.
Assuntos
Linfócitos T CD8-Positivos , Inibidores de Checkpoint Imunológico , Nefrite Intersticial , Linfócitos T Reguladores , Humanos , Nefrite Intersticial/induzido quimicamente , Nefrite Intersticial/patologia , Nefrite Intersticial/imunologia , Inibidores de Checkpoint Imunológico/efeitos adversos , Masculino , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/patologia , Linfócitos T Reguladores/efeitos dos fármacos , Feminino , Idoso , Linfócitos T CD8-Positivos/patologia , Linfócitos T CD8-Positivos/imunologia , Pessoa de Meia-Idade , Adulto , Idoso de 80 Anos ou maisRESUMO
AIM: To clarify the clinicopathological characteristics and role of periglomerular angiogenesis in IgA nephropathy. METHODS AND RESULTS: The renal biopsy specimens of 114 patients with IgA nephropathy were examined. Among them, 46 (40%) showed periglomerular angiogenesis around the glomeruli. CD34 and α-smooth muscle actin (α-SMA) staining in serial sections revealed that these vessels contained CD34+ α-SMA+ microarterioles along with CD34+ α-SMA- capillaries. We termed these "periglomerular microvessels (PGMVs)". Patients with PGMVs (PGMV group) had clinically and histologically more severe disease than those without PGMVs (non-PGMV group) at the time of biopsy. Even after adjusting for age, there were significant differences in the degree of proteinuria and estimated glomerular filtration rate reduction between the PGMV and non-PGMV groups. The PGMV group showed a higher incidence of segmental and global glomerulosclerosis and crescentic lesions than the non-PGMV group (P < 0.01). Here, PGMVs were undetectable in the acute and active inflammation phase, but were observed in the acute to chronic or chronic glomerular remodelling phase. PGMVs mainly developed around glomerular adherent lesions to the Bowman's capsule with small or minimal glomerular sclerotic lesions. Conversely, they were rarely observed in segmental sclerosis areas. CONCLUSION: The PGMV group is clinically and pathologically more severe than the non-PGMV group; however, they were undetectable in segmental sclerosis with mesangial matrix accumulation. PGMVs might occur after acute/active glomerular lesions, suggesting that PGMVs may inhibit segmental glomerulosclerosis progression and could be a marker for good repair response after acute/active glomerular injury in severe IgA nephropathy cases.
Assuntos
Glomerulonefrite por IGA , Glomerulosclerose Segmentar e Focal , Humanos , Glomerulonefrite por IGA/patologia , Esclerose/patologia , Glomérulos Renais/patologia , Glomerulosclerose Segmentar e Focal/patologia , Biópsia , Capilares/patologiaRESUMO
BACKGROUND: The intrauterine adverse environment during nephrogenesis reduces the nephron number, probably associates with impaired ureteric bud (UB) branching. METHODS: The kidneys in C57/BL6 mice were irradiated with a single dose of 10 gray (10 Gy) as adverse environment on postnatal day 3 (irradiated PND3 kidneys) after UB branching ceased. The renal functions and pathological findings of irradiated PND3 kidneys were compared with those of non-irradiated control and 10 Gy irradiation on PND14 (irradiated PND14 kidney) from 1 to 18 months. RESULTS: The number and density of glomeruli in irradiated PND3 kidneys were reduced by 1 month with renal dysfunction at 6 months. The morphologically incomplete glomeruli with insufficient capillaries were involuted by 1 month in the superficial cortex. Reduced tubular numbers and developmental disability with shortening renal tubules occurred in irradiated PND3 kidneys with impaired urine concentration at 6 months. Hypertrophy of glomeruli developed, and occasional sclerotic glomeruli appeared in the juxtamedullary cortex with hypertension and albuminuria at 12 to 18 months. CONCLUSIONS: The reduced number of nephrons with shortening renal tubules occurred with impaired renal functions in a postnatal adverse environment after cessation of UB branching, and glomerular hypertrophy with occasional glomerulosclerosis developed accompanied with hypertension and albuminuria in the adulthood. IMPACT: The reduced number of nephrons with shortening renal tubules occurred with impaired renal functions in a postnatal adverse environment after cessation of ureteric bud branching. The reduced number of glomeruli were associated with not only the impaired formation of glomeruli but also involution of morphologically small incomplete glomeruli after an adverse environment. The insufficiently developed nephrons were characterized by the shortening renal tubules with impaired urine concentration. In addition, glomerular hypertrophy and occasional glomerulosclerosis developed with hypertension and albuminuria in adulthood. The present study can help to understand the risk of alternations of premature nephrons in preterm neonates.
Assuntos
Albuminúria , Hipertensão , Camundongos , Animais , Albuminúria/etiologia , Néfrons/patologia , Túbulos Renais , Rim/patologia , Hipertensão/etiologia , Hipertrofia/patologiaRESUMO
BACKGROUND: Low-vacuum scanning electron microscopy (LV-SEM) is applied to diagnostic renal pathology. METHODS: To demonstrate the usefulness of LV-SEM and to clarify the optimal conditions of pathology samples, we investigated the alterations of glomerular basement membrane (GBM) and podocytes in control and experimental active Heymann nephritis (AHN) rats by LV-SEM. RESULTS: On week 15 following induction of AHN, spike formation on GBM with diffuse deposition of IgG and C3 developed. Using LV-SEM, diffuse crater-like protrusions were clearly noted three-dimensionally (3D) on surface of GBM in the same specimens of light microscopy (LM) and immunofluorescence (IF) studies only after removal coverslips or further adding periodic acid-silver methenamine (PAM) staining. These 3D ultrastructural findings of GBM surface could be detected in PAM-stained specimens by LV-SEM, although true GBM surface findings could not be obtained in acellular glomeruli, because some subepithelial deposits remained on surface of GBM. Adequate thickness was 1.5-5 µm for 10% formalin-fixed paraffin-embedded (FFPE) and 5-10 µm for the unfixed frozen sections. The foot processes and their effacement of podocytes could be observed by LV-SEM using 10%FFPE specimens with platinum blue (Pt-blue) staining or double staining of PAM and Pt-blue. These findings were obtained more large areas in 2.5% glutaraldehyde-fixed paraffin-embedded (2.5%GFPE) specimens. CONCLUSION: Our findings suggest that LV-SEM is a useful assessment tool for evaluating the alterations of GBM and podocytes in renal pathology using routine LM and IF specimens, as well as 2.5%GFPE specimens.
Assuntos
Membrana Basal Glomerular , Podócitos , Animais , Membrana Basal Glomerular/patologia , Humanos , Rim/ultraestrutura , Microscopia Eletrônica de Varredura , Podócitos/patologia , Ratos , VácuoRESUMO
AIMS: Activated neutrophils release neutrophil extracellular traps (NETs), resulting in a form of cell death called NETosis. NET formation is reportedly involved in the onset of systemic lupus erythematosus and antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). Citrullination of histones is a key step in NET formation, and the presence of citrullinated histones in neutrophils may be associated with disease induction and activity. The aim of this study was to investigate the relationship between infiltrating citrullinated histone H3 (H3Cit)-positive neutrophils and disease specificity and activity in various glomerulonephritides. METHODS AND RESULTS: We selected 32 kidney biopsies with glomerulonephritides, including AAV, lupus nephritis (LN), Henoch-Schönlein purpura nephritis (HSPN), and poststreptococcal acute glomerulonephritis (PSAGN). We examined the presence of H3Cit in infiltrating neutrophils and their association with necrotising, crescentic lesions and tubulointerstitial lesions. In PSAGN and HSPN, we found many myeloperoxidase (MPO)+ neutrophils in glomeruli; however, only a few were H3Cit+. In LN, MPO+ neutrophils mainly existed in the margins of glomerular tufts forming wire-loop lesions, and some of these were noted to be H3Cit+ neutrophils. In contrast, we found a significantly higher frequency of H3Cit+ neutrophils, despite the small number of MPO+ neutrophils, in microscopic polyangiitis in AAV. In particular, H3Cit+ neutrophils were prominent in necrotising lesions along the glomerular capillaries. Moreover, we also found H3Cit+ neutrophils in the interstitium, with marked peritubular capillaritis in AAV. CONCLUSIONS: H3Cit immunostaining is a useful tool for identifying activated neutrophils. The frequency of H3Cit+ neutrophils is not only a disease-specific marker but also a potential marker for disease activity in AAV.
Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/imunologia , Armadilhas Extracelulares/imunologia , Glomerulonefrite/imunologia , Histonas/imunologia , Ativação de Neutrófilo/imunologia , Adulto , Idoso , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/patologia , Biópsia , Citrulinação , Feminino , Glomerulonefrite/patologia , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Neutrófilos/imunologia , Neutrófilos/patologia , Adulto JovemRESUMO
BACKGROUND: Depletion of ATP in renal tubular cells plays the central role in the pathogenesis of kidney diseases. Nevertheless, inability to visualize spatiotemporal in vivo ATP distribution and dynamics has hindered further analysis. METHODS: A novel mouse line systemically expressing an ATP biosensor (an ATP synthase subunit and two fluorophores) revealed spatiotemporal ATP dynamics at single-cell resolution during warm and cold ischemic reperfusion (IR) with two-photon microscopy. This experimental system enabled quantification of fibrosis 2 weeks after IR and assessment of the relationship between the ATP recovery in acute phase and fibrosis in chronic phase. RESULTS: Upon ischemia induction, the ATP levels of proximal tubule (PT) cells decreased to the nadir within a few minutes, whereas those of distal tubule (DT) cells decreased gradually up to 1 hour. Upon reperfusion, the recovery rate of ATP in PTs was slower with longer ischemia. In stark contrast, ATP in DTs was quickly rebounded irrespective of ischemia duration. Morphologic changes of mitochondria in the acute phase support the observation of different ATP dynamics in the two segments. Furthermore, slow and incomplete ATP recovery of PTs in the acute phase inversely correlated with fibrosis in the chronic phase. Ischemia under conditions of hypothermia resulted in more rapid and complete ATP recovery with less fibrosis, providing a proof of concept for use of hypothermia to protect kidney tissues. CONCLUSIONS: Visualizing spatiotemporal ATP dynamics during IR injury revealed higher sensitivity of PT cells to ischemia compared with DT cells in terms of energy metabolism. The ATP dynamics of PTs in AKI might provide prognostic information.
Assuntos
Injúria Renal Aguda/metabolismo , Injúria Renal Aguda/patologia , Trifosfato de Adenosina/metabolismo , Túbulos Renais Proximais/metabolismo , Túbulos Renais Proximais/patologia , Injúria Renal Aguda/etiologia , Animais , Modelos Animais de Doenças , Camundongos , Valor Preditivo dos Testes , Prognóstico , Traumatismo por Reperfusão/etiologia , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Fatores de TempoRESUMO
BACKGROUND: Acute kidney injury (AKI) and chronic kidney disease (CKD) are considered common complications after allogeneic hematopoietic stem cell transplantation (allo-HSCT). OBJECTIVES AND METHOD: In this study, 114 patients who had undergone allo-HSCT were retrospectively analyzed to investigate the risk factors for onset of posttransplant AKI and CKD as defined by the new Kidney Disease Improving Global Outcomes criteria. RESULTS: Seventy-four patients (64.9%) developed AKI and 25 (21.9%) developed CKD. The multivariate analysis showed that the risk factors for developing stage 1 or higher AKI were age ≥46 years at the time of transplant (p = 0.001) and use of ≥3 nephrotoxic drugs (p = 0.036). For CKD, the associated risk factors were disease status other than complete remission at the time of transplantation (p = 0.018) and onset of AKI after transplant (p = 0.035). The 5-year overall survival (OS) was significantly reduced by development of AKI (p < 0.001), but not CKD. Posttransplant AKI significantly increased the 5-year nonrelapse mortality (p < 0.001), whereas posttransplant CKD showed an increasing tendency, but the difference was not significant. CONCLUSIONS: Posttransplant AKI impacts OS, significantly increases the risk of CKD, and is significantly associated with disseminated intravascular coagulation and use of Ë3 nephrotoxic drugs.
Assuntos
Injúria Renal Aguda/etiologia , Neoplasias Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Insuficiência Renal Crônica/etiologia , Injúria Renal Aguda/patologia , Adolescente , Adulto , Criança , Feminino , Neoplasias Hematológicas/mortalidade , Neoplasias Hematológicas/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Razão de Chances , Prognóstico , Indução de Remissão , Insuficiência Renal Crônica/patologia , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida , Transplante Homólogo , Adulto JovemRESUMO
The neutrophil gelatinase-associated lipocalin (NGAL) receptor (24p3R) is expressed in distal nephron and contributes to the endocytosis of NGAL in urine. This study was undertaken to evaluate an influence of renal ischaemia-reperfusion injury on 24p3R. Unilateral renal pedicle was clamped for 0, 10, 20, 30, or 45 minutes in male Wistar rats. Urine was collected for 24 hours after reperfusion, and ischaemic kidney and blood sample were obtained. Apparent histological injury in the ischaemic kidney was detected in the 30 and 45 minutes-treated groups. Urinary NGAL excretion elevated in rats with renal ischaemia for more than 20 minutes, while serum creatinine increased in rats for more than 30 minutes of ischaemia. Renal protein expression of NGAL did not significantly change. Renal mRNA expressions of megalin and cubilin, which are expressed at renal proximal tubules and uptake NGAL, decreased in animals with renal ischaemia for more than 20 minutes. Renal protein expression of 24p3R, which is expressed at renal distal tubules and uptake NGAL, decreased in rats with renal ischaemia for 45 min. This study showed for the first time that renal 24p3R decreased in response to renal ischaemia. As relatively longer renal ischaemia (45 minutes) decreased renal 24p3R protein and increased urinary NGAL excretion, the down-regulation of 24p3R protein might contribute to the elevated urinary excretion of NGAL in rats with unilateral ischaemia-reperfusion injury.
Assuntos
Injúria Renal Aguda/genética , Rim/metabolismo , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/metabolismo , Traumatismo por Reperfusão/genética , Injúria Renal Aguda/metabolismo , Injúria Renal Aguda/patologia , Animais , Biomarcadores/metabolismo , Células Cultivadas , Regulação da Expressão Gênica , Túbulos Renais Proximais/metabolismo , Lipocalina-2/metabolismo , Lipocalina-2/urina , Masculino , Néfrons/metabolismo , Ratos , Ratos Wistar , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologiaRESUMO
BACKGROUND: Thin basement membrane nephropathy (TBMN) is diagnosed by diffuse thinning of the glomerular basement membrane (GBM) without any clinical and pathologic findings of Alport syndrome and the other renal diseases. TBMN is characterized clinically by benign familial hematuria but rarely develops into end-stage renal disease. METHODS: In 27 cases of biopsy-proven TBMN, we evaluated the pathologic characteristics of TBMN, and examined the correlation between these pathologic characterizations and renal dysfunction. RESULTS: All patients had hematuria, and 21 patients (77.8%) had proteinuria. In six patients (28.6%) who were more than 50 years of age, the estimated glomerular filtration rate (eGFR) decreased from G3a to G4 in the chronic kidney disease stage. Pathologically, an irregular decrease in intensity of type IV collagen α5(IV) chain was seen in GBM, and irregular thinning with diffuse rough etched images was observed on the GBM surface with several sizes of holes by low-vacuum scanning electron microscopy. The glomerular morphology of TBMN was characterized by an increased number of small glomerular capillaries with an increased extracellular matrix (ECM). These characteristic morphologic alterations were evident from a young age in patients with TBMN, but were not correlated directly with the decrease of eGFR, the degree of hematuria, and proteinuria. The decrease of eGFR in patients with TBMN who were more than 50 years of age might be primarily mediated by arteriolosclerosis-associated glomerulosclerosis and interstitial fibrosis. CONCLUSION: Characteristic pathological glomerular findings and GBM alterations occurred from a young age but were not associated directly with renal impairment in biopsy-proven TBMN.
Assuntos
Membrana Basal Glomerular/ultraestrutura , Hematúria/patologia , Adolescente , Adulto , Biópsia , Criança , Pré-Escolar , Feminino , Taxa de Filtração Glomerular , Hematúria/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto JovemRESUMO
Immunoglobulin G4-related disease is a rare immune-mediated disease characterized by the infiltration of IgG4-positive plasma cells and unique storiform fibrosis of multiple organs. The majority of IgG4-related disease patients respond to glucocorticoids, yet the precise mechanism of their action remains unclear. Pathological sections of the submaxillary gland, kidney, and retroperitoneum from 20 patients in total diagnosed with IgG4-related disease were analyzed for glucocorticoid receptor expression and the cell types expressing glucocorticoid receptor. Strong and abundant expression of glucocorticoid receptor was observed in the submaxillary gland, kidney, and retroperitoneum of IgG4-related disease patients, while glucocorticoid receptor was rarely or only faintly observed in the submaxillary gland of patients with Sjögren's syndrome, radicular cysts and sialolithiasis or in the healthy kidney. Glucocorticoid receptor was mainly expressed in fibro/myofibroblasts, CD4-positive T cells and IgG4-positive plasma cells in the submandibular glands and kidneys of IgG4-related disease patients. The abundant expression of glucocorticoid receptor in various types of cells, including resident fibro/myofibroblasts in IgG4-related disease patients might provide clues to the mechanism of steroid responsiveness in IgG4-related disease patients.
Assuntos
Doença Relacionada a Imunoglobulina G4/metabolismo , Rim/metabolismo , Receptores de Glucocorticoides/metabolismo , Glândula Submandibular/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Doença Relacionada a Imunoglobulina G4/patologia , Rim/patologia , Masculino , Pessoa de Meia-Idade , Miofibroblastos/metabolismo , Miofibroblastos/patologia , Peritônio/metabolismo , Peritônio/patologia , Síndrome de Sjogren/metabolismo , Síndrome de Sjogren/patologia , Glândula Submandibular/patologiaRESUMO
AIM: Albuminuria and a low estimated glomerular filtration rate (eGFR) are widely recognized indices of kidney dysfunction and have been linked to cardiovascular events, including stroke. We evaluated albuminuria, measured using the urinary albumin/creatinine ratio (UACR), and the eGFR in the acute phase of ischaemic stroke, and investigated the clinical characteristics of ischaemic stroke patients with and those without kidney dysfunction. METHODS: The study included 422 consecutive patients admitted between June 2010 and May 2012. General blood and urine examinations were performed at admission. Kidney dysfunction was defined as a low eGFR (<60 mL/min per 1.73 m2 ), high albuminuria (≥30 mg/g creatinine), or both. Neurological severity was evaluated using the National Institutes of Health Stroke Scale (NIHSS) at admission and the modified Rankin scale (mRS) at discharge. A poor outcome was defined as a mRS score of 3-5 or death. The impacts of the eGFR and UACR on outcomes at discharge were evaluated using multiple logistic regression analysis. RESULTS: Kidney dysfunction was diagnosed in 278 of the 422 patients (65.9%). The eGFR was significantly lower and UACR was significantly higher in patients with a poor outcome than in those with a good outcome. In multivariate analyses performed after adjusting for confounding factors, UACR >31.2 mg/g creatinine (OR, 2.58; 95% CI, 1.52-4.43; P = 0.0005) was independently associated with a poor outcome, while a low eGFR was not associated. CONCLUSIONS: A high UACR at admission may predict a poor outcome at discharge in patients with acute ischaemic stroke.
Assuntos
Albuminúria/diagnóstico , Creatinina/urina , Hospitalização , Insuficiência Renal/diagnóstico , Acidente Vascular Cerebral/metabolismo , Idoso , Idoso de 80 Anos ou mais , Albuminúria/urina , Estudos de Casos e Controles , Feminino , Taxa de Filtração Glomerular , Humanos , Masculino , Pessoa de Meia-Idade , Avaliação de Resultados em Cuidados de Saúde , Valor Preditivo dos Testes , Recuperação de Função Fisiológica , Insuficiência Renal/complicações , Fatores de Risco , Acidente Vascular Cerebral/complicaçõesRESUMO
Atrial fibrillation (AF) is one of the major risk factor for ischemic stroke, and oral anticoagulation is generally indicated for prevention of stroke. However, the utility of oral anticoagulation for AF in dialysis patients remains controversial. In this single-center, retrospective, observational study, data from 1120 patients on maintenance hemodialysis were analyzed. Baseline medical data were collected from dialysis records including age, gender, the cause of end-stage renal disease, dialysis vintage, and comorbidities. We evaluated outcomes including stroke, major hemorrhage, and death. A total of 106 (11.4 %) patients had AF. After exclusion criteria were applied, 84 patients had analyzable data. Warfarin was prescribed in 30 (35.7 %) of these patients. The remaining 54 patients were classified as the non-warfarin group. CHADS2 score was not significantly different between the warfarin and non-warfarin group. During the mean 47 months of follow up, 7 strokes occurred. However, warfarin use was not associated with the risk for stroke [hazard ratio (HR) 1.07; 95 % confidence interval (CI) 0.20-5.74]. Kaplan-Meier analysis showed no statistically significant difference in the overall survival, stroke-free survival or bleeding-free survival between the warfarin and non-warfarin group. AF is common in Japanese dialysis patients. Despite a certain prevalence of oral anticoagulation, the present study demonstrated neither beneficial nor detrimental effects. A large randomized controlled trial should be considered.
Assuntos
Anticoagulantes/efeitos adversos , Fibrilação Atrial/tratamento farmacológico , Hemorragia/mortalidade , Falência Renal Crônica/complicações , Acidente Vascular Cerebral/mortalidade , Varfarina/efeitos adversos , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Incidência , Japão , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Diálise Renal , Estudos Retrospectivos , Fatores de RiscoRESUMO
Immunoglobulin G (IgG) nephropathy refers to a rare group of diseases characterized by deposits of IgG in the mesangial region. However, IgG nephropathy is controversial as a single disease entity, and its pathogenesis remains to be elucidated. In the present report, we discuss a case of IgG nephropathy in which we observed activation of the classical complement pathway.A 47-year-old woman was admitted to our hospital with nephrotic syndrome. Light-microscopic examination revealed neither proliferative nor sclerotic lesions in the glomeruli. However, unusual and large deposits were observed in the paramesangial area. An immunofluorescence study revealed predominant IgG and C1q and slight C3 deposits in the paramesangial area, suggesting immune-complex-type glomerular disease. An electron microscopic study also revealed different sizes of non-organized electron-dense deposits with a similar pattern of distribution, which were accompanied by foot process effacement. Clinically, there was no evidence of systemic diseases, such as infectious or autoimmune diseases (including systemic lupus erythematosus). Based on these findings, she was diagnosed with IgG nephropathy and treated with prednisolone. Steroid therapy was effective, and complete remission was maintained.Additional immunological examination revealed that IgG deposits were polyclonal and consisted mainly of the IgG1 and IgG3 subclasses. Furthermore, staining was positive for C4d and C5b-9. The present findings indicate that the pathogenesis of IgG nephropathy in our patient may have involved activation of the classical complement pathway.
Assuntos
Imunoglobulina G , Síndrome Nefrótica , Feminino , Humanos , Pessoa de Meia-Idade , Via Clássica do Complemento , Glomérulos Renais/patologia , Síndrome Nefrótica/diagnóstico , Síndrome Nefrótica/etiologia , Síndrome Nefrótica/patologia , Mesângio Glomerular/patologiaRESUMO
Ponatinib is a novel multi-tyrosine kinase inhibitor (TKI) with potent inhibitory activity against refractory chronic myeloid leukemia (CML). Despite its high clinical efficacy, ponatinib induces various adverse events due to its multi-target characteristic. However, renal complications associated with ponatinib are rare. A 76-year-old woman had a history of chronic myeloid leukemia (CML) resistant to imatinib and nilotinib. Our patient developed proteinuria and renal function deterioration during treatment with ponatinib but not with imatinib or nilotinib. We herein report the first case of a patient with secondary focal segmental glomerulosclerosis (FSGS) with partial glomerular collapse induced by ponatinib treatment.
Assuntos
Antineoplásicos , Leucemia Mielogênica Crônica BCR-ABL Positiva , Piridazinas , Feminino , Humanos , Idoso , Mesilato de Imatinib/uso terapêutico , Antineoplásicos/efeitos adversos , Esclerose , Resistencia a Medicamentos Antineoplásicos , Inibidores de Proteínas Quinases/efeitos adversos , Piridazinas/efeitos adversos , Pirimidinas/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/complicações , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológicoRESUMO
BACKGROUND/AIMS: Renal tubular cell death in ischemia-reperfusion does not follow the classical apoptosis or necrosis phenotype. We characterized the morphological and biochemical features of injured tubular epithelial cells in ischemic acute kidney injury (AKI). METHODS: Ischemic AKI was induced in rats by 60 min of ischemia followed by 24 h of reperfusion. Light and electron microscopic TUNEL (LM-TUNEL and EM-TUNEL), gel electrophoresis of extracted DNA, and caspase-3 involvement were examined during the development of death. RESULTS: Damaged tubular epithelial cells with condensed and LM-TUNEL-positive (+) nuclei were prominent at 12 and 18 h after reperfusion with DNA 'ladder' pattern on gel electrophoresis. EM-TUNEL+ cells were characterized by nuclei with condensed and clumping chromatin, whereas the cytoplasm showed irreversible necrosis. The protein levels and activity of caspase-3 did not increase in kidneys after reperfusion. In addition, caspase inhibitor (ZVAD-fmk) failed to inhibit DNA fragmentation and prevent tubular epithelial cell death in ischemic AKI. CONCLUSION: Caspase-3-independent internucleosomal DNA fragmentation occurs in injured tubular epithelial cells undergoing irreversible necrosis in ischemic AKI. The manner of this cell death may be identical to the cell death termed apoptotic necrosis, aponecrosis, or necrapoptosis. Ischemia-reperfusion injury activates caspase-3-independent endonuclease, which in turn induces irreversible damage of tubular epithelial cells, and may contribute to the initiation and development of AKI.
Assuntos
Injúria Renal Aguda/fisiopatologia , Apoptose/fisiologia , Caspase 3/metabolismo , Fragmentação do DNA , Rim/fisiopatologia , Injúria Renal Aguda/etiologia , Clorometilcetonas de Aminoácidos/farmacologia , Animais , Apoptose/efeitos dos fármacos , Western Blotting , Eletroforese em Gel de Ágar , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Células Epiteliais/ultraestrutura , Marcação In Situ das Extremidades Cortadas , Isquemia/complicações , Rim/metabolismo , Rim/patologia , Túbulos Renais/metabolismo , Túbulos Renais/patologia , Túbulos Renais/fisiopatologia , Masculino , Microscopia Eletrônica , Necrose , Nucleossomos/genética , Ratos , Ratos Wistar , Traumatismo por Reperfusão/etiologia , Traumatismo por Reperfusão/fisiopatologiaRESUMO
BACKGROUND/AIMS: Matrix metalloproteinases (MMPs) are zinc endopeptidases that degrade extracellular matrix and are involved in the pathogenesis of ischemic damage in acute kidney injury (AKI). In the present study, we analyzed the role of MMP-2 in the repair process in ischemic AKI. METHODS: AKI was induced in MMP-2 wild-type (MMP-2(+/+)) and MMP-2-deficient (MMP-2(-/-)) mice by 90-min renal artery clamping followed by reperfusion. Renal histology and the activity and distribution of MMP-2 were examined from day 1 to day 14. During the recovery from AKI, MMP-2(+/+) mice were also treated with MMP-2/MMP-9 inhibitor. RESULTS: In both MMP-2(+/+) and MMP-2(-/-) mice, AKI developed on day 1 after ischemia/reperfusion with widespread acute tubular injury, but subsequent epithelial cell proliferation was evident on days 3-7. During the repair process, active MMP-2 and MMP-9 increased in regenerating tubular epithelial cells in MMP-2(+/+) mice on days 7-14, and the tubular repair process was almost complete by day 14. On the other hand, in MMP-2(-/-) mice, less prominent proliferation of tubular epithelial cells was evident on days 3 and 7, and damaged tubules that were covered with elongated and immature regenerated epithelial cells were identified on days 7 and 14. Incomplete recovery of injured microvasculature was also noted with persistent macrophage infiltration. Similarly, treatment with MMP-2/MMP-9 inhibitor resulted in impaired recovery in MMP-2(+/+) mice. CONCLUSION: MMP-2 is involved in tubular repair after AKI. The use of the MMP-2/MMP-9 inhibitor was a disadvantage when it was administered during the repair stage of ischemic AKI. Treatment with MMP inhibitor for AKI needs to be modified to enhance recovery from AKI.
Assuntos
Injúria Renal Aguda/enzimologia , Metaloproteinase 2 da Matriz/metabolismo , Injúria Renal Aguda/patologia , Animais , Células Epiteliais/patologia , Túbulos Renais/efeitos dos fármacos , Túbulos Renais/enzimologia , Túbulos Renais/patologia , Masculino , Metaloproteinase 2 da Matriz/deficiência , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Inibidores de Metaloproteinases de Matriz/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Regeneração/efeitos dos fármacos , Regeneração/fisiologia , Traumatismo por Reperfusão/enzimologia , Traumatismo por Reperfusão/patologiaRESUMO
A 63-year-old man with hepatitis C virus infection was admitted to our hospital for nephrotic syndrome. Light microscopic analysis of a percutaneous renal biopsy showed thickening of the glomerular capillary walls and spike formation. Immunofluorescence revealed granular deposition of monoclonal immunoglobulin G1-lambda and C3 complement along the glomerular basement membrane. Urinary protein excretion decreased slightly after combined treatment with steroid and an immunosuppressive agent. Monoclonal immunoglobulin deposition disease with membranous feature is rare. Additional reports of such cases are needed to elucidate the mechanisms and optimal therapy for this rare entity.
Assuntos
Glomerulonefrite Membranosa/complicações , Hepatite C/complicações , Imunoglobulina G/metabolismo , Cadeias lambda de Imunoglobulina/metabolismo , Síndrome Nefrótica/complicações , Membrana Basal Glomerular/patologia , Humanos , Glomérulos Renais/patologia , Masculino , Pessoa de Meia-Idade , Proteinúria/complicaçõesRESUMO
BACKGROUND: The mechanisms and morphological characteristics of lymphatic vascular development in embryonic kidneys remain uncertain. METHODS: We examined the distribution and characteristics of lymphatic vessels in developing rat kidneys using immunostaining for podoplanin, prox-1, Ki-67, type IV collagen (basement membrane: BM), and α-smooth muscle actin (αSMA: pericytes or mural cells). We also examined the expression of VEGF-C. RESULTS: At embryonic day 17 (E17), podoplanin-positive lymphatic vessels were observed mainly in the kidney hilus. At E20, lymphatic vessels extended further into the developing kidneys along the interlobar vasculature. In 1-day-old pups (P1) to P20, lymphatic vessels appeared around the arcuate arteries and veins of the kidneys, with some reaching the developing cortex via interlobular vessels. In 8-week-old adult rats, lymphatic vessels were extensively distributed around the blood vasculature from the renal hilus to cortex. Only lymphatic capillaries lacking continuous BM and αSMA-positive cells were present within adult kidneys, with none observed in renal medulla. VEGF-C was upregulated in the developing kidneys and expressed mainly in tubules. Importantly, the developing lymphatic vessels were characterized by endothelial cells immunopositive for podoplanin, prox-1, and Ki-67, with no surrounding BM or αSMA-positive cells. CONCLUSION: During nephrogenesis, lymphatic vessels extend from the renal hilus into the renal cortex along the renal blood vasculature. Podoplanin, prox-1, Ki-67, type IV collagen, and αSMA immunostaining can detect lymphatic vessels during lymphangiogenesis.