RESUMO
INTRODUCTION: After kidney transplantation, rejection and drug-related toxicity occur despite tacrolimus whole-blood pre-dose concentrations ([Tac]blood) being within the target range. The tacrolimus concentration within peripheral blood mononuclear cells ([Tac]cells) might correlate better with clinical outcomes. The aim of this study was to investigate the correlation between [Tac]blood and [Tac]cells, the evolution of [Tac]cells and the [Tac]cells/[Tac]blood ratio, and to assess the relationship between tacrolimus concentrations and the occurrence of rejection. METHODS: In this prospective study, samples for the measurement of [Tac]blood and [Tac]cells were collected on days 3 and 10 after kidney transplantation, and on the morning of a for-cause kidney transplant biopsy. Biopsies were reviewed according to the Banff 2019 update. RESULTS: Eighty-three [Tac]cells samples were measured of 44 kidney transplant recipients. The correlation between [Tac]cells and [Tac]blood was poor (Pearson's r = 0.56 (day 3); r = 0.20 (day 10)). Both the dose-corrected [Tac]cells and the [Tac]cells/[Tac]blood ratio were not significantly different between days 3 and 10, and the median inter-occasion variability of the dose-corrected [Tac]cells and the [Tac]cells/[Tac]blood ratio were 19.4% and 23.4%, respectively (n = 24). Neither [Tac]cells, [Tac]blood, nor the [Tac]cells/[Tac]blood ratio were significantly different between patients with biopsy-proven acute rejection (n = 4) and patients with acute tubular necrosis (n = 4) or a cancelled biopsy (n = 9; p > 0.05). CONCLUSION: Tacrolimus exposure and distribution appeared stable in the early phase after transplantation. [Tac]cells was not significantly associated with the occurrence of rejection. A possible explanation for these results might be related to the low number of patients included in this study and also due to the fact that PBMCs are not a specific enough matrix to monitor tacrolimus concentrations.
Assuntos
Rejeição de Enxerto/diagnóstico , Transplante de Rim/efeitos adversos , Tacrolimo/sangue , Idoso , Monitoramento de Medicamentos , Rejeição de Enxerto/sangue , Humanos , Necrose Tubular Aguda/sangue , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos ProspectivosRESUMO
Intravascular hemolysis of any cause can induce acute kidney injury (AKI). Hemolysis-derived product heme activates the innate immune complement system and contributes to renal damage. Therefore, we explored the role of the master complement regulator Factor H (FH) in the kidney's resistance to hemolysis-mediated AKI. Acute systemic hemolysis was induced in mice lacking liver expression of FH (hepatoFH-/-, ~20% residual FH) and in WT controls, by phenylhydrazine injection. The impaired complement regulation in hepatoFH-/- mice resulted in a delayed but aggravated phenotype of hemolysis-related kidney injuries. Plasma urea as well as markers for tubular (NGAL, Kim-1) and vascular aggression peaked at day 1 in WT mice and normalized at day 2, while they increased more in hepatoFH-/- compared to the WT and still persisted at day 4. These were accompanied by exacerbated tubular dilatation and the appearance of tubular casts in the kidneys of hemolytic hepatoFH-/- mice. Complement activation in hemolytic mice occurred in the circulation and C3b/iC3b was deposited in glomeruli in both strains. Both genotypes presented with positive staining of FH in the glomeruli, but hepatoFH-/- mice had reduced staining in the tubular compartment. Despite the clear phenotype of tubular injury, no complement activation was detected in the tubulointerstitium of the phenylhydrazin-injected mice irrespective of the genotype. Nevertheless, phenylhydrazin triggered overexpression of C5aR1 in tubules, predominantly in hepatoFH-/- mice. Moreover, C5b-9 was deposited only in the glomeruli of the hemolytic hepatoFH-/- mice. Therefore, we hypothesize that C5a, generated in the glomeruli, could be filtered into the tubulointerstitium to activate C5aR1 expressed by tubular cells injured by hemolysis-derived products and will aggravate the tissue injury. Plasma-derived FH is critical for the tubular protection, since pre-treatment of the hemolytic hepatoFH-/- mice with purified FH attenuated the tubular injury. Worsening of acute tubular necrosis in the hepatoFH-/- mice was trigger-dependent, as it was also observed in LPS-induced septic AKI model but not in chemotherapy-induced AKI upon cisplatin injection. In conclusion, plasma FH plays a key role in protecting the kidneys, especially the tubules, against hemolysis-mediated injury. Thus, FH-based molecules might be explored as promising therapeutic agents in a context of AKI.
Assuntos
Ativação do Complemento , Fator H do Complemento/metabolismo , Hemólise , Hepatócitos/metabolismo , Glomérulos Renais/metabolismo , Necrose Tubular Aguda/prevenção & controle , Túbulos Renais/metabolismo , Animais , Complemento C5a/genética , Complemento C5a/metabolismo , Fator H do Complemento/genética , Modelos Animais de Doenças , Regulação da Expressão Gênica , Glomérulos Renais/patologia , Necrose Tubular Aguda/sangue , Necrose Tubular Aguda/induzido quimicamente , Necrose Tubular Aguda/patologia , Túbulos Renais/patologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fenil-Hidrazinas , Receptor da Anafilatoxina C5a/genética , Receptor da Anafilatoxina C5a/metabolismo , Transdução de SinaisRESUMO
BACKGROUND: The seroprevalence of human Parvovirus B19 (PVB19) is 70-85% in adults worldwide. PVB19 is the etiologic agent of the fifth disease, is a cause of aplastic anemia, and can be associated with kidney injury. We aimed to describe the cases of 4 patients with kidney injury related to PVB19 primary infection, and to evaluate the seroprevalence of PVB19 and the incidence of PVB19 primary infection in patients undergoing a native kidney biopsy. METHODS: Cases of PVB19 infection with kidney injury were reviewed from the archives of the department of Nephrology. A systematic screening of anti-PVB19 IgG and IgM antibodies and viral DNA was performed in sera from 100 consecutive patients with a kidney biopsy in 2017-2018. RESULTS: The 4 patients with PVB19 infection-associated kidney disease displayed: one lupus-like glomerulonephritis (GN) without lupus auto-antibodies, one minimal change disease with tubular necrosis, one secondary hemolytic and uremic syndrome and one membrano-proliferative GN. In the 100 patients biopsied, 67 had elevated anti-PVB19 IgG, among whom 8 had elevated IgM, without circulating viral DNA, without any particular renal pathological pattern. One additional patient showed a seroconversion at the time of kidney biopsy, which revealed a class V lupus nephritis. CONCLUSION: PVB19 primary infection can be associated with different kidney diseases. The seroprevalence of PVB19 among patients with a kidney biopsy is similar to the overall population, and primary infection is rarely documented (1%) after systematic screening. Whether PV19 is nephrotoxic, or triggers renal endothelial injury and immune activation, remains to be elucidated.
Assuntos
Injúria Renal Aguda/virologia , Anticorpos Antivirais/imunologia , DNA Viral/sangue , Eritema Infeccioso/imunologia , Parvovirus B19 Humano/imunologia , Injúria Renal Aguda/sangue , Injúria Renal Aguda/imunologia , Injúria Renal Aguda/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biópsia , Eritema Infeccioso/sangue , Eritema Infeccioso/complicações , Feminino , Glomerulonefrite/sangue , Glomerulonefrite/imunologia , Glomerulonefrite/patologia , Glomerulonefrite/virologia , Glomerulonefrite Membranoproliferativa/sangue , Glomerulonefrite Membranoproliferativa/imunologia , Glomerulonefrite Membranoproliferativa/patologia , Glomerulonefrite Membranoproliferativa/virologia , Síndrome Hemolítico-Urêmica/sangue , Síndrome Hemolítico-Urêmica/imunologia , Síndrome Hemolítico-Urêmica/patologia , Síndrome Hemolítico-Urêmica/virologia , Humanos , Imunoglobulina G/imunologia , Imunoglobulina M/imunologia , Incidência , Rim , Necrose Tubular Aguda/sangue , Necrose Tubular Aguda/imunologia , Necrose Tubular Aguda/patologia , Necrose Tubular Aguda/virologia , Masculino , Pessoa de Meia-Idade , Nefrose Lipoide/sangue , Nefrose Lipoide/imunologia , Nefrose Lipoide/patologia , Nefrose Lipoide/virologia , Parvovirus B19 Humano/genética , Estudos Soroepidemiológicos , Viremia/sangue , Adulto JovemRESUMO
BACKGROUND AND AIM: For appropriate management of acute kidney injury (AKI) in cirrhotic patients, accurate differentiation of the types of AKI, prerenal azotemia (PRA), hepatorenal syndrome (HRS), and acute tubular necrosis (ATN) is very important. Urine N-acetyl-ß-D-glucosaminidase (NAG) has been proposed as a good tubular injury marker in many studies, but its efficacy in cirrhosis is unclear. This study was performed to evaluate the usefulness of urine NAG in patients with decompensated cirrhosis. METHODS: In 114 hospitalized patients with decompensated cirrhosis, we assessed serum creatinine, cystatin C, and urine NAG levels as markers for AKI differentiation and development and patient mortality. RESULTS: Thirty patients diagnosed with AKI at baseline had significantly higher serum creatinine and cystatin C levels, urine NAG levels, and Child-Pugh scores than those without AKI. Only urine NAG levels were significantly higher in patients with ATN than those with PRA or HRS (116.1 ± 46.8 U/g vs 39.4 ± 20.2 or 54.0 ± 19.2 U/g urinary creatinine, all P < 0.05). During a median follow up of 6.1 months, AKI developed in 17 of 84 patients: PRA in nine, HRS in six, and ATN in three. Higher serum cystatin C and urine NAG levels were independent predictors of AKI development in patients with decompensated cirrhosis. Survival was significantly associated with low serum cystatin C and urine NAG levels. CONCLUSION: Serum cystatin C and urine NAG levels are useful to differentiate types of AKI and are strong predictors for AKI development and mortality in patients with decompensated cirrhosis.
Assuntos
Acetilglucosaminidase/urina , Cistatina C/sangue , Nefropatias/sangue , Nefropatias/urina , Cirrose Hepática/fisiopatologia , Injúria Renal Aguda/sangue , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/urina , Idoso , Azotemia/sangue , Azotemia/etiologia , Azotemia/urina , Biomarcadores/sangue , Biomarcadores/urina , Creatinina/sangue , Feminino , Síndrome Hepatorrenal/sangue , Síndrome Hepatorrenal/etiologia , Síndrome Hepatorrenal/urina , Humanos , Nefropatias/etiologia , Necrose Tubular Aguda/sangue , Necrose Tubular Aguda/etiologia , Necrose Tubular Aguda/urina , Cirrose Hepática/complicações , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Taxa de SobrevidaRESUMO
BACKGROUND: Acyclovir is one of the most common prescribed antiviral drugs. Acyclovir nephrotoxicity occurs in approximately 12-48% of cases. It can present in clinical practice as acute kidney injury (AKI), crystal-induced nephropathy, acute tubulointerstitial nephritis, and rarely, as tubular dysfunction. Electrolytes abnormalities like hypokalemia, were previously described only when given intravenously. CASE PRESENTATION: A 54 year-old female presented with weakness and lower extremities paresis, nausea and vomiting after receiving oral acyclovir. Physical examination disclosed a decrease in the patellar osteotendinous reflexes (++ / ++++). Laboratory data showed a serum creatinine level of 2.1 mg/dL; serum potassium 2.1 mmol/L. Kidney biopsy was obtained; histological findings were consistent with acute tubular necrosis and acute tubulointerstitial nephritis. The patient was advised to stop the medications and to start with oral and intravenous potassium supplement, symptoms improved and continued until serum potassium levels were > 3.5 meq/L. CONCLUSIONS: The case reported in this vignette is unique since it is the first one to describe hypokalemia associated to acute tubular necrosis induced by oral acyclovir.
Assuntos
Aciclovir/efeitos adversos , Antivirais/efeitos adversos , Hipopotassemia/induzido quimicamente , Hipopotassemia/patologia , Necrose Tubular Aguda/induzido quimicamente , Necrose Tubular Aguda/patologia , Aciclovir/administração & dosagem , Administração Oral , Antivirais/administração & dosagem , Feminino , Humanos , Hipopotassemia/sangue , Necrose Tubular Aguda/sangue , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Acute kidney injury (AKI) in cirrhotic patients may be functional (hepatorenal syndrome [HRS]) or structural (acute tubular necrosis [ATN]). The differentiation between these two conditions remains challenging; no definite biomarker with a clear cutoff value had been declared. miRNAs seem to be attractive innovative biomarkers to identify the nature of kidney injury in cirrhotic patients. This study aimed to investigate the possibility of using miR-21, miR-210 and miR-146a as differentiating markers between HRS and ATN. METHODS: This pilot case control study included 50 patients with liver cirrhosis; 25 with HRS and another 25 with ATN beside 30 healthy controls. Real-time qPCR was used to measure the circulating miRNA tested. RESULTS: Higher levels of miR-21 were observed in both ATN and HRS vs. controls with statistically significant difference between ATN and HRS. The means were 9.466±3.21 in ATN, 2.670±1.387 in HRS and 1.090±0.586 in controls. miR-146a and miR-210 were both significantly lower in ATN and HRS compared to controls with statistically significant differences between ATN and HRS. The means of miR-210 were 1.020±0.643, 1.640±0.605 and 3.0±0.532 in ATN, HRS and controls, respectively. The means of miR-146a were 2.543±1.929, 4.98±1.353 and 6.553±0.426 in ATN, HRS and controls, respectively. ROC analyses proved that the three studied mi-RNAs can be used as differentiating biomarkers between ATN and HRS with the best performance observed with mi-21 achieving specificity and sensitivity equal 96%. CONCLUSIONS: miR-21, miR-210 and miR-146a may be candidate differentiating markers between HRS and ATN in cirrhotic patients.
Assuntos
Síndrome Hepatorrenal/sangue , Necrose Tubular Aguda/sangue , Cirrose Hepática/diagnóstico , MicroRNAs/sangue , Biomarcadores/sangue , Diagnóstico Diferencial , Feminino , Humanos , Cirrose Hepática/sangue , Masculino , MicroRNAs/genética , Pessoa de Meia-Idade , Projetos Piloto , Reação em Cadeia da Polimerase em Tempo RealRESUMO
BACKGROUND: Hyperchloremia produces renal vasoconstriction and fall in glomerular filtration rate. In 90% of brain-dead organ donors, diabetes insipidus develops, characterized by inappropriate diuresis, hyperosmolality, and hyperchloremia. The aim of this study was to determine the relationship between the serum concentration of chlorides of the donor and the onset of the function of the kidney allograft in the recipient. METHODS: We retrospectively studied 213 donors and kidney allograft recipients. Serum creatinine concentrations and glomerular filtration rates on the 1st, 7th, and 30th days after transplantation of the recipients from hyperchloremic donors were compared with the recipients from normochloremic donors, as well as the incidences of acute tubular necrosis and delayed graft function. RESULTS: On the 1st day, serum creatinine concentrations of the recipients from hyperchloremic and normochloremic donors, respectively, were 448.2 ± 212.1 µmol/L and 502.2 ± 197.8 µmol/L (P = .1), on the 7th day, 168.6 ± 102.6 µmol/L and 196.9 ± 120.6 µmol/L (P = .13), and on the 30th day, 129.4 ± 43.3 µmol/L and 131.8 ± 43.6 µmol/L (P = .73). The differences were statistically significant. The groups also did not differ significantly in glomerular filtration rates and incidences of acute tubular necrosis and delayed graft function. CONCLUSIONS: In this study, no significant correlation between serum chloride concentrations of the organ donors and the onset of the function of kidney allografts in the recipients was found.
Assuntos
Acidose/fisiopatologia , Aloenxertos/fisiopatologia , Morte Encefálica/fisiopatologia , Cloretos/sangue , Transplante de Rim , Doadores de Tecidos , Acidose/complicações , Adulto , Cloretos/fisiologia , Creatinina/sangue , Função Retardada do Enxerto/sangue , Função Retardada do Enxerto/epidemiologia , Função Retardada do Enxerto/etiologia , Feminino , Taxa de Filtração Glomerular , Humanos , Incidência , Rim/fisiopatologia , Testes de Função Renal , Necrose Tubular Aguda/sangue , Necrose Tubular Aguda/epidemiologia , Necrose Tubular Aguda/etiologia , Masculino , Complicações Pós-Operatórias/sangue , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Estudos Retrospectivos , Resultado do TratamentoRESUMO
We analyzed microRNA (miR)-142-3p expression in leucocytes of the peripheral blood and urinary sediment cell samples obtained from kidney transplant recipients who developed graft dysfunction. Forty-one kidney transplant recipients with kidney graft dysfunction and 8 stable patients were included in the study. The groups were divided according to histological analysis into acute rejection group (n=23), acute tubular necrosis group (n=18) and stable patients group used as a control for gene expression (n=8). Percutaneous biopsies were performed and peripheral blood samples and urine samples were obtained. miR-142-3p was analyzed by real-time polymerase chain reaction. The group of patients with acute tubular necrosis presented significantly higher expressions in peripheral blood (P<0.05) and urine (P<0.001) compared to the stable patients group. Also, in the peripheral blood, miR-142-3p expression was significantly higher in the acute tubular necrosis group compared to the acute rejection group (P<0.05). Urine samples of the acute rejection group presented higher expression compared to the stable patients group (P<0.001) but the difference between acute tubular necrosis and acute rejection groups was not significant in the urinary analyzes (P=0.079). miR-142-3p expression has a distinct pattern of expression in the setting of post-operative acute tubular necrosis after kidney transplantation and may potentially be used as a non-invasive biomarker for renal graft dysfunction.
Assuntos
Rejeição de Enxerto/patologia , Transplante de Rim/efeitos adversos , Necrose Tubular Aguda/patologia , MicroRNAs/sangue , MicroRNAs/urina , Regulação para Cima/fisiologia , Adulto , Idoso , Biomarcadores/sangue , Biomarcadores/urina , Feminino , Expressão Gênica , Rejeição de Enxerto/sangue , Rejeição de Enxerto/urina , Humanos , Biópsia Guiada por Imagem , Rim/patologia , Necrose Tubular Aguda/sangue , Necrose Tubular Aguda/urina , Masculino , Pessoa de Meia-Idade , Disfunção Primária do Enxerto/sangue , Disfunção Primária do Enxerto/patologia , Disfunção Primária do Enxerto/urina , Reação em Cadeia da Polimerase em Tempo Real , Valores de Referência , Sensibilidade e Especificidade , Estatísticas não Paramétricas , Transplantados , Resultado do TratamentoAssuntos
Hemoglobinúria Paroxística/diagnóstico , Hemólise , Necrose Tubular Aguda/diagnóstico , Biópsia , Feminino , Testes Hematológicos , Hemoglobinúria Paroxística/sangue , Hemoglobinúria Paroxística/complicações , Hemoglobinúria Paroxística/terapia , Humanos , Necrose Tubular Aguda/sangue , Necrose Tubular Aguda/etiologia , Necrose Tubular Aguda/terapia , Túbulos Renais/patologia , Pessoa de Meia-Idade , Diálise RenalRESUMO
This study investigated the pretreatment and post-treatment effects of dipyridamole (20 mg/kg/day, p.o.) in gentamicin-induced acute nephrotoxicity in rats. Rats were administered gentamicin (100 mg/kg/day, i.p.) for 8 days. Gentamicin-administered rats exhibited renal structural and functional changes as assessed in terms of a significant increase in serum creatinine and urea and kidney weight to body weight ratio as compared to normal rats. Renal histopathological studies revealed a marked incidence of acute tubular necrosis in gentamicin-administered rats. These renal structural and functional abnormalities in gentamicin-administered rats were accompanied with elevated serum uric acid level, and renal inflammation as assessed in terms of decrease in interleukin-10 levels. Dipyridamole pretreatment in gentamicin-administered rats afforded a noticeable renoprotection by markedly preventing renal structural and functional abnormalities, renal inflammation and serum uric acid elevation. On the other hand, dipyridamole post-treatment did not significantly prevent uric acid elevation and renal inflammation, and resulted in comparatively less protection on renal function although it markedly reduced the incidence of tubular necrosis. In conclusion, uric acid elevation and renal inflammation could play key roles in gentamicin-nephrotoxicity. Dipyridamole pretreatment markedly prevented gentamicin-induced acute nephrotoxicity, while its post-treatment resulted in comparatively less renal functional protection.
Assuntos
Anti-Inflamatórios/farmacologia , Dipiridamol/farmacologia , Gentamicinas , Necrose Tubular Aguda/tratamento farmacológico , Necrose Tubular Aguda/prevenção & controle , Rim/efeitos dos fármacos , Nefrite/tratamento farmacológico , Nefrite/prevenção & controle , Animais , Biomarcadores/sangue , Creatinina/sangue , Citoproteção , Modelos Animais de Doenças , Interleucina-10/sangue , Rim/metabolismo , Rim/patologia , Necrose Tubular Aguda/sangue , Necrose Tubular Aguda/induzido quimicamente , Masculino , Nefrite/sangue , Nefrite/induzido quimicamente , Ratos Sprague-Dawley , Fatores de Tempo , Ácido Úrico/sangueRESUMO
We analyzed microRNA (miR)-142-3p expression in leucocytes of the peripheral blood and urinary sediment cell samples obtained from kidney transplant recipients who developed graft dysfunction. Forty-one kidney transplant recipients with kidney graft dysfunction and 8 stable patients were included in the study. The groups were divided according to histological analysis into acute rejection group (n=23), acute tubular necrosis group (n=18) and stable patients group used as a control for gene expression (n=8). Percutaneous biopsies were performed and peripheral blood samples and urine samples were obtained. miR-142-3p was analyzed by real-time polymerase chain reaction. The group of patients with acute tubular necrosis presented significantly higher expressions in peripheral blood (P<0.05) and urine (P<0.001) compared to the stable patients group. Also, in the peripheral blood, miR-142-3p expression was significantly higher in the acute tubular necrosis group compared to the acute rejection group (P<0.05). Urine samples of the acute rejection group presented higher expression compared to the stable patients group (P<0.001) but the difference between acute tubular necrosis and acute rejection groups was not significant in the urinary analyzes (P=0.079). miR-142-3p expression has a distinct pattern of expression in the setting of post-operative acute tubular necrosis after kidney transplantation and may potentially be used as a non-invasive biomarker for renal graft dysfunction.
Assuntos
Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Idoso , Rejeição de Enxerto/patologia , Transplante de Rim/efeitos adversos , Necrose Tubular Aguda/patologia , MicroRNAs/sangue , MicroRNAs/urina , Regulação para Cima/fisiologia , Biomarcadores/sangue , Biomarcadores/urina , Expressão Gênica , Rejeição de Enxerto/sangue , Rejeição de Enxerto/urina , Biópsia Guiada por Imagem , Necrose Tubular Aguda/sangue , Necrose Tubular Aguda/urina , Rim/patologia , Disfunção Primária do Enxerto/sangue , Disfunção Primária do Enxerto/patologia , Disfunção Primária do Enxerto/urina , Reação em Cadeia da Polimerase em Tempo Real , Valores de Referência , Sensibilidade e Especificidade , Estatísticas não Paramétricas , Transplantados , Resultado do TratamentoRESUMO
The use of novel biomarkers of acute kidney injury (AKI) in clinical trials may help evaluate treatments for AKI. Here we explore potential applications of biomarkers in simulated clinical trials of AKI using data from the TRIBE-AKI multicenter, prospective cohort study of patients undergoing cardiac surgery. First, in a hypothetical trial of an effective therapy at the time of acute tubular necrosis to prevent kidney injury progression, use of an indirect kidney injury marker such as creatinine compared to a new direct biomarker of kidney injury reduces the proportion of true acute tubular necrosis cases enrolled. The result is a lower observed relative risk reduction with the therapy, and lower statistical power to detect a therapy effect at a given sample size. Second, the addition of AKI biomarkers (interleukin-18 and NGAL) to clinical risk factors as eligibility criteria for trial enrollment in early AKI has the potential to increase the proportion of patients who will experience AKI progression and reduce trial cost. Third, we examine AKI biomarkers as outcome measures for the purposes of identifying therapies that warrant further testing in larger, multicenter, multi-country trials. In the hypothetical trial of lower cardiopulmonary bypass time to reduce the risk of postoperative AKI, the sample size required to detect a reduction in AKI is lower if new biomarkers are used to define AKI rather than serum creatinine. Thus, incorporation of new biomarkers of AKI has the potential to increase statistical power, decrease the sample size, and lower the cost of AKI trials.
Assuntos
Injúria Renal Aguda/sangue , Ponte Cardiopulmonar/efeitos adversos , Creatinina/sangue , Interleucina-18/sangue , Testes de Função Renal/métodos , Lipocalina-2/sangue , Injúria Renal Aguda/terapia , Biomarcadores/sangue , Progressão da Doença , Humanos , Necrose Tubular Aguda/sangue , Necrose Tubular Aguda/terapia , Estudos Prospectivos , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de RiscoRESUMO
BACKGROUND: Although renal ischemia-reperfusion injury (IRI) can cause delayed graft function, a targeted therapy is not yet available. Because phosphoinositide 3-kinases (PI3K) p110γ and p110δ play important roles in immune cell migration and function, we investigated the effects of PI3K p110γ- and p110δ-specific inhibitors in a murine renal IRI model. METHODS: Renal function was assessed by serum creatine and hematoxylin-eosin staining. Immune cell migration was assessed by flow cytometry and an in vitro cell migration assay using Transwell plates. Gene expression analysis and a multiplex cytokine/chemokine assay were performed to find cytokines/chemokines whose expression was upregulated in renal IRI and affected by p110γ-specific inhibitor. RESULTS: The PI3K p110γ-specific inhibitor, but not p110δ-specific inhibitor, significantly reduced serum creatine levels and acute tubular necrosis. These were accompanied by reduced infiltration of B cells and reduced expression of CXCL9, a CXCR3 ligand, suggesting that p110γ plays an important role in B-cell migration toward injured kidneys. An in vitro cell migration assay revealed for the first time that B-cell migration to injured kidney cells and to CXCL9 requires p110γ. CONCLUSIONS: p110γ-specific inhibitor ameliorates renal IRI by reducing necrosis and immune cell migration. This inhibitor may have the potential to reduce renal graft failure caused by renal IRI.
Assuntos
Classe Ib de Fosfatidilinositol 3-Quinase/metabolismo , Inibidores Enzimáticos/química , Rim/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Traumatismo por Reperfusão/patologia , Animais , Movimento Celular , Quimiocina CXCL9/metabolismo , Classe I de Fosfatidilinositol 3-Quinases , Creatina/sangue , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Sobrevivência de Enxerto , Necrose Tubular Aguda/sangue , Necrose Tubular Aguda/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , NecroseRESUMO
OBJECTIVES: Despite significant advances in the epidemiology of acute kidney injury (AKI), there is no reliable method to predict renal recovery. Using acute kidney injury network (AKIN) criteria, we tested whether higher urinary L-FABP (uL-FABP) concentrations in the patients with AKIN stage 3 (AKIN3) after nephrology consultation would predict failure to recover. METHODS: This is a prospective cohort study of 114 patients with AKIN3 at WuXi People's Hospital from August 2011 to July 2014. The levels of serum creatinine, urine creatinine, and uL-FABP were obtained at the time of nephrology consultation. RESULTS: Patients who recovered had lower uL-FABP than those who failed to recover at time of nephrology consultation (71.42 (11.1 - 118.3) vs. 335.18 (103.9 - 422.3) ng/mg × creatinine, p < 0.001). Urinary L-FABP predicted failure to recover with an area under the receiver operating characteristic curve of 0.906 (95% CI 0.837 - 0.953). A clinical model using age, APACHE II score and acute tubular necrosis severity scoring index (ATN-ISS) predicted failure to recover with an area under the curve of 0.825 (95% CI 0.743 - 0.890). When uL-FABP was compared to the clinical model, the reclassification of risk of renal recovery had significantly improved by 35.1%. CONCLUSION: Urinary L-FABP appears to be a useful biomarker to predict failure to recover during hospitalization in the cohort of patients with AKIN3.
Assuntos
Injúria Renal Aguda/urina , Biomarcadores/urina , Proteínas de Ligação a Ácido Graxo/urina , Estudos de Coortes , Creatinina/sangue , Creatinina/urina , Feminino , Humanos , Testes de Função Renal , Necrose Tubular Aguda/sangue , Necrose Tubular Aguda/urina , Masculino , Estudos Prospectivos , Curva ROCRESUMO
BACKGROUND: Human leukocyte antigen (HLA)-G is a nonclassical HLA class I molecule that displays strong immune-inhibitory properties and has been associated with allograft acceptance. However, there are conflicting data on the correlation of soluble HLA-G (sHLA-G) and acute rejection and no data on the correlation with acute tubular necrosis in kidney transplantation. OBJECTIVE: To evaluate the association of sHLA-G level in early post-transplant period and allograft rejection/ and acute tubular necrosis (ATN) in kidney transplant recipients. METHODS: The sera procured before transplantation and serially on day 3 and day 7 after transplantation from 76 kidney transplant recipients were analyzed for the level of sHLA-G by enzyme-linked immunosorbent assay. RESULTS: The levels of sHLA-G from three serial sera did not differ between patients with acute rejection and patients without rejection. However, the sHLA-G levels on day 3 post-transplant and day 7 post-transplant in patients with ATN were significantly higher than that in patients without ATN (16.3 vs 9.85 U/ml, p = 0.018, for day 3 post-transplant and 12.47 vs 5.42 U/ml, p = 0.044, for day 7 post-transplant). In addition, the ROC analysis of sHLA-G for identifying patients with ATN showed that the area under curve was 0.67 (95% confidence interval 0.54-0.80). CONCLUSIONS: There was no significant difference for sHLA-G levels between patients with acute rejection and without rejection. Interestingly, high levels of sHLA-G in day 3 and day 7 after transplantation were associated with acute tubular necrosis. Our findings raise the question whether the increased levels of sHLA-G in patients with acute tubular necrosis after transplantation might be a result of ischemia and reperfusion injury.
Assuntos
Rejeição de Enxerto/imunologia , Antígenos HLA-G/imunologia , Transplante de Rim/efeitos adversos , Necrose Tubular Aguda/imunologia , Adulto , Aloenxertos , Área Sob a Curva , Biomarcadores/sangue , Estudos de Casos e Controles , Ensaio de Imunoadsorção Enzimática , Feminino , Rejeição de Enxerto/sangue , Rejeição de Enxerto/diagnóstico , Antígenos HLA-G/sangue , Humanos , Necrose Tubular Aguda/sangue , Necrose Tubular Aguda/diagnóstico , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Curva ROC , Solubilidade , Fatores de Tempo , Regulação para CimaRESUMO
OBJECTIVES: Systemic inflammatory responses are a major cause of morbidity and mortality in patients undergoing cardiac surgery with cardiopulmonary bypass. However, the underlying molecular mechanisms for systemic inflammation in response to cardiopulmonary bypass are poorly understood. METHODS: A porcine model was established to study the signaling pathways that promote systemic inflammation in response to cardiac surgery with cardiopulmonary bypass under well-controlled experimental conditions. The influence of sulforaphane, an anti-inflammatory compound derived from green vegetables, on inflammation and injury in response to cardiopulmonary bypass was also studied. Intracellular staining and flow cytometry were performed to measure phosphorylation of p38 mitogen-activated protein kinase and the transcription factor nuclear factor-κB in granulocytes and mononuclear cells. RESULTS: Surgery with cardiopulmonary bypass for 1 to 2 hours enhanced phosphorylation of p38 (2.5-fold) and nuclear factor-κB (1.6-fold) in circulating mononuclear cells. Cardiopulmonary bypass also modified granulocytes by activating nuclear factor-κB (1.6-fold), whereas p38 was not altered. Histologic analyses revealed that cardiopulmonary bypass promoted acute tubular necrosis. Pretreatment of animals with sulforaphane reduced p38 (90% reduction) and nuclear factor-κB (50% reduction) phosphorylation in leukocytes and protected kidneys from injury. CONCLUSIONS: Systemic inflammatory responses after cardiopulmonary bypass were associated with activation of p38 and nuclear factor-κB pathways in circulating leukocytes. Inflammatory responses to cardiopulmonary bypass can be reduced by sulforaphane, which reduced leukocyte activation and protected against renal injury.
Assuntos
Injúria Renal Aguda/prevenção & controle , Anti-Inflamatórios/farmacologia , Ponte Cardiopulmonar/efeitos adversos , Inflamação/prevenção & controle , Isotiocianatos/farmacologia , Necrose Tubular Aguda/prevenção & controle , Injúria Renal Aguda/sangue , Injúria Renal Aguda/etiologia , Animais , Células Cultivadas , Modelos Animais de Doenças , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Feminino , Granulócitos/efeitos dos fármacos , Granulócitos/metabolismo , Inflamação/sangue , Inflamação/etiologia , Necrose Tubular Aguda/sangue , Necrose Tubular Aguda/etiologia , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , NF-kappa B/metabolismo , Fosforilação , Transdução de Sinais/efeitos dos fármacos , Sulfóxidos , Suínos , Fatores de Tempo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
BACKGROUND: Renal ischemia/reperfusion (I/R) injury is manifested by acute renal failure (ARF) and acute tubular necrosis (ATN). The aim of this study was to evaluate the effectiveness of preconditioning with 3, 3, 5 triiodothyronine (T3) to prevent I/R renal injury. METHODOLOGY/PRINCIPAL FINDINGS: The rats were divided into four groups: sham-operated, placebo-treated (SO-P), sham-operated T3- treated (SO- T3), I/R-injured placebo-treated (IR-P), and I/R-injured T3-treated (IR- T3) groups. At 24 h before ischemia, the animals received a single dose of T3 (100 µg/kg). Renal function and plasma, urinary, and tissue variables were studied at 4, 24, and 48 h of reperfusion, including biochemical, oxidative stress, and inflammation variables, PARP-1 immunohistochemical expression, and ATN morphology. In comparison to the SO groups, the IR-P groups had higher plasma urea and creatinine levels and greater proteinuria (at all reperfusion times) and also showed: increased oxidative stress-related plasma, urinary, and tissue variables; higher plasma levels of IL6 (proinflammatory cytokine); increased glomerular and tubular nuclear PARP-1 expression; and a greater degree of ATN. The IR-T3 group showed a marked reduction in all of these variables, especially at 48 h of reperfusion. No significant differences were observed between SO-P and SO-T3 groups. CONCLUSIONS: This study demonstrates that preconditioning rats with a single dose of T3 improves the clinical signs and ATN of renal I/R injury. These beneficial effects are accompanied by reductions in oxidative stress, inflammation, and renal PARP-1 expression, indicating that this sequence of factors plays an important role in the ATN induced by I/R injury.
Assuntos
Precondicionamento Isquêmico , Necrose Tubular Aguda/etiologia , Traumatismo por Reperfusão/complicações , Tri-Iodotironina/farmacologia , Animais , Biópsia , Glutationa/sangue , Imuno-Histoquímica , Inflamação/complicações , Inflamação/patologia , Interleucina-6/sangue , Rim/efeitos dos fármacos , Rim/patologia , Rim/fisiopatologia , Testes de Função Renal , Necrose Tubular Aguda/sangue , Necrose Tubular Aguda/fisiopatologia , Necrose Tubular Aguda/urina , Masculino , Malondialdeído/sangue , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar , Traumatismo por Reperfusão/sangue , Traumatismo por Reperfusão/fisiopatologia , Traumatismo por Reperfusão/urinaRESUMO
Effects of laparoscopic donor nephrectomy (LDN) on graft function, especially early post-transplant, have been controversial. To assess and compare early and late graft function in kidneys procured by open and laparoscopic methods, a retrospective observational study was carried out on 37 recipients-donors who underwent LDN after introduction of this technique in February 2007 at our center, a tertiary care nephrology referral center. Demographic, immunological and intraoperative variables as well as immunosuppressive protocols and number of human leukocyte antigen (HLA) mismatches were noted. Early graft function was assessed by serum creatinine on Days two, five, seven, 14 and 28 and at the time of discharge. Serum creatinine values at three months and at one year post-transplant were considered as the surrogates of late graft function. Data obtained were compared with the data from 33 randomly selected kidney transplants performed after January 2000 by the same surgical team, in whom open donor nephrectomy was used. Pearson's chi square test, Student's t test and Mann-Whitney U test were used for statistical analysis. Early graft function (serum creatinine on Day five 2.15 mg/dL vs 1.49 mg/dL, P = 0.027) was poorer in the LDN group. Late graft function as assessed by serum creatinine at three months (1.45 mg/dL vs 1.31 mg/dL, P = 0.335) and one year (1.56 mg/dL vs 1.34 mg/dL, P = 0.275) was equivalent in the two groups. Episodes of early acute graft dysfunction due to acute tubular necrosis were significantly higher in the LDN group (37.8% vs 12.1%, Z score 2.457, P = 0.014). Warm ischemia time was significantly prolonged in the LDN group (255 s vs 132.5 s, P = 0.002). LDN is associated with slower recovery of graft function and higher incidence of early acute graft dysfunction due to acute tubular necrosis. Late graft function at one year is however comparable.
Assuntos
Transplante de Rim/métodos , Laparoscopia , Nefrectomia/métodos , Adulto , Biomarcadores/sangue , Distribuição de Qui-Quadrado , Creatinina/sangue , Feminino , Antígenos HLA/imunologia , Histocompatibilidade , Humanos , Imunossupressores/uso terapêutico , Índia , Transplante de Rim/efeitos adversos , Necrose Tubular Aguda/sangue , Necrose Tubular Aguda/etiologia , Laparoscopia/efeitos adversos , Masculino , Pessoa de Meia-Idade , Nefrectomia/efeitos adversos , Segurança do Paciente , Disfunção Primária do Enxerto/sangue , Disfunção Primária do Enxerto/etiologia , Recuperação de Função Fisiológica , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Centros de Atenção Terciária , Fatores de Tempo , Resultado do Tratamento , Isquemia Quente/efeitos adversosRESUMO
BACKGROUND AND OBJECTIVES: Multiple myeloma is responsible for a wide variety of renal pathologies. Urinary protein and monoclonal spike cannot be used to diagnose cast nephropathy (CN). Because albuminuria is a hallmark of glomerular disease, this study evaluated the percentage of urinary albumin excretion (%UAE) as a tool to differentiate CN from Ig light chain amyloidosis (AL), light chain deposition disease (LCDD), and acute tubular necrosis (ATN). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Patients were selected from the Renal Biopsy Database and the Dysproteinemia Database. Participants were excluded if laboratory data were missing within 1 week of the renal biopsy. The %UAE was obtained from urine protein electrophoresis. RESULTS: From 1992 to 2011, 260 patients were biopsied (177 with AL, 28 with LCDD, 43 with CN, and 12 with ATN). The %UAE for CN patients was significantly lower (7%) than for ATN (25%), LCDD (55%), and AL (70%) patients (P<0.001). Significant differences were also found in serum creatinine, serum albumin, free light chain ratio, total urine protein, and urine monoclonal spike; only the %UAE remained independently associated with CN in a logistic regression model (P<0.001). The area under the curve for the receiver operator characteristic curve for %UAE was 0.99. At <25%, the %UAE had a sensitivity of 0.98, specificity of 0.94, positive predictive value of 0.75, and negative predictive value of 0.99. CONCLUSIONS: This study showed that %UAE was significantly less in CN than the other three renal lesions and %UAE may thus be helpful in diagnosis of CN.
Assuntos
Albuminúria/urina , Amiloidose/urina , Necrose Tubular Aguda/urina , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/urina , Adulto , Idoso , Idoso de 80 Anos ou mais , Albuminúria/sangue , Amiloidose/sangue , Amiloidose/diagnóstico , Análise de Variância , Área Sob a Curva , Distribuição de Qui-Quadrado , Creatinina/sangue , Feminino , Humanos , Cadeias Leves de Imunoglobulina/sangue , Cadeias Leves de Imunoglobulina/urina , Necrose Tubular Aguda/sangue , Necrose Tubular Aguda/diagnóstico , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/sangue , Valor Preditivo dos Testes , Curva ROC , Albumina Sérica/metabolismo , Estatísticas não ParamétricasRESUMO
Experimental aristolochic acid nephropathy is characterized by early tubulointerstitial injury followed by fibrosis, reproducing chronic lesions seen in humans. In vitro, probenecid inhibits aristolochic acid entry through organic anion transporters, reduces specific aristolochic acid-DNA adduct formation, and preserves cellular viability. To test this in vivo, we used a mouse model of aristolochic acid nephropathy displaying severe tubulointerstitial injuries consisting of proximal tubular epithelial cell necrosis associated to transient acute kidney injury followed by mononuclear cell infiltration, tubular atrophy, and interstitial fibrosis. Treatment with probenecid prevented increased plasma creatinine and tubulointerstitial injuries, and reduced both the extent and the severity of ultrastructural lesions induced by aristolochic acid, such as the loss of brush border, mitochondrial edema, and the disappearance of mitochondrial crests. Further, the number of proliferating cell nuclear antigen-positive cells and total aristolochic acid-DNA adducts were significantly reduced in mice receiving aristolochic acid plus probenecid compared with mice treated with aristolochic acid alone. Thus, we establish the nephroprotective effect of probenecid, an inhibitor of organic acid transporters, in vivo toward acute proximal tubular epithelial cell toxicity in a mouse model of aristolochic acid nephropathy.