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1.
Biochem Biophys Res Commun ; 675: 54-60, 2023 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-37451218

RESUMO

A disintegrin and metalloprotease 10 (ADAM10) regulates the expression of cell surface receptors such as tumor necrosis factor receptor 1, toll-like receptor 4, and the receptor for advanced glycation end products (RAGE) by cleaving their extracellular regions. To function as a sheddase, ADAM10 should translocate from the intracellular compartments to the cell surface, but the translocation mechanism remains unclear. In this study, we explored the possible role of adenosine monophosphate-activated protein kinase (AMPK) in the induction of ADAM10 shedding activity. In cultured human aortic endothelial cells (HAECs), 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR), an AMPK activator, boosted ADAM10 cell surface translocation and ectodomain shedding of RAGE. ADAM10 inhibition with GI 254023X and ADAM10 siRNA silencing both prevented AICAR-induced RAGE ectodomain shedding. AICAR increased AMPK phosphorylation as well. Both Compound C-mediated AMPK inhibition and AMPKα1-siRNA-mediated AMPK depletion suppressed AICAR-induced ADAM10 cell surface translocation and RAGE ectodomain shedding. On the other hand, siRNA knockdown of Rab14, a small GTPase that facilitates the intracellular trafficking of transmembrane proteins, prevented AICAR-induced ADAM10 cell surface translocation and RAGE ectodomain shedding. In conclusion, AMPK activation is an obvious inducer of ADAM10 shedding activity. Our findings suggest that AMPK boosts ADAM10 shedding activity in HAECs by promoting Rab14-dependent ADAM10 cell surface translocation.


Assuntos
Proteínas Quinases Ativadas por AMP , Células Endoteliais , Humanos , Células Endoteliais/metabolismo , Proteínas Quinases Ativadas por AMP/metabolismo , Proteína ADAM10/metabolismo , Membrana Celular/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Secretases da Proteína Precursora do Amiloide/metabolismo , Proteínas de Membrana/metabolismo , Proteínas rab de Ligação ao GTP/metabolismo
2.
Clin Genet ; 104(3): 298-312, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37270787

RESUMO

The genetic spectrum of genetic kidney diseases (GKD) and the application of genetic diagnoses to patient care were assessed by whole exome sequencing (WES) of the DNA of 172 pediatric or adult patients with various kidney diseases. WES diagnosed genetic diseases in 63 (36.6%) patients. The diagnostic yields in patients with glomerulopathy were 33.8% (25/74 pts) due to variants in 10 genes, 58.8% (20/34) in patients with tubulointerstitial disease due to variants in 18 genes, 33.3% (15/45) in patients with cystic disease/ciliopathy due to variants in 10 genes, 18.2% (2/11) in patients with congenital anomalies of the kidneys and urinary tract (CAKUT) due to variants in two genes, and 12.5% (1/8) in patients with end stage kidney disease (ESKD). The diagnosis rate was high in patients aged <1-6 years (46-50.0%), and low in patients aged ≥40 years (9.1%). Renal phenotype was reclassified in 10 (15.9%) of 63 patients and clinical management altered in 10 (15.9%) of 63 patients after genetic diagnosis. In conclusion, these findings demonstrated the diagnostic utility of WES and its effective clinical application in patients, with various kinds of kidney diseases, across the different age groups.


Assuntos
Nefrite Intersticial , Sistema Urinário , Humanos , Sequenciamento do Exoma , Rim/anormalidades , Fenótipo
3.
BMC Nephrol ; 24(1): 53, 2023 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-36922759

RESUMO

BACKGROUND: Recurrent focal segmental glomerulosclerosis (FSGS) after kidney transplantation (KT) is a serious complication and a significant risk factor for graft failure. However, there is no clear evidence of the effectiveness of pre-transplant treatment using plasmapheresis (PP) or rituximab in preventing post-operative FSGS recurrence after KT. METHODS: This single-center retrospective study included 99 adult patients with biopsy-proven primary FSGS who underwent KT between 2007 and 2018. The patients were divided into the pre-treatment group (N = 53, 53.5%) and no pre-treatment group (N = 46, 46.5%). In the pre-transplant group, prophylactic PP was administered before KT in patients undergoing living donor transplantation and the day after KT in those undergoing deceased donor transplantation. RESULTS: The rate of immediate post-operative recurrence was significantly higher in the no pre-treatment group (16 [34.8%]) than in the pre-treatment group (5 [9.4%]; P = 0.002). There were three cases of graft failure due to recurrent FSGS, all of which were in the no pre-treatment group. After adjusting for possible confounding factors, age (per 10-year increase; OR = 0.61, CI, 0.42-0.90; P = 0.012) and pre-transplant treatment (vs. no pre-transplant treatment; OR = 0.17, CI, 0.05-0.54; P = 0.003) were identified as significant factors associated with FSGS recurrence. The rate of death-censored graft survival was significantly superior in the pretransplant treatment group (P = 0.042). CONCLUSION: Pre-transplant treatment with PP was associated with beneficial effects on preventing FSGS recurrence after KT.


Assuntos
Glomerulosclerose Segmentar e Focal , Transplante de Rim , Adulto , Humanos , Transplante de Rim/efeitos adversos , Glomerulosclerose Segmentar e Focal/cirurgia , Glomerulosclerose Segmentar e Focal/etiologia , Estudos Retrospectivos , Rituximab , Doadores Vivos , Plasmaferese , Recidiva
4.
Clin Exp Nephrol ; 24(3): 205-215, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31677062

RESUMO

BACKGROUND: Endoplasmic reticulum (ER) stress has been implicated in the development of various renal diseases. Thus, inhibition of ER stress using pharmacological agents may serve as a promising therapeutic approach. We postulated that febuxostat, a novel xanthine oxidase inhibitor, could suppress the ER stress through upregulation of SIRT1 (silent mating type information regulation 2 homolog 1)-AMPK (AMP activated protein kinase)-HO-1 (heme oxygenase-1)/thioredoxin expression. METHODS: We examined the effect of febuxostat on the ER stress induced by a chemical inducer, tunicamycin and non-chemical agents such as angiotensin II, aldosterone, high glucose, and albumin in renal tubular cells. We further examined the in vivo effects of febuxostat using mouse model of kidney disease induced by unilateral ureteral obstruction (UUO). Expression of ER stress was measured by western blot analysis and immunohistochemical stain. RESULTS: Febuxostat suppressed the ER stress induced by tunicamycin and non-chemical agents, as shown by inhibition of increased GRP78 (glucose-related protein78) and p-eIF2α (phosphospecific-eukaryotic translation initiation factor 2α) expression. Inhibitory effect of febuxostat was mediated through upregulation of SIRT1-AMPK followed by induction of HO-1 and thioredoxin. In animal model of UUO, febuxostat reduced the UUO-induced ER stress, which was abolished by pretreatment with SIRT1 inhibitor (sirtinol) and AMPK inhibitor (compound C). CONCLUSION: Febuxostat could suppress the ER stress caused by various ER stress inducers through upregulation of SIRT1-AMPK-HO-1/thioredoxin expression. Targeting these pathways might serve as one of the possible therapeutic approaches in kidney diseases under excessive ER stress.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Febuxostat/farmacologia , Insuficiência Renal Crônica/tratamento farmacológico , Sirtuína 1/metabolismo , Animais , Benzamidas , Linhagem Celular , Avaliação Pré-Clínica de Medicamentos , Chaperona BiP do Retículo Endoplasmático , Febuxostat/uso terapêutico , Heme Oxigenase-1/metabolismo , Humanos , Camundongos , Naftóis , Transdução de Sinais/efeitos dos fármacos , Tiorredoxinas/metabolismo , Tunicamicina , Xantina Oxidase/antagonistas & inibidores
5.
Am J Transplant ; 19(1): 145-155, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29718591

RESUMO

The prognosis of patients with allograft IgA nephropathy (IgAN) requires further investigation. We performed a bicenter retrospective cohort study on kidney transplant recipients diagnosed with IgAN in allograft biopsy. Recipients without allograft IgAN but with known IgAN before transplantation were included as the control group. We investigated the associations between clinicopathological characteristics, including allograft crescents, and the risk of death-censored graft failure. In total, 1256 IgAN patients in both pre- and posttransplant stages were included. Among them, 559 were diagnosed with allograft IgAN, which was a time-dependent risk factor for worse prognosis (adjusted hazard ratio = 5.009 [3.610-6.951]; P < .001) during a median of 8.1 years of follow-up. Of the patients with allograft IgAN, 88 (15.9%) had glomerular crescents, including 40 patients (7.2%) with >10% crescent formation in the total biopsied glomeruli. The presence of glomerular crescents in IgAN was associated with a worse graft prognosis, and the association was still valid with the C scores of the current Oxford classification. In conclusion, allograft IgAN is a time-dependent event and is associated with worse graft outcomes. The pathological characteristics of allograft, particularly the degree of glomerular crescent formation, may represent important risk factors for a poor prognosis.


Assuntos
Glomerulonefrite por IGA/patologia , Sobrevivência de Enxerto , Falência Renal Crônica/cirurgia , Glomérulos Renais/patologia , Transplante de Rim/efeitos adversos , Adulto , Aloenxertos , Biópsia , Feminino , Seguimentos , Glomerulonefrite por IGA/mortalidade , Humanos , Estimativa de Kaplan-Meier , Rim/patologia , Falência Renal Crônica/complicações , Masculino , Pessoa de Meia-Idade , Período Pós-Operatório , Prognóstico , Modelos de Riscos Proporcionais , Recidiva , República da Coreia , Estudos Retrospectivos , Fatores de Risco , Transplante Homólogo/efeitos adversos , Resultado do Tratamento
6.
Am J Transplant ; 19(10): 2855-2864, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31017369

RESUMO

With the recent update to the Oxford classification for allograft IgA nephropathy (IgAN), additional investigations on the clinical significance of the updated components are warranted. We performed a retrospective cohort study at two tertiary hospitals. Kidney transplant recipients diagnosed with allograft IgAN were included in the study after additional review by specialized pathologists. We applied the updated Oxford classification and determined the MEST-C scores of the patients. The main study outcome was death-censored graft failure within 10 years after the establishment of allograft IgAN diagnosis and was assessed using the Cox regression analysis. Three hundred thirty-three allograft IgAN patients were reviewed: 100 patients with confirmed native IgAN and 233 patients with other, clinical, or unknown primary causes for end-stage renal disease (ESRD). The updated Oxford classification for allograft IgAN demonstrated prognostic value for graft failure, and patients with multiple MEST-C components had worse outcomes. M, E, S, and C were significantly associated with the prognosis of recurred IgAN and T was the only independent prognostic parameter for allograft IgAN without confirmed native IgAN. Therefore, we suggest reporting MEST-C scores in allograft biopsies and careful interpretation of the results according to the primary cause of ESRD.


Assuntos
Glomerulonefrite por IGA/classificação , Glomerulonefrite por IGA/diagnóstico , Rejeição de Enxerto/diagnóstico , Falência Renal Crônica/patologia , Transplante de Rim/efeitos adversos , Rim/patologia , Complicações Pós-Operatórias/diagnóstico , Adulto , Feminino , Seguimentos , Taxa de Filtração Glomerular , Glomerulonefrite por IGA/etiologia , Rejeição de Enxerto/etiologia , Sobrevivência de Enxerto , Humanos , Falência Renal Crônica/cirurgia , Testes de Função Renal , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/etiologia , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Transplante Homólogo
7.
Kidney Blood Press Res ; 44(1): 22-32, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30808840

RESUMO

BACKGROUND/AIMS: Additional validation study was warranted to confirm the clinical significance of C score, which was recently added to the Oxford classification for immunoglobulin A nephropathy (IgAN). METHODS: We performed a multicenter retrospective cohort study in four hospitals in Korea. Patients who had biopsied glomeruli less than eight or inadequate follow-up information were excluded. Clinicopathologic parameters, including the degree of cellular or fibrocellular crescents, were collected and included in multivariable models for Cox regression analysis. The main outcome was a composite renal outcome, defined as a merge of progression to end-stage renal disease (ESRD) and halving of estimated glomerular filtration rate (eGFR) from baseline. RESULTS: Among included 3,380 biopsy-confirmed IgAN patients, there were 664 (19.6%) patients with C1 and 60 (1.8%) patients with C2 scores in the study population. Although C0 and C1 patients shared similar baseline characteristics, C2 patients frequently had more clinicopathologic risk factors for poor prognosis of IgAN. Both C1 [adjusted HR 1.33 (1.11-1.58), P=0.002] and C2 [adjusted HR 2.24 (1.46-3.43), P< 0.001] scores were associated with an increased risk of the composite outcome. C2 was a strong predictive parameter associated with both progression to ESRD and halving of eGFR, whereas C1 was mainly associated with the increased risk of halving of eGFR. Notably, the proportion of crescent showed a linear association with the risk of adverse renal outcome. CONCLUSION: The C score in the Oxford classification is a valid predictive parameter for IgAN prognosis. Additional clinical attention is necessary for IgAN patients with identified cellular or fibrocellular crescents.


Assuntos
Glomerulonefrite por IGA/diagnóstico , Adulto , Forma Celular , Estudos de Coortes , Progressão da Doença , Feminino , Taxa de Filtração Glomerular , Glomerulonefrite por IGA/classificação , Glomerulonefrite por IGA/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , República da Coreia , Estudos Retrospectivos , Adulto Jovem
8.
Nephrology (Carlton) ; 24(6): 654-660, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29877001

RESUMO

AIM: ABO-incompatible (ABOi) kidney transplantation (KT) has become a routine procedure with graft survival rates comparable to those of ABO-compatible KT. However, the clinical significance of the isoagglutinin titre in ABOi KT remains uncertain. Therefore, in this study, we analysed the clinical outcomes of ABOi KT according to the baseline and post-operative isoagglutinin titre. METHODS: All patients who received ABOi KT between 2009 and 2013 were reviewed and followed up until December 2016. The patients were classified according to baseline (<1:128 or ≥1:128) and post-operative rebound isoagglutinin titre (<1:16 or ≥1:16), and the clinical outcomes of KT were compared. RESULTS: Patients with a high baseline isoagglutinin titre showed a poor titre reduction rate (1.48 ± 0.41 vs 1.32 ± 0.34, P = 0.008), and more patients experienced titre rebound ≥1:16 after KT (15.0% vs 35.8%, P = 0.002). The occurrence of both T-cell-mediated rejection and antibody-mediated rejection did not show a significant difference (P = 0.805 and 0.714, respectively). The rate of rejection-free survival was not different among groups (P = 0.680, log-rank test). Furthermore, the rate of death-censored graft survival was not different among groups (P = 0.701, log-rank test). Urinary tract infection was the most frequently reported infectious complication overall. The incidence of urinary tract infection, pneumonia and viral infections (BK virus and cytomegalovirus) was not different among groups. CONCLUSION: In conclusion, high baseline isoagglutinin titre was associated with a high rebound isoagglutinin titre, low titre reduction rates and more sessions of plasmapheresis. However, the isoagglutinin titre may not be as important as it was in the past in ABOi KT if appropriate desensitization is performed.


Assuntos
Sistema ABO de Grupos Sanguíneos/imunologia , Aglutininas/sangue , Incompatibilidade de Grupos Sanguíneos/imunologia , Dessensibilização Imunológica/métodos , Histocompatibilidade , Transplante de Rim/métodos , Plasmaferese , Adulto , Dessensibilização Imunológica/efeitos adversos , Feminino , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/prevenção & controle , Sobrevivência de Enxerto , Humanos , Transplante de Rim/efeitos adversos , Masculino , Pessoa de Meia-Idade , Plasmaferese/efeitos adversos , Estudos Retrospectivos , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento
9.
BMC Nephrol ; 20(1): 295, 2019 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-31375077

RESUMO

BACKGROUND: Short-term hemoglobin (Hb) variability related to volume status is observed in chronic kidney disease (CKD) patients receiving hemodialysis (HD). Given the lack of studies regarding outcomes according to the day of Hb sampling, the existing guidelines do not strongly recommend regarding measurement timing. Pre-dialysis mid-week sampling (Wednesday and Thursday) is preferable to minimize short-term Hb variability, although numerous HD centers perform early-week sampling (Monday and Tuesday). The different measurement days may influence the prescribed dose of erythropoiesis-stimulating agent (ESA) and related patient outcomes. We investigated changes in Hb levels and ESA doses according to the Hb measurement day among HD patients. METHODS: Starting September 2013, the day for pre-dialysis Hb measurement at the Asan Medical Center was changed from early-week days to mid-week days. This single-center retrospective study evaluated medical records of 92 patients who received maintenance HD between September 2012 and August 2014. RESULTS: There was no significant difference in the mean Hb levels between early-week days and mid-week days (10.71 ± 0.06 g/dL vs. 10.78 ± 0.47 g/dL, p = 0.105). However, the mean doses of darbepoetin-α on early-week days were higher than those on mid-week days (175.4 ± 72.5 µg/month vs. 163.7 ± 83.6 µg/month, p = 0.022). The mean doses of intravenous iron hydroxide sucrose for early-week measurements were also higher than those for mid-week measurements (623.0 ± 489.0 mg/year vs. 447.0 ± 505.2 mg/year, p = 0.001). The mean interdialytic weight gains were 2.81 ± 0.82 kg on early-week days and 1.99 ± 0.61 kg on mid-week days (p < 0.001). CONCLUSIONS: Compared with early-week measurements, mid-week pre-dialysis Hb measurements were significantly associated with lower ESA doses without a change in Hb levels.


Assuntos
Anemia/sangue , Anemia/tratamento farmacológico , Darbepoetina alfa/administração & dosagem , Hematínicos/administração & dosagem , Hemoglobina A/análise , Falência Renal Crônica/sangue , Diálise Renal , Feminino , Compostos Férricos/administração & dosagem , Humanos , Falência Renal Crônica/terapia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Sacarose/administração & dosagem , Fatores de Tempo , Aumento de Peso
10.
BMC Nephrol ; 20(1): 354, 2019 09 11.
Artigo em Inglês | MEDLINE | ID: mdl-31510954

RESUMO

BACKGROUND: Although immunoglobulin A nephropathy (IgAN) is associated with an increased risk of renal allograft failure, evidences for its treatment, including renin-angiotensin-aldosterone system blockade (RAASB) usage, remain limited. METHODS: In this bi-center retrospective cohort study, we included patients who were recently diagnosed with IgAN through allograft biopsies. We identified their 6-month antihypertensive medication prescriptions and investigated the association between the medication types, albuminuria changes, and risk of 5-year death-censored-graft-failure (DCGF). The mixed effect model and cox regression analysis were used. RESULTS: A total of 464 allograft IgAN patients were included: 272, 38, 33, and 121 patients in the no antihypertensive medication, single agent RAASB, single agent beta blocker (BB)/calcium channel blocker (CCB), and combination therapy groups, respectively. High-degree albuminuria after 6 months of allograft IgAN diagnosis was an important prognostic parameter and a partial mediator for the association between the subgroups and 5-year DCGF. The usage of single RAASB was associated with decrement of albuminuria from allograft IgAN diagnosis (P for interaction = 0.03). The single BB/CCB group demonstrated significantly worse prognosis than the single RAASB group (adjusted hazard ratio, 2.76 [1.09-6.98]; P = 0.03). CONCLUSIONS: In conclusion, RAASB may be beneficial for graft prognosis in early allograft IgAN patients who require single antihypertensive medication therapy, by means of reducing albuminuria. Further investigation of treatment strategy in allograft IgAN is warranted.


Assuntos
Aloenxertos/efeitos dos fármacos , Glomerulonefrite por IGA/diagnóstico , Glomerulonefrite por IGA/tratamento farmacológico , Sobrevivência de Enxerto/efeitos dos fármacos , Sistema Renina-Angiotensina/efeitos dos fármacos , Adulto , Aloenxertos/fisiologia , Aloenxertos/transplante , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Anti-Hipertensivos/farmacologia , Anti-Hipertensivos/uso terapêutico , Bloqueadores dos Canais de Cálcio/farmacologia , Bloqueadores dos Canais de Cálcio/uso terapêutico , Estudos de Coortes , Feminino , Rejeição de Enxerto/diagnóstico , Rejeição de Enxerto/prevenção & controle , Sobrevivência de Enxerto/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Antagonistas de Receptores de Mineralocorticoides/farmacologia , Antagonistas de Receptores de Mineralocorticoides/uso terapêutico , Prognóstico , Sistema Renina-Angiotensina/fisiologia , Estudos Retrospectivos , Transplante Homólogo/efeitos adversos , Transplante Homólogo/tendências
11.
Transpl Infect Dis ; 19(5)2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28741797

RESUMO

BACKGROUND: Parvovirus B19 is a small, non-enveloped, single-stranded DNA virus with a special affinity for the erythroid progenitor cells of the bone marrow. The first case of parvovirus B19 infection in a kidney transplant recipient (KTR) was reported in 1986. Data on the risk factors and specific clinical characteristics of parvovirus B19 infection remain insufficient. METHODS: We screened 602 KTRs for parvovirus B19 infection using parvovirus B19 polymerase chain reaction (PCR) from January 1990 to April 2016, and the clinical characteristics of patients with positive results were compared to those of age- and gender-matched patients with negative PCR results. RESULTS: A total of 39 KTRs tested positive for parvovirus B19, and they were compared to 78 age- and gender-matched patients among 563 KTRs who had negative PCR results. In all, 89.7% of positive cases were reported within the first year after kidney transplantation. In multivariate analyses, deceased-donor kidney transplantation (odds ratio [OR] 9.067, 95% confidence interval [CI] 1.668-49.275, P = .011), use of tacrolimus (OR 3.607, 95% CI 1.024-12.706, P = .046), PCR test within 1 year of kidney transplantation (OR 12.456, 95% CI 2.674-58.036, P = .001), and hemoglobin levels (OR 0.559, 95% CI 0.351-0.889, P = .014) showed significant correlations with parvovirus B19 infection. Graft survival did not differ between the two groups during the follow-up period of 111.68 ± 54.54 months (P = .685 by log-rank test). CONCLUSION: The identification of factors related to positive parvovirus B19 PCR results may promote the early detection of parvovirus B19 infection. Further studies are needed to elucidate the characteristics of parvovirus B19 infection in kidney transplantation.


Assuntos
Eritema Infeccioso/diagnóstico , Eritema Infeccioso/virologia , Transplante de Rim/efeitos adversos , Adulto , Eritema Infeccioso/tratamento farmacológico , Feminino , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Masculino , Pessoa de Meia-Idade , Razão de Chances , Estudos Retrospectivos , Fatores de Risco
12.
Artif Organs ; 41(4): 381-391, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27653963

RESUMO

The outcomes of transplantation have improved, but more than 50% of kidney transplantation (KT) recipients are still reported to have renal function of chronic kidney disease (CKD) stage 3 at 1 year after KT. We reviewed all 1235 patients who received a KT in our institution between 2008 and 2012. Among these recipients, 77 and 289 cases were included in the estimated glomerular filtration rate (eGFR) at 1 year after KT 30-44 (CKD stage 3b) group and eGFR 45-59 (CKD stage 3a) group, respectively. Longer duration of dialysis (odds ratio [OR] = 1.007, 95% confidence interval [CI], 1.000-1.014, P = 0.047), older donors (OR = 1.064, 95% CI, 1.031-1.098, P < 0.001), delayed graft function (OR = 3.601, 95% CI, 1.031-1.098, P < 0.001), BK virus infection (OR = 2.567, 95% CI, 1.242-5.305, P = 0.011), and pneumonia (OR = 4.451, 95% CI, 1.388-14.279, P = 0.012) were contributing factors to eGFR 30-44 mL/min. Especially, ureteral stricture occurred more frequently in eGFR 30-44 group of deceased donor KT. However, acute rejection was not a significant risk factor of lower eGFR. Graft survival was better in the eGFR 45-59 group. However, this difference was smaller in deceased donor KT. Infections and urologic complications are also important contributing factors of lower graft function in CKD stage 3. In addition, dividing CKD stage 3 into subgroups might be more useful in living donor kidney transplantation.


Assuntos
Função Retardada do Enxerto/epidemiologia , Taxa de Filtração Glomerular , Sobrevivência de Enxerto , Transplante de Rim/efeitos adversos , Diálise Renal/estatística & dados numéricos , Insuficiência Renal Crônica/cirurgia , Transplantados/estatística & dados numéricos , Adulto , Aloenxertos/patologia , Biópsia , Feminino , Rejeição de Enxerto/tratamento farmacológico , Rejeição de Enxerto/epidemiologia , Rejeição de Enxerto/patologia , Humanos , Terapia de Imunossupressão/métodos , Transplante de Rim/métodos , Transplante de Rim/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Resultado do Tratamento
13.
Int J Mol Sci ; 18(2)2017 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-28146117

RESUMO

Endoplasmic reticulum (ER) stress is increasingly identified as modulator of fibrosis. Losartan, an angiotensin II receptor blocker, has been widely used as the first choice of treatment in chronic renal diseases. We postulated that anti-fibrotic effect of losartan is mediated through inhibition of ER stress via SIRT1 (silent mating type information regulation 2 homolog 1) hemeoxygenase-1 (HO-1)/thioredoxin pathway. Renal tubular cells, tunicamycin (TM)-induced ER stress, and unilateral ureteral obstruction (UUO) mouse model were used. Expression of ER stress was assessed by Western blot analysis and immunohistochemical stain. ER stress was induced by chemical ER stress inducer, tunicamycin, and non-chemical inducers such as TGF-ß, angiotensin II, high glucose, and albumin. Losartan suppressed the TM-induced ER stress, as shown by inhibition of TM-induced expression of GRP78 (glucose related protein 78) and p-eIF2α (phosphospecific-eukaryotic translation initiation factor-2α), through up-regulation of SIRT1 via HO-1 and thioredoxin. Losartan also suppressed the ER stress by non-chemical inducers. In both animal models, losartan reduced the tubular expression of GRP78, which were abolished by pretreatment with sirtinol (SIRT1 inhibitor). Sirtinol also blocked the inhibitory effect of losartan on the UUO-induced renal fibrosis. These findings provide new insights into renoprotective effects of losartan and suggest that SIRT1, HO-1, and thioredoxin may be potential pharmacological targets in kidney diseases under excessive ER stress condition.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Heme Oxigenase-1/metabolismo , Losartan/farmacologia , Sirtuína 1/metabolismo , Tiorredoxinas/metabolismo , Angiotensina II/metabolismo , Animais , Glicemia , Modelos Animais de Doenças , Chaperona BiP do Retículo Endoplasmático , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Expressão Gênica , Heme Oxigenase-1/genética , Nefropatias/genética , Nefropatias/metabolismo , Nefropatias/patologia , Camundongos , Sirtuína 1/genética , Tiorredoxinas/genética , Fator de Crescimento Transformador beta/metabolismo , Tunicamicina/farmacologia
14.
Transpl Infect Dis ; 18(6): 844-849, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27622599

RESUMO

BACKGROUND: Although high-dose steroid therapy has been attempted for the management of clinically suspected allograft rejection, before testing for BK viral activity or acute cellular rejection accompanied by BK polyomavirus nephropathy, its long-term outcome remains unknown. We investigated the impact of high-dose steroids on BK viral activity and long-term graft outcomes in patients with BK viremia. METHODS: The study population comprised 144 kidney transplant recipients with BK viremia. They were divided into 2 groups based on the amount of steroids administered: low-dose group (<2 g, n=123) or high-dose group (≥2 g, n=21). RESULTS: The baseline serum BK viral loads were 5.4±1.1 log cp/mL in the low-dose group and 6.0±1.3 in the high-dose group (P=.054). These changed to 5.2±1.3 and 6.1±1.4, 1 month after steroid treatment (P=.03) and 4.9±1.3 and 5.9±1.4 at 2 months (P=.033), respectively. From 3 months to 1 year, the serum BK viral titers were not different between groups. Kaplan-Meier analyses demonstrated that the rates of the decline of graft function and graft failure were higher in the high-dose group (P=.02 and P=.04, respectively). High-dose steroids (P=.012, hazard ratio [HR] 5.04, 95% confidence interval [CI] 1.42-17.85) and log serum BK viral load at 2 months after steroid treatment (P=.042, HR 1.52, 95% CI 1.02-2.28) were independent risk factors for the decline of graft function. CONCLUSION: High-dose steroids induced BK viral activation and subsequently resulted in poor long-term graft function and early graft failure in patients with BK viremia.


Assuntos
Vírus BK/fisiologia , Glucocorticoides/administração & dosagem , Glucocorticoides/efeitos adversos , Rejeição de Enxerto/virologia , Transplante de Rim/efeitos adversos , Infecções por Polyomavirus/induzido quimicamente , Infecções Tumorais por Vírus/tratamento farmacológico , Carga Viral/efeitos dos fármacos , Viremia/induzido quimicamente , Ativação Viral/efeitos dos fármacos , Adulto , Idoso , Vírus BK/isolamento & purificação , Biópsia , Feminino , Glucocorticoides/uso terapêutico , Rejeição de Enxerto/tratamento farmacológico , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Infecções por Polyomavirus/sangue , Infecções por Polyomavirus/virologia , Pulsoterapia/efeitos adversos , Estudos Retrospectivos , Fatores de Risco , Transplantados , Infecções Tumorais por Vírus/virologia , Viremia/sangue , Viremia/virologia
15.
Clin Nephrol ; 86(2): 87-93, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27345187

RESUMO

BACKGROUND: Recurrent IgA nephropathy (IgAN) after kidney transplantation (KT) has been reported to range between 12 and 65%. However, few data are available on second transplantation in recurrent IgAN. Therefore, this study aimed to build bottom-line data for the possibility of second transplantation in patients who lost first transplanted kidney due to recurrent IgAN. METHODS: Patients who received KT twice due to recurrent IgAN at four large academic hospitals in Korea between March 1985 and December 2013 were reviewed. They were followed up until October 2014. All patients were identified as having recurrent IgAN in the first graft biopsies. The clinical outcomes of the second KT in these patients were compared with the first KT and with all cases of second KT (n = 169) performed at one center in the same period. RESULTS: 28 patients were enrolled in this study. First grafts failed after 106.64 ± 48.72 months (mean ± SD). Following the second transplantation, recurrent IgAN was identified in only 2 patients during the follow-up of 61.61 ± 47.23 months. In 1 patient, the second graft was lost due to chronic rejection without mesangial IgA deposit. The second KT showed comparable graft survival compared with the first KT and the overall second KT (p = 0.308 by log-rank test). At the final follow-up, the serum creatinine level was 1.16 ± 0.33 mg/dL in the second graft except in 1 patient. CONCLUSIONS: Second KT in recurrent IgAN showed reasonably good long-term results. Therefore, clinicians might be able to suggest second transplantation as an option for patients who lost the first graft due to recurrent IgAN.


Assuntos
Glomerulonefrite por IGA/cirurgia , Rejeição de Enxerto/cirurgia , Falência Renal Crônica/etiologia , Transplante de Rim/métodos , Adulto , Biópsia , Feminino , Glomerulonefrite por IGA/complicações , Rejeição de Enxerto/epidemiologia , Sobrevivência de Enxerto , Humanos , Incidência , Falência Renal Crônica/epidemiologia , Falência Renal Crônica/cirurgia , Masculino , Pessoa de Meia-Idade , Recidiva , Reoperação , República da Coreia/epidemiologia , Estudos Retrospectivos
16.
BMC Nephrol ; 17(1): 106, 2016 07 29.
Artigo em Inglês | MEDLINE | ID: mdl-27473469

RESUMO

BACKGROUND: New-onset diabetes mellitus after transplantation (NODAT) is a serious complication following renal transplantation. The aim of this study was to identify the risk factors for the development of NODAT in Korean transplant patients. METHODS: Recipients who underwent living donor kidney transplantation between January 2009 and April 2012 at Asan Medical Center were reviewed. Diagnosis of NODAT was defined according to the American Diabetes Association criteria. RESULTS: A total of 418 patients were enrolled. NODAT was diagnosed in 85 (20.4 %) patients within 1 year. By multivariate analysis, old age (odds ratio [OR], 1.05; 95 % Confidence interval [CI]: 1.01-1.08), family history of diabetes mellitus (OR, 2.48; 95 % CI: 1.04-5.94), pre-transplant high serum glucose level (OR, 1.04; 95 % CI: 1.01-1.08), and obesity (OR, 3.46; 95 % CI: 1.55-7.73) were independent risk factors for NODAT. CONCLUSION: Old age, family history of diabetes, pre-transplant high plasma glucose level, and obesity are independent factors associated with the development of diabetes after renal transplantation. In contrast, serum magnesium levels and the use of tacrolimus are not associated with the development of NODAT.


Assuntos
Diabetes Mellitus/epidemiologia , Diabetes Mellitus/etiologia , Transplante de Rim/efeitos adversos , Adulto , Fatores Etários , Glicemia/metabolismo , Diabetes Mellitus/genética , Feminino , Humanos , Imunossupressores/uso terapêutico , Doadores Vivos , Magnésio/sangue , Masculino , Pessoa de Meia-Idade , Obesidade/epidemiologia , Período Pré-Operatório , República da Coreia/epidemiologia , Estudos Retrospectivos , Fatores de Risco , Tacrolimo/uso terapêutico
17.
Am J Physiol Renal Physiol ; 308(3): F226-36, 2015 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-25428127

RESUMO

It has been suggested that endoplasmic reticulum (ER) stress facilitates fibrotic remodeling. Therefore, modulation of ER stress may serve as one of the possible therapeutic approaches to renal fibrosis. We examined whether and how activation of AMP-activated protein kinase (AMPK) suppressed ER stress induced by chemical ER stress inducers [tunicamycin (TM) and thapsigargin (TG)] and also nonchemical inducers in tubular HK-2 cells. We further investigated the in vivo effects of AMPK on ER stress and renal fibrosis. Western blot analysis, immunofluorescence, small interfering (si)RNA experiments, and immunohistochemical staining were performed. Metformin (the best known clinical activator of AMPK) suppressed TM- or TG-induced ER stress, as shown by the inhibition of TM- or TG-induced upregulation of glucose-related protein (GRP)78 and phosphorylated eukaryotic initiation factor-2α through induction of heme oxygenase-1. Metformin inhibited TM- or TG-induced epithelial-mesenchymal transitions as well. Compound C (AMPK inhibitor) blocked the effect of metformin, and 5-aminoimidazole-4-carboxamide-1ß riboside (another AMPK activator) exerted the same effects as metformin. Transfection with siRNA targeting AMPK blocked the effect of metformin. Consistent with the results of cell culture experiments, metformin reduced renal cortical GRP78 expression and increased heme oxygenase-1 expression in a mouse model of ER stress-induced acute kidney injury by TM. Activation of AMPK also suppressed ER stress by transforming growth factor-ß, ANG II, aldosterone, and high glucose. Furthermore, metformin reduced GRP78 expression and renal fibrosis in a mouse model of unilateral ureteral obstruction. In conclusion, AMPK may serve as a promising therapeutic target through reducing ER stress and renal fibrosis.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Heme Oxigenase-1/metabolismo , Nefropatias/tratamento farmacológico , Metformina/farmacologia , Animais , Modelos Animais de Doenças , Chaperona BiP do Retículo Endoplasmático , Ativação Enzimática , Fibrose/metabolismo , Proteínas de Choque Térmico/metabolismo , Humanos , Masculino , Camundongos Endogâmicos C57BL , Tunicamicina/farmacologia
18.
Ann Hematol ; 94(9): 1457-61, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25933676

RESUMO

Uremia is associated with platelet dysfunction and can cause a bleeding tendency resulting in a major bleeding event after an invasive procedure or surgery that may be aggravated by antiplatelet agents. We prospectively investigated the potential of desmopressin to improve platelet dysfunction and to lower bleeding risk after emergent invasive procedures in uremic patients taking antiplatelet drugs. Twenty-three patients were enrolled with a mean age of 60.2 ± 11.7 years. Baseline blood urea nitrogen and creatinine were 70.5 ± 29.4 and 10.02 ± 4.52 mg/dL, respectively. Twenty-one patients took aspirin. All patients were infused with desmopressin before their invasive procedures, which were a central catheter insertion for emergent hemodialysis in 13 patients, percutaneous nephrostomy in 7 patients, and angiography through arm or leg vessels in 3 patients. After desmopressin infusion, both the hematocrit and platelet count were slightly decreased without changes in prothrombin time or activated partial thrombin time. Collagen/epinephrine-closure time was significantly shortened from 252.7 ± 40.7 to 144.6 ± 51.0 s (p < 0.001). There were minimal bleeding in 20 patients and mild bleeding in 3 patients. None experienced severe bleeding event or required additional intervention for bleeding control. There were no adverse events including the decrease of serum sodium concentration. In conclusion, a single infusion of desmopressin before invasive procedures in uremic patients on antiplatelet drugs appeared to be well tolerated and improved platelet dysfunction measured by collagen/epinephrine-closure time.


Assuntos
Antidiuréticos/administração & dosagem , Plaquetas/metabolismo , Desamino Arginina Vasopressina/administração & dosagem , Nefrostomia Percutânea , Inibidores da Agregação Plaquetária/administração & dosagem , Diálise Renal , Uremia , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Tempo de Tromboplastina Parcial , Contagem de Plaquetas , Estudos Prospectivos , Uremia/sangue , Uremia/terapia
19.
BMC Nephrol ; 16: 201, 2015 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-26637210

RESUMO

BACKGROUND: Rituximab is widely used in kidney transplantation. However, it is not clear whether the conventional doses of maintenance immunosuppressant in rituximab-treated kidney transplantation (KT) are appropriate. In our previous study, decreasing mycophenolate mofetil (MMF) dose due to infection did not increase the incidence of rejection or graft failure. Based on these experiences, we developed a new protocol with a lower dose of MMF and studied its clinical outcomes in rituximab-treated KT. METHODS: We enrolled all patients who underwent ABO-incompatible or human leukocyte antigen (HLA)-sensitized living donor KT with the new immunosuppressant protocol after preconditioning with rituximab, but without splenectomy from November 2011 to May 2013. Seventy-two patients (group 1) were consecutively enrolled in this study and followed until November 2013. Patients from our previous study served as control groups. Sixty-seven patients received KT using rituximab with a conventional dose of MMF (group 2), and 87 patients received ABO compatible KT without need for rituximab (group 3). Clinical outcomes, including rejection, infection, and graft survival, were compared between the groups. The χ (2) test and Fisher's exact test were used for categorical variables, the Student's t-test and Mann-Whitney U test were used for continuous variables, and a log-rank test was used for mortality analysis. RESULTS: Doses of postoperative MMF (g/day) were lower in group 1 than in the other groups (1.03 ± 0.19, 1.48 ± 0.34 and 1.48 ± 0.32 g/day at 1 week, p < 0.001). Infectious complications occurred more often in groups with conventional MMF doses (group 2 and 3) than in group 1 (16.7 vs. 37.3 %, p = 0.007 and 16.7 vs. 34.5 %, p = 0.012, respectively). Notably, group 1 showed a lower incidence of cytomegalovirus infection than group 2. However, reduction in MMF dose did not increase the incidence of acute rejection (4.2, 4.5 and 10.3 %). Only one graft failure occurred in group 2 due to vessel kinking after operation. There were no significant differences in the incidence of malignancy and mortality between groups. CONCLUSIONS: A low MMF dose reduces infection without increasing rejection or graft loss and it may be appropriate to reduce the dose of MMF for rituximab-treated KT patients.


Assuntos
Rejeição de Enxerto/etiologia , Rejeição de Enxerto/prevenção & controle , Transplante de Rim/efeitos adversos , Ácido Micofenólico/análogos & derivados , Nefrite/induzido quimicamente , Rituximab/administração & dosagem , Adulto , Anti-Inflamatórios não Esteroides/administração & dosagem , Esquema de Medicação , Quimioterapia Combinada/métodos , Feminino , Humanos , Fatores Imunológicos/administração & dosagem , Imunossupressores/administração & dosagem , Masculino , Ácido Micofenólico/administração & dosagem , Nefrite/prevenção & controle , Resultado do Tratamento
20.
Kidney Res Clin Pract ; 43(1): 82-92, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37448281

RESUMO

BACKGROUND: Pathologic diagnosis of antibody-mediated rejection (ABMR) in ABO-incompatible (ABOi) transplantation patients is often challenging because patients without ABMR are frequently immunopositive for C4d. The aim of this study was to determine whether C4d positivity with microvascular inflammation (MVI), in the absence of any detectable donor-specific antibodies (DSAs) in ABOi patients, could be considered as ABMR. METHODS: A retrospective study of 214 for-cause biopsies from 126 ABOi kidney transplantation patients was performed. Patients with MVI score of ≥2 and glomerulitis score of ≥1 (n = 62) were divided into three groups: the absolute ABMR group (DSA-positive, C4d-positive or C4d-negative; n = 36), the C4d-positive group (DSA-negative, C4d-positive; n = 22), and the C4d-negative group (DSA-negative, C4d-negative; n = 4). The Banff scores, estimated glomerular filtration rates (eGFRs), and graft failure rates were compared among groups. RESULTS: C4d-positive biopsies showed higher glomerulitis, peritubular capillaritis, and MVI scores compared with C4d-negative specimens. The C4d-positive group did not show significant differences in eGFRs and graft survival compared with the absolute ABMR group. CONCLUSION: The results indicate that C4d positivity, MVI score of ≥2, and glomerulitis score of ≥1 in ABOi allograft biopsies may be categorized and treated as ABMR cases.

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