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1.
Am J Cardiol ; 151: 105-113, 2021 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-34049674

RESUMO

Left atrial (LA) enlargement predicts adverse cardiovascular events in patients with chronic kidney disease (CKD). The aim of our study was to evaluate the value of LA reservoir strain, a novel measure of LA function, as a prognostic marker for adverse renal outcomes. A total of 280 patients (65.8 ± 12.2years, 63% male) with stable Stage 3 and 4 CKD without prior cardiac history were evaluated with transthoracic echocardiography and prospectively followed for up to 5 years. The primary end point was progressive renal failure, which was the composite of death from renal cause, end-stage renal failure and/or doubling of serum creatinine. Over a mean follow up of 3.9 ± 2.7years, 56 patients reached the composite endpoint. By log rank test, older age, lower baseline eGFR, anemia, diabetes mellitus, higher urinary albumin/creatinine ratio, number of antihypertensive medications, higher indexed left ventricular mass, larger LA volumes, and impaired LA reservoir strain were significant predictors of the composite outcome (p <0.01 for all). Multi-variable Cox regression analysis found LA reservoir strain, eGFR, number of antihypertensive medications and urinary albumin/creatinine ratio were independent predictors for progressive renal failure (p <0.01 for all). Impaired LA reservoir strain was associated with a 2.5-fold higher risk of the composite outcome (HR 2.51, 95% CI 1.19 to 5.30, p = 0.02) and was the only echocardiographic parameter that predicted progressive renal failure independent of established clinical risk factors for end-stage renal failure. Its utility requires validation in high risk CKD patients with cardiac disease.


Assuntos
Função do Átrio Esquerdo , Átrios do Coração/diagnóstico por imagem , Falência Renal Crônica/fisiopatologia , Insuficiência Renal Crônica/fisiopatologia , Idoso , Creatinina/sangue , Progressão da Doença , Ecocardiografia , Feminino , Seguimentos , Átrios do Coração/fisiopatologia , Humanos , Falência Renal Crônica/sangue , Falência Renal Crônica/mortalidade , Masculino , Pessoa de Meia-Idade , Prognóstico , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/mortalidade
2.
Transplantation ; 2021 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-33908382

RESUMO

Polyomavirus BK virus (BKPyV) infection is an important complication of kidney transplantation and allograft failure. The prevalence of viremia is 10-15%, compared with BK associated nephropathy (BKPyVAN) at 3-5%. Given that there are no effective anti-viral prophylaxis or treatment strategies for BKPyVAN, active screening to detect BKPyV viraemia is recommended, particularly during the early post-transplant period. Immunosuppression reduction to allow viral clearance may avoid progression to severe and irreversible allograft damage. The frequency and duration of screening are highly variable between transplant centers because the evidence is reliant largely on observational data. Whilst the primary treatment goals center on achieving viral clearance through immunosuppression reduction, prevention of subsequent acute rejection, premature graft loss and return to dialysis remain as major challenges. Treatment strategies for BKPyV infection should be individualised to the recipient's underlying immunological risk and severity of the allograft infection. Efficacy data for adjuvant therapies including intravenous immunoglobulin and cidofovir are sparse. Future well-powered and high-quality randomized controlled trials are needed to inform evidence-based clinical practice for the management of BKPy infection.

3.
Am J Transplant ; 21(2): 727-739, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-32870598

RESUMO

ß-Catenin is an important co-factor which binds multiple transcriptional molecules and mediates fibrogenic signaling pathways. Its role in kidney transplantation is unknown. We quantified binding of ß-catenin within renal tubular epithelial cells to transcription factors, TCF1 and FoxO1, using a proximity ligation assay in 240 transplanted kidneys, and evaluated their pathological and clinical outcomes. ß-Catenin/FoxO1 binding in 1-month protocol biopsies inversely correlated with contemporaneous chronic fibrosis, subsequent inflammation. and inflammatory fibrosis (P < .001). The relative binding of ß-catenin/TCF1 versus ß-catenin/FoxO1 (TF ratio) was the optimal biomarker, and abnormal in diverse fibrotic transplant diseases. A high 1-month TF ratio was followed by greater tubular atrophy and interstitial fibrosis scores, cortical inflammation, renal impairment, and proteinuria at 1 year (n = 131, all P < .001). The TF ratio was associated with reduced eGFR (AUC 0.817), mild fibrosis (AUC 0.717), and moderate fibrosis (AUC 0.769) using receiver operating characteristic analysis. An independent validation cohort (n = 76) confirmed 1-month TF was associated with 12-month moderate fibrosis (15.8% vs. 2.6%, P = .047), however, not with other outcomes or 10-year graft survival, which limits generalizabilty of these findings. In summary, differential binding of ß-catenin to TCF1 rather than FoxO1 in renal tubular cells was associated with the fibrogenic response in transplanted kidneys.


Assuntos
Nefropatias , beta Catenina , Células Epiteliais , Fibrose , Proteína Forkhead Box O1 , Humanos , Rim/patologia , Nefropatias/patologia , Túbulos Renais/patologia
4.
5.
Kidney Int ; 98(2): 278-280, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32709286

RESUMO

Borderline T cell-mediated rejection is a diagnostic category of the Banff schema that uses a lower diagnostic threshold. Subclinical borderline T cell-mediated rejection detected by surveillance sampling is not entirely benign. Studies demonstrate increased rates of late rejection, progressive nephron loss, functional impairment, donor-specific antibody formation, and allograft failure. It can be conceptualized as a failure to control the cellular alloimmune response. Mixed results are reported for its treatment, and randomized controlled trials are needed.


Assuntos
Transplante de Rim , Rejeição de Enxerto , Humanos , Transplante de Rim/efeitos adversos , Linfócitos T , Doadores de Tecidos , Transplante Homólogo
6.
Clin J Am Soc Nephrol ; 15(7): 1015-1023, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32601093

RESUMO

BACKGROUND AND OBJECTIVES: The published tissue adequacy requirement of kidney medulla for BK virus allograft nephropathy diagnosis lacks systematic verification and competes against potential increased procedural risks from deeper sampling. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We evaluated whether the presence of kidney medulla improved the diagnostic rate of BK nephropathy in 2244 consecutive biopsy samples from 856 kidney transplants with detailed histologic and virologic results. RESULTS: Medulla was present in 821 samples (37%) and correlated with maximal core length (r=0.35; P<0.001). BK virus allograft nephropathy occurred in 74 (3% overall) but increased to 5% (42 of 821) with medulla compared with 2% (32 of 1423) for cortical samples (P<0.001). Biopsy medulla was associated with infection after comprehensive multivariable adjustment of confounders, including core length, glomerular number, and number of cores (adjusted odds ratio, 1.81; 95% confidence interval, 1.02 to 3.21; P=0.04). In viremic cases (n=275), medulla was associated with BK virus nephropathy diagnosis (39% versus 19% for cortex; P<0.001) and tissue polyomavirus load (Banff polyomavirus score 0.64±0.96 versus 0.33±1.00; P=0.006). Biopsy medulla was associated with BK virus allograft nephropathy using generalized estimating equation (odds ratio, 2.04; 95% confidence interval, 1.05 to 3.96; n=275) and propensity matched score comparison (odds ratio, 2.24; 95% confidence interval, 1.11 to 4.54; P=0.03 for 156 balanced pairs). Morphometric evaluation of Simian virus 40 large T immunohistochemistry found maximal infected tubules within the inner cortex and medullary regions (P<0.001 versus outer cortex). CONCLUSIONS: Active BK virus replication concentrated around the corticomedullary junction can explain the higher detection rates for BK virus allograft nephropathy with deep sampling. The current adequacy requirement specifying targeting medulla can be justified to minimize a missed diagnosis from undersampling.

7.
Transpl Int ; 33(11): 1393-1404, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32578221

RESUMO

For patients with type 1 diabetes mellitus who progress to the point of requiring renal replacement therapy, the relative benefits of simultaneous pancreas and kidney transplantation (SPK) and deceased donor kidney transplantation across different age categories compared to dialysis are uncertain. Using Australian and New Zealand registry data from 2006 to 2016, a probabilistic Markov model (n = 10 000) was built comparing patient survival between SPK and deceased donor kidney transplantation with dialysis. Compared to dialysis, the average life years saved (LYS) and quality-adjusted life years (QALY) for SPK and deceased donor kidney transplantation were 5.48 [95% CI 5.47, 5.49] LYS and 6.48 [6.47, 6.49] QALY, and 3.38 [3.36, 3.40] LYS and 2.46 [2.45, 2.47] QALY, respectively. For recipients aged 50 years or younger, receiving a deceased donor kidney, the average incremental gains compared to dialysis were 4.13 [4.10, 4.16] LYS and 2.99 [2.97, 3.01] QALY, and for recipients older than 50 years, 3.05 [3.02, 3.08] LYS and 2.25 [2.23, 2.27] QALY. Compared to dialysis, SPK transplantation incurs the greatest benefits in LYS and QALY for patients with type 1 diabetes requiring renal replacement therapy. Patients older than 50 years still experience survival benefits from deceased donor kidney transplantation compared to dialysis.


Assuntos
Diabetes Mellitus Tipo 1 , Transplante de Rim , Transplante de Pâncreas , Austrália , Diabetes Mellitus Tipo 1/cirurgia , Sobrevivência de Enxerto , Humanos , Rim , Doadores Vivos , Nova Zelândia , Pâncreas , Qualidade de Vida , Diálise Renal
8.
Pathology ; 52(5): 546-551, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32564921

RESUMO

Distinguishing between primary and secondary subtypes of membranous glomerulonephritis (MGN) is critical for its clinical management. We prospectively compared direct immunofluorescence (DIF) staining for phospholipase A2 receptor (PLA2R) on frozen renal biopsy with the presence of detectable serum PLA2R antibody assessed by enzyme linked immunosorbent assay (ELISA) in the diagnosis of primary MGN. Forty-six patients with biopsy-proven MGN were enrolled from April 2017 to June 2019 with 31/46 (67.4%) being primary and 15/46 (32.6%) being secondary as determined by comprehensive clinical assessment. This is currently deemed to be the gold standard for distinguishing primary from secondary MGN. Amongst the 31 primary MGN patients, 24/31 were positive on PLA2R DIF staining compared to 18/31 being positive on the PLA2R ELISA (p=0.03). Amongst the 15 secondary MGN patients, 1/15 was positive on PLA2R DIF compared to 0/15 on PLA2R ELISA (p=1.0). In conclusion, the presence of PLA2R staining on DIF demonstrated superior sensitivity and similar specificity compared to the detection of circulating PLA2R antibodies by ELISA in the diagnosis of primary MGN in a cohort of 46 patients with biopsy-proven MGN. We suggest that DIF should be considered as part of routine work-up in all newly diagnosed cases of MGN.


Assuntos
Técnica Direta de Fluorescência para Anticorpo/métodos , Glomerulonefrite Membranosa/diagnóstico , Rim/metabolismo , Receptores da Fosfolipase A2/metabolismo , Adulto , Idoso , Autoanticorpos/sangue , Ensaio de Imunoadsorção Enzimática/métodos , Feminino , Glomerulonefrite Membranosa/metabolismo , Glomerulonefrite Membranosa/patologia , Humanos , Rim/patologia , Masculino , Pessoa de Meia-Idade , Receptores da Fosfolipase A2/imunologia
9.
Am J Transplant ; 20(9): 2318-2331, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32463180

RESUMO

The XV. Banff conference for allograft pathology was held in conjunction with the annual meeting of the American Society for Histocompatibility and Immunogenetics in Pittsburgh, PA (USA) and focused on refining recent updates to the classification, advances from the Banff working groups, and standardization of molecular diagnostics. This report on kidney transplant pathology details clarifications and refinements to the criteria for chronic active (CA) T cell-mediated rejection (TCMR), borderline, and antibody-mediated rejection (ABMR). The main focus of kidney sessions was on how to address biopsies meeting criteria for CA TCMR plus borderline or acute TCMR. Recent studies on the clinical impact of borderline infiltrates were also presented to clarify whether the threshold for interstitial inflammation in diagnosis of borderline should be i0 or i1. Sessions on ABMR focused on biopsies showing microvascular inflammation in the absence of C4d staining or detectable donor-specific antibodies; the potential value of molecular diagnostics in such cases and recommendations for use of the latter in the setting of solid organ transplantation are presented in the accompanying meeting report. Finally, several speakers discussed the capabilities of artificial intelligence and the potential for use of machine learning algorithms in diagnosis and personalized therapeutics in solid organ transplantation.


Assuntos
Rejeição de Enxerto , Transplante de Rim , Inteligência Artificial , Rejeição de Enxerto/diagnóstico , Rim , Transplante de Rim/efeitos adversos , Linfócitos T
10.
Lab Invest ; 100(9): 1184-1196, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32366943

RESUMO

Acute kidney injury triggers a complex cascade of molecular responses that can culminate in maladaptive repair and fibrosis. We have previously reported that the matrix protein thrombospondin-1 (TSP1), binding its high affinity its receptor CD47, promotes acute kidney injury. However, the role of this pathway in promoting fibrosis is less clear. Hypothesizing that limiting TSP1-CD47 signaling is protective against fibrosis, we interrogated this pathway in a mouse model of chronic ischemic kidney injury. Plasma and renal parenchymal expression of TSP1 in patients with chronic kidney disease was also assessed. We found that CD47-/- mice or wild-type mice treated with a CD47 blocking antibody showed clear amelioration of fibrotic histological changes compared to control animals. Wild-type mice showed upregulated TSP1 and pro-fibrotic markers which were significantly abrogated in CD47-/- and antibody-treated cohorts. Renal tubular epithelial cells isolated from WT mice showed robust upregulation of pro-fibrotic markers following hypoxic stress or exogenous TSP1, which was mitigated in CD47-/- cells. Patient sera showed a proportionate correlation between TSP1 levels and worsening glomerular filtration rate. Immunohistochemistry of human kidney tissue demonstrated tubular and glomerular matrix localization of TSP1 expression in patients with CKD. These data suggest that renal tubular epithelial cells contribute to fibrosis by activating TSP1-CD47 signaling, and point to CD47 as a potential target to limit fibrosis following ischemic injury.


Assuntos
Antígeno CD47/metabolismo , Rim/metabolismo , Transdução de Sinais , Trombospondina 1/metabolismo , Animais , Antígeno CD47/genética , Células Cultivadas , Modelos Animais de Doenças , Células Epiteliais/metabolismo , Fibrose , Humanos , Isquemia , Rim/irrigação sanguínea , Rim/patologia , Túbulos Renais/citologia , Túbulos Renais/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout
11.
Microbiol Resour Announc ; 9(5)2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-32001567

RESUMO

BK polyomavirus (BKPyV) is an important pathogen in transplant recipients. We report four draft BKPyV genomes, three of BKPyV genotype I (subtype I-b2) (AUS-105, AUS-106, and AUS-108) and one of genotype II (AUS-107). These draft genomes were identified in longitudinal urine samples collected from a single hematopoietic stem cell transplant recipient.

12.
Transplantation ; 104(4): 835-846, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31369519

RESUMO

BACKGROUND: Interstitial inflammation (i-INT) is the driver of T-cell-mediated rejection. Its causes, pathophysiology, kinetics, and outcomes are poorly documented. METHODS: The role of i-INT was evaluated in 2055 biopsies from 775 renal transplant recipients. RESULTS: i-INT was present in 374 (18.2% prevalence) from acute and subclinical rejection (67.4%); interstitial fibrosis and tubular atrophy (14.4%); BK virus nephropathy (BKVAN) 9.9%; and acute tubular necrosis (ATN with i-INT) in 5.9% of cases. i-INT was predicted by prior T-cell-mediated rejection and BKVAN, human leukocyte antigen mismatch, cyclosporine therapy, and indication biopsy for dysfunction. It correlated with tubulitis, arteritis, and antibody markers within concurrent histology (P < 0.001). After treatment, renal functional recovery was best with histological ATN, milder i-INT, and early posttransplant biopsy times. The initial histological improvement of inflammation depended on baseline i-INT severity. Complete resolution to Banff i0 was predicted by early biopsy time, antilymphocyte therapy, recipient age, and medication compliance (all P < 0.001). Clearance i-INT was followed by delayed resolution of tubulitis (P < 0.001). i-INT was associated with histological ATN, renal dysfunction, and increased incident fibrosis on sequential pathology. Progressive fibrosis following related-rejection i-INT was dependent on tubulitis using multivariable analysis. In contrast, fibrogenesis after BKVAN or ATN was unrelated to inflammation. i-INT cases were followed by recurrent rejection in 35.3%, increased graft loss, and greater patient mortality. Multiple complementary outcome analyses determined the optimal lower diagnostic threshold for inflammation was Banff i1 score. CONCLUSIONS: i-INT is a heterogeneous pathological phenotype that results in adverse functional and structural outcomes, for which active and robust therapy should be considered.


Assuntos
Rejeição de Enxerto/patologia , Transplante de Rim/efeitos adversos , Rim/patologia , Nefrite/patologia , Adulto , Atrofia , Biópsia , Feminino , Fibrose , Rejeição de Enxerto/tratamento farmacológico , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/fisiopatologia , Sobrevivência de Enxerto , Humanos , Imunidade Celular , Imunossupressores/uso terapêutico , Rim/efeitos dos fármacos , Rim/imunologia , Rim/fisiopatologia , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Nefrite/tratamento farmacológico , Nefrite/imunologia , Nefrite/fisiopatologia , Fenótipo , Valor Preditivo dos Testes , Medição de Risco , Fatores de Risco , Linfócitos T/imunologia , Fatores de Tempo , Resultado do Tratamento
14.
Lab Invest ; 99(11): 1689-1701, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31243340

RESUMO

Transforming growth factor ß (TGF-ß) is the key cytokine involved in causing fibrosis through cross-talk with major profibrotic pathways. However, inhibition of TGF-ß to prevent fibrosis would also abrogate its anti-inflammatory and wound-healing effects. ß-catenin is a common co-factor in most TGF-ß signaling pathways. ß-catenin binds to T-cell factor (TCF) to activate profibrotic genes and binds to Forkhead box O (Foxo) to promote cell survival under oxidative stress. Using a proximity ligation assay in human kidney biopsies, we found that ß-catenin/Foxo interactions were higher in kidney with little fibrosis, whereas ß-catenin/TCF interactions were upregulated in the kidney of patients with fibrosis. We hypothesised that ß-catenin/Foxo is protective against kidney fibrosis. We found that Foxo1 protected against rhTGF-ß1-induced profibrotic protein expression using a CRISPR/cas9 knockout of Foxo1 or TCF1 in murine kidney tubular epithelial C1.1 cells. Co-administration of TGF-ß with a small molecule inhibitor of ß-catenin/TCF (ICG-001), protected against kidney fibrosis in unilateral ureteral obstruction. Collectively, our human, animal and in vitro findings suggest ß-catenin/Foxo as a therapeutic target in kidney fibrosis.


Assuntos
Proteína Forkhead Box O1/metabolismo , Nefropatias/metabolismo , Rim/metabolismo , beta Catenina/metabolismo , Animais , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Linhagem Celular , Modelos Animais de Doenças , Fibrose , Proteína Forkhead Box O1/deficiência , Proteína Forkhead Box O1/genética , Técnicas de Inativação de Genes , Fator 1-alfa Nuclear de Hepatócito/deficiência , Fator 1-alfa Nuclear de Hepatócito/genética , Fator 1-alfa Nuclear de Hepatócito/metabolismo , Humanos , Rim/efeitos dos fármacos , Rim/patologia , Nefropatias/patologia , Nefropatias/prevenção & controle , Masculino , Camundongos , Pirimidinonas/farmacologia , Transdução de Sinais , Fator de Crescimento Transformador beta1/metabolismo , beta Catenina/antagonistas & inibidores
15.
Am J Transplant ; 19(5): 1452-1463, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30501008

RESUMO

The pathological diagnosis of borderline rejection (BL-R) denotes possible T cell-mediated rejection (TCMR), but its clinical significance is uncertain. This single-center, cross-sectional cohort study compared the functional and histological outcomes of consecutive BL-R diagnoses (n = 146) against normal controls (n = 826) and acute TCMR (n = 55) from 551 renal transplant recipients. BL-R was associated with the following: contemporaneous renal dysfunction, acute tubular necrosis, and chronic tubular atrophy (P < .001); progressive tubular injury with fibrosis by longitudinal sequential histology (45.3% at 1 year); increased subsequent acute rejection (39.4%), allograft failure (P < .001), and patient mortality (P = .007). BL-R detected by biopsy indicated for impaired function was followed by suboptimal functional recovery (46.3%), persistent inflammation (27.2%), and acute rejection episodes (50.0%) despite antirejection treatment in 83.3%. By 1 year after BL-R, the incidence of new-onset microvascular inflammation (9.3%), C4d staining (22.3%), transplant glomerulopathy (13.3%), and de novo donor-specific antibodies (31.5%) exceeded normal controls (P < .05-.001). BL-R inflammation in protocol biopsy persisted in 28.0% and progressed to acute rejection in 32.6%; however, it resolved in 61.6% of the untreated cases. In summary, BL-R is a heterogeneous diagnostic grouping, ranging from mild inconsequential inflammation to clinically significant TCMR, which is capable of immune-mediated tubular injury resulting in inferior functional, immunological, and histological consequences.


Assuntos
Rejeição de Enxerto/patologia , Sobrevivência de Enxerto/imunologia , Isoanticorpos/imunologia , Falência Renal Crônica/cirurgia , Transplante de Rim/efeitos adversos , Complicações Pós-Operatórias , Linfócitos T/imunologia , Complemento C4b/imunologia , Feminino , Seguimentos , Taxa de Filtração Glomerular , Rejeição de Enxerto/etiologia , Humanos , Falência Renal Crônica/patologia , Testes de Função Renal , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Doadores de Tecidos , Transplantados , Transplante Homólogo
16.
Am J Transplant ; 19(1): 132-144, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29687946

RESUMO

Tubulitis without interstitial inflammation (Banff i0), termed "isolated tubulitis" (ISO-T), has been controversially included within the Banff "borderline" category of acute T cell mediated rejection (TCMR). This single-center, retrospective, observational study of 2055 consecutive biopsies from 775 recipients, determined the clinical significance of ISO-T. ISO-T prevalence was 19.1%, comprising mild tubulitis (i0t1) in 97.2%. Independent clinical predictors of tubulitis were HLA mismatch, prior TCMR and antibody-mediated rejection, pulse corticosteroids, and BKVAN (P = .006 to P < .001 by multivariable analysis). Histological associations of tubulitis included interstitial inflammation, peritubular capillaritis, tubular atrophy, and SV40T (P = .005 to <.001). The dominant pathological diagnoses in ISO-T (n = 393) were interstitial fibrosis/tubular atrophy (IF/TA, 44.5%) or normal/minimal (31.8%). Subanalysis of ISO-T from indication biopsies (n = 107) found acute tubular injury (37.4%), IF/TA (28.0%), normal/minimal (12.1%), acute rejection (9.3%, vascular or antibody), chronic-active TCMR (2.8%), and BKVAN (5.6%). Allograft function of ISO-T frequently improved, affected by early biopsy timing and underlying disease diagnosis. Subsequent histology of 1197 ISO-T biopsy-pairs was generally benign. The 1- and 5-year death-censored graft survivals of ISO-T were 98.8% and 92.7%. In summary, tubulitis without inflammation does not represent borderline TCMR. We suggest its removal from the borderline category, and reinstatement of i1 as the diagnostic threshold.


Assuntos
Rejeição de Enxerto/imunologia , Inflamação/imunologia , Nefropatias/diagnóstico , Nefropatias/imunologia , Túbulos Renais/patologia , Linfócitos T/imunologia , Adulto , Algoritmos , Biópsia , Feminino , Sobrevivência de Enxerto , Humanos , Inflamação/patologia , Estimativa de Kaplan-Meier , Transplante de Rim/efeitos adversos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Prevalência , Análise de Componente Principal , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Resultado do Tratamento
18.
Am J Transplant ; 18(2): 364-376, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29194971

RESUMO

Inflammation within areas of interstitial fibrosis and tubular atrophy (i-IFTA) is associated with adverse outcomes in kidney transplantation. We evaluated i-IFTA in 429 indication- and 2052 protocol-driven biopsy samples from a longitudinal cohort of 362 kidney-pancreas recipients to determine its prevalence, time course, and relationships with T cell-mediated rejection (TCMR), immunosuppression, and outcome. Sequential histology demonstrated that i-IFTA was preceded by cellular interstitial inflammation and followed by IF/TA. The prevalence and intensity of i-IFTA increased with developing chronic fibrosis and correlated with inflammation, tubulitis, and immunosuppression era (P < .001). Tacrolimus era-based immunosuppression was associated with reduced histologic inflammation in unscarred and scarred i-IFTA compartments, ameliorated progression of IF, and increased conversion to inactive IF/TA (compared with cyclosporine era, P < .001). Prior acute (including borderline) TCMR and subclinical TCMR were followed by greater 1-year i-IFTA, remaining predictive by multivariate analysis and independent of humoral markers. One-year i-IFTA was associated with accelerated IF/TA, arterial fibrointimal hyperplasia, and chronic glomerulopathy and with reduced renal function (P < .001 versus no i-IFTA). In summary, i-IFTA is the histologic consequence of active T cell-mediated alloimmunity, representing the interface between inflammation and tubular injury with fibrotic healing. Uncontrolled i-IFTA is associated with adverse structural and functional outcomes.


Assuntos
Fibrose/patologia , Rejeição de Enxerto/etiologia , Inflamação/patologia , Nefropatias/patologia , Transplante de Rim/efeitos adversos , Túbulos Renais/patologia , Complicações Pós-Operatórias , Adulto , Feminino , Fibrose/imunologia , Seguimentos , Taxa de Filtração Glomerular , Rejeição de Enxerto/patologia , Sobrevivência de Enxerto , Histocompatibilidade , Humanos , Inflamação/imunologia , Isoanticorpos , Nefropatias/imunologia , Nefropatias/cirurgia , Testes de Função Renal , Túbulos Renais/imunologia , Estudos Longitudinais , Masculino , Prognóstico , Estudos Prospectivos , Fatores de Risco , Linfócitos T/imunologia , Linfócitos T/patologia
20.
Transplant Direct ; 3(4): e142, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28405598

RESUMO

BACKGROUND: Reactivation of BK polyoma virus causes a destructive virus allograft nephropathy (BKVAN) with graft loss in 46%. Treatment options are limited to reduced immunosuppression and largely ineffective antiviral agents. Some studies suggest benefit from intravenous immunoglobulin (IVIG). METHODS: We evaluated effectiveness of adjuvant IVIG to eliminate virus from blood and tissue, in a retrospective, single-center cohort study, against standard-of-care controls. Both groups underwent reduced immunosuppression; conversion of tacrolimus to cyclosporine; and mycophenolate to leflunomide, oral ciprofloxacin, and intravenous cidofovir. RESULTS: Biopsy-proven BKVAN occurred in 50 kidneys at 7 (median interquartile range, 3-12) months after transplantation, predominantly as histological stage B (92%), diagnosed following by dysfunction in 46%, screening viremia in 20%, and protocol biopsy in 34%. After treatment, mean viral loads fell from 1581 ± 4220 × 103 copies at diagnosis to 1434 ± 70 639 midtreatment, and 0.138 ± 0.331 after 3 months (P < 0.001). IVIG at 1.01 ± 0.18 g/kg was given to 22 (44%) patients. The IVIG group more effectively cleared viremia (hazard ratio, 3.68; 95% confidence interval, 1.56-8.68; P = 0.003) and BK immunohistochemistry from repeated tissue sampling (hazard ratio, 2.24; 95% confidence interval, 1.09-4.58; P = 0.028), and resulted in faster (11.3 ± 10.4 months vs 29.1 ± 31.8 months, P = 0.015) and more complete resolution of viremia (33.3% vs 77.3%, P = 0.044). Numerically, fewer graft losses occurred with IVIG (27.3% vs 53.6% for control, P = 0.06), although graft and patient survivals were not statistically different. Acute renal dysfunction requiring pulse corticosteroid was common (59.1% vs 78.6%, P = 0.09), respectively, after immunosuppression reduction. CONCLUSIONS: Combination treatment incorporating adjuvant IVIG was more effective eliminating virus from BKVAN, compared with conventional therapy. Validation by multicenter randomized trial is needed.

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