RESUMO
Kidney transplantation is the best option for kidney replacement therapy, even considering that most of the times the grafts do not survive as long as their recipients. In the Khalil et al's experience, published in this issue of the Journal, they analyze their second kidney graft survival and describe those significant predictors of early loss. This editorial comments on the results and put in perspec tive that most of the times, long-term graft survival could be inadvertently jeopardized if the immunosuppressive therapy is reduced or withdrawn for any reason, and that it could happen frequently if the transplant physician intends to innovate with the clinical care without proper evidence-based data.
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OBJECTIVE: To assess the effect of tubulointerstitial inflammation (TII) and interstitial fibrosis and tubular atrophy (IFTA) on kidney survival in lupus nephritis (LN). METHODS: Two hundred eighty five patients with biopsy-proven LN were retrospectively studied. Kidney survival was defined as the time from initial biopsy to end-stage kidney disease (ESKD), dialysis, or transplant. Kidney survival analysis was performed by the Kaplan-Meier method and the statistical difference between survival curves compared by the log-rank test. Cumulative incidence functions with competing risk of death for kidney survival were also graphed. Multivariable Cox proportional hazards regression and competing-risk analyses were performed to identify independent predictors of ESKD. RESULTS: Fifty-seven patients (20%) progressed to ESKD during a median time of 4.2 (2.0-55.2) months after biopsy. TII was present in 206 (72.3%) biopsies, while IFTA in 99 (34.7%) biopsies. Patients with moderate-to-severe IFTA had worse kidney survival than those with none or mild IFTA in both the Kaplan-Meier (p = 0.018) and the competing-risk analyses (p = 0.017). Patients with class IV ± V LN had worse kidney survival than those with non-class IV LN by the Kaplan-Meier method (p = 0.050), but not in the competing-risk analysis (p = 0.154). Worse kidney survival was also found among those with fibrous crescents than those without, in both the Kaplan-Meier (p = 0.010) and the competing-risk (p = 0.011) analyses. By multivariable Cox regression analysis, older age (HR 1.04, 95% CI 1.01-1.07) and class IV ± V LN (HR 5.06, 95% CI 1.82-14.09) were associated with higher risk of ESKD after adjusting for sex, ethnicity, TII, and IFTA. By competing-risk analyses, class IV ± V LN (SHR 3.32, 95% CI 1.25-8.83) and no response to immunosuppressive therapy (SHR 4.55, 95% CI 1.54-13.41) were associated with a higher risk of ESKD, while eGFR >90 mL/min/1.73 m2 (SHR 0.98 for each ml/min/1.73 m2, 95% 0.97-0.99) with a lower risk. CONCLUSIONS: Patients with moderate-to-severe IFTA had worse kidney survival than those with none or mild IFTA. Worse kidney survival was also found among those with class IV LN and fibrous crescents versus those without IV LN and fibrous crescents, respectively.
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Falência Renal Crônica , Lúpus Eritematoso Sistêmico , Nefrite Lúpica , Humanos , Nefrite Lúpica/patologia , Prognóstico , Estudos Retrospectivos , América Latina , Lúpus Eritematoso Sistêmico/patologia , Rim/patologia , Inflamação , Falência Renal Crônica/patologia , Biópsia , Fibrose , Atrofia/patologiaRESUMO
ABSTRACT Despite improvements in patient survival and quality of life, long-term renal survival has not changed significantly in the recent decades and nephritis relapses affect over 50% of patients with lupus nephritis. Renal fibrosis affecting the tubulointerstitial compartment is a central determinant of the prognosis of any kidney disease. Notwithstanding this evidence, the current 2003 ISN/RPS classification still focuses on glomerular pathology and does not include a mandatory score with clear subcategories of the tubulointerstitial injury in the biopsy. The pathogenesis, and the morphological and molecular characteristics of this process in patients with lupus nephritis will be considered, together with a discussion about the concepts the clinician needs to efficiently address in this injury during daily practice and in future clinical trials. Both tubulointerstitial inflammation and fibrosis are strongly correlated with poor renal outcomes in lupus nephritis, regardless of the extent of glomerular damage. Therefore, it is essential to develop reliable and noninvasive approaches to predict which patients are most likely to develop CKD so that appropriate interventions can be adopted before ESRD is established. Currently, no ideal method for monitoring kidney fibrosis exists, since repeated renal biopsies are invasive. Promising methods for assessing and monitoring fibrosis non-invasively include imaging techniques, such as magnetic resonance imaging or ex vivo confocal microscopy, integrated in computational and digital pathology techniques. Finally, beyond specific immunosuppressive treatment in Lupus Nephritis, identifying and treating cardiovascular risk factors should be a cornerstone of treatment in these patients.
RESUMEN A pesar de las mejoras en la sobrevida de los pacientes y su calidad de vida, la sobrevida renal en el largo plazo no ha cambiado significativamente durante las últimas décadas, y las recidivas nefríticas afectan a más del 50% de los pacientes con nefritis lúpica. La fibrosis renal, que afecta el compartimiento tubulointersticial, es un factor determinante central en el pronóstico de todas las patologías renales. A pesar de la evidencia, la actual clasificación ISN/RPS del 2003 todavía se concentra en la patología glomerular y no incluye un score obligatorio con claras subcategorías de la lesión tubulointersticial en la biopsia. Se hablará de la patogenia y las características morfológicas y moleculares de este proceso en pacientes con nefritis lúpica, así como de los conceptos que el clínico necesita para abordar esta lesión de manera eficiente en su práctica cotidiana y en los estudios clínicos a futuro. Tanto la inflamación tubulointersticial como la fibrosis se relacionan fuertemente con desenlaces renales pobres en la nefritis lúpica, con independencia de la extensión del dañío glomerular. Resulta por lo tanto esencial desarrollar sistemas confiables y no invasivos para predecir cuáles pacientes tendrán mayor probabilidad de desarrollar enfermedad renal crónica, a fin de realizar las intervenciones apropiadas antes de que se establezca la enfermedad renal terminal (ERT). En la actualidad, no existe un método ideal para monitorear la fibrosis renal, dado que las biopsias repetidas son procedimientos invasivos. Algunos de los métodos promisorios para evaluar y monitorear la fibrosis de manera no invasiva son las técnicas de imágenes, tales como la resonancia magnética o la microscopía confocal ex vivo, integradas en técnicas de patología computarizadas y digitales. Finalmente, más allá del tratamiento inmunosupresor específico para la nefritis lúpica, identificar y tratar los factores de riesgo cardiovascular deberá ser uno de los pilares de tratamiento en estos pacientes.
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Humanos , Condições Patológicas, Sinais e Sintomas , Processos Patológicos , Fibrose , Nefrite Lúpica , Doenças Urogenitais Femininas , VaricoceleRESUMO
Previously, we found a substantial number of regulatory T cells (Tregs ) and fewer senescent and T helper type 17 (Th17) and a decrease in interstitial fibrosis (IF) in 12-month graft biopsies in belatacept versus cyclosporin (CNI)-treated patients [Belatacept Evaluation of Nephroprotection and Efficacy as First-line Immunosuppression Trial (BENEFIT) study]. Seven years after kidney transplantation (KT), mean estimated glomerular filtration rate (eGFR), patient and graft survival were significantly higher with belatacept versus CNI treatment. The aim of this study was to determine whether the immunophenotypes of inflammatory and regulatory cell subsets infiltrating the grafts contribute to the BENEFIT's clinical findings a decade after KT. Twenty-three adult patients with functionally stable KT treated with belatacept and 10 treated with CNI were enrolled. Biopsies were analyzed by histomorphometry and immunohistochemistry for proliferation, senescence, apoptosis, inflammatory and regulatory cell markers in a blinded manner. Significantly lower percentages of inflammatory/fibrogenic cells [interleukin (IL)-22+ /Th17/Th2/M1 macrophages] were observed in patients treated with belatacept than in patients treated with CNI. By contrast, remarkably higher percentages of regulatory cells [Tregs /Bregs / plasmacytoid dendritic regulatory cells (pDCregs )/M2] were found in belatacept-treated patients than in CNI-treated patients. Conspicuously lower percentages of apoptosis and senescence and higher proliferation markers were found in belatacept-treated patients than in CNI-treated patients. Consequently, there was significantly more inflammation in the microvascular compartments as well as increased tubular atrophy and IF in CNI-treated patients. These findings strongly suggest that regulatory mechanisms, along with the absence of deleterious effects of CNI, contribute to the long-term graft histology and function stability in patients treated with belatacept.
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Abatacepte/uso terapêutico , Ciclosporinas/uso terapêutico , Sobrevivência de Enxerto/efeitos dos fármacos , Imunossupressores/uso terapêutico , Transplante de Rim/métodos , Adulto , Contagem de Linfócito CD4 , Senescência Celular/efeitos dos fármacos , Feminino , Taxa de Filtração Glomerular/fisiologia , Humanos , Imunofenotipagem , Masculino , México , Linfócitos T Reguladores/imunologia , Tacrolimo/uso terapêutico , Células Th17/imunologiaRESUMO
AIM: The objective of this study was to investigate the correlation between the urinary excretion of cystatin C (CysC) and the presence of interstitial fibrosis/tubular atrophy (IF/TA) in renal transplant (RT) recipients. METHODS: This prospective study included 21 adult patients who had undergone renal biopsy and RT ≥6 months prior. According to the renal biopsy reports, the patients were divided into groups with (n=12) or without (n=9) IF/TA. Analytical parameters included the following: serum and urinary levels of CysC, creatinine (Cr) and sodium (Na), total urinary protein, urinary CysC/creatinine ratio [u(CysC/Cr)], fractional excretion of sodium (FENa) and estimated glomerular filtration rate (eGFR) based on the Chronic Kidney Disease Epidemiology Collaboration equation. RESULTS: The values of uCysC, u(CysC/Cr), proteinuria, and FENa were significantly higher in patients with IF/TA than in patients without IF/TA. The values of eGFR were statistically lower in patients with IF/TA (p=0.001). Values of uCysC significantly correlated with those of serum Cr, FENa, and eGFR (p<0.001). Among the patients with IF/TA, 67% presented with glomerulosclerosis (segmental/global). CONCLUSION: Elevated levels of urinary CysC are associated with interstitial fibrosis and tubular atrophy in RT recipients and may become a useful tool for monitoring kidney allografts.
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Cistatina C/análise , Fibrose/urina , Túbulos Renais/patologia , Adulto , Aloenxertos , Creatinina/sangue , Creatinina/urina , Cistatina C/sangue , Feminino , Taxa de Filtração Glomerular , Humanos , Transplante de Rim , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Sódio/análiseRESUMO
Chronic renal allograft injury is reflected by interstitial fibrosis and tubular atrophy (IF/TA) and by the accumulation of extracellular matrix (ECM). Metalloproteinases (MMPs) are renal physiologic regulators of ECM degradation. Changes in MMPs expression or activity may disturb ECM turnover leading to glomerular scarring and worsening renal function. Our goal was to investigate intragraft MMP2 and MMP9 activities and their correlation with renal dysfunction. Plasma MMP2 and MMP9 activities were analyzed as noninvasive markers of renal allograft deterioration. Transplanted patients were biopsied and histopathologically characterized as IF/TA+ or IF/TA-. Renal function was evaluated by serum creatinine, glomerular filtration rate (GFR) estimated by Modification of Diet in Renal Disease equation and urinary protein/creatinine ratio. Kidney and plasma MMP2 and MMP9 activities were analyzed by zymography. A significant renal dysfunction was observed in IF/TA+ patients. Intragraft proMMP9 showed a significant higher activity in IF/TA+ than in IF/TA- samples and was inversely correlated with the GFR. Intragraft proMMP2 activity tended to increase in IF/TA+ samples, although no statistic significance was reached. Circulating proMMP2 and proMMP9 activities did not show significant differences between groups. Our data provide evidence that correlates intragraft proMMP9 activity with the fibrotic changes and renal dysfunction observed in IF/TA.
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Fibrose/fisiopatologia , Transplante de Rim , Túbulos Renais/patologia , Rim/fisiopatologia , Adulto , Atrofia/cirurgia , Biópsia , Estudos de Coortes , Nefropatias Diabéticas/complicações , Nefropatias Diabéticas/terapia , Dieta , Feminino , Fibrose/cirurgia , Taxa de Filtração Glomerular , Rejeição de Enxerto , Sobrevivência de Enxerto , Humanos , Hipertensão Renal/complicações , Hipertensão Renal/terapia , Rim/metabolismo , Rim/cirurgia , Testes de Função Renal , Masculino , Metaloproteinase 2 da Matriz/sangue , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/sangue , Metaloproteinase 9 da Matriz/metabolismo , Pessoa de Meia-Idade , Nefrite/complicações , Nefrite/terapiaRESUMO
The purpose of this study was to evaluate the association of post-transplant soluble CD30 (sCD30) levels, isolated or in combination with of anti-HLA class II antibodies and of serum creatinine levels, with kidney graft loss due to chronic allograft nephropathy (CAN), and type of lesions in graft biopsies for cause. The study comprised 511 first kidney graft recipients, transplanted at a single center, with a graft functioning for at least 2.8 years. A single blood sample was collected from each patient. sCD30 levels were determined by ELISA, and HLA antibodies by Luminex assay. The minimum follow-up after testing was 9.3 years. High sCD30 levels, set at sCD30 ≥ 34.15 ng/mL, the presence of HLA class II antibodies, and serum creatinine ≥ 1.9 mg/dL were independently associated with CAN-graft loss (P values <0.0001, 0.05, <0.0001, respectively), and the combined hazard ratio for CAN-graft loss was 20.2. Analyses of 166 biopsies for cause showed that high sCD30 levels and creatinine were independently associated with interstitial lesions. Post-transplant sCD30 serum levels, especially in conjunction with information regarding HLA class II antibodies and serum creatinine levels, provide valuable information regarding graft outcome and could be useful for the management of kidney transplant recipients.