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1.
Transplantation ; 103(10): 1990-2002, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31568231

RESUMO

Membranous nephropathy (MN) is a common cause of nephrotic syndrome after transplantation and is associated with an increased risk of allograft loss. MN may occur either as a recurrent or as a de novo disease. As in native kidneys, the pathophysiology of the MN recurrence is in most cases associated with antiphospholipid A2 receptor antibodies. However, the posttransplant course has some distinct features when compared with primary MN, including a lower chance of spontaneous remission and a greater requirement for adjuvant immunosuppressive therapy to induce complete remission. Although the efficacy of rituximab in primary MN is now well established, no randomized studies have assessed its effectiveness in MN after transplant, and there are no specific recommendations for the management of these patients. This review aims to synthesize and update the pathophysiology of posttransplant MN, as well as to address unsolved issues specific to transplantation, including the prognostic value of antiphospholipid A2 receptor, the risk of living-related donation, the link between de novo MN and rejection, and different therapeutic strategies so far deployed in posttransplant MN. Lastly, we propose a management algorithm for patients with MN who are planning to receive a kidney transplant, including pretransplant considerations, posttransplant monitoring, and the clinical approach after the diagnosis of recurrence.

2.
Nephrol Ther ; 15(6): 469-484, 2019 Nov.
Artigo em Francês | MEDLINE | ID: mdl-31640943

RESUMO

More than fifty years after the success of the two first renal transplantations in Boston and in Necker hospital in Paris, renal transplantation became the treatment of choice of end stage renal failure, because it improves not only the quality of life of the patients but also their long-term survival. In France, more than 3,700 kidney transplantations are performed every year and more than 40,000 patients are living with a functioning kidney allograft. This treatment of end stage renal disease requires a fine-tuned pre-transplant evaluation and a multidisciplinary post-transplant care in order to prevent, to detect and to treat comorbidities and complications of immunosuppression. The ambition of this manuscript is not to describe in an exhaustive way all the aspects of renal transplantation but starting from the experience of a team, recently published data, and national and international guidelines, to try to provide a synthetic and chronological view of the early post-transplant monitoring.

3.
Proc Natl Acad Sci U S A ; 116(22): 10899-10904, 2019 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-31085644

RESUMO

At this time, pretransplant viral screening of donors and recipients is based on serological status and limited to certain viruses. After transplantation, patient follow-up is based on a monitoring strategy using ELISA or PCR. Such approaches exclude other emerging viruses that can affect the transplant outcome. Recently, a multiplex unbiased array, VirScan, was developed. This tool allows the detection of antibodies against viruses, using a synthetic human virome, with minimal serum and cost. We decided to test the value of VirScan in the follow-up of a cohort of transplant recipients. We enrolled 45 kidney transplant recipients and performed virus serological profiling at day 0 and day +365, using VirScan. We compared the results obtained with ELISA/PCR assays. We detected antibody responses to 39 of the 206 species of virus present in the VirScan library, with an average of 12 species of virus per sample. VirScan gave similar results to PCR/ELISA screening tests. Using VirScan, we found that anti-viral antibody responses were largely conserved in patients during the first year after transplantation, regardless of immunosuppressive treatment. Our study suggests VirScan offers an unprecedented opportunity to screen and monitor posttransplant virus infection in a cost-effective, easy, and unbiased manner.

4.
Transplantation ; 2019 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-30985736

RESUMO

Membranous nephropathy (MN) is a common cause of nephrotic syndrome after transplantation and is associated with an increased risk of allograft loss. MN may occur either as a recurrent or as a de novo disease. As in native kidneys, the pathophysiology of the MN recurrence is in most cases associated with anti-phospholipid A2 receptor antibodies (antiPLA2R). However, the post-transplant course has some distinct features when compared to primary MN, including a lower chance of spontaneous remission and a greater requirement for adjuvant immunosuppressive therapy to induce complete remission. Whereas the efficacy of rituximab in primary MN is now well established, no randomized studies have assessed its effectiveness in MN after transplant, and there are no specific recommendations for the management of these patients. This review aims to synthesize and update the pathophysiology of post-transplant MN, as well as to address unsolved issues specific to transplantation, including the prognostic value of antiPLA2R, the risk of living-related donation, the link between de novo MN and rejection, and different therapeutic strategies so far deployed in post-transplant MN. Lastly, we propose a management algorithm for patients with MN who are planning to receive a kidney transplant, including pre-transplant considerations, post-transplant monitoring and the clinical approach after the diagnosis of recurrence.

6.
Sci Transl Med ; 11(476)2019 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-30674655

RESUMO

Fibrosis contributes to the progression of chronic kidney disease (CKD). Severe acute kidney injury can lead to CKD through proximal tubular cell (PTC) cycle arrest in the G2-M phase, with secretion of profibrotic factors. Here, we show that epithelial cells in the G2-M phase form target of rapamycin (TOR)-autophagy spatial coupling compartments (TASCCs), which promote profibrotic secretion similar to the senescence-associated secretory phenotype. Cyclin G1 (CG1), an atypical cyclin, promoted G2-M arrest in PTCs and up-regulated TASCC formation. PTC TASCC formation was also present in humans with CKD. Prevention of TASCC formation in cultured PTCs blocked secretion of profibrotic factors. PTC-specific knockout of a key TASCC component reduced the rate of kidney fibrosis progression in mice with CKD. CG1 induction and TASCC formation also occur in liver fibrosis. Deletion of CG1 reduced G2-M phase cells and TASCC formation in vivo. This study provides mechanistic evidence supporting how profibrotic G2-M arrest is induced in kidney injury and how G2-M-arrested PTCs promote fibrosis, identifying new therapeutic targets to mitigate kidney fibrosis.

7.
BMC Nephrol ; 19(1): 331, 2018 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-30458703

RESUMO

BACKGROUND: Human immunodeficiency virus (HIV) is associated with diverse glomerular diseases. Characteristics of minimal change nephrotic syndrome (MCNS) in this setting have been little studied, and the specific features of this uncommon association remain to be determined. METHODS: We conduct a retrospective study. Clinical, biological and pathological characteristics of patients with MCNS and HIV infection were assessed. We evaluated HIV infection by in situ hybridization and CMIP expression by immunochemistry on kidney biopsies and compared it to HIV-associated nephropathy (HIVAN) and idiopathic MCNS. RESULTS: Eight patients were identifies. In all but one of these cases, MCNS occurred after HIV diagnosis (mean of 9.5 years). Acute kidney injury was detected in three cases. Mean CD4+ lymphocyte count was 733/mm3 and three patients had a detectable HIV viral load. In situ hybridization for HIV-1 RNA detection yielded a positive signal in a few tubular cells in the renal parenchyma in two of four patients with HIV infection associated with MCNS. Podocytes of these patients presented strong positive immunostaining for CMIP (4/4). Three patients suffered steroid-dependent nephrotic syndrome, and another two patients had at least one relapse. Rituximab treatment was initiated in four cases. After a median follow-up of 20 months, all patients were in remission (complete in 5 cases). CONCLUSIONS: In patients with MCNS occurring in a context of HIV infection, podocyte injury seems to be associated with CMIP induction rather than renal HIV infection but further studies are needed to determine the molecular link between these two conditions.

8.
Kidney Int ; 2018 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-30471880

RESUMO

Mitochondrial diseases represent a significant clinical challenge. Substantial efforts have been devoted to identifying therapeutic strategies for mitochondrial disorders, but effective interventions have remained elusive. Recently, we reported attenuation of disease in a mouse model of the human mitochondrial disease Leigh syndrome through pharmacological inhibition of the mechanistic target of rapamycin (mTOR). The human mitochondrial disorder MELAS/MIDD (Mitochondrial Encephalopathy with Lactic Acidosis and Stroke-like Episodes/Maternally Inherited Diabetes and Deafness) shares many phenotypic characteristics with Leigh syndrome. MELAS/MIDD often leads to organ failure and transplantation and there are currently no effective treatments. To examine the therapeutic potential of mTOR inhibition in human mitochondrial disease, four kidney transplant recipients with MELAS/MIDD were switched from calcineurin inhibitors to mTOR inhibitors for immunosuppression. Primary fibroblast lines were generated from patient dermal biopsies and the impact of rapamycin was studied using cell-based end points. Metabolomic profiles of the four patients were obtained before and after the switch. pS6, a measure of mTOR signaling, was significantly increased in MELAS/MIDD cells compared to controls in the absence of treatment, demonstrating mTOR overactivation. Rapamycin rescued multiple deficits in cultured cells including mitochondrial morphology, mitochondrial membrane potential, and replicative capacity. Clinical measures of health and mitochondrial disease progression were improved in all four patients following the switch to an mTOR inhibitor. Metabolomic analysis was consistent with mitochondrial function improvement in all patients.

9.
Nature ; 558(7711): 540-546, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29899452

RESUMO

CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal naevi, scoliosis/skeletal and spinal syndrome) is a genetic disorder that results from somatic, mosaic gain-of-function mutations of the PIK3CA gene, and belongs to the spectrum of PIK3CA-related overgrowth syndromes (PROS). This rare condition has no specific treatment and a poor survival rate. Here, we describe a postnatal mouse model of PROS/CLOVES that partially recapitulates the human disease, and demonstrate the efficacy of BYL719, an inhibitor of PIK3CA, in preventing and improving organ dysfunction. On the basis of these results, we used BYL719 to treat nineteen patients with PROS. The drug improved the disease symptoms in all patients. Previously intractable vascular tumours became smaller, congestive heart failure was improved, hemihypertrophy was reduced, and scoliosis was attenuated. The treatment was not associated with any substantial side effects. In conclusion, this study provides the first direct evidence supporting PIK3CA inhibition as a promising therapeutic strategy in patients with PROS.

11.
Rheumatology (Oxford) ; 57(6): 1011-1020, 2018 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-29506143

RESUMO

Objectives: Takayasu arteritis (TA) and GCA are large-vessel vasculitides characterized by vascular remodelling involving endothelial cells (ECs) and vascular smooth muscle cells. Mammalian target of rapamycin (mTOR) pathway has been involved in vascular remodelling. We hypothesized that the mTOR pathway was involved in the pathogenesis of large-vessel vasculitis. Methods: We used IF analysis on aortic and temporal artery biopsies from patients with TA and GCA to assess the involvement of the mTOR pathway and searched for antibodies targeting ECs in serum by IIF and cellular ELISA. We evaluated in vitro the effect of purified IgG from patients on mTOR pathway activation and cell proliferation. Results: IF analyses on tissues revealed that both mTORC1 and mTORC2 are activated specifically in ECs from TA patients but not in ECs from GCA patients and healthy controls (HCs). Using IIF and ELISA, we observed higher levels of antibodies binding to ECs in TA patients compared with GCA patients and HCs. Using western blot, we demonstrated that purified IgG from TA patients caused mTORC1 activation in ECs, whereas this effect was not observed with purified IgG from GCA patients or HCs. Purified IgG from TA patients induced a significant EC proliferation compared with to GCA and HC IgG, and this effect was decreased after EC exposure with sirolimus, a specific mTOR inhibitor and PI3K inhibitor. Conclusion: Our results suggest that antibodies targeting ECs drive endothelial remodelling in TA through activation of the mTOR pathway, but not in GCA. Inhibition of the mTOR pathway could represent a therapeutic option in TA.


Assuntos
Anticorpos/imunologia , Células Endoteliais/metabolismo , Imunoglobulina G/sangue , Serina-Treonina Quinases TOR/metabolismo , Arterite de Takayasu/metabolismo , Artérias Temporais/fisiopatologia , Remodelação Vascular , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos/sangue , Western Blotting , Sobrevivência Celular , Células Cultivadas , Células Endoteliais/imunologia , Células Endoteliais/patologia , Endotélio Vascular/metabolismo , Endotélio Vascular/patologia , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Imunoglobulina G/imunologia , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Serina-Treonina Quinases TOR/imunologia , Arterite de Takayasu/patologia , Arterite de Takayasu/fisiopatologia , Artérias Temporais/metabolismo , Artérias Temporais/patologia , Adulto Jovem
12.
Artigo em Inglês | MEDLINE | ID: mdl-29346631

RESUMO

Background: In kidney transplant recipients, anticardiolipin (ACL) antibodies without antiphospholipid syndrome (APS) are found in up to 38% of patients and could be associated with thrombotic events (TEs). However, the prognostic role of ACL regarding kidney transplant and patients outcomes have still not been well defined. Methods: We conducted an observational, monocentric, retrospective cohort study including 446 kidney transplant recipients and standardized follow-up: 36-month allograft and patient survival, 12-month estimated glomerular filtration rate (eGFR) and 3- and 12-month screening biopsies. Results: ACL tests were run on 247 patients, 101 were positive (ACL+ group, 41%) and 146 were negative (ACL- group, 59%). Allografts and patient survival within 36 months as TE were similar between both groups [hazard ratio (HR) = 1.18 and HR = 0.98, respectively]. The 12-month eGFR was significantly lower in the ACL+ group [median (95% confidence interval) 48.5 (35.1-60.3) versus 51.9 (39.1-65.0) mL/min/1.73 m2, P= 0.042]. ACL+ was independently associated with eGFR decrease (P = 0.04). In 12-month screening biopsies, tubular atrophy was significantly more severe in the ACL+ group compared with the ACL- group (P = 0.02). Conclusions: ACL without APS before kidney transplantation is an independent risk factor of eGFR decline within the first year post-transplant without over-incidence of TEs. Specific immunosuppressive therapy including mammalian target of rapamycin inhibitors should be discussed in the future.

13.
Curr Rheumatol Rep ; 19(10): 64, 2017 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-28871481

RESUMO

PURPOSE OF REVIEW: Antiphospholipid antibody syndrome (APS) is characterized primarily by thrombosis and pregnancy morbidity. Chronic vascular lesions can also occur. While the underlying mechanisms of these vascular lesions are not entirely known, there have been multiple theories describing the potential process of vasculopathy in APS and the various clinical manifestations associated with it. RECENT FINDINGS: Recently, it has been demonstrated that endothelial proliferation in kidneys can be explained by the activation of the mammalian target of rapamycin complex (mTORC) pathway by antiphospholipid antibodies (aPL). These data support the existence of an APS-related vasculopathy in different locations which can explain-in part-the different manifestations of APS. This review focuses on the various manifestations of APS as a result of APS-related vasculopathy, as well as pathophysiology, current screening, and treatment options for clinicians to be aware of.


Assuntos
Síndrome Antifosfolipídica/fisiopatologia , Doenças Vasculares/fisiopatologia , Síndrome Antifosfolipídica/complicações , Síndrome Antifosfolipídica/diagnóstico , Síndrome Antifosfolipídica/tratamento farmacológico , Humanos , Trombofilia/fisiopatologia , Doenças Vasculares/diagnóstico , Doenças Vasculares/tratamento farmacológico , Doenças Vasculares/etiologia , Vasculite/fisiopatologia
14.
Nephrol Ther ; 13 Suppl 1: S155-S156, 2017 Apr.
Artigo em Francês | MEDLINE | ID: mdl-28577738

RESUMO

This review presents an overview of a recently characterized spectrum of overgrowth syndrome: phosphoinositide-3 kinase (PI3K)-related overgrowth spectrum (PROS). This spectrum encompasses overgrowth syndromes associated with somatic mosaic activating PIK3CA mutations such as megalencephaly-capillary malformation (MCAP) syndrome, dysplatic megalencephaly (DMEG), congenital lipomatous asymmetric overgrowth of the trunk, lymphatic, capillary, venous, and combined-type vascular malformations, epidermal nevi, skeletal and spinal anomalies (CLOVES) syndrome, hemihyperplasia-multiple lipomatosis (HHML), fibroadipose overgrowth and Klippel-Trenaunay syndrome. Mosaic gain of function mutation in PIK3CA gene leads to abnormal AKT-mTOR pathway activation and is responsible of the clinical manifestations. Here, we summarize the current knowledge on this disorder.


Assuntos
Anormalidades Múltiplas/genética , Classe I de Fosfatidilinositol 3-Quinases/genética , Transtornos do Crescimento/genética , Mutação , Anormalidades Múltiplas/diagnóstico , Biomarcadores/sangue , Transtornos do Crescimento/diagnóstico , Humanos , Lipomatose/genética , Anormalidades Musculoesqueléticas/genética , Fenótipo , Síndrome , Malformações Vasculares/genética
15.
Transplantation ; 101(9): 2003-2008, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28196049

RESUMO

The native kidney is a reservoir for human immunodeficiency virus (HIV)-1 and a site of viral replication, similar to lymphoid tissue, gut-associated lymphoid tissue or semen. The ability of the virus to persist may result from either a true latency or sequestration in an anatomic site that is not effectively exposed to antiretroviral therapy. The presence of HIV in kidney epithelial cells will lead progressively to end-stage renal disease. For decades, HIV-infected patients were excluded from consideration for kidney transplantation. Hemodialysis and peritoneal dialysis were the only forms of treatment available to these patients. The introduction of combined antiretroviral therapy has changed the overall prognosis of these patients and allowed them to benefit from kidney transplantation without an increased risk of opportunistic infections or cancer. However, we recently established that HIV-1 can infect kidney transplant epithelial cells in the absence of detectable viremia. The presence of HIV in kidney cells can manifest itself in multiple ways, ranging from indolent nephropathy and inflammation to proteinuria with glomerular abnormalities. Because the tools that are available to diagnose the presence of HIV in kidney cells are complex, the rate of infection is certainly underestimated. This finding will certainly have implications in the management of patients, particularly for HIV-positive donors. The purpose of this review is to highlight recent evidence that the allograft kidney can be infected by the virus after transplantation as well as the associated consequences.


Assuntos
Nefropatia Associada a AIDS/cirurgia , Infecções por HIV/complicações , HIV-1/patogenicidade , Falência Renal Crônica/cirurgia , Transplante de Rim/métodos , Rim/cirurgia , Nefropatia Associada a AIDS/diagnóstico , Nefropatia Associada a AIDS/virologia , Aloenxertos , Fármacos Anti-HIV/uso terapêutico , Seleção do Doador , Infecções por HIV/diagnóstico , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , HIV-1/crescimento & desenvolvimento , Humanos , Rim/efeitos dos fármacos , Rim/virologia , Falência Renal Crônica/diagnóstico , Falência Renal Crônica/virologia , Transplante de Rim/efeitos adversos , Seleção de Pacientes , Medição de Risco , Fatores de Risco , Doadores de Tecidos/provisão & distribução , Resultado do Tratamento , Replicação Viral
16.
Transplantation ; 101(3): 649-656, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-27043407

RESUMO

BACKGROUND: Rituximab has shown encouraging results for the treatment of kidney transplantation recipients with focal segmental glomerulosclerosis (FSGS) recurrence. However, the correct, opportune, and safe use of rituximab for this indication remains to be determined. METHODS: This multicenter retrospective study reports on 19 new cases aged 35 (15-66) years who developed FSGS recurrence at 12 (1.5-27) days posttransplantation. Initial treatment consisted of plasma exchanges (PE), high doses of calcineurin inhibitors, and steroids. Rituximab was introduced either immediately (N = 6) or after failure of the initial treatment (N = 10) or failed attempted weaning from PE (N = 3). RESULTS: Overall, we observed 9 of 19 complete remissions and 3 of 19 partial remissions. Estimated glomerular filtration rates (Modification of Diet in Renal Disease 4) were significantly higher in the responding patients than in nonresponding patients at month (M)12, M36, and M60. Overall, kidney survival at 5 years was 77.4% (95% range, 41.9-92.7). The 5-year graft survival rates in the responding patients and the nonresponding patients were 100% and 36.5%, respectively (P = 0.01). A further course of rituximab was required for 4 patients as a result of FSGS relapse, with good results. During the first year after renal transplantation, 14 patients developed severe infections (16 bacterial, 4 viral, 1 parasitic). CONCLUSIONS: In kidney transplantation recipients with recurrent FSGS, rituximab therapy may be a recommended treatment for cases that have failed either the initial treatment or weaning from PE.


Assuntos
Glomerulosclerose Segmentar e Focal/tratamento farmacológico , Glomerulosclerose Segmentar e Focal/cirurgia , Imunossupressores/uso terapêutico , Transplante de Rim/efeitos adversos , Rim/efeitos dos fármacos , Rituximab/uso terapêutico , Adolescente , Adulto , Idoso , Inibidores de Calcineurina/uso terapêutico , Criança , Pré-Escolar , Feminino , França , Taxa de Filtração Glomerular/efeitos dos fármacos , Glomerulosclerose Segmentar e Focal/diagnóstico , Glomerulosclerose Segmentar e Focal/fisiopatologia , Sobrevivência de Enxerto/efeitos dos fármacos , Humanos , Imunossupressores/efeitos adversos , Lactente , Rim/fisiopatologia , Masculino , Pessoa de Meia-Idade , Troca Plasmática , Recidiva , Indução de Remissão , Retratamento , Estudos Retrospectivos , Rituximab/efeitos adversos , Esteroides/uso terapêutico , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
17.
Kidney Int ; 91(1): 34-44, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27555120

RESUMO

The antiphospholipid syndrome is a common autoimmune disease caused by pathogenic antiphospholipid antibodies, leading to recurrent thrombosis and/or obstetrical complications. Importantly for nephrologists, antiphospholipid antibodies are associated with various renal manifestations including large renal vessel thrombosis, renal artery stenosis, and a constellation of intrarenal lesions that has been termed antiphospholipid nephropathy. This last condition associates various degrees of acute thrombotic microangiopathy, proliferative and fibrotic lesions of the intrarenal vessels, and ischemic modifications of the renal parenchyma. The course of the disease can range from indolent nephropathy to devastating acute renal failure. The pejorative impact of antiphospholipid antibody-related renal complication is well established in the context of systemic lupus erythematous or after renal transplantation. In contrast, the exact significance of isolated antiphospholipid nephropathy remains uncertain. The evidence to guide management of the renal complications of antiphospholipid syndrome is limited. However, the recent recognition of the heterogeneous molecular mechanisms underlying the progression of intrarenal vascular lesions in antiphospholipid syndrome have opened promising tracks for patient monitoring and targeted therapeutic intervention.


Assuntos
Anticorpos Antifosfolipídeos/imunologia , Síndrome Antifosfolipídica/complicações , Nefropatias/imunologia , Nefropatias/terapia , Obstrução da Artéria Renal/imunologia , Trombose/imunologia , Aloenxertos/irrigação sanguínea , Aloenxertos/imunologia , Aloenxertos/patologia , Antagonistas de Receptores de Angiotensina/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Animais , Anticoagulantes/uso terapêutico , Síndrome Antifosfolipídica/imunologia , Síndrome Antifosfolipídica/terapia , Progressão da Doença , Humanos , Hipertensão/etiologia , Imunossupressores/uso terapêutico , Rim/irrigação sanguínea , Rim/imunologia , Rim/patologia , Nefropatias/diagnóstico , Transplante de Rim/efeitos adversos , Imagem por Ressonância Magnética , Troca Plasmática , Obstrução da Artéria Renal/complicações , Obstrução da Artéria Renal/diagnóstico por imagem , Obstrução da Artéria Renal/tratamento farmacológico , Trombose/diagnóstico por imagem , Trombose/tratamento farmacológico , Trombose/epidemiologia , beta 2-Glicoproteína I/imunologia
18.
Kidney Int ; 90(5): 1037-1044, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27528551

RESUMO

Recent research on podocytes has proposed B7-1 as an important player in podocyte biology and as a potential new therapeutic target. B7-1 was upregulated in injured podocytes and described as a biomarker to identify patients who may benefit from abatacept, a B7-1 blocker. However, after this initial enthusiasm, several reports have not confirmed the efficiency of abatacept at inducing proteinuria remission in patients. In order to resolve these discrepancies, we explored the role of B7-1 in the injured podocyte. Both primary cultured and immortalized podocytes were exposed to lipopolysaccharides, but this failed to induce B7-1 expression at the mRNA and protein levels. Importantly, TLR-4 engagement confirmed lipopolysaccharide efficacy. We then evaluated B7-1 expression in several mouse models of podocyte injury including treatment with lipopolysaccharide or Adriamycin, a lupus prone model (NZB/W F1) and subtotal nephrectomy. Using 3 commercially available anti-B7-1 antibodies and appropriate controls, we could not find B7-1 expression in podocytes, whereas some infiltrating cells were positive. Thus, our findings do not support a role for B7-1 in podocyte biology. Hence, further studies are mandatory before treating proteinuric patients with B7-1 blockers.


Assuntos
Antígeno B7-1/metabolismo , Podócitos/metabolismo , Animais , Glomerulosclerose Segmentar e Focal/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Cultura Primária de Células
19.
Nephrol Ther ; 12 Suppl 1: S35-8, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26972095

RESUMO

Chronic kidney disease is characterized by the progressive loss of functional nephrons. This loss means that the remaining nephrons are put under stress and are forced to adapt in order to maintain kidney function. Over the time, the strains imposed by these adaptations result in a vicious circle in which the loss of damaged nephrons results in the damage of the so far healthy nephrons. Hence, the rate of chronic kidney disease progression depends on the ability of the remaining nephrons to cope with stress. This article reviews the molecular pathways involved in the compensation and deterioration process after nephron reduction. In particular, we examine the role of mammalian target of rapamycin complex (mTORC)/serine-threonine protein kinase AKT, epidermal growth factor receptor (EGFR) and unfolded protein response pathways, as well as the pleiotropic function of Lipocalin 2. We also discuss the dual role played by some of these pathways in acute and chronic kidney disease. Finally, the relevance of these experimental finding to human chronic kidney disease is discussed.


Assuntos
Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/patologia , Serina-Treonina Quinases TOR/metabolismo , Animais , Biomarcadores/metabolismo , Progressão da Doença , Receptores ErbB/metabolismo , Humanos , Lipocalina-2/metabolismo , Néfrons/metabolismo , Néfrons/patologia , Insuficiência Renal Crônica/genética , Transdução de Sinais/genética
20.
Transplantation ; 100(2): 284-7, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26247557

RESUMO

Focal segmental glomerulosclerosis, which is a common glomerular disorder, manifests clinically with a nephrotic syndrome and has a high propensity for recurrence after kidney transplantation. The pathophysiology is currently unknown, and podocytes appear to be the target of one or several circulating factor(s) that lead to the recurrence of proteinuria after kidney transplantation. Identifying these circulating factor(s) and cells involved in its synthesis remains elusive; however, recently, our research on podocyte cytoskeleton biology has opened a new era of treatment. This review will highlight recent progress in the physiopathology of focal segmental glomerulosclerosis recurrence after transplantation and its treatment.


Assuntos
Glomerulosclerose Segmentar e Focal/cirurgia , Falência Renal Crônica/cirurgia , Transplante de Rim/efeitos adversos , Rim/cirurgia , Animais , Glomerulosclerose Segmentar e Focal/sangue , Glomerulosclerose Segmentar e Focal/diagnóstico , Glomerulosclerose Segmentar e Focal/imunologia , Humanos , Rim/imunologia , Rim/metabolismo , Rim/patologia , Falência Renal Crônica/sangue , Falência Renal Crônica/diagnóstico , Falência Renal Crônica/imunologia , Recidiva , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento
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