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OBJECTIVE: The optimal induction therapy for severe glomerulonephritis of ANCA-associated vasculitis (AAV) is debated. We compared the efficacy of glucocorticoid and rituximab (RTX) or CYC induction therapy for severe AAV-related glomerulonephritis and evaluated the potential benefit of plasma exchange (PE) as adjunct therapy to CYC. METHODS: This retrospective, multicentre study included AAV patients with severe renal active disease (serum creatinine level ≥350 µmol/l and/or estimated glomerular filtration ratio ≤15 ml/min/1.73 m2). Propensity-score analysis was used to adjust for potential confounders. RESULTS: Between 2005 and 2017, 153 patients with AAV-related glomerulonephritis were studied (96 [60%] men; mean [s.d.] age 63 [13.1] years): 19 (12%) were treated with RTX and 134 (88%) with CYC. Remission rates did not differ between RTX- and CYC-treated groups. Although more patients with RTX than CYC were dialysis-free at month (M) 12 (79% vs 68%), the difference was not significant after adjustment. Among 134 patients with CYC-treated glomerulonephritis, 76 (57%) also had PE. M3 and M6 remission rates were comparable for weighted CYC groups with or without PE. For weighted groups, the dialysis-free survival rate with CYC was higher with than without PE at M6 (72% vs 64%; odds ratio 2.58) and M12 (74% vs 60%; odds ratio 2.78) reaching statistical significance at M12. CONCLUSION: We could not find any difference between RTX and CYC as induction therapy for patients with severe AAV-related glomerulonephritis. In patients receiving CYC induction regimen, the addition of PE conferred short-term benefits with higher dialysis-free rate at M12.
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Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos , Glomerulonefritis , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/complicaciones , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/tratamiento farmacológico , Creatinina , Ciclofosfamida , Femenino , Glomerulonefritis/tratamiento farmacológico , Glucocorticoides/uso terapéutico , Humanos , Inmunosupresores/efectos adversos , Masculino , Persona de Mediana Edad , Intercambio Plasmático , Inducción de Remisión , Estudios Retrospectivos , Rituximab/uso terapéutico , Resultado del TratamientoRESUMEN
BACKGROUND: Basophils were recently shown to contribute to lupus nephritis (LN). This study assessed blood basophil activation markers (BAMs) for the diagnosis of LN severity and as pre-treatment prognostic markers of the response to treatment in patients with severe LN. METHOD: The diagnostic study included all the patients of a monocentric prospective observational cohort built with consecutive patients diagnosed with LN on the basis of a renal biopsy. The prognostic study selected patients of this cohort according to the following inclusion criteria: ≥18 years old, Class III or IV A ± C ± Class V or pure Class V LN at the time of inclusion and treated with an induction treatment for LN. Clinical data and BAMs were obtained at the time of the kidney biopsy. LN remission status was recorded 12 months after induction therapy initiation. Associations between baseline data and histological severity of LN or LN remission were assessed using logistic regression. RESULTS: No significant association was found between BAMs and the histological severity of LN in 101 patients. Among the 83 patients included in the prognostic study, 64 reached renal remission. CD62L expression on blood basophils at baseline was independently negatively associated with remission at 12 months [odds ratio = 0.26, 95% confidence interval 0.08-0.82, P = 0.02 for quantitative CD62L expression >105 (geometric fluorescent intensity) gMFI]. CD62L <105 gMFI was associated with a probability of 0.87 of LN remission in the next 12 months after the start of induction therapy. CONCLUSION: Pre-treatment CD62L expression on blood basophils could be a first predictive biomarker of renal response to induction therapy at 12 months in patients with severe LN.
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Fallo Renal Crónico , Nefritis Lúpica , Adolescente , Basófilos , Humanos , Riñón , Nefritis Lúpica/diagnóstico , Nefritis Lúpica/tratamiento farmacológico , Inducción de Remisión , Estudios RetrospectivosAsunto(s)
Acalasia del Esófago/complicaciones , Gastroplastia/efectos adversos , Hipopotasemia/diagnóstico , Nefritis Intersticial/complicaciones , Complicaciones Hematológicas del Embarazo/etiología , Adulto , Diagnóstico Diferencial , Acalasia del Esófago/diagnóstico , Femenino , Humanos , Nefritis Intersticial/diagnóstico , Embarazo , Complicaciones Hematológicas del Embarazo/diagnóstico , Tomografía Computarizada por Rayos XRESUMEN
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by anti-nuclear autoantibodies whose production is promoted by autoreactive T follicular helper (TFH) cells. During SLE pathogenesis, basophils accumulate in secondary lymphoid organs (SLO), amplify autoantibody production and disease progression through mechanisms that remain to be defined. Here, we provide evidence for a direct functional relationship between TFH cells and basophils during lupus pathogenesis, both in humans and mice. PD-L1 upregulation on basophils and IL-4 production are associated with TFH and TFH2 cell expansions and with disease activity. Pathogenic TFH cell accumulation, maintenance, and function in SLO were dependent on PD-L1 and IL-4 in basophils, which induced a transcriptional program allowing TFH2 cell differentiation and function. Our study establishes a direct mechanistic link between basophils and TFH cells in SLE that promotes autoantibody production and lupus nephritis.
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Antígeno B7-H1 , Basófilos , Interleucina-4 , Lupus Eritematoso Sistémico , Células T Auxiliares Foliculares , Adulto , Animales , Femenino , Humanos , Masculino , Ratones , Persona de Mediana Edad , Autoanticuerpos/inmunología , Antígeno B7-H1/metabolismo , Antígeno B7-H1/genética , Basófilos/inmunología , Basófilos/metabolismo , Diferenciación Celular/inmunología , Interleucina-4/metabolismo , Interleucina-4/inmunología , Lupus Eritematoso Sistémico/inmunología , Lupus Eritematoso Sistémico/metabolismo , Lupus Eritematoso Sistémico/patología , Nefritis Lúpica/inmunología , Nefritis Lúpica/patología , Nefritis Lúpica/metabolismo , Ratones Endogámicos C57BL , Células T Auxiliares Foliculares/inmunología , Células T Auxiliares Foliculares/metabolismo , Linfocitos T Colaboradores-Inductores/inmunología , Linfocitos T Colaboradores-Inductores/metabolismoAsunto(s)
Deficiencia de IgA/patología , Mieloma Múltiple/inmunología , Diagnóstico por Imagen , Enfermedad de las Cadenas Pesadas , Humanos , Inmunoglobulina A/inmunología , Cadenas Pesadas de Inmunoglobulina/metabolismo , Cadenas Ligeras de Inmunoglobulina/metabolismo , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas , Cadenas kappa de Inmunoglobulina/metabolismo , Mieloma Múltiple/diagnóstico por imagenRESUMEN
OBJECTIVE: Catastrophic antiphospholipid syndrome (CAPS) is a life-threatening disease caused by the onset of rapidly progressive and widespread small-vessel thromboses in the presence of aPLs. The aim of this study was to examine pregnancy-related CAPS. METHODS: Retrospective series of 13 patients with pregnancy-related CAPS with special focus on the follow-up. RESULTS; Eleven patients had known APS and had been treated with low-molecular-weight heparin (n = 10), aspirin (n = 8), oral anticoagulants (n = 1), HCQ (n = 3) and/or steroids (n = 1) during pregnancy. The most frequent manifestations of CAPS were cutaneous (n = 11), hepatic (n = 11), renal (n = 10), cardiac (n = 8) and neurological (n = 5). CAPS usually followed haemolysis, elevated liver enzymes and low platelet count (HELLP) syndrome (n = 12), which was associated with pre-eclampsia (n = 6) or with eclampsia (n = 3). No maternal death was observed. The perinatal mortality of 54% was related to prematurity with a mean gestational age of 26.6 weeks at onset of CAPS or HELLP syndrome. During a mean follow-up of 4.8 years (range 2-8 years), seven new pregnancies occurred in five patients and led to one miscarriage, four successful pregnancies and two HELLP syndrome with pre-eclampsia or eclampsia that occurred at 28 weeks gestation in both cases despite optimal treatment. No relapse of CAPS was observed. Two mothers suddenly died 2.5 and 6 years after CAPS. CONCLUSION: The occurrence of HELLP syndrome in a patient with APS should raise the suspicion of CAPS in the following days, and anticoagulation should be maintained post-partum or post-abortum. Subsequent pregnancies are at very high risk.
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Aborto Espontáneo/etiología , Síndrome Antifosfolípido/complicaciones , Eclampsia/etiología , Síndrome HELLP/etiología , Adulto , Enfermedad Catastrófica , Femenino , Humanos , EmbarazoRESUMEN
Introduction: Systemic lupus erythematosus (SLE) is an autoimmune disease in which circulating immune complexes can cause different types of glomerulonephritis, according to immune deposits and to the type of glomerular cell injury. Proliferative lesions represent the most severe form of lupus nephritis (LN) and often lead to kidney failure and death. Mucosal-associated invariant T (MAIT) cells are a subset of innate-like T cells that recognize microbial-derived ligands from the riboflavin synthesis pathway. Although abundant in peripheral blood, MAIT cells are enriched in mucosal and inflamed tissues. While previous studies have reported concordant results concerning lower MAIT cell frequencies in the blood of SLE patients, no information is known about MAIT cell function and LN severity and outcome. Methods: In the current study, we analyzed the baseline phenotype and function of peripheral blood MAIT cells by flow cytometry in 26 patients with LN and in a control group of 16 healthy individuals. Results: We observe that MAIT cell frequencies are markedly reduced in blood of LN patients. MAIT cells from patients have an altered phenotype in terms of migration, proliferation and differentiation markers, notably in most severe forms of LN. Frequencies of PMA/ionomycin stimulated MAIT cells secreting effector molecules, such as proinflammatory IL-17 and cytotoxic protein granzyme B, are higher in LN patients. Patients undergoing a complete renal remission after immunosuppressive therapy had higher MAIT cell frequency, lower expression of proliferation marker Ki-67 and granzyme B (GzB) at inclusion. Remarkably, GzB production defines a predictive model for complete remission. Discussion: We report here that blood MAIT cells display proinflammatory and cytotoxic function in severe lupus nephritis which may play a pathogenesis role, but without association with systemic lupus activity. Finally, low cytotoxic profile of MAIT cells may represent a promising prognostic factor of lupus nephritis remission one year after induction therapy.
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Lupus Eritematoso Sistémico , Nefritis Lúpica , Células T Invariantes Asociadas a Mucosa , Humanos , Granzimas , Fenotipo , Gravedad del PacienteRESUMEN
BACKGROUND: IgG4-related kidney disease is a major manifestation of IgG4-related disease, a systemic fibroinflammatory disorder. However, the clinical and prognostic kidney-related factors in patients with IgG4-related kidney disease are insufficiently defined. METHODS: We conducted an observational cohort study using data from 35 sites in two European countries. Clinical, biologic, imaging, and histopathologic data; treatment modalities; and outcomes were collected from medical records. Logistic regression was performed to identify the possible factors related to an eGFR ≤30 ml/min per 1.73 m 2 at the last follow-up. Cox proportional hazards model was performed to assess the factors associated with the risk of relapse. RESULTS: We studied 101 adult patients with IgG4-related disease with a median follow-up of 24 (11-58) months. Of these, 87 (86%) patients were male, and the median age was 68 (57-76) years. Eighty-three (82%) patients had IgG4-related kidney disease confirmed by kidney biopsy, with all biopsies showing tubulointerstitial involvement and 16 showing glomerular lesions. Ninety (89%) patients were treated with corticosteroids, and 18 (18%) patients received rituximab as first-line therapy. At the last follow-up, the eGFR was below 30 ml/min per 1.73 m 2 in 32% of patients; 34 (34%) patients experienced a relapse, while 12 (13%) patients had died. By Cox survival analysis, the number of organs involved (hazard ratio [HR], 1.26; 95% confidence interval [CI], 1.01 to 1.55) and low C3 and C4 concentrations (HR, 2.31; 95% CI, 1.10 to 4.85) were independently associated with a higher risk of relapse, whereas first-line therapy with rituximab was protective (HR, 0.22; 95% CI, 0.06 to 0.78). At their last follow-up, 19 (19%) patients had an eGFR ≤30 ml/min per 1.73 m 2 . Age (odd ratio [OR], 1.11; 95% CI, 1.03 to 1.20), peak serum creatinine (OR, 2.74; 95% CI, 1.71 to 5.47), and serum IgG4 level ≥5 g/L (OR, 4.46; 95% CI, 1.23 to 19.40) were independently predictive for severe CKD. CONCLUSIONS: IgG4-related kidney disease predominantly affected middle-aged men and manifested as tubulointerstitial nephritis with potential glomerular involvement. Complement consumption and the number of organs involved were associated with a higher relapse rate, whereas first-line therapy with rituximab was associated with lower relapse rate. Patients with high serum IgG4 concentrations (≥5 g/L) had more severe kidney disease.
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Enfermedad Relacionada con Inmunoglobulina G4 , Nefritis Intersticial , Adulto , Persona de Mediana Edad , Humanos , Masculino , Anciano , Femenino , Enfermedad Relacionada con Inmunoglobulina G4/complicaciones , Enfermedad Relacionada con Inmunoglobulina G4/diagnóstico , Enfermedad Relacionada con Inmunoglobulina G4/tratamiento farmacológico , Rituximab/efectos adversos , Estudios de Cohortes , Pronóstico , Riñón/patología , Nefritis Intersticial/patología , Inmunoglobulina G , Recurrencia , Estudios RetrospectivosRESUMEN
Background: Lupus nephritis (LN) is a severe manifestation of Systemic Lupus Erythematosus (SLE). The therapeutic strategy relies on kidney biopsy (KB) results. We tested whether urinary peptidome analysis could non-invasively differentiate active from non-active LN. Design: Urinary samples were collected from 93 patients (55 with active LN and 38 with non-active LN), forming a discovery (n = 42) and an independent validation (n = 51) cohort. Clinical characteristics were collected at inclusion and prospectively for 24 months. The urinary peptidome was analyzed by capillary-electrophoresis coupled to mass-spectrometry, comparing active LN to non-active LN, and assessing chronic lesions and response to therapy. The value of previously validated prognostic (CKD273) and differential diagnostic (LN172) signatures was evaluated. Results: Urinary peptides could not discriminate between active and non-active LN or predict early response to therapy. Tubulo-interstitial fibrosis was correlated to the CKD273. The LN172 score identified 92.5% of samples as LN. Few patients developed new-onset CKD. Conclusions: We validated the CKD273 and LN172 classifiers but did not identify a robust signature that could predict active LN and replace KB. The value of urinary peptidome to predict long-term CKD, or renal flares in SLE, remains to be evaluated.
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Calpains, intracellular proteases specifically inhibited by calpastatin, play a major role in neoangiogenesis involved in tumor invasiveness and metastasis. They are partly exteriorized via the ATP-binding cassette transporter A1(ABCA1) transporter, but the importance of this process in tumor growth is still unknown. The aim of our study was to investigate the role of extracellular calpains in a model of melanoma by blocking their extracellular activity or exteriorization. In the first approach, a B16-F10 model of melanoma was developed in transgenic mice expressing high extracellular levels of calpastatin. In these mice, tumor growth was inhibited by â¼ 3-fold compared with wild-type animals. In vitro cytotoxicity assays and in vivo tumor studies have demonstrated that this protection was associated with a defect in tumor neoangiogenesis. Similarly, in wild-type animals given probenecid to blunt ABCA1 activity, melanoma tumor growth was inhibited by â¼ 3-fold. Again, this response was associated with a defect in neoangiogenesis. In vitro studies confirmed that probenecid limited endothelial cell migration and capillary formation from vascular explants. The observed reduction in fibronectin cleavage under these conditions is potentially involved in the response. Collectively, these studies demonstrate that probenecid, by blunting ABCA1 activity and thereby calpain exteriorization, limits melanoma tumor neoangiogenesis and invasiveness.
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Transportador 1 de Casete de Unión a ATP/antagonistas & inhibidores , Calpaína/metabolismo , Melanoma Experimental/tratamiento farmacológico , Neovascularización Patológica/tratamiento farmacológico , Probenecid/farmacología , Neoplasias Cutáneas/tratamiento farmacológico , Transportador 1 de Casete de Unión a ATP/genética , Transportador 1 de Casete de Unión a ATP/metabolismo , Animales , Proteínas de Unión al Calcio/genética , Proteínas de Unión al Calcio/metabolismo , Línea Celular Tumoral/trasplante , Proliferación Celular/efectos de los fármacos , Humanos , Masculino , Melanoma Experimental/irrigación sanguínea , Melanoma Experimental/patología , Ratones , Ratones Transgénicos , Neovascularización Patológica/patología , Probenecid/uso terapéutico , Neoplasias Cutáneas/irrigación sanguínea , Neoplasias Cutáneas/patologíaRESUMEN
Diabetic nephropathy is usually a presumptive diagnosis based on clinical and biological evidence. Renal biopsies are performed in diabetic patients with atypical findings evoking non-diabetic renal disease who could benefit from specific therapies. French speaking nephrologists were asked which criteria they retain to indicate renal biopsy in patients with type 2 diabetes and albuminuria>0.5g/day or equivalent through an online anonymous questionnaire. Among the suggested criteria were absence of diabetic retinopathy, hematuria, rapid decrease in GFR, short diabetes duration or rapid raise of proteinuria. 188 people answered the poll among whom interns (12%), fellows (13%), university hospital practitioners (26%), general hospital practitioners (24%), practitioners in a non-profit organization (13%), practitioners on private activity (10%), multi-modal practitioners (3%) and people without clinical activity (2%). Increasing proteinuria was retained as an indication criterion for renal biopsy by 51% of respondents, nephrotic syndrome by 56% of respondents, absence of diabetic retinopathy by 57% of respondents, short diabetes duration by 65% of respondents, rapid GFR decline by 75% of respondents and hematuria by 78% of respondents. These data highlight the high diversity of opinions on this topic and their discrepancies with guidelines and current literature regarding the association between non-diabetic renal disease and clinical and biological features. The lack of adhesion of nephrologists to guidelines was especially noteworthy regarding the absence of diabetic retinopathy. These results emphasize the need for studies focusing on biopsy indication criteria in patients with type 2 diabetes.
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Biopsia , Diabetes Mellitus Tipo 2/complicaciones , Nefropatías Diabéticas/patología , Enfermedades Renales/patología , Nefrólogos/estadística & datos numéricos , Pautas de la Práctica en Medicina , Proteinuria/patología , Adulto , Anciano , Nefropatías Diabéticas/diagnóstico , Nefropatías Diabéticas/etiología , Retinopatía Diabética , Diagnóstico Diferencial , Progresión de la Enfermedad , Femenino , Francia , Tasa de Filtración Glomerular , Adhesión a Directriz , Encuestas de Atención de la Salud , Humanos , Enfermedades Renales/diagnóstico , Enfermedades Renales/etiología , Masculino , Persona de Mediana Edad , Guías de Práctica Clínica como Asunto , Práctica Profesional , Proteinuria/etiologíaRESUMEN
RATIONALE: Malakoplakia is a rare disease characterized by the presence of nongranulomatous macrophage infiltration. In most cases, it affects the urinary tract. Malakoplakia can cause acute kidney injury when it is localized in the kidneys. PATIENT CONCERNS: Here, we report the case of a 65-year-old female patient with renal malakoplakia responsible for hypercalcemia. During her initial assessment, she was also diagnosed 25-OH vitamin D insufficiency, for which she was prescribed oral cholecalciferol. Three months later, she developed severe hypercalcemia with normal 25-OH vitamin D and parathyroid hormone levels and high 1,25-dihydroxyvitamin D levels. DIAGNOSES: After a superimposed granulomatous disease was excluded, malakoplakia cells were suspected to be responsible for the abnormal 25-hydroxyvitamin D3 1-alpha-hydroxylase activity, which was confirmed by immunohistochemistry. INTERVENTIONS: Cholecalciferol was stopped, the patient was rehydrated with intravenous physiological saline, and prednisone was initiated to decrease the enzyme activity. OUTCOMES: Six months later, she displayed normal serum calcium, 25-OH vitamin D and 1,25-dihydroxyvitamin D levels. LESSONS: This case illustrates that malakoplakia may exhibit ectopic 25-hydroxyvitamin D3 1-alpha-hydroxylase activity and cause severe hypercalcemia upon vitamin D supplementation. Therefore, such supplementation should not be given in malakoplakia patients without an actual deficiency and requires careful monitoring of serum calcium.
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25-Hidroxivitamina D3 1-alfa-Hidroxilasa/metabolismo , Hipercalcemia/genética , Enfermedades Renales/complicaciones , Malacoplasia/complicaciones , Deficiencia de Vitamina D/terapia , Anciano , Calcio/sangre , Colecalciferol/efectos adversos , Suplementos Dietéticos , Expresión Génica Ectópica , Femenino , Humanos , Enfermedades Renales/sangre , Enfermedades Renales/genética , Malacoplasia/sangre , Malacoplasia/genética , Hormona Paratiroidea/sangre , Deficiencia de Vitamina D/complicaciones , Vitaminas/efectos adversosRESUMEN
Calpains are ubiquitous pro-inflammatory proteases, whose activity is controlled by calpastatin, their specific inhibitor. Transgenic mice over-expressing rabbit calpastatin (CalpTG) are protected against vascular remodelling and angiotensin II-dependent inflammation. We hypothesized that specific calpain inhibition would protect against aging-related lesions in arteries and kidneys. We analysed tissues from 2-months and 2-years-old CalpTG and wild-type mice and performed high throughput RNA-Sequencing of kidney tissue in aged mice. In addition, we analysed inflammatory response in the kidney of aged CalpTG and wild-type mice, and in both in vivo (monosodium urate peritonitis) and in vitro models of inflammation. At two years, CalpTG mice had preserved kidney tissue, less vascular remodelling and less markers of senescence than wild-type mice. Nevertheless, CalpTG mice lifespan was not extended, due to the development of lethal spleen tumors. Inflammatory pathways were less expressed in aged CalpTG mice, especially cytokines related to NF-κB and NLRP3 inflammasome activation. CalpTG mice had reduced macrophage infiltration with aging and CalpTG mice produced less IL-1α and IL-1ß in vivo in response to inflammasome activators. In vitro, macrophages from CalpTG mice produced less IL-1α in response to particulate activators of inflammasome. Calpains inhibition protects against inflammaging, limiting kidney and vascular lesions related to aging.
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Envejecimiento/efectos de los fármacos , Proteínas de Unión al Calcio/farmacología , Calpaína/antagonistas & inhibidores , Inhibidores de Cisteína Proteinasa/farmacología , Peritonitis/tratamiento farmacológico , Animales , Arterias/efectos de los fármacos , Arterias/crecimiento & desarrollo , Proteínas de Unión al Calcio/uso terapéutico , Calpaína/metabolismo , Células Cultivadas , Inhibidores de Cisteína Proteinasa/uso terapéutico , Citocinas/metabolismo , Inflamasomas/metabolismo , Riñón/efectos de los fármacos , Riñón/crecimiento & desarrollo , Ratones , Ratones Endogámicos C57BL , FN-kappa B/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , ConejosRESUMEN
Antidiuretic hormone or arginine vasopressin (AVP) increases water reabsorption in the collecting ducts of the kidney. Three decades ago, experimental models have shown that AVP may increase calcium reabsorption in rat kidney. The objective of this study was to assess whether AVP modulates renal calcium excretion in humans. We analyzed calcium, potassium, and sodium fractional excretion in eight patients affected by insipidus diabetes (nephrogenic or central) under acute vasopressin receptor agonist action and in 10 patients undergoing oral water load test affected or not by inappropriate antidiuretic hormone secretion (SIADH). Synthetic V2 receptor agonist (dDAVP) reduced significantly calcium fractional excretion from 1.71% to 0.58% (P < 0.05) in patients with central diabetes insipidus. In patients with nephrogenic diabetes insipidus (resistant to AVP), calcium fractional excretion did not change significantly after injection (0.48-0.68%, P = NS). In normal subjects undergoing oral water load test, calcium fractional excretion increased significantly from 1.02% to 2.54% (P < 0.05). Patients affected by SIADH had a high calcium fractional excretion at baseline that remained stable during test from 3.30% to 3.33% (P = NS), possibly resulting from a reduced calcium absorption in renal proximal tubule. In both groups, there was a significant correlation between urine output and calcium renal excretion. In humans, dDAVP decreases calcium fractional excretion in the short term. Conversely, water intake, which lowers AVP concentration, increases calcium fractional excretion. The correlation between urine output and calcium excretion suggests that AVP-related antidiuresis increases calcium reabsorption in collecting ducts.
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Lactamas Macrocíclicas/efectos adversos , Nefrosis Lipoidea/inducido químicamente , Adenocarcinoma del Pulmón/tratamiento farmacológico , Aminopiridinas , Femenino , Humanos , Lactamas , Neoplasias Pulmonares/tratamiento farmacológico , Persona de Mediana Edad , Nefrosis Lipoidea/patología , PirazolesRESUMEN
Conventional calpains are ubiquitous cysteine proteases whose activity is promoted by calcium signaling and specifically limited by calpastatin. Calpain expression has been shown to be increased in human malignant cells, but the contribution of the calpain/calpastatin system in tumorigenesis remains unclear. It may play an important role in tumor cells themselves (cell growth, migration, and a contrario cell death) and/or in tumor niche (tissue infiltration by immune cells, neo-angiogenesis). In this study, we have used a mouse model of melanoma as a tool to gain further understanding of the role of calpains in tumor progression. To determine the respective importance of each target, we overexpressed calpastatin in tumor and/or host in isolation. Our data demonstrate that calpain inhibition in both tumor and host blunts tumor growth, while paradoxically increasing metastatic dissemination to regional lymph nodes. Specifically, calpain inhibition in melanoma cells limits tumor growth in vitro and in vivo but increases dissemination by amplifying cell resistance to apoptosis and accelerating migration process. Meanwhile, calpain inhibition restricted to host cells blunts tumor infiltration by immune cells and angiogenesis required for antitumor immunity, allowing tumor cells to escape tumor niche and disseminate. The development of highly specific calpain inhibitors with potential medical applications in cancer should take into account the opposing roles of the calpain/calpastatin system in initial tumor growth and subsequent metastatic dissemination.