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- / Background: Endothelin-1 (ET-1), a strong vasoconstrictive substance acting via stimulation of specific receptors (ET-A and ET-B), has been implicated in the development of renal scarring. Activation of endothelin system was observed in experimental models of glomerular diseases and this was attributed to the toxic action of proteinuria to the tubular epithelial cells. However, we have not enough information about the role of endothelin system in human glomerular diseases and in renal diseases without proteinuria like obstructive nephropathy. The aim of this study was to examine the endothelin system in patients with primary glomerular diseases and in experimental animals with unilateral ureteric obstruction. Patients and Methods: Thirty-seven patients with different types of primary glomerulonephritides and 14 controls were included in the study. Patients presented by either nephrotic syndrome (n=25) or mild proteinuria (<1g/24h, n=12). The expression of ET-A and ET-B receptors in the renal tissue was examined immunohistochemically. At the time of biopsy, urinary ET-1 was determined by RIA. Experimental animals and Methods: Twenty –day old opossum pups (n=6) underwent surgical ligation of the left ureter. Sham operated animals, non-operated controls and normal human kidneys were also used. Animals were sacrificed at 2 (n=2), 3 (n=1), 4 (n=1), 5(n=1) and 8 (n=1) weeks post surgery and their kidneys were examined. Sham operation was performed at equivalent times in pups that served as control. The expression of ET-A and ET-B receptors in the renal tissue was examined immunohistochemically. Results: The expression of both receptors was mainly localized within tubular epithelial cells and was significantly higher in patients with glomerulonephritides compared to controls. The expression of ET-B receptors was higher in nephrotic compared to non-nephrotic patients while no difference was observed in the expression of ET-A receptors. Urinary excretion of ET-1 was increased in patients compared to healthy subjects (579±146 ng/24h vs. 410±78 ng/24h, p<0.01) and it was higher in nephrotic compared to non-nephrotic patients (617±167 ng/24h vs. 485±71 ng/24h, p<0.05). A significant positive correlation of the excreted ET-1 with the degree of proteinuria (r= 0.338, p<0.05) and the extent of immunostaining for ET-B receptors (r=0.427, p<0.05) was observed. The expression of ET-B receptors and the excretion of ET-1 were significantly decreased in patients who present remission of the nephrotic syndrome under immunosuppressive therapy. In tubular epithelial cells of the experimental animals there was a temporal increase in the expression of ET-A receptors with duration of obstruction while there was no significant difference between the expression of ET-B receptors in obstructed kidneys and controls. Conclusions: this study provides evidence that the endothelin system is activated in renal diseases and proteinuria seems to be related only in part to this activation. Further investigation is needed to ascertain if the activation of endothelin system has a causative role in the progression of renal diseases.

Made available in DSpace on 2014-06-11T19:23:05Z (GMT). No. of bitstreams: 0 Previous issue date: 2012-06-12Bitstream added on 2014-06-13T20:49:56Z : No. of bitstreams: 1 assis_rp_me_arafcf.pdf: 669368 bytes, checksum: 5167073ebf2654252dd757e5430bcd0c (MD5) / Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) / Universidade Estadual Paulista (UNESP) / Em pacientes com doença renal crônica é observado à presença de estresse oxidativo e a exacerbação desse estresse com o tratamento hemodialítico, bem como tem se postulado a ação antioxidante de alguns solutos urêmicos. Esse contexto instigou-nos explorar, a ação antioxidante dos solutos urêmicos: L-arginina, Ácido Úrico, Ácido Hipúrico, Creatinina, Fenol, Metilguanidina, p-Cresol, L-tirosina e Uréia, utilizando sistemas-modelo in vitro. Quatro desses solutos mostraram eficiência (expressa via o IC50 em µmol/L) para os sistemas-modelo: Capacidade de captura sobre o ABTS + , p-Cresol (3,99 ± 0,01), L-tirosina (5,23 ± 0,02), Fenol (12,98 ± 0,09) e o Ácido Úrico (16,75 ± 0,14); Capacidade de captura sobre o HOCl / OCl -, L-tirosina (2,83 ± 0,04), Ácido Úrico (5,75 ± 0,13), Fenol (8,95 ± 0,10) e p- Cresol (15,75 ± 0,12), e o bleaching da crocina (lipoperoxidação), Ácido Úrico (6,90), Fenol (1125,81) e p-Cresol (1162,31). Em relação à capacidade de captura sobre o Ânion Radical Superóxido e o Peróxido de Hidrogênio nenhum dos solutos apresentou atividade significativa. Em todos os ensaios onde não foi observada atividade antioxidante, investigou-se desde concentrações fisiológicas, urêmicas e até 10 vezes maior que as concentrações urêmicas médias. Como os solutos urêmicos, Ácido Úrico, p-Cresol, Fenol e L-tirosina capturaram significativamente as espécies reativas, ABTS + , HOCl / OCl - e ROO  , estudou-se o comportamento da mistura desses solutos, tendo como referência o IC50 de cada soluto. Obteve-se nos ensaios de captura do ABTS + e do HOCl / OCl - os IC50, como uma fração de concentração de 26 e 27%, respectivamente, para cada soluto na mistura, o que demonstrou um efeito aditivo... / Patients with chronic kidney disease suffer from oxidative stress and this stress is exacerbated by hemodialysis. It has been postulated that some uremic solutes have antioxidant effects. This context prompted us to explore the antioxidant action of the uremic solutes: L-arginine, uric acid, hippuric acid, creatinine, phenol, methylguanidine, p-cresol, L-tyrosine and urea, by means of 5 in vitro model systems. Only four of these solutes were effective antioxidants (assessed by their IC50 in µmol/L) in 3 model systems: ABTS + scavenging: p-cresol (3.99±0.01), L-tyrosine (5.23±0.02), phenol (12.98±0.09) and uric acid (16.75±0.14); hypochlorous acid scavenging: L-tyrosine (2.83±0.04), uric acid (5.75±0.13), phenol (8.95±0.10) and p-cresol (15.75±0.12); and crocin bleaching (lipoperoxidation): uric acid (6.90), phenol (1,125.81) and p-cresol (1,162.31). In tests with the superoxide radical anion and hydrogen peroxide, none of the solutes showed antioxidant activity. In each of the assays in which no activity was detected, tests were carried out over a range of solute concentrations, from normal physiological levels, through typical uremic up to ten times higher than mean uremic concentrations. As the 4 uremic solutes, uric acid, p-cresol, phenol and L-tyrosine showed significant scavenging activity for 3 reactive species, ABTS + , HOCl / OCl - and ROO  , the behavior of mixture of these solutes was investigated, with reference to the IC50 of each solute. In the ABTS + and HOCl / OCl - scavenging assays, the IC50 involved a concentration of 26% and 27%, respectively, of each solute in the mixture, demonstrating... (Complete abstract click electronic access below)

A sobrecarga de proteínas nas células tubulares proximais pode levar a lesão intersticial por mecanismos não claros que podem envolver a ativação da imunidade inata. Nós investigamos a hipótese de que a exposição prolongada de células tubulares a altas concentrações de proteínas estimula a imunidade inata, desencadeando inflamação intersticial progressiva e lesão renal. Além disso, investigamos se a inibição específica da imunidade inata ou adaptativa proporcionaria renoproteção em um modelo estabelecido de proteinúria maciça, nefropatia por adriamicina (ADR). Os ratos adultos Munich-Wistar receberam uma dose única de ADR (5 mg / kg iv), sendo acompanhados por 2, 4 e 20 semanas. A albuminúria maciça foi associada à ativação precoce das vias da imunidade inata NF-?B e NLRP3, cuja intensidade correlacionou-se fortemente com a densidade da infiltração de linfócitos. Além disso, os ratos ADR exibiram sinais claros de estresse oxidativo renal. Vinte semanas após a administração de ADR, observaram-se fibrose intersticial intensa, glomerulosclerose e perda da função renal. A administração de micofenolato de mofetil (MMF), 10 mg / Kg / dia, impediu a ativação da imunidade inata e adaptativa, bem como do estresse oxidativo renal e fibrose renal. Além disso, o tratamento MMF foi associado com a mudança de MØ do tipo M1 para o fenótipo M2. Nas células cultivadas de NRK52-E, o excesso de albumina aumentou o teor de proteína de TLR4, NLRP3, Caspase-1, IL6, IL1-beta, MCP-1, alfa-SMA e COLL-1. O silenciamento do TLR4 e / ou NLRP3 mRNA atenuou esse comportamento proinflamatório / profibrótico. A ativação simultânea de imunidade inata e adaptativa podem ser fundamentais para o desenvolvimento de lesão renal em doenças altamente proteinúricas. A inibição da imunidade inata e/ou adaptativa podem constituir uma estratégia para prevenir a DRC nesse contexto / Protein overload of proximal tubular cells can promote interstitial injury by unclear mechanisms that may involve activation of innate immunity. We investigated the hypothesis that prolonged exposure of tubular cells to high protein concentrations stimulates innate immunity, triggering progressive interstitial inflammation and renal injury. In addition, we investigated whether specific inhibition of innate or adaptive immunity would provide renoprotection in an established model of massive proteinuria, adriamycin (ADR) nephropathy. Adult male Munich-Wistar rats received a single dose of ADR (5 mg/kg iv), being followed for 2, 4 or 20 weeks. Massive albuminuria was associated with early activation of both the NF-kB and NLRP3 innate immunity pathways, whose intensity correlated strongly with the density of lymphocyte infiltration. In addition, ADR rats exhibited clear signs of renal oxidative stress. Twenty weeks after ADR administration, marked interstitial fibrosis, glomerulosclerosis and renal functional loss were observed. Administration of mycophenolate mofetil (MMF), 10 mg/Kg/day, prevented activation of both innate and adaptive immunity, as well as renal oxidative stress and renal fibrosis. Moreover, MMF treatment was associated with shifting of M0 from the M1 to the M2 phenotype. In cultivated NRK52-E cells, excess albumin increased the protein content of TLR4, NLRP3, Caspase-1, IL6, IL- 1beta, MCP-1, alpha-actin and collagen-1. Silencing of TLR4 and/or NLRP3 mRNA abrogated this proinflammatory/profibrotic behavior. Simultaneous activation of innate and adaptive immunity may be key to the development of renal injury in heavily proteinuric disease. Inhibition of innate and/or adaptive immunity may constitute a strategy to prevent CKD in this setting

Les maladies rénales ont un impact socio-économique majeur sur la santé publique nécessitant le développement de nouvelles stratégies thérapeutiques. Le Récepteur à Domaine Discoïdine de type 1 (DDR1) est un récepteur non-intégrine des collagènes, à activité tyrosine-kinase. Son expression anormale est un facteur clé de la pathologie rénale qui promeut le développement de l’inflammation et de la fibrose.Ces travaux de thèse nous ont permis de démontrer que l'inhibition de DDR1 freinait la progression des maladies rénales dans trois modèles, dont l'un d'évolution aiguë, l'ischémie-reperfusion (I/R). Après I/R, les cellules épithéliales tubulaires proximales (CETP) exprimaient anormalement DDR1 et l'inhibition de ce récepteur empêchait l'acquisition d'un phénotype pro-inflammatoire par ce type cellulaire. Nous avons démontré in vitro que le stress du réticulum endoplasmique (RE), secondaire à l'hypoxie, était responsable de l'induction de DDR1, via l'activation du facteur de transcription CHOP. De plus, le profil d'expression de DDR1 dans des biopsies de patients transplantés était similaire à celui obtenu dans l'I/R expérimentale.Enfin, les résultats préliminaires obtenus dans un nouveau modèle de souris triples transgéniques ont montré l'installation d'une inflammation et d'une fibrose rénales secondaires à la surexpression génétiquement définie de DDR1 durant 4 semaines dans les cellules épithéliales tubulaires.En conclusion, nos résultats suggèrent que la surexpression de DDR1 joue un rôle délétère dans les néphropathies chroniques et aiguës, ce qui renforce l’intérêt du développement d’inhibiteurs spécifiques de DDR1 capables de bloquer la fonction de ce récepteur. / Renal diseases lead to severe long-term complications of kidney function and only few preventive and therapeutic options exist. Discoidin Domain Receptor 1 (DDR1) is a non-integrin collagen receptor expressed in several cell types within the kidney. Its abnormal expression has a deleterious role in experimental chronic kidney diseases (CKD) by promoting renal inflammation and fibrosis.The inhibition of DDR1 stopped the progression of renal disease in two models of experimental CKD and protected renal function and structure in a model of acute kidney disease, ischemia-reperfusion (I/R). DDR1 expression was strongly induced in proximal epithelial tubular cells (PETCs) after I/R. Moreover, isolated PETCs from DDR1 heterozygous mice after I/R did not acquire the pro-inflammatory phenotype displayed by PETCs from WT mice. Endoplasmic reticulum (ER) stress was responsible for DDR1 pathological expression in hypoxic PETCs after I/R through the activation of CHOP transcription factor. Interestingly, biopsies of transplant patients with prolonged ischemia during transplantation had a very similar expression profile of DDR1 in proximal tubules as in experimental I/R.Finally, DDR1 overexpression in epithelial tubular cells for four weeks, in a new conditional transgenic mouse model, led to the development of renal inflammation and fibrosis.To conclude, our results suggest that the genetically-induced or the pathological overexpression of DDR1 promotes renal inflammation and fibrosis. Thus, targeting DDR1 can be a promising strategy in the treatment of renal diseases.

Orientador: Iguatemy Lourenço Brunetti / Banca: Mariza Pires de Melo / Banca: Eduardo Maffud Cilli / Resumo: Em pacientes com doença renal crônica é observado à presença de estresse oxidativo e a exacerbação desse estresse com o tratamento hemodialítico, bem como tem se postulado a ação antioxidante de alguns solutos urêmicos. Esse contexto instigou-nos explorar, a ação antioxidante dos solutos urêmicos: L-arginina, Ácido Úrico, Ácido Hipúrico, Creatinina, Fenol, Metilguanidina, p-Cresol, L-tirosina e Uréia, utilizando sistemas-modelo in vitro. Quatro desses solutos mostraram eficiência (expressa via o IC50 em µmol/L) para os sistemas-modelo: Capacidade de captura sobre o ABTS + , p-Cresol (3,99 ± 0,01), L-tirosina (5,23 ± 0,02), Fenol (12,98 ± 0,09) e o Ácido Úrico (16,75 ± 0,14); Capacidade de captura sobre o HOCl / OCl -, L-tirosina (2,83 ± 0,04), Ácido Úrico (5,75 ± 0,13), Fenol (8,95 ± 0,10) e p- Cresol (15,75 ± 0,12), e o bleaching da crocina (lipoperoxidação), Ácido Úrico (6,90), Fenol (1125,81) e p-Cresol (1162,31). Em relação à capacidade de captura sobre o Ânion Radical Superóxido e o Peróxido de Hidrogênio nenhum dos solutos apresentou atividade significativa. Em todos os ensaios onde não foi observada atividade antioxidante, investigou-se desde concentrações fisiológicas, urêmicas e até 10 vezes maior que as concentrações urêmicas médias. Como os solutos urêmicos, Ácido Úrico, p-Cresol, Fenol e L-tirosina capturaram significativamente as espécies reativas, ABTS + , HOCl / OCl - e ROO  , estudou-se o comportamento da mistura desses solutos, tendo como referência o IC50 de cada soluto. Obteve-se nos ensaios de captura do ABTS + e do HOCl / OCl - os IC50, como uma fração de concentração de 26 e 27%, respectivamente, para cada soluto na mistura, o que demonstrou um efeito aditivo... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Patients with chronic kidney disease suffer from oxidative stress and this stress is exacerbated by hemodialysis. It has been postulated that some uremic solutes have antioxidant effects. This context prompted us to explore the antioxidant action of the uremic solutes: L-arginine, uric acid, hippuric acid, creatinine, phenol, methylguanidine, p-cresol, L-tyrosine and urea, by means of 5 in vitro model systems. Only four of these solutes were effective antioxidants (assessed by their IC50 in µmol/L) in 3 model systems: ABTS + scavenging: p-cresol (3.99±0.01), L-tyrosine (5.23±0.02), phenol (12.98±0.09) and uric acid (16.75±0.14); hypochlorous acid scavenging: L-tyrosine (2.83±0.04), uric acid (5.75±0.13), phenol (8.95±0.10) and p-cresol (15.75±0.12); and crocin bleaching (lipoperoxidation): uric acid (6.90), phenol (1,125.81) and p-cresol (1,162.31). In tests with the superoxide radical anion and hydrogen peroxide, none of the solutes showed antioxidant activity. In each of the assays in which no activity was detected, tests were carried out over a range of solute concentrations, from normal physiological levels, through typical uremic up to ten times higher than mean uremic concentrations. As the 4 uremic solutes, uric acid, p-cresol, phenol and L-tyrosine showed significant scavenging activity for 3 reactive species, ABTS + , HOCl / OCl - and ROO  , the behavior of mixture of these solutes was investigated, with reference to the IC50 of each solute. In the ABTS + and HOCl / OCl - scavenging assays, the IC50 involved a concentration of 26% and 27%, respectively, of each solute in the mixture, demonstrating... (Complete abstract click electronic access below) / Mestre

A sobrecarga de proteínas nas células tubulares proximais pode levar a lesão intersticial por mecanismos não claros que podem envolver a ativação da imunidade inata. Nós investigamos a hipótese de que a exposição prolongada de células tubulares a altas concentrações de proteínas estimula a imunidade inata, desencadeando inflamação intersticial progressiva e lesão renal. Além disso, investigamos se a inibição específica da imunidade inata ou adaptativa proporcionaria renoproteção em um modelo estabelecido de proteinúria maciça, nefropatia por adriamicina (ADR). Os ratos adultos Munich-Wistar receberam uma dose única de ADR (5 mg / kg iv), sendo acompanhados por 2, 4 e 20 semanas. A albuminúria maciça foi associada à ativação precoce das vias da imunidade inata NF-?B e NLRP3, cuja intensidade correlacionou-se fortemente com a densidade da infiltração de linfócitos. Além disso, os ratos ADR exibiram sinais claros de estresse oxidativo renal. Vinte semanas após a administração de ADR, observaram-se fibrose intersticial intensa, glomerulosclerose e perda da função renal. A administração de micofenolato de mofetil (MMF), 10 mg / Kg / dia, impediu a ativação da imunidade inata e adaptativa, bem como do estresse oxidativo renal e fibrose renal. Além disso, o tratamento MMF foi associado com a mudança de MØ do tipo M1 para o fenótipo M2. Nas células cultivadas de NRK52-E, o excesso de albumina aumentou o teor de proteína de TLR4, NLRP3, Caspase-1, IL6, IL1-beta, MCP-1, alfa-SMA e COLL-1. O silenciamento do TLR4 e / ou NLRP3 mRNA atenuou esse comportamento proinflamatório / profibrótico. A ativação simultânea de imunidade inata e adaptativa podem ser fundamentais para o desenvolvimento de lesão renal em doenças altamente proteinúricas. A inibição da imunidade inata e/ou adaptativa podem constituir uma estratégia para prevenir a DRC nesse contexto / Protein overload of proximal tubular cells can promote interstitial injury by unclear mechanisms that may involve activation of innate immunity. We investigated the hypothesis that prolonged exposure of tubular cells to high protein concentrations stimulates innate immunity, triggering progressive interstitial inflammation and renal injury. In addition, we investigated whether specific inhibition of innate or adaptive immunity would provide renoprotection in an established model of massive proteinuria, adriamycin (ADR) nephropathy. Adult male Munich-Wistar rats received a single dose of ADR (5 mg/kg iv), being followed for 2, 4 or 20 weeks. Massive albuminuria was associated with early activation of both the NF-kB and NLRP3 innate immunity pathways, whose intensity correlated strongly with the density of lymphocyte infiltration. In addition, ADR rats exhibited clear signs of renal oxidative stress. Twenty weeks after ADR administration, marked interstitial fibrosis, glomerulosclerosis and renal functional loss were observed. Administration of mycophenolate mofetil (MMF), 10 mg/Kg/day, prevented activation of both innate and adaptive immunity, as well as renal oxidative stress and renal fibrosis. Moreover, MMF treatment was associated with shifting of M0 from the M1 to the M2 phenotype. In cultivated NRK52-E cells, excess albumin increased the protein content of TLR4, NLRP3, Caspase-1, IL6, IL- 1beta, MCP-1, alpha-actin and collagen-1. Silencing of TLR4 and/or NLRP3 mRNA abrogated this proinflammatory/profibrotic behavior. Simultaneous activation of innate and adaptive immunity may be key to the development of renal injury in heavily proteinuric disease. Inhibition of innate and/or adaptive immunity may constitute a strategy to prevent CKD in this setting

Les progrès thérapeutiques ont conduit à une augmentation de la survie à 5 ans des enfants traités pour un un cancer et qui dépasse actuellement 80%. En France il a été estimé que 50 000 adultes guéris d’un cancer pédiatrique, mais la prévalence des complications à long terme causées par la maladie et par ses traitement dépasse 60% après un suivi de 30 ans. L’objectif général de cette thèse était de faire avancer les connaissances actuelles sur la mortalité et la morbidité à long terme liées aux cancers pédiatriques.Avec les données de la cohorte FCCSS (French Childhood Cancer Survivor Study) qui inclut des sujets ayant été traités pour entre 1946 et 2000 pour un cancer pédiatrique solide, nous avons observé que le risque de mortalité chez ces patients demeure plus élevé que la population générale même à plus de 40 ans après le diagnostic de leur premier cancer. D’autre part, la mortalité liée plus aux effets à long terme des traitements anticancéreux, plus spécifiquement les seconds cancers et maladies circulatoires, a significativement baissé parmi les sujets traités plus récemment.Par ailleurs, nous avons aussi confirmé le rôle des anthracyclines dans la survenue de l’insuffisance cardiaque et montré que la fraction du volume médian du cœur ayant reçu 30 Gray était beaucoup plus élevés chez les sujets ayant développé une insuffisance cardiaque par rapport aux autres. Nous avons aussi observé que des faibles volumes du cœur (10% du volume du ventricule gauche) ayant reçus ≥30 Gy sont associés à un risque élevé de développer une insuffisance cardiaque. Cette étude est la première à rapporter une relation dose-effet basée sur des indicateurs dose-volume et ces résultats peuvent être utilisés dans la pratique clinique couranteNos travaux ont aussi montré que les patients ayant subi une néphrectomie unilatérale étaient à risque de développer une maladie rénale chronique à très long terme. L’effet de la dose de radiation reçue aux reins différait selon si les patients ayant subi une néphrectomie unilatérale ou non . En effet, une dose au seul rein même <5Gy était associée à un risque élevé de dysfonctionnement rénal. Par ailleurs, grâce aux données du registre REIN, nous avons pu montrer que l’incidence de l’insuffisance rénale terminale liée aux anticancéreux était en train d’augmenter au fil des années. Cependant ces patients étaient moins inscrits en liste d'attente comparés à d’autres malades rénaux et avaient par conséquent un accès très limité à la transplantation rénale.En conclusion, le travail effectué courant cette thèse pourrait aider à identifier les patients à risque accru de complications tardives majeures liées aux traitements anticancéreux. Nos résultats pourraient être utilisés dans la pratique clinique courante pour l’adaptation de la prise en charge thérapeutique des enfants atteints de cancer et pour les recommandations de leurs suivi à long terme. / Advances in treatment have increased the overall 5-year survival rate for childhood cancers to approximately 80%. In France, it estimated that about 50,000 adults have survived childhood cancer. However, previous studies have demonstrated that by the second decade of life, more than 60% of survivor of childhood malignancies (CCS) will suffer from at least one chronic disease related to the treatment they have received.The general objective of this thesis was to advance knowledge about the very long morbidity associated with childhood cancer, with the ultimate target to improve both the long term outcome and quality of life of survivors.Using data from the French Childhood Cancer Survivor Study (FCCSS) cohort, which includes patients treated for a solid pediatric malignancy between 1942 and 2000, we found that that mortality among CCS remained higher than the general population even after more than 40 years of the primary cancer diagnosis. A major finding of this study was that mortality attributed to adverse effects of cancer treatments (secondary primary neoplasm and circulatory disease) declined among patients treated in more recent treatment periods. We also conducted a case control study nested in the FCCSS cohort and further affirmed the role of anthracycline in the occurrence of heart failure. We demonstrated that the median heart volume that received at least 30Gy was higher among heart failure cases and that exposing small volumes of the heart (10% of the volume of the left ventricle) to at least 30Gy was associated with an elevated risk of cardiac failure. This study was the first to derive a dose response relationship based on dose-volume metrics which can be used in current clinical practice.Our results also showed that unilateral nephrectomy was associated with a high risk of renal impairment. The effect of radiation dose to the kidneys was also different among nephrectomized patients for whom any exposure to radiation was associated with an elevated risk of chronic kidney disease even at doses less than 5 Gy.Furthermore, data from the renal epidemiology and information network (REIN) registry allowed us to investigated ESKD (end stage kidney disease) related to nephrotoxic chemotherapy and/or radiation. Our registry-based study showed that ESKD related to nephrotoxic cancer treatment has been steadily increasing over the past decade in the French population. These patients experienced a much lower rate of wait-listing than matched controls with other causes of ESKD, despite similar survival on dialysis.To conclude the results of this thesis are useful to identify survivors of childhood malignancies who are at risk of developing severe long term adverse effects related to the treatment of their primary cancer. Our results could be applied in current clinical practice to help adapt current treatment strategies and improve the long-term follow-up recommendations of childhood cancer survivors.