No description available.

Chronic kidney disease is an urgent public health problem in the U.S., affecting 15% of all adults, and more than 740,000 have progressed to end-stage renal disease (ESRD), requiring life-sustaining renal replacement therapy (RRT). ESRD has devastating health, quality-of-life, and economic consequences, rendering most patients unable to maintain employment and costing Medicare $36 billion in 2017. Arguably, the most disadvantaged subgroup is the subset of patients that received no or minimal pre-ESRD nephrology care, which currently accounts for one third of the total ESRD population. This subgroup suffers increased morbidity and mortality, and has limited access to kidney transplantation, the optimal RRT. Despite this subgroup representing a large minority of the ESRD patient population, there has been no U.S.-based examination of their ESRD diagnosis experiences, coping styles and strategies, and RRT decision-making preferences. Therefore, we conducted a study that compared the ESRD diagnosis experiences, coping styles and strategies, and RRT decision-making preferences among patients with varying amounts of pre-ESRD nephrology care. We also assessed nephrologists’ current practices and perspectives on the manner and timing of RRT education for patients with varying amounts of pre-ESRD care. This mixed methods study provides a comprehensive understanding of the diagnosis experiences, coping styles and strategies, and RRT decision-making preferences of patients facing sudden and unexpected ESRD diagnosis. The study contributes important knowledge about this subgroup of patients that can influence and improve health care delivery. The results of this research will inform future intervention-based investigations to improve care for patients with minimal or no pre-ESRD nephrology care. / Public Health

<p> Physical activity improves physical and psychological functioning in patients with chronic kidney disease (CKD). However, no studies have investigated the determinants of physical activity in the CKD population. The purpose of the study was to evaluate the utility of the Theory of Planned Behaviour (TPB) for understanding physical activity in the CKD population. A secondary purpose of this study was to examine alternate conceptualizations of the subjective norm construct within the TPB framework. We hypothesized that attitude, subjective norm (injunctive and descriptive norms), perceived behavioural control (PBC), and social support would predict intention to engage in physical activity and that both intention and PBC would predict physical activity behaviour.</p> <p> Participants (52 male, 28 female, mean age = 68.43 (13.21)) were recruited from nephrologists' clinics and were all predialysis (mean serum creatinine = 310.55 (148.75) μmol/L). Participants completed a questionnaire assessing attitude, subjective norm, PBC, and social support. One week later, participants were phoned for a follow-up interview to assess their physical activity during the preceding week.</p> <p> In a regression model, 61% of the variance in intention to perform physical activity was explained, with PBC (β=.69,p<.001) emerging as the sole significant predictor, while attitude (β=.17, p=.10), subjective norm (β=.02, p=.89), informational support from family (β=-.10,p=.33), and informational support from doctors (β=-.05, p=.54) were non-significant predictors. In a regression model to explain physical activity, 28% of the variance in physical activity was explained, with intention emerging as a significant predictor (β=.53, p=.02), but not PBC (β=.18, p=.29).</p> <p> The hypotheses were only partially supported, as PBC emerged as a significant predictor of physical activity intention, while attitude, subjective norm, and social support did not. Furthermore, intention, but not PBC, predicted physical activity behaviour. These results demonstrate the utility of the TPB for explaining physical activity in the CKD population. Additional research is required to clarify if targeting PBC may be an effective means for intervention to increase physical activity in the CKD population.</p> / Thesis / Master of Science (MSc)

The global prevalence of chronic kidney disease (CKD) has risen at an accelerating rate, increasing the global healthcare burden for long-term and chronic care costs. Multiple risk factors including hypertension, diabetes, and dyslipidemia synergistically induce the progression of CKD. Chief among these factors are dyslipidemia and obesity; increased free fatty acid uptake due to excess consumption of lipid-rich diets has been shown to promote intra-renal lipid accumulation in several in vivo models and in patients in various stages of CKD. Furthermore, patients with renal disease are also at a substantially higher risk for atherosclerotic cardiovascular disease (CVD). In the general population, as well as in patients with renal disease, circulating low-density lipoprotein cholesterol (LDLc) is a well-established driver of atherosclerotic lesion development and CVD progression. In 2003, the proprotein convertase subtilisin/kexin type-9 (PCSK9) was identified as the third locus of familial hypercholesterolemia and was further characterized for its ability to enhance the degradation of the low-density lipoprotein receptor (LDLR). Since this seminal discovery, the development of monoclonal antibodies targeted against PCSK9 demonstrated a significant reduction in LDLc and subsequent CVD risk, establishing the remarkable ‘bench to bedside’ transition. However, the inherent role of PCSK9 in regulating lipid homeostasis remained unknown in different pathological conditions. In the first chapter of my thesis, I demonstrate that PCSK9 regulates the LDLR as a feedback mechanism to protect against non-alcoholic steatohepatitis (NASH) progression induced by a high-fat diet (HFD) challenge. Since its seminal discovery, PCSK9 was also characterized to modulate a wide variety of receptors known to play a crucial role in lipid metabolism including the cluster of differentiation 36 (CD36), the very low-density lipoprotein receptor (VLDLR), and the apolipoprotein E receptor 2 (ApoER2). Previously, we have demonstrated that the absence of PCSK9 promotes diet-induced non-alcoholic steatohepatitis and liver injury through increased surface expression of CD36. Given that these same receptors are well-expressed on renal epithelia, the second chapter of my thesis demonstrates that PCSK9 is also able to modulate renal lipid metabolism by attenuating tubular lipid accumulation and subsequent renal injury. Furthermore, when PCSK9 was first characterized by Seidah and colleagues in 2003, in situ hybridization of murine PCSK9 demonstrated that it was primarily expressed in the liver, but also well-expressed in the kidney cortex, cerebellum, and small intestines. Despite its expression in a wide range of tissues, the secretion of PCSK9 was exclusive to the liver, thus, questioning what the intracellular role of PCSK9 may be. Hence, my last chapter of my masters studies lies in establishing the role of intracellular PCSK9 expression in a cellular process known as endoplasmic reticulum (ER) stress in the kidney. ER stress is a phenomena which primarily occurs due to increased accumulation of misfolded polypeptides, and has been implicated in numerous metabolic diseases including hepatic steatosis, CKD, and neurodegenerative pathologies. Previously, we have demonstrated that overexpressing wild-type and variants of PCSK9 in a Pcsk9-/- mouse does not induce the activation of the unfolded protein response (UPR) and attenuates hepatic ER stress. Using a well-established CKD model, I show that Pcsk9-/- mice exhibit increased renal ER stress and injury relative to wild-type controls. Overall, my findings demonstrate for the first time that both extracellular and intracellular PCSK9 has the ability to modulate renal injury using two distinct mechanism to protect against CKD progression. / Thesis / Master of Health Sciences (MSc)

The prevalence of diabetes is sufficiently high to be classified as an epidemic, and 20-40% of these patients are expected to develop diabetic nephropathy, a leading cause of end-stage renal failure. Studies have identified a correlation between diabetic nephropathy and hypoxia in renal tissue in human studies. Increased oxygen consumption has been associated with the proton transport protein, uncoupling protein-2 (UCP-2), which uncouples the mitochondria. Previous research has reported elevated levels of UCP-2 in diabetic renal tissue. Consequently, it is crucial to determine how different preservation methods affect the detectability of UCP-2 in renal tissue for clinical applications. This study aimed to evaluate the effectiveness of Western blotting for detecting UCP-2 in snap frozen, fresh untreated, formalin-fixed, methyl carnoy-fixed, and RNA later-preserved rat kidneys. Preliminary trials were conducted to identify the optimal antibody combinations, followed by testing on various preserved tissues. The antibodies produced non-reproducible, unspecific, and unselective results. Additionally, technical challenges, such as gels adhering to membranes and low protein concentrations in some samples, rendered the results inconclusive. Further investigations are necessary to explore additional antibodies and variables that may influence the detection of UCP-2 in differently preserved tissues. Overall, this study highlights the complexity and challenges in developing reliable protocols for UCP-2 detection in preserved renal tissue, indicating that significant optimization is still required for consistent results.

Diabetes mellitus and its complications stands as arguably the most formidable pandemic of the 21st century. While rodent models of diabetes mellitus have been extensively explored, none have managed to faithfully replicate the full spectrum of pathological hallmarks and secondary complications witnessed in diabetic patients. Among the commonly affected organs is the kidney, manifesting in the form of diabetic kidney disease (DKD). Recently, our clinical understanding of incretins as critical regulators of disease progression in diabetic patients including DKD has undergone significant expansion. In particular, the incretin hormone gastric inhibitory polypeptide (GIP) axis has taken central stage. A ground-breaking development in this realm was the creation of a GIP receptor dominant negative (GIPRdn) mouse, exhibiting all the characteristic features observed in DKD patients. This study sheds light on the heightened susceptibility of these mice to lethal acute kidney injury (AKI) induced by ischemia-reperfusion injury (IRI). Notably, isolated renal GIPRdn-tubules displayed accelerated cell death propagation and increased tubular necrosis. Expanding on previous cell culture experiments involving hyperglycemia, it became apparent that tubules of GIPRdn mice express elevated levels of the intracellular thioredoxin interacting protein (TXNIP), previously reported to be responsible for the degradation of glucose transporter 1 (GLUT1). This phenomenon is crucial in maintaining intracellular glucose homeostasis. The study further indicates an association between TXNIP and the downregulation of thioredoxin reductase 1 (TXNRD1), a selenoenzyme playing a pivotal role in protecting renal tubules from ferroptosis in a glutathione-independent manner. Intriguingly, the inhibition of TXNRD1 with the small molecule ferroptocide (FTC) in GIPRdn tubules resulted in severe tubular necrosis, a condition effectively reversed by the ferroptosis inhibitor ferrostatin 1 (Fer-1). This nuanced exploration establishes a connection between DKD and a heightened sensitivity to kidney tubular ferroptosis, thereby presenting a potential avenue for intervention with ferrostatins. Importantly, the administration of a single dose of Fer-1 significantly prolonged the survival of GIPRdn mice following IRI. In conclusion, this study illuminates the intricate dynamics of DKD, highlighting a pronounced sensitization to kidney tubular ferroptosis. The findings suggest that ferrostatins, particularly exemplified by Fer-1, hold promise as potential therapeutic agents in mitigating the severity of this condition, offering hope for improved outcomes in individuals struggling with diabetes-related kidney complications.:Acknowledgments Abstract Zusammenfassung List of abbreviations List of tables List of Figures 1. Introduction 1.1. Diabetes mellitus 1.1.1. Definition and description 1.1.2. Epidemiology 1.1.3. Classification of diabetes mellitus 1.1.4. Diagnosis of diabetes mellitus 1.1.5. Type 2 Diabetes Mellitus 1.1.6. Long-term complications of T2DM 1.1.6.1. Diabetic Nephropathy 1.1.6.2. Therapies for diabetic nephropathy 1.1.7. Animal models for diabetic kidney disease 1.1.7.1. Diabetic eNOS knockout mouse 1.1.7.2. Bradykinin B2 Receptor (B2R) deficient Ins2Akita/+ mouse 1.1.7.3. Decorin-deficient streptozotocin diabetic mouse 1.1.7.4. NONcNZO mouse 1.1.7.5. OVE26 mouse 1.1.7.6. Black and tan, brachyuric (BTBR) ob/ob mouse 1.1.8. Incretin hormones and GIPRdn diabetic mouse model 1.1.8.1. Generation of GIPRdn diabetic mouse model 1.2. Regulated cell death 1.3. Ferroptosis 1.3.1 Mechanism of ferroptosis 1.3.1.1 Sensitization to ferroptosis by ether phospholipids 1.3.1.2 Hydropersulfides and ferroptosis 1.3.2 Ferroptosis inducers (FINs) and inhibitors 1.3.3 Ferroptosis in the kidney 1.4 Aims 2. Materials and Methods 2.1. Reagents 2.2. Experimental models: cell lines and mouse strains 2.2.1. Cell culture conditions 2.2.2. Mice 2.2.2.1. Genotyping 2.2.2.1.1. DNA isolation 2.2.2.1.2. Polymerase Chain Reaction (PCR) 2.2.2.1.3. Gel electrophoresis 2.2.2.2. Body weight 2.2.2.3. Blood glucose 2.2.2.4. Blood collection and serum parameters 2.2.3. Isolation of primary murine renal tubules 2.2.4. Generation of a 3D-printed double chamber 2.3. Experimental procedures 2.3.1. Plating and treatment of cells 2.3.2. Fluorescence activated cell sorting (FACS) 2.3.3. Western Blotting (WB) 2.3.4. Induction of cell death on isolated murine tubules 2.3.5. LDH release assay 2.3.6. Evaluation of speed of cell death propagation (exponential plateau – growth equation) 2.3.7. Time lapse imaging and processing of the time lapse data 2.3.8. Fluorescence Lifetime Imaging Microscopy (FLIM) 2.3.8.1. Time domain data analysis 2.3.8.2. FLIM time lapse video generation 2.3.9. Thioredoxin Reductase Activity assay 2.3.10. Bilateral kidney Ischemia and Reperfusion injury (IRI) 2.3.11. Immunohistology and semi-quantitative scoring 2.3.12. Measurements of sulfur-containing metabolites by ultra-performance liquid chromatography-mass spectroscopy (LC-MS) 2.4. Statistical analysis 3. Results 3.1. Characterization of diabetic kidney disease in GIPRdn mice 3.1.1. Blood glucose viii 3.1.2. Body weight 3.1.3. Serum parameters 3.1.4. Histological analysis of the kidneys 3.2. The spontaneous death of GIPRdn tubules is characterized by a non-random pattern of necrotic cell death 3.3. GIPRdn tubules are more prone to undergo spontaneous death compared to WT tubules 3.4. Spontaneous necrosis of GIPRdn and WT tubules is partially mediated by ferroptosis 3.5. GIPRdn tubules show downregulation of the PRX pathway compared to the non-diabetic tubules 3.6. GIPRdn tubules show altered hydropersulfides pathway 3.7. GIPRdn tubules show altered etherglycerophospholipids (etherPLs) pathway. 3.8. Ferrostatin-1 but not Empagliflozin reverses ferroptosis induction in different cell lines as well as in isolated kidney tubules 3.9. GIPRdn mice are more sensitive to IRI-induced acute kidney injury compared to their WT littermates 3.10. Ferrostatin-1 ameliorates the sensitivity of GIPRdn to ischemia reperfusion injury-induced acute kidney injury 4. Discussion 4.1. The GIPRdn mouse model 4.2 Ferroptosis in diabetic nephropathy 4.2.1. Ferroptotic cell death is involved in the spontaneous death of diabetic tubules 4.2.2. Possible mechanisms behind the enhanced sensitivity of the GIPRdn kidney tubules to ferroptosis 4.3. Therapeutic consequences of the study 4.3.1. SGLT2 inhibitor empagliflozin does not have a protective effect on diabetic tubules undergoing spontaneous death 4.4. Outlook and limitations of the study References

Faible masse musculaire a été peu étudiée chez les patients avant le stade terminal de la maladie rénale chronique (MRC). Nous avons évalué la masse musculaire à partir de la créatininurie des 24h pour étudier ses déterminants, son évolution avec le déclin de la fonction rénale ainsi que ses liens avec les risques de progression vers l’insuffisance rénale terminale traitée (IRTT) et de décès avant IRTT. Dans la cohorte NephroTest incluant 1429 patients avec une MRC stades 1 à 4, le débit de filtration glomérulaire a été mesuré par la clairance du 51Cr-EDTA (DFGm) et estimé par l’équation CKD EPI (DFGe). La créatininurie moyenne à l’inclusion diminuait de 15.3±3.1 à 12.1±3.3 mmol/24 chez les hommes et de 9.6±1.9 à 7.6±2.5 chez les femmes, pour une baisse du DFGm de ≥ 60 à < 15 mL/min/1.73 m2. Être plus âgé, avoir un diabète, un faible IMC ou un niveau faible de protéinurie et d’apports protidiques était associé à un niveau faible de créatininurie. Un déclin annuel du DFGm de 5 mL/min/1.73 m2 était lié à une baisse de créatininurie, indépendamment de ces déterminants. Au cours d’un suivi médian de 3.6 ans, 229 patients ont développé une IRTT, et 113 sont décédés avant IRTT. Après ajustement sur les facteurs de confusion, le hasard ratio (HR) était de 1.6 (0.88-2.9) pour le risque de décès et de 0.60 (0.39-0.91) pour le risque d’IRTT, dans le 1er vs 4ème quartile de créatininurie. La baisse de la créatininurie apparait précocement dans la MRC et est liée au décès avant dialyse. La diminution du risque d’IRTT pourrait s’expliquer par un démarrage plus tardif de la dialyse en raison d’une surestimation du DFGm par le DFGe chez les patients avec une faible créatininurie. / Mainly described in patients on dialysis, muscle wasting has received little attention in early stage chronic kidney disease (CKD). We used 24-hour creatininuria to assess determinants of low muscle mass and its putative associations with CKD outcomes, using data from the NephroTest cohort, including 1429 non-dialysis patients with CKD stages 1 to 5. Kidney function was assessed with both measured (mGFR, by 51Cr-EDTA renal clearance) and estimated glomerular filtration rate (eGFR, by CKD-EPI equation). End-stage renal disease (ESRD) and pre-ESRD death were the main studied outcomes. The mean baseline creatininuria decreased from 15.3±3.1 to 12.1±3.3 mmol/24 h in men and from 9.6±1.9 to 7.6±2.5 in women, when mGFR fell from ≥ 60 to < 15 mL/min/1.73 m2. Other determinants of low creatininuria were an older age, diabetes, a lower body mass index, a lower level of proteinuria or protein intake. A fast annual decline in mGFR of 5 mL/min/1.73 m2 was linked with a 2-fold decrease in creatininuria, independent of changes in protein intake and other determinants of muscle mass. Over a median follow-up of 3.6 years, 229 patients developed ESRD and 113 patients died before ESRD. After adjustment for confounders, patients with low muscle mass showed a significantly higher risk for pre-ESRD death (HR 1.6, 95% CI 0.88-2.9), but a lower risk for ESRD (HR 0.60, 95% CI 0.39-0.91). The latter was reversed (HR 1.5, 95% CI 1.01-2.4) when mGFR was replaced by eGFR. Decrease in 24-hour creatininuria may appear early in CKD patients, is related to pre-ESRD death. The lower risk for ESRD may reflect later dialysis start due to overestimation of true GFR by eGFR in patients with low muscle mass.

Autosomal dominant polycystic disease (ADPKD) is the most common hereditary renal disease and is characterized by renal cyst growth and enlargement. Hypertension occurs early when renal function is normal and is characterized by decreased renal blood flow. Accordingly, the measurement of blood flow in the renal arteries can be a valuable tool in evaluating disease progression. In studies performed in conjunction with this work, blood flow was measured through the renal arteries using magnetic resonance imaging (MRI). In order to validate these in vivo measurements, a vascular phantom was created using polyvinyl alcohol (PVA) and also scanned using MRI under controlled steady flow conditions. Ranges of vessel diameters and flow velocities were used to simulate actual flow in a normal and diseased population of adults and children. With the vessel diameters studied in this experiment, minimization of field of view and an increase in spatial resolution is important in obtaining accurate data. However, a significant difference does not exist between the results when using the 160 or 200 mm FOV. An increase in the number of phase encodings provides improved results, although an increase in image acquisition time is observed. Velocity-encoding in all three orthogonal directions does not improve image data. This method of using MRI to measure flow through a vessel is shown to be both accurate and reproducible, and the protocol providing the most correct results is prescribed. Breath-hold phase-velocity encoded MRI proves to be an accurate and reproducible technique in capturing flow and has the potential to be used for the purpose of observing hemodynamic changes in the renal arteries with the progression of ADPKD.

Aim of this study was to determine, which area (social, psychical, physical) is for the patient with chronic kidney disease considered most important and whether we can help the patient to improve his quality of life in this area. A qualitative form of research was used for achieving the aim of this paper. Collection of data has been performed by the method of semi-structured interview in 10 patients using additional (so-called probe) questions. Case reports of individual patients have been performed on the basis of interview results. These case reports form a base for workup of categorized tables and graphs (frame analysis approach), in which most important research results have been summarised. Research set has been chosen as target-oriented by the snowball technique and is formed by 10 respondents with chronic kidney disease, who are patients with chronic kidney disease since their childhood. The research has proven that respondents perceive as most important issues the family and health, but their conception differs for each of them. Research results can be used in social contacts and consultation and education working directly with patients and improving their compliance.

Les maladies rénales chroniques sont devenues un enjeu majeur de santé publique. Qu’elle qu’en soit la cause initiale, la MRC est caractérisée par une réduction néphronique progressive, aboutissant au remplacement des néphrons sains par un tissu fibreux et au déclin de la fonction rénale. Les mécanismes de progression de la MRC sont encore mal compris, mais il a été suggéré que le développement des lésions tubulo-interstitielles joue un rôle essentiel dans le déclin de la fonction rénale. Deux éléments physiopathologiques cruciaux dans le développement de ces lésions sont représentés par (i) l’activation de la voie du récepteur à l’EGF (epidermal growth factor) (EGFR), et (ii) la protéinurie et ses conséquences pour les cellules tubulaires. Les médiateurs communs à ces deux phénomènes ne sont pas connus. Mon travail de thèse a consisté à caractériser une protéine commune à ces deux voies d’activation, ie la lipocaline2 (Lcn2), petite protéine de transport de fer, en étudiant ses voies d'activation et ses conséquences physiopathologiques. Nous montrons que le rôle pathologique de la voie de l’EGFR est gouverné par la surexpression de Lcn2. En effet, dans le contexte de réduction néphronique chirurgicale, (i) les animaux invalidés pour Lcn2 sont protégés du développement des lésions, et (ii) les souris exprimant un dominant négatif de l’EGFR dans le tubule rénal présentent une diminution de l’expression de Lcn2. Nous montrons également que l’invalidation de Lcn2 permet de ralentir la progression de la MRC dans un modèle de polykystose rénale dépendante de l’EGFR, les souris jck (juvenile cystic kidney). Parallèlement, nous montrons que la protéinurie induit également l’expression de Lcn2 dans les cellules tubulaires rénales dans différents modèles expérimentaux. De plus, nous montrons le rôle majeur de Lcn2 dans la progression de la MRC protéinurique, l’invalidation de Lcn2 limitant le développement des lésions rénales et la mortalité des animaux protéinuriques. Si le rôle délétère de Lcn2 est démontré dans différents modèles de néphropathie chronique, nous montrons que les voies moléculaires impliquées dans l’activation de Lcn2 et le rôle de cette protéine dépendent du contexte cellulaire. Nous prouvons que Lcn2 est un médiateur de l'effet mitogénique de l'EGFR, phénomène essentiel de la progression de la MRC, et nous montrons que l’activation de Lcn2 via l’EGFR est dépendante du facteur HIF1α. Cependant, nous démontrons également que l'expression de Lcn2 dans le contexte de protéinurie est dépendante du facteur ATF4 activé par le stress du reticulum endoplasmique (ER), et que Lcn2 est un médiateur de l'apoptose dépendante du stress de l'ER. Enfin, nous prouvons que l’inhibition pharmacologique du stress de l'ER permet une réduction de l’expression de Lcn2 dans les cellules tubulaires, et surtout, un ralentissement du déclin de la fonction rénale des animaux protéinuriques. Nous démontrons également l’importance de ces résultats chez les patients atteints de MRC. Nous identifions NGAL, l'analogue humain de Lcn2, comme un biomarqueur de progression dans la polykystose rénale dominante, et nous montrons qu’elle est fortement surexprimée dans le tissu rénal de patients protéinuriques. L’ensemble de ce travail permet de montrer que Lcn2 est un nouveau médiateur essentiel de multiples néphropathies chroniques. Lcn2 est impliquée dans l’effet mitogénique de l’EGFR ou la réponse apoptotique associée à la protéinurie durant la MRC. Nous ouvrons également de nouvelles perspectives thérapeutiques avec l'utilisation d'inhibiteurs du stress de l'ER dans les néphropathies protéinuriques humaines / Chronic kidney disease (CKD) is now a major public health concern. Whatever the initial kidney injury, CKD is characterized by progressive nephron reduction and kidney function decline. Tubulointerstitial lesions are an essential component of CKD progression, and are mediated by two crucial pathophysiologic elements: epidermal growth factor receptor (EGFR) activation, and proteinuria responsible of tubular cell damage. The aim of this study was to describe a common mediator of both these pathways, ie lipocalin2, an iron carrier protein, by identifying its activation pathways and its pathophysiologic consequences. We show the deleterious effects of the EGFR pathway during nephron reduction is mediated by the activation of Lcn2, which controls the mitogenic effect of EGFR. In fact, after nephron reduction, animals invalidated for Lcn2 are protected from lesions developpement. Moreover, a similar protective effect is seen in jck (juvenile cytic kidney) mice invalidated for Lcn2, a model of polycystic kidney disease EGFR-dependant. Otherwise, we show proteinuria induces Lcn2 expression in tubular cells of different experimental models, and Lcn2 invalidation slows lesion developpement and reduces mortality of proteinuric mice. We demonstrate that the Lcn2 role and activation pathways are dependant of these different models. We show Lcn2 is a mediator of the mitogenic effect of the EGFR, and Lcn2 activation is dependant of HIF1α stabilisation. However, we also show ATF4 is an activator of Lcn2 during endoplasmic reticulum (ER) stress induced by proteinuria in tubular cells. In this context, Lcn2 controls ER stress-induced apoptosis. Pharmacologic inhibition of ER stress in proteinuric animals decreases Lcn2 overexpression, and slows renal function decline. In patients suffering from CKD, we demonstrated NGAL (neutrophil gelatinase-associated lipocalin), the human analog of Lcn2, appears as a critical biomarker of autosomal dominant polycystic kidney disease progression. NGAL is also highly overexpressed in tubular cells in kidney biopsies of proteinuric patients. This work demonstrates Lcn2 is an essential mediator of multiple pathophysiologic components of CKD progression. Moreover, we open new therapeutic perspectives with the use ER stress modulators in proteinuric CKD