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Kidney allograft rejection is a major issue because it causes graft failure and because immunosuppressive treatments used for its prevention increase the risk of infections and cancers. In systemic lupus patients, hydroxychloroquine is used to prevent immune flares with decreased doses of immunosuppressants. Hydroxychloroquine can be safely used in kidney transplant recipients when indicated for autoimmune disease, but its effect on allograft rejection is unknown. We hypothesized that it may prevent kidney allograft rejection. We conducted a nationwide retrospective propensity-matched study on kidney transplantations of patients treated with hydroxychloroquine in France between 2008 and 2018. We analyzed the incidence of allograft rejection or failure within the first year after transplantation. The rates of rejection or allograft failure were not different between the 188 patients treated with hydroxychloroquine at the time of transplantation and their propensity matched controls. Hydroxychloroquine treatment in association with standard immunosuppressive treatment does not prevent rejection in kidney allograft recipients., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Renin is the key enzyme of the systemic renin-angiotensin-aldosterone system, which plays an essential role in regulating blood pressure and maintaining electrolyte and extracellular volume homeostasis. Renin is mainly produced and secreted by specialized juxtaglomerular (JG) cells in the kidney. In the present study, we report for the first time that the conserved transmembrane receptor neuropilin-1 (NRP1) participates in the development of JG cells and plays a key role in renin production. We used the myelin protein zero-Cre (P0-Cre) to abrogate Nrp1 constitutively in P0-Cre lineage-labelled cells of the kidney. We found that the P0-Cre precursor cells differentiate into renin-producing JG cells. We employed a lineage-tracing strategy combined with RNAscope quantification and metabolic studies to reveal a cell-autonomous role for NRP1 in JG cell function. Nrp1-deficient animals displayed abnormal levels of tissue renin expression and failed to adapt properly to a homeostatic challenge to sodium balance. These findings provide new insights into cell fate decisions and cellular plasticity operating in P0-Cre-expressing precursors and identify NRP1 as a novel key regulator of JG cell maturation. KEY POINTS: Renin is a centrepiece of the renin-angiotensin-aldosterone system and is produced by specialized juxtaglomerular cells (JG) of the kidney. Neuropilin-1 (NRP1) is a conserved membrane-bound receptor that regulates vascular and neuronal development, cancer aggressiveness and fibrosis progression. We used conditional mutagenesis and lineage tracing to show that NRP1 is expressed in JG cells where it regulates their function. Cell-specific Nrp1 knockout mice present with renin paucity in JG cells and struggle to adapt to a homeostatic challenge to sodium balance. The results support the versatility of renin-producing cells in the kidney and may open new avenues for therapeutic approaches., (© 2024 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

Acute kidney injury activates both proliferative and antiproliferative pathways, the consequences of which are not fully elucidated. If an initial proliferation of the renal epithelium is necessary for the successful repair, the persistence of proliferation markers is associated with the occurrence of chronic kidney disease. We hypothesized that proliferation in stress conditions impacts cell viability and renal outcomes. We found that proliferation is associated with cell death after various stresses in kidney cells. In vitro, the ATP/ADP ratio oscillates reproducibly throughout the cell cycle, and cell proliferation is associated with a decreased intracellular ATP/ADP ratio. In vivo, transcriptomic data from transplanted kidneys revealed that proliferation was strongly associated with a decrease in the expression of the mitochondria-encoded genes of the oxidative phosphorylation pathway, but not of the nucleus-encoded ones. These observations suggest that mitochondrial function is a limiting factor for energy production in proliferative kidney cells after injury. The association of increased proliferation and decreased mitochondrial function was indeed associated with poor renal outcomes. In summary, proliferation is an energy-demanding process impairing the cellular ability to cope with an injury, highlighting proliferative repair and metabolic recovery as indispensable and interdependent features for successful kidney repair. NEW & NOTEWORTHY ATP depletion is a hallmark of acute kidney injury. Proliferation is instrumental to kidney repair. We show that ATP levels vary during the cell cycle and that proliferation sensitizes renal epithelial cells to superimposed injuries in vitro. More proliferation and less energy production by the mitochondria are associated with adverse outcomes in injured kidney allografts. This suggests that controlling the timing of kidney repair might be beneficial to mitigate the extent of acute kidney injury.

Background: Cardiac arrest (CA) causes renal ischemia in one-third of brain-dead kidney donors before procurement. We hypothesized that the graft function depends on the time interval between CA and organ procurement., Methods: We conducted a retrospective population-based study on a prospectively curated database. We included 1469 kidney transplantations from donors with a history of resuscitated CA in 2015-2017 in France. CA was the cause of death (primary CA) or an intercurrent event (secondary CA). The main outcome was the percentage of delayed graft function, defined by the use of renal replacement therapy within the first week posttransplantation., Results: Delayed graft function occurred in 31.7% of kidney transplantations and was associated with donor function, vasopressors, cardiovascular history, donor and recipient age, body mass index, cold ischemia time, and time to procurement after primary cardiac arrest. Short cold ischemia time, perfusion device use, and the absence of cardiovascular comorbidities were protected by multivariate analysis, whereas time <3 d from primary CA to procurement was associated with delayed graft function (odds ratio 1.38)., Conclusions: This is the first description of time to procurement after a primary CA as a risk factor for delayed graft function. Delaying procurement after CA should be evaluated in interventional studies., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: During glomerular diseases, podocyte-specific pathways can modulate the intensity of histological disease and prognosis. The therapeutic targeting of these pathways could thus improve the management and prognosis of kidney diseases. The Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) pathway, classically described in immune cells, has been recently described in detail in intrinsic kidney cells., Methods: We describe STAT5 expression in human kidney biopsies from patients with focal segmental glomerulosclerosis (FSGS) and studied mice with a podocyte-specific Stat5 deletion in experimental glomerular diseases., Results: Here, we show, for the first time, that STAT5 is activated in human podocytes in FSGS. In addition, podocyte-specific Stat5 inactivation aggravates the structural and functional alterations in a mouse model of FSGS. This could be due, at least in part, to an inhibition of autophagic flux. Finally, interleukin 15 (IL-15), a classical activator of STAT5 in immune cells, increases STAT5 phosphorylation in human podocytes, and its administration alleviates glomerular injury in vivo by maintaining autophagic flux in podocytes., Conclusion: Activating podocyte STAT5 with commercially available IL-15 represents a potential new therapeutic avenue for FSGS., (© 2024 International Society of Nephrology. Published by Elsevier Inc.)

Objective: Data about efficacy and safety of the latest COVID-19 treatments as nirmatrelvir/ritonavir (n/r) or Sotrovimab is scarce in solid organ transplant recipients in the Omicron era. This study aims at describing the outcome of kidney transplant recipients (KTRs) presenting Omicron infection according to their management: n/r, sotrovimab or no specific treatment., Patients and Methods: We conducted a monocentric, retrospective observational study, including KTRs diagnosed Omicron infection between January and May 1st 2022 and compared their outcome (primary outcome defined as hospital admission for COVID-19 within a month after symptoms onset) according to early COVID-19 management., Results: Forty-five patients were included: 22 treated (12 n/r, 10 sotrovimab) and 23 with no specific treatment. The groups were statistically comparable. Two patients were admitted for COVID-19: one in each group, resulting in a non-different probability of the primary outcome at on month (p=0.9). Three patients presented tacrolimus overdose including two with acute kidney injury., Conclusions: There was no difference in outcome according to early therapeutic management: n/r, sotrovimab or no specific treatment. Our study both underlines a decreased severity of Omicron COVID-19 in KTRs (probably related to vaccinal immunity and decreased virulence of Omicron) and a potential severe adverse effects with n/r.

Whether immunoadsorption (IADS) as part of desensitization protocols could facilitate deceased donor kidney transplantation (KT) in highly sensitized (HS) patients remains to be proven. We retrospectively analyzed our IADS based desensitization protocol for deceased donor KTs between 2013 and 2018. Fifteen HS patients (age 52 years [40-56]) were included. Waiting time before IADS was 6 years [5-10] and the interval between IADS initiation and KT was 5 months [1-12] for the 14 transplanted patients. Nine patients had prior KT. Calculated panel reactive antibody decreased significantly during the protocol (99.3% [92.5-99.9] vs. 79.4% [56.7-81.9]; p = 0.004). Death-censored graft survival was 85.7% at 1 and 2 years post-transplantation. One-year median plasma creatinine level was 135 µmol/L [111-202]. Six developed active antibody mediated rejection (ABMR) at 1 year, with a median delay of 13 days [11-26]. Eight patients developed severe infections, including two fatal outcomes. Finally, compared to 93% of patients who received desensitization receiving a KT, only 43% of a control with similar characteristics underwent transplantation. However, no difference was found in overall probability of being alive with a functioning graft at the end of follow-up. The results indicate that our IADS-based desensitization strategy was not effective due to a high rate of ABMR and severe infectious complications which pose a challenge to its universalization., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Bureau, Rafat, Taupin, Malard, Mesnard, François, Petit-Hoang, Ouali, Hertig, Jamme, Buob, Rondeau, Galichon and Luque.)

Cardiorenal syndromes type 1 and 2 are complex disorders in which cardiac dysfunction leads to kidney dysfunction. However, the mechanisms remain incompletely explained, during pulmonary hypertension in particular. The objective of this study is to develop an original preclinical model of cardiorenal syndrome secondary to a pulmonary hypertension in piglets. Twelve 2-month-old Large White piglets were randomized in two groups: (1) induction of pulmonary hypertension by ligation of the left pulmonary artery and iterative embolizations of the right lower pulmonary artery, or (2) Sham interventions. We evaluated the cardiac function using right heart catheterization, echocardiography and measurement of biochemistry markers). Kidney was characterized using laboratory blood and urine tests, histological evaluation, immunostainings for renal damage and repair, and a longitudinal weekly assessment of the glomerular filtration rate using creatinine-based estimation and intravenous injection of an exogenous tracer on one piglet. At the end of the protocol (6 weeks), the mean pulmonary artery pressure (32 ± 10 vs. 13 ± 2 mmHg; p = 0.001), pulmonary vascular resistance (9.3 ± 4.7 vs. 2.5 ± 0.4 WU; p = 0.004) and central venous pressure were significantly higher in the pulmonary hypertension group while the cardiac index was not different. Piglets with pulmonary hypertension had higher troponin I. We found significant tubular damage and an increase in albuminuria in the pulmonary hypertension group and negative correlation between pulmonary hypertension and renal function. We report here the first porcine model of cardiorenal syndrome secondary to pulmonary hypertension., (© 2023. The Author(s).)

Drug nephrotoxicity is a common healthcare problem in hospitalized patients and a major limitation during drug development. Multi-segmented kidney organoids derived from human pluripotent stem cells may complement traditional cell culture and animal experiments for nephrotoxicity assessment. Here we evaluate the capability of kidney organoids to investigate drug toxicity in vitro . Kidney organoids express renal drug transporters, OAT1, OAT3, and OCT2, while a human proximal tubular cell line shows the absence of OAT1 and OAT3. Tenofovir and aristolochic acid (AA) induce proximal tubular injury in organoids which is ameliorated by an OAT inhibitor, probenecid, without damage to podocytes. Similarly, cisplatin causes proximal tubular damage that can be relieved by an OCT inhibitor, cimetidine, collectively suggesting the presence of functional OATs and OCTs in organoid proximal tubules. Puromycin aminonucleoside (PAN) induced segment-specific injury in glomerular podocytes in kidney organoids in the absence of tubular injury. Reporter organoids were generated with an ATP/ADP biosensor, which may be applicable to high-throughput screening in the future. In conclusion, the kidney organoid is a useful tool for toxicity assessment in the multicellular context and may contribute to nephrotoxicity assessment during drug development., (Copyright © 2023 Susa, Kobayashi, Galichon, Matsumoto, Tamura, Hiratsuka, Gupta, Yazdi, Bonventre and Morizane.)

Purpose: Living kidney donors (LKD) partially compensate the initial loss of glomerular filtration rate (GFR), a phenomenon known as renal functional reserve (RFR). RFR is reduced in the elderly, a population with increased prevalence of chronic kidney disease. We hypothesized that the selected, healthy population of LKD, would specifically inform about the physiological determinants of the RFR and studied it using measured GFR (mGFR)., Methods: We retrospectively analyzed pre-donation and post-donation mGFR in 76 LKD from Tenon Hospital (Paris, France) between 2002 and 2018. In addition to GFR measurements, we collected pre-donation morphologic parameters, demographic data, and kidney volumes., Results: Mean pre-donation mGFR was 90.11 ± 12.64 mL/min/1.73 m 2 and decreased to 61.26 ± 9.57 mL/min/1.73 m 2 1 year after donation. Pre-donation mGFR correlated with age (p = 0.0003), total kidney volume (p = 0.0004) and pre-donation serum creatinine (p = 0.0453). Pre-donation mGFR strongly predicted 1-year post-donation mGFR. Mean RFR (increase in GFR of the remnant kidney between pre-donation and post-donation) was 36.67 ± 16.67% 1 year after donation. In the multivariate linear model, RFR was negatively correlated to total kidney volume (p = 0.02) but not with age or pre-donation serum creatinine., Conclusions: We found that pre-donation mGFR decreases with age and identified low total kidney volume as a predictor of RFR in healthy individuals. This suggests an adaptative and reversible decrease in kidney function rather than age-related damage. Older subjects may have reduced metabolic requirements with subsequent reduction in glomerular filtration and kidney volume and preserved RFR. Therefore, low GFR in older subjects should not preclude kidney donation., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Bone mass in adulthood depends on growth and mineralization acquired during childhood and adolescence. It is well known that these stages of life are crucial for bone development, where genetic, nutritional, hormonal, and lifestyle factors play a significant role. Bone loss is normally a natural and slow process that begins years later after the peak bone mass is achieved and continues throughout the lifespan. Lifestyle choices in childhood and adolescence such as minimal physical activity, excessive caffeine or carbonated beverages intake, malnutrition, cigarette use, or high alcohol consumption and other factors like environmental pollutants can also negatively affect bone health and accelerate the bone loss process. The aim of this work is an overview of risk factors associated with inadequate bone health in early life., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Kidneys have the capacity for intrinsic repair, preserving kidney architecture with return to a basal state after tubular injury. When injury is overwhelming or repetitive, however, that capacity is exceeded and incomplete repair results in fibrotic tissue replacing normal kidney parenchyma. Loss of nephrons correlates with reduced kidney function, which defines chronic kidney disease (CKD) and confers substantial morbidity and mortality to the worldwide population. Despite the identification of pathways involved in intrinsic repair, limited treatments for CKD exist, partly because of the limited throughput and predictivity of animal studies. Here, we showed that kidney organoids can model the transition from intrinsic to incomplete repair. Single-nuclear RNA sequencing of kidney organoids after cisplatin exposure identified 159 differentially expressed genes and 29 signal pathways in tubular cells undergoing intrinsic repair. Homology-directed repair (HDR) genes including Fanconi anemia complementation group D2 ( FANCD2 ) and RAD51 recombinase ( RAD51 ) were transiently up-regulated during intrinsic repair but were down-regulated in incomplete repair. Single cellular transcriptomics in mouse models of obstructive and hemodynamic kidney injury and human kidney samples of immune-mediated injury validated HDR gene up-regulation during tubular repair. Kidney biopsy samples with tubular injury and varying degrees of fibrosis confirmed loss of FANCD2 during incomplete repair. Last, we performed targeted drug screening that identified the DNA ligase IV inhibitor, SCR7, as a therapeutic candidate that rescued FANCD2/RAD51-mediated repair to prevent the progression of CKD in the cisplatin-induced organoid injury model. Our findings demonstrate the translational utility of kidney organoids to identify pathologic pathways and potential therapies.

Competing Interests: None.

The biosynthetic routes leading to de novo nicotinamide adenine dinucleotide (NAD+) production are involved in acute kidney injury (AKI), with a critical role for quinolinate phosphoribosyl transferase (QPRT), a bottleneck enzyme of de novo NAD+ biosynthesis. The molecular mechanisms determining reduced QPRT in AKI, and the role of impaired NAD+ biosynthesis in the progression to chronic kidney disease (CKD), are unknown. We demonstrate that a high urinary quinolinate-to-tryptophan ratio, an indirect indicator of impaired QPRT activity and reduced de novo NAD+ biosynthesis in the kidney, is a clinically applicable early marker of AKI after cardiac surgery and is predictive of progression to CKD in kidney transplant recipients. We also provide evidence that the endoplasmic reticulum (ER) stress response may impair de novo NAD+ biosynthesis by repressing QPRT transcription. In conclusion, NAD+ biosynthesis impairment is an early event in AKI embedded with the ER stress response, and persistent reduction of QPRT expression is associated with AKI to CKD progression. This finding may lead to identification of noninvasive metabolic biomarkers of kidney injury with prognostic and therapeutic implications.

Ischemia is a common cause of acute kidney injury worldwide, frequently occurring in patients undergoing cardiac surgery or admitted to the intensive care unit (ICU). Thus, ischemia-reperfusion injury (IRI) remains one of the main experimental models for the study of kidney diseases. However, the classical technique, based on non-traumatic surgical clamps, suffers from several limitations. It does not allow the induction of multiple episodes of acute kidney injury (AKI) in the same animal, which would be relevant from a human perspective. It also requires a deep and long sedation, raising the question of potential anaesthesia-related biases. We designed a vascular occluding device that can be activated remotely in conscious mice. We first assessed the intensity and the reproducibility of the acute kidney injury induced by this new device. We finally investigated the role played by the anaesthesia in the IRI models at the histological, functional and transcriptomic levels. We showed that this technique allows the rapid induction of renal ischemia in a repeatable and reproducible manner, breaking several classical limitations. In addition, we used its unique specificities to highlight the renal protective effect conferred by the anaesthesia, related to the mitigation of the IRI transcriptomic program.

Recent studies demonstrate that metabolic disturbance, such as augmented glycolysis, contributes to fibrosis. The molecular regulation of this metabolic perturbation in fibrosis, however, has been elusive. COUP-TFII (also known as NR2F2) is an important regulator of glucose and lipid metabolism. Its contribution to organ fibrosis is undefined. Here, we found increased COUP-TFII expression in myofibroblasts in human fibrotic kidneys, lungs, kidney organoids, and mouse kidneys after injury. Genetic ablation of COUP-TFII in mice resulted in attenuation of injury-induced kidney fibrosis. A non-biased proteomic study revealed the suppression of fatty acid oxidation and the enhancement of glycolysis pathways in COUP-TFII overexpressing fibroblasts. Overexpression of COUP-TFII in fibroblasts also induced production of alpha-smooth muscle actin (αSMA) and collagen 1. Knockout of COUP-TFII decreased glycolysis and collagen 1 levels in fibroblasts. Chip-qPCR revealed the binding of COUP-TFII on the promoter of PGC1α. Overexpression of COUP-TFII reduced the cellular level of PGC1α. Targeting COUP-TFII serves as a novel treatment approach for mitigating fibrosis in chronic kidney disease and potentially fibrosis in other organs., (© 2021 The Authors.)

Tubulointerstitial abnormalities are predictive of the progression of diabetic kidney disease (DKD), and their targeting may be an effective means for prevention. Proximal tubular (PT) expression of kidney injury molecule (KIM)-1, as well as blood and urinary levels, are increased early in human diabetes and can predict the rate of disease progression. Here, we report that KIM-1 mediates PT uptake of palmitic acid (PA)-bound albumin, leading to enhanced tubule injury with DNA damage, PT cell-cycle arrest, interstitial inflammation and fibrosis, and secondary glomerulosclerosis. Such injury can be ameliorated by genetic ablation of the KIM-1 mucin domain in a high-fat-fed streptozotocin mouse model of DKD. We also identified TW-37 as a small molecule inhibitor of KIM-1-mediated PA-albumin uptake and showed in vivo in a kidney injury model in mice that it ameliorates renal inflammation and fibrosis. Together, our findings support KIM-1 as a new therapeutic target for DKD., Competing Interests: Declaration of interests J.V.B. and T.I. are co-inventors on KIM-1 patents assigned to Mass General Brigham. J.V.B. and A.K.A. have filed a patent for the discovery of TW-37 as inhibitor of KIM-1 to alleviate chronic kidney disease. J.V.B. is a consultant to Cadent, Praxis, Seattle Genetics, Aldeyra, Sarepta, Praxis, and Angion and owns equity in Goldfinch, Innoviva, MediBeacon, DxNow, Verinano, Autonomous Medical Devices, Renalytix, Pacific Biosciences, and Sentien. V.K.K. has an ownership interest in Tizona Therapeutics, Celsius Therapeutics, and Bicara Therapeutics. V.K.K. has financial interests in Biocon Biologic, BioLegend, Elpiscience Biopharmaceutical Ltd., Equilium Inc., and Syngene Intl. V.K.K. is a member of SABs for Elpiscience Biopharmaceutical Ltd., GSK, Rubius Therapeutics, and Tizona Therapeutics. J.V.B.’s and V.K.K.’s interests were reviewed and are managed by Brigham and Women’s Hospital and Mass General Brigham in accordance with their conflict-of-interest policies. S.X. is an employee and shareholder of Celsius Therapeutics. J.H. is a full-time employee of Boehringer Ingelheim Pharmaceuticals, Inc. TW-37 was identified as a KIM-1 inhibitor in a screen supported by Boehringer Ingelheim Pharmaceuticals, Inc., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection leads to 5% to 16% hospitalization in intensive care units (ICU) and is associated with 23% to 75% of kidney impairments, including acute kidney injury (AKI). The current work aims to precisely characterize the renal impairment associated to SARS-CoV-2 in ICU patients. Forty-two patients consecutively admitted to the ICU of a French university hospital who tested positive for SARS-CoV-2 between 25 March 2020, and 29 April 2020, were included and classified in categories according to their renal function. Complete renal profiles and evolution during ICU stay were fully characterized in 34 patients. Univariate analyses were performed to determine risk factors associated with AKI. In a second step, we conducted a logistic regression model with inverse probability of treatment weighting (IPTW) analyses to assess major comorbidities as predictors of AKI. Thirty-two patients (94.1%) met diagnostic criteria for intrinsic renal injury with a mixed pattern of tubular and glomerular injuries within the first week of ICU admission, which lasted upon discharge. During their ICU stay, 24 patients (57.1%) presented AKI which was associated with increased mortality ( p = 0.007), hemodynamic failure ( p = 0.022), and more altered clearance at hospital discharge ( p = 0.001). AKI occurrence was associated with lower pH ( p = 0.024), higher PaCO 2 (CO 2 partial pressure in the arterial blood) ( p = 0.027), PEEP (positive end-expiratory pressure) ( p = 0.027), procalcitonin ( p = 0.015), and CRP (C-reactive protein) ( p = 0.045) on ICU admission. AKI was found to be independently associated with chronic kidney disease (adjusted OR (odd ratio) 5.97 (2.1-19.69), p = 0.00149). Critical SARS-CoV-2 infection is associated with persistent intrinsic renal injury and AKI, which is a risk factor of mortality. Mechanical ventilation settings seem to be a critical factor of kidney impairment.

Pre-transplant serum screening of anti-HLA antibodies is recommended for solid organ transplantations. Many laboratories use the less expensive bead-based screening assay as the main technique and, if positive, turn to single-antigen beads (SAB). We studied the correlations between these two immunoassays. We re-analyzed the raw data of the two assays in 3030 first organ transplant recipients, explored with the two tests. We performed a ROC curve analysis of the screening ratio to predict a positive SAB assay. The AUC were 0.72 and 0.64 for class I and class II. The optimal thresholds of screening ratios were 3.28 (class I) and 2.11 (class II). Whatever the class, the negative predictive value was low, around 40%, with 36% of discordant sera, as defined by negative screening and positive SAB. Testing class I discordant sera on acid-treated SAB showed that 54% of antibodies reacted against denatured HLA molecules. However, these screening-negative sera may contain donor-specific antibodies in 13.9% and 28.7% of cases for class I and class II, respectively, involved in antibody-mediated rejection with the same frequency as non-discordant sera. Given the low predictive value of screening, both assays should be performed at least once on the same serum before transplantation., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Acute tubular necrosis (ATN), a frequent histopathological feature in the early post-renal transplant biopsy, affects long-term graft function. Appropriate markers to identify patients at risk of no or incomplete recovery after delayed graft function are lacking. In this study, we first included 41 renal transplant patients whose biopsy for cause during the first month after transplantation showed ATN lesions. Using partial microvasculature endothelial (fascin, vimentin) and tubular epithelial (vimentin) to mesenchymal transition markers, detected by immunohistochemistry, we found a significant association between partial endothelial to mesenchymal transition and poor graft function recovery (Spearman's rho = -0.55, P = .0005). Transforming growth factor-β1 was strongly expressed in these phenotypic changed endothelial cells. Extent of ATN was also correlated with short- and long-term graft dysfunction. However, the association of extensive ATN with long-term graft dysfunction (24 months posttransplant) was observed only in patients with partial endothelial to mesenchymal transition marker expression in their grafts (Spearman's rho = -0.64, P = .003), but not in those without. The association of partial endothelial to mesenchymal transition with worse renal graft outcome was confirmed on 34 other early biopsies with ATN from a second transplant center. Our results suggest that endothelial cell activation at the early phase of renal transplantation plays a detrimental role., (© 2020 The American Society of Transplantation and the American Society of Transplant Surgeons.)

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Acute kidney injury (AKI) is strongly associated with mortality, independently of its cause. The kidney contributes to up to 40% of systemic glucose production by gluconeogenesis during fasting and under stress conditions. Whether kidney gluconeogenesis is impaired during AKI and how this might influence systemic metabolism remain unknown. Here we show that glucose production and lactate clearance are impaired during human and experimental AKI by using renal arteriovenous catheterization in patients, lactate tolerance testing in mice and glucose isotope labelling in rats. Single-cell transcriptomics reveal that gluconeogenesis is impaired in proximal tubule cells during AKI. In a retrospective cohort of critically ill patients, we demonstrate that altered glucose metabolism during AKI is a major determinant of systemic glucose and lactate levels and is strongly associated with mortality. Thiamine supplementation increases lactate clearance without modifying renal function in mice with AKI, enhances glucose production by renal tubular cells ex vivo and is associated with reduced mortality and improvement of the metabolic pattern in a retrospective cohort of critically ill patients with AKI. This study highlights an unappreciated systemic role of renal glucose and lactate metabolism under stress conditions, delineates general mechanisms of AKI-associated mortality and introduces a potential intervention targeting metabolism for a highly prevalent clinical condition with limited therapeutic options.

Maladaptive proximal tubule (PT) repair has been implicated in kidney fibrosis through induction of cell-cycle arrest at G2/M. We explored the relative importance of the PT DNA damage response (DDR) in kidney fibrosis by genetically inactivating ataxia telangiectasia and Rad3-related (ATR), which is a sensor and upstream initiator of the DDR. In human chronic kidney disease, ATR expression inversely correlates with DNA damage. ATR was upregulated in approximately 70% of Lotus tetragonolobus lectin-positive (LTL+) PT cells in cisplatin-exposed human kidney organoids. Inhibition of ATR resulted in greater PT cell injury in organoids and cultured PT cells. PT-specific Atr-knockout (ATRRPTC-/-) mice exhibited greater kidney function impairment, DNA damage, and fibrosis than did WT mice in response to kidney injury induced by either cisplatin, bilateral ischemia-reperfusion, or unilateral ureteral obstruction. ATRRPTC-/- mice had more cells in the G2/M phase after injury than did WT mice after similar treatments. In conclusion, PT ATR activation is a key component of the DDR, which confers a protective effect mitigating the maladaptive repair and consequent fibrosis that follow kidney injury.

Background: Chronic kidney disease (CKD) is a frequent and serious complication of cardiac surgery. This study was designed to establish a scoring system, calculated in the immediate postoperative period, to assess the risk of CKD at 1 yr in patients undergoing cardiac surgery with cardiopulmonary bypass., Methods: We conducted a cohort study including patients with preoperative estimated glomerular filtration rate above 60 ml min -1 (1.73 m) -2 who underwent cardiac surgery with cardiopulmonary bypass. We identified risk factors for de novo CKD at 1 yr using logistic regression. We derived a risk score for CKD, and externally validated this score in a second cohort., Results: The incidence of CKD was 18% and 23% in the derivation and validation cohorts, respectively. We developed a scoring system that included (i) the occurrence of postoperative acute kidney injury according to the Kidney Disease: Improving Global Outcomes criteria, (ii) age older than 65 yr, (iii) preoperative glomerular filtration rate <80 ml min -1 (1.73 m) -2 , (iv) aortic cross-clamping time longer than 50 min, and (v) the type of surgery (aortic or cardiac transplantation). This score predicted CKD with good accuracy (area under the receiver operating characteristic curve: 0.81; 95% confidence interval: 0.77-0.86 in the derivation cohort), and with fair accuracy in the validation cohort (area under the receiver operating characteristic curve: 0.78; 95% confidence interval: 0.72-0.83)., Conclusions: We provide an easy-to-calculate scoring system to identify patients at high risk of developing CKD after cardiac surgery with cardiopulmonary bypass. This system might help clinicians to target more accurately patients requiring monitoring of renal function after cardiac surgery, and to design appropriate interventional trials aimed at preventing CKD or mitigating its consequences., (Copyright © 2018 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

Introduction: Estrogens and progesterone play critical roles in angiogenesis and vasodilation. Moreover, placental aromatase deficiency is detected in women with preeclampsia (PE) at delivery. We hypothesized that abnormal steroidogenesis occurs much earlier than typical PE diagnosis. Thus, we investigated whether the circulating steroid profile was already disturbed at 24-29 weeks of gestation in women with subsequent PE, and compared the profile with that of women with "placental" small gestational age (SGA) without PE., Methods: We selected nulliparous women (n = 90) from the MOMA trial, including women with PE (n = 25), SGA (n = 25), and controls (NP; n = 40), for plasma steroid profiling by gas chromatography/mass spectrometry and to measure placental growth factor and soluble fms-like tyrosine kinase-1. Placental aromatase expression was evaluated in a new set of women., Results: Compared with that of controls, the women with PE had a significantly lower estrone/androstenedione ratio, and exhibited a decreasing trend for estradiol and estrone levels. Lower estriol levels were observed in the SGA group compared to the NP group. Compared with that of controls, the women with PE and SGA had significantly higher levels of 20α-dihydroprogesterone (20α-DHP) and 20α-DHP/progesterone ratios. Pregnenolone sulfate levels were lower in the PE group than in the NP and SGA groups. Decreased expression of aromatase was observed in the PE group compared to the control group., Discussion: Preeclampsia appears to be characterized by specific steroidogenesis dysregulation long before PE diagnosis, highlighting potential new biomarkers of PE., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Renal allograft loss is most often a chronic process, irrespective of the mechanism at stake. In this prospective study, we studied the expression of epithelial to mesenchymal transition (EMT) markers vimentin and β-catenin by immunohistochemistry in the surveillance biopsy and measured the mRNA encoding vimentin (VIM), CD45, GAPDH and uroplakin 1a (UPK) by quantitative PCR in urinary cells in 75 renal transplant patients. The aim is to establish a simple screening test for chronic renal allograft dysfunction. We found that the value of the mRNA of vimentin and CD45 relative to the uroplakin 1a (UPK) mRNA is correlated with the score in vimentin immunostaining in routine biopsies. These biomarkers could be used as a noninvasive tool to monitor the renal graft fibrogenesis. This test could be used for early detection of fibrotic diseases of the kidney transplant., (Copyright © 2017 Société francophone de néphrologie, dialyse et transplantation. Published by Elsevier Masson SAS. All rights reserved.)

Aim: Subclinical pathological features in renal allograft biopsies predict poor outcomes, and noninvasive biomarkers are wanted. RNA quantification in urine predicts overt rejection. We hypothesized that a whole transcriptome analysis would be informative, even for discrete injury., Patients & Methods: We performed an mRNA microarray with an optimized normalization method on 26 urinary cell pellets to study renal partial epithelial to mesenchymal transition (pEMT) in stable kidney allografts., Results & Conclusion: Unbiased pathway analysis revealed immune response as the main underlying biological process. In a subgroup of pristine biopsies, isolated pEMT was associated with reduced metabolic functions. Thus, pEMT translates into specific urinary mRNA patterns, in other words, increased inflammation and decreased metabolic functions. Deposited in Gene Expression Omnibus (GSE89652).

Background/aims: Fatty acid oxidation (FAO), the main source of energy produced by tubular epithelial cells in the kidney, was found to be defective in tubulo-interstitial samples dissected out in kidney biopsies from patients with chronic kidney disease (CKD). Experimental data indicated that this decrease was a strong determinant of renal fibrogenesis, hence a focus for therapeutic interventions. Nevertheless, whether persistently differentiated renal tubules, surviving in a pro-fibrotic environment, also suffer from a decrease in FAO, is currently unknown., Methods: To address this question, we isolated proximal tubules captured ex vivo on the basis of the expression of an intact brush border antigen (Prominin-1) in C57BL6/J mice subjected to a controlled, two-hit model of renal fibrosis (reversible ischemic acute kidney injury (AKI) or sham surgery, followed by angiotensin 2 administration). A transcriptomic high throughput sequencing was performed on total mRNA from these cells, and on whole kidneys., Results: In contrast to mice subjected to sham surgery, mice with a history of AKI displayed histologically more renal fibrosis when exposed to angiotensin 2. High throughput RNA sequencing, principal component analysis and clustering showed marked consistency within experimental groups. As expected, FAO transcripts were decreased in whole fibrotic kidneys. Surprisingly, however, up- rather than down-regulation of metabolic pathways (oxidative phosphorylation, fatty acid metabolism, glycolysis, and PPAR signalling pathway) was a hallmark of the differentiated tubules captured from fibrotic kidneys. Immunofluorescence co-staining analysis confirmed that the expression of FAO enzymes was dependent of tubular trophicity., Conclusions: These data suggest that in differentiated proximal tubules energetic hyperactivity is promoted concurrently with organ fibrogenesis., (© 2018 The Author(s). Published by S. Karger AG, Basel.)

Purpose: Data for ANCA-associated vasculitis (AAV) patients requiring intensive care are scarce., Methods: We included 97 consecutive patients with acute AAV manifestations (new onset or relapsing disease), admitted to 18 intensive care units (ICUs) over a 10-year period (2002-2012). A group of 95 consecutive AAV patients with new onset or relapsing disease, admitted to two nephrology departments with acute vasculitis manifestations, constituted the control group., Results: In the ICU group, patients predominantly showed granulomatosis with polyangiitis and proteinase-3 ANCAs. Compared with the non-ICU group, the ICU group showed comparable Birmingham vasculitis activity score and a higher frequency of heart, central nervous system and lungs involvements. Respiratory assistance, renal replacement therapy and vasopressors were required in 68.0, 56.7 and 26.8% of ICU patients, respectively. All but one patient (99%) received glucocorticoids, 85.6% received cyclophosphamide, and 49.5% had plasma exchanges as remission induction regimens. Fifteen (15.5%) patients died during the ICU stay. The following were significantly associated with ICU mortality in the univariate analysis: the need for respiratory assistance, the use of vasopressors, the occurrence of at least one infection event in ICU, cyclophosphamide treatment, sequential organ failure assessment at admission and simplified acute physiology score II. After adjustment on sequential organ failure assessment or infection, cyclophosphamide was no longer a risk factor for mortality. Despite a higher initial mortality rate of ICU patients within the first hospital stay (p < 0.0001), the long-term mortality of hospital survivors did not differ between ICU and non-ICU groups (18.6 and 20.4%, respectively, p = 0.36). Moreover, we observed no renal survival difference between groups after a 1-year follow-up (82.1 and 80.5%, p = 0.94)., Conclusion: This study supports the idea that experiencing an ICU challenge does not impact the long-term prognosis of AAV patients.

Acute tubular damage is a major cause of renal failure, especially at the early phase of kidney transplant when ischemia-reperfusion injury and cyclosporin A toxicity may coexist. The mechanisms of the latter are largely unknown. Using an mRNA microarray on microdissected tubules from a rat model of cyclosporin A toxicity to describe the related epithelial-specific transcriptional signature in vivo, we found that cyclosporin A induces pathways dependent on the transcription factor ATF4 and identified nuclear protein transcriptional regulator 1 (Nupr1), a stress response gene induced by ATF4, as the gene most strongly upregulated. Upon cyclosporin A treatment, Nupr1-deficient mice exhibited worse renal tubular lesions than wild-type mice. In primary cultures treated with cyclosporin A, renal tubular cells isolated from Nupr1-deficient mice exhibited more apoptosis and ATP depletion than cells from wild-type mice. Furthermore, cyclosporin A decreased protein synthesis and abolished proliferation in wild-type tubular cells, but only reduced proliferation in Nupr1-deficient cells. Compared with controls, mouse models of ischemia-reperfusion injury, urinary obstruction, and hypertension exhibited upregulated expression of renal NUPR1, and cyclosporin A induced Nupr1 expression in cultured human tubular epithelial cells. Finally, immunohistochemical analysis revealed strong expression of NUPR1 in the nuclei of renal proximal tubules of injured human kidney allografts, but not in those of stable allografts. Taken together, these results suggest that epithelial expression of NUPR1 has a protective role in response to injury after renal transplant and, presumably, in other forms of acute tubular damage., (Copyright © 2017 by the American Society of Nephrology.)

Background: There is recent evidence to show that patients suffering from acute kidney injury are at increased risk of developing chronic kidney disease despite the fact that surviving tubular epithelial cells have the capacity to fully regenerate renal tubules and restore renal function within days or weeks. The aim of the study was to investigate the impact of acute kidney injury on de novo chronic kidney disease., Methods: The authors conducted a retrospective population-based cohort study of patients initially free from chronic kidney disease who were scheduled for elective cardiac surgery with cardiopulmonary bypass and who developed an episode of acute kidney injury from which they recovered. The study was conducted at two French university hospitals between 2005 and 2015. These individuals were matched with patients without acute kidney injury according to a propensity score for developing acute kidney injury., Results: Among the 4,791 patients meeting the authors' inclusion criteria, 1,375 (29%) developed acute kidney injury and 685 fully recovered. Propensity score matching was used to balance the distribution of covariates between acute kidney injury and non- acute kidney injury control patients. Matching was possible for 597 cases. During follow-up, 34 (5.7%) had reached a diagnosis of chronic kidney disease as opposed to 17 (2.8%) in the control population (hazard ratio, 2.3; bootstrapping 95% CI, 1.9 to 2.6)., Conclusions: The authors' data consolidate the recent paradigm shift, reporting acute kidney injury as a strong risk factor for the rapid development of chronic kidney disease.

Urinary messenger RNA (mRNA) quantification is a promising method for noninvasive diagnosis of renal allograft rejection (AR), but the quantification of mRNAs in urine remains challenging due to degradation. RNA normalization may be warranted to overcome these issues, but the strategies of gene normalization have been poorly evaluated. Herein, we address this issue in a case-control study of 108 urine samples collected at time of allograft biopsy in kidney recipients with (n = 52) or without (n = 56) AR by comparing the diagnostic value of IP-10 and CD3ε mRNAs-two biomarkers of AR-after normalization by the total amount of RNA, normalization by one of the three widely used reference RNAs-18S, glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and Hypoxanthine-guanine phosphoribosyltransferase (HPRT)-or normalization using uroplakin 1A (UPK) mRNA as a possible urine-specific reference mRNA. Our results show that normalization based on the total quantity of RNA is not substantially improved by additional normalization and may even be worsened with some classical reference genes that are overexpressed during rejection. However, considering that normalization by a reference gene is necessary to ensure polymerase chain reaction (PCR) quality and reproducibility and to suppress the effect of RNA degradation, we suggest that GAPDH and UPK1A are preferable to 18S or HPRT RNA., (© Copyright 2016 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background: There is an unresolved debate on the best screening method for hematuria as a symptom of glomerulonephritis or urological malignancies. The urinary dipstick is generally considered as an imperfect surrogate for urine microscopy analysis., Results: We designed a study to compare urine microscopy analysis, urinary dipstick and flow cytometry, using controlled dilutions of blood in urine samples from volunteers collected in two different physiologically-relevant conditions (basal state and hyperhydration). We found that although all techniques were 100 % effective in detecting hematuria at basal state, these results were variably reproduced when testing the same final amount of hematuria in urine collected after hyperhydration. Our data shows a variable sensitivity for the detection of hematuria by urine microscopy analysis or flow cytometry, but not by urinary dipstick., Conclusions: Urinary dipstick qualifies as a better screening test for hematuria than urine microscopy analysis or flow cytometry, as it is sensitive and performs better in unstandardized conditions. It is universally available and also faster and cheaper than cytometric techniques.

Antiglomerular basement membrane (GBM) disease is known as a super-acute proliferative glomerulonephritis caused by auto-antibodies targeting the NC1 domain of the α3 chain of type IV collagen.Here, we describe a case of atypical anti-GBM disease presenting as a dialysis-dependent acute renal failure with unusual mild glomerular involvement. We found that immunoglobulin G (IgG) deposits were restricted to the uncommon IgG2 and IgG4 subclasses, and that blood was positive for anti-GBM antibodies by immunofluorescence, but not by Enzyme Linked Immunosorbent Assay (ELISA). The patient was treated with plasma exchanges, corticosteroids, and cyclosphosphamide. He eventually regained a normal renal function.This case demonstrates that biopsy-proven anti-GBM disease can have reduced pathogenicity. Referring to previous studies of anti-GBM detection in the blood from healthy or minimally ill individuals, we discuss the antigenic specificities, the IgG subclasses, and the involvement of complement in this observation.We suggest that anti-GBM disease is a heterogeneous entity and that the study of IgG subclasses by immunofluorescence may help to distinguish categories with different severities.

It has been suggested that bone marrow derived stem cells have the ability to engraft the kidney and improve the outcome of severe acute kidney injury (AKI) in mice exposed to high doses of cisplatin, providing hope for cancer patients in whom irreversible renal damage occasionally occurs following the use of this highly effective anti-tumor drug. We tested the therapeutic potential of bone marrow derived cells injected during the acute phase (day 3 after cisplatin administration) of experimentally-induced AKI in C57Bl6/J mice, characterized by massive tubular necrosis, apoptosis, and a low proliferation capacity. We failed to show any benefit of bone marrow derived cells versus a regular homogenate of intact renal cells, or normal saline. Using cell tracers and flow cytometry, we demonstrated that bone marrow derived cells did indeed home to the bone marrow of the recipients but failed to settle in the kidney. Conversely, renal cells homed to injured kidneys. However, neither cell therapy protected the animals against cisplatin-induced death. We therefore question the short-term efficacy of bone marrow derived cells used to repair established injuries of the tubular epithelium.

Epigenetics is the study of how cells, organs, and even individuals utilize their genes over specific periods of time, and under specific environmental constraints. Very importantly, epigenetics is now expanding into the field of medicine and hence should provide new information for the development of drugs. Bomsztyk and colleagues have detected major epigenetic changes occurring in several organs as early as 6 h after the onset of a mouse model of multiple organ dysfunction syndrome induced by Staphylococcus aureus lung injury. Decrease in mRNA of key genes involved in endothelial function was found to be associated with (and potentially explained by) a decrease in permissive histone marks, while repressive marks were unchanged. We discuss here the limitations of a whole-organ as opposed to a cell-specific approach, the nature of the controls that were chosen, and the pitfalls of histone modifications as a cause of the eventual phenotype. While the use of 'epidrugs' is definitely welcome in the clinic, how and when they will be used in sepsis-related multiple organ dysfunction will require further experimental studies.

Background: Experimental models are inevitably a compromise between accurately reproducing a pathological situation and schematically simplifying it, which is intended to provide both relevance and conclusiveness. In-vivo models are very relevant, but multiple cell-types undergoing various changes may hinder the observation of individual molecular events., Results: Here, we describe a method for analyzing and isolating specific cell types from the kidney and studying the phenotype they have acquired in vivo. Using flow cytometry, immunofluorescence, and RT-PCR, we show that our method is suitable for studying and isolating proximal tubular cells with an anti Prominin-1 antibody. Kidneys are subjected to mechanical dissociation followed by flow-cytometry analysis. Hundreds of thousands of proximal tubular cells are then isolated by magnetic separation followed by direct analysis or primary cell culture. Using our method, we detect phenotypic changes in the proximal tubular cells after renal ischemia reperfusion, and we isolate the proximal tubular cells, with a purity over 80%., Conclusions: This method is efficient, quick, simple, and cheap, and should be useful for studying cell-type specific parameters after in vivo experimental studies. It is also a simple method to obtain a specific primary cell culture from any animal strain.

Epithelial-mesenchymal transition (EMT) is a process by which differentiated epithelial cells undergo a phenotypic conversion and acquire a mesenchymal phenotype, including elongated morphology, enhanced migratory and invasion capacity, and greatly increased production of extracellular matrix (ECM) components. This phenomenon plays a pivotal role in embryonic development, wound healing and tissue regeneration. It has also been involved in organ fibrosis. Some studies suggest that following injury, renal tubular epithelial cells undergo reprograming in mesenchymal cells, and thus constitute an important source of de novo myofibroblasts invading the renal interstitium and contributing to fibrosis. However, an increasing number of studies raise doubts about the existence of this process in vivo. The role of EMT in the development of renal fibrosis remains a matter of intense debate and may depend on the model studied. In this review, we describe the role of EMT in the development of fibrosis of renal graft, and then we propose approaches for detecting and treating renal fibrogenesis by targeting TEM., (© 2015 médecine/sciences – Inserm.)

Introduction: Warfarin-related nephropathy (WRN) is a newly recognized entity, which is characterized by the occlusion of renal tubules by red blood cells following glomerular hemorrhage in a patient overexposed to warfarin (international normalized ratio>3)., Case Report: We report a 70-year-old man with no previous renal condition who developed WRN when his INR was>12. He did not fully recover his previous renal function., Conclusion: The diagnosis of WRN should be considered whenever INR exceeds 3 in patients exposed to warfarin, particularly in the presence of hematuria. Vitamin K is the only therapeutic option., (Copyright © 2013 Société nationale française de médecine interne (SNFMI). Published by Elsevier SAS. All rights reserved.)

Background: The epithelial response to injury is stereotypical and reminiscent of epithelial-to-mesenchymal transitions (EMTs), such as those observed during embryogenesis and tumour metastasis. In the context of solid organ transplantation, EMT-like features are often acquired by epithelial cells and are predictive of graft fibrosis. Here, we studied the possible involvement of several major transcriptional regulators, including snail1, phospho-Smad 2/3 and zeb1, in EMT induction in human renal grafts., Methods: We used immunohistochemistry to detect the presence of these EMT transcriptional regulators along with that of two validated EMT markers (intra-cytoplasmic translocation of β-catenin, de novo expression of vimentin), in 103 renal graft biopsy samples taken for routine surveillance or for a clinical indication., Results: We observed the nuclear accumulation of snail1 and phospho-smad2/3 in tubular cells displaying EMT. The level of snail1 was significantly correlated with the scores of EMT markers (β-catenin: ρ = 0.94, P < 0.0001; vimentin: ρ = 0.93, P < 0.0001) and with deteriorated graft function and proteinuria at the time of biopsy. Furthermore, intense staining for both snail1 and vimentin in tubular cells (≥10% of tubules) was predictive of graft dysfunction 21 months post-biopsy, independently of the other known risk factor for long-term graft dysfunction. In contrast, in both normal and diseased graft, zeb1 expression was detected exclusively in the endothelial cells of glomeruli and peritubular capillaries., Conclusion: This study suggests that snail1 is closely related to the fibrogenic, EMT-like response of the tubular epithelium in human renal grafts and predictive of graft function loss., (© The Author 2013. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

Renal epithelial cells arise during embryogenesis by mesenchymal to epithelial transition (MET). In the context of renal diseases, these cells can switch back to a mesenchymal phenotype, in a process thus reminiscent of an epithelial-to-mesenchymal transition (EMT) in which we referred to as "Epithelial Phenotypic Changes" (EPC). The pathophysiological consequence of EPC is controversial: in particular, to what extent EPC contribute to the pool of disease-associated renal fibroblasts is very uncertain. However, there is strong evidence that EPC correlate with a poor renal outcome. EPC indeed reflect an exposure to a profibrotic environment, at an early and potentially reversible stage. Detecting EPC has potential therapeutic implications for patients prone to renal fibrosis, both as a marker of efficacy or more directly as a target. In opposition to the EMT occurring during embryogenesis, EMT in fibrosis as well as in cancer is an anarchic cellular process actually developing at the expense of the whole organ(ism)., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)