Late Kidney Effects of Nephron-Sparing vs Radical Nephrectomy for Wilms Tumor: A Systematic Review and Meta-Analysis.

PURPOSE: We compare differences in long-term kidney function between patients undergoing either radical nephrectomy (RN) or nephron-sparing surgery (NSS) in unilateral and bilateral Wilms tumor (WT), respectively. MATERIALS AND METHODS: A systematic search was performed in September 2020. Comparative studies were evaluated according to Cochrane collaboration recommendations. Assessed long-term (>1-year postoperative) outcomes included chronic kidney disease, hypertension and glomerular filtration rate, among others. Odds ratio and mean difference with 95% confidence interval were extrapolated from available data for quantitative synthesis. Random-effects meta-analysis and meta-regression were performed according to study design and techniques. The systematic review was prospectively registered on PROSPERO (CRD42020205378). RESULTS: A total of 23 studies describing 293 cases of unilateral WT and 386 cases of bilateral WT were included in the qualitative synthesis. Overall effect estimates demonstrate that patients undergoing RN have significantly increased odds of developing abnormal kidney function (OR 4.29, 95% CI 1.02, 18.00) and lower estimated glomerular filtration rate at long-term followup (mean difference -8.99, 95% CI -16.40, -1.58) compared to those undergoing NSS. In bilateral WT, patients undergoing RN with contralateral NSS have higher odds of developing abnormal kidney function (OR 3.82, 95% CI 1.76, 8.33) and hypertension (OR 5.81, 95% CI 1.31, 25.68) compared to bilateral NSS. CONCLUSIONS: Current evidence is low quality but suggests that NSS for unilateral and bilateral WT may be associated with better kidney function or blood pressure at late followup. Further research to investigate sources of heterogeneity is recommended.

A Canadian Study of Cisplatin Metabolomics and Nephrotoxicity (ACCENT): A Clinical Research Protocol.

BACKGROUND: Cisplatin, a chemotherapy used to treat solid tumors, causes acute kidney injury (AKI), a known risk factor for chronic kidney disease and mortality. AKI diagnosis relies on biomarkers which are only measurable after kidney damage has occurred and functional impairment is apparent; this prevents timely AKI diagnosis and treatment. Metabolomics seeks to identify metabolite patterns involved in cell tissue metabolism related to disease or patient factors. The A Canadian study of Cisplatin mEtabolomics and NephroToxicity (ACCENT) team was established to harness the power of metabolomics to identify novel biomarkers that predict risk and discriminate for presence of cisplatin nephrotoxicity, so that early intervention strategies to mitigate onset and severity of AKI can be implemented. OBJECTIVE: Describe the design and methods of the ACCENT study which aims to identify and validate metabolomic profiles in urine and serum associated with risk for cisplatin-mediated nephrotoxicity in children and adults. DESIGN: Observational prospective cohort study. SETTING: Six Canadian oncology centers (3 pediatric, 1 adult and 2 both). PATIENTS: Three hundred adults and 300 children planned to receive cisplatin therapy. MEASUREMENTS: During two cisplatin infusion cycles, serum and urine will be measured for creatinine and electrolytes to ascertain AKI. Many patient and disease variables will be collected prospectively at baseline and throughout therapy. Metabolomic analyses of serum and urine will be done using mass spectrometry. An untargeted metabolomics approach will be used to analyze serum and urine samples before and after cisplatin infusions to identify candidate biomarkers of cisplatin AKI. Candidate metabolites will be validated using an independent cohort. METHODS: Patients will be recruited before their first cycle of cisplatin. Blood and urine will be collected at specified time points before and after cisplatin during the first infusion and an infusion later during cancer treatment. The primary outcome is AKI, defined using a traditional serum creatinine-based definition and an electrolyte abnormality-based definition. Chart review 3 months after cisplatin therapy end will be conducted to document kidney health and survival. LIMITATIONS: It may not be possible to adjust for all measured and unmeasured confounders when evaluating prediction of AKI using metabolite profiles. Collection of data across multiple sites will be a challenge. CONCLUSIONS: ACCENT is the largest study of children and adults treated with cisplatin and aims to reimagine the current model for AKI diagnoses using metabolomics. The identification of biomarkers predicting and detecting AKI in children and adults treated with cisplatin can greatly inform future clinical investigations and practices.

CONTEXTE: Le cisplatine, un agent utilisé en chimiothérapie pour traiter les tumeurs solides, entraîne de l'insuffisance rénale aiguë (IRA); un facteur de risque connu de néphropathie chronique et de mortalité. Le diagnostic de l'IRA repose sur des biomarqueurs qui ne sont mesurables qu'après l'apparition d'une lésion rénale et d'une déficience fonctionnelle; ce qui empêche le diagnostic et le traitement précoce de la maladie. La métabolomique s'efforce d'établir le profil des métabolites impliqués dans le métabolisme des tissus cellulaires en relation avec des facteurs liés à la maladie ou au patient. Une étude canadienne portant sur la métabolomique et la néphrotoxicité du cisplatine (ACCENT) s'est amorcée, elle explore la puissance de la métabolomique dans l'identification de nouveaux biomarqueurs permettant de prédire le risque de néphrotoxicité du cisplatine et d'en distinguer la présence. L'objectif étant de mettre en œuvre des stratégies d'intervention précoce, dès l'apparition de l'IRA, et de limiter la gravité de la maladie. OBJECTIFS: Décrire la conception et la méthodologie de l'étude ACCENT. Cette étude vise à établir et à valider des profils métabolomiques, dans l'urine et le sérum, associés au risque de néphrotoxicité médiée par le cisplatine chez les enfants et les adultes. TYPE D'ÉTUDE: Étude de cohorte prospective. CADRE: Six centres canadiens d'oncologie (trois centres pédiatriques, un centre pour adultes et deux centres mixtes). SUJETS: L'étude porte sur 300 adultes et 300 enfants pour qui un traitement par cisplatine est prévu. MESURES: L'IRA sera confirmée par mesure de la créatinine et des électrolytes dans le sérum et l'urine au cours de deux cycles de perfusion de cisplatine. De nombreuses variables relatives au patient et à la maladie seront recueillies prospectivement avant et pendant le traitement. Les analyses métabolomiques des échantillons de sérum et d'urine seront effectuées par spectrométrie de masse. Une approche métabolomique non ciblée sera utilisée pour analyser les échantillons avant et après les perfusions de cisplatine pour identifier les biomarqueurs candidats d'une IRA découlant du traitement par cisplatine. Les métabolites candidats seront validés dans une cohorte indépendante. MÉTHODOLOGIE: Les patients seront recrutés avant le premier cycle de cisplatine. Le sang et l'urine seront recueillis à des moments précis, soit avant et pendant le traitement; plus précisément lors de la première perfusion, puis d'une perfusion subséquente au cours du traitement contre le cancer. Le principal critère d'évaluation est la présence d'IRA, laquelle sera établie selon la définition classique fondée sur la mesure de la créatinine sérique et d'une autre définition fondée sur les anomalies électrolytiques. Un examen des dossiers trois mois après la fin du traitement par cisplatine sera effectué afin de documenter la santé rénale et la survie des patients. LIMITES: Il pourrait être impossible de corriger tous les facteurs confusionnels mesurés et non mesurés lors de l'évaluation de la prédiction de l'IRA à l'aide de profils de métabolites. La collecte de données sur plusieurs sites sera un défi. CONCLUSION: ACCENT est la plus vaste étude portant sur des enfants et des adultes traités avec le cisplatine; cette étude tente de revoir le modèle actuel en utilisant la métabolomique pour diagnostiquer l'IRA. L'identification de biomarqueurs permettant de prédire et de détecter l'IRA chez les enfants et les adultes traités par cisplatine pourrait grandement éclairer les futures études et pratiques cliniques. RENSEIGNEMENTS SUR L'ENREGISTREMENT DE L'ESSAI CLINIQUE: ClinicalTrials.gov, insuffisance rénale induite par le cisplatine, NCT04442516.

Mechanisms of cellular iron sensing, regulation of erythropoiesis and mitochondrial iron utilization.

To maintain an adequate iron supply for hemoglobin synthesis and essential metabolic functions while counteracting iron toxicity, humans and other vertebrates have evolved effective mechanisms to conserve and finely regulate iron concentration, storage, and distribution to tissues. At the systemic level, the iron-regulatory hormone hepcidin is secreted by the liver in response to serum iron levels and inflammation. Hepcidin regulates the expression of the sole known mammalian iron exporter, ferroportin, to control dietary absorption, storage and tissue distribution of iron. At the cellular level, iron regulatory proteins 1 and 2 (IRP1 and IRP2) register cytosolic iron concentrations and post-transcriptionally regulate the expression of iron metabolism genes to optimize iron availability for essential cellular processes, including heme biosynthesis and iron-sulfur cluster biogenesis. Genetic malfunctions affecting the iron sensing mechanisms or the main pathways that utilize iron in the cell cause a broad range of human diseases, some of which are characterized by mitochondrial iron accumulation. This review will discuss the mechanisms of systemic and cellular iron sensing with a focus on the main iron utilization pathways in the cell, and on human conditions that arise from compromised function of the regulatory axes that control iron homeostasis.

Mammalian iron-sulfur cluster biogenesis: Recent insights into the roles of frataxin, acyl carrier protein and ATPase-mediated transfer to recipient proteins.

The recently solved crystal structures of the human cysteine desulfurase NFS1, in complex with the LYR protein ISD11, the acyl carrier protein ACP, and the main scaffold ISCU, have shed light on the molecular interactions that govern initial cluster assembly on ISCU. Here, we aim to highlight recent insights into iron-sulfur (Fe-S) cluster (ISC) biogenesis in mammalian cells that have arisen from the crystal structures of the core ISC assembly complex. We will also discuss how ISCs are delivered to recipient proteins and the challenges that remain in dissecting the pathways that deliver clusters to numerous Fe-S recipient proteins in both the mitochondrial matrix and cytosolic compartments of mammalian cells.

Mitochondrial Iron Transporters (MIT1 and MIT2) Are Essential for Iron Homeostasis and Embryogenesis in Arabidopsis thaliana.

Iron (Fe) is an essential nutrient for virtually all organisms, where it functions in critical electron transfer processes, like those involved in respiration. Photosynthetic organisms have special requirements for Fe due to its importance in photosynthesis. While the importance of Fe for mitochondria- and chloroplast-localized processes is clear, our understanding of the molecular mechanisms that underlie the trafficking of Fe to these compartments is not complete. Here, we describe the Arabidopsis mitochondrial iron transporters, MIT1 and MIT2, that belong to the mitochondrial carrier family (MCF) of transport proteins. MIT1 and MIT2 display considerable homology with known mitochondrial Fe transporters of other organisms. Expression of MIT1 or MIT2 rescues the phenotype of the yeast mrs3mrs4 mutant, which is defective in mitochondrial iron transport. Although the Arabidopsis mit1 and mit2 single mutants do not show any significant visible phenotypes, the double mutant mit1mit2 displays embryo lethality. Analysis of a mit1 -- /mit2 + - line revealed that MIT1 and MIT2 are essential for iron acquisition by mitochondria and proper mitochondrial function. In addition, loss of MIT function results in mislocalization of Fe, which in turn causes upregulation of the root high affinity Fe uptake pathway. Thus, MIT1 and MIT2 are required for the maintenance of both mitochondrial and whole plant Fe homeostasis, which, in turn, is important for the proper growth and development of the plant.

The diverse roles of FRO family metalloreductases in iron and copper homeostasis.

Iron and copper are essential for plants and are important for the function of a number of protein complexes involved in photosynthesis and respiration. As the molecular mechanisms that control uptake, trafficking and storage of these nutrients emerge, the importance of metalloreductase-catalyzed reactions in iron and copper metabolism has become clear. This review focuses on the ferric reductase oxidase (FRO) family of metalloreductases in plants and highlights new insights into the roles of FRO family members in metal homeostasis. Arabidopsis FRO2 was first identified as the ferric chelate reductase that reduces ferric iron-chelates at the root surface-rhizosphere interface. The resulting ferrous iron is subsequently transported across the plasma membrane of root epidermal cells by the ferrous iron transporter, IRT1. Recent work has shown that two other members of the FRO family (FRO4 and FRO5) function redundantly to reduce copper to facilitate its uptake from the soil. In addition, FROs appear to play important roles in subcellular compartmentalization of iron as FRO7 is known to contribute to delivery of iron to chloroplasts while mitochondrial family members FRO3 and FRO8 are hypothesized to influence mitochondrial metal ion homeostasis. Finally, recent studies have underscored the importance of plasma membrane-localized ferric reductase activity in leaves for photosynthetic efficiency. Taken together, these studies highlight a number of diverse roles for FROs in both iron and copper metabolism in plants.

Mitochondrial iron transport and homeostasis in plants.

Iron (Fe) is an essential nutrient for plants and although the mechanisms controlling iron uptake from the soil are relatively well understood, comparatively little is known about subcellular trafficking of iron in plant cells. Mitochondria represent a significant iron sink within cells, as iron is required for the proper functioning of respiratory chain protein complexes. Mitochondria are a site of Fe-S cluster synthesis, and possibly heme synthesis as well. Here we review recent insights into the molecular mechanisms controlling mitochondrial iron transport and homeostasis. We focus on the recent identification of a mitochondrial iron uptake transporter in rice and a possible role for metalloreductases in iron uptake by mitochondria. In addition, we highlight recent advances in mitochondrial iron homeostasis with an emphasis on the roles of frataxin and ferritin in iron trafficking and storage within mitochondria.