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| Open AccessInhibition of ALKBH5 attenuates I/R-induced renal injury in male mice by promoting Ccl28 m6A modification and increasing Treg recruitment
m6A modification has been reported to play roles in many developmental and pathological processes, but its role in AKI remains poorly understood. Here, the authors show the role and the mechanism of the m6A demethylase, ALKBH5 on IRI induced AKI.
- Juntao Chen
- , Cuidi Xu
- & Tongyu Zhu
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Article
| Open AccessNext-Generation Morphometry for pathomics-data mining in histopathology
Pathology diagnostics still rely on tissue morphology assessment by trained experts. Here, the authors perform deep-learning-based segmentation followed by large-scale feature extraction of histological images, i.e., next-generation morphometry, to enable outcome-relevant and disease-specific pathomics analysis of non-tumor kidney pathology.
- David L. Hölscher
- , Nassim Bouteldja
- & Peter Boor
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Article
| Open AccessThe classical pathway triggers pathogenic complement activation in membranous nephropathy
It is generally thought that complement activation in human membranous nephropathy (MN) occurs predominantly via the lectin or alternative pathway. Here, the authors show that the classical pathway is the dominant form of complement activation in MN and a pathogenic driver of the disease.
- Larissa Seifert
- , Gunther Zahner
- & Nicola M. Tomas
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Article
| Open AccessLong-term statins administration exacerbates diabetic nephropathy via ectopic fat deposition in diabetic mice
Huang et al. investigated the effects of long-term statins administration in a mouse model for diabetes and found that it can worsen insulin resistance, renal inflammation and fibrosis. Statins increased renal lipid uptake and inhibited fatty acid oxidation, contributing to diabetic nephropathy.
- Tong-sheng Huang
- , Teng Wu
- & Wei-bin Cai
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Article
| Open AccessEpigenome-wide meta-analysis identifies DNA methylation biomarkers associated with diabetic kidney disease
Approximately 40 percent of people with type 1 diabetes develop kidney disease, but the risk factors are not well understood. Here, the authors identify DNA methylation signatures associated with diabetic kidney disease, of which 21 biomarkers predict the development of kidney failure.
- Laura J. Smyth
- , Emma H. Dahlström
- & Amy Jayne McKnight
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Article
| Open AccessSingle-cell profiling of healthy human kidney reveals features of sex-based transcriptional programs and tissue-specific immunity
Knowledge of the transcriptional programs of human kidney cell populations at homeostasis is limited. Here, the authors show sex-based differences in gene expression of kidney parenchymal cells and examine the complexity of kidney-resident immune cells using single cell RNA sequencing of healthy living kidney donors.
- Caitriona M. McEvoy
- , Julia M. Murphy
- & Sarah Q. Crome
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Article
| Open AccessTargeting endogenous kidney regeneration using anti-IL11 therapy in acute and chronic models of kidney disease
Repair processes in kidney are impaired in severe disease. Here, the authors show that in kidney failure, genetic or pharmacologic inhibition of IL11 releases the brake on regeneration, reverses tissue damage and restores kidney function.
- Anissa A. Widjaja
- , Sivakumar Viswanathan
- & Stuart A. Cook
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Article
| Open AccessChromatin accessibility dynamics dictate renal tubular epithelial cell response to injury
Renal tubular epithelial cells (TECs) can initiate an adaptive or maladaptive response after injuries of different severity. Here, the authors elucidate a chromatin-mediated mechanism underlying the responses of TECs to varying kidney injuries.
- Xinyi Cao
- , Jiuchen Wang
- & Lirong Zhang
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Article
| Open AccessGenetic regulation of serum IgA levels and susceptibility to common immune, infectious, kidney, and cardio-metabolic traits
Immunoglobulin A protects against infectious disease and contributes to autoimmune and inflammatory disorders. Here, the authors perform a genome-wide association study for serum IgA levels, identifying 20 genome-wide significant loci, providing new insights into the genetic regulation of IgA levels.
- Lili Liu
- , Atlas Khan
- & Krzysztof Kiryluk
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Article
| Open AccessCircular RNA circBNC2 inhibits epithelial cell G2-M arrest to prevent fibrotic maladaptive repair
G2/M arrest of epithelial cells leads to fibrosis with unclear mechanisms. This study identifies a protein-encoding circRNA, circBNC2, which inhibits epithelial cells G2/M arrest to prevent fibrotic maladaptive repair in damaged kidney and liver, revealing a potential intervention target for fibrosis.
- Peng Wang
- , Zhitao Huang
- & Fan Fan Hou
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Article
| Open AccessUnderstanding fibrosis pathogenesis via modeling macrophage-fibroblast interplay in immune-metabolic context
Renal fibrosis is a progressive process with complex etiopathology, causing organ failure. Here authors present a mathematical model, based on an in vitro system faithfully contemplating macrophage-fibroblast interaction and the metabolic-immunologic signals that are affecting kidney fibrosis, that is applicable to kidney transplant failure.
- Elisa Setten
- , Alessandra Castagna
- & Massimo Locati
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Article
| Open AccessDefining cellular complexity in human autosomal dominant polycystic kidney disease by multimodal single cell analysis
Autosomal dominant polycystic kidney disease (ADPKD) is a complicated disease that involves numerous cell types. Here the authors used a multiomics approach consisting of single nucleus transcriptomes and epigenomes to redefine cell states in ADPKD and to dissect the cellular interactions and molecular mechanisms of ADPKD.
- Yoshiharu Muto
- , Eryn E. Dixon
- & Benjamin D. Humphreys
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Article
| Open AccessTubular cell polyploidy protects from lethal acute kidney injury but promotes consequent chronic kidney disease
Acute kidney injury is frequent, often fatal and can leave survivors with chronic kidney disease. Here the authors show that tubular cell polyploidy reduces early fatality sustaining residual function but promotes chronic kidney disease, which can be prevented by blocking YAP1
- Letizia De Chiara
- , Carolina Conte
- & Paola Romagnani
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Article
| Open AccessImmune-mediated tubule atrophy promotes acute kidney injury to chronic kidney disease transition
Acute kidney injury can lead to chronic kidney disease. Here the authors show that the transition is related to a macrophage-mediated second wave of inflammatory cells that promote late tubule injury, dedifferentiation and fibrosis. Suppressing this second wave reduced tubular loss and kidney atrophy.
- Leyuan Xu
- , Jiankan Guo
- & Lloyd G. Cantley
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Article
| Open AccessPKD1 and PKD2 mRNA cis-inhibition drives polycystic kidney disease progression
ADPKD, a common aetiology of kidney failure, is caused by heterozygous PKD1 or PKD2 mutations. Here the authors show that preventing 3′-UTR cis-inhibition of mRNAs produced by the non-inactivated PKD1/2 alleles ameliorates preclinical ADPKD.
- Ronak Lakhia
- , Harini Ramalingam
- & Vishal Patel
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Article
| Open AccessRenal UTX-PHGDH-serine axis regulates metabolic disorders in the kidney and liver
Chen et al. report on a renal UTX-phosphoglycerate dehydrogenase axis that regulates serine secretion to affect lipid metabolism in the kidney and liver upon over-nutrition, suggesting potential treatment targets for obesity-related diseases.
- Hong Chen
- , Chong Liu
- & Ling Zheng
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Article
| Open AccessOpposite physiological and pathological mTORC1-mediated roles of the CB1 receptor in regulating renal tubular function
Renal proximal tubules modulate whole-body homeostasis by sensing various nutrients. Here the authors describe the existence and importance of a unique CB1/mTORC1/GLUT2 signaling axis in regulating nutrient homeostasis in healthy and diseased kidney.
- Liad Hinden
- , Majdoleen Ahmad
- & Joseph Tam
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Article
| Open AccessLoss of CLDN5 in podocytes deregulates WIF1 to activate WNT signaling and contributes to kidney disease
Claudin-5 is a tight junction integral membrane protein, but it is also expressed in mature podocytes which lack tight junctions. Here the authors report that podocyte claudin-5 regulates WNT signaling activity by modulating WIF1 expression, and its downregulation contributes to kidney disease progression in mice.
- Hui Sun
- , Hui Li
- & Yongfeng Gong
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Article
| Open AccessA Klotho-derived peptide protects against kidney fibrosis by targeting TGF-β signaling
Klotho is an anti-ageing protein whose expression is downregulated in chronic kidney disease, but the large size of the protein makes it challenging to deliver therapeutically. Here, the authors develop a Klotho-derived peptide, and show that it recapitulates the anti-fibrotic action of Klotho and prevents kidney fibrosis in mice by targeting TGF-β signalling.
- Qian Yuan
- , Qian Ren
- & Youhua Liu
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Article
| Open AccessMeta-analyses identify DNA methylation associated with kidney function and damage
Many genetic loci have been identified to be associated with kidney disease, but the molecular mechanisms are not well understood. Here, the authors perform epigenome-wide association studies on kidney function measures to identify epigenetic marks and pathways involved in kidney function.
- Pascal Schlosser
- , Adrienne Tin
- & Alexander Teumer
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Article
| Open AccessInsulin-activated store-operated Ca2+ entry via Orai1 induces podocyte actin remodeling and causes proteinuria
Perturbations of Ca2+ signaling in podocytes may deteriorate kidney function and eventually lead to proteinuria. Here the authors show that insulin can affect the function of the calcium regulator Ora1 in podocytes, which is critical for maintaining kidney filter integrity.
- Ji-Hee Kim
- , Kyu-Hee Hwang
- & Seung-Kuy Cha
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Article
| Open AccessChromatin-accessibility estimation from single-cell ATAC-seq data with scOpen
scATAC-Seq yields data that is extremely sparse. Here, the authors present a computationally efficient imputation method called scOpen that improves the downstream analyses of scATAC-Seq data and use it to identify transcriptional regulators of kidney fibrosis.
- Zhijian Li
- , Christoph Kuppe
- & Ivan G. Costa
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Article
| Open AccessA single genetic locus controls both expression of DPEP1/CHMP1A and kidney disease development via ferroptosis
Identifying causal variants and genes is an essential step in interpreting GWAS loci. Here, the authors investigate a kidney disease GWAS locus with functional genomics data, CRISPR editing and mouse experiments to identify DPEP1 and CHMP1A as putative kidney disease genes via ferroptosis.
- Yuting Guan
- , Xiujie Liang
- & Katalin Susztak
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Article
| Open AccessCompounds targeting OSBPL7 increase ABCA1-dependent cholesterol efflux preserving kidney function in two models of kidney disease
This study describes a class of small molecule compounds that promote ABCA1-dependent cholesterol efflux via a non-transcriptional mechanism, the identification of the molecular target by a chemical biology approach, and the potential of these agents for the treatment of chronic kidney diseases and potentially other diseases where lipid accumulation drives disease progression.
- Matthew B. Wright
- , Javier Varona Santos
- & Alessia Fornoni
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Article
| Open AccessExtracellular vesicles and exosomes generated from cystic renal epithelial cells promote cyst growth in autosomal dominant polycystic kidney disease
Autosomal dominant polycystic kidney disease is characterized by the formation of cysts in the kidney. Here the authors show that cystic extracellular vesicles/exosomes play a critical role in regulating the biology and function of adjacent cells, including renal epithelial cells, fibroblasts and macrophages, and contribute to renal cyst growth.
- Hao Ding
- , Linda Xiaoyan Li
- & Xiaogang Li
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Article
| Open AccessDysfunction of the key ferroptosis-surveilling systems hypersensitizes mice to tubular necrosis during acute kidney injury
Necroptosis, a form of cell death, occurs in acute renal injury. Here, the authors show that ferroptosis—a form of cell death dependent on iron - also occurs during acute kidney injury, and show that an inhibitor of ferroptosis can improve survival in a mouse model of acute kidney damage.
- Wulf Tonnus
- , Claudia Meyer
- & Andreas Linkermann
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Article
| Open AccessImportance of the renal ion channel TRPM6 in the circadian secretion of renin to raise blood pressure
Circadian variation of blood pressure, with higher values in the active period, is associated with the risk of fatal cardiovascular events. Here, we show the importance of renal TRPM6, a Magnesium-permeable cation channel, in raising blood pressure by stimulating renin secretion.
- Yosuke Funato
- , Daisuke Yamazaki
- & Hiroaki Miki
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Article
| Open AccessHuman kidney is a target for novel severe acute respiratory syndrome coronavirus 2 infection
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can lead to acute kidney injury. The authors describe that SARS-COV-2 can directly infect human kidney, possibly mediating tubular pathogenesis.
- Bo Diao
- , Chenhui Wang
- & Yongwen Chen
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Article
| Open AccessKidney intercalated cells are phagocytic and acidify internalized uropathogenic Escherichia coli
Kidney intercalated cells are involved in acid-base homeostasis in the kidneys. Here, the authors use single cell transcriptomics and find that interalated cells exhibit a transcriptional response conducive to defense and can engulf and acidify internalized bacteria, similarly to professional phagocytes.
- Vijay Saxena
- , Hongyu Gao
- & Andrew L. Schwaderer
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Article
| Open AccessLoss of endothelial glucocorticoid receptor accelerates diabetic nephropathy
The endothelial glucocorticoid receptor plays a key role in the regulation of many diseases, including diabetes. Loss of this receptor results in accelerated renal fibrosis, a heightened inflammatory milieu, augmented Wnt signaling and suppression of fatty acid oxidation in diabetic kidneys.
- Swayam Prakash Srivastava
- , Han Zhou
- & Julie Goodwin
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Article
| Open AccessSingle cell transcriptional and chromatin accessibility profiling redefine cellular heterogeneity in the adult human kidney
Single cell transcriptomic and epigenomic sequencing of human kidney highlight diverse cell types and states. These findings help characterize a novel population of injured proximal tubule cells and illustrate the power of multi-omic approaches to characterizing human tissue.
- Yoshiharu Muto
- , Parker C. Wilson
- & Benjamin D. Humphreys
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Article
| Open AccessSingle-cell RNA sequencing reveals the mesangial identity and species diversity of glomerular cell transcriptomes
The molecular identity of renal glomerular cells is poorly characterized and rodent glomerulopathy models translate poorly to humans. Here, the authors show molecular signatures of glomerulus-associated cells using single cell RNA sequencing and highlight differences between mouse and human cells.
- Bing He
- , Ping Chen
- & Jaakko Patrakka
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Article
| Open AccessCatalytic activity tunable ceria nanoparticles prevent chemotherapy-induced acute kidney injury without interference with chemotherapeutics
Reactive oxygen species management is a practical strategy that can reduce the risk of chemotherapy-induced acute kidney injury, but at the cost of chemotherapeutic efficacy. Here the authors report catalytic activity tunable ceria nanoparticles as context-dependent reactive oxygen species scavengers, which can prevent chemotherapy-induced acute kidney injury without interfering with chemotherapeutic agents.
- Qinjie Weng
- , Heng Sun
- & Daishun Ling
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Review Article
| Open AccessRenal metabolism and hypertension
Hypertension is one of the most important risk factors for cardiovascular disease. The kidneys, which have a very high metabolic rate, play a fundamental role in blood pressure regulation. In this review, the authors discuss recent studies on the role of renal metabolism in the development of hypertension.
- Zhongmin Tian
- & Mingyu Liang
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Article
| Open AccessA metabolically stable apelin-17 analog decreases AVP-induced antidiuresis and improves hyponatremia
Apelin and AVP have opposing effects water balance in humans and rodents. Here, the authors report that a metabolically stable apelin-17 analog, by acting at the kidney level, reduces AVP-induced antidiuresis and improves hyponatremia in rodents, demonstrating a potential approach for treating water metabolism disorders.
- Adrien Flahault
- , Pierre-Emmanuel Girault-Sotias
- & Catherine Llorens-Cortes
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Article
| Open AccessCross-site transportability of an explainable artificial intelligence model for acute kidney injury prediction
Artificial intelligence (AI) has demonstrated promise in predicting acutekidney injury (AKI), however, clinical adoption of these models requires interpretability and transportability across sites. Here, the authors develop an AKI prediction model and a measure for model transportability across six independent health systems.
- Xing Song
- , Alan S. L. Yu
- & Mei Liu
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Article
| Open AccessInherited salt-losing tubulopathies are associated with immunodeficiency due to impaired IL-17 responses
Salt levels in culture affect the polarisation of Th17 cells, which normally protect the host from fungal and bacterial infections. Here, the authors study patients with salt-losing tubulopathies (SLT) to find that, while Th17 immunity is dampened in SLT patients, their Th17-inducing signaling pathways are intact and can be reinvigorated by exogenous salt.
- Rhys D. R. Evans
- , Marilina Antonelou
- & Alan D. Salama
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Article
| Open AccessCyst growth in ADPKD is prevented by pharmacological and genetic inhibition of TMEM16A in vivo
Polycystic kidney disease (PKD) is characterized by the formation of large renal cysts, which lead to a decline in renal function. Here the authors show that genetic and chemical inhibition of TMEM16A largely reduces cyst enlargement in an in vivo model of autosomal dominant PKD.
- Ines Cabrita
- , Andre Kraus
- & Björn Buchholz
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Article
| Open AccessEnhancer and super-enhancer dynamics in repair after ischemic acute kidney injury
Acute kidney injury is a major health problem amongst hospitalized patients. Here the authors provide a comprehensive characterization of enhancer and super-enhancer elements, and the transcription factor motifs associated with these elements in response to kidney injury in vivo; providing insight into the regulation of kidney repair.
- Julia Wilflingseder
- , Michaela Willi
- & Joseph V. Bonventre
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Article
| Open AccessDevelopment of an exon skipping therapy for X-linked Alport syndrome with truncating variants in COL4A5
Alport syndrome is a progressive inherited nephritis accompanied by sensorineural loss of hearing and ocular abnormalities, for which there is currently no effective therapy. Here, the authors develop an exon-skipping therapy using an antisense-oligonucleotide and show it is effective in mouse models.
- Tomohiko Yamamura
- , Tomoko Horinouchi
- & Kandai Nozu
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Article
| Open AccessThe ABCG2 Q141K hyperuricemia and gout associated variant illuminates the physiology of human urate excretion
The common ABCG2 variant Q141K contributes to hyperuricemia and gout risk. Here, using a human interventional study and a new orthologous mouse model, the authors report a tissue specific pathobiology of the Q141K variant, and support a significant role for ABCG2 in urate excretion in both the kidney and intestine.
- Kazi Mirajul Hoque
- , Eryn E. Dixon
- & Owen M. Woodward
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Article
| Open AccessA kinome-wide screen identifies a CDKL5-SOX9 regulatory axis in epithelial cell death and kidney injury
Protein kinases have emerged as critical regulators of disease pathogenesis. Here, the authors have utilized kinome-wide screening approaches to reveal a pathogenic role of CDKL5 kinase in acute kidney injury, which is dependent on suppression of a SOX9-associated transcriptional network.
- Ji Young Kim
- , Yuntao Bai
- & Navjot Singh Pabla
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Article
| Open AccessThe genetic architecture of membranous nephropathy and its potential to improve non-invasive diagnosis
Membranous nephropathy (MN) is a rare autoimmune disease of podocyte-directed antibodies, such as anti-phospholipase A2 receptor. Here, the authors report a genome-wide association study for MN and identify two previously unreported loci encompassing the NFKB1 and IRF4 genes and additional ancestry-specific effects.
- Jingyuan Xie
- , Lili Liu
- & Krzysztof Kiryluk
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Article
| Open AccessImpaired mitophagy links mitochondrial disease to epithelial stress in methylmalonyl-CoA mutase deficiency
Methylmalonic acidemia is an inherited metabolic disease caused by loss or mutation of the enzyme MMUT. Here the authors use cell and animal models to show that MMUT mutations lead to defective mitophagy and stress in kidney cells, contributing to the pathogenesis in methylmalonic acidemia patients.
- Alessandro Luciani
- , Anke Schumann
- & Olivier Devuyst
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Article
| Open AccessGut uropathogen abundance is a risk factor for development of bacteriuria and urinary tract infection
Urinary tract infections (UTIs) are associated with changes in the gut microbiome. Here, the authors evaluate the relationship between the gut microbiome and development of UTI in kidney transplant patients and show that uropathogenic gut abundance might represent a risk factor for development of bacteriuria and UTI.
- Matthew Magruder
- , Adam N. Sholi
- & John Richard Lee
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Article
| Open AccessSingle cell census of human kidney organoids shows reproducibility and diminished off-target cells after transplantation
How reproducible human kidney organoids derived from different iPSC lines are, and how faithful they are to human kidney tissue remain unclear. Here, the authors use four human iPSC lines to derive kidney organoids and show how organoid composition is reproducible, comparable to human tissue and of improved quality after transplantation.
- Ayshwarya Subramanian
- , Eriene-Heidi Sidhom
- & Anna Greka
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Article
| Open AccessGenetic variants of calcium and vitamin D metabolism in kidney stone disease
Kidney stones form in the presence of overabundance of crystal-forming substances such as Ca2+ and oxalate. Here, the authors report genome-wide association analyses for kidney stone disease, report seven previously unknown loci and find that some of these loci also associate with Ca2+ concentration and excretion.
- Sarah A. Howles
- , Akira Wiberg
- & Dominic Furniss
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Article
| Open AccessTargeting the mTOR pathway uncouples the efficacy and toxicity of PD-1 blockade in renal transplantation
The use of immune checkpoint inhibitors (ICI) in cancer patients with solid organ allografts is hampered due to potential organ rejection. Here, the authors present a case report of a patient with kidney allograft and show that treatment with the mTOR inhibitor sirolimus preserves peripheral tolerance and anti-tumour efficacy of ICI therapy.
- Khashayar Esfahani
- , Tho-Alfakar Al-Aubodah
- & Wilson H. Miller
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Article
| Open AccessArctigenin attenuates diabetic kidney disease through the activation of PP2A in podocytes
Arctigenin (ATG) is the major active component of a Chinese herbal remedy known to reduce proteinuria in patients with diabetic kidney disease (DKD). Here, Zhong et al. identify PP2A as a pharmacological target of ATG in podocytes, and find that PP2A is responsible for some of the beneficial effects of ATG in mouse models of DKD.
- Yifei Zhong
- , Kyung Lee
- & Ruijie Liu