Nephrology
Abstract
Background Cancer accounts for over 20% of late post-transplant mortality, yet the contribution of genetic susceptibility to post-transplant cancer risk remains unclear. This study investigates germline genetic risk factors for post-transplant cancer in the Finnish population using data from the FinnGen cohort. Methods A pan-cancer polygenic risk score (PRS) was constructed using genetic variants identified in UK and US populations to assess the influence of common germline variants on time to first cancer diagnosis in 1,802 Finnish kidney transplant recipients (KTRs), of whom 317 developed post-transplant cancer. The PRS was first validated in the FinnGen non-transplantation cohort and subsequently applied to KTRs, with replication in lung and liver transplant recipients (n = 476). Functional relevance was explored by assessing associations between the PRS and expression levels of 2,923 plasma proteins in the UK Biobank (n = 53,013). Results Compared to a matched non-transplantation cohort (n = 68,294), KTRs exhibited earlier cancer onset. The PRS was significantly associated with time to first cancer diagnosis in the non-transplantation population (HR 1.04; 95% CI 1.038-1.056; p = 3.75 x 10-25). Among KTRs younger than 40 years, higher PRS was associated with earlier cancer onset (HR, 1.08; 95% CI ,1.01-1.17; p = 0.036), indicating a stronger genetic effect at younger ages. The PRS significantly (Bonferroni < 0.05) altered the regulation of 87 plasma proteins, several of which were known cancer-related markers. Conclusion Inherited genetic predisposition, captured by pan-cancer PRS, may contribute to individual susceptibility to cancer after solid organ transplantation, particularly at younger ages.
Authors
Jarmo Ritari, Kati Hyvärinen, Kirsi Jahnukainen, Jukka Partanen, Ilkka Helanterä, Timo Jahnukainen
Abstract
Donnai-Barrow Syndrome (DBS) arises from loss-of-function (LoF) variants in the endocytic receptor LRP2/megalin and is characterized by low molecular weight (LMW) proteinuria and developmental abnormalities. Urinary proteomics of nine DBS patients revealed that the urinary proteome of a DBS patient with the missense variant LRP2 p.C1400R was indistinguishable from that of patients with splice site, nonsense, or frameshift mutations. A CRISPR mouse model of the variant was generated to determine the mechanism of LoF and proteinuria. The mutant LRP2 was expressed and observed to dimerize and localize to the proximal tubule apical membrane. However, both fluid-phase and receptor-mediated endocytosis were impaired in the context of a general perturbation of endocytic flux. Immunofluorescence revealed aberrant endocytic recycling with mislocalized RAB11+ and TFR1+ compartments and enlarged lysosomes. Structural modeling showed the LRP2 assembly likely tolerates the cysteine to arginine substitution at the cell surface, but at endosomal pH the variant introduced steric clashes that may disrupt intramolecular interfaces and disturb receptor recycling. These findings point to the importance of LRP2 recycling for global endocytic flux and offer a blueprint for leveraging patient-specific alleles to dissect proximal tubule function.
Authors
Andrew Beenken, Tian H. Shen, Aryan Ghotra, Hediye Erdjument-Bromage, Jeong Lee, Jared S. Kushner, Rachel E. Sturley, Atlas Khan, Jeffrey R. Arace, Leora Kronenberg, Lucy D. Shen, Gabriel H. Rahmani, Patricia K. Donahoe, Thomas A. Neubert, Frances A. High, Ora A. Weisz, Jonathan Barasch
Abstract
High dietary salt intake elevates blood pressure and drives multi-organ damage. However, the molecular programs underlying progressive organ injury remain poorly defined. Here, we present a longitudinal multi-organ transcriptomic atlas of salt-induced hypertensive injury. We profiled kidney cortex, kidney medulla, heart, and liver across four stages spanning early hypertension to advanced pathology in Dahl salt-sensitive rats. We identified dynamic and tissue-specific molecular trajectories, including a shared early proliferative response that converges on proinflammatory and fibrotic remodeling. Notably, we uncovered compartment-specific renal responses, showing that the cortex and medulla, despite their proximity, follow distinct molecular trajectories during disease progression. We further identified 79 stage- and tissue-specific transcription factors that drive gene expression dynamics in salt-induced hypertensive injury. Integration with human genome-wide association studies revealed conserved pathways in endocrine signaling, ion transport, lipid metabolism, and detoxification, establishing cross-species relevance and highlighting mechanistic targets of clinical importance. Compound–transcriptome analysis revealed stage- and organ-specific therapeutic opportunities, prioritizing kinase and epigenetic modulators as candidates to rebalance maladaptive gene programs. Overall, this study provides a resource for understanding molecular mechanisms from early salt-induced hypertension to tissue-specific injury and underscores the need for precision interventions.
Authors
Ratnakar Tiwari, Olha Kravtsova, Lashodya V. Dissanayake, Melissa Lowe, Biyang Xu, Vladislav Levchenko, Steven Didik, Ruslan Bohovyk, Daria V. Ilatovskaya, Oleg Palygin, Alexander Staruschenko
Abstract
Heat stroke (HS) is the most severe heat-related emergency, and its pathophysiology remains largely unknown, especially for exertional HS (EHS), which affects younger populations, athletes, and manual workers. Herein, we performed single-cell-transcriptomics, T cell receptor sequencing, and flow cytometry of PBMCs from 9 healthy control participants, 9 patients with heat exhaustion, and 9 patients with EHS to explore complex immunological responses associated with HS pathobiology. We showcased that granzyme-positive T cells and CD56dim NK cells with high cytotoxicity features and IL-1B+NLRP3+ monocytes with high inflammation and pyroptosis scores were enriched in HS, while the CD161+ T cells with innate immune-like, low cytotoxicity, and clonal expansion features were reduced in HS. Importantly, elevated granzyme-positive T and NK cells might interact with monocytes to induce pyroptosis of hepatic and renal cells and target organ injuries, and blocking the NLRP3 inflammasome pathway prior to the induction could alleviate organ injury in HS. This study offers deeper insights into the pathogenesis of HS, supporting the development of optimal treatment strategies.
Authors
Min Zhang, Bin Wang, Ding Sun, Xizhao Chen, Yena Zhou, Jin Yao, Liwen Du, Zehao Zhang, Hao Li, Zeyu Qu, Lu Chen, Qing Luo, Jie Zhang, Xinye Jin, Xiaowei Cheng, Jingxue Niu, Qinrui Xing, Xuezeng Tan, Tao Wang, Jie Liu, Lei Li, Qing Song, Xiangmei Chen, Yizhi Chen
Abstract
Modulation of miRNA expression in glomerular cells is associated with renal disease. Here, we investigated the role of miR-93-5p in mitigating glomerular damage in Alport syndrome and whether the disease-modifying activity of extracellular vesicles from human amniotic fluid stem cells (hAFSC-EVs) is mediated by their miR-93-5p cargo. We identified downregulation of miR-93-5p specifically in glomerular endothelial cells in Alport syndrome along disease progression. Silencing of miR-93-5p in hAFSC-EVs changed the transcriptomic and proteomic profile, regulating EV disease-modifying activity. Compared with naive hAFSC-EVs, silenced hAFSC-EVs did not rescue glomerular endothelial function in vitro and did not restore kidney function in vivo. We established that hAFSC-EVs regulate VEGFR1 and VEGFR2 signaling by miR-93-5p cargo transfer, highlighting that miR-93-5p can restore glomerular endothelial cell biology. Spatial transcriptomics analysis of hAFSC-EV–injected kidneys showed that these EVs can reverse pathways altered during disease progression by stimulating proregenerative processes, specifically in the glomerulus, by regulating miR-93-5p targets. Alteration of glomerular endothelial cell transcriptomics and miR-93-5p targets was also confirmed in biopsies of patients with Alport syndrome using spatial molecular imaging. We demonstrated the critical role of miR-93-5p in glomerular endothelial cells and the capability of hAFSC-EVs to regulate miR-93-5p and its targets in Alport syndrome.
Authors
Charmi Dedhia, Valentina Villani, Xiaogang Hou, Paolo Neviani, Geremy Clair, Mohammadreza Kasravi, Cristina Grange, Paolo Cravedi, Paola Aguiari, Velia Alcala, Giuseppe Orlando, Xue-Ying Song, Jonathan E. Zuckerman, Roger E. De Filippo, Stefano Da Sacco, Sargis Sedrakyan, Benedetta Bussolati, Laura Perin
Abstract
Introduction: BK polyomavirus (BKV) infection is associated with injury and subsequent graft loss due to the extent of injury or rejection. However, the molecular mechanisms driving injury and subsequent adverse outcomes remain poorly understood. Methods: In a cross-sectional study, single-cell RNA sequencing from kidney allograft biopsies was used to assess cell type-specific responses between uninfected controls and two distinct phases of BKV infection: peaking (increasing viral blood titers) and resolving (decreasing viral titers following immunosuppression reduction). Results: Genes upregulated in BK viral nephropathy (BKVN) were enriched for polyomavirus infection hallmarks, including ribosome biogenesis, translation, and energy restructuring. Additionally enriched pathways included wound healing, cellular stress, antigen presentation and immune signaling. Even without BKVN (peaking BK viremia alone), epithelial cells expressed signatures for wound healing, cellular stress, and extracellular matrix remodeling. In vivo tubular cell responses at single-cell resolution were validated against single cell transcriptomic data of BKV infected cells in a cell culture model. Despite similarities, in vivo tubular cells underwent metabolic adaptation favoring fatty acid oxidation and proinflammatory responses not observed in culture models likely due to an absent innate and adaptive immune system. Despite lymphopenia and immunosuppressive therapies, the proportion of recipient derived intrarenal adaptive immune cells was increased in biopsies associated with peaking viremia alongside activation of innate immune responses. Adaptive immune cells exhibited persistent inflammatory signaling and remodeling of energy metabolism during the resolving phase of infection. Conclusion: These not previously reported insights into BKV-associated injury may have implications for clinical management and improved allograft outcomes.
Authors
Tess Marvin, Rachel Sealfon, Phillip J. McCown, Fadhl AlAkwaa, Evan A. Farkash, Edgar A. Otto, Felix Eichinger, Ping An, Rajasree Menon, Celine C. Berthier, Tavis J. Reed, Paula Arrowsmith, Lalita Subramanian, Kelly J. Shaffer, Silas P. Norman, Ramnika Gumber, Michael J. Imperiale, James M. Pipas, Olga G. Troyanskaya, Matthias Kretzler, Chandra L. Theesfeld, Abhijit S. Naik
Abstract
Macrophages (MΦ), endowed with remarkable phenotypic plasticity are essential for orchestrating injury responses and regulating iron homeostasis. Given the central role of ferritin heavy chain (FtH) as a molecular rheostat linking iron sequestration to redox-dependent signaling, we examined how myeloid FtH governs renal iron trafficking and ensuing oxidative-stress pathways during acute kidney injury (AKI). Transcriptome analysis revealed coupling of FtH deficiency in monocytes and MΦ with ferroptosis activation, a regulated cell death associated with iron accumulation. Moreover, myeloid FtH deletion worsened AKI, increasing leukocyte infiltration and iron deposition, together with ferroptosis‐associated gene induction, oxidative stress, and lipid peroxidation. Notably, ⍺-synuclein (SNCA), an iron-binding protein and the main pathological driver of Parkinson’s disease, was robustly induced by both FtH deficiency and following AKI. Mechanistic studies showed that monomeric SNCA exhibits ferrireductase activity, amplifying redox cycling and promoting ferroptotic cell death. Furthermore, SNCA expression was elevated in kidney pathologies characterized by leukocyte expansion in both mouse models and human cohorts, suggesting that inflammatory microenvironments promote SNCA accumulation and redox imbalance. These findings define a MΦ FtH-SNCA regulatory axis as a key driver of ferroptosis in AKI, implicating SNCA as a pathological nexus between iron dyshomeostasis and inflammatory kidney injury.
Authors
Tanima Chatterjee, Sarah Machado, Kellen Cowen, Mary E. Miller, Bronte Johnson, Yanfeng Zhang, Laura A. Volpicelli-Daley, Lauren A. Fielding, Rudradip Pattanayak, Frida Rosenblum, László Potor, György Balla, Jozsef Balla, Christian Faul, Abolfazl Zarjou
Abstract
Low nephron endowment constitutes a risk factor for hypertension and renal disease. Epigenetic regulation is crucial for nephron progenitor cell differentiation, affecting nephron number and renal function. The role of many epigenetic modulators, such as Lysine-specific histone demethylase 1a (LSD1 or KDM1A), remains unclear. We used Kdm1a-KO mice to demonstrate that Kdm1a depletion in nephron progenitor cells results in reduced kidney size in neonates and led to glomerulosclerosis, proteinuria, and renal cysts in adults. Notably, Kdm1a deletion in podocytes or tubular cells did not replicate these effects. CRISPR/Cas9-mediated KDM1A deletion in human kidney organoids caused cyst formation and altered gene expression, with snRNA-seq revealing downregulation of podocyte genes and upregulation of metabolic genes. The presence of noncoding RNAs indicated roles in cell proliferation. Our study reveals the critical role of Kdm1a function in nephron development and highlights its affect on transcriptional programming for long-term renal function and susceptibility to cyst formation.
Authors
Nicola Wanner, Julia Keller, Nastassia Liaukouskaya, Geoffroy Andrieux, Sandra D. Laufer, Manuel Rogg, Tillmann Bork, Wei Liang, Fabian Braun, Fabian Haas, Milagros N. Wong, Victor G. Puelles, Sydney E. Gies, Charlotte Meyer, Melanie Boerries, Martin Helmstädter, Oliver Kretz, Iris Hild, Eric Metzger, Roland Schüle, Wibke Bechtel-Walz, Tobias B. Huber
Abstract
Immune checkpoint inhibitors (ICIs) can cause immune-related adverse events (irAEs), with acute interstitial nephritis (ICI-AIN) being the most common irAE. While the exact mechanism remains unclear, upregulation of interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α) pathways has been implicated. This study used a humanized chimeric PD-1/PD-L1 mouse model to assess renal effects of ICIs, alone or combined with pro-inflammatory cytokines, and to test if selective TNF-α blockade could prevent ICI-AIN. Mice were randomly divided into four experimental groups: Control, ICI-Only, ICI-Cytokines (ICI-Cyt), and ICI-Block (ICI-TNF-α blockade). Renal function and cytokine profiles were assessed, while kidney tissue was analyzed using microscopy and single-cell RNA sequencing. Histology revealed increased renal infiltration of CD4⁺/CD8⁺ T cells in ICI-treated groups and decreased TNF-α expression following TNF-α blockade. Additionally, kidney tissue ELISA demonstrated reduced IFN-γ levels following TNF-α blockade. Plasma IL-6, MCP-1, and TNF-α were lower in ICI-Block mice. Single-cell RNA sequencing revealed shifts in immune cell populations and genes of interest including: Bcl2a1, Icos, Il18r1, Ccr2, and Jaml. This humanized model replicates ICI-AIN key features, revealing a synergistic role of ICIs and pro-inflammatory cytokines. TNF-α blockade demonstrated protective effects, supporting its potential role in mitigating the risk of ICI-AIN.
Authors
Victor D. Cuenca Narvaez, Coraima Nava Chavez, Omar Al Refai, Johanna E. J. Jacobs, Luis E. Gutierrez, Song Zhang, Xiaoyan Li, Jacob B. Hirdler, Michael F. Romero, Joerg Herrmann, Xiaogang Li, Haidong Dong, Alfonso Eirin, Sandra M. Herrmann
Abstract
While the pathogenic role of autoantibodies targeting the podocyte protein THSD7A in membranous nephropathy (MN) is well described, the consequences of autoantibody binding for podocyte homeostasis and the function of THSD7A remain unclear. Here, we induced an MN model in control and podocyte-specific Thsd7a knockout (Thsd7a–/–) mice using rabbit anti-THSD7A antibodies, followed by transcriptome and proteome analyses. Anti-THSD7A antibodies in WT mice caused significant loss of key slit diaphragm (SD) proteins such as nephrin and NEPH1, without transcriptional downregulation. Glomeruli showed substantial transcriptomic and proteomic reconfiguration indicative of extensive podocyte injury, including disruptions in podocyte adhesion, cytoskeletal dynamics, and marked upregulation of ubiquitin-proteasome system components, cathepsins and ADAM proteases. Notably, experiments in C3-deficient mice revealed that proteolytic activation and SD protein loss are driven by complement-independent pathways. While Thsd7a–/– mice only displayed a mild phenotype under basal conditions, they were completely protected from MN development upon anti-THSD7A antibody transfer. Finally, interactomic analysis identified a protein complex including THSD7A and integrin α3, linking THSD7A complexes to pathogenic regulation of cytoskeleton, adhesion, and membrane signaling in MN. Thus, anti-THSD7A antibodies induce profound molecular reconfiguration, including dysregulated proteolytic systems via a complement-independent pathway, revealing potential therapeutic targets in MN.
Authors
Ming Huang, Moritz Lassé, Silke Dehde, Felicitas E. Hengel, Fatih Demir, Anja M. Billing, Ning Song, Larissa Seifert, Oliver Kretz, Florian Grahammer, Ulf Panzer, Sebastian Brähler, Tobias B. Huber, Gunther Zahner, Markus M. Rinschen, Nicola M. Tomas
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