Sandeep K. Mallipattu

Organ crosstalk plays a vital role in maintaining physiological homeostasis and adapting to environmental cues. The kidney is increasingly recognized as an integrative organ that participates in bidirectional communication with distant tissues through hemodynamic, endocrine, metabolic, immune, and neural pathways. Dysfunction of the kidney is now viewed as a systemic disease rather than organ injury. Yet, kidney-organ crosstalk is usually described broadly and associatively. This review examines recent mechanistic advances in kidney–organ signaling, with an emphasis on experimentally supported molecular mediators and causal models. We highlight emerging circulating mediators, neuroimmune circuits, microbial pathways, and tissue-specific signaling mechanisms, placing the kidney as both recipient and active sender of mediators in systemic health and diseases. We also highlight the limitations of the current approaches in studying kidney-organ signaling, including reliance on global genetic manipulation, indirect measures of signal transfer, and isolated organ-pair frameworks. In addition, we discuss how advancements in technology may help us recognize new mediators and help identify cellular origins, routes, and consequences of interorgan communication with greater resolution. A better integrated understanding of the interorgan signaling in kidney health and disease is mandatory to identify biomarkers and develop new therapies to treat kidney diseases with fewer adverse effects on other organs.

Was not provided for this article.

Direct antibody labeling is essential for immunoassays, multiplexed imaging, and biosensing; however, current methods are often time-consuming, restricted by antibody source, risk compromising protein performance, or vary with multiple steps. We introduce multiplex in situ tagging (MIST) Linker, a rapid and Fc-site-specific labeling tool that conjugates fluorophores or DNA oligonucleotides to antibodies from diverse commercial sources in as fast as 10 min using minimal starting material. MIST Linker achieves >90% cleavage upon UV exposure, facilitating rapid cyclic imaging on a single specimen. Validated across multiple species and sources, the platform outperforms conventional two-step immunofluorescence and immunohistochemistry in various tissues and cell lines. By enabling the rapid, cost-effective customization of antibody panels, MIST Linker significantly lowers the barrier to accessing antibody–DNA conjugates for spatial biology. When integrated with the spatial MIST platform and MIST-Explorer, it enables high-plex, single-cell spatial proteomics at high signal-to-noise ratios in human clinical biopsies, mouse specimens and cell lines. This toolkit provides an efficient, accessible solution for high-resolution spatial mapping, allowing for the in-depth analysis of cell subpopulations, biomarker distributions, and signaling events in complex biological specimens. Thus, MIST Linker offers a versatile, accessible, and scalable solution for antibody-labeling-based research and clinical diagnosis.

To date, this is the first study to demonstrate that intercellular bridges form between podocytes and parietal epithelial cells in the setting of rapid podocyte loss in subtypes of glomerulonephritis and FSGS.

In this study, we offer a novel spatial analysis of markers relevant to CKD, which may provide useful insights into disease progression. By using this spatial proximity data, we created a GNN model that is capable of classifying disease severity and identifying markers that are most important for its classification. This integrative approach offers a foundation for future studies aimed at developing clinically actionable tools for CKD diagnosis and prognosis.

Activation and proliferation of parietal epithelial cells (PECs), located along the inner rim of Bowman’s capsule, drives disease progression in subtypes of glomerulonephritis and focal segmental glomerulosclerosis. In examining the mechanisms contributing to PEC activation two established mouse models were utilized in this study, nephrotoxic serum nephritis (transient model) and podocyte-specific Klf4 knockout (progressive model). A role for transcription factor FRA2 ( Fosl2 ) was uncovered through single nuclear multiomic approaches relating to the regulation of PEC transcriptional/chromatin dynamics. Co-immunoprecipitation followed by mass spectrometry assessed the FRA2 protein interactome in cultured PECs, revealing a potential role for FRA2 in alternative splicing. Fosl2 expression was then blunted through CRISPR-Cas9 gene editing in cultured PECs, revealing reduced proliferative capacity and the downregulation of myofibroblast markers. In-vivo genetic lineage tracing of PECs after nephrotoxic serum revealed PEC-to-myofibroblast trans-differentiation events. Finally, immunostaining of human kidney biopsies with varied subtypes of glomerulonephritis confirmed Fosl2 expression in activated PECs within crescentic lesions, with single cell deconvolution strategies assigning PEC-skewed proportion ratios to bulk RNA-seq patient data from the NEPTUNE consortium. These results suggest that FRA2 ( Fosl2 ) directs a conserved molecular program of PEC-specific responses in subtypes of glomerulonephritis and focal segmental glomerulosclerosis.

Key Points: Residual kidney function does not modify the response of left ventricular mass (LVM) to frequent hemodialysis in patients with ESKD. Both anuric and nonanuric patients showed similar improvements in LVM with intensive hemodialysis. Changes in residual kidney function were not associated with response of LVM to frequent hemodialysis. Background: Frequent (6 times/wk) hemodialysis has been shown to reduce left ventricular mass (LVM) more than conventional (3 times/wk) hemodialysis in patients with ESKD. Previous work suggested that the LVM benefits of frequent hemodialysis might be attenuated in the presence of residual kidney function (RKF). We hypothesized that patients without RKF would have greater LVM reduction with frequent hemodialysis compared with patients with RKF. Methods: We analyzed data from the Frequent Hemodialysis Network (FHN) Daily (in-center) and Nocturnal (home-based) trials, which randomized patients with ESKD to either frequent or conventional hemodialysis over 12 months. RKF was evaluated through timed 24-hour urine collections, with anuria defined as urine output P = 0.18). At 12 months, both anuric and nonanuric patients experienced similar LVM reductions with frequent hemodialysis (mean change in log LVM: −0.11±0.23 versus −0.08±0.23; P = 0.44). No association was found between baseline urine volume and LVM response (rho=−0.002, P = 0.98 for frequent; rho=0.003, P = 0.97 for conventional hemodialysis). Changes in urine volume over 12 months did not correlate with LVM changes. In an exploratory analysis, LVM reduction correlated with urine volume decline in men (rho=0.23; P < 0.01) but not in women (rho= −0.19; P = 0.10; P _interaction = 0.003). Conclusions: Both anuric and nonanuric patients experienced similar LVM reductions with frequent hemodialysis, and no association between urine output and LVM response was observed in the FHN trials. These data suggest that the response of LVM to frequent hemodialysis is independent of baseline RKF.

Key Points: Detrimental effects of Krüppel-like factor 4 knockdown in podocytes were eliminated with the inhibition of signal transducer and activator of transcription 3 (STAT3) signaling specifically in podocytes. Human kidney biopsies with renal vasculitis demonstrated a glomerular enrichment of STAT3 downstream genes, which negatively correlated with eGFR. Deconvolution of the bulk RNA-seq from Nephrotic Syndrome Study Network showed an enrichment of STAT3 downstream genes in podocytes as compared with other cell clusters. Background: Podocyte loss and parietal epithelial cell activation are features of subtypes of glomerulonephritis and FSGS. We recently reported that the podocyte-specific loss of Krüppel-like factor 4 ( Klf4 ^ΔPod ) triggers dysregulated glomerular signal transducer and activator of transcription 3 (STAT3) activation, podocyte loss with parietal epithelial cell activation and proliferation, leading to FSGS. Although pharmacologic systemic STAT3 inhibition attenuated this phenotype, it remains unclear whether the detrimental effects of Klf4 loss are primarily a result of dysregulated STAT3 activation intrinsically in podocytes. Methods: Mice with the concurrent and conditional knockdown of Stat3 and Klf4 ( Klf4 ^ΔPod Stat3 ^ΔPod ) were generated and characterized. Expression arrays from kidney biopsies with various types of glomerular diseases, deposited in Nephroseq, were interrogated for glomerular expression of genes downstream of STAT3 signaling. Cell-specific modulation of STAT3 genes was determined using single-cell RNA sequencing–based proportional cell type deconvolution of bulk RNA-seq obtained from the Nephrotic Syndrome Study Network (NEPTUNE) FSGS and healthy controls. Results: Klf4 ^ΔPod Stat3 ^ΔPod mice demonstrated no significant podocyte loss, parietal epithelial cell activation and proliferation, FSGS lesions, albuminuria, kidney dysfunction, and tubulointerstitial fibrosis and inflammation compared with the Klf4 ^ΔPod mice. Klf4 ^ΔPod Stat3 ^ΔPod mice also exhibited less glomerular myofibroblasts (+ α -smooth muscle actin) as compared with Klf4 ^ΔPod mice. Overall survival was restored in Klf4 ^ΔPod Stat3 ^ΔPod mice as compared with Klf4 ^ΔPod mice. Interrogation of expression arrays from human kidney biopsies with renal vasculitis demonstrated a glomerular enrichment of genes involved in canonical STAT3 signaling as compared with healthy controls, which negatively correlated with eGFR. Deconvolution of the bulk RNA-seq data from NEPTUNE showed an enrichment of these STAT3 genes in podocytes as compared with other glomerular cell clusters. Conclusions: Collectively, these data demonstrate that inhibiting podocyte-specific STAT3 signaling was sufficient to counter the detrimental effects of Klf4 loss in podocytes and prevented albuminuria, accelerated podocyte loss, activation and proliferation of parietal epithelial cells, FSGS lesions, and kidney failure.