June 2025 Edition
Impact Factor 2024
Gut reactions & glomeruli: New kidney research in focus
Recent studies in Kidney International ® shed new light on molecular pathways, disease mechanisms, and therapeutic targets related to podocyte injury.
From CKD progression to uric acid balance and rare stone disorders, new research published in Kidney International Reports® explores how gut microbial shifts impact kidney health.
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KIDNEY INTERNATIONAL ARTICLES |
Melanocortin 5 receptor signaling protects against podocyte injury in proteinuric glomerulopathies
The melanocortinergic pathway plays a protective role in the glomerulus and podocytes. However, there is a gap in the understanding of melanocortin receptor function and its potential role in therapy. Beneficial effects of MC5R occur through improving proteinuria, mitigating podocytopathy, and reducing glomerular damage.
The authors demonstrate that the absence of MC5R exacerbated kidney damage and glomerulopathy in mouse models, while a selective MC5R agonist showed therapeutic promise by improving outcomes.
Mechanistically, the study reveals that MC5R agonism counteracts podocyte damage by restoring the inhibitory phosphorylation of glycogen synthase kinase 3β. Modulation of this key signaling molecule leads to improved actin cytoskeleton integrity and reduced expression of harmful mediators of podocyte injury.
This study establishes MC5R as a novel and promising therapeutic target for glomerular diseases, potentially paving the way for new treatments that directly address podocyte pathology and offer a significant advancement in managing chronic kidney disease.
A kidney organoid-based readout to assess disease activity in primary and recurrent focal segmental glomerulosclerosis
Primary focal segmental glomerulosclerosis (pFSGS) remains a formidable clinical challenge, particularly due to its elusive pathophysiology and high post-transplantation recurrence.
This study represents a major step forward in disease modeling, leveraging human pluripotent stem cell-derived kidney organoids to simulate podocyte injury in response to patient plasma. The organoid platform not only recapitulated classic features of pFSGS, such as nephrin/podocin loss and matrix accumulation but also differentiated between recurrent and non-recurrent cases based on plasma exposure. Remarkably, therapeutic modulation via plasma exchange was also mirrored in reduced organoid damage, raising the tantalizing possibility that these structures could serve as a personalized pre-transplant screening tool.
This research signals a paradigm shift toward functional diagnostics for FSGS recurrence, underscoring the promise of organoid models in mechanistic nephrology.
Transgenic human nephrin in Drosophila nephrocytes facilitates variant analysis
Drosophila, commonly known as the fruit fly, is considered an ideal organism for genetic research as everything from a single gene to an entire genome can be studied.
This study introduces Drosophila nephrocytes as a novel and viable model for analyzing human nephrin (NPHS1) variants implicated in congenital nephrotic syndrome. By expressing human nephrin in these cells after silencing Drosophila’s ortholog, researchers observed the formation of a hybrid linear architecture resembling mammalian slit diaphragms. This model allows for functional characterization of patient-derived NPHS1 variants, with altered protein patterns correlating with clinical severity — including a novel V1241G variant.
The use of Drosophila nephrocytes as a surrogate system for studying human nephrin function highlights the versatility and power of cross-species approaches in understanding complex biological processes. While the transgenic nephrin complex was assembled, it did not fully restore signaling, endocytic function, or cellular survival — indicating a need for additional cofactors.
Anti-nephrin antibodies in adult Chinese patients with minimal change disease and primary focal segmental glomerulosclerosis
Recently, anti-nephrin autoantibodies have been recognized as a potential mechanism underlying minimal change disease (MCD) and primary focal segmental glomerulosclerosis (FSGS), especially in those with active nephrotic syndrome. This study explored the prevalence and clinical significance of anti-nephrin antibodies in a cohort of 596 adult Chinese patients with biopsy-proven MCD and primary FSGS.
Anti-nephrin IgG and IgM were detected using ELISA, with validation through antigen-inhibition ELISA and Western blotting. Clinical data at biopsy and during the follow-up period were analyzed. Anti-nephrin antibodies were detected in 43% of all patients, with 30% testing positive for anti-nephrin IgG, 26% for anti-nephrin IgM, and 13.1% for both antibodies. Clinical features were similar between those with IgG and IgM. Patients with both anti-nephrin IgG and IgM had the most severe proteinuria and the highest relapse frequency. Notably, the prevalence of anti-nephrin antibodies was higher in patients with nephrotic-range proteinuria who were not receiving steroids or immunosuppressants. Patients with positive anti-nephrin antibodies exhibited more severe nephrotic syndrome, higher rates of relapse, and a shorter relapse-free period compared to those negative for these antibodies.
Anti-nephrin antibodies significantly decreased during clinical remission, while they reappeared prior to proteinuria relapse. These results provide hope that the antibodies may serve as valuable biomarkers and potential therapeutic targets in the future.
Regulation of podocyte surface proteins by the enzyme A Disintegrin and Metalloproteinase 10 (ADAM10)
This study sheds light on the intricate regulatory mechanisms governing podocyte surface protein dynamics, revealing ADAM10 as a key protease that modulates the shedding of crucial membrane proteins, such as THSD7A and PLA2R1, both implicated in primary membranous nephropathy.
By demonstrating that ADAM10 deficiency leads to the accumulation of these antigens and alters podocyte cytoskeletal behavior, the authors enhance our understanding of filtration barrier remodeling and provide mechanistic insight into autoantigen exposure and injury.
The identification of a THSD7A/ADAM10/Tspan15 complex further underscores the therapeutic potential of targeting proteolytic regulation pathways in glomerular diseases.
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KIDNEY INTERNATIONAL REPORTS ARTICLES |
This study offers compelling evidence for the role of the gut microbiome in uric acid homeostasis, highlighting that higher microbial — particularly as measured by the Shannon index — is associated with lower serum uric acid (SUA) and enhanced renal excretion of uric acid (FEUA).
Notably, these associations remained significant even after adjusting for sex, waist-hip ratio, and kidney function, underscoring the independent influence of gut microbial composition on purine metabolism.
Interestingly, dietary patterns did not correlate directly with SUA or FEUA, suggesting that microbiota-specific mechanisms, rather than dietary intake alone, may drive these metabolic effects. These findings pave the way for future microbiome-targeted interventions as a novel strategy to manage hyperuricemia and potentially prevent urate-related kidney and cardiovascular diseases.
The gut–kidney axis continues to gain attention as a modifiable contributor to chronic kidney disease (CKD) progression.
The TarGut-CKD study explored the use of prebiotic therapy in modulating the gut microbiome in patients with CKD stages 3–4.
Over the course of the intervention, patients receiving prebiotics showed favorable shifts in gut microbial composition, particularly increases in short-chain fatty acid-producing bacteria. These microbial changes were associated with modest reductions in systemic inflammation, suggesting potential renal and cardiovascular benefits. While the clinical endpoints,
such as eGFR and uremic toxin levels, showed no significant changes over the short duration of the study, the results offer proof of concept that prebiotic supplementation can beneficially alter the gut microbiota in CKD.
These findings lay the groundwork for larger and longer trials to determine whether gut-targeted therapies can delay CKD progression or reduce complications, reinforcing the microbiome as a novel therapeutic target in nephrology.
Emerging research suggests that the gut microbiome may influence the development of chronic kidney disease (CKD), extending beyond traditional risk factors like hypertension and diabetes.
In this prospective study from the FINRISK 2002 cohort, researchers examined gut microbial profiles in 6,699 individuals and tracked incident CKD over a median of 18.6 years. They found that higher baseline gut microbiome alpha diversity was significantly associated with a lower risk of developing CKD (HR per 1 SD: 0.84; P = 0.04), while beta diversity and specific taxa were not linked to incident disease.
In cross-sectional analysis, both alpha and beta diversity were associated with serum creatinine levels, and 43 microbial species — especially those from the Lachnospiraceae family — showed significant inverse associations. No meaningful relationship was observed with urine albumin-to-creatinine ratio.
These findings provide some of the first prospective evidence that lower gut microbial diversity may be a modifiable risk factor for CKD, opening new avenues for prevention and risk stratification through microbiome-based strategies.
In this study, the authors measured serum total IgA, galactose-deficient IgA1 (gd-IgA1), secretory IgA (SIgA), B cell-activating factor (BAFF), and A proliferation-inducing ligand (APRIL) in patients with IgAN and healthy controls (HCs). They quantified the total IgA and gd-IgA1 in stool supernatant, along with the same molecules coated on bacteria. In a subset of patients and controls, they additionally performed extensive phenotyping of circulating immune cells, including unconventional T cells. These unconventional T cells are key players in mucosal immunity. They include mucosal-associated invariant T (MAIT) cells, γδ T cells, and natural killer (NK) T cells. The results were validated using RNAseq data from a larger cohort of patients with IgAN, patients with minimal change disease, and HCs.
The results show that patients with IgAN had higher circulating levels of total IgA, gd-IgA1, and APRIL, and higher IgA- and gd-IgA1-coated gut bacteria than controls, whereas serum levels of SIgA and BAFF did not differ between groups. Patients with IgAN showed more class-switched memory (CSM) and double-negative (DN) B cells than controls. MAIT cells and γδ T cells were significantly lower, and CD4−CD8− NK T cells were significantly higher in patients with IgAN than in HCs. The significant decrease in MAIT cells was validated in an independent cohort of patients with IgAN.
These findings suggest that patients with IgAN have increased circulating CSM and DN B cells associated with abnormal T cell immunity, involving defects in unconventional T cell frequency. This may reflect mucosal immune alterations due to cell migration, leading to altered IgA production.
Understanding the gut-kidney axis in oxalate metabolism has never been more relevant, particularly in rare yet impactful conditions like primary and enteric hyperoxaluria.
In this novel multiomics investigation, the authors provide a microbial fingerprint of hyperoxaluric phenotypes. Despite similar microbial diversity
among groups, PH and EH showed distinct functional imprints. EH was characterized by a reduction in oxalate-degrading bacteria, suggesting impaired intestinal oxalate clearance, while PH harbored a more complex microbial interaction network, perhaps a compensatory adaptation. Importantly, idiopathic stone formers showed intermediate features, hinting at shared but nuanced microbiome alterations.
These findings pave the way for microbiome-targeted therapies and reinforce the need to stratify hyperoxaluric diseases by their microbial architecture. A truly integrative approach to stone prevention may soon involve not just urologists and nephrologists but also microbiome engineers.