The study, published in the journal Immunity, Inflammation and Disease, began with a rigorous chemical inventory of the decoction, which combines Angelicae Sinensis Radix, the root of Angelica sinensis, with Astragali Radix, the root of Astragalus membranaceus, in a precise 1:5 ratio. Using a Vanquish ultra-high-performance liquid chromatograph coupled to a QExactive HFX mass spectrometer, the researchers separated compounds on a Waters HSS T3 column at 40 degrees Celsius with a formic acid-acetonitrile gradient and electrospray ionization in both positive and negative ion modes. The analysis identified 104 compounds, dominated by phenylpropanoids and polyketides, lipids and lipid-like molecules, and organoheterocyclic compounds. This chemical fingerprint became the foundation for everything that followed.

With the compound list in hand, the team turned to network pharmacology, a computational approach that treats a multi-component herbal formula as a network of interacting molecules rather than a single active ingredient. Predicting targets for the identified compounds through SwissTargetPrediction yielded 499 drug-related targets, while searching GeneCards and OMIM for chronic glomerulonephritis produced 2,821 disease targets after redundancy removal. The intersection contained 166 overlapping targets, suggesting a substantial molecular interface between the formula and the disease. Building a protein-protein interaction network in Cytoscape and ranking targets with the CytoHubba MCC algorithm highlighted ten core targets, including B-cell lymphoma-2 (Bcl-2) and Caspase-3, both central players in apoptosis, the genetically programmed form of cell death.

Enrichment analysis through the Metascape platform pointed decisively toward the NF-κB signaling pathway, a master regulator of inflammation. To test whether this computational prediction reflected real biology, the researchers mined two independent gene expression datasets from the Gene Expression Omnibus, GSE116626 with 74 chronic glomerulonephritis samples and GSE104066 with 70 samples. After batch correction and standardization, differential expression analysis identified 414 significantly upregulated genes and 379 downregulated genes, and KEGG pathway analysis showed these genes were also significantly enriched in the NF-κB signaling pathway. The convergence of network pharmacology and patient gene expression data on the same pathway gave the team strong grounds to pursue experimental validation.

Molecular docking provided a structural bridge between chemistry and biology. Five active ingredients with high network centrality, 3-Hexen-1-ol O-β-d-glucopyranoside, 4-hydroxybenzoic acid, caffeic acid, calycosin, and lucidal, were docked against Bcl-2, Caspase-3, and TLR4. All fifteen compound-target pairs showed binding energies below the -5 kcal/mol threshold generally considered indicative of strong binding. Calycosin bound Caspase-3 at -7.2 kcal/mol, while lucidal achieved -8.5 kcal/mol against Caspase-3 and -7.8 kcal/mol against Bcl-2, stabilized by multiple hydrogen bonds with key amino acid residues. These docking scores suggested the herbal compounds could physically engage the apoptotic and inflammatory machinery implicated in the disease.

The first line of experimental evidence came from cell studies using HBZY-1 rat glomerular mesangial cells, whose abnormal behavior is a central driver of chronic glomerulonephritis progression. Rather than applying crude herbal extracts, the team prepared drug-containing serum by administering DBD to rats at three doses, 1.89, 3.78, and 7.56 grams per kilogram, then collecting the resulting serum, an approach that captures only the compounds that actually enter the bloodstream after metabolism. When LPS-stimulated mesangial cells were treated with DBD-containing serum, the abnormally elevated cell viability dropped, secretion of the anti-inflammatory cytokines IL-4 and IL-10 recovered, and Transwell assays showed markedly reduced migration and invasion. Immunofluorescence confirmed that TLR4 and NF-κB protein expression, which LPS had pushed upward, fell significantly after treatment.

The in vivo experiments used a classic adriamycin-induced rat model of chronic glomerulonephritis, established through two tail-vein injections and confirmed by 24-hour urinary protein exceeding 50 milligrams per kilogram. Rats receiving DBD for 30 days showed striking improvements across the board: 24-hour urine protein, serum creatinine, and blood urea nitrogen all fell significantly, while body weight recovered and the kidney index normalized. Pro-inflammatory TNF-α and IL-6 levels declined, and the previously suppressed IL-4 and IL-10 rose. Histological staining with hematoxylin and eosin, Masson, and PAS revealed that the adriamycin-induced damage, including glomerular atrophy, basement membrane thickening, collagen fiber deposition, and inflammatory cell infiltration, was substantially reversed in the treated animals.

The mechanistic heart of the study lies in its analysis of apoptosis and the TLR4/NF-κB axis. In the diseased rats, apoptotic activity was paradoxically suppressed: Cleaved Caspase-3 staining was weak, TUNEL-positive cells were scarce, and mitochondrial membrane potential measured by JC-1 staining indicated inhibited apoptosis. Western blotting showed downregulation of the pro-apoptotic proteins Bax, cytochrome C, Caspase-9, and Caspase-3, alongside upregulation of the anti-apoptotic Bcl-2. DBD treatment reversed this pattern, restoring pro-apoptotic signaling and promoting the controlled cell death needed to clear damaged glomerular cells. Simultaneously, RT-qPCR, Western blotting, immunohistochemistry, and immunofluorescence all demonstrated that DBD downregulated TLR4, MyD88, IκBα, and NF-κB, damping the inflammatory cascade that LPS and adriamycin normally ignite.

This dual action makes biological sense in light of the disease mechanism. When TLR4 on mesangial cell surfaces is activated, it recruits MyD88, promotes IκB phosphorylation and degradation, and triggers NF-κB nuclear translocation, where the transcription factor drives expression of inflammatory cytokines such as TNF-α and IL-1β and of the anti-apoptotic protein Bcl-2. By suppressing this pathway, DBD reduces inflammatory cytokine release; by simultaneously promoting Bax-mediated cytochrome C release and Caspase-9 and Caspase-3 activation, it restores the apoptotic balance whose disruption drives both pathological mesangial accumulation and loss of kidney filtering cells. The authors note that apoptosis is a double-edged sword, but their data indicate that reactivating it in this context slows disease progression rather than accelerating tissue damage.

The findings carry practical significance beyond the laboratory. Current clinical management of chronic glomerulonephritis relies on angiotensin-converting enzyme inhibitors, corticosteroids, and immunosuppressants, all of which carry limitations including variable drug sensitivity, symptom recurrence, and long-term adverse effects such as hyperkalemia, dry cough, increased infection risk, and digestive reactions. A multi-component, multi-target herbal formula that modulates both inflammation and apoptosis could offer a gentler complementary strategy, and the study’s systematic workflow, from chemical profiling through network prediction to animal and cellular validation, provides a template for scientifically grounding other traditional formulas. The researchers conclude that DBD exerts its therapeutic effects on chronic glomerulonephritis by regulating the TLR4/NF-κB signaling pathway, promoting apoptosis, and alleviating inflammation, laying an experimental foundation for explaining its clinical efficacy in modern pharmacological terms.

Subject of Research: Mechanism of action of Danggui Buxue Decoction in treating chronic glomerulonephritis via the TLR4/NF-κB signaling pathway

Article Title: Exploring the Mechanism of Action of Danggui Buxue Decoction in Treating Chronic Glomerulonephritis Based on UPLC‐MS/MS and Network Pharmacology

Article References: Liu, Q., Wang, Y., Wang, X., Yang, H., Pan, Z., & Guo, D. (2026). Exploring the Mechanism of Action of Danggui Buxue Decoction in Treating Chronic Glomerulonephritis Based on UPLC‐MS/MS and Network Pharmacology. Immunity, Inflammation and Disease, 14(9), Article e70497. https://doi.org/10.1002/iid3.70497

Image Credits: AI Generated

DOI: 10.1002/iid3.70497

Keywords: Danggui Buxue Decoction, chronic glomerulonephritis, network pharmacology, UPLC-MS/MS, TLR4/NF-κB pathway, apoptosis, traditional Chinese medicine, kidney disease, HBZY-1 mesangial cells, molecular docking, inflammation, astragalus

IgA nephropathy, often abbreviated IgAN, is the most common primary glomerular disease worldwide and a leading cause of kidney failure in young and middle-aged adults. The disease arises from a subtle but destructive immunological misstep: the body produces abnormally high quantities of galactose-deficient IgA1, a poorly glycosylated version of a common antibody. These aberrant molecules accumulate in the bloodstream, provoke the formation of immune complexes, and ultimately deposit in the glomeruli, the delicate filtering units of the kidney. The resulting inflammation and scarring progressively erode the kidney’s ability to filter waste, a process that can unfold silently over decades. Many patients reach advanced chronic kidney disease or dialysis before they fully grasp how much function they have lost, a reality that has made IgAN a notorious ‘silent’ threat in nephrology.

For decades, treatment options were blunt. Non-specific immunosuppression with systemic corticosteroids could slow the disease, but at the cost of exposing the entire body to high steroid doses, with well-documented risks including infections, diabetes, weight gain, and cardiovascular complications. The intellectual breakthrough behind Nefecon was anatomical rather than chemical. Recognizing that mucosal immunity, particularly in the gut-associated lymphoid tissue concentrated near the ileocecal region, drives much of the overproduction of galactose-deficient IgA1, researchers engineered a capsule coated to withstand stomach acid and release budesonide precisely where Peyer’s patches are densest. The drug then exerts a local immunomodulatory effect on the lymphoid tissue that seeds the disease, while first-pass hepatic metabolism limits systemic steroid exposure. It is, in effect, a precision strike on the disease’s immunological engine room.

The concept was validated in controlled settings by the phase 2b NEFIGAN trial and the pivotal phase 3 NefIgArd program, which demonstrated statistically significant proteinuria reduction and, in two-year results, meaningful preservation of estimated glomerular filtration rate. But clinical trials enroll selected patients under idealized conditions, and regulators and clinicians alike have increasingly demanded confirmation that the benefit translates to the messy, heterogeneous reality of routine practice. The Xinjiang study was designed to address exactly this gap. Between September 2024 and March 2025, the investigators consecutively enrolled 28 patients with biopsy-confirmed primary IgAN who had been treated with Nefecon for more than nine months, collecting standardized data on demographics, laboratory outcomes, and adverse events in a retrospective real-world cohort.

The headline results are dramatic. After nine months of therapy, mean proteinuria fell from 1.7 plus or minus 1.2 grams per day to 0.6 plus or minus 0.5 grams per day, a reduction of 55.8 percent. That figure matters enormously because proteinuria is one of the most powerful modifiable predictors of long-term renal prognosis in IgAN; cohort studies have repeatedly shown that each gram of persistent protein in the urine compounds the risk of progression toward kidney failure. Equally notable was the change in kidney function itself. Estimated glomerular filtration rate, the standard measure of how well the kidneys filter, improved from 80.3 to 86.2 mL/min/1.73 m2, a gain of roughly five percent. Any functional improvement during active autoimmune disease is unusual and suggests the treatment is not merely suppressing symptoms but genuinely interrupting inflammatory injury.

Perhaps the most clinically provocative finding concerns baseline proteinuria. Patients entered the study across a range of proteinuria levels, and Nefecon appeared to deliver renal protection regardless of where a patient started, with signals suggesting greater benefit when treatment was initiated earlier in the disease course. This challenges a lingering clinical conservatism in which the most aggressive therapies are reserved for patients already showing heavy proteinuria and declining function. If low-level proteinuria is treated as a warning sign rather than a tolerated quirk, the window in which kidney tissue can still be rescued widens considerably. The study’s authors suggest that this supports a strategy of early intervention following diagnosis, an approach now echoed in evolving international treatment guidance, including the KDIGO 2025 clinical practice guideline for IgA nephropathy.

Safety data from the cohort will reassure clinicians who have watched the therapeutic landscape expand rapidly. Seventeen of the 28 patients, or 60.7 percent, experienced at least one adverse event, but the spectrum was mild and predictable for a locally targeted steroid. The most common event was acne, affecting 21.4 percent of patients. Crucially, no severe adverse events and no treatment-related deaths were observed, and the tolerated profile contrasts sharply with the serious corticosteroid toxicities documented with systemic steroid regimens in earlier IgAN trials. Because Nefecon releases budesonide in the distal small intestine and is largely cleared on first pass through the liver, systemic exposure remains a fraction of what conventional oral prednisone produces, and this real-world dataset supports that pharmacokinetic advantage in routine use.

The study’s significance extends beyond a single drug. IgAN has recently become one of the most dynamic fields in nephrology, with endothelin receptor antagonists, SGLT2 inhibitors, and complement-targeted therapies all entering the treatment algorithm alongside Nefecon. Real-world evidence like this cohort study functions as a crucial bridge between regulatory trials and everyday clinical decision-making, confirming that the antiproteinuric effects seen in the randomized NefIgArd population, including the mainland China substudy, reproduce in a broader, unselected patient group. It also provides nephrologists with practical dosing-and-response expectations: a majority proteinuria reduction at nine months is a realistic and clinically meaningful benchmark when patients are treated under standard care conditions.

Limitations remain, and the investigators are appropriately measured about them. The cohort is small, retrospective, and drawn from a single center, and nine months, while sufficient to capture established treatment response, cannot reveal whether functional gains persist after therapy stops or whether the drug alters the long-term risk of kidney failure. These caveats notwithstanding, the consistency of the findings with the randomized trial evidence strengthens the case that Nefecon has earned a genuine place in routine care. For the millions of people living with IgA nephropathy worldwide, the message from this study is quietly radical: the disease can be attacked at its immunological source, the kidneys can be protected before they are irreversibly damaged, and treatment can begin early, safely, and effectively. As real-world experience accumulates, the era of watchful waiting in IgAN is steadily giving way to one of early, targeted intervention.

Subject of Research: Real-world effectiveness and safety of targeted-release budesonide (Nefecon) in primary IgA nephropathy across baseline proteinuria levels

Article Title: Effectiveness and Safety of Nefecon in Primary IgA Nephropathy Across Different Baseline Proteinuria Levels: A Real-World Study

Article References: Suolinge, C., Dema, C., Wu, X., Jiang, B., Lu, C., & Li, J. (2026). Effectiveness and Safety of Nefecon in Primary IgA Nephropathy Across Different Baseline Proteinuria Levels: A Real-World Study. Advances in Therapy. https://doi.org/10.1007/s12325-026-03784-0

Image Credits: AI Generated

DOI: 10.1007/s12325-026-03784-0

Keywords: IgA nephropathy, Nefecon, targeted-release budesonide, proteinuria, kidney function, estimated glomerular filtration rate, real-world evidence, galactose-deficient IgA1, chronic kidney disease, early intervention, nephrology, autoimmune kidney disease

The core problem the researchers set out to solve is a scarcity mismatch. In primary care, general practitioners record diagnostic codes for chronic kidney disease stages, and these GP-recorded labels carry the weight of clinical judgement: they reflect not only laboratory measurements but also the broader context of a patient’s history, comorbidities, and the physician’s overall assessment. The trouble is that such expert annotations are scarce, because coding is inconsistent, incomplete, and dependent on individual practice. On the other side of the ledger sits a far more abundant label source: estimated glomerular filtration rate, or eGFR, the workhorse blood-test-derived measure of kidney function. Simple rule-based systems can automatically assign a disease stage to virtually any patient who has an eGFR reading, producing labels at population scale. But these rule-based labels are mechanical. They capture a single biochemical threshold and may miss the wider clinical picture that a GP weighs when assigning a stage, which means the two label sources are complementary but only partially consistent with one another.

Previous approaches to this dilemma have tended to treat it in binary terms. Either the label sources are assumed to agree, in which case they can simply be pooled into one training set, or they are assumed to conflict, in which case one is trusted and the other discarded or down-weighted. The Swansea team, led by doctoral researcher Ali Guran together with Avishek Siris, Gary K. L. Tam and Xianghua Xie from the Department of Computer Science, with clinical interpretation provided by James Chess of the Renal Unit at Morriston Hospital, took a different view. They argued that agreement between a GP annotation and a rule-based eGFR label is not a yes-or-no question but a matter of degree. Two labels might match exactly, or they might be adjacent stages, or they might diverge by several stages. That graded structure, they reasoned, contains real information about how confident and clinically meaningful any given case is, and a learning algorithm should be able to exploit it.

The vehicle for that idea is contrastive learning, a technique that has transformed fields from computer vision to medical imaging. In a standard contrastive setup, a neural network is trained to pull representations of similar examples close together in an abstract embedding space while pushing dissimilar examples apart. The Swansea framework generalises this binary pull-and-push logic into a hierarchy. Cases where the GP label and the eGFR rule-based label agree perfectly are treated as strongly concordant and drawn into tight clusters. Cases where the two sources disagree by one stage are pushed apart, but less forcefully. Cases with larger discrepancies are separated progressively more. The result is an embedding space with a graded, clinically interpretable geometry: distance in that space corresponds to the degree of discordance between supervision sources, rather than to an arbitrary similarity metric learned from unlabeled statistics alone. This hierarchical contrastive objective runs alongside a conventional classification loss, so the model still learns to predict stages explicitly while simultaneously absorbing the relational structure of its heterogeneous supervision.

Technically, the framework had to be architecture-agnostic, because longitudinal clinical data, sequences of measurements and events recorded over years of patient care, can be modelled in many ways. The researchers evaluated their approach across a broad portfolio of neural backbones: recurrent networks in the LSTM tradition, standard convolutional architectures, temporal convolutional networks that process long sequences with dilated causal filters, Transformer models built on self-attention, and hybrid designs that combine convolutional feature extraction with attention-based sequence modelling. The hierarchical contrastive loss was layered onto each of these in turn, allowing the team to isolate the contribution of the supervision strategy from the choice of architecture. Across the board, the structured contrastive supervision delivered consistent improvements over two natural baselines: classification-only training, which ignores the relational structure entirely, and binary contrastive training, which treats all disagreements as equivalent.

The strongest overall performance came from a hybrid backbone that couples a temporal convolutional network with a Transformer, an architecture that appears well suited to the rhythm of primary-care records, where long stretches of routine measurements are punctuated by clinically dense episodes. The consistency of the gains across architectures is arguably the most important finding, because it suggests the benefit flows from the supervision design itself rather than from a lucky interaction with one particular model family. For practitioners, that means the hierarchical contrastive recipe is a portable tool: it can be dropped onto whatever sequence model a research group already uses, and it asks only for the two label sources that health systems already generate as a by-product of care.

The study was conducted on data from the Secure Anonymised Information Linkage Databank, a national privacy-protecting research resource in Wales that links primary-care, hospital and other health records for millions of people. All analysis took place inside the SAIL Trusted Research Environment, with the project approved by the databank’s independent Information Governance Review Panel under project number 1220, and only disclosure-controlled aggregate outputs leaving the secure environment. Because the researchers worked exclusively with anonymised, routinely collected data and never accessed identifiable patient information, individual informed consent was not required under the applicable governance framework. This kind of privacy-preserving infrastructure is increasingly the template for large-scale clinical machine learning, and the study demonstrates that such environments can support sophisticated deep learning workflows without compromising patient confidentiality.

The implications reach well beyond nephrology. The mismatch the team addressed, a small reservoir of rich expert labels sitting alongside an ocean of cheap, rule-derived labels, is endemic in medicine. Oncology registries, cardiovascular coding, respiratory diagnostics: nearly every specialty has its own version of the same asymmetry. By showing that graded agreement between label sources can be converted into a training signal, the Swansea framework offers a general template for longitudinal disease modelling under heterogeneous supervision. The authors note that the approach could transfer to other chronic conditions where clinician judgement and algorithmic rules coexist, and where the gap between them is itself informative. In effect, the method treats the healthcare system’s own inconsistencies as a feature to be learned from, rather than a defect to be cleaned away.

There are, of course, caveats. The underlying data cannot be shared publicly, and code components tied to the secure environment are available only on reasonable request subject to governance review, which means independent replication will require comparable trusted-research arrangements. The rule-based eGFR labels themselves inherit the limitations of the KDIGO-style staging criteria from which they derive, and the framework does not resolve which source is ‘right’ when they disagree; instead it encodes the disagreement as structure. But that reframing is precisely the contribution. Rather than forcing a choice between clinical nuance and population scale, the study shows how to have both, and it does so with an elegance that machine learning researchers will recognise immediately: when your labels disagree, teach your model the shape of the disagreement. For a disease that silently erodes kidney function in roughly one in ten adults worldwide, tools that squeeze more signal from the records health systems already collect could translate into earlier detection, better staging, and ultimately better outcomes for patients who today slip through the diagnostic cracks.

Subject of Research: Hierarchical contrastive learning combining GP-recorded and eGFR labels for chronic kidney disease staging

Article Title: Hierarchical contrastive learning from GP-recorded and eGFR labels for CKD staging

Article References: Guran, A., Siris, A., Tam, G. K. L., Chess, J., & Xie, X. (2026). Hierarchical contrastive learning from GP-recorded and eGFR labels for CKD staging. Medical & Biological Engineering & Computing. https://doi.org/10.1007/s11517-026-03668-z

Image Credits: AI Generated

DOI: 10.1007/s11517-026-03668-z

Keywords: chronic kidney disease, contrastive learning, machine learning, eGFR, clinical labels, longitudinal data, Transformer, temporal convolutional network, SAIL Databank, primary care, deep learning, disease staging

Chronic kidney disease is a slow, often silent condition in which the kidneys progressively lose their ability to filter waste from the blood. Because symptoms frequently do not appear until substantial function has been lost, researchers have long searched for early, readily measurable signals that identify people at risk before the damage becomes irreversible. Dyslipidemia—an abnormal level of lipids in the blood—is extremely common in patients who already have CKD, typically manifesting as elevated triglycerides, reduced high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) levels that are normal or only slightly raised. What has remained less clear is whether this distinctive dyslipidemic pattern precedes the onset of kidney disease and can therefore serve as a warning sign rather than simply a consequence.

To address that question, the research team, led by Dandan Li of the First Affiliated Hospital of Henan University of Science and Technology and colleagues at Huaihe Hospital of Henan University and collaborating institutions in China, analyzed data from adults aged 40 years and older whose baseline estimated glomerular filtration rate (eGFR)—the standard measure of kidney filtering capacity—exceeded 60 mL/min/1.73 m². The participants were followed for six years. The team examined eight lipid parameters: triglycerides (TG), total cholesterol (TC), HDL-C, LDL-C, the triglyceride-to-HDL-C ratio (TG/HDL-C), the total-cholesterol-to-HDL-C ratio (TC/HDL-C), the non-HDL-cholesterol-to-HDL-C ratio (NHHR), and residual cholesterol (RC), a measure of cholesterol carried in triglyceride-rich lipoprotein remnants that is increasingly studied for its role in cardiovascular disease.

The main outcome was carefully defined: incident CKD was recorded when a participant’s eGFR fell by at least 30 percent from its baseline value and finished the follow-up period below 60 mL/min/1.73 m². This dual criterion helps ensure that the classification captures a genuine, clinically meaningful decline in kidney function rather than ordinary measurement variability. Using multivariate logistic regression, the researchers adjusted for a range of potential confounders, including demographic factors and clinical covariates, and employed restricted cubic spline analyses to explore the shape of the relationships and subgroup analyses to test whether the associations differed across patient characteristics.

The results were striking in their consistency. Over the six years of follow-up, 453 of the 3,856 participants—11.7 percent of the cohort—developed incident CKD. After full statistical adjustment, participants in the highest tertile of log-transformed triglycerides had 59 percent higher odds of developing CKD compared with those in the lowest tertile, with an odds ratio of 1.59 and a 95 percent confidence interval of 1.24 to 2.05. Total cholesterol told a similar story, with an odds ratio of 1.49 (95 percent CI: 1.15 to 1.92) for the highest versus lowest tertile.

The composite indices performed at least as well as the conventional parameters. The TC/HDL-C ratio was associated with an odds ratio of 1.51 (95 percent CI: 1.17 to 1.95), while the TG/HDL-C ratio produced the largest effect estimate in the analysis, at 1.63 (95 percent CI: 1.26 to 2.10). The non-HDL-cholesterol-to-HDL-C ratio, a composite measure that captures the balance between atherogenic and protective cholesterol fractions, yielded an odds ratio of 1.51 (95 percent CI: 1.17 to 1.95), and residual cholesterol was associated with an odds ratio of 1.50 (95 percent CI: 1.18 to 1.92). In other words, every one of the pro-atherogenic lipid measures examined—whether conventional or composite—pointed in the same direction: higher levels corresponded to higher odds of future kidney disease.

There was one notable exception, and it was protective. Higher levels of HDL-C, often described as the “good” cholesterol because of its role in reverse cholesterol transport, were associated with lower odds of incident CKD, with an odds ratio of 0.75 (95 percent CI: 0.58 to 0.96). This inverse relationship fits mechanistically with HDL’s established anti-inflammatory and antioxidant functions, which some researchers believe may extend to protecting the delicate filtration structures of the kidney from lipid-mediated injury.

The subgroup analyses added an intriguing nuance. Most of the associations held steady across prespecified subgroups of participants, but the TG/HDL-C ratio showed a higher effect estimate in people without diabetes. This observation is scientifically interesting because diabetic kidney disease has its own well-characterized risk architecture; the suggestion that the triglyceride-HDL balance may be an especially informative predictor among non-diabetic adults raises the possibility that composite lipid indices could help identify kidney risk in a population where clinical vigilance is often lower. The authors also employed restricted cubic spline analysis, a flexible statistical technique that models non-linear dose-response relationships, to characterize how risk varied across the full range of lipid values rather than only at arbitrary cutoffs.

From a mechanistic standpoint, several pathways could link lipid disturbances to kidney damage. Elevated triglycerides and residual cholesterol reflect an abundance of triglyceride-rich lipoproteins and their remnants, particles that can deposit in tissues, provoke inflammation, and injure the glomeruli—the microscopic filtration units of the kidney. Lipid accumulation within kidney cells can trigger oxidative stress and fibrosis, processes that progressively scar renal tissue and erode filtering capacity. At the same time, the possibility of reverse causation cannot be fully dismissed in an observational, retrospective design: subtle early kidney dysfunction may itself alter lipid metabolism, and the study’s reliance on routinely collected clinical data means that unmeasured confounding remains a possibility. The authors note that the study received no external funding and was approved by the Clinical Research Ethics Committee of Huaihe Hospital, Henan University, which waived individual informed consent owing to the retrospective nature of the analysis.

The practical implications, however, are immediately relevant to everyday medicine. Lipid panels are among the most commonly ordered laboratory tests in the world, and the parameters highlighted in this study—triglycerides, HDL-C, and simple ratios derived from them—require no additional blood draws, no specialized equipment, and no added cost. If the findings are confirmed in prospective and ethnically diverse cohorts, clinicians could conceivably incorporate composite lipid indices into routine kidney risk stratification, flagging patients whose blood fat profiles warrant closer monitoring of eGFR and earlier intervention with lifestyle modification or lipid-lowering therapy. With chronic kidney disease affecting hundreds of millions of people globally and often progressing unnoticed until dialysis or transplantation becomes necessary, the idea that a number already printed on nearly every routine lab report might help predict who will lose kidney function is a compelling—and potentially consequential—step forward for preventive nephrology.

Subject of Research: The association between conventional and composite blood lipid parameters and the risk of developing incident chronic kidney disease in adults

Article Title: Lipid parameters and the risk of incident CKD: an analysis of conventional and composite lipid indices

Article References: Li, D., Song, Z., Wang, X., Xu, H., Li, X., Yan, S., Yu, T., Liu, Y., Liu, Z., & Jiang, H. (2026). Lipid parameters and the risk of incident CKD: an analysis of conventional and composite lipid indices. BMC Endocrine Disorders. https://doi.org/10.1186/s12902-026-02529-y

Image Credits: AI Generated

DOI: 10.1186/s12902-026-02529-y

Keywords: chronic kidney disease, triglycerides, HDL cholesterol, LDL cholesterol, lipid ratios, residual cholesterol, dyslipidemia, eGFR, cohort study, nephrology, cardiovascular risk, kidney disease prevention

The numbers behind the review are sobering. Between 1990 and 2021, the global burden of chronic kidney disease driven by type 2 diabetes nearly doubled, reflecting an increase of roughly 80 to 90 percent. In the United States, annual all-cause healthcare costs for an insured patient with diabetic kidney disease climb from about 30,000 dollars in early stages to approximately 119,000 dollars as the disease advances. These figures capture more than economic strain; they reflect a disease whose cellular and molecular underpinnings remain only partially mapped, and whose progression is rarely reversible once structural injury takes hold. The authors of the review, Grace LeBleu and Fawaz G. Haj, contend that aberrant tyrosine phosphorylation—a reversible chemical switch that controls how cells respond to insulin, growth factors, and inflammatory cues—is a hallmark of diabetic kidney injury, and that the enzymes which remove these phosphate marks deserve far greater therapeutic attention.

Tyrosine phosphorylation is governed by a tug of war between two enzyme families: protein tyrosine kinases, which add phosphate groups to proteins, and protein tyrosine phosphatases, which remove them. While kinases have long been celebrated drug targets, phosphatases were for years dismissed as undruggable, largely because their catalytic pockets are highly conserved and positively charged, making selective inhibition difficult. The human genome encodes more than 100 phosphatase genes, of which 38 are classical phosphatases that specifically target phosphotyrosine residues—21 of the receptor-type and 17 of the non-receptor-type. The review systematically catalogs the evidence linking each of these 38 enzymes to diabetic kidney disease, ranging from directly established contributors to those implicated only indirectly or not at all.

Among the most firmly established is PTP1B, encoded by the PTPN1 gene. Discovered in the late 1980s and early 1990s as a negative regulator of insulin signaling, PTP1B dephosphorylates the insulin receptor and dampens downstream cascades. In podocytes—the specialized cells whose foot processes form the kidney’s filtration barrier—PTP1B knockdown stabilizes the cytoskeleton and preserves insulin signaling under high-glucose conditions. Recent work identified the cytoskeletal protein alpha-actinin-4 as a PTP1B substrate in insulin-stimulated podocytes, linking the enzyme directly to podocyte motility. In mouse models, global PTP1B deletion markedly attenuates glomerular injury and reduces albuminuria without major changes in blood glucose or pressure, while podocyte-specific deletion or pharmacological inhibition preserves podocyte architecture and blunts glomerular basement membrane thickening. Notably, PTP1B expression has been reported to be elevated in glomerular biopsies from patients with diabetic kidney disease, lending human relevance to the animal findings.

SHP2, the product of PTPN11, has emerged as another central player. In podocytes exposed to high glucose, SHP2 expression rises alongside increased endoplasmic reticulum stress, activation of the inflammatory transcription factor NF-κB, and heightened cell motility; silencing the enzyme prevents these changes. In diabetic mice, elevated SHP2 phosphorylation appears in macrophages, glomeruli, and podocytes, and podocyte-specific genetic deletion or pharmacological inhibition preserves renal function, lowering albuminuria and blood urea nitrogen. Immunohistochemical analysis of renal biopsies from patients with diabetic kidney disease reveals elevated phosphorylated SHP2 at a key activating site, and small-molecule inhibitors such as SHP099 and PHPS1 have shown renoprotective effects in rodent models of both type 1 and type 2 diabetes. SHP1, encoded by PTPN6, tells a similar story: hyperglycemia raises its expression in podocytes, disrupting insulin signaling and promoting apoptosis, while podocyte-specific deletion of SHP1 reduces albuminuria and reverses features of disease progression, apparently by restoring SUMOylation of the slit diaphragm protein podocin.

The review also spotlights endothelial and podocyte receptor-type phosphatases with distinctive renal roles. VEPTP, encoded by PTPRB, is largely restricted to endothelial cells in the adult kidney, where it dephosphorylates the angiopoietin receptor TIE2. Hyperglycemia, osmotic stress, and hypoxia all increase VEPTP expression, and inducible genetic deletion in diabetic mice improves glomerular filtration rate, reduces matrix accumulation, and preserves podocyte integrity—although an antibody-based inhibition approach alone failed to improve albuminuria, hinting that endothelial protection must be paired with therapies addressing the filtration barrier itself. CD148, encoded by PTPRJ, dephosphorylates growth factor receptors including VEGFR2 and EGFR, and an agonistic anti-CD148 antibody that boosts the enzyme’s activity attenuated albuminuria and mesangial expansion in diabetic mice. GLEPP1, encoded by PTPRO, sits on the apical surface of podocytes, and its deletion produces structurally abnormal foot processes, hypertension, and reduced filtration capacity, while its expression is diminished in sclerosed glomeruli from patients with diabetic kidney disease.

Beyond these established players, the review traces a broader web of phosphatases implicated in diabetes and renal pathology. TCPTP dephosphorylates the insulin receptor non-redundantly with PTP1B; its overexpression via gene therapy ameliorated albuminuria and renal morphology in diabetic mice, and its levels are reduced in patients with early-stage diabetic kidney disease. PEZ, or PTPN14, modulates the Hippo pathway through YAP and drives inflammatory and fibrotic signaling via TRIP6, with elevated expression detected in diabetic glomeruli and patient kidneys. RPTPζ serves as a receptor for interleukin-34, recruiting macrophages to injured tubules, while RPTPγ functions as a carbon dioxide and bicarbonate sensor in proximal tubular cells and rises in the serum as diabetic kidney disease progresses. Immune-associated phosphatases such as CD45, PTPN22, and HePTP connect renal inflammation and fibrosis to leukocyte signaling, and a cluster of enzymes including LAR, RPTPε, RPTPσ, and PTP-MEG2 modulate insulin signaling in muscle, liver, and adipose tissue, with several genetic variants linked to type 2 diabetes risk.

What makes the moment ripe for phosphatase-directed therapy is a confluence of pharmacological progress. Current standard care—RAAS blockade with ACE inhibitors or angiotensin receptor blockers, SGLT2 inhibitors validated by the DAPA-CKD, EMPA-KIDNEY, and CREDENCE trials, GLP-1 receptor agonists demonstrated in the FLOW trial, and the nonsteroidal mineralocorticoid receptor antagonist finerenone—slows disease but rarely reverses injury. Combination regimens are increasingly viewed as the path forward, and phosphatase modulators could slot into this framework as complementary agents. SHP2 inhibitors have already advanced through phase I, II, and III oncology trials, while the allosteric inhibitor SHP099 reduced albuminuria and blood urea nitrogen in diabetic mouse models. PTP1B inhibitors including ertiprotafib and trodusquemine reached clinical trials for type 2 diabetes and obesity, and an antisense oligonucleotide, IONIS-PTP-1BRx, lowered HbA1c and body weight in overweight patients with type 2 diabetes. VEPTP inhibition with AKB-9778 progressed to phase II trials for diabetic retinopathy, where patients showed a modest reduction in urinary albumin-to-creatinine ratio.

Novel modalities are expanding the toolbox further. Allosteric inhibitors that bind sites outside the conserved catalytic pocket promise improved selectivity, bivalent ligands engage both active and adjacent sites, and targeted protein degradation via PROTAC technology—exemplified by the SHP2 degrader SHP2-D26—offers a route to eliminate rather than merely inhibit the enzyme. Artificial intelligence and machine learning workflows have already been applied to PTP1B and SHP2 inhibitor discovery, helping overcome the historical barrier of conserved catalytic pockets by identifying selective binding modes and optimized physicochemical properties. The authors emphasize that pharmacological modulation need not mean inhibition in every case: for CD148, whose activity appears protective, an activation strategy is the goal, illustrating the nuanced directionality of phosphatase drug development.

The review’s bottom line is a call to translational action. Diabetic kidney disease remains the leading cause of end-stage renal failure, and existing therapies, however effective at slowing decline, rarely restore lost function. Classical protein tyrosine phosphatases sit upstream of the insulin, inflammatory, oxidative stress, and cytoskeletal cascades that converge to destroy the kidney in diabetes, and several are now pharmacologically tractable. The challenge ahead lies in bridging preclinical promise to clinical reality—defining cell-type-specific roles, establishing context-dependent effects in human disease, and testing phosphatase-targeted agents in combination with established therapies. If that bridge can be built, enzymes once written off as undruggable may finally deliver the precision treatments that patients with diabetic kidney disease have been waiting for.

Subject of Research: The roles of classical protein tyrosine phosphatases in the pathogenesis and treatment of diabetic kidney disease

Article Title: The role of classical protein tyrosine phosphatases in diabetic kidney disease and therapeutic implications

Article References: LeBleu, G., & Haj, F. G. (2026). The role of classical protein tyrosine phosphatases in diabetic kidney disease and therapeutic implications. Journal of Biomedical Science, 33(1), Article 89. https://doi.org/10.1186/s12929-026-01282-7

Image Credits: AI Generated

DOI: 10.1186/s12929-026-01282-7

Keywords: diabetic kidney disease, protein tyrosine phosphatases, PTP1B, SHP2, podocytes, insulin signaling, renal fibrosis, SGLT2 inhibitors, phosphatase inhibitors, drug discovery, chronic kidney disease, inflammation

The clinical starting point for the study is well established. Moderate-to-severe chronic kidney disease-associated pruritus, abbreviated CKD-aP, affects up to 40 per cent of people with kidney failure receiving haemodialysis. Beyond the obvious suffering it causes, the condition has been linked to increased mortality, higher rates of depression and sleep disorders, and markedly diminished health-related quality of life. Crucially for the new analysis, patients with CKD-aP also experience higher rates of infection and infection-related hospitalisation, with risks rising as itch severity worsens. Because hospitalisations for sepsis, catheter infections, endocarditis and skin infections are among the most expensive events in the dialysis population, the researchers reasoned that any therapy capable of resolving pruritus might pay back part of its cost through avoided admissions.

Difelikefalin, a peripherally restricted kappa-opioid receptor agonist administered intravenously at the end of each dialysis session, is currently the only therapy approved in both the United States and Europe specifically for moderate-to-severe CKD-aP in patients on haemodialysis. Its approval rested on the double-blind, randomised, placebo-controlled phase 3 trials KALM-1 and KALM-2, which demonstrated significant reductions in pruritus severity as measured by the Worst Itch Intensity Numerical Rating Scale, with clinically meaningful improvement defined as a score of 4 or higher at baseline. While alternatives such as gabapentin, pregabalin and antihistamines are sometimes used off-label, they are not specifically indicated for CKD-aP and carry variable effectiveness and tolerability in this population, including concerns about adverse outcomes with gabapentinoids in dialysis patients.

To quantify the infection burden attributable to pruritus, the team turned to the Stockholm Creatinine Measurements project, or SCREAM, a healthcare cohort study encompassing the entire population of the Stockholm region and linked through Sweden’s unique personal identity numbers to the Swedish Renal Registry, the National Patient Registry, the Prescribed Drug Registry and the Cause of Death Registry. From 2329 patients on maintenance haemodialysis who were free from CKD-aP at baseline, the researchers identified 411 patients, or 17.6 per cent, who developed clinically recognised pruritus during follow-up between 2006 and 2021. Because Sweden lacks a dedicated itch registry, the team defined clinically recognised pruritus using a combination of surrogate markers: ICD-10 diagnostic codes for pruritus, at least two consecutive dispensations of antipruritic medications such as hydroxyzine, clemastine, gabapentin or pregabalin in the absence of diabetes, peripheral neuropathy or epilepsy, use of an extemporaneously compounded topical itch ointment known in Swedish as klådsalva, or ultraviolet therapy without a psoriasis diagnosis. These criteria were chosen because they align with the moderate-to-severe threshold used in the KALM trials and are likely to capture patients experiencing clinically meaningful itch.

The epidemiological finding at the heart of the study is stark. Infection-related hospitalisation rates were 1.5-fold higher among patients who developed incident CKD-aP than among those who remained itch-free, with an unadjusted incidence rate ratio of 1.48 and a 95 per cent confidence interval of 1.19 to 1.83, a difference that was highly statistically significant. Infection-related hospitalisations occurred at a rate of 16.98 per 100 person-years among patients with incident CKD-aP, compared with 11.60 per 100 person-years in those without. The burden was driven chiefly by sepsis due to Staphylococcus species, which showed a significantly elevated rate in the pruritus group with an incidence rate ratio of 1.55, followed by skin infections including erysipelas, cellulitis, abscess and impetigo, which were also more common in the itch group although the difference did not reach statistical significance. The biological plausibility of these associations rests on immune dysregulation, skin breakdown from chronic scratching and excoriation, and the frequent presence of central venous catheters in this population.

The economic modelling then married these real-world event rates to the treatment effect observed in the clinical trials. Using pooled data from KALM-1 and KALM-2, supplemented by longer-term extrapolation from the SHAREHD stepped-wedge cluster randomised trial, the model projected that over a two-year horizon patients treated with difelikefalin would spend 61.7 weeks free of moderate-to-severe CKD-aP, compared with just 38.1 weeks for those receiving standard care, a difference of roughly 23.6 weeks. The model, adapted from a previously published cost-effectiveness framework, used four health states defined by itch severity, with moderate and severe states combined to represent the presence of CKD-aP and none and mild combined to represent its resolution. It operated on 28-day cycles over two years, applied a 3.5 per cent discount rate in the second year, and adopted the perspective of each country’s healthcare payer. Importantly, drug acquisition costs were deliberately excluded because the study aimed to isolate the infection-related contribution rather than perform a full economic evaluation, meaning the figures represent cost offsets rather than net savings.

Scaled to national dialysis populations using prevalence data from the European Renal Association Registry and country-specific unit costs, the projected two-year infection-related cost offsets were substantial everywhere the model was applied. In the base case using SCREAM-derived assumptions, offsets ranged from approximately €231,000 in Sweden to just over €2 million in France. Across all scenario analyses, the estimated national two-year offsets spanned €2 million to €6.4 million in France, €1.2 million to €3.5 million in Spain, €1.1 million to €2.6 million in Italy, €1 million to €3 million in the United Kingdom, €500,000 to €1.4 million in Portugal, €250,000 to €730,000 in Switzerland, and €230,000 to €660,000 in Sweden. Probabilistic sensitivity analyses, running the model 1000 times with parameters sampled from their confidence intervals and Dirichlet distributions, produced narrow confidence bands, indicating that the conclusions were stable despite uncertainty in individual inputs.

The scenario analyses are particularly revealing about how conservative the base case may be. Catheter-associated infection rates in the SCREAM data were only 1.89 per 100 person-years, a figure the authors attribute to coding practices in hospital records, where catheter infections may be displaced by codes reflecting kidney failure or secondary infections, and to the requirement that events result in hospital admission to be captured. Alternative sources paint a different picture: a systematic review and meta-analysis by van Meurs and colleagues reported pooled catheter infection rates of 20.3 per 100 person-years, while analyses from the Dialysis Outcomes and Practice Patterns Study, or DOPPS, found rates between 3.5 and 10.2 per 100 person-years depending on country. Similarly, while SCREAM suggested a CKD-aP prevalence of 17.6 per cent, the European CENSUS survey and DOPPS reported figures between 26.8 and 40.1 per cent. Substituting these higher prevalence and infection rates increased the estimated cost offsets by 48 per cent with higher prevalence and by 103 to 179 per cent with higher catheter infection rates, and a scenario adding pruritus-associated excess mortality slightly reduced offsets because more surviving patients continue to incur costs.

The authors are careful to acknowledge the limitations inherent in real-world evidence of this kind. Misclassification of pruritus is possible where cases go unrecognised by clinicians or unreported by patients, and gabapentin and pregabalin dispensations may partly reflect treatment of restless legs syndrome rather than itch, although use of these drugs was low overall and similar between groups. Patients who developed incident CKD-aP also differed systematically at baseline, with more heart failure, prior skin infection, sleep and mood disorders, and longer time on dialysis, factors that could confound the association with infection; however, a previously published adjusted analysis showed a similar elevation in infection-related hospitalisation risk, with an adjusted hazard ratio of 1.36, suggesting the association is robust. The model also assumes that the relationship between incident pruritus and outcomes is exchangeable with symptom resolution in a prevalent population, whereas in clinical practice most difelikefalin is prescribed to patients with existing pruritus, which is why the higher-prevalence scenarios may better reflect reality.

Beyond the headline figures, the study’s significance lies in how it reframes the economics of a symptom that has historically been underdiagnosed and undertreated in dialysis units. Because the analysis counted only infection-related hospitalisations, it almost certainly understates the full economic case: previous work by the same Scandinavian collaboration showed that CKD-aP is associated with increased use of antidepressants, anxiolytics and sleep aids, and the documented improvements in health-related quality of life from trials represent additional value not captured in a cost-offset framework. The authors suggest that extending the model over a longer horizon would likely yield greater offsets, since early reductions in itch severity with difelikefalin would be sustained over time, and that further treatment-related gains through reduced mortality are plausible given the established association between pruritus and death in dialysis populations. For health system decision-makers weighing whether to fund CKD-aP treatment within bundled dialysis payments or as a separate per-patient mechanism, the message of this analysis is that treating the itch may not merely make patients more comfortable; it may also keep them out of hospital, and that difference carries a price tag measured in millions of euros across Europe every two years.

Peritoneal dialysis is a form of renal replacement therapy in which the lining of the patient’s abdomen filters waste products from the blood, offering an alternative to hemodialysis for many people with end-stage kidney disease. Although fractures are a recognized and serious complication of chronic kidney disease in general, contributing to pain, disability, institutionalization, and death, patients treated with peritoneal dialysis have been comparatively understudied. Most fracture research in dialysis populations has centered on hemodialysis, leaving clinicians with limited evidence to guide fracture prevention decisions for the peritoneal dialysis cohort. The new study was designed to fill that gap by quantifying how often fragility fractures occur during peritoneal dialysis follow-up, identifying the factors that predict them, and testing whether a standard risk calculator works in this setting.

The research team conducted a single-center retrospective cohort study at their Portuguese institution, including adult patients who had been receiving peritoneal dialysis for at least twelve months. In total, 325 patients were analyzed, with a mean age of 53 years and a majority, 57 percent, being male. Fragility fractures occurring during peritoneal dialysis follow-up were identified through two complementary routes: systematic review of clinical records and review of spine radiographs. This dual approach mattered, because it allowed the investigators to capture vertebral fractures that had never caused symptoms and therefore never prompted clinical attention. Vascular calcification, a hallmark of the disordered mineral metabolism that accompanies kidney failure, was quantified using the Adragão vascular calcification score, a simple radiographic tool originally developed for hemodialysis patients that evaluates calcification in the pelvic and hand arteries on plain films.

To evaluate whether existing risk tools could be applied to these patients, the researchers calculated FRAX® probabilities for each individual without incorporating bone mineral density measurements. FRAX®, the Fracture Risk Assessment Tool developed by the World Health Organization collaboration led by John Kanis and colleagues, integrates clinical risk factors such as age, sex, prior fracture, parental hip fracture history, smoking, glucocorticoid use, and secondary causes of osteoporosis to estimate ten-year fracture probability. The investigators then used logistic regression to determine which variables independently predicted fracture occurrence, and constructed receiver operating characteristic curves to judge how well FRAX® discriminated between patients who fractured and those who did not. Statistical analyses were performed by the joint first authors, Diz-Lopes and Fernandes, who contributed equally to the work.

The headline finding was that fragility fractures were far from rare. Thirty-two of the 325 patients, or 9.8 percent, sustained at least one fragility fracture during peritoneal dialysis follow-up. Strikingly, the majority of these were asymptomatic vertebral fractures, accounting for 23 of the 32 fracture events, or 7.1 percent of the entire cohort. In other words, roughly seven in every hundred peritoneal dialysis patients in the study had vertebral fractures that were detectable on radiographs but had produced no clinical symptoms. Only a minority of fractures were the clinically obvious events, such as hip or other peripheral fractures, that typically bring a dialysis patient to medical attention.

When the researchers ran multivariable logistic regression to isolate independent predictors of fracture, two factors emerged. A history of previous fracture was the strongest, conferring nearly a five-fold increase in odds of sustaining a new fragility fracture during follow-up, with an odds ratio of 4.85 and a 95 percent confidence interval of 1.22 to 19.27. This aligns with a large body of literature, including a 2023 meta-analysis used to update FRAX® itself, establishing prior fracture as one of the most potent predictors of subsequent fracture in the general population. The second independent predictor was a higher Adragão vascular calcification score, with an odds ratio of 2.10 and a 95 percent confidence interval of 1.10 to 4.03, meaning each increment in the score roughly doubled the odds of fracture.

The link between vascular calcification and skeletal fragility is a recurring theme in dialysis research. Prior studies in hemodialysis populations, including work by Fusaro and colleagues using quantitative morphometry and by Rodriguez-Garcia and colleagues in the Asturias cohort, have documented strong associations between vascular calcifications, vertebral fractures, and mortality. The prevailing explanation, articulated by Cannata-Andia and colleagues, is that the connections between vascular and bone health run deep: the same disturbances of mineral metabolism, inflammation, and bone turnover that drive calcium deposition in arteries can also impair bone quality. Some investigators, including Adragao’s group, have shown that higher mineralized bone volume is associated with lower plain radiographic vascular calcification scores, suggesting that the two processes may be two faces of a shared underlying pathology. The new peritoneal dialysis data extend this vascular-bone axis to a population where it had not been well characterized.

The performance of FRAX® in this cohort was the study’s most sobering result. The tool showed only modest discriminatory ability for any fragility fracture, with an area under the receiver operating characteristic curve of 0.69. An AUC of 0.69 falls well short of what is generally considered good discrimination and implies limited practical utility for individual decision-making. More concerning still, sensitivity at the standard intervention thresholds was very low, meaning that the great majority of patients who actually fractured would not have been flagged for treatment under existing guidelines. Notably, this remained true even when the researchers classified chronic kidney disease as a secondary cause of osteoporosis within the FRAX® algorithm, the most favorable adjustment available to them. The conclusion is that FRAX® systematically underestimates fracture risk in peritoneal dialysis patients.

This finding has context in a growing literature on FRAX® and kidney disease. Studies by Whitlock and colleagues in 2019 showed that FRAX® can predict fracture risk in chronic kidney disease populations, while other work by Przedlacki and colleagues in hemodialysis and by Hayashi and colleagues in Japanese hemodialysis patients has produced more mixed results. A recent overview of systematic reviews by Cruz-Priego and colleagues in 2025 examined the predictive capacity of fracture risk assessment tools broadly and highlighted persistent questions about their transportability across populations. The FRAX® algorithm was derived from population-based cohorts that excluded or underrepresented patients with advanced kidney disease, whose bone disease differs fundamentally from postmenopausal or age-related osteoporosis. In dialysis patients, the spectrum of skeletal pathology, encompassing high-turnover bone disease, adynamic bone disease, and mixed uremic osteodystrophy under the umbrella of chronic kidney disease-mineral and bone disorder, is far more heterogeneous than the bone loss captured by standard osteoporosis models.

The implications for clinical practice are significant. The European consensus statement on the diagnosis and management of osteoporosis in chronic kidney disease stages G4 to G5D, published by Evenepoel and colleagues in 2021, acknowledged the difficulty of distinguishing the causes of bone fragility in advanced kidney disease, and recent KDIGO Controversies Conference conclusions from Ketteler and colleagues in 2025 similarly emphasized unresolved questions in chronic kidney disease-mineral and bone disorder. Given that bone mineral density by dual-energy X-ray absorptiometry, the cornerstone of conventional osteoporosis assessment, may not fully capture bone quality in uremic patients, and given that DXA studies in peritoneal dialysis patients have shown discordance between lumbar spine and femoral neck measurements, the study’s authors argue that improved fracture risk assessment strategies tailored specifically to peritoneal dialysis patients are needed. The identification of vascular calcification as an independent risk factor is particularly appealing from a practical standpoint, because the Adragão score relies on simple plain radiographs already obtained for other reasons in many dialysis patients, making it a feasible and inexpensive addition to risk stratification.

The authors are careful to frame their findings within the limits of the study design. As a retrospective, single-center cohort of 325 patients at one Portuguese institution, the study cannot establish causation, is subject to the ascertainment biases inherent in clinical record review, and may not generalize to peritoneal dialysis populations with different demographic or clinical characteristics, or to healthcare systems with different screening practices. The confidence interval around the odds ratio for prior fracture is wide, from 1.22 to 19.27, reflecting the relatively small number of fracture events and the uncertainty that accompanies estimates derived from them. Verbal informed consent was obtained from subjects given the retrospective design, and ethical approval was granted by the local ethics committee of Hospital de São João under approval number CE 90/2024. The authors declared no conflicts of interest and no external funding. Data supporting the findings are available from the corresponding author upon reasonable request.

Even with these caveats, the study delivers a clear message to nephrologists and rheumatologists who care for peritoneal dialysis patients. Fragility fractures are common in this group, driven disproportionately by vertebral fractures that remain invisible unless deliberately sought, and the standard risk calculator that guides osteoporosis treatment decisions in the general population cannot be trusted here. Patients with a prior fracture or with vascular calcification on plain radiographs deserve heightened vigilance. Until tools validated specifically for the peritoneal dialysis population are developed, clinicians may need to rely on clinical judgment, attention to prior fracture history, and simple radiographic markers of vascular calcification to identify those at greatest skeletal risk. As the population of people living long-term on dialysis grows, and as reports of increasing hip fractures in both hemodialysis and peritoneal dialysis patients accumulate, closing the evidence gap in bone health for peritoneal dialysis patients becomes an increasingly urgent priority for the kidney and bone research communities alike.

Tricuspid regurgitation occurs when the tricuspid valve, which separates the right atrium from the right ventricle, fails to close tightly. With each heartbeat, some blood flows backward instead of moving efficiently toward the lungs. Over time, this reverse flow can enlarge the right-sided chambers of the heart and raise pressure in the veins that return blood from the body. Patients may develop swelling in the legs and abdomen, liver congestion, fatigue and severe shortness of breath. The kidneys can suffer as well. In heart failure, reduced forward blood flow may limit renal perfusion, while elevated venous pressure can transmit backward into the veins surrounding the kidneys. This combination can reduce the pressure gradient that drives filtration. Fluid accumulation may then prompt clinicians to use diuretics, which relieve congestion but can further challenge kidney function if circulating volume falls too quickly. The resulting interaction is often described as cardiorenal syndrome, in which deterioration of one organ accelerates dysfunction in the other.

T-TEER is designed to reduce the backward leak without open-heart surgery. During the procedure, physicians guide a catheter through a vein into the heart and position a small clipping device across the tricuspid valve leaflets. The device grasps and brings portions of the leaflets together, creating a more effective seal and reducing the regurgitant opening. Unlike valve replacement, the technique leaves the native valve in place and is performed through a catheter rather than through a large chest incision. It is therefore particularly attractive for older patients or people whose surgical risk is elevated because of heart failure, kidney disease or other illnesses. By reducing the volume of blood pushed backward with each contraction, the repair can lower right-sided filling pressures and lessen systemic venous congestion. The Stuttgart researchers set out to determine whether that altered circulation was reflected in measurable changes in kidney function and in the frequency of acute kidney injury.

The retrospective study included 181 consecutive patients who underwent T-TEER at Robert Bosch Hospital between March 2021 and February 2023. The investigators analysed routine electronic health-record data collected before and after the intervention, excluding patients whose records did not contain sufficient information. Follow-up lasted a median of 125 days, although the range extended from six days to 506 days for the central interval reported, with some patients followed for as long as 1,280 days. The cohort was examined according to the severity of pre-existing chronic kidney disease, using estimated glomerular filtration rate, or eGFR, as a central measure. eGFR is calculated from blood markers and demographic variables to approximate how much plasma the kidneys filter each minute, with the result normalized to a standard body-surface area of 1.73 square metres. Lower values generally indicate more advanced renal impairment. The analysis also tracked markers associated with congestion and metabolic balance, including gamma-glutamyl transferase, or GGT, and blood potassium, as well as acute kidney injury after the procedure.

Across the study population, eGFR rose by a median of 4.8 millilitres per minute per 1.73 square metres, with the improvement reaching statistical significance at p less than 0.001. The reported interquartile range was 3.1 to 6.5 millilitres per minute per 1.73 square metres, indicating the central spread of individual changes. The increase was accompanied by reductions in GGT and potassium. GGT is an enzyme often used to assess hepatobiliary stress and can rise when the liver is affected by systemic venous congestion; a decline may therefore be consistent with relief of pressure in the right-sided circulation, although it is not a direct measurement of kidney filtration. Potassium is tightly regulated by the kidneys and can accumulate when renal excretion is impaired. Its reduction after repair may reflect improved renal handling, changes in medications or altered clinical status. Patients with chronic kidney disease showed improvement across nearly all disease stages, whereas those who began with preserved renal function, defined in the report as eGFR of at least 60, largely remained stable rather than improving.

The most striking signal involved acute kidney injury. According to the study, the incidence of AKI decreased in every chronic kidney disease group after T-TEER. Rate ratios ranged from 0.18 to 0.39, corresponding to an estimated 60 to 80 per cent reduction compared with the relevant pre-procedure or baseline period. Following the intervention, AKI rates no longer differed between the various CKD stages. That finding is important because patients with poorer kidney function are usually more vulnerable to abrupt declines in filtration during hospitalization or after invasive cardiovascular procedures. AKI can result from several mechanisms, including reduced perfusion, venous congestion, contrast exposure, inflammation and medication effects. The study does not establish which of these mechanisms changed after valve repair. However, the disappearance of the difference between CKD categories suggests that reducing the hemodynamic burden of severe tricuspid regurgitation may have helped narrow a risk gap that normally favours patients with healthier kidneys.

The biological explanation proposed by the results centres on congestion rather than on a direct effect of the clipping device on renal tissue. When right atrial and central venous pressures remain high, pressure can be transmitted through the large veins into the renal veins and the low-pressure compartments around the kidneys. This may compress small vessels and tubules, a concept sometimes described as renal tamponade or renal compression. At the same time, heart failure can reduce effective arterial blood flow reaching the kidneys. Filtration depends on the balance between pressures entering and leaving the glomerular capillaries, the microscopic structures where blood is filtered. Excessive venous pressure can reduce that gradient even when arterial pressure appears acceptable. Repairing the tricuspid valve could therefore improve filtration by lowering downstream pressure and allowing more effective forward circulation. The reductions in GGT and potassium provide additional, though indirect, evidence that the procedure was accompanied by less systemic congestion and improved physiological stability.

The investigators caution that their work is not a randomized clinical trial and cannot demonstrate that T-TEER itself caused the renal recovery. The study was conducted at a single hospital, involved 181 patients and relied on routine electronic records, which can contain missing measurements and variation in the timing of laboratory tests. Follow-up duration also varied substantially between individuals. Changes in diuretic treatment, blood pressure, fluid management, contrast use, infection, nutrition or other aspects of care could have influenced eGFR and AKI risk. In addition, eGFR can fluctuate with hydration and acute illness, and a modest numerical increase does not necessarily mean that structural kidney damage has reversed. The findings nevertheless align with the clinical logic that relieving severe right-sided congestion may benefit the kidneys, particularly in patients whose renal function is already compromised. Prospective studies with standardized measurements, longer follow-up and comparison groups will be needed to determine whether the renal changes translate into fewer hospitalizations, slower progression of CKD or improved survival. For now, the study adds kidney preservation to the growing list of potential consequences of successful transcatheter treatment for severe tricuspid regurgitation.

The study, published in BMC Complementary Medicine and Therapies, was conducted at Bu-Ali Sina Educational Medical Center in Qazvin, Iran, between November 2024 and January 2025. The researchers enrolled 78 adults undergoing maintenance hemodialysis and assigned them to an intervention group or a routine-care control group using block randomization, with 39 participants initially placed in each group. Randomization is designed to distribute known and unknown characteristics—such as age, illness burden, motivation or previous experience with psychological treatment—more evenly between groups, strengthening the credibility of comparisons. Participants in the intervention arm received eight weekly sessions, each lasting 30 to 45 minutes. The training took place during dialysis sessions, an approach that may reduce the practical burden of attending additional appointments. The program was adapted from the mindfulness-based protocol associated with Jon Kabat-Zinn, which generally emphasizes deliberate attention to present-moment experiences, awareness of thoughts and bodily sensations, and a less reactive attitude toward discomfort.

Mindfulness is not intended to remove the medical demands of dialysis. Instead, it is a behavioral and psychological technique that may alter how patients respond to stress, fatigue, unpleasant sensations and recurring treatment decisions. During hemodialysis, a machine circulates blood through a filter called a dialyzer, removing excess water and waste products that damaged kidneys can no longer clear effectively. Between sessions, however, patients must carefully regulate how much fluid and certain nutrients they consume. Excessive fluid intake can contribute to interdialytic weight gain—the increase in body weight between dialysis treatments—raising the risk of swelling, high blood pressure and cardiovascular strain. Dietary and medication decisions also accumulate over time, and missed dialysis sessions can have serious consequences. Mindfulness could theoretically support adherence by improving attention, reducing automatic or impulsive responses, and helping patients tolerate distress. But the technique cannot substitute for individualized nutritional guidance, medication management, transportation support or clinical care.

Treatment adherence in dialysis is also difficult to measure, which helps explain why published estimates of non-adherence vary widely. The researchers note that studies in Iranian populations have reported non-adherence rates ranging from 2 percent to 87 percent. Such a broad range does not necessarily mean that patient behavior is changing dramatically from one study to another. It can reflect differences in definitions, questionnaires, clinical settings and the specific behaviors being measured. One investigation may focus on missed dialysis appointments, while another may emphasize fluid restriction, medication use or dietary recommendations. In this trial, adherence was assessed with the End-Stage Renal Disease Adherence Questionnaire, or ESRD-AQ, at three points: before treatment, immediately after the eight-week intervention and one month later. A composite questionnaire can capture a broader picture of self-management, but it may also obscure improvements in one domain when other domains remain unchanged.

Of the 78 people randomized, 70 completed the study: 36 in the mindfulness group and 34 in the control group. At baseline, the groups were broadly comparable in their adherence scores. The intervention group had a mean score of 862.83, with a standard deviation of 166.29, while the control group had a mean of 842.82 and a standard deviation of 187.80. The difference was not statistically significant, with a p-value of 0.638, indicating no clear evidence that one group began with better adherence than the other. At the one-month follow-up, however, the mindfulness group showed a significantly greater improvement in adherence change scores than the control group, with p = 0.005. That result is the most attention-grabbing finding in the study, but it should not be interpreted as proof that mindfulness broadly transformed treatment behavior. A statistically significant comparison at one time point is different from demonstrating a consistent treatment effect across the entire follow-up period.

The more comprehensive repeated-measures analysis did not find a significant group-by-time interaction. This interaction asks whether the pattern of change over time differed between the mindfulness and routine-care groups. In the trial, the interaction had a p-value of 0.223 and a partial eta squared of 0.022, a small effect-size estimate. In practical terms, the data did not establish that the intervention group followed a reliably different trajectory from the control group across baseline, post-intervention and follow-up assessments. The apparent advantage at one month may therefore reflect improvement concentrated in a particular adherence domain, natural fluctuations in behavior, measurement variability or the limited statistical power of a small trial. The distinction matters because repeated assessments can reveal whether an intervention produces durable and consistently different change, rather than an isolated difference. The authors consequently conclude that mindfulness did not show a significant overall effect on treatment adherence in the primary repeated-measures analysis.

Exploratory results offered a possible explanation for the mixed picture: dietary adherence appeared to improve more than other components of self-management. Mindfulness may be especially relevant when eating decisions are shaped by habit, emotion, boredom or momentary urges. A brief pause between craving and action could help some patients notice what they are experiencing and make a choice more consistent with their dietary plan. That possibility remains hypothetical in this study, however, because the trial was not large enough to establish a definitive domain-specific mechanism. The intervention did not demonstrate broad, statistically confirmed improvements in fluid restriction, medication adherence or attendance at dialysis sessions. Each of those behaviors is influenced by different barriers. Fluid control can be affected by thirst, dry mouth, heat and social routines; medication adherence may depend on side effects, cost, complicated schedules or memory; and dialysis attendance can be limited by transportation, work, caregiving responsibilities or severe illness. A single psychological strategy may not address all of them.

The study has several features that make the intervention clinically interesting, particularly its delivery during treatment rather than in separate clinic visits. Dialysis sessions already require patients to spend substantial time in a medical setting, so integrating a 30-to-45-minute activity into that period could make mindfulness more accessible. It may also allow nurses or other trained staff to incorporate behavioral support into routine care without adding travel requirements. At the same time, the trial’s scale and short follow-up limit what can be concluded about long-term benefits. Eight sessions and one additional month of observation cannot show whether any improvement persists for six months or a year, when treatment fatigue and changing health circumstances may become more important. The source material also does not report that the intervention was blinded—an inherently difficult condition for behavioral training—or provide evidence that the results would generalize to other hospitals, healthcare systems or cultural settings. Larger trials with longer follow-up, objective measures such as interdialytic weight gain and attendance records, and analyses of specific adherence barriers could provide a clearer test.

The researchers frame mindfulness as a feasible adjunct to nursing care, not as a replacement for medical treatment. That restrained conclusion is important because adherence problems are rarely caused by attention or motivation alone. Patients on hemodialysis may be coping with depression, anxiety, pain, sleep disruption, cognitive symptoms, financial stress and the relentless schedule of chronic illness. Effective support may therefore need to combine mindfulness with motivational interviewing, cognitive-behavioral therapy, dietitian-led education, medication simplification, family involvement and practical assistance with transport or appointments. The trial’s result is best understood as a signal rather than a breakthrough: a low-cost, non-pharmacological intervention may help some patients—possibly particularly with dietary decisions—but the evidence does not yet show that it can reliably improve every aspect of dialysis adherence. For a treatment regimen in which small daily choices can have major physiological consequences, the next scientific challenge is determining which patients benefit, which behaviors are most responsive and how psychological training can be combined with concrete clinical and social support.

Subject of Research: Mindfulness-based intervention and treatment adherence among patients undergoing maintenance hemodialysis

Article Title: Mindfulness-based intervention on treatment adherence in hemodialysis patients: a randomized controlled trial

Article References: Jirandehi, F. M., Hosseinigolafshani, S., Ranjbaran, M. et al. “Mindfulness-based intervention on treatment adherence in hemodialysis patients: a randomized controlled trial.” BMC Complementary Medicine and Therapies (2026). Original research article

Image Credits: AI Generated

DOI: 10.1186/s12906-026-05546-5

Keywords: hemodialysis, treatment adherence, mindfulness, chronic kidney disease, end-stage renal disease, dietary adherence, randomized controlled trial, self-management, nursing care

Chronic kidney disease refers to persistent abnormalities in kidney structure or function, usually lasting at least three months. The kidneys regulate fluid balance, remove metabolic waste, control electrolytes, and contribute to blood-pressure regulation and red-blood-cell production. When kidney function deteriorates, toxins and excess fluid accumulate, while hormonal and vascular systems become dysregulated. CKD is often clinically silent until substantial damage has occurred, which is why it is frequently described as a “silent killer.” In women, the consequences extend beyond kidney failure. Reduced kidney function increases the risk of ischemic heart disease, stroke, heart failure, and other cardiovascular complications, while pregnancy-related disorders can both reveal previously unrecognized kidney damage and contribute to future disease.

The new analysis found that the number of deaths from CKD among women increased by 180.89 percent between 1990 and 2021, while disability-adjusted life-years, a measure combining years lost to premature death with years lived with disability, rose by 114 percent. Unlike a simple case count, age-standardized rates adjust for changes in population size and age structure, allowing researchers to examine whether the underlying risk or severity of disease is changing. The investigators reported continuous increases in age-standardized mortality and DALY rates among women, indicating that the worsening burden cannot be explained only by global population growth or the increasing number of older adults. The findings point to a persistent deterioration in health outcomes that requires earlier detection and more effective prevention.

Age was one of the clearest dividing lines in the study. Women aged 50 years and older, a group that includes most postmenopausal women, accounted for nearly 90 percent of CKD-related deaths and approximately 73 percent of CKD-related DALYs among women in 2021. Their age-standardized mortality rate reached 64.03 deaths per 100,000 women, while their age-standardized DALY rate was 1,493.31 per 100,000. Both measures continued to rise over the study period. Biological changes after menopause may contribute to this vulnerability. Declining estrogen levels can affect vascular function, blood pressure, inflammation, and metabolic health, while the accumulation of diabetes, obesity, and hypertension over the life course places additional stress on the kidneys. These interacting mechanisms can accelerate the progression from mild kidney impairment to advanced disease.

At the same time, the analysis identified reproductive-age women as an increasingly important population in the global CKD picture. Among women aged 15 to 49 years, prevalent CKD cases increased by 64.01 percent between 1990 and 2021. This group was also the only age category in which the age-standardized prevalence rate continued to rise, with an average annual percentage change of 0.13 percent. A rising age-standardized prevalence rate suggests that the increase reflects more than population growth or demographic change. Pregnancy-related hypertension, pre-eclampsia, gestational diabetes, obesity, and pre-existing kidney abnormalities may all contribute to this pattern. Kidney disease can complicate pregnancy, while pregnancy complications can increase a woman’s later risk of hypertension, cardiovascular disease, and CKD, creating a feedback loop that begins during the reproductive years and becomes more visible in midlife.

Metabolic kidney disease emerged as a major driver of the changing burden. Type 2 diabetic kidney disease showed the largest increase in age-standardized mortality among the CKD subtypes examined, rising by 36.93 percent. The prevalence of hypertensive kidney disease effectively doubled. High fasting plasma glucose, high systolic blood pressure, and high body mass index were the dominant attributable risk factors across age groups. These factors damage the kidneys through several pathways: persistent hyperglycemia alters the glomerular filtration barrier and promotes scarring; elevated blood pressure injures small renal vessels; and excess adiposity increases inflammation, insulin resistance, and intraglomerular pressure. Once kidney function declines, the kidneys become less able to regulate blood pressure, further intensifying the cycle of injury.

The investigators also detected troubling changes in lifestyle-associated risk among younger women. In reproductive-age women, the burden attributable to high body mass index increased by 112.17 percent, while the burden linked to sugar-sweetened beverages rose by 132.97 percent. These estimates do not mean that a single food or beverage directly causes CKD in every individual, but they indicate that population-level exposure to metabolic risk is expanding. Frequent consumption of sugar-sweetened drinks can increase total energy intake and contribute to weight gain, insulin resistance, and type 2 diabetes. Obesity may also affect kidney function independently of diabetes by increasing filtration pressure and provoking inflammatory changes in renal tissue. The results suggest that prevention cannot wait until women reach older age; metabolic and kidney health may need to be protected from adolescence and early adulthood.

Kidney dysfunction was closely tied to cardiovascular disease in the study. In 2021, cardiovascular disease attributable to impaired kidney function in women accounted for 18.19 million DALYs, representing approximately 46.70 percent of the total burden associated with kidney dysfunction. Ischemic heart disease contributed about 60 percent of this cardiovascular burden, followed by cerebral hemorrhage and ischemic stroke. The connection is biologically plausible because damaged kidneys promote hypertension, vascular calcification, anemia, chronic inflammation, and disturbances in mineral metabolism. These changes can accelerate atherosclerosis and impair the heart’s ability to function. The findings reinforce the concept of a cardio-renal-metabolic continuum in which kidney disease, diabetes, obesity, hypertension, and cardiovascular disease are not isolated conditions but mutually reinforcing components of a single long-term health crisis.

Geographic and socioeconomic differences were also prominent. Women living in low and low-middle sociodemographic regions carried the highest CKD burden, consistent with disparities in access to screening, blood-pressure treatment, diabetes care, specialist nephrology services, and kidney-protective medicines. However, high-income North America recorded the fastest growth in CKD-related mortality, showing that wealth at the national level does not eliminate the problem. Researchers used decomposition analysis to estimate how demographic changes contributed to the rise in CKD-related DALYs. Population growth accounted for 58.63 percent of the increase, while population aging contributed 26.64 percent. The remaining change reflects shifts in disease risk, detection, treatment, and other factors. These results indicate that health systems must prepare for a larger and older population of women with kidney disease while also addressing preventable metabolic risks.

The authors argue that the response should be tailored to women’s lives rather than limited to treatment after kidney damage becomes advanced. Integrating kidney screening into preconception and antenatal care could help identify reduced filtration or albuminuria, an early marker of glomerular injury, before pregnancy complications occur. Regular monitoring of blood pressure, blood glucose, body weight, and kidney function could also identify high-risk women during the reproductive years. For older women, more systematic screening after menopause may help detect the combined effects of vascular and metabolic aging. Treatments such as sodium–glucose cotransporter 2 inhibitors can reduce kidney and cardiovascular risk in appropriate patients, although cost, availability, and clinical infrastructure remain major barriers in low-resource settings. The researchers call for sex-specific CKD registries, multidisciplinary cardio-kidney-metabolic clinics, and policies that make prevention and kidney-protective therapies more accessible. Their central message is that women’s CKD burden is growing across the life course, but earlier action could still change its trajectory.

Subject of Research: People

Article Title: Chronic kidney disease in women: Global trends and metabolic-cardiovascular associations

News Publication Date: 1-Jun-2026

Web References: https://doi.org/10.1097/CM9.0000000000004100

References: Chinese Medical Journal; Global Burden of Disease Study 2021

Image Credits: Prof. Lin Sun and Prof. Zhifeng Sheng, The Second Xiangya Hospital of Central South University

Keywords: chronic kidney disease, women’s health, nephrology, diabetes, hypertension, obesity, cardiovascular disease, metabolic health, kidney disease prevention, Global Burden of Disease, epidemiology, public health