Regardless of recent progress, there is still unmet need for the treatment of chronic kidney disease (CKD). This has led to increased interest in using alternative medicine, such as Traditional Chinese Medicine (TCM), to treat CKD, particularly in China and other Asia countries. Indeed, many CKD patients experience improvement of proteinuria and renal function with appropriate TCM management. However, TCM practice is mostly based on the experiences accumulated over years, which has not been proven by modern well-designed clinical trials. Even though the number of TCM-related randomized controlled trials has been increasing in recent years, these studies still suffer from issues such as small sample sizes, inadequate randomization, and a lack of long-term follow-up. Also, trials with TCM in combination with recently approved new drugs have not been done. Additionally, the complexity and variability of TCM formulas, combined with a lack of standardized quality control for herbs and the heterogeneity of TCM practices, make the study designs very challenging. Safety concerns also arise owing to insufficient systematic monitoring and reporting of potential adverse herb-drug interactions and the nephrotoxicity of certain herbs. TCM uses a holistic medical approach; however, the underlying molecular mechanisms remain unclear. Most published studies are limited to examining the anti-inflammatory and antioxidative stress effects without knowing the exact targets of these drugs and the precise bioactive compounds are often not well defined. In this review, we discuss the challenges and opportunities related to the clinical and basic science research in the field of TCM and describe the pros and cons of several new approaches that have been used in recent years to discover new drugs from TCM.
Vascular calcification (VC) is a major independent risk factor for cardiovascular events in patients with chronic kidney disease (CKD), yet no effective clinical treatment is currently available. Quercetin, a natural flavonoid abundant in fruits and vegetables, demonstrates promising therapeutic potential in CKD-related VC (CKD-VC). This review systematically summarizes the molecular mechanisms by which quercetin ameliorates CKD-VC from two principal aspects: directly targeting the vascular smooth muscle cells (VSMCs) phenotypic transition and indirectly alleviating the procalcification microenvironment. At the cellular level, quercetin inhibits osteoblastic transdifferentiation, restores calcium-phosphorus homeostasis, enhances calcification inhibitor expression, and effectively alleviates pathologic processes, including oxidative stress, inflammation, cellular senescence, and apoptosis, while also regulating epigenetic modifications. In terms of the procalcification microenvironment, quercetin mitigates CKD-VC by improving gut microbiota dysbiosis, reducing uremic toxin accumulation, protecting endothelial barrier function, and inhibiting ferroptosis. In conclusion, based on existing research evidence, quercetin demonstrates the potential to exert anticalcification effects through multitarget and multipathway mechanisms.
Acute kidney injury (AKI) is common in hospitalized patients and is strongly associated with subsequent acute kidney disease (AKD), chronic kidney disease (CKD), end-stage kidney disease, and increased mortality. The Kidney Disease: Improving Global Outcomes 2026 AKI/AKD public review draft emphasizes the AKI-AKD-CKD continuum and the need for structured follow-up, kidney function and proteinuria reassessment, and risk stratification after AKI or AKD. Mechanistically, the AKI-to-CKD transition is driven by maladaptive tubular repair, characterized by G2/M arrest and sustained profibrotic signaling, microvascular rarefaction-induced hypoxia, mitochondrial dysfunction with impaired fatty acid oxidation, and amplification of injury by regulated cell death pathways, including ferroptosis and necroptosis, in concert with chronic inflammation. Cellular senescence in tubular epithelial cells and immune cells further perpetuates a senescence-associated secretory phenotype-mediated proinflammatory and profibrotic milieu, thereby promoting irreversible fibrosis. Effective targeted therapies remain lacking. Traditional Chinese medicine-derived agents may provide mechanistically plausible multitarget candidates for modulating tubular injury and interstitial fibrosis.
Chronic kidney disease (CKD) is characterized by progressive disturbances in phosphorus homeostasis that contribute to the development of cardiovascular disease and CKD-mineral and bone disorder. Because dietary phosphorus intake is frequently excessive in Western diets, phosphorus restriction has emerged as a potential strategy to improve clinical outcomes in CKD. This review summarizes the current evidence linking dietary phosphorus intake with cardiovascular disease, mortality, and bone health in CKD. Experimental studies consistently demonstrate that phosphorus excess promotes vascular calcification, endothelial dysfunction, cardiac hypertrophy, inflammation, and increased fibroblast growth factor 23 secretion, providing strong mechanistic support for a causal role in cardiovascular injury. However, observational studies examining dietary phosphorus intake or oral phosphorus binder use and cardiovascular outcomes have yielded inconsistent findings, likely reflecting limitations in dietary assessment, differences in phosphorus bioavailability, and residual confounding by dietary protein intake, nutritional status, and other factors. By contrast, evidence linking dietary phosphorus intake with bone disease is more consistent. Controlled feeding studies demonstrate that higher phosphorus intake increases parathyroid hormone concentrations, whereas reducing total phosphorus intake or limiting phosphorus-containing food additives lowers parathyroid hormone and fibroblast growth factor 23 concentrations, often without changes in serum phosphorus. Collectively, current evidence suggests that therapeutic strategies focusing on phosphorus source and bioavailability may be more important than those targeting total phosphorus intake alone for optimizing cardiovascular and bone health in CKD. Future clinical trials are needed to determine whether reducing highly absorbable inorganic phosphorus additives improves cardiovascular, skeletal, and survival outcomes in patients with CKD.
Arsenic is a toxic element that is widely present in both natural and clinical environments, posing a significant threat to human health. Long-term exposure to arsenic may lead to multiorgan damage, with the kidneys, as the primary target organs for arsenic metabolism and excretion, being particularly vulnerable to its toxic effects. Increasing evidence suggests that arsenic exposure is associated with the occurrence of acute kidney injury and the progression of chronic kidney disease. Previous studies have primarily focused on mechanisms such as oxidative stress, mitochondrial dysfunction, and programmed cell death. However, these mechanisms do not fully explain the complexity of arsenic nephrotoxicity. In this review, we systematically review recent advancements in the understanding of arsenic-induced renal injury, with a particular focus on novel mechanisms, including epigenetic regulation, noncoding RNA-mediated gene expression regulation, and metabolic reprogramming, as revealed by omics techniques. These new mechanisms provide a theoretical foundation for enhancing our understanding of arsenic nephrotoxicity, discovering potential biomarkers, and developing targeted intervention strategies. Additionally, we assess the effectiveness and limitations of current management approaches, such as chelation therapy, antioxidant applications, and supportive treatments. It is worth noting that a growing body of evidence suggests that traditional Chinese medicine might offer renal protection through antioxidant, anti-inflammatory, and immunomodulatory pathways. Our previous studies have also demonstrated that the Chuanhuang formula and its active ingredient, tetramethylpyrazine, could effectively alleviate arsenic-induced acute kidney injury. Finally, we hope to mitigate the potential health risks posed by arsenic exposure through multidisciplinary collaboration and comprehensive intervention.
Potassium-containing food additives are a broad class of compounds used in food processing and food preparation to enhance the quality, flavor, safety, stability, and health of foods. In 2023, the US Food and Drug Administration encouraged food manufacturers to replace salt with potassium-based salt substitutes, and although this change was intended to reduce hypertension in the general population, excess intake of potassium-based salt substitutes may increase the risk of hyperkalemia in people with kidney failure on dialysis. To assess and address this concern, the American Society of Nephrology produced a kidney health guidance report, which included basic, advanced, and intensive dietary strategies for mitigating hyperkalemia risk from food additives in people with reduced kidney function. The purpose of this review was to refine these recommendations to reduce hyperkalemia risk from potassium additives in patients on dialysis.
Diabetic kidney disease (DKD) persists as the predominant etiology of end-stage renal disease globally. Despite advances in conventional pharmacotherapies, which primarily target single pathogenic pathways, a considerable residual risk of renal function decline and end-stage renal disease progression remains unresolved, highlighting the need for alternative therapeutic paradigms. This review involves dissecting and integrating mechanistic insights derived from preclinical investigations, including in vitro cellular models, in vivo animal models of DKD, and molecular biology-based analyses. It uses Tangshen formula, a classic traditional Chinese medicine (TCM) for DKD, to detail TCM's protective mechanisms and concisely summarizes the DKD-related preclinical progress of other TCMs over 5 years. Unlike monotarget strategies, TCM interventions exert synergistic effects across multiple organ systems: they reshape the renal microenvironment by mitigating oxidative stress and extracellular matrix accumulation, reprogram hepatic glucose and lipid metabolism to alleviate insulin resistance, and fortify the intestinal mucosal barrier to prevent endotoxemia-induced systemic inflammation. At the microscopic and molecular levels, these TCM-derived agents orchestrate coordinated crosstalk among key pathogenic cascades, including chronic inflammation, renal fibrosis, gut microbiota dysbiosis, metabolic flux dysregulation, microcirculatory impairment, and hypoxic injury. By targeting these interconnected pathways simultaneously, TCM facilitates the restoration of systemic homeostasis, thereby addressing the complex, multifactorial pathogenesis of DKD more comprehensively than pathway-specific interventions.
Kidney diseases, represented by chronic kidney disease (CKD) and acute kidney injury (AKI), pose significant global public health challenges due to their complex pathogenesis and limited therapeutic options. In recent years, epigenetic regulation-including DNA methylation, histone modifications, and non-coding RNAs-has been shown to play a crucial role in the progression of kidney diseases, offering new directions for therapeutic strategies. Natural herbal compounds have emerged as a research focus for modulating epigenetic mechanisms owing to their multi-target effects, low toxicity, and broad bioactivity. This review outlines the regulatory functions of epigenetic mechanisms across various kidney diseases and illustrates how natural herbal compounds can mitigate renal injury via multi-target epigenetic modulation. These compounds have been shown to reverse renal fibrosis, attenuate inflammatory responses, suppress oxidative stress, and protect podocytes and renal tubular epithelial cells by targeting DNA methyltransferases, histone-modifying enzymes, and non-coding RNAs, including microRNAs and long non-coding RNAs. However, challenges such as limited bioavailability and insufficiently elucidated in vivo mechanisms impede clinical translation. Future research should prioritize structural optimization, advanced delivery systems, and investigations into gut microbiome interactions to enhance therapeutic applicability. Overall, this review highlights the promise of epigenetics-based therapeutic strategies using herbal active ingredients for kidney disease intervention, though further validation and optimization are needed for clinical application.
Cellular senescence, a key driver of kidney aging and functional decline, manifests in 2 primary forms: (1) replicative senescence, primarily caused by telomere shortening; and (2) stress-induced senescence, triggered by factors such as oxidative stress and DNA damage. Senescent cells are characterized by permanent cell cycle arrest, activation of senescence-associated secretory phenotype (SASP), and epigenetic alterations, among others. It is important to note that cellular senescence is not exclusively detrimental; it also serves necessary, programmed functions in physiologic tissue remodeling and tumor suppression. However, its chronic accumulation with age is a major driver of organ decline. Currently, specific treatments targeting senescent cells are lacking. Strategies to counteract senescent cells fall into 2 main categories: (1) senolytics, which eliminate senescent cells; and (2) senomorphics, which mitigate their detrimental paracrine effects, including SASP inhibitors. Traditional Chinese Medicine (TCM) has demonstrated potential in combating aging through both senolytic and senomorphic mechanisms. Current evidence suggests that several TCM-derived compounds and formulations may modulate renal senescence-related pathways, including BCL-2 family-dependent apoptosis resistance, NF-κB/JAK2-STAT3/NLRP3-mediated SASP, NOX4-ROS/Nrf2 oxidative stress signaling, AMPK/mTOR/SIRT1 nutrient-sensing pathways, Klotho expression, and the gut-kidney axis. This review explores the emerging role of TCM in addressing renal aging, highlighting its advantages as a multi-targeted, low-toxicity therapeutic strategy to mitigate aging-related kidney diseases.
Glomerular disease (GD) is common in Vietnam. In the absence of suitable pathology laboratories, well-trained renal pathologists and etiologic laboratory tests, the diagnosis of GD mainly relies on the recognition of clinical syndromes. Support from the International Society of Nephrology has been crucial for the clinical and pathologic diagnosis of GD in Vietnam. The high cost of new immunosuppressant agents has precluded their widespread adoption and low-cost steroids remain the main immunosuppressants prescribed for GD in Vietnam.
Chronic kidney disease progresses through convergent mechanisms involving hemodynamic stress, proteinuria, inflammation, fibrosis, and metabolic disturbance. Barry Brenner's hyperfiltration hypothesis established these processes as drivers of ongoing injury, and landmark trials established that renin-angiotensin-aldosterone system (RAAS) inhibition slows progression and improves clinical outcomes, marking a shift from supportive care to disease-modifying treatment. Treatment options have since expanded, with newer therapeutic classes providing additional kidney and cardiovascular benefit alongside emerging agents with more targeted mechanisms of action. Approaches to prognostic assessment have also advanced through biomarkers, genetics, imaging, and digital tools, although integration into clinical practice remains incomplete. More than 4 decades after their introduction, RAAS inhibitors remain a core component of kidney protection, with newer therapies complementing rather than replacing them.
Glomerular capillary hypertension plays a key role in the pathophysiologic response to kidney injury, including glomerulonephritis, diabetes mellitus, and congenital or acquired nephron loss. The discovery of this phenomenon was a transforming period in the history of nephrology. This essay describes this event and how it impacted the field, with an emphasis on the seminal contributions of Barry M. Brenner and his colleagues.
While leading groundbreaking research into glomerular function and diseases, Barry Brenner developed a world-leading division of nephrology which made important discoveries in other aspects of renal function and disease. Barry’s superb intellect, insistence on high standards and driving curiosity forged the careers of many fellows and junior faculty members who did not work on the glomerulus. As an example of this “mentorship at a distance” (along the nephron, that is) I describe here his role in developing my own line of investigation into the control of distal nephron function, starting with a series of studies on the role of atrial peptides in regulating sodium transport in inner medullary collecting duct cells. With Barry’s help and encouragement, these initial studies extended to a series of articles on the mechanisms of action of several regulators of salt excretion, work which launched my career as an independent investigator. My own story serves as a case study of the outstanding mentoring that Barry provided, even to trainees who were not focused on his own work in the glomerulus.
Cardiovascular disease (CVD) remains the leading disability burden and cause of mortality worldwide. As emphasized by the cardiovascular-kidney-metabolic health construct, enhanced screening mechanisms are needed for the identification and prediction of subclinical endothelial injury and silent CVD. We hypothesized that urinary podocyte shedding (podocyturia), as a biomarker of ongoing glomerular endothelial injury, may be an earlier predictor of CVD than moderate albuminuria. Urinary podocin and nephrin messenger RNAs (podocyturia), as candidate biomarkers of endothelial/podocyte injury, were measured by quantitative polymerase chain reaction in type 2 diabetics with normal albumin excretion rates at baseline, at 3-4 years, and at 7 years. The development of CVD was collected as the outcome. On visit 1, podocyturia was significantly higher in individuals who subsequently developed CVD versus those who did not. We also found a significant association between podocyturia and obstructive coronary artery disease. Moreover, individuals with CVD risk factors that included male sex, metabolic syndrome, and type 2 diabetes were found to have significantly higher urinary podocin levels than individuals without these risk factors. Podocyturia may be an earlier predictor of cardiovascular events than moderate albuminuria. Semin Nephrol 36:x-xx © 20XX Elsevier Inc. All rights reserved.
The therapeutic advantage of angiotensin-converting enzyme inhibitors was first described more than 40 years ago by Brenner and colleagues. Since then, a number of clinical trials have demonstrated the utility of drugs that modify the renin-angiotensin system (RAS) to slow the rate of progression of kidney disease in patients with and without diabetes. However, despite the well-known benefits of these drugs in reducing cardiorenal events, most clinicians are not using them consistently in their practice. The lack of use is related to concerns about increases in serum creatinine and the development of hyperkalemia. With the advent of many newer drugs to delay the progression of kidney disease and reduce the likelihood of cardiovascular events which have lesser effects on increasing serum creatinine or potassium, clinicians may prefer to use these therapies. Although trials of the newer cardiorenal protective therapies were conducted on the background of RAS inhibition, only the highest tolerated dose of RAS inhibition was used, a dose not shown to provide cardiorenal protection in a clinical trial. As multimodal therapy for slowing the progression of chronic kidney disease and reducing cardiovascular events moves into prime time, one has to wonder whether RAS inhibition will remain a foundation therapy.
