Chronic kidney disease (CKD) disproportionately affects people of African ancestry worldwide including those living in Europe and the United States (US), with overrepresentation among those with advanced CKD and kidney failure. This excess burden reflects the convergence of genetic susceptibility, including Apolipoprotein-L1 (APOL1) risk variants and sickle-cell-related nephropathy, with early-life factors such as low birth weight, high rates of hypertension and diabetes, and recurrent acute kidney injury from infections or environmental exposures. Social and structural drivers including poverty, limited nephrology access, systemic racism, and medical mistrust may further accelerate disease progression. Accurate diagnosis is hampered by historic reliance on race in estimating kidney function. The inclusion of a race coefficient in eGFR equations embeds a social label into a biological formula, delaying CKD recognition and treatment. Current guidance supports race-free equations and the selective use of ancestry-informed genetic tools, such as APOL1 testing, within ethical frameworks. Management requires attention to both biology and context. Hypertension remains the leading modifiable risk factor but is often more severe and less well controlled; culturally tailored community programmes, including barbershop and church-based interventions, improve blood pressure and engagement. Glomerulonephritis, infections such as HIV, and heat- or toxin-related kidney injury remain major causes of CKD across Africa, compounded by scarce diagnostic capacity and low nephrologist density, and are likely to contribute to disease in Diaspora.This review outlines the global burden, key causes, diagnostic challenges, and socioeconomic and health-system barriers specific to African ancestry populations in Europe, and highlights precision strategies (genetic, clinical, and community-based) to promote equitable kidney care.
BACKGROUND AND HYPOTHESIS:Proton pump inhibitors (PPIs) are widely used for acid suppression but have been associated with kidney injury. Potassium-competitive acid blockers (P-CABs) such as tegoprazan provide rapid, reversible inhibition of gastric H⁺/K⁺-ATPase, yet their renal safety remains unclear. We compared the risk of incident chronic kidney disease (CKD) between tegoprazan and PPIs in a nationwide population-based cohort. METHODS:Using the Korean Health Insurance Review and Assessment database, we identified adults without prior kidney disease who initiated tegoprazan or a PPI during 2020-2021. After 1:3 propensity score matching, we compared the risk of incident CKD using Cox proportional hazards models. Sensitivity and subgroup analyses examined robustness and effect modification by age, sex, and comorbidities. RESULTS:Among 901,606 new users (43,864 tegoprazan; 857,742 PPIs), PPI use was associated with a higher CKD incidence (6.16 vs 4.63 per 1,000 person-years). In the matched cohort, PPI initiation was associated with a higher risk of CKD than tegoprazan initiation (hazard ratio 1.22; 95% CI 1.09-1.37; P < 0.01). Findings were consistent across subgroups and sensitivity analyses, including the unmatched cohort (HR 1.34; 95% CI 1.20-1.48; P < 0.01). CONCLUSION:In this large real-world analysis, PPI initiation was associated with a higher rate of newly coded CKD than tegoprazan initiation. These findings provide comparative kidney safety data and suggest that risk of kidney injury may be one consideration, alongside efficacy and cost, when prolonged acid suppression is required.
Lupus nephritis represents one of the most severe manifestations of systemic lupus erythematosus. Despite major advances in the therapeutical armamentarium over the last two decades, the number of patients reaching end stage kidney disease or dying has not changed significantly. One of the main reasons is that many patients relapse, and with each relapse, further damage is done to the kidney, contributing to the development of progressive chronic kidney disease. This has led to the increased practice of doing protocol biopsy to guide decision regarding risk for relapses and/or discontinuation of immunosuppression. However, this practice has been based on the assumption that the answer is in the kidney, while in reality the kidney reflects the downgrade effect of what is going on upstream, i.e. the immunological milieu. We provide an in-dept review on the use of repeat protocol kidney biopsies in LN with the hope to demonstrate that this practice is based on faulty evidence and of limited benefit in the management of patients with proliferative class III/IV lupus nephritis. Rather, physicians treating these patients should focus on markers of immunological activity (anti-ds-DNA levels) and clinical activity (C3/C4 complement levels), to better predict risk for relapses and in deciding when to reduce/discontinue immunosuppression. As such, this review represents a paradigm shift in the approach of evaluating activity in patients with LN, that is not done by performing protocol kidney biopsies, but rather by looking at the serological activity instead, and as such proposing a new vision on the subject that we believe will improve patient care and kidney outcomes.
BACKGROUND:Polypharmacy in chronic kidney disease (CKD) is substantial. Clinicians and patients are often reluctant to add medications to already complex regimens, partly due to concerns about diminishing efficacy and increased adverse effects. We assessed whether efficacy and safety of canagliflozin is modified by polypharmacy status in patients with type 2 diabetes and CKD. METHODS:We conducted a post-hoc analysis of the CREDENCE trial, which evaluated the effects of canagliflozin on outcomes in patients with type 2 diabetes and CKD. Participants were categorized as no polypharmacy (0-4 medicines), polypharmacy (5-9 medicines), or hyperpolypharmacy (≥10 medicines). We assessed the relative effects of canagliflozin on clinical and safety outcomes by polypharmacy status using Cox proportional hazards models. We assessed absolute benefits using Poisson regression. The primary outcome was a composite of doubling of serum creatinine, kidney failure or death due to cardiovascular or kidney disease. RESULTS:Among 4401 participants, 612 (14%), 2404 (55%), and 1385 (31%) were categorized as no polypharmacy, polypharmacy and hyperpolypharmacy, respectively. Mean number of medications was 8.3 (SD 3.77). The effect of canagliflozin on kidney and cardiovascular outcomes was consistent irrespective of polypharmacy status, with no interaction observed for safety outcomes (all P-interaction > 0.06). Rates of treatment discontinuation increased with medication burden, but were lower with canagliflozin versus placebo, regardless of polypharmacy status (P-interaction = 0.16). Incidence of all-cause hospitalization, and heart failure hospitalization or cardiovascular death increased with higher medication burden, thus absolute risk reductions were estimated to be substantially greater in patients with polypharmacy and hyperpolypharmacy. CONCLUSION:Among patients with type 2 diabetes and CKD, the efficacy and safety of canagliflozin appears consistent regardless of polypharmacy status, with larger estimated absolute reductions in hospitalizations and cardiovascular events in those experiencing polypharmacy or hyperpolypharmacy. These findings suggest that polypharmacy alone should not preclude consideration of SGLT2 inhibitor therapy in patients with CKD and type 2 diabetes for whom treatment is otherwise indicated.
BACKGROUND:Chronic kidney disease (CKD) is characterized by proximal tubule (PT) stress, oxidative injury, and metabolic dysfunction. Human kidney single-nucleus RNA-sequencing (snRNA-seq) identified enrichment of ubiquitin-dependent protein catabolic processes in injured PT cells, suggesting activation of the ubiquitin-proteasome system during tubular stress. Because Cullin 3 (CUL3), scaffold of ubiquitin ligases, regulates oxidative stress signaling through the KEAP1-NRF2 axis, we investigated its role in PT injury and stress adaptation. METHODS:Human CKD snRNA-seq data and kidney immunostaining were used to define PT cell states, CUL3-associated pathways, and CUL3 localization. Injury-associated CUL3 regulation was examined in wildtype mice after ischemia-reperfusion injury (IRI). Inducible PT-specific knockout mice (Slc34a1-CreER; Cul3flox/flox) were analyzed at baseline and after injury by histology, immunostaining, proteomics, and injury assessment. In addition, proteomic analysis of a whole-tubule epithelial knockout model (Pax8-rtTA/LC1; Cul3flox/flox) was performed. In immortalized human PT cells, CUL3 was suppressed or activated using CRISPR interference and CRISPR activation, followed by bulk RNA sequencing. RESULTS:CUL3 transcript and protein expression was enriched in stressed PT states in human CKD. In mice, CUL3 protein abundance increased after injury, supporting injury-associated induction in vivo. PT-specific CUL3 deletion increased antioxidant NQO1 expression without causing overt baseline injury. Proteomic analysis of isolated CUL3-deficient PT cells revealed induction of antioxidant, detoxification, proteostasis, and lipid metabolic programs, together with suppression of mitochondrial oxidative metabolism. Similar changes were observed in whole-tubule Cul3 knockout model. In gene-edited human PT cells, CUL3 suppression recapitulated stress-associated and metabolic remodeling programs, whereas CUL3 activation induced reciprocal transcriptional changes. Despite induction of antioxidant pathways, PT-specific CUL3 deletion did not alter disease severity after IRI or aristolochic acid nephropathy. CONCLUSION:CUL3 is an injury-induced regulator of PT metabolic and stress-associated states and modulates antioxidant defense and mitochondrial metabolism in PT cells.
BACKGROUND:Women comprise a substantial proportion of the chronic kidney disease (CKD) population and differ from men in disease phenotype, progression, and treatment exposure. Underrepresentation of women and limited sex-specific reporting may therefore reduce the generalizability of evidence from contemporary CKD trials. METHODS:We conducted a meta-epidemiological study of randomized trials evaluating sodium-glucose cotransporter-2 inhibitors, glucagon-like peptide-1 receptor agonists, and non-steroidal mineralocorticoid receptor antagonists in adults with CKD. Female representation was quantified using the enrollment disparity difference (EDD), defined as the observed proportion of female trial participants minus the expected proportion derived from sex-specific Global Burden of Disease CKD prevalence estimates matched to trial population characteristics. Trial-level EDDs were pooled using random-effects meta-analysis. Meta-regression was used to examine trial-level correlates of EDD. Historical analyses extended the cohort to earlier cardiorenal pharmacotherapies to evaluate temporal trends, with pivotal CKD trials examined descriptively. Reporting of sex-specific cardiovascular and kidney outcomes was also assessed. RESULTS:Fifty-five randomized trials were included. Median female enrollment was 33.1%, and 52 trials (94.5%) enrolled fewer women than expected. The pooled EDD was -0.17 (95% CI, -0.20; -0.14), with negative estimates across all intervention classes. In meta-regression, phase II design and albuminuria requirement were associated with greater female underrepresentation, whereas diabetes requirement and female first authorship were associated with smaller enrollment disparity, including after adjustment for other key trial characteristics. Sex-specific outcomes were reported in 13 trials (23.6%). Extension to 117 trials provided no statistically supported evidence of improvement in female representation over time, including after adjustment for intervention class; all 38 pivotal CKD trials enrolled fewer women than expected. CONCLUSIONS:Women remain underrepresented in cardiorenoprotective therapy trials, with limited sex-specific outcome reporting. Historical benchmarking indicates that successive advances in CKD pharmacotherapy have not been accompanied by demonstrable improvement in the sex representativeness of the evidence base.
In both clinical research and study design, the definition of outcomes for chronic kidney disease (CKD) is changing. New molecules available for testing in humans, and the fact that kidney diseases are best treated earlier in their course, make the duration of studies requiring 'hard endpoints' longer than is feasible for registration purposes and funding agencies. Improved mathematical modelling and statistical analyses, and the availability of electronic medical records and registries have also impacted nephrology clinical research. Thus, eGFR slopes have been promoted as surrogate endpoints for kidney failure, competing-risk methods have exposed the limitations of standard survival analysis in high-mortality CKD and dialysis populations, and pragmatic, registry-based trials enroll patients who resemble those seen in daily practice. This review suggests that eGFR slopes, time to kidney failure, and competing risk factors must be considered in their totality, so that CKD and cardiovascular (CV) evidence can be understood in clinical practice by patients and clinicians. We propose that eGFR slopes may provide a clinically intuitive summary of 'kidney time', showing how, under appropriate conditions, chronic slope differences may be translated into approximate 'years of dialysis delayed' at the population level. We frame competing risks as a clinical, not only statistical, issue, and we examine how pragmatic CKD trials can and should integrate slope-based endpoints and competing-risk analyses into their design and reporting. To advance nephrology research, we must embrace these changes in study design and methodology to ensure that clinicians and patients understand them, and thus are more prepared to implement trial results.
BACKGROUND AND HYPOTHESIS:The paracellular absorption of phosphate (Pi) contributes the bulk of intestinal absorption under conditions of high dietary Pi availability. Here, we hypothesized that dietary Pi content and reduced renal function affect intestinal paracellular Pi transport. METHODS:Wildtype male mice received low (<0.1%, LP) or high (1.2%, HP) diet for 7 days. Urine, blood, intestinal segments and kidneys were collected and analyzed for urinary and plasma concentrations of Pi and Ca2+, plasma levels of Pi-regulating hormones, evaluation of trans- and paracellular Pi transport across jejunum and ileum and intestinal claudin expression. Additionally, wildtype male mice underwent sham operation or 5/6 nephrectomy followed by 14 days of HP diet to mimic the pathophysiological features of CKD and intestinal Pi transport was assessed. RESULTS:Mice displayed the expected systemic adaptation to LP/HP diets but showed no differences in ileal paracellular Pi transport upon different dietary Pi. The protein expression of several barrier-associated claudins (claudin-3, -4 and -7) was upregulated upon HP diet, specifically in the ileum. 5/6 nephrectomized mice showed the expected disturbed mineral metabolism, lacked downregulation of active intestinal Pi transport, and showed higher ileal paracellular Pi transport. Claudin-3 and claudin-7 were mislocalized in the ileum. In human intestinal cells, the uremic toxin p-cresol enhanced Pi permeability. CONCLUSION:Changes in dietary Pi intake do not alter paracellular Pi fluxes. In a mouse model of CKD, active intestinal Pi transport is not downregulated despite hyperphosphatemia and paracellular Pi fluxes elevated. The loss of junctional barrier integrity might be driven driven by uremic toxins such as p-cresol and could contribute to systemic phosphate imbalance in CKD. Our findings highlight the intestinal epithelial tight junction (TJ) and uremic toxins as potential therapeutic targets to prevent disturbed phosphate homeostasis in CKD.
BACKGROUND AND HYPOTHESIS:Evidence supporting renin-angiotensin system (RAS) inhibition in dialysis-dependent patients with heart failure with reduced ejection fraction (HFrEF) remains limited. We performed a systematic review and meta-analysis to assess the efficacy and safety of angiotensin receptor-neprilysin inhibitors (ARNIs) and angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACEi/ARBs) in this population (PROSPERO ID: CRD420251274393). METHODS:Outcomes of interest included all-cause mortality and cardiovascular mortality. Eligible studies included adult patients with chronic HFrEF on maintenance hemodialysis or peritoneal dialysis, comparing ARNI versus non-ARNI regimens and ACEi/ARB versus control regimens. Literature searches were conducted through December 2025 in PubMed, EMBASE, Google Scholar, and Web of Science. Hazard ratios (HRs) and their respective 95% confidence intervals (CIs) were pooled and meta-analyzed across studies. RESULTS:Overall, six studies evaluated ARNIs (3,818 treated; 4,344 controls), and three studies evaluated ACEi/ARBs (3,293 treated; 1,982 controls). ARNI use versus non-ARNI regimens was associated with significantly lower all-cause mortality (pooled HR 0.78, 95% CI 0.71-0.87), as was ACEi/ARB initiation versus placebo or no RAS blockade (pooled HR 0.76, 95% CI 0.68-0.84). ACEi/ARB therapy was also associated with lower cardiovascular mortality (pooled HR 0.62, 95% CI 0.54-0.71), whereas no significant association was observed with ARNIs (pooled HR 0.91, 95% CI 0.79-1.04). Safety data were available only for ARNI studies, suggesting no excess hypotension and a lower risk of hyperkalemia compared with ACEi/ARBs. CONCLUSIONS:In dialysis-dependent patients with HFrEF, ARNI use versus non-ARNI regimens, and ACEi/ARB use versus placebo or no RAS blockade, were each associated with lower all-cause mortality, while lower cardiovascular mortality was observed only with ACEi/ARB therapy. These findings suggest a potential overall benefit of RAS blockade in this population; however, they are derived predominantly from observational studies, remain susceptible to residual confounding and should not be interpreted as demonstrating causal treatment effects.
C3 glomerulopathy (C3G) is an ultra-rare, complement-mediated glomerular disease characterized by dysregulation of the alternative complement pathway and a high propensity for recurrence after kidney transplantation. Although kidney transplantation remains the optimal treatment for patients reaching kidney failure, post-transplant recurrence continues to be a major cause of graft dysfunction and loss. Over the past decade, improved histopathologic recognition and the increasing adoption of protocol biopsies have revealed that C3G frequently recurs early after transplantation, often in a subclinical form. At present, no validated clinical, genetic, or functional biomarkers reliably predict recurrence, and preventive strategies remain unproven. Consequently, from our standpoint, management of recurrent C3G requires a pragmatic, surveillance-driven approach rather than prophylactic intervention. In this review, we provide a practical framework for managing recurrent C3G after kidney transplantation, from transplant candidacy and pre-transplant evaluation to post-transplant monitoring and therapeutic decision-making. We discuss the role of protocol biopsies, the limitations of conventional immunosuppression, and the emerging place of proximal complement inhibitors. Finally, we highlight several unmet needs that continue to limit optimal care, including persistent uncertainty about therapeutic goals, management of subclinical histologic recurrence, and interpretation of treatment response. This review reflects a transplant-centered clinical perspective aimed at supporting nephrologists in real-world decision-making.
BACKGROUND:Kidney disease is a significant global public health and economic burden, with unmet clinical requirements for early diagnostic biomarkers and targeted therapies. Exosomes, nanoscale lipid bilayer vesicles that facilitate intercellular communication through bioactive cargo, have emerged as a promising translational tool for addressing these gaps. OBJECTIVE:This review summarizes the classification, biological functions, technical workflows (isolation, characterization, and storage), and physiological/pathological roles of exosomes in kidney disease. It also emphasizes clinically actionable advances in exosome-based diagnosis and therapy and identifies translational barriers. METHODS:This narrative review was conducted through a comprehensive literature search across PubMed, Web of Science, and Scopus databases up to April 2026. KEY FINDINGS:Exosomes regulate renal pathological processes, including inflammation, oxidative stress, and fibrosis. Urinary/blood exosomal molecules are potential non-invasive biomarkers for acute/chronic kidney disease. Cell-derived exosomes demonstrate preclinical therapeutic efficacy for renal repairs. However, technical standardization and large-scale clinical validation remain significant challenges. CONCLUSION:Exosomes have a high translational potential for the diagnosis and treatment of kidney diseases. Addressing standardization, validation, and regulatory challenges is crucial for clinical adoption, and this review provides a roadmap for bridging preclinical findings to clinical practice.
ABSTRACT Rationale Hyponatremia is the most common electrolyte disorder found in hospitalized patients and is associated with an increased mortality. Urea has been proposed as an alternative to vasopressin receptor antagonists (VRAs) in the treatment of syndrome of inappropriate antidiuresis (SIAD), though comparative data are scarce. The aim was to evaluate the effectiveness and safety of urea compared with tolvaptan for treating SIAD in hospitalized patients. Methods Retrospective cohort study of adult inpatients with SIAD (serum sodium <130 mmol/l) treated with either urea or tolvaptan at a single institution between January 2015 and December 2023. Inverse probability of treatment weighting adjusted for confounders. Primary outcome was the proportion of patients achieving a serum sodium of >130 mmol/l. Secondary outcomes included time to treatment goal, serum sodium changes at 24, 48, and 72 h, proportion of overcorrection (>10 mmol/l per 24 h), and resource utilization. Results Of 537 patients, 463 received urea (median age 78 years; 57% female; baseline serum sodium 124.2 mmol/l, mean starting dose: 26 ± 6.1 g daily) and 74 received tolvaptan (68 years; 56% female; 123.6 mmol/l, mean starting dose 12.9 ± 6.5 mg daily). Similar proportions reached a serum sodium >130 mmol/l (79.7% vs 78.0%, P = 0.986). Time to target showed a trend favoring tolvaptan {2 [interquartile range (IQR) 1–4] vs 3 (IQR 2–5)} days, P = 0.077). Tolvaptan produced faster sodium increases at 48 h (8.3 (IQR 4.4–12.0) vs 5.6 (IQR 2.9–9.0) mmol/l), P = 0.001) but also more overcorrections (>10 mmol/l per 24 h: 10.8% vs 3.2%, P = 0.011). Treatment duration was longer with tolvaptan (7 (IQR 4–11) versus 5 (IQR 3–8) days, P = 0.001), with substantially higher costs (€468 vs €12, P < 0.001). Conclusions Urea may have a comparable effectiveness to tolvaptan with similar success rates but fewer overcorrections and substantially lower costs. These findings support urea as a safe and cost-effective first-line treatment option for appropriate patients with SIAD.
BACKGROUND:Urinary Dickkopf-3 (uDKK3) is a tubular-stress glycoprotein linked experimentally to tubular injury, context-dependent Wnt signaling and tubulointerstitial remodeling. Human studies now span CKD, kidney histology, cardiorenal disease and transplantation, but the clinical estimands and assay platforms differ. METHODS:We searched PubMed, Embase, CENTRAL/Cochrane, ClinicalTrials.gov and conference sources to 28 May 2026 for human urinary DKK3 studies reporting kidney-function decline/progression, kidney failure, fibrosis/histology or transplant/donor outcomes. Risk of bias was assessed with QUIPS. The primary progression synthesis pooled one threshold/categorical HR or OR per cohort using Paule-Mandel random effects with HKSJ intervals; fibrosis correlations were Fisher-z pooled. We also performed an exploratory assay-aware sensitivity analysis using platform classifications extracted from the source articles. RESULTS:We included 24 full-text studies, 6 unique abstracts and relevant registry/parent-trial records. Across 8 native-kidney estimates, higher uDKK3 was associated with kidney-function decline or progression (pooled relative effect [HR/OR composite] 1.82, 95% CI 1.44-2.30; I2=32%; 95% prediction interval 1.15-2.89). The HR-only sensitivity estimate was 1.70 (95% CI 1.20-2.41). Assay-stratified analyses were directionally positive in ReFiNE/DiaRen or urine-validated assays and in other/RUO/unclear platforms, with overlapping and imprecise intervals. In 3 biopsy cohorts, the pooled fibrosis correlation was directionally positive but imprecise after HKSJ correction (r=0.62, 95% CI -0.04 to 0.91; conventional CI 0.36-0.80; I2=86%). Pathology-discrimination studies supported a fibrosis-enriched, rather than fibrosis-specific, signal. Prediction and transplant data were promising but less mature. CONCLUSIONS:Higher uDKK3 was consistently associated with kidney-function decline and showed a fibrosis-enriched signal in biopsy cohorts, supporting its use as a complementary tubular-stress biomarker for risk enrichment alongside, not instead of, eGFR and albuminuria. Demonstrating incremental clinical value will require assay-aware interpretation, cross-platform harmonization, population-specific cut-off validation and prospective tests of utility.
Diabetic kidney disease (DKD) now has more proven kidney-protective therapies than at any previous time: renin-angiotensin system inhibitors (RASi), sodium-glucose cotransporter-2 (SGLT2) inhibitors, glucagon-like peptide-1 receptor agonists (GLP-1 RAs), and the nonsteroidal mineralocorticoid receptor antagonist (nsMRA) finerenone. However, no head-to-head randomized controlled trial (RCT) has compared these classes, no Phase 3 trial has confirmed that specific multi-class combinations improve hard outcomes beyond well-selected monotherapy; and long-term safety of sustained combination therapy has not been fully characterized. This review synthesizes contemporary evidence for kidney-protective therapy in adults with DKD, emphasizing that non-pharmacologic measures-blood pressure control, individualized glycemic targets, sodium and protein moderation, structured exercise, weight management, and smoking cessation-should be intensified concurrently with drug therapy. We propose an individualization framework that selects agents whose mechanisms address more than one of the patient's clinical problems simultaneously and avoids those whose adverse effects conflict with active comorbidities. Combination therapy is biologically rational and supported by additive albuminuria reduction (CONFIDENCE) and lifetime modeling, but hard-outcome confirmation is absent. Until such trials are available, the most defensible framework is an individualized, monitoring-based strategy that adapts through addition, hold, or deprescribing based on clinical evolution.
Acute kidney injury (AKI) affects 10-15% of hospitalized patients, and nearly one-quarter progress to chronic kidney disease (CKD), reflecting a failure to recognize the temporally dynamic continuum linking these conditions. This review synthesizes emerging evidence demonstrating that AKI-to-CKD continuum unfolds through four mechanistically distinct phases: (1) hyperacute injury (0-24 h), defined by bioenergetic collapse, mitochondrial permeability transition, oxidative stress, and early inflammatory priming; (2) acute response - persistent AKI (1-7 days), dominated by coordinated pyroptotic-apoptotic-necroptotic cell death (PANoptosis) and lipid peroxidation-driven ferroptosis, impaired mitophagy, aberrant G2/M arrest, and amplified cytokine release; (3) acute kidney disease (AKD) (2-8 weeks) characterized by maladaptive repair mechanisms, encompassing persistent TGF-β/SMAD signaling, metabolic reprogramming toward glycolysis, mechanotransductive YAP/TAZ activation, endothelial rarefaction, and stabilization of pro-fibrotic non-coding RNA networks; and (4) CKD (>12 weeks), where irreversible extracellular matrix deposition, chronic hypoxia, immune dysregulation, and established myofibroblast phenotypes perpetuate fibrosis. Three universal processes integrate these stages: (1) epigenetic injury memory through chromatin remodeling at pro-fibrotic loci, (2) metabolic reprogramming and epigenetic crosstalk, involving substrates such as S-adenosylmethionine and α-ketoglutarate, reinforcing self-perpetuating renal fibrosis and (3) renal functional reserve. However, substrate availability and cellular contexts are temporally variable, rendering phase-agnostic, single-target approaches ineffective because they fail to align with the evolving molecular environments. A temporally informed, multi-phase strategy that targets these universal mechanisms at optimal time-windows is crucial for preventing or attenuating this irreversible AKI-to-CKD continuum.
