Search Results (6,572)

Hepcidin, a 25-amino-acid peptide hormone produced primarily by hepatocytes, is the master regulator of systemic iron homeostasis. By binding the cellular iron exporter ferroportin and inducing its internalization and lysosomal degradation, hepcidin restricts iron entry into plasma from enterocytes, macrophages, and hepatocytes. Its transcription is governed by an intricate molecular network that integrates iron status, erythropoietic demand, oxygen tension, and inflammation, with the BMP–HJV–ALK2/SMAD axis acting as the canonical activating pathway and erythroferrone (ERFE) and matriptase-2 (TMPRSS6) as physiological suppressors. Dysregulation of hepcidin underpins a wide spectrum of human diseases: insufficient hepcidin drives hereditary hemochromatosis and the iron overload of congenital and acquired ineffective erythropoiesis diseases and other ineffective erythropoiesis syndromes, whereas excessive or inappropriate hepcidin contributes to anemia of inflammation, anemia of chronic kidney disease, iron-restricted erythropoiesis in cancer, the iron-restrictive anemia of myelofibrosis, and pathogen-restrictive nutritional immunity. Within the myeloproliferative neoplasm spectrum, the divergent hepcidin patterns observed in polycythemia vera (suppressed) and myelofibrosis (inappropriately elevated through dual BMP/ACVR1/SMAD and IL-6/STAT3 hyperactivation) exemplify the clinical relevance of this axis and underpin two opposite pharmacologic strategies. Over the past decade, hepcidin pathway pharmacology has matured from proof-of-concept to regulatory milestones, shifting perspectives on several diseases and markedly improving clinical approaches. Full article

Background: Hyperhomocysteinemia (homocysteine [Hcy] ≥15 μmol/L) is frequently observed in patients with impaired kidney function and has been associated with vascular remodeling and increased cardiovascular risk. We aimed to evaluate the relationship between Hcy, arterial stiffness, coronary artery disease (CAD), peripheral arterial disease, and biomarkers of kidney injury in patients undergoing elective coronary angiography. Methods: In this prospective observational study, 133 patients undergoing elective coronary angiography were stratified according to serum Hcy levels (Hcy <15 vs. Hcy ≥15 μmol/L). CAD severity was assessed angiographically. Arterial stiffness was evaluated using carotid–femoral pulse wave velocity (cfPWV), while peripheral arterial disease was assessed using ankle–brachial index (ABI). Kidney function was evaluated using serum creatinine, estimated glomerular filtration rate (eGFR), cystatin C, and urinary albumin-to-creatinine ratio (UACR). Correlation, multivariable regression, logistic regression, and receiver operating characteristic (ROC) analyses were performed. Results: Patients with hyperhomocysteinemia demonstrated significantly worse kidney function, including higher serum creatinine, cystatin C, and UACR levels, and lower eGFR (all p < 0.01). Patients with elevated Hcy levels also exhibited significantly higher cfPWV values (11.4 ± 3.3 vs. 9.7 ± 2.1 m/s, p < 0.001). Hcy correlated positively with cystatin C, creatinine, UACR, and cfPWV, and inversely with eGFR. In multivariable linear regression analysis, Hcy remained independently associated with increased cfPWV after adjustment for age, sex, and eGFR (β = 0.137, 95% CI 0.047–0.226, and p = 0.003). This association remained significant in sensitivity analyses incorporating hypertension, diabetes mellitus, LDL cholesterol, and statin therapy (β = 0.124, 95% CI 0.032–0.216, and p = 0.008). No independent associations were observed between Hcy and angiographic CAD severity or ABI values. ROC analysis demonstrated modest discrimination for elevated arterial stiffness (AUC = 0.66, 95% CI 0.56–0.76) and good discrimination for impaired kidney function (AUC = 0.82, 95% CI 0.69–0.92). Conclusions: Elevated Hcy levels were independently associated with impaired kidney function and increased central arterial stiffness, but not with angiographic CAD severity or peripheral arterial disease. These findings suggest that hyperhomocysteinemia may reflect cardiorenal vascular dysfunction and diffuse vascular remodeling rather than focal obstructive atherosclerotic disease. Further studies are needed to determine its clinical utility and prognostic value. Full article

Background/Objectives: Chronic kidney disease (CKD) is associated with numerous oral manifestations that may negatively affect quality of life, nutrition, and overall health. This narrative review aimed to summarize current evidence regarding oral manifestations of CKD and kidney transplantation, examine their proposed underlying mechanisms, and discuss implications for dental management. Methods: A structured literature search of PubMed/MEDLINE was conducted for English-language publications from January 2000 to March 2026. Original studies, systematic reviews, meta-analyses, clinical guidelines, and relevant narrative reviews were included. Additional references were identified through manual screening of bibliographies. Results: Oral manifestations associated with CKD include xerostomia, periodontal disease, oral infections, anemia-related mucosal pallor, developmental enamel defects, and medication-related gingival overgrowth. Kidney transplant recipients are additionally at risk of opportunistic infections and oral malignancies related to long-term immunosuppressive therapy. While oral diseases, particularly periodontal disease and oral infections, may contribute to systemic inflammation, much of the available evidence remains observational. Similarly, many recommendations for dental management are based on expert consensus and clinical experience rather than high-quality interventional studies. Conclusions: Oral complications are common throughout the CKD continuum and warrant regular assessment and preventive care. Multidisciplinary collaboration is essential, while further prospective studies are needed to strengthen the evidence base for clinical management. Full article

Background: The 2022 Kidney Disease: Improving Global Outcomes (KDIGO) guidelines suggest the use of Renin–angiotensin–aldosterone system inhibitors (RAASIs) in chronic Kidney Disease (CKD) stages IV–V, in contrast to the 2012 KDIGO guidelines, which discouraged it. This study aims to assess the impact of RAASIs on kalemia and mortality in a large sample of dialysis patients, where longitudinal data remain scarce, comparing traditional statistical methods with machine learning (ML) algorithms. Methods: This observational longitudinal analysis included 4764 hemodialysis (HD) patients from the Sicilian Registry of Nephrology, Dialysis and Transplantation, with a total of 56,964 longitudinal measurements. We evaluated the impact of RAASIs on serum potassium levels and all-cause mortality in the dialysis setting, comparing traditional statistics and ML. Linear Mixed Models (LMM) and Cox models with mixed effects were used for longitudinal and survival analyses. These were compared with ML approaches, including Random Forest (RF) for potassium variability and Lasso-regularized models for mortality, using four-fold cross-validation. Results: The study included 4764 patients, of whom 1207 (25%) were treated with RAASis. The mean age was 66 ± 15 years, 62% were male, 33% were diabetic, and a history of arterial hypertension was reported in 74% of patients. Hyperkalaemia at baseline was present in 1848 patients. The longitudinal model showed a statistically significant increase in kalemia [adjβ = 0.10 mmol/L, 95%CI 0.05/0.15, p < 0.001], but it was clinically negligible. Indeed, RF did not detect RAASIS as a relevant variable. Association between RAASIs and mortality was not detected either with Cox or ML models. Furthermore, the RF model outperformed traditional LMMs in explaining total potassium variability (56% vs. 43%). Conclusions: RAASI therapy in HD patients is associated with a minimal, non-clinically significant increase in serum potassium and does not impact all-cause mortality. The integration of ML reinforces the robustness of these findings, supporting the safety of RAASIs in the dialysis setting. Full article

Background: The kidney is an organ rich in peroxisomes, which play a pivotal role in fatty acid oxidation and ROS decomposition. Importantly, peroxisomal dysfunction contributes to the development and progression of various renal diseases. Therefore, we aimed to elucidate whether peroxisomes affect renal damage and fibrosis over time using a unilateral ureteral obstruction (UUO) mouse model. Methods: Expression levels of peroxisome-related factors and ROS- and hypoxia-related genes in UUO mice were measured in a time-dependent manner. Results: UUO led to renal damage and fibrosis progression over time; it significantly increased the protein expression levels of ATG5 and ATG7, while it decreased PMP70 and PEX14 protein expression. In particular, UUO increased the protein expression level of pexophagy receptor NBR1. Although the number of peroxisomes decreased, the protein expression levels of peroxisomal biogenesis-related proteins such as PEX11b, PEX16, and PEX19 remained constant. Decreased lipid metabolism due to reductions in ACOX1, DBP, and catalase caused by UUO and increased ROS production through peroxisomal degradation and mitochondrial antioxidant enzyme dysfunction were observed. Additionally, HIF-1α protein levels gradually increased in the UUO mice, whereas those of HIF-2α initially increased and then decreased. Conclusions: UUO is characterized by a progressive, chronological reduction in peroxisomal markers. Our findings indicate that peroxisomal degradation and associated metabolic dysfunction are tightly correlated with the progression of kidney injury and fibrosis, suggesting a potential involvement of compromised peroxisomal homeostasis in renal pathogenesis rather than proving a direct causal mechanism. Maintaining peroxisomal quality control may nevertheless represent a potential therapeutic avenue for chronic kidney disease. Full article

Background and Objectives: Sarcopenia is highly prevalent among maintenance hemodialysis (HD) patients, particularly in the presence of diabetes mellitus (DM). Dietary glycemic and insulinemic characteristics may contribute to metabolic disturbances associated with muscle deterioration, although evidence in HD populations remains limited. This study aimed to investigate the associations between dietary indices, sarcopenia, nutritional status, and clinical outcomes in diabetic (DM+) and non-diabetic (DM−) HD patients. Materials and Methods: This cross-sectional study included 92 maintenance HD patients (43 DM+ and 49 DM−). Dietary intake was assessed using three-day food records, and dietary insulin index (DII), dietary insulin load (DIL), dietary glycemic index (DGI), and dietary glycemic load (DGL) were calculated. Sarcopenia was evaluated using handgrip strength, bioelectrical impedance analysis, gait speed, and SARC-F. Anthropometric, biochemical, nutritional, and sarcopenia-related parameters were compared across tertiles of dietary indices. Results: Sarcopenia was identified in 32.6% of patients with diabetes and 36.7% of those without diabetes. Diabetic patients exhibited significantly lower handgrip strength, slower walking speed, longer walking time, and higher SARC-F scores (p < 0.01). Across DGL tertiles in DM+ patients, significant progressive increases were observed in body weight (p < 0.05), body mass index (p < 0.05), lean mass (p < 0.05), mid-upper arm circumference (p < 0.01), and triceps skinfold thickness (p < 0.01). Higher DIL and DGL tertiles were also associated with elevated serum phosphorus, LDL cholesterol, triglycerides, and total cholesterol levels (p < 0.05). DIL and DGL showed stronger associations with overall energy and nutrient intake compared with DII and DGI. However, no significant associations were identified between dietary indices and sarcopenia diagnosis or sarcopenia-related risk indicators after adjustment for age and sex. Conclusions: Dietary indices were associated with various anthropometric, biochemical, and nutritional parameters in HD patients, with more pronounced associations observed among patients with DM, suggesting a potential role of dietary quality in the nutritional and metabolic profile of this population. Full article

Background/Objectives: Obesity-associated non-alcoholic fatty liver disease (NAFLD) drives systemic metabolic stress and accelerates chronic kidney disease, yet the mechanistic links remain unclear. Mitochondrial dysfunction has emerged as a central mediator of obesity-induced organ injury. Here, we investigated renal mitochondrial remodeling in a rat model of obesity-associated NAFLD (Ob-NAFLD) and examined the effects of metformin. Methods: Female Zucker rats (obese fa/fa and lean Fa/Fa) were fed an AIN-93G diet for eight weeks, followed by 10 weeks of metformin treatment in designated groups. Kidney tissues were analyzed using biochemical assays, immunoblotting, blue native PAGE, in-gel activity assays, and histological evaluation. Results: In Ob-NAFLD rats, renal ATP levels were elevated despite reduced electron transport chain (ETC) Complex III and increased Complex V expression, reflecting compensatory ATP synthase hyperactivity uncoupled from efficient oxidative phosphorylation. Mitochondrial dynamics were disrupted such that inhibitory phosphorylation of DRP1 was reduced, promoting fission, and total OPA1 expression was decreased with a shift in short-to-long isoform balance, indicating impaired fusion and cristae remodeling. Notably, ATPase inhibitory factor 1 (IF1), a checkpoint that limits ATP synthase overdrive, remained stably expressed, suggesting an adaptive ceiling or failed protective control under chronic metabolic stress. Metformin partially alleviated bioenergetic stress by lowering ATP and modestly restoring Complex III, yet ETC imbalance and structural remodeling persisted, revealing the limitations of metabolic modulation alone. Conclusions: These findings position entrenched mitochondrial dysregulation as a mechanistic bridge linking obesity-driven liver disease to kidney injury. Therapeutic strategies combining metabolic interventions with targeted restoration of ETC coordination, mitochondrial dynamics, and regulatory checkpoints such as IF1 may be required to fully restore renal mitochondrial health and prevent the progression of metabolic kidney disease. Full article

Background: Kidney transplantation is the preferred treatment for end-stage kidney disease (ESKD), but long-term outcomes remain limited by chronic allograft injury, infections, metabolic complications, and cardiovascular risk. Gut microbiota alterations and microbiota-derived metabolites may influence immune regulation, inflammation, drug metabolism, and graft outcomes through the gut–kidney axis. This review summarizes evidence on the gut microbiota in kidney transplantation, emphasizing immune tolerance, complications, cardiovascular risk, graft function, and perspectives. Methods: A structured search was conducted in PubMed, Scopus, and Web of Science to May 2026. Eligible publications included studies involving kidney transplant recipients (KTR), kidney disease or solid organ transplant populations, and mechanistic models. Evidence was synthesized narratively. Results: Gut microbiota alterations in KTR reflect pre-transplant dysbiosis and post-transplant exposures, including antibiotics, immunosuppression, infection, diet, hospitalization, and graft function. Dietary factors and nutrient-derived substrates may modulate microbial composition and production of relevant metabolites, including short-chain fatty acids (SCFAs), trimethylamine N-oxide (TMAO), tryptophan-derived compounds, bile acid derivatives, and uremic toxins. Microbiota-related pathways may involve barrier dysfunction, microbial translocation, innate immune activation, altered regulatory T cell/T helper 17 (Treg/Th17) balance, metabolite signaling, uremic toxin generation, and endothelial stress. Clinical studies associate dysbiosis and microbial metabolites with diarrhea, infections, delayed graft function (DGF), rejection-related shifts, tacrolimus variability, cardiovascular risk, graft dysfunction, graft failure, and mortality. Most findings need validation. Conclusions: Gut microbiota signatures and microbial metabolites are promising markers of transplant-related risk, but not established causal determinants or therapeutic targets. Clinical translation requires standardized methods, multi-omics integration, and prospective patient- and graft-centered trials. Full article

Membranous nephropathy (MN) and minimal change disease (MCD) are the most common causes of nephrotic syndrome following hematopoietic stem cell transplantation (HSCT), a complication conventionally attributed to chronic graft-versus-host disease (GVHD). Paraneoplastic MCD is well described in lymphoid malignancies but is rarely reported in myeloid neoplasms. We report two cases of biopsy-confirmed MCD presenting as the initial manifestation of acute myeloid leukemia (AML) relapse following allogeneic HSCT. Both patients were White men in their sixties with relapsed/refractory AML who developed nephrotic-range proteinuria and acute kidney injury after matched unrelated donor HSCT without histologic evidence of GVHD. Renal biopsies confirmed MCD in both cases. Corticosteroid therapy was ineffective in halting renal deterioration; renal function improved only after initiation of leukemia-directed therapy, with one patient achieving dialysis independence. These cases highlight a rare paraneoplastic presentation of AML relapse. Nephrotic syndrome due to MCD may signal post-HSCT leukemia recurrence, and evaluation for AML relapse warrants consideration in steroid-refractory cases or those without concurrent GVHD. In such cases, control of the underlying malignancy, rather than escalation of immunosuppression, may be central to renal recovery. Full article

Background/Objectives: Pediatric IgA nephropathy (IgAN) is often considered to have a favorable early course. However, its progression is variable, and the prognostic value of histopathological classifications, such as MEST-C, remains incompletely defined in children. This study aimed to characterize clinicopathological features and the early disease course in pediatric IgAN and to descriptively examine histopathological findings and clinical outcomes. Methods: This retrospective, single-center study included children with biopsy-confirmed IgAN diagnosed between 2016 and 2025. Clinical, laboratory, and histopathological data were collected, and biopsies were assessed using the Oxford MEST-C classification. Follow-up data, including estimated glomerular filtration rate (eGFR), were analyzed descriptively, with follow-up extending from diagnosis to early 2026. Results: Fourteen patients were included, showing heterogeneous clinical presentations. Mesangial hypercellularity was observed in all cases (100%), with frequent endocapillary hypercellularity (78.6%) and segmental sclerosis (57.1%), consistent with a predominance of active lesions. Over a median follow-up of approximately five years, renal function remained stable in 57.1% of patients, declined in 21.4%, and improved in 14.3%, indicating variability in renal function during follow-up and potential reversibility in a subset of patients. One patient (7.1%) developed severe acute kidney injury requiring temporary dialysis, followed by full recovery. Given the descriptive design and limited sample size, no conclusions regarding associations between histopathological findings and renal outcomes can be drawn. Conclusions: Within this small cohort, pediatric IgAN showed variable renal function courses ranging from stability to decline or partial recovery. These findings should be considered descriptive and hypothesis-generating, supporting longitudinal monitoring in larger pediatric cohorts. Full article

Diabetic kidney disease (DKD) represents the single most common etiology of chronic kidney disease and end stage kidney disease globally, a burden that continues to expand in direct proportion to the worldwide growth of the diabetes epidemic. The pathogenesis of DKD is multifactorial, involving metabolic, hemodynamic, inflammatory, and fibrotic pathways. Among these, aldosterone has emerged as a key mediator of kidney injury, extending beyond its traditional role in sodium balance and blood pressure regulation. Through activation of both MR-dependent transcriptional processes and MR-independent signaling cascades, aldosterone drives a coordinated pattern of renal injury encompassing oxidative stress generation, endothelial dysfunction, podocyte damage, inflammatory cell recruitment, and progressive interstitial fibrosis. Current therapies targeting the renin–angiotensin–aldosterone system (RAAS), including angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and mineralocorticoid receptor antagonists, have significantly improved outcomes in DKD. Despite these advances, a considerable degree of residual cardiovascular and renal risk persists, attributable in part to the incomplete attenuation of aldosterone activity and the well-characterized phenomenon of aldosterone escape under sustained RAAS blockade. Aldosterone synthase inhibitors (ASIs) represent a mechanistically distinct therapeutic approach that targets aldosterone overproduction at its enzymatic source, potentially addressing both MR-dependent and independent pathways. Early clinical trials evaluating the efficacy of ASIs have demonstrated promising effects on blood pressure and albuminuria. This review summarizes the role of aldosterone in DKD pathogenesis, evaluates current therapeutic approaches, and discusses emerging evidence supporting ASIs as a potential addition to the evolving treatment landscape. Full article

Renal cell carcinoma (RCC) is a biologically heterogeneous malignancy characterized by variable clinical behavior and diverse molecular phenotypes. Although immune checkpoint inhibitors and targeted therapies have transformed the treatment landscape of advanced RCC, clinically validated biomarkers capable of improving risk stratification, therapeutic-decision making and disease monitoring remain lacking. Kidney injury molecule-1 (KIM-1), also known as hepatitis A virus cellular receptor-1 (HAVCR1) or T-cell immunoglobulin and mucin domain-containing protein-1 (TIM-1), has emerged as a biologically compelling investigational biomarker e because of its close relationship to proximal tubular epithelial injury and renal carcinogenesis. KIM-1 is a transmembrane glycoprotein minimally expressed in normal kidney tissue but markedly upregulated in dedifferentiated proximal tubular epithelial cells following injury, and in clear cell RCC, where its extracellular domain can be shed into plasma and urine. Beyond its role as a marker of tubular injury, KIM-1 participates in immune regulation, phagocytosis, inflammatory signaling and tissue remodeling, supporting its potential relevance to tumor biology. Clinical studies have demonstrated associations between elevated circulating KIM-1 levels and RCC diagnosis, recurrence risk, and survival outcomes, particularly in localized and postoperative disease settings. KIM-1 has additionally been investigated as a therapeutic target through antibody–drug conjugate approaches. Despite promising translational data, important limitations yet remain. Current evidence is predominantly prognostic rather than predictive, and substantial analytical and biological challenges continue to limit implementation. Assay standardization, clinically meaningful cutoffs, specimen selection, timing of sampling, and confounding by chronic kidney disease or nonmalignant renal injury remain incompletely resolved. Furthermore, evidence supporting incremental value beyond established clinicopathologic models remains limited. This review critically evaluates the biological rationale, analytical considerations and clinical evidence supporting KIM-1 in RCC. Particular emphasis is placed on distinguishing prognostic, predictive, pharmacodynamic, and therapeutic applications, as well as defining the evidentiary gaps that must be addressed before clinical implementation. Current evidence is derived predominantly from retrospective and exploratory analyses, and important limitations remain regarding assay standardization, biological specificity, chronic kidney disease-related confounding, and prospective validation. The review concludes with a summary of the evolving landscape of KIM-1-directed biomarker strategies in RCC, which may ultimately contribute to improved biologic risk stratification and biomarker-driven clinical investigation in RCC. Full article

Dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 inhibitor remains the cornerstone of antithrombotic management after myocardial revascularization. However, the traditional “one-size-fits-all” approach to DAPT duration and intensity fails to account for marked interindividual variability in drug response—driven by genetic polymorphisms, notably CYP2C19 variants like CYP2C19*2, which reach a frequency of up to 75% in specific groups like the Melanesian population—comorbidities such as diabetes and chronic kidney disease, and dynamic clinical factors including age and concomitant medications. We examine the current landscape of precision medicine tools for individualizing DAPT, including platelet function testing, point-of-care genotyping, validated clinical risk scores, and emerging artificial intelligence (AI)–based predictive models. Evidence from landmark trials is synthesized to evaluate escalation, de-escalation, and duration-tailoring strategies within the ischemic–bleeding trade-off framework. Special populations requiring individualized approaches are reviewed, including patients with atrial fibrillation, the elderly, and those requiring urgent noncardiac surgery with perioperative bridging. Future directions, including multi-omics integration, novel antiplatelet agents, and AI-driven clinical decision support systems, are also explored. As a narrative review, conclusions should be interpreted as reflective of current evidence synthesis rather than systematic-review-grade evidence, given the absence of formal risk-of-bias scoring or meta-analytic pooling. Personalized DAPT guided by complementary genetic and phenotypic testing, integrated with dynamic risk stratification, offers a paradigm shift from empiric therapy toward precision-guided antithrombotic management with the potential to simultaneously reduce ischemic and bleeding complications. Full article

Posterior urethral valves (PUV) cause congenital urinary tract obstruction and often lead to chronic kidney disease (CKD) despite treatment; however, DNA methylation remains underexplored in PUV. This cross-sectional study aimed to compare peripheral-blood global DNA methylation, measured as 5-methylcytosine content (5-mC%), between boys with PUV and age-matched male controls, and to assess its association with kidney function, CKD stage, and kidney scarring. The study included 45 boys with PUV and 45 age-matched boys as controls. Peripheral-blood global 5-mC% was quantified using an ELISA-based assay. Glomerular filtration rate and kidney scarring were assessed by nuclear scintigraphy, and PUV patients were categorized according to CKD stage and scarring status. Statistical comparisons were performed using the Kruskal–Wallis test followed by Dunn’s test, with exploratory trend analysis used to evaluate the association between global 5-mC% and CKD severity. Global 5-mC content was significantly higher in PUV patients than in controls (median 5-mC%: 0.4336 vs. 0.3732, p < 0.001). Within the PUV cohort, global 5-mC% increased with CKD severity (p < 0.05) and showed a logarithmic association with CKD stage (R² = 0.8012). Patients with kidney scarring also had significantly higher global 5-mC% than controls (p < 0.001), although differences across individual CKD stages and scarring subgroups were not statistically significant. These findings suggest altered systemic global 5-mC content in boys with PUV and support larger, longitudinal studies incorporating locus-specific methylation profiling. Full article

The endothelin system is critical in chronic kidney disease (CKD) pathogenesis. However, the relative contribution of circulating endothelin-related biomarkers versus genetic variability remains unclear, particularly in diabetic nephropathy (DN) and after kidney transplantation (KTx). This study evaluated plasma concentrations of endothelin-1 (ET-1), endothelin A receptor (ETAR), and anti-ETAR antibodies (ETAR-Ab) in healthy controls, diabetic nephropathy (DN) patients, and DN patients after kidney transplantation (post-KTx). The influence of polymorphisms rs5370 (EDN1) and rs5333 (EDNRA) on endothelin-related parameters was analyzed. Polymorphisms were genotyped via PCR-RFLP, and endothelial-related parameters were determined by ELISA. Significant endothelin system activation was observed in both DN and post-KTx patients. ET-1 and ETAR concentrations were markedly elevated compared to controls, with the highest ET-1 levels detected in the post-KTx group, whereas ETAR-Ab levels were reduced. A sex-specific association for rs5370 was observed in male patients with the TG genotype (a nearly 4.5-fold higher risk of renal replacement therapy than in female patients). In proteinuric DN patients, the TC genotype (rs5333) was associated with elevated ETAR and ETAR-Ab. Endothelin system dysregulation is a prominent and persistent feature of CKD, noted after kidney transplantation. The endothelin activation, observed in transplant patients particularly, highlights the potential clinical relevance of endothelin-related biomarkers and supports the rationale for therapeutic strategies targeting the endothelin pathway, including endothelin receptor antagonists. Full article