Search Results (169)

The progression of chronic kidney disease (CKD) entails the development of complications, such as anemia and disturbances in mineral homeostasis, among others, and both of them have been shown to be closely related. In fact, high phosphorus (P) and excessive production of fibroblast growth factor 23 (FGF23) are hallmarks of the mineral alterations found in CKD, both of which have been associated with the development of anemia. The objective of this study was to evaluate whether the modulation of P load may impact the severity of CKD-related anemia as well as to separate the effects of FGF23 from those of P by the administration of an AntiFGF23 antibody while also investigating the involvement of hypoxia-inducible factor (HIF) signaling in these actions. To address this objective, we used a CKD model based on 5/6 nephrectomy (Nx). In a first experiment, CKD rats received diets with 0.2, 0.6, or 1.2% of P for 4 weeks. In a second study, Nx rats fed a 1.2% P diet were treated with an AntiFGF23 antibody for the same period. In an additional experiment, the effect of the exogenous administration of FGF23 and AntiFGF23 was evaluated. In all the experiments, we analyzed the hematological status, parameters of renal function and mineral metabolism, and HIF signaling. In CKD, the increase in P load was associated with an expected progressive elevation in FGF23 and an aggravation of anemia. In a situation of uremia with high P load, the neutralization of FGF23 restored hematological alterations while producing a significant inhibition in renal HIF1Alpha. In the absence of renal damage, the administration of recombinant FGF23 produced a decrease in serum iron and reticulocytes without changes in HIF signaling. In conclusion, progressive and concomitant increases in P and FGF23 produce an aggravation of anemia of renal origin. In this setting, the normalization of hematological parameters induced by FGF23 blockade is associated with the inhibition of renal HIF signaling. Thus, the implementation of FGF23-targeting therapies might constitute an additional strategy for the clinical management of CKD-related anemia. Full article

Uremia is the most common pathophysiological symptom in chronic kidney disease (CKD) patients, particularly in end-stage kidney disease (ESKD) patients. Uremia can lead to several vein-specific vascular diseases, such as renal vein thrombosis (RVT), deep vein thrombosis (DVT) and dialysis access-induced venous stenosis. One of our previous studies demonstrated that uremic serum exposure induced different cellular responses in pig venous smooth muscle cells (vSMCs) compared with arterial smooth muscle cells (aSMCs). To explore the underlying mechanisms responsible for vein-specific cellular responses, bulk RNA sequencing was utilized to examine differential gene expression in porcine vSMCs after uremic serum exposure. Differentially expressed genes (DEG) analysis revealed that 408 genes were upregulated, and 387 genes were downregulated after uremic serum treatment. Gene Ontology Biological Process analysis demonstrated that uremic serum exposure led to transcriptomic downregulation of cellular energy expenditure activities, such as the Cell Cycle, and positive transcriptomic enrichment of Cellular Response to Endoplasmic Reticulum (ER) stress, unfolded protein response and hypoxia. Both Gene Set Enrichment Analysis (GSEA) and Overrepresentation Analysis (ORA) obtained similar results. ORA revealed additional signaling pathways predicted to be transcriptomically downregulated, such as the Hippo signaling pathway and Focal Adhesion and Cytoskeletal Structure Regulating pathways. ORA also predicted several positively enriched signaling pathways related to cellular stress responses and waste disposal. To precisely identify vSMCs-specific alterations, an interaction-based KEGG GSEA was performed. The analysis revealed several significantly different responses between vSMCs and aSMCs, such as Protein Processing in the Endoplasmic Reticulum, Integrated Stress Response signaling pathway and Mitophagy, which showed more positive responses in vSMCs, while Oxidative Phosphorylation showed a more positive response in aSMCs. These altered signaling pathways may be responsible for vein-specific clinical symptoms, such as venous segment stenosis in arteriovenous fistula, observed in CKD/ESKD patients. Full article

Uremic conditions are common in end-stage kidney disease (ESKD) patients. Accelerated vascular diseases in uremic patients lead to heart failure, stroke, and hypertension. To investigate the effects of uremia on porcine arterial smooth muscle cells (aSMCs), bulk RNA sequencing was used to identify uremia-induced alterations in signaling pathways of aSMCs that might explain the aggressive cardiovascular diseases seen in patients with chronic kidney disease (CKD) and ESKD. Bulk RNA sequencing was performed on porcine aSMCs cultured with serum from normal or uremic pigs. Differentially expressed gene (DEG) analysis revealed that 295 genes were upregulated and 138 genes were downregulated after uremic serum exposure. Gene Ontology molecular function analysis demonstrated that ATP-dependent activity, translation factor activity, and ATP-dependent protein folding chaperones were predicted to be negatively enriched after uremic serum exposure, while proton transmembrane transporter activity, antioxidant activity, and glutathione peroxidase activity were predicted to be positively enriched. Gene set enrichment analysis indicated that the cell cycle was predicted to be negatively enriched after uremic serum exposure in aSMCs. Overrepresentation analysis found that focal adhesion, protein processing in the endoplasmic reticulum (ER) and cell senescence were predicted to be negatively enriched, while lysosome, phagosome, apoptosis, and autophagy were predicted to be positively enriched after uremic serum exposure. This study suggests that the signaling pathways that regulate cellular redox homeostasis, the cellular waste disposal system, ER stress and autophagy are major signaling pathways involved in aSMCs’ responses to uremic serum exposure. These pathways may contribute to the severe arterial-specific clinical symptoms observed in CKD/ESKD patients, such as arterial stiffness, vascular calcification and cardiovascular disease. Full article

Objective: To investigate the effects of parathyroidectomy (PTX) on muscle mass, muscle strength, and motor function at different postoperative stages in uremic patients with secondary hyperparathyroidism (SHPT). Methods: A total of 47 uremic patients with SHPT who underwent PTX were enrolled in this study. General clinical data, including age and blood biochemical parameters, were collected. Pre- and postoperative measurements of lean body mass, the appendicular skeletal muscle index (ASMI), skinfold thickness, grip strength, and 6-m walk time were recorded. Patients were divided into three groups—short-term, mid-term, and long-term—based on the timing of postoperative follow-up, and the patterns of change in muscle mass, strength, and function at different time points following PTX were analyzed. Results: In the short-term postoperative period, patients’ grip strength increased significantly, and their 6-m walk time decreased significantly (p < 0.05), whilst lean body mass, the ASMI and skinfold thickness showed no significant changes compared with preoperative levels (p > 0.05). In the mid-term postoperative period, lean body mass, the ASMI and grip strength all increased significantly, whilst the 6-m walk time decreased significantly (p < 0.05); there was no significant change in skinfold thickness (p > 0.05). In the long-term postoperative period, skinfold thickness and grip strength increased significantly, and the 6-m walk time was significantly reduced (p < 0.05), whilst lean body mass and the ASMI showed no statistically significant difference compared to preoperative levels (p > 0.05). Conclusions: PTX can effectively improve muscle strength and lower limb motor function in uremic patients with SHPT, and these improvements persist during long-term postoperative follow-up; improvements in muscle mass-related indicators exhibit a phased pattern, with significant increases observed in the mid-postoperative period, suggesting that the improvement in muscle mass following PTX is subject to a certain time-dependent effect. Full article

The present study was designed to evaluate the structural and biochemical efficacy of Omega-3 fatty acids in preventing renal injury in streptozotocin (STZ)-induced diabetic kidney injury and to correlate systemic oxidative stress parameters with histological and ultrastructural parameters. Twenty-eight male Wistar Albino rats were randomly divided into four groups (n = 7) as follows: Control, Omega-3 (500 mg/kg, orally), Diabetes Mellitus (DM; 50 mg/kg STZ, i.p.), and DM+Omega-3 (STZ, followed by 500 mg/kg Omega-3 for 42 days). Biochemical analysis of renal function (blood urea nitrogen (BUN) and creatinine) and oxidative status (malondialdehyde (MDA), glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), total antioxidant status (TAS), total oxidant status (TOS) and oxidative stress index (OSI)) was measured by ELISA. Histopathological scoring and Caspase-3 staining were performed by Hematoxylin and Eosin (H&E) and immunohistochemically, respectively. Transmission Electron Microscopy (TEM) was used to examine the renal tissues. Our results showed that the DM group presented with severe hyperglycemia, uremia, and a significant oxidative shift, as evidenced by increased MDA/TOS levels and depleted antioxidant defenses. Light microscopy showed extensive glomerular damage, tubular degeneration and inflammatory infiltration in the kidneys of diabetic rats. Immunohistochemical analysis revealed strong Caspase-3 expression in the tubular and glomerular compartments. TEM showed severe podocyte effacement and damage to the glomerular basement membrane (GBM). Notably, Omega-3 supplementation significantly reversed renal dysfunction, restored the pro-oxidant/antioxidant balance and reduced histopathological injury scores. Moreover, Omega-3 treatment efficiently blocked Caspase-3-mediated apoptotic signaling and preserved the ultrastructural integrity of the glomerular filtration barrier (GFB) and tubular mitochondria. Our results demonstrate the potent nephroprotective effects of Omega-3 fatty acids in reducing oxidative stress, preventing programmed cell death and maintaining the stability of the renal parenchyma’s microarchitecture. These findings suggest that Omega-3 fatty acids could be an effective adjuvant therapeutic agent for the management of diabetic nephropathy. Full article

Short-chain fatty acids (SCFAs) and medium-chain fatty acids (MCFAs) include small organic anions derived from the gut microbiome that interact with organic anion transporters of the SLC22 family, many of which are expressed in the kidney proximal tubule. According to the Remote Sensing and Signaling Theory (RSST), crosstalk between organs (e.g., gut–liver–kidney axis, gut–brain axis) and the gut microbiome is mediated by metabolites and signaling molecules transported by multi-specific “drug” transporters. The renal drug transporter OAT1 (SLC22A6) is also a major transporter of gut-microbiome products and uremic toxins (e.g., indoxyl sulfate); it has been shown to act as part of a regulatory feedback loop involving the gut microbiome. SCFAs, especially propionate and butyrate, have been shown to play a central role in the transcriptional regulation of OAT1 through HDAC inhibition. By fecal metagenomics analyses of Oat1 knockout mice, we now find that propionate synthesis is among the most altered pathways in the gut microbiome. In contrast, these pathways were only minimally altered in the Oat3 (Slc22a8) knockout. Metabolomics analyses indicate that serum propionate derivatives (e.g., propionyl glycine) and 3-hydroxybutyrate are dependent on OAT1 in the knockout mice and in humans treated with probenecid, an OAT1 inhibitor. The gut microbiome of the Oat1 knockout mice also exhibited greater fatty acid synthesis, which generates odd-chain-length fatty acids (e.g. heptanoate) when propionate is available. Overall, the data, especially when considered in light of in vitro experiments of others, indicates the in vivo existence of a feedback loop connecting gut-microbiome-derived SCFAs and MCFAs to kidney proximal tubule uptake via OAT1. This bidirectional feedback loop in turn regulates OAT1 expression through HDAC inhibition. The feedback loop is clearly consistent with the Remote Sensing and Signaling Theory—in particular, the centrality of multi-specific “drug” transporters in organ crosstalk and host–microbiome interactions via small molecules with “high information content.” The key role of OAT1 function in maintaining tubular secretion in CKD supports the importance of this RSST loop in renal pathophysiology. Modulating this RSST loop could have therapeutic value in chronic kidney disease and other contexts. Full article

Background: Central nervous system (CNS) involvement in multiple myeloma (MM) represents an extramedullary manifestation of the disease, which is often really challenging for clinicians, as the neurological symptoms could easily overlap with those related to hypercalcemia, uremia, high viscosity of the blood, or treatment-related neuropathy. Objectives: this retrospective study was conducted at Fundeni Clinical Institute in Bucharest, aiming to identify and systematically analyze a series of clinical cases diagnosed with extramedullary disease. Methods: We have identified 6 out of 583 patients with CNS involvement in our centre between 2019 and 2025. The diagnosis of meningeal myelomatosis was established through cerebrospinal fluid analysis, whereas CNS plasmacytomas were confirmed by CT-guided biopsy followed by immunohistochemistry evaluation. Results: All cases of CNS involvement occurred at relapse, with intervals from initial MM diagnosis to CNS involvement ranging from 9 months to 10 years. CNS-MM was linked to particular features, such as high-risk cytogenetics (four out of six patients), elevated lactate dehydrogenase, and the presence of extramedullary disease, highlighting its association with aggressive disease behaviour. Discussions: Although CNS-MM is correlated with poor prognosis, prolonged survival in one of our patients resulted from multimodal treatment, which included craniospinal radiotherapy, DPd systemic treatment, and intrathecal therapy (over 39 months). This aggressive approach effectively controlled both systemic disease and high-risk CNS involvement. Immunoglobulin isotype switching is a rare form of clonal evolution in MM, illustrated by the same patient whose disease evolved from IgA kappa at diagnosis to IgA lambda at CNS relapse, showing clonal heterogeneity and providing clinical evidence of clonal evolution. Conclusions: CNS involvement in MM usually occurs in a relapsed/refractory setting in patients with advanced, high-risk disease, and it is usually associated with extramedullary disease. Despite using multimodal therapies, outcomes remain poor, highlighting the need for novel and tailored agents. Full article

The endothelial glycocalyx (EG) is a dynamic endothelial surface layer composed of proteoglycans, glycosaminoglycans, glycoproteins, and adsorbed plasma proteins that regulates permeability, mechanotransduction, leukocyte trafficking, coagulation, and nitric oxide signaling. In kidney transplantation (KT), the EG is exposed to cumulative injury from recipient uremia, donor instability, preservation, machine perfusion, reperfusion, rejection, and immunosuppressive toxicity. This narrative review summarizes EG biology in KT, with emphasis on biomolecular findings relevant to ischemia–reperfusion injury, delayed graft function, rejection, and chronic allograft injury. Particular attention is given to syndecan-1, heparan sulfate, heparanase, soluble thrombomodulin, matrix metalloproteinases, angiopoietin-2/Tie2 signaling, selectins, miR-126, extracellular vesicles, and urinary or perfusate-derived readouts. Current evidence is biologically coherent but uneven: human data are largely observational, whereas many therapeutic concepts remain preclinical or exploratory. Glycocalyx-centered phenotyping may eventually improve risk stratification and trial enrichment, but clinical implementation will require standardized sampling, sample-source-aware biomarker panels, prospective validation, and clear separation between mechanistic plausibility and proven clinical utility. Full article

Myostatin is associated with inflammatory processes; however, its renal expression and impact on mitochondrial homeostasis during chronic kidney disease (CKD) remain poorly defined. This study investigated whether omega-3 fatty acids (FAs) modulate renal myostatin and mitochondrial integrity under uremic conditions using both in vivo and in vitro models. In rats with adenine-induced CKD, omega-3 FA supplementation attenuated the increase in renal myostatin expression. Uremia was associated with impaired mitochondrial homeostasis, evidenced by decreased peroxisome proliferator-activated receptor gamma coactivator-1 alpha levels and increased dynamin-related protein 1 levels, alongside the upregulation of mitophagy and inflammatory markers. Furthermore, mitochondrial structural damage and reduced mitochondrial DNA (mtDNA) content were observed in uremic kidneys. Omega-3 FA treatment partially reversed these alterations, restored mtDNA levels, and preserved mitochondrial cristae integrity. In vitro, HK-2 cells treated with indoxyl sulfate exhibited increases in myostatin expression and mitochondrial impairment, which were mitigated by eicosapentaenoic acid, docosahexaenoic acid, or their combination. These findings suggest that omega-3 FAs exert protective effects against uremia-induced renal injury by suppressing myostatin and preserving mitochondrial homeostasis, specifically by modulating biogenesis, dynamics, and structural integrity. Consequently, omega-3 FAs may serve as a potential therapeutic strategy with which to preserve mitochondrial homeostasis in patients with CKD. Full article

Background: Cardiovascular risk in chronic kidney disease (CKD) remains high despite frequently normal conventional lipid parameters. The extent to which lipid patterns vary across CKD severity and metabolic complications remains incompletely characterized. Therefore, this study evaluated lipid patterns and their associations with renal function and CKD-related metabolic complications. Methods: This retrospective cross-sectional study included 229 CKD patients from the nephrology clinic at King Saud Medical City. Single-time-point laboratory data and clinical variables were extracted from medical records. Patients were stratified by KDIGO eGFR stage, uremia, and phosphate status. Lipid parameters were analyzed using nonparametric tests, multivariable regression, and ROC analysis. Results: Among 229 CKD patients, the most prevalent lipid abnormalities were low HDL-C (49.8%) and elevated remnant cholesterol (RC) (31.4%). HDL-C was reduced and RC increased with declining eGFR, while TC, LDL-C, and TG remained unchanged. In uremia, HDL-C remained reduced and RC increased, with additional reductions in TC and LDL-C, whereas TG did not differ. No significant lipid changes were observed with hyperphosphatemia. In multivariable analyses, HDL-C was positively associated with eGFR (β = 48.8, q = 0.003) and inversely associated with BUN (β = −14.3, q = 0.0014), while RC showed an inverse association with eGFR (β = −19.9, q = 0.0005) and a positive association with BUN (β = 3.37, q = 0.0315). These relationships remained independent of age, sex, BMI, smoking status, hypertension, and type 2 diabetes. ROC analysis further demonstrated the moderate discriminatory ability of HDL-C and RC for identifying CKD stages and uremia. Conclusions: Alterations in HDL-C and RC were independently associated with renal function and uremic status. These findings suggest that lipoprotein composition may reflect metabolic disturbances accompanying CKD progression. Full article

Kidney transplantation (KTx) corrects many uremia-related metabolic disturbances; however, dyslipidemia remains common in kidney transplant recipients and contributes to persistent cardiovascular risk. Lipoprotein(a) [Lp(a)] is a largely genetically determined proatherogenic lipoprotein that increases in advanced chronic kidney disease (CKD) and may decrease after restoration of renal function. Autotaxin (ATX), an enzyme involved in proinflammatory lipid signaling through the ATX–lysophosphatidic acid axis, has also been implicated in cardiovascular pathology, but its early post-transplant dynamics remain poorly characterized. In addition to quantitative lipid abnormalities, CKD is associated with high-density lipoprotein (HDL) dysfunction and reduced paraoxonase-1 (PON-1) activity; however, data on early post-transplant changes in PON-1 activity are limited. In this prospective observational study, lipid profile parameters, Lp(a) concentration, ATX activity, and PON-1 activity were assessed in 55 Caucasian patients with CKD stage 5, most of whom were dialysis-dependent, before and 2–3 weeks after KTx. All recipients received tacrolimus-based maintenance immunosuppression with corticosteroids and mycophenolate mofetil. After KTx, Lp(a) levels decreased by a median of 21% and ATX activity by 28% (both p < 0.001). Lp(a) and ATX showed no cross-sectional or longitudinal association either before or after transplantation, and their percentage changes were not correlated. In contrast, conventional lipid fractions increased significantly, including total cholesterol (+22%), LDL cholesterol (+27%), HDL cholesterol (+24%), and triglycerides (+55%) (all p < 0.001). PON-1 activity increased by approximately 13% after KTx (p < 0.001), and its percentage change correlated positively with the increase in HDL cholesterol. In exploratory analyses, the magnitude of Lp(a) reduction was associated with early graft function: patients with eGFR <45 mL/min/1.73 m² exhibited a significantly smaller decline in Lp(a) than those with better graft function (−4.8% vs. −26.7%, p = 0.009). Multivariable analysis showed that demographic characteristics, body mass index, tacrolimus exposure, and post-transplant eGFR did not independently predict the magnitude of Lp(a) reduction. Tacrolimus trough concentrations and cumulative corticosteroid exposure were not associated with lipid parameters or their changes, except for a single subgroup difference in PON-1 activity of uncertain clinical significance. In summary, in the early period after KTx under tacrolimus-based immunosuppression, Lp(a) concentration and ATX activity decrease, whereas conventional lipid fractions increase and PON-1 activity improves. These changes were not associated with tacrolimus exposure or cumulative corticosteroid dose. The reduction in Lp(a) was associated with early graft function in exploratory analyses, suggesting that recovery of renal function may contribute to early post-transplant Lp(a) dynamics; however, no independent causal relationship was established, and the findings should be interpreted cautiously given the limited sample size and exploratory design. The clinical significance of these changes for long-term cardiovascular and graft outcomes requires further investigation. Full article

Background/Objectives: Posterior reversible encephalopathy syndrome (PRES) is a neurological condition characterized by acute neurological symptoms and vasogenic edema, usually affecting the posterior circulation. It is described in end-stage renal disease (ESRD), but its presentation in peritoneal dialysis (PD) is not well defined. We aimed to describe the clinical, radiological, and dialysis-related features of PRES in PD patients and highlight factors relevant for diagnosis and management. Materials and Methods: We conducted a retrospective descriptive case series of four ESRD patients on PD or recently transitioned from PD to hemodialysis (HD) who developed PRES at a single center. Clinical data, laboratory results, dialysis characteristics, and neuroimaging findings were obtained from medical records. PRES was diagnosed based on acute neurological symptoms in the setting of severe hypertension and uremia, with CT and/or MRI findings supportive of PRES when present and exclusion of alternative diagnoses. Results: All patients presented with acute neurological manifestations, including headache, visual disturbances, seizures, and/or altered consciousness, in the context of marked hypertension and uremia. Neuroimaging findings ranged from normal CT/MRI to subtle bilateral occipital hypodensities and, in one case, extensive supra- and infratentorial vasogenic edema with internal hydrocephalus and subependymal edema. In three patients, inadequate volume or solute control on PD prompted temporary or permanent transition to HD to improve blood pressure and fluid management. With antihypertensive therapy, seizure control when required, correction of metabolic disturbances, and optimization of dialysis, all patients recovered clinically, with time to PRES resolution ranging from 7 to 43 days. Conclusions: PRES should be considered in PD patients with new-onset seizures, visual symptoms, or unexplained changes in mental status, particularly during hypertensive crises and uremia. Early CT/MRI, prompt blood pressure control, and careful adjustment of dialysis modality appear important for achieving favorable neurological outcomes. Full article

Advanced chronic kidney disease (CKD) is associated with impaired humoral immunity, contributing to increased infection-related mortality and suboptimal vaccine responses, as notably observed during the COVID-19 pandemic. CKD is also marked by the accumulation of uremic toxins, but whether they directly influence T and B cell functionality remains unclear. In this translational study, we integrated clinical and biological data from 106 CKD patients with mechanistic insights from in vitro and in vivo murine models to identify the mechanisms underlying CKD-associated defects in humoral responses against T cell-dependent antigens. Contrary to our initial hypothesis, indoxyl sulfate—despite its known ability to activate Aryl hydrocarbon Receptor signaling in monocytes—did not directly impair T–B cell cooperation in coculture assays. Similarly, plasma levels of ten major uremic toxins showed no correlations with vaccine-induced antibody titers in patients. Instead, systemic inflammation emerged as the primary driver of defective humoral immunity. Murine models further confirmed that inflammation, rather than uremia alone, induces lymphopenia, disrupts lymphoid architecture, and ultimately impairs antibody production. These findings indicate that CKD-associated inflammation, rather than a direct effect of uremic toxins on adaptive immune effectors, underlies humoral immune dysfunction in CKD. Targeting inflammation may, therefore, offer a promising strategy to improve vaccine efficacy and reduce infection-related complications in this vulnerable population. Full article

Sarcopenia, the progressive loss of muscle mass and strength, is a common complication in patients with chronic kidney disease (CKD). This condition arises from a combination of factors including reduced physical activity, insufficient protein intake, hyperphosphatemia, chronic inflammation, and uremia itself; however, the underlying molecular mechanisms remain poorly understood. Proteolysis in skeletal muscle is primarily controlled by the ubiquitin–proteasome system, autophagy–lysosome system, and calpains (CAPNs) cysteine proteases, which degrade structural proteins and mediate cell signaling. This study aims to investigate the role of CAPNs in CKD-associated muscle deterioration. CKD was induced in mice through an adenine-rich diet for 2, 4 and 6 weeks. The involvement of CAPNs in CKD-related sarcopenia was assessed using mice that overexpressed the CAPNs endogenous inhibitor, calpastatin (CAST). Gastrocnemius muscle strength, structural integrity, and function were evaluated. Mice with CKD showed elevated CAPNs, particularly CAPN2, expression and activity in the gastrocnemius, in parallel with significant muscle deterioration, including strength loss, structural damage, and impaired muscle performance. Overexpression of CAST prevented muscle strength loss, improved muscle function and structure without affecting renal function, and reversed fibrosis, inflammation and adipogenesis expression markers. Targeting CAPN2 could be a promising therapeutic strategy to mitigate muscle damage and improve physical performance in CKD patients. Full article

Background: While experimental models show that leptin and adiponectin have inverse effects on the cardiovascular system, it has been suggested that the leptin-to-adiponectin (L/A) ratio may be an important predictor of cardiovascular disease and death. Higher circulating leptin and adiponectin levels are observed in uremia due to decreased renal degradation and/or clearance and increased production. We sought to examine the association between the L/A ratio and mortality in a prospective hemodialysis cohort. Methods: Among a prospective cohort of 448 hemodialysis patients from the NIH “Malnutrition, Diet, and Racial Disparities in Chronic Kidney Disease (CKD) (MADRAD) study who underwent leptin and adiponectin measurements, we examined characteristics associated with high leptin and adiponectin (defined as the highest tertile) using logistic regression. We then examined the association of L/A ratio levels (categorized as tertiles) with all-cause mortality using Cox regression. Results: Multivariable logistic regression analyses showed female sex, diabetes, presence of an arteriovenous fistula/graft, and lower serum albumin, IL-6, and adiponectin were associated with high leptin, whereas female sex, longer vintage, Black race, higher IL-6, and lower leptin were associated with high adiponectin. When examining L/A ratios, the highest tertile was associated with lower mortality in case-mix Cox models (ref: lowest tertile): HR (95% CI) 0.14 (0.06–0.35). These associations were robust in analyses that additionally adjusted for laboratory covariates: (HR 95% CI) 0.18 (0.07–0.46). Conclusions: In a prospective cohort of hemodialysis patients, inflammation and malnutrition markers were associated with lower leptin and higher adiponectin levels. Additionally, high L/A ratio levels were associated with lower mortality. Further studies are needed to determine the mechanisms relating adipocytokines, inflammation and nutrition, and survival in this population. Full article