CVOT Summit Report 2023: new cardiovascular, kidney, and metabolic outcomes.

The 9th Cardiovascular Outcome Trial (CVOT) Summit: Congress on Cardiovascular, Kidney, and Metabolic Outcomes was held virtually on November 30-December 1, 2023. This reference congress served as a platform for in-depth discussions and exchange on recently completed outcomes trials including dapagliflozin (DAPA-MI), semaglutide (SELECT and STEP-HFpEF) and bempedoic acid (CLEAR Outcomes), and the advances they represent in reducing the risk of major adverse cardiovascular events (MACE), improving metabolic outcomes, and treating obesity-related heart failure with preserved ejection fraction (HFpEF). A broad audience of endocrinologists, diabetologists, cardiologists, nephrologists and primary care physicians participated in online discussions on guideline updates for the management of cardiovascular disease (CVD) in diabetes, heart failure (HF) and chronic kidney disease (CKD); advances in the management of type 1 diabetes (T1D) and its comorbidities; advances in the management of CKD with SGLT2 inhibitors and non-steroidal mineralocorticoid receptor antagonists (nsMRAs); and advances in the treatment of obesity with GLP-1 and dual GIP/GLP-1 receptor agonists. The association of diabetes and obesity with nonalcoholic steatohepatitis (NASH; metabolic dysfunction-associated steatohepatitis, MASH) and cancer and possible treatments for these complications were also explored. It is generally assumed that treatment of chronic diseases is equally effective for all patients. However, as discussed at the Summit, this assumption may not be true. Therefore, it is important to enroll patients from diverse racial and ethnic groups in clinical trials and to analyze patient-reported outcomes to assess treatment efficacy, and to develop innovative approaches to tailor medications to those who benefit most with minimal side effects. Other keys to a successful management of diabetes and comorbidities, including dementia, entail the use of continuous glucose monitoring (CGM) technology and the implementation of appropriate patient-physician communication strategies. The 10th Cardiovascular Outcome Trial Summit will be held virtually on December 5-6, 2024 ( http://www.cvot.org ).

Gender-specific risk factors and outcomes of hyperkalemia in CKD patients: smoking as a driver of hyperkalemia in men.

Background: Hyperkalemia is common among patients with chronic kidney disease (CKD) but there is scarce information on differential risk factors and outcomes for men and women. For instance, smoking has been suggested to be a risk factor for hyperkalemia, but specific analysis of the sex-specific impact of smoking on hyperkalemia in CKD is lacking. Methods: We studied serum potassium levels in 2891 participants from the NEFRONA cohort: 483 controls (47% women) and 2408 CKD patients (38% women) without prior cardiovascular disease (CVD), assessing whether smoking is a risk factor for hyperkalemia, and if hyperkalemia is associated with outcomes separately for men and women. Results: Median potassium levels and prevalence of hypo and hyperkalemia were higher in CKD participants than in controls. Serum potassium levels were higher and hyperkalemia and severe hyperkalemia more prevalent in men than in women with non-dialysis CKD (G3-G5). The highest prevalence of hyperkalemia for each gender was found in CKD G4-G5 and hemodialysis patients for men (46%) and in hemodialysis (54%) for women. Gender-specific etiological multivariate analysis identified current smoking as a risk factor for hyperkalemia only in men. Hyperkalemia was independently associated with stopping RAASi, an outcome which was more common in women. Hyperkalemia was also associated to higher risk of cardiovascular events within 4 years in men. In conclusion, hyperkalemia is common among men and women with CKD, but the prevalence, risk factors and outcomes may differ by gender. Specifically, current smoking is a driver of hyperkalemia in men.

The coexistence of diabetic retinopathy and diabetic nephropathy is associated with worse kidney outcomes.

Background: Up to 50-60% of patients with diabetes have non-diabetic kidney disease (NDKD) on kidney biopsy. Diabetic retinopathy (DR) is a microvascular complication of diabetes frequently associated with diabetic nephropathy (DN). The objective of the current study was to investigate the kidney outcomes and survival in patients with biopsy diagnoses of DN and NDKD according to the presence of DR. Methods: We conducted an observational, multicentre and retrospective study of the pathological findings of renal biopsies from 832 consecutive patients with diabetes from 2002 to 2014 from 18 nephrology departments. The association of DR with kidney replacement therapy (KRT) or survival was assessed by Kaplan-Meier and Cox regression analyses. Results: Of 832 patients with diabetes and renal biopsy, 768 had a retinal examination and 221/768 (22.6%) had DR. During a follow-up of 10 years, 288/760 (37.9%) patients with follow-up data needed KRT and 157/760 (20.7%) died. The incidence of KRT was higher among patients with DN (alone or with NDKD) and DR [103/175 (58.9%)] than among patients without DR [88/216 (40.7%), P < .0001]. The incidence of KRT was also higher among patients with only NDKD and DR than among those without DR [18/46 (39.1%) versus 79/331 (23.9%), P < .0001]. In multivariate analysis, DR or DN were independent risk factors for KRT {hazard ratio [HR] 2.48 [confidence interval (CI) 1.85-3.31], P < .001}. DN (with or without DR) was also identified as an independent risk factor for mortality [HR 1.81 (CI 1.26-2.62), P = .001]. Conclusions: DR is associated with a higher risk of progression to kidney failure in patients with histological DN and in patients with NDKD.

EMPA-KIDNEY: expanding the range of kidney protection by SGLT2 inhibitors.

In the EMPA-KIDNEY (The Study of Heart and Kidney Protection With Empagliflozin) trial, empagliflozin reduced cardiorenal outcomes by 28% (hazard ratio 0.72; 95% confidence interval 0.64-0.82; P < .0001) in a diverse population of over 6000 chronic kidney disease (CKD) patients, of whom >50% were not diabetic. It expanded the spectrum of CKD that may benefit from sodium-glucose cotransporter 2 (SGLT2) inhibition to participants with urinary albumin: creatinine ratio <30 mg/g and estimated glomerular filtration rate (eGFR) >20 mL/min/1.73 m2 or even lower (254 participants had an eGFR 15-20 mL/min/1.73 m2). EMPA-KIDNEY was stopped prematurely because of efficacy, thus limiting the ability to confirm benefit on the primary outcome in every pre-specified subgroup, especially in those with more slowly progressive CKD. However, data on chronic eGFR slopes were consistent with benefit at any eGFR or urinary albumin:creatinine ratio level potentially delaying kidney replacement therapy by 2-27 years, depending on baseline eGFR. The representation of diverse causes of CKD (>1600 participants with glomerular disease, >1400 with hypertensive kidney disease, >450 with tubulointerstitial disease and >600 with unknown cause) was higher than in prior SGLT2 inhibitor trials, although polycystic kidney disease was excluded. Around 15% (almost 1000) of participants were not on renin-angiotensin system blockade. The clinical characteristics of the cohort differed from DAPA-CKD (A Study to Evaluate the Effect of Dapagliflozin on Renal Outcomes and Cardiovascular Mortality in Patients With Chronic Kidney Disease), as did the frequency of individual components of the primary outcome in the placebo arm. Thus, rather than compare EMPA-KIDNEY with DAPA-CKD, the results of both trials should be seen as complementary to those of other SGLT2 inhibitor trials. Overall, EMPA-KIDNEY, a recent meta-analysis and post hoc analyses of participants with type 2 diabetes mellitus (T2DM) but no baseline CKD in other trials, indicates that SGLT2 inhibitor treatment will benefit an expanded CKD population with diverse baseline albuminuria or eGFR values, presence of T2DM or cause of CKD, as well as providing primary prevention of CKD in at least the T2DM setting.

Tirzepatide and prevention of chronic kidney disease.

Tirzepatide is a twincretin recently approved to improve glycemic control in type 2 diabetes mellitus (T2DM). More specifically, tirzepatide is an agonist of both the glucose-dependent insulinotropic polypeptide (GIP) and the glucagon-like peptide-1 (GLP1) receptors. In recent clinical trials in persons with obesity or overweight with associated conditions, tirzepatide decreased body weight and other cardiorenal risk factors (blood pressure, low-density lipoprotein cholesterol, glycated hemoglobin and albuminuria). Moreover, in a post hoc analysis of the SURPASS-4 randomized clinical trial, tirzepatide decreased albuminuria and total estimated glomerular filtration rate (eGFR) slopes and nearly halved the risk of a pre-specified composite kidney endpoint (eGFR decline ≥40%, renal death, kidney failure or new-onset macroalbuminuria) in participants with T2DM and high cardiovascular risk when compared with insulin glargine. Similar to other kidney-protective drugs, tirzepatide, alone or combined with sodium-glucose co-transporter 2 inhibitors, caused an early dip in eGFR. Moreover, tirzepatide also decreased eGFR slopes in participants with eGFR >60 mL/min/1.73 m2 or with normoalbuminuria. We now review the potential kidney health implications of tirzepatide, addressing its structure and function, relationship to current GLP1 receptor agonists, impact of recent results for the treatment and prevention of kidney disease, and expectations for the future.

Sodium-glucose co-transporter-2 inhibitors increase Klotho in patients with diabetic kidney disease: A clinical and experimental study.

Sodium-glucose co-transporter-2 inhibitors (SGLT2i) provide cardiorenal protection. However, the molecular mechanisms remain poorly understood. We explored the impact of SGLT2i on Klotho, a kidney-derived protein with antiaging, renal-protective and heart-protective properties. A real world prospective observational study addressed the impact of initiating SGLT2i (canagliflozin, dapagliflozin, empagliflozin) or dipeptidyl peptidase-4 inhibitors (DPP4i) in patients with early diabetic kidney disease (DKD). Serum and urinary soluble Klotho, albuminuria and serum and urinary tumor necrosis factor-alpha (TNFa) were measured. The effect of SGLT2i on Klotho mRNA and protein was explored in vitro in kidney proximal tubular cells stressed with high glucose concentrations to simulate the diabetic milieu, albumin to simulate albuminuria, and the inflammatory cytokine TWEAK to simulate the inflammatory environment in DKD. Baseline urinary Klotho was negatively associated with albuminuria (r - 0.45, P < 0.001) and urinary TNFa (r - 0.40, P < 0.01). Both DPP4i and SGLT2i reduced HbA1c similarly, but only SGLT2i decreased eGFR, albuminuria and urinary TNFa and increased (P < 0.001) serum (5.2 %) and urinary Klotho (38.9 %). Changes in urinary TNFa (ß - 0.53, P = 0.001) and albuminuria (ß - 0.31, P < 0.05) were independently associated with changes in urinary Klotho (adjusted R2 = 0.54, P < 0.001). Studies in renal tubular cells demonstrated that high glucose, albumin and TWEAK decreased Klotho mRNA expression and protein levels, an effect similarly prevented by SGLT2i. SGLT2i increase Klotho availability in type 2 diabetic patients with poorly controlled diabetes and early DKD, as well as in stressed tubular cells. This effect on Klotho may contribute to the kidney and heart protection afforded by SGLT2i.

Albuminuria Downregulation of the Anti-Aging Factor Klotho: The Missing Link Potentially Explaining the Association of Pathological Albuminuria with Premature Death.

Ten percent of the adult population has chronic kidney disease (CKD), which is diagnosed when the glomerular filtration rate (GFR) is below 60 mL/min per 1.73 m2 or when albuminuria is above 30 mg/day. The numerical thresholds were chosen because they are associated with an increased risk of CKD progression or premature death within a wider scenario of accelerated aging. Indeed, CKD is one of the fastest growing causes of death worldwide. A decreased GFR is associated with the accumulation of uraemic toxins that may promote tissue and organ damage. However, CKD may be diagnosed when the GFR is completely normal, as long as there is pathological albuminuria. A key unanswered question to stem the rise of CKD-associated deaths is whether the association between isolated albuminuria (when the GFR is normal) and premature death is causal. The recent demonstration that albuminuria per se directly suppresses the production of the anti-aging factor Klotho by kidney tubular cells may be one of the first steps to address the causality of the albuminuria-premature death-accelerated aging association. This hypothesis should be tested in interventional studies that should draw from translational science advances. Thus, the observation that albuminuria decreases Klotho production through epigenetic mechanisms implies that Klotho downregulation may persist after the correction of albuminuria, and innovative therapeutic approaches are needed to restore Klotho production. On the basis of recent literature, these may include manipulation of NF-kappaB regulators such as B cell lymphoma 3 protein (BCL-3), and epigenetic regulators such as histone deacetylases, or the repurposing of drugs such as pentoxifylline.

MAP3K kinases and kidney injury.

Mitogen-activated protein kinases (MAP kinases) are functionally connected kinases that regulate key cellular process involved in kidney disease such as all survival, death, differentiation and proliferation. The typical MAP kinase module is composed by a cascade of three kinases: a MAP kinase kinase kinase (MAP3K) that phosphorylates and activates a MAP kinase kinase (MAP2K) which phosphorylates a MAP kinase (MAPK). While the role of MAPKs such as ERK, p38 and JNK has been well characterized in experimental kidney injury, much less is known about the apical kinases in the cascade, the MAP3Ks. There are 24 characterized MAP3K (MAP3K1 to MAP3K21 plus RAF1, BRAF and ARAF). We now review current knowledge on the involvement of MAP3K in non-malignant kidney disease and the therapeutic tools available. There is in vivo interventional evidence clearly supporting a role for MAP3K5 (ASK1) and MAP3K14 (NIK) in the pathogenesis of experimental kidney disease. Indeed, the ASK1 inhibitor Selonsertib has undergone clinical trials for diabetic kidney disease. Additionally, although MAP3K7 (MEKK7, TAK1) is required for kidney development, acutely targeting MAP3K7 protected from acute and chronic kidney injury; and targeting MAP3K8 (TPL2/Cot) protected from acute kidney injury. By contrast MAP3K15 (ASK3) may protect from hypertension and BRAF inhibitors in clinical use may induced acute kidney injury and nephrotic syndrome. Given their role as upstream regulators of intracellular signaling, MAP3K are potential therapeutic targets in kidney injury, as demonstrated for some of them. However, the role of most MAP3K in kidney disease remains unexplored.

2017 update on the relationship between diabetes and colorectal cancer: epidemiology, potential molecular mechanisms and therapeutic implications.

Worldwide deaths from diabetes mellitus (DM) and colorectal cancer increased by 90% and 57%, respectively, over the past 20 years. The risk of colorectal cancer was estimated to be 27% higher in patients with type 2 DM than in non-diabetic controls. However, there are potential confounders, information from lower income countries is scarce, across the globe there is no correlation between DM prevalence and colorectal cancer incidence and the association has evolved over time, suggesting the impact of additional environmental factors. The clinical relevance of these associations depends on understanding the mechanism involved. Although evidence is limited, insulin use has been associated with increased and metformin with decreased incidence of colorectal cancer. In addition, colorectal cancer shares some cellular and molecular pathways with diabetes target organ damage, exemplified by diabetic kidney disease. These include epithelial cell injury, activation of inflammation and Wnt/ß-catenin pathways and iron homeostasis defects, among others. Indeed, some drugs have undergone clinical trials for both cancer and diabetic kidney disease. Genome-wide association studies have identified diabetes-associated genes (e.g. TCF7L2) that may also contribute to colorectal cancer. We review the epidemiological evidence, potential pathophysiological mechanisms and therapeutic implications of the association between DM and colorectal cancer. Further studies should clarify the worldwide association between DM and colorectal cancer, strengthen the biological plausibility of a cause-and-effect relationship through characterization of the molecular pathways involved, search for specific molecular signatures of colorectal cancer under diabetic conditions, and eventually explore DM-specific strategies to prevent or treat colorectal cancer.

MXRA5 is a TGF-ß1-regulated human protein with anti-inflammatory and anti-fibrotic properties.

Current therapy for chronic kidney disease (CKD) is unsatisfactory because of an insufficient understanding of its pathogenesis. Matrix remodelling-associated protein 5 (MXRA5, adlican) is a human protein of unknown function with high kidney tissue expression, not present in rodents. Given the increased expression of MXRA5 in injured tissues, including the kidneys, we have suggested that MXRA5 may modulate kidney injury. MXRA5 immunoreactivity was observed in tubular cells in human renal biopsies and in urine from CKD patients. We then explored factors regulating MXRA5 expression and MXRA5 function in cultured human proximal tubular epithelial cells and explored MXRA5 expression in kidney cancer cells and kidney tissue. The fibrogenic cytokine transforming growth factor-ß1 (TGFß1) up-regulated MXRA5 mRNA and protein expression. TGFß1-induced MXRA5 up-regulation was prevented by either interference with TGFß1 activation of the TGFß receptor 1 (TGFBR1, ALK5) or by the vitamin D receptor agonist paricalcitol. By contrast, the pro-inflammatory cytokine TWEAK did not modulate MXRA5 expression. MXRA5 siRNA-induced down-regulation of constitutive MXRA5 expression resulted in higher TWEAK-induced expression of chemokines. In addition, MXRA5 down-regulation resulted in a magnified expression of genes encoding extracellular matrix proteins in response to TGFß1. Furthermore, in clear cell renal cancer, von Hippel-Lindau (VHL) regulated MXRA5 expression. In conclusion, MXRA5 is a TGFß1- and VHL-regulated protein and, for the first time, we identify MXRA5 functions as an anti-inflammatory and anti-fibrotic molecule. This information may yield clues to design novel therapeutic strategies in diseases characterized by inflammation and fibrosis.

Kidney Injury Marker 1 and Neutrophil Gelatinase-Associated Lipocalin in Chronic Kidney Disease.

The current categorization of chronic kidney disease (CKD) is based on biomarkers of the glomerular function (estimated glomerular filtration rate, eGFR) and injury (urinary albumin creatinine ratio, UACR) and provides information on the risk of death and of progression of kidney disease. However, there are gaps in knowledge regarding the risk stratification of elderly patients with eGFR 45-60 ml/min/1.73 m2 and of younger patients with higher eGFR but physiological albuminuria. In this regard, most of the kidney cell mass is composed of tubules. Recent studies have explored whether biomarkers derived from the acute kidney injury literature, which are mainly tubular injury markers, may improve the information provided by eGFR and UACR. We now review the potential role of kidney injury molecule 1 (KIM-1), hepatitis A virus cellular receptor 1, T-cell immunoglobulin and mucin domain-1 and neutrophil gelatinase-associated lipocalin (NGAL)/lipocalin 2 as biomarkers for kidney or cardiovascular outcomes in CKD patients. In general, neither urinary KIM-1 nor urinary NGAL (uNGAL) outperform or add relevant information to eGFR or UACR. However, promising results were obtained for circulating KIM-1 prediction of renal outcomes in type 1 diabetes. Additionally, uNGAL may have some value in non-proteinuric patients and increased values have been observed in persons at risk for Mesoamerican nephropathy. Further studies are warranted in these niche populations.

Small vessel microembolization and acute glomerulonephritis following infection of aesthetic filler implants.

BACKGROUND: The systemic consequences of esthetic filler injections are poorly understood. CASE PRESENTATION: We report a patient with a past history of subcutaneous injection of aesthetic filler material in the lower legs, who presented with post-infectious glomerulonephritis following necrotic leg ulcers at the injection site. Kidney biopsy revealed the presence of translucent, non-birefringent microspherical bodies compatible with polymethylmetacrylate (PMMA) microspheres in some capillary lumens. This had not previously been described. PMMA is a biphasic aesthetical filler composed of polymethylmetacrylate microspheres suspended in a biodegradable bovine collagen carrier. The solid phase (PMMA microspheres) persists in tissues for years. Although PMMA was thought to not disseminate systemically, tissue necrosis may have favored systemic dissemination of the microspheres, although entry in the circulation and microembolization at the time of administration cannot be ruled out. CONCLUSIONS: In conclusion, aesthetic filler implants may cause microembolization into small vessels. Recognition of the characteristic morphology may expedite diagnosis and avoid unnecessary further testing.

Modifiable risk factors for increased arterial stiffness in outpatient nephrology.

Arterial stiffness, as measured by pulse wave velocity (PWV), is an independent predictor of cardiovascular events and mortality. Arterial stiffness increases with age. However, modifiable risk factors such as smoking, BP and salt intake also impact on PWV. The finding of modifiable risk factors may lead to the identification of treatable factors, and, thus, is of interest to practicing nephrologist. We have now studied the prevalence and correlates of arterial stiffness, assessed by PWV, in 191 patients from nephrology outpatient clinics in order to identify modifiable risk factors for arterial stiffness that may in the future guide therapeutic decision-making. PWV was above normal levels for age in 85/191 (44.5%) patients. Multivariate analysis showed that advanced age, systolic BP, diabetes mellitus, serum uric acid and calcium polystyrene sulfonate therapy or calcium-containing medication were independent predictors of PWV. A new parameter, Delta above upper limit of normal PWV (Delta PWV) was defined to decrease the weight of age on PWV values. Delta PWV was calculated as (measured PWV) - (upper limit of the age-adjusted PWV values for the general population). Mean±SD Delta PWV was 0.76±1.60 m/sec. In multivariate analysis, systolic blood pressure, active smoking and calcium polystyrene sulfonate therapy remained independent predictors of higher delta PWV, while age, urinary potassium and beta blocker therapy were independent predictors of lower delta PWV. In conclusion, arterial stiffness was frequent in nephrology outpatients. Systolic blood pressure, smoking, serum uric acid, calcium-containing medications, potassium metabolism and non-use of beta blockers are modifiable factors associated with increased arterial stiffness in Nephrology outpatients.

Next-generation phosphate binders: focus on iron-based binders.

Phosphate excess is associated with increased mortality in patients with chronic kidney disease (CKD) and has recently been linked to accelerated aging. Oral phosphate binders are prescribed to patients with CKD to prevent absorption of dietary phosphate. Currently available binders have been associated with impaired outcomes (calcium-based binders) or are expensive (non-calcium-based binders). Iron-based phosphate binders represent a new class of phosphate binders. Four iron-based phosphate binders have undergone testing in clinical trials. The development of fermagate and SBR759 is currently on hold due to suboptimal and adverse effect profiles in at least some clinical trials. Ferric citrate and sucroferric oxyhydroxide (PA21) are at different stages of application for regulatory approval after being found safe and efficacious in decreasing serum phosphate. Iron from ferric citrate is more readily absorbed than that from sucroferric oxyhydroxide. Sucroferric oxyhydroxide was launched in the USA in 2014 for the treatment of hyperphosphatemia in adult dialysis patients. Ferric citrate may be more suited for chronic treatment of hyperphosphatemia in CKD patients requiring iron supplements but its use may have to be limited in time because of potential for iron overload in patients not needing iron or not receiving erythropoiesis-stimulating agents. In contrast, sucroferric oxyhydroxide may be more suited for hyperphosphatemic CKD patients not requiring iron supplements.

Osteoprotegerin in exosome-like vesicles from human cultured tubular cells and urine.

Urinary exosomes have been proposed as potential diagnostic tools. TNF superfamily cytokines and receptors may be present in exosomes and are expressed by proximal tubular cells. We have now studied the expression of selected TNF superfamily proteins in exosome-like vesicles from cultured human proximal tubular cells and human urine and have identified additional proteins in these vesicles by LC-MS/MS proteomics. Human proximal tubular cells constitutively released exosome-like vesicles that did not contain the TNF superfamily cytokines TRAIL or TWEAK. However, exosome-like vesicles contained osteoprotegerin (OPG), a TNF receptor superfamily protein, as assessed by Western blot, ELISA or selected reaction monitoring by nLC-(QQQ)MS/MS. Twenty-one additional proteins were identified in tubular cell exosome-like vesicles, including one (vitamin D binding protein) that had not been previously reported in exosome-like vesicles. Twelve were extracellular matrix proteins, including the basement membrane proteins type IV collagen, nidogen-1, agrin and fibulin-1. Urine from chronic kidney disease patients contained a higher amount of exosomal protein and exosomal OPG than urine from healthy volunteers. Specifically OPG was increased in autosomal dominant polycystic kidney disease urinary exosome-like vesicles and expressed by cystic epithelium in vivo. In conclusion, OPG is present in exosome-like vesicles secreted by proximal tubular epithelial cells and isolated from Chronic Kidney Disease urine.

Fn14 in podocytes and proteinuric kidney disease.

Non-proliferative proteinuric diseases are the most common primary glomerular disorders causing end-stage renal disease. These disorders may associate low level glomerular inflammation and podocyte expression of inflammatory mediators. However, the factors regulating podocyte expression of inflammatory mediators in vivo in non-immune disorders are poorly understood. We have now explored the regulation and role of TWEAK receptor Fn14 in mediating glomerular inflammation in cultured podocytes and in experimental and human non-immune proteinuria. Transcriptomics disclosed Fn14 and MCP-1 mRNA upregulation in glomeruli from patients with focal segmental glomerulosclerosis, as well as a correlation between the expression of both transcripts. Increased glomerular Fn14 and MCP-1 mRNA was confirmed in a second focal segmental glomerulosclerosis cohort and was also observed in membranous nephropathy. In human non-proliferative proteinuric kidney diseases podocytes displayed Fn14 and MCP-1 expression and NFκB activation. Podocyte Fn14 was increased in murine protein overload-induced proteinuria. In Fn14 knock-out mice with protein overload-induced proteinuria, glomerular and periglomerular macrophage infiltrates were reduced, as were MCP-1 mRNA and podocyte MCP-1 staining and podocyte numbers preserved as compared to wild-type counterparts. Adenovirus-mediated overexpression of TWEAK increased periglomerular macrophage infiltration in mice without prior kidney injury. In cultured podocytes inflammatory cytokines increased Fn14 mRNA and protein levels. TWEAK activated NFκB and increased MCP-1 mRNA and protein, an effect prevented by the NFκB inhibitor parthenolide. In conclusion, Fn14 activation results in NFκB-mediated pro-inflammatory effects on podocytes that may be relevant for the pathogenesis of non-proliferative proteinuric kidney disease of non-immune origin.