BACKGROUND:CAR T cell therapy has revolutionized the treatment of hematological malignancies by effectively eliminating tumor cells. In the field of kidney transplantation, comparable cellular therapies are being explored to facilitate transplantation and prevent graft rejection. Chimeric HLA antibody receptor (CHAR) T cells are a promising therapy for eliminating HLA-specific B cells in sensitized patients and potentially ameliorating antibody-mediated rejection. We previously demonstrated that HLA class I CHAR T cells selectively eliminated HLA class I-specific B cells with high specificity. Since HLA sensitization is most often directed against HLA-DQ of the allograft, we developed HLA-DQ2 and HLA-DQ7 CHAR T cells to target B cells with corresponding HLA specificity. METHODS:We designed viral vectors encoding HLA-DQ CHARs composed of HLA-DQA1*05:01 alpha chain with either HLA-DQB1*02:01 (HLA-DQ2) or HLA-DQB1*03:01 (HLA-DQ7) beta chains, CLIP peptide, and intracellular 4-1BB costimulatory and CD3ζ signaling domains. Upon production of HLA-DQ CHAR T cells, we evaluated CHAR expression, cytotoxic activity, production of cytokines and cytotoxic mediators, and sensitivity to immunosuppressive drugs in in vitro models. We further assessed the cytotoxic activity of HLA-DQ CHAR T cells in an immunodeficient mouse model and in primary material from sensitized individuals. RESULTS:CHAR-transduced Jurkat Triple Parameter Reporter (JurkatTPR) cells expressing reporter constructs for T cell activation markers showed robust activation upon specific stimulation. Primary CD8+ T cells expressing HLA-DQ2 and HLA-DQ7 CHAR molecules specifically eliminated HLA-DQ2- or HLA-DQ7-specific B cells, respectively, and produced interferon gamma, soluble Fas ligand, perforin, and granzyme B. Maintenance immunosuppressive drug regimens initiated at the time of co-incubation with target cells had limited effects on CHAR T-cell functionality. Finally, HLA-DQ CHAR T cells effectively eliminated HLA-DQ-specific B cells in an in vivo mouse model, as well as in primary material from sensitized individuals. CONCLUSIONS:HLA-DQ2 and HLA-DQ7 CHAR T cells, the first HLA class II CHAR T cells, selectively and effectively eliminated corresponding HLA-DQ-specific B cells in vitro, in vivo, and in primary material from sensitized individuals.
Background: Obesity-related glomerulopathy is increasingly common, yet its pathogenesis remains poorly understood. This study aimed to elucidate the mechanisms by which nonspecific glomerular IgG deposition promotes podocyte senescence in obesity-related glomerulopathy, thereby expanding potential therapeutic options. Methods: Kidney samples from patients with obesity-related glomerulopathy and diet-induced obese mice were used to compare glomerular IgG localization and abundance in obese versus control states. Causality between glomerular IgG accumulation and podocyte senescence was assessed by exogenous IgG supplementation and B cell deficiency mice. Primary podocytes were IgG-stimulated for transcriptomic and lipidomic profiling, and sphingomyelin phosphodiesterase 3 (Smpd3) was validated by in vitro and in vivo loss-of-function studies. Macrophage-specific FcRn deletion and anti-CD20 therapy were further used to evaluate IgG-targeted strategies for mitigating podocyte senescence and injury in ORG. Results: Glomerular IgG deposition was markedly increased in both patients with obesity-related glomerulopathy and mice with diet-induced obesity. Exogenous IgG supplementation in non-obese mice reproduced the glomerular IgG accumulation and podocyte senescence observed in HFD fed mice. Conversely, B-cell null diet-induced obese mice and anti-CD20 treated diet-induced obese mice showed greatly reduced glomerular IgG levels and attenuated podocyte injury. Mechanistically, IgG exposure activated podocyte sphingolipid metabolism, notably upregulating Smpd3 and increasing intra-podocyte ceramide. In vitro and in vivo Smpd3 knockdown prevented IgG induced ceramide accumulation and podocyte senescence. Obesity also heightened glomerular macrophage infiltration, and macrophage depletion or macrophage-specific FcRn knockout significantly reduced glomerular IgG deposition and protected against podocyte injury and senescence. Conclusions: FcRn-expressing macrophages increased obesity-induced IgG retention in glomeruli, which led to podocyte ceramide overload and senescence.
KEY POINTS:The cardiovascular-kidney-metabolic (CKM) syndrome framework has important implications in the care of people with kidney diseases. Cardiovascular screening is important in people with kidney diseases, but the approach may differ in this high-risk population. Multiple pharmacotherapies for CKM syndrome offer significant cardiovascular and kidney benefits. Cardiovascular-kidney-metabolic (CKM) syndrome highlights the interconnected nature of cardiovascular disease, CKD, and metabolic dysfunction and underscores the need for integrated approaches to prevention and treatment. Patients with kidney diseases are at markedly elevated risk for atherosclerotic cardiovascular events, heart failure, kidney failure, and premature mortality across the spectrum of kidney disease severity. Recent advances in therapeutics, including sodium-glucose cotransporter 2 (SGLT2) inhibitors, glucagon-like peptide-1 (GLP-1)-based therapies, and nonsteroidal mineralocorticoid receptor antagonists, alongside established renin-angiotensin system inhibitors and lipid-lowering therapies, have transformed the management of CKM by demonstrating both cardiovascular and kidney benefits. However, important gaps remain in applying the CKM framework to patients with kidney diseases, particularly among individuals with advanced CKD, kidney failure treated with dialysis, kidney transplant recipients, younger and older individuals, and those with nonmetabolic kidney diseases including glomerular disorders. This American Society of Nephrology Kidney Health Guidance provides practical guidance for nephrology clinicians on screening, risk stratification, and pharmacologic management across the CKM spectrum. The guidance emphasizes the importance of longitudinal assessment of estimated glomerular filtration rate and albuminuria as foundational markers of cardiovascular and kidney risk, including the role of cardiac biomarkers and imaging. Integration of cardiovascular and kidney risk prediction models, including the American Heart Association Predicting Risk of Cardiovascular Disease EVENTs (PREVENT) equations and the Kidney Failure Risk Equation (KFRE), may support early identification of high-risk patients and guide treatment intensification. The guidance also reviews evidence supporting sequential and combination approaches to CKM therapies, strategies for managing adverse effects, and special considerations for CKD subpopulations where data are more limited. Adoption of a CKM framework in nephrology practice promotes coordinated, multidisciplinary care and provides an opportunity to shift from organ-specific management toward a more holistic approach aimed at reducing cardiovascular events, slowing kidney disease progression, and improving patient-centered outcomes across the continuum of kidney disease.
KEY POINTS:The cardiovascular‑kidney‑metabolic framework encourages routine assessment of cardiovascular risk, metabolic health, and kidney function. Cardiovascular risk equations should be used in patients with CKD to direct preventive therapies and promote coordination of care to optimize outcomes. Comprehensive therapy building upon foundational CKD management is essential to minimize treatment gaps and improve cardiovascular‑kidney‑metabolic outcomes. The recent release of the inaugural AHA/ACC/ADA/ASN Guideline for the Prevention, Detection, Evaluation, and Management of Cardiovascular-Kidney-Metabolic (CKM) Syndrome calls for health care professionals across disciplines to broaden their practice to include the full spectrum of these interconnected disease states. This ASN Kidney Health Guidance aims to unite the nephrology community in this effort, highlighting the central role kidney disease plays in CKM syndrome and providing CKD-specific considerations. CKD is often complicated by comorbid cardiovascular and metabolic diseases, and regular evaluation of patients should include screening and management across disease states. The Predicting Risk of Cardiovascular Disease EVENTs (PREVENT) equation should be integrated along with kidney outcome predictors for routine patient counseling and risk assessment. Lifestyle modifications, including regular physical activity, avoidance of tobacco products, and adoption of a healthy diet and sleep patterns, underpin CKM management. Both renin-angiotensin system inhibitors and sodium-glucose cotransporter 2 inhibitors are foundational therapies in CKD for the prevention of cardiovascular and kidney end points, and glucagon-like peptide-1-based therapies and nonsteroidal mineralocorticoid receptor antagonists may be added according to an individual patient's cardiovascular and metabolic risk profile. CKM therapies may be initiated simultaneously or in rapid sequence according to shared decision making, but therapeutic inertia must be avoided. Cardiovascular disease mitigation should also include lipid management for primary and secondary prevention. Evidence supporting the benefits of CKM treatments in people with glomerulonephritis, those with kidney transplant, those on dialysis with kidney failure treated with maintenance dialysis, pediatric populations, older adults, and those with frailty is limited. However, screening and diagnosis of CKM syndrome are critical, and these cardiokidney protective therapies may be used with shared decision making. Diabetes and obesity are extremely common in people living with kidney disease; both are major contributors to CKD progression. CKD poses a major risk of cardiovascular morbidity and mortality. Hence, nephrology team members should play a vital role in the diagnosis, treatment, and implementation of a holistic and multidisciplinary approach for the well-being of patients with kidney diseases.
BACKGROUND:Peritoneal dialysis (PD) is a life-sustaining therapy for kidney failure, yet its long-term viability is compromised by progressive peritoneal fibrosis in some patients. Currently, reliable treatment options are lacking as the pathogenesis remains poorly understood, with the metabolic underpinnings of fibrotic progression remaining particularly elusive. METHODS:Using a physiologically relevant framework comprising human primary mesothelial cells and a PD fluid-exposed mouse model, we performed bidirectional genetic and pharmacological modulation of branched-chain amino acid catabolism. Integrated proteomic and metabolomic analyses were conducted to investigate downstream metabolic consequences. RESULTS:We identified profound impairment in branched-chain amino acid (BCAA) catabolism, centered on a functional bottleneck at the rate-limiting branched-chain α-ketoacid dehydrogenase complex, as a metabolic hallmark of peritoneal fibrosis. Functional uncoupling of the amino acids from their ketoacid derivatives indicated that branched-chain α-ketoacid (BCKA) burden was more closely linked to the fibrotic phenotype than BCAA abundance alone. Mechanistically, BCKA burden was associated with reduced glucose-6-phosphate dehydrogenase expression and activity, lower NADPH-generating capacity, and increased intracellular oxidant burden. CONCLUSIONS:Together, these findings showed that BCKA burden, rather than BCAA abundance alone, more closely tracked fibrotic responses and was linked to reduced pentose phosphate pathway-associated redox capacity in peritoneal fibrosis.
Large, pragmatic, randomized trials are needed to identify which components of routine hemodialysis care improve outcomes, but conventional processes, including individual written consent for every eligible patient, can make some trials infeasible. Alterations to the consent process refer to departures from the usual written informed consent requirements: consent may be waived for a specific trial element; the process may be modified through notification with an opt-out; preferences may be documented in usual clinical records; or separate consent may be used for selected data collection. These alterations may be ethically acceptable when the research poses no more than minimal incremental risk beyond usual care, usual written consent is impracticable or would compromise the validity of the trial, participant welfare is maintained, and communication with participants remains appropriate. We describe our experience with five pragmatic randomized trials of hemodialysis care interventions, including trials of dialysate temperature, magnesium, bicarbonate, expanded solute removal, and transplant access. These trials used different approaches to consent for trial participation, receipt of the allocated intervention, and use of routinely collected data. When designed with patient notification, opt-out opportunities, independent oversight, attention to vulnerability and inclusivity, and acceptable intervention delivery, alterations to the consent process can remain respectful, transparent, and attentive to patients’ interests, while enabling rigorous trials that might otherwise not be done.
Kidney injury associated with the tubulointerstitial disease that occurs in multiple myeloma is a multi-factorial and potentially reversible process that centers on the monoclonal free light chain (FLC). FLCs promote kidney damage through mechanisms that include precipitation with uromodulin to initiate the formation of obstructing casts in the distal nephron and activation and injury to proximal tubule epithelium. These processes generate tubulointerstitial inflammatory and fibrotic pathways that lead to progressive kidney failure if not interrupted. Important predisposing factors include the physicochemical characteristics and the amount of the FLC present in the tubular nephron. Precipitating factors for the two lesions - cast formation and proximal tubulopathy - are also discussed. Current evidence shows both pathomechanisms can occur independently or synergize to promote kidney failure. This narrative review integrates obstructive cast formation and proximal tubulopathy to consider a unified translational therapeutic approach for myeloma kidney to improve outcomes in this devastating complication of multiple myeloma.
BACKGROUND:Randomized trials suggest that high-volume post-dilution hemodiafiltration (HDF) may improve survival compared with high-flux hemodialysis (HD), but evidence from routine clinical practice and from regions underrepresented in trials remains limited. METHODS:We emulated a target trial comparing HDF with high-flux HD using data from EuCliD®, a multinational registry of dialysis patients treated in eight European countries. Adults receiving thrice-weekly in-center dialysis between 2014 and 2019 were eligible. Follow-up began 91 days after dialysis initiation. Sustained treatment strategies were defined as receipt of the assigned modality for at least 90% of sessions. Inverse probability weighting was used to emulate randomized treatment assignment. The primary outcome was all-cause mortality, with kidney transplantation treated as a competing event. RESULTS:Among 19,539 eligible patients at day 91, inverse probability weighting created a weighted pseudo-population of 19,758 patients (8,641 HDF; 11,117 HD). During a median follow-up of 16 months (interquartile range 6-32), 4,282 deaths occurred. Hemodiafiltration was associated with a lower risk of all-cause mortality compared with high-flux HD (hazard ratio 0.72; 95% confidence interval 0.67-0.77). At 2 years, the weighted cumulative incidence of death was 20.6% in the HDF group and 22.3% in the HD group, corresponding to an absolute risk reduction of 1.7 percentage points. Results were consistent across sensitivity analyses, including analyses accounting for country, competing risks, informative censoring, protocol adherence, and an ITT-like exposure definition. The association was broadly similar across prespecified subgroups, with only a stronger relative benefit observed among patients with pre-existing cardiovascular disease (interaction p<0.001). Higher delivered convective volumes were associated with greater survival benefit; however, these findings should be interpreted cautiously, as higher convective volumes may reflect patient stability and center expertise rather than a causal dose-response relationship. CONCLUSIONS:In this large multinational target trial emulation, sustained high-volume post-dilution hemodiafiltration was associated with lower mortality than high-flux hemodialysis.
BACKGROUND:Antibody-mediated rejection (AMR) is the main driver of late kidney allograft loss. Anti-HLA donor-specific antibodies (DSA) are strongly associated with AMR. However, 30-60% of DSA+ patients do not develop AMR, raising the possibility of local tissue adaptations to DSA. METHODS:We performed unbiased proteomic analysis on glomeruli and tubulointerstitium isolated using laser-capture microdissection from the kidney biopsies of 116 DSA+ kidney transplant recipients with Banff-classified active AMR, chronic active AMR, mixed AMR or no rejection. The 'Significant Latent factor Interaction Discovery and Exploration' (SLIDE) machine-learning algorithm was used to identify latent factors linked to graft loss amongst individuals with AMR. RESULTS:We quantified 1917 glomerular and 2758 tubulointerstitial proteins by mass spectrometry, with 127 glomerular and 389 tubulointerstitial proteins significantly differentially expressed between all 4 patient groups (one-way ANOVA p<0.05, Tukey FDR<0.05). In glomeruli, chronic active AMR had the most differentially expressed proteins, consisting primarily of complement and basement membrane components. Tubulointerstitial terminal complement proteins were also significantly increased in chronic active AMR but did not correlate with C4d deposition. Mixed AMR contained the most differentially expressed proteins in the tubulointerstitium, which were linked to IFNγ-associated immune activation, stress responses and mitochondrial metabolism. DSA+ biopsies without rejection were characterized by preservation of podocyte and tubular proteins in glomeruli and tubulointerstitium, respectively, but did not show conventional markers of accommodation. SLIDE identified 3 latent factors from the glomerular proteome and 4 from the tubulointerstitial proteome that significantly distinguished AMR patients with and without graft loss, correlated significantly with allograft injury, and improved prediction of graft loss beyond standard clinical variables in a multivariable risk model. Top proteins within the glomerular SLIDE model included complement components while top proteins for the tubulointerstitial SLIDE model included tubular and mitochondrial proteins. CONCLUSIONS:AMR and graft loss following kidney transplantation were defined by compartment-specific disruptions in complement and mitochondrial proteins.
Podocytes are key structural components of the glomerular filtration barrier and are essential for maintaining selective protein filtration. Podocyte dysfunction is closely associated with proteinuria and the progression of glomerulosclerosis, constituting the common pathological basis of various chronic kidney diseases such as diabetic nephropathy and focal segmental glomerulosclerosis. While histone post-translational modifications have been extensively studied in podocyte biology, recent attention has shifted toward the regulatory roles of nonhistone post-translational modifications. By modulating protein stability, activity, localization, and interactions, these modifications participate in core biological processes such as apoptosis, cytoskeletal remodeling, inflammatory signaling, and metabolic reprogramming. Nevertheless, the strength of evidence is not uniform across post-translational modification categories. While some mechanisms have been directly demonstrated in podocytes, others are inferred mainly from broader kidney injury models or from studies in non-podocyte cell types. Accordingly, not all reported post-translational modification changes should be interpreted as equally well-established causal drivers of podocyte injury. This review focuses on the molecular regulatory networks and pathophysiological significance of major nonhistone post-translational modifications, including acetylation, phosphorylation, methylation, lactylation, ubiquitination, and SUMOylation. We further propose a hypothesis-generating and integrative conceptual model of podocyte deterioration, linking initiating pathological stimuli to stress transduction and downstream effector decompensation that may culminate in structural collapse. Importantly, this proposed cascade is not intended to represent a universally validated linear sequence or a definitive disease mechanism. Rather, it provides an organizing framework to generate testable hypotheses. We further highlight the therapeutic promise of targeting nonhistone post-translational modification pathways while acknowledging the considerable translational challenges that remain. By synthesizing the mechanistic landscape of nonhistone post-translational modifications, this review provides an integrated framework for advancing our understanding of podocytopathy pathogenesis and fostering the development of precision-targeted therapies.
