Katalin Susztak

Diabetic kidney disease is the leading cause of kidney failure worldwide, yet the molecular events underlying disease initiation and progression remain unclear. We measured 5,420 circulating proteins in 830 adults with type 1 diabetes and examined their longitudinal associations with onset and progression of kidney disease over 10 years of follow-up. We identified 130 proteins associated with at least one outcome independent of established clinical risk factors, of which 59 replicated in an independent cohort. HAVCR1/KIM-1, GFRA1, CD14 and GDF15 predicted albuminuria onset up to a decade before detectable disease. Albuminuria progression pointed to the kidney—liver axis (ASGR1, RBP4), whereas rapid kidney function decline and incident kidney failure pointed to immune and tumor necrosis factor receptor signaling. Mendelian randomization prioritized UMOD, SORT1, CLSPN, MAST4 and EGF as potential targets. These findings reveal molecular perturbations preceding clinical manifestations of diabetic kidney disease and identify distinct pathways associated with disease progression.

Estimated glomerular filtration rate (eGFR) is indispensable for detecting, staging, prognosticating, and managing chronic kidney disease (CKD), but it measures filtration rather than defining the underlying disease. A reduced eGFR can reflect many different processes, including nephron loss, altered renal hemodynamics, glomerular injury, tubulointerstitial disease, vascular damage, congenital abnormalities, obstruction, systemic inflammation, recurrent acute kidney injury, or combinations of these mechanisms. Thus, patients with the same eGFR may have different kidneys, diseases, trajectories, prognoses, and treatment opportunities. Current CKD classification already incorporates cause, GFR category, and albuminuria category, but in clinical practice and research eGFR often remains disproportionately influential in language, referral pathways, trial eligibility, and treatment decisions. This simplification can obscure active or treatable disease, encourage over‐investigation of stable vascular or age‐related impairment, and create biologically heterogeneous trial populations that dilute treatment effects. Albuminuria substantially improves risk stratification, but it does not by itself define disease phenotype or mechanism. This review argues for broader implementation of the cause–GFR–albuminuria framework and for interpreting eGFR within a broader clinical and biological phenotype. A more comprehensive assessment should integrate albuminuria or proteinuria, urine sediment, longitudinal eGFR and albuminuria trajectories, hemodynamic context, medication and nephrotoxin exposure, systemic features, family history, kidney imaging, and targeted use of cystatin C, serology, monoclonal protein testing, genetic testing, kidney biopsy, and molecular biomarkers when clinically appropriate. The aim is not to replace eGFR but to place it in context. Precision nephrology will depend on distinguishing filtration level from disease identity, activity, chronicity, reversibility, and treatment responsiveness.

Background and Aims: Vascular calcification predicts cardiovascular mortality more strongly than traditional risk factors, yet its molecular basis remains poorly understood. The burden is greatest in chronic kidney disease (CKD), where disordered mineral metabolism accelerates arterial mineral deposition. Methods: Cross-trait genome-wide and phenome-wide association analyses were combined with single-cell RNA-seq and ATAC-seq from human kidneys and coronary arteries to identify upstream regulators. Chromatin immunoprecipitation sequencing and expression profiling were used to assess direct transcriptional control. Functional relevance was evaluated in multiple gene-edited mouse lines and in primary vascular smooth muscle cells (VSMCs) targeting T-box transcription factor 2 (TBX2), Runt-related transcription factor 2 (RUNX2), NLRP3, CASP1, and GSDMD. Results: GWAS followed by expression quantitative trait loci (eQTL) and Bayesian colocalization analysis prioritized TBX2 as a shared genetic locus associated with kidney function and calcification-related cardiometabolic traits. TBX2-deficient mice exhibited increased susceptibility to vascular calcification, hypercalciuria, kidney injury, bone demineralization, and systemic phosphate dysregulation under CKD-like phosphate stress conditions. TBX2 deficiency promoted VSMC calcification and osteochondrogenic differentiation in vitro. Mechanistically, TBX2 acted as a transcriptional repressor by binding the promoter of RUNX2, a key osteogenic transcription factor, and suppressing its expression. Deletion of RUNX2 in TBX2-deficient VSMCs abolished TBX2 loss–induced calcification. TBX2-deficient VSMCs were also more sensitive to activation of the NLRP3 inflammasome by microcrystals generated from osteogenic VSMCs. Genetic deletion of NLRP3, CASP1, or GSDMD in TBX2-deficient mice attenuated vascular calcification and renal injury. In human samples, TBX2 expression inversely correlated with the severity of kidney fibrosis and was reduced in calcified vascular lesions. Conclusions: Integrative genetic, cellular, and animal studies identify TBX2 as a central transcriptional repressor linking mineral dysregulation, osteogenic signalling, and sterile inflammation in CKD-associated vascular calcification. Therapeutic strategies that restore TBX2 function or target its RUNX2–NLRP3 axis may reduce cardiovascular risk in patients with CKD.

Cardiovascular–kidney–metabolic (CKM) syndrome is a multisystem disorder in which obesity, diabetes, chronic kidney disease, and cardiovascular disease reinforce one another through shared pathobiological characteristics and bidirectional organ crosstalk. Rather than representing the mere coexistence of diseases, CKM syndrome can be understood as a mitochondrial systems disorder. In energy-intensive tissues such as the myocardium and renal tubules, chronic haemodynamic stress, substrate excess, hypoxia and neurohormonal activation converge on mitochondrial programmes governing oxidative phosphorylation, redox balance, organelle dynamics and quality control. Disruption of these programmes, including impaired fatty acid oxidation, suppressed biogenesis, defective mitophagy and mitochondrial DNA instability, reduces bioenergetic reserve and promotes reactive oxygen species generation, inflammatory signalling and progressive organ dysfunction. Mitochondrial dysfunction in other metabolic tissues further amplifies these processes. In the liver, reduced fatty acid oxidation promotes steatosis, insulin resistance and the release of lipids, whereas in skeletal muscle and adipose tissue, impaired oxidative capacity and insulin resistance increases lipid spillover and systemic inflammation. Mitochondria-derived signals — including FGF21, GDF15, succinate and circulating mitochondrial DNA — enable bidirectional communication between organs, reinforcing multi-organ decline in a positive-feedback loop. Advancing our understanding of mitochondrial dysfunction and inter-organ communication may provide new mechanistic insights into CKM syndrome progression and inform the development of mitochondria-targeted therapeutic strategies.

Hyperglycaemia is a hallmark of diabetes and a major risk factor for diabetic kidney disease (DKD). However, the molecular consequences of long-term cumulative hyperglycaemia (CH) remain unclear. As a stable epigenetic modification, DNA methylation may capture past glycaemic exposure. Here, we assessed CH-associated DNA methylation in 1,245 participants with type 1 diabetes (T1D) from Finland and the United Kingdom-Republic of Ireland cohorts. We identified 17 CH-associated CpGs, with the strongest association at cg19693031 ( TXNIP ). Longitudinal analyses demonstrate that these CH-associated DNA methylation levels remain stable despite short-term glycaemic fluctuations, suggesting lasting epigenetic imprints of earlier metabolic control. Integrative analyses combining genomic, epigenetic, and proteomic data characterized these CpGs and potential target proteins. Mendelian randomization suggested a causal association between cg20853880 ( KLF11 ) and DKD, supported by chromatin accessibility and kidney KLF11 expression. Our findings suggest that epigenetic changes contribute to metabolic memory and may mediate the effects of hyperglycaemia on DKD.