Senescence as a pathogenic driver in chronic kidney disease: From cellular fate to clinical stratification

Abstract

Chronic kidney disease (CKD) is increasingly viewed through the lens of premature ageing.¹ Among the many cellular processes implicated in CKD progression, senescence—defined as a stable cell cycle arrest in metabolically active cells—has gained prominence in recent years.² Initially studied in the context of ageing, senescence has now been implicated in a range of chronic conditions, including cardiovascular disease, pulmonary fibrosis, and more recently, renal pathology.³

Within the kidney, senescence has been observed both in aging and in disease states across species, including human and murine models.^{4, 5} While the full spectrum of mechanisms driving lesion development remains unclear, growing evidence suggests that the senescence-associated secretory phenotype (SASP)—a complex network of pro-inflammatory cytokines, chemokines and proteases—plays a key role. The SASP may mediate its effects locally (cell-autonomous) or by influencing the surrounding microenvironment (non-autonomous), promoting inflammation, fibrosis and tubular atrophy.⁶

Experimental studies have demonstrated that SASP components can drive tissue damage in both the tubulo-interstitial compartment^{4, 7} and the glomerulus.⁵ However, SASP molecules are not exclusive to senescent cells; they can also be produced by other cell types in response to injury. As such, establishing the direct contribution of senescence to kidney damage remains a challenge.

The advent of omics technologies, coupled with the availability of large-scale public datasets, has opened new avenues to study SASP in the context of human disease. Proteomic profiling and transcriptomic analyses now enable us to identify signatures of senescence beyond histology, and potentially, without the need for invasive tissue sampling.

The recent article by McLarnon et al. represents a significant advance in this field.⁸ Leveraging multi-omic approaches, including plasma proteomics, kidney biopsy transcriptomics and injury-induced kidney organoid models, the authors propose a novel stratification method for CKD patients based on senescence profiles.

Using proximity extension assays, they identified a 16-protein panel enriched in senescence-associated markers, which could reliably cluster CKD patients into two major groups—or ‘sendotypes’—corresponding to disease severity. These sendotypes correlated with current and future measures of renal function, such as estimated Glomerular Filtration Rate (eGFR) and serum creatinine, validating their potential as prognostic indicators.

Among the most differentially expressed proteins were TNFR1, EFNA4, N2DL2 and TNFRSF14, all implicated in inflammatory signalling and previously linked to senescence. Importantly, transcriptomic analyses from human kidney biopsies and TNF-α (Tumor Necrosis Factor alpha) treated organoids confirmed enrichment of NF-κB (Nuclear Factor kappa B), TNF (Tumor Necrosis Factor), MAPK (Mitogen-activated protein kinases), and apoptosis pathways in sendotype-positive patients—pathways known to intersect both senescence and CKD progression.

The ability to detect senescence-related patterns in plasma has far-reaching implications. In clinical nephrology, renal biopsies are often avoided unless necessary for diagnosis or management. Thus, identifying SASP signatures in blood could enable non-invasive detection of senescent activity, facilitating early identification of high-risk patients.

Nevertheless, caution is warranted. SASP proteins lack cell-type specificity, and systemic inflammation or comorbidities could confound their interpretation. Rigorous validation in larger, phenotypically diverse CKD cohorts will be critical. Moreover, it remains to be clarified whether the sendotype reflects a primary pathogenic process or merely a surrogate marker of advanced disease.

Senescence profiling also opens the door to therapeutic interventions. Senolytic drugs—agents that selectively eliminate senescent cells—have shown promise in preclinical models of kidney injury and are under active investigation in human studies. Identifying patients with a dominant senescent profile could guide precision therapy, aligning with emerging frameworks in nephrology and geroscience.⁹

Another intriguing avenue lies in dissecting the functional relevance of individual SASP components. It is plausible that a limited set of molecules within the SASP network drive tissue injury, while others may play homeostatic or compensatory roles. Pinpointing these effectors could yield novel drug targets, ideally sparing beneficial aspects of the SASP.

Lastly, deeper characterisation of sendotypes across CKD aetiologies—diabetic nephropathy, immunoglobulin A nephropathy and hypertensive nephrosclerosis—may help clarify whether senescence is a common final pathway or a distinct disease modifier in select contexts.

Defining sendotypes in the context of CKD is a timely and important contribution to our understanding of CKD pathophysiology. By integrating clinical data, molecular profiling and systems biology, the authors demonstrate that senescence is not just a cellular hallmark of ageing but a potentially actionable axis in CKD progression. Their identification of ‘sendotypes’ introduces a novel framework for stratifying patients and paves the way for senescence-targeted therapies in nephrology (See Figure 1)

Ongoing efforts should focus on expanding these findings to larger cohorts, exploring the mechanistic underpinnings of SASP-related damage, and developing clinical-grade tools for senescence detection. With senolytics already entering the clinical arena, nephrology may soon join the ranks of specialties poised to benefit from senescence-directed precision medicine.

The authors declare no conflict of interest.