Year: 2025
Type: article
Abstract: Chronic kidney disease (CKD) represents a major global health burden, characterized by high prevalence, rising mortality and disability, and substantial economic and environmental impact. New therapies to tackle this disease spectrum are therefore urgently needed. For decades, nephrology has focused on structural and hemodynamic paradigms of CKD, emphasizing albuminuria, blood pressure control and glycemic control as key treatment targets. This concept suggested that slowing CKD progression required glomerular pressure reduction through angiotensin II inhibition, with limited targeting of the underlying metabolic dysfunction. However, despite optimized renin–angiotensin–aldosterone system blockade, patients with CKD continued to face high residual risks for kidney failure and cardiovascular death. Even as sodium–glucose cotransporter 2 (SGLT2) inhibitors demonstrated clear benefits in outcome trials, their efficacy was initially attributed to glycemic control or hemodynamic effects in diabetes. Yet, these explanations proved insufficient: this drug class reduced CKD progression in patients without diabetes, improved heart failure outcomes independent of albuminuria, and were effective across a wide range of estimated glomerular filtration rate (eGFR) and proteinuria levels [1]. Moreover, no single pathway could fully account for their broad effects [2]. Despite growing evidence and the long-known role of the kidney as the main excretory metabolic organ, its complex metabolic functions as central contributors to disease progression has been overlooked. In the last decade, metabolism has emerged as an underlying principle of kidney disease. Kidneys under chronic stress exhibit metabolic changes, marking a shift in our understanding of CKD pathogenesis. While glomerular injury and hemodynamic overload have long been considered key drivers, recent genetic, translational and experimental data have repositioned the proximal tubule as the metabolic core of the diseased kidney [3]. Mechanistically, chronic insults—such as hypertension, hyperglycemia or aging—activate a hierarchy of nutrient- and injury-sensing pathways that culminate in mitochondrial dysfunction [4, 5]. The failure of the mitochondria, the powerhouses of the cell, is central to disease progression with fibrosis and nephron loss. But how do we get there? Proximal tubular cells, with their high energy demand, rely on several substrates to maintain their energy metabolism. Glucose, amino acids and fatty acids are therefore constantly transported with high fluxes into the cells. If the kidney is overloaded with metabolites in constant exposure (increased workload) [6] bioenergetic mismatch develops through the activation of various metabolite sensing mechanisms. As a result, in both diabetic and non-diabetic models, CKD progression is accompanied by suppressed mitochondrial biogenesis, excess mitochondrial fission, impaired mitophagy and increased reactive oxygen species (ROS), leading to oxidative stress and inflammation. These changes are reflected by decreased nicotinamide adenine dinucleotide (NADH)/NAD⁺ and adenosine triphosphate (ATP)/adenosine diphosphate (ADP) ratios in glomeruli and tubules [7, 8]. Disruption of lipid metabolism further compounds this energy imbalance. CKD kidneys exhibit decreased FAO and accumulation of lipid droplets containing saturated fats and ceramides, which exacerbate oxidative stress and mitochondrial dysfunction [4]. In parallel, the kidney's central role in amino acid metabolism has gained renewed attention [5]. The proximal tubule contributes to amino acid reabsorption, de novo synthesis, gluconeogenesis, ammoniagenesis and urea cycle flux [5]. On a cellular protein level, the metabolic imbalance activates various signaling and sensing pathways such as Akt, mechanistic target of rapamycin (mTOR) and AMP-activated protein kinase (AMPK) [3]. The failure of the mitochondria, the powerhouses of the kidney, has also profound implications for the human body. Receiving 20% of each heartbeat's output, the kidney actively reabsorbs approximately 180 g of glucose and 50 g of amino acids daily, while simultaneously excreting metabolic waste—all through energy-dependent processes. These processes are responsible for maintaining a physiological acid–base balance as well as excretion of toxic waste products linked to cardiovascular disease [3]. Building on these mechanistic insights, several existing therapies can be re-evaluated through the lens of kidney metabolism. SGLT2 inhibitors reduce nutrient uptake and glucotoxicity in the proximal tubule, activating energy-sensing pathways such as AMPK and mTOR, and promoting a fasting-like metabolic state [2]. Notably, SGLT2 inhibition also appears to influence amino acid handling beyond the kidney. Recent data show that these agents reduce systemic levels of gut-derived uremic toxins like p-cresol sulfate by affecting microbial amino acid fermentation, highlighting a kidney–gut–heart metabolic axis as a potential contributor to their cardiovascular and renal benefits [2]. Also other, newer therapies have effects affecting metabolism. glucagon-like peptide-1 (GLP-1) receptor agonists, beyond their glucose-lowering, weight-loss and appetite-inhibiting effects, appear to reduce albuminuria and oxidative stress independently of glycemia [9]. Finerenone, a selective nonsteroidal mineralocorticoid receptor antagonist, further contributes by suppressing pro-fibrotic and inflammatory gene programs—potentially via mitochondrial mechanisms not yet fully characterized [7]. Taken together, these data suggest that CKD should not solely be treated as a hemodynamic or glycemic disorder, but as a systemic metabolic disease affecting metabolism across organ borders. This reconceptualization encourages nephrologists to move beyond proteinuria and GFR, and to begin considering bioenergetic state, substrate overload, and metabolic signaling across organs as modifiable therapeutic targets. Now, with increasing evidence linking metabolic dysfunction to disease progression, nephrology is beginning to recognize metabolism as a key driver and, thus, a promising therapeutic target in CKD. The therapeutic landscape is evolving accordingly (Fig. 1). Several major treatment strategies are thus emerging: a first strategy is workload reduction: SGLT2 inhibitors target a broader array of proximal tubules reabsorption machinery, in conjunction with reducing the secretion load of the kidney [2]. For the future, one can envision to improve metabolic dysfunction by reducing the workload of the proximal tubule cell and the entire nephron [6]. Targeting other high-capacity metabolite transporters will be thus relevant. For instance, it is conceivable that modulating transporters involved in amino acid uptake may reduce tubular metabolic burden, as potentially seen with decreased injury and fibrosis following genetic or pharmacological inhibition of SLC6A19 [10]. A second option is to use metabolic signals to improve metabolism. Typical signals controlling metabolism are usually G-protein coupled receptors. GLP-1 receptor agonists would fit this category, although the direct role in the kidney is under investigation) [9]. Furthermore, many other metabolic signals by both hormones and metabolites per se are conveyed by G-protein coupled receptors. Third, new strategies are being investigated to support renal metabolism more directly in a metabolic fortification approach. For instance, preclinical studies have shown that acute kidney injury is associated with a decline in renal NAD⁺ levels. A recent crossover trial in patients with CKD demonstrated that 6 weeks of nicotinamide riboside, a NAD⁺ precursor that feeds the NAD+ salvage pathway led to shifts in tricarboxylic acid cycle intermediates, consistent with improved mitochondrial efficiency, even in the absence of short-term improvements in GFR or functional status [8]. Further targeted metabolite supplementations or dietary interventions based on physiological concepts could emerge. Finally, the metabolic communication involving microbiome activity remains on the horizon, potentially finding additional clues for cardiometabolic diseases—exemplified by the detrimental role of many so-called uremic toxins for cardiovascular disease, and their perturbation through SGLT2 inhibition. Examples for proximal tubular metabolism as a therapeutic target in CKD. The proximal tubule integrates signals from diet, the gut microbiome and the systemic circulation, and plays a central role in substrate reabsorption, metabolic waste secretion, energy metabolism and metabolic signaling [created in BioRender, Kleer J (2025), https://BioRender.com/aiky5gb]. This illustration highlights four interrelated domains of therapeutic intervention strategies. (1) Workload reduction via inhibition of SGLT2 and experimental blockade of amino acid transporters such as SLC6A19, aimed at decreasing apical substrate uptake and mitochondrial energy demand. (2) Metabolic fortification, including the use of NAD⁺ precursors to restore redox balance, preserve mitochondrial integrity and limit ROS-induced injury. (3) Metabolic signaling through modulation of intracellular pathways, including G-protein-coupled receptor ligands and mineralocorticoid receptor (MR) antagonists, which suppress inflammatory transcriptional responses and improve metabolic kidney function. (4) Gut–kidney–heart metabolic communication, in which dietary inputs and microbial fermentation products influence renal metabolic stress and systemic cardiometabolic risk through uremic toxins and altered tubular metabolism. As these interconnect concepts advance, clinical assessment of renal metabolic function alongside known function measures such as eGFR and albuminuria will be important and insightful. Strategies to monitor metabolism could involve detailed circulating metabolite profiles, inter-organ metabolic signaling pathways. On a kidney level, approaches are measurement of tubular secretion, renal oxygen utilization or physiological responses to metabolites, such as recruitment of the renal reserve [6]. To make sense out of molecular omics data, more basic and translational research in understanding how the kidney regulates its metabolism and its implication for the body is needed. Our understanding of these processes remains limited: many renal transporters remain uncharacterized, and the enzymatic activity of the human kidney is still poorly defined compared with the rodent kidney. This trend is the nephrologist's friend: modulating the metabolic environment of the kidney represents a strategy to alter CKD progression and its many complications. The authors apologize to all authors whose foundational work could not be cited because of space and reference limitations. J.S.K. was supported by Swiss National Science Foundation (SNSF) postdoc mobility grant. J.S.K. and M.M.R. jointly wrote the article. M.M.R. received research funding from Novo Nordisk A/S.
DOI: 10.1093/ndt/gfaf155
Authors: Jessica S Kleer, Markus M Rinschen
Language: English
Subfield: Nephrology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W4413110359