Role of obesity in chronic kidney disease progression

Abstract

Obesity is a global health epidemic linked to numerous chronic disease conditions and consequences, including type 2 diabetes mellitus (T2DM), cardiovascular disease, chronic kidney disease (CKD) and premature mortality. CKD, which can progress to end stage renal disease (ESRD) and/or dialysis with limited treatment options beyond slowing its advancement, is increasingly being recognized as a result or consequence of obesity. This review examines the pathophysiological mechanisms connecting obesity to the development and progression of CKD, via a condition known as obesity related kidney disease (ORKD). Importantly, ORKD has a distinct set of pathophysiological lesions from diabetic nephropathy, as free fatty acid and triglyceride deposition in ORKD dominates over hyperglycemia-induced renal injury in the context of diabetes. Since T2DM is commonly associated with obesity, it is important to recognize ORKD as a distinct entity which likely needs a distinct approach towards its management. Although CKD is the end result of many pathophysiological processes including obesity, the process by which it develops in each condition is vastly different. By synthesizing current preclinical and clinical evidence, we highlight the role of obesity as a modifiable risk factor for CKD and explore obesity-targeted interventions that reduce hyperfiltration among potential strategies to reduce CKD incidence and delay progression to ESRD.

1. Obesity

Obesity remains a growing public health concern in the United States and worldwide, approximately affecting a billion individuals and continuing to increase in prevalence annually (Ogden et al., 2006, 2014; Flegal et al., 2010; World Obesity Atlas, 2024, 2024, 2024). The widespread adoption of the Western diet—characterized by high intake of refined fat and sugars—alongside sedentary lifestyles, has contributed to a dramatic rise in obesity rates over the past four decades (Ogden et al., 2006, 2014; Flegal et al., 2010) with dramatic increases seen in poorer countries (World Obesity Atlas, 2024, 2024, 2024). Clinically, obesity is defined by a body mass index (BMI) greater than 30 kg/m² (de Boer et al., 2017). Alarmingly, this trend spans across adult and pediatric populations and is observed across diverse racial and ethnic groups (Ogden et al., 2006, 2014; Flegal et al., 2010; World Obesity Atlas, 2024, 2024, 2024). Obesity is associated with numerous comorbid conditions, including type 2 diabetes mellitus (T2DM), cardiovascular disease (CVD), chronic kidney disease (CKD) and obstructive sleep apnea, among others (World Obesity Atlas, 2024, 2024, 2024; Kambham et al., 2001; Allcock et al., 2009; Barton, 2010; Chertow et al., 2006; Hall, 2003; Safar et al., 2006). Among these conditions, obesity is a major accelerator of CKD progression to end stage renal disease (ESRD) and/or dialysis and is the topic for discussion in this review.

2. Obesity-related kidney disease

In addition to the well-known obesity association with various comorbid conditions listed above, the entity of obesity related kidney disease (ORKD) is increasingly recognized as a distinct set of pathophysiologic conditions which may independently lead to progression of CKD (Kambham et al., 2001; Hall, 2003; Kramer et al., 2006; Adelman et al., 2001; Bagby, 2004; Chang et al., 2018; Chen et al., 2004, 2006; Ejerblad et al., 2006; Eknoyan, 2011; Mathew et al., 2011; Stenvinkel et al., 2013; Tsuboi et al., 2017). A systematic meta-analysis by Garofalo et al. demonstrated a strong association between obesity and hallmark clinical features of CKD, such as albuminuria and decreased glomerular filtration rate (GFR) (Garofalo et al., 2017). Importantly, this association persisted even in the absence of metabolic syndrome, suggesting that obesity itself may be an independent risk factor for CKD development and progression. In contrast, patients within a non-obese BMI range did not exhibit the same pattern of increased albuminuria or reduced GFR (Garofalo et al., 2017).

Further support for the role of obesity in kidney disease comes from findings by Kambham et al., who identified a specific pathological entity termed obesity-related glomerulopathy (ORG) (Kambham et al., 2001). ORG is characterized histologically by glomerulomegaly, mesangial expansion and sclerosis, basement membrane thickening and foot process fusion with or without focal segmental glomerulosclerosis (FSGS) (Kambham et al., 2001). While this condition tends to be less aggressive than idiopathic FSGS—with a lower incidence of nephrotic syndrome and likelihood of progression to end-stage renal disease (ESRD)—its existence underscores the direct renal consequences of excess adiposity (Kambham et al., 2001; Chen et al., 2006; Mathew et al., 2011; Tsuboi et al., 2017; Praga and Morales, 2017). However, ORKD and co-existence of metabolic syndrome (MetS) with hypertension can easily accelerate CKD progression in the absence of T2DM and/or CVD (Chang et al., 2018; Wickman and Kramer, 2013), with the overall progression resembling that of diabetic kidney disease (DKD). This correlation was clinically established in a study by Kramer and colleagues who demonstrated that patients with obesity and hypertension-irrespective of T2DM status-were at increased risk of developing CKD over the course of the 5 year follow-up time period (Kramer et al., 2005).

3. Pathophysiology of ORKD

Several obesity-driven alterations in renal hemodynamics, sodium handling, inflammation, and neurohormonal activation interact to promote kidney injury and subsequent ORKD. The hallmark pathophysiologic alteration in ORKD is an entity called “hyperfiltration”. Hyperfiltration can be defined as an increase in whole kidney GFR above two standard deviations of normal healthy individuals (125 ml/min) or an increase in single nephron GFR or increased filtration fraction (Helal et al., 2012). Examples of hyperfiltration at the whole kidney level include pregnancy and DKD while at the snGFR level (due to reductions in nephron number) polycystic kidney disease, focal segmental glomerulosclerosis and pyelonephritis may be representative. Obesity is thought to involve hyperfiltration at the whole kidney level. Physiological studies have shown that there are increases in GFR and renal plasma flow (RPF) early on in the disease process, in obese subjects compared to non-obese subjects (Hall, 2003; Tsuboi et al., 2017; Wickman and Kramer, 2013; Wuerzner et al., 2010; Kovesdy et al., 2017; Navaneethan et al., 2009; Chagnac et al., 2000; Myers et al., 1991; Basolo et al., 2023). Similar findings were obtained in dogs and rodent models of obesity during adulthood (Hall et al., 1993; de Paula et al., 2004) (unpublished data). When the increases in GFR and RPF are corrected for increases in body size or body mass index (BMI), there is some mitigation in the difference between obese and non-obese patients (Chagnac et al., 2000), although single-nephron GFR remains very high, validating the overall paradigm of hyperfiltration (Cortinovis et al., 2022). However, there is no absolute number of GFR for it to be considered hyperfiltration as GFR may vary at various stages of disease progression and a seemingly normal GFR in an obese individual with overt proteinuria or uncontrolled/resistant hypertension or difficult to control MetS or severe AKI from seemingly normal appearing kidney function should raise suspicion for hyperfiltration. Taken together, the number of nephrons in the kidneys do not increase in response to weight gain that results in obesity; the resulting hyperfiltration likely leads to increased glomerular intracapillary pressure/intraglomerular hypertension and promotes glomerulosclerosis, which accompanied with inflammation and oxidative stress leads to eventual nephron injury and drop-off (tubular atrophy and interstitial fibrosis), causing decreased GFR (Kramer et al., 2005) (Fig. 1).

Fig. 1.

The schematic illustrates the underlying mechanisms in obesity that contribute to obesity related kidney disease (ORKD). Hyperfiltration is a prominent feature of ORKD. While the contributing proportion of each of the factors to ORKD may not be known, eventually the combination leads to proteinuria, tubular atrophy and interstitial fibrosis and decreases in GFR, which result in CKD progression.

Abbreviation

ROS = Reactive Oxygen Species, GFR = Glomerular Filtration Rate, NHE3 = Sodium Hydrogen Exchanger Isoform 3, CKD = Chronic Kidney Disease, HTN = Hypertension.

In addition to changes in renal hemodynamics other mechanisms are at play in ORKD. The progression of ORKD to more severe renal disease is facilitated by compensatory hyperproliferation of mesangial cells and hypertrophy of podocytes (Nawaz et al., 2023). ORKD is characterized by intense inflammation which starts around the arterioles and spreads to the tubules leading to glomerular sclerosis, tubular atrophy and interstitial fibrosis (Borgeson and Sharma, 2013; Ferrante, 2007; Feuerer et al., 2009; Gregor and Hotamisligil, 2011; Hall et al., 2019; Jiang et al., 2023; Wahba and Mak, 2007; Nistala et al., 2014a). Obesity increases fat deposition in (lipid vacuoles can be seen in the proximal tubules and lipid droplets in the kidney) and around the renal (peri-renal) structures (Fig. 2, Fig. 3) (Bobulescu, 2010). Increased renal sinus fat compresses renal structures resulting in local ischemia and renal hypoxia (Hall et al., 2019; Lamacchia et al., 2011). Obesity is associated with increased salt consumption and salt sensitivity to blood pressure, whereby higher blood pressures are needed to dump the same amount of salt as a result of rightward shift of the pressure-natriuresis curve (Hall, 1997; Kawarazaki and Fujita, 2016). Obesity is characterized by increased tubular reabsorption via activation of the renin-angiotensin-aldosterone system (RAAS) and the sympathetic nervous system and insulin resistance (Hall, 1997). Taken together, the result is increased sodium reabsorption via augmented Sodium-Hydrogen (Na-H) exchanger 3 (NHE3) activity, renal hypertension and development and/or progression of CKD (Hall, 2003; Hall et al., 2019; Ye et al., 2023) (Fig. 1).

Fig. 2.

Immunohistochemistry sections highlighting intra-renal fat absorption and accumulation. PAS stain (left panels, black arrows) demonstrates WD-fed mice develop vacuoles in the brush border membranes of tubules and fat droplets are visible (Right panels, black arrows) on Oil Red O stain only in the WD-fed mouse. (CD = Common Diet; WD = Western Diet).

Fig. 3.

Peri-renal fat depots in obese mouse (WD-fed) and lean mouse (CD-fed). As is evident, the obese mouse has increased amounts of peri-renal and other fat depots compared to the lean mouse. Increased peri-renal adiposity serves as a pathway to development and progression of ORCKD. Blue arrowheads = Peri-renal fat, Green arrowheads = kidneys, Red arrowheads = Epididymal fat.

4. Preclinical studies on ORKD and CKD progression

The pathophysiology of ORKD and its progression has been elucidated with several obese animal models that show renal effects (Nistala et al., 2014a, 2014b; Wicks et al., 2016; Sun et al., 2020). Nistala et al. observed many of the histopathologic features of ORKD such as glomerulomegaly, FSGS, mesangial expansion, proteinuria and inflammation/immune cell activation in their diet induced obesity model with a Western Diet (high in refined fat and sugars) (Nistala et al., 2014a, 2014b) (Fig. 2). Moreover, they observed that C57BL/6NJ mice were more susceptible to WD feeding than C57BL/6 J mice in that the kidney pathology was more accelerated as these mice tend to die earlier (unpublished observations). Similarly, the obese mice study by Wicks and colleagues shows that susceptibility to diet-induced kidney injury in mice differs by the strain used (Wicks et al., 2016). In their study, the C57BL/6 J strain was more resistant to renal injury and the DBA2/J strain was more susceptible to renal injury when compared with one another. While the C57BL/6 J strain did not show any structural renal damage, increases in glomerular reactive oxygen species (ROS) suggested that obesity contributed to renal changes that promote CKD development. Meanwhile, the DBA2/J strain showed pathological signs of ORKD: fibrosis, oxidative stress, albuminuria, and early podocyte loss. However, the C57BL/6 J mice that had restrictive diets that reduced adiposity, did have decreased levels of renal ROS suggesting that reduction in obesity may have salutary effects on kidney injury. Taken together, the differences in kidney injury seen by Wicks et al. in C57Bl/6 J mice when compared to Nistala et al., could also be attributed to the differences in obesogenic diet (high fat alone vs. high fat and high sugars), the age at which the feeding is started (10 weeks adults vs. 4 weeks young mice) and the duration of feeding (12 weeks vs. 20 weeks or more). Additional support for obesity induced kidney injury is provided by Sun and colleagues, who had a similar study looking at the impacts of high fat diets on C57BL/6 J mice. These obese mice not only showed signs of oxidative damage, but they also demonstrated glomerular fibrosis. These renal changes led to severe glomerulopathy in these mice with increases in BUN, albumin and creatinine (Sun et al., 2020). In summary, all the studies so far have clearly demonstrated kidney injury in obesity alone with no underlying diabetes, although the extent of injury may differ based on the diet, duration of obesity and strain of mice used.

Obesity is widely recognized for its numerous downstream pathophysiologic consequences; however, it is preceded by chronic overnutrition, which serves as a key upstream driver (Mann et al., 2024). The Randle Effect, first described in 1963, pertains to the regulation of the glucose–fatty acid cycle (Hue and Taegtmeyer, 2009; Randle et al., 1963; Meyer et al., 1997; Palmer and Clegg, 2022). Under normal physiological conditions, as free fatty acid (FFA) uptake increases in the kidney, more abundant FFA's are available in the post-absorptive (fasting state), glucose oxidation is suppressed via decrease in pyruvate dehydrogenase (PDH) (increased availability of glucose for the brain and kidney medulla) and increase in carnitine palmitoyltransferase 1 (CPT1) levels (Hue and Taegtmeyer, 2009; Randle et al., 1963; Palmer and Clegg, 2022). To the contrary, when glucose availability is increased in the absorptive state (fed state), glycolysis (glucose oxidation) and uptake into various tissues is increased, fatty acid oxidation is suppressed via increase in PDH and Acetyl CoA that enters the citric acid cycle and generates malonyl CoA (Hue and Taegtmeyer, 2009; Randle et al., 1963; Palmer and Clegg, 2022). Malonyl CoA inhibits β-oxidation of fatty acids and promotes FFA synthesis (Hue and Taegtmeyer, 2009; Randle et al., 1963; Palmer and Clegg, 2022). In the obese individual, there is persistent abundance of both glucose and FFA leading to very little recovery period between absorptive and post-absorptive states leading to “metabolic inflexibility” as both β-oxidation of fatty acids and glucose uptake/oxidation into peripheral organs is inhibited (Palmer and Clegg, 2022). This leads to increased storage of FFAs as triglycerides and other fat products and hyperglycemia (glucotoxicity) (Palmer and Clegg, 2022). In addition, the abundance of FFAs and glucose as fuel leads to excessive generation of reactive oxygen species through the respiratory chain leading to injury of the tissues (Palmer and Clegg, 2022). Interestingly, an animal study by Koves and colleagues demonstrated that obesity and high-fat feeding are associated with increased mitochondrial β-oxidation in skeletal muscle (Koves et al., 2008). Despite this elevation, a substantial proportion of fatty acids undergo incomplete oxidation, resulting in the accumulation of lipid intermediates (Koves et al., 2008). These intermediates impair insulin signaling, promoting the development of insulin resistance. This metabolic dysfunction reflects a central feature of the Randle cycle, wherein impaired substrate flexibility and mitochondrial inefficiency contribute to obesity-associated insulin resistance (Koves et al., 2008).

BMI is used to determine obesity and high numbers can be associated with CKD development and progression (Peng et al., 2023). However, BMI can be influenced by not only body fat, but also muscle. In elderly patients, there is typically a higher rate of body mass loss, however the elderly population accounts for the highest rates of CKD (Table 1) (Peng et al., 2023). As patients get older, they lose lean body tissue and gain more visceral fat (Palmer and Jensen, 2022). Peng et al. looked at visceral body fat indices (VAI's) as a possible factor in the development and progression of CKD (Peng et al., 2023). Their cross-sectional study found an association between increases in VAI and increases in the rate of CKD in elderly patients 60 years and older (Peng et al., 2023). VAI is a calculation based on the following: gender, BMI, waist circumference, triglycerides and high-density lipoprotein cholesterol (HDL-C) (Peng et al., 2023). It is suggested that visceral fat can impair renal blood flow due to compression of the renal hilum and parenchyma leading to decreased GFR and proteinuria (Garofalo et al., 2017).

Table 1.

Clinical Studies on ORKD progression.

Study Name	Study population	Number of study participants	Duration of Study	Comorbidities	Key findings
NHANES VAI & CKD (Peng et al., 2023)	Elderly (60+ years of age)	6085	7 years	Obesity	Higher VAI associated with increased CKD risk
Kramer et al. AJKD (Kramer et al., 2005)	Ages 30–69; ideal, overweight and obese BMIs	9685	5 years	Obese BMI: DM(16 %), CKD (22 %)	Association between obesity and risk of CKD
SELECT Trial (Colhoun et al., 2024a)	Obese patients with CKD without T2DM	17,604	4 years	Obesity	Semaglutide improves renal outcomes related to CKD
Semaglutide effect on CKD in T2DM patients (Perkovic et al., 2024)	Patients with T2DM and CKD	3533	4.5 years	T2DM (100 %)	GLP-1 slowed progression of CKD decreased risk of renal failure, transplant or related death
SMART (Apperloo et al., 2025)	Obese patients with CKD without T2DM	101	2 years	Unspecified	Reduction in UACR in patients on Semaglutide

Abbreviations: VAI = visceral adiposity index; DM = Diabetes Mellitus; CKD = Chronic Kidney Disease; UACR = urinary creatinine.

Visceral fat is highly associated with obesity, which is another way in which obesity plays a key role in the development and progression of CKD (Peng et al., 2023). Excess visceral fat accumulation contributes to a cascade of pathophysiological processes that impact systemic and renal function (Kataoka et al., 2023). Adipose tissue expansion secondary to obesity is associated with inflammation and dysregulation of adipokine secretion, which in turn promotes dyslipidemia, insulin resistance, chronic low-grade systemic inflammation, and oxidative stress (Gregor and Hotamisligil, 2011; Hosogai et al., 2007; Hall et al., 2010; Ouchi et al., 2011; Sharma et al., 2008). These changes are further compounded by activation of central and peripheral neurohormonal pathways, including stimulation of the brain melanocortin system, sympathetic nervous system overactivity, and upregulation of the RAAS (de Paula et al., 2004; Hall et al., 2019; Achard et al., 2007). Downstream effects include mineralocorticoid receptor activation, enhanced sodium retention, and expansion of extracellular fluid volume (Kataoka et al., 2023). These effects further contribute to hyperfiltration of the glomerulus leading to pathological development of ORKD (Kataoka et al., 2023).

Visceral adiposity is also closely linked to the accumulation of fat in perirenal and renal sinus regions (Hall et al., 2019; Lamacchia et al., 2011). This ectopic fat deposition exerts mechanical pressure on renal structures, increasing intrarenal pressure and compressing the vasa recta and thin limbs of the loop of Henle (Fig. 3) (Hall et al., 2019). These hemodynamic alterations impair medullary blood flow, enhance sodium reabsorption in the loop of Henle, and further stimulate RAAS activation, similar to visceral fat as mentioned above (Hall et al., 2019). This system overactivation and impairment promotes a perpetual cycle of sodium retention and kidney injury (Praga and Morales, 2017; Hall et al., 2019; Kataoka et al., 2023; Kotsis et al., 2021). RAAS inhibitors and weight loss provide some protection against the development of ORKD, however most patients develop progressive CKD that leads to ESRD despite treatment (Jiang et al., 2023).

5. Therapies targeting ORKD progression

5.1. Bariatric surgery procedures

Given the association between overweight/obesity and ORKD, therapies targeting weight loss have been demonstrated to be effective at reducing its progression (Chang et al., 2017). One such set of therapies that have shown success in promoting and sustaining weight loss are bariatric surgery procedures (Henao-Carrillo et al., 2024; Puzziferri et al., 2014). These procedures have been most effective in patients with moderate to severe obesity. The surgeries involve various procedures such as Roux-en-Y gastric bypass (RYGB), laparoscopic sleeve gastrectomy (LSG) and laparoscopic assisted gastric banding (LAGB) which produce weight loss by several complementary effects that involve gastric surface area restriction, promotion of nutrient malabsorption and modulation of GI hormone effects to promote weight loss (Chang et al., 2017). Weight loss promoted by bariatric surgery also decreases intraabdominal pressure, which attenuates downstream effects of ORKD (Ardiles, 2023). In addition, sustained weight loss improves renal blood flow, GFR, as well as renin and aldosterone activity (Ardiles, 2023). These effects by bariatric surgery allow it to decrease or reverse proteinuria and reverse hyperfiltration, an integral step in the pathology of ORKD development and progression (Ardiles, 2023; Doty et al., 1999; Brøchner-Mortensen et al., 1980; Chagnac et al., 2003; Lieske et al., 2014). Interestingly, in patients with CKD (based on eGFR), bariatric surgeries improved indexed GFR (corrected to body surface area) by increasing from 50 ml/min to 64 ml/min, suggesting that when the GFR has decreased and is no longer hyperfiltrating (such as in advanced CKD), weight loss slowed the progression of CKD (Navaneethan et al., 2009; von Scholten et al., 2017; Chintam and Chang, 2021).

5.2. RAAS inhibition

Although ORKD is a chronic disease that risks progression to ESRD, there are now several pharmaceutical options outside of simple weight loss that may provide protection against development of ORKD and its progression (Martínez-Montoro et al., 2022). The most well-known of these medications are the RAAS inhibitors which until recently, were the only options for treatment to mitigate kidney injury in obese, hypertensive, insulin resistant and proteinuric patients (Hall, 2003; Mathew et al., 2011; Praga and Morales, 2017; Helal et al., 2012; Hall et al., 1977, 2019; Martínez-Montoro et al., 2022; Rüster and Wolf, 2013). RAAS inhibitors primarily work by relaxing efferent arteriole constriction, thereby lowering GFR (Apperloo et al., 1997; Heller et al., 2008; Bakris and Weir, 2000). In addition, other mechanisms include reduction in NADPH oxidase and ROS-mediated injury and kidney immune cell-mediated injury (Rüster and Wolf, 2013; Griendling et al., 2021; Nistala et al., 2008, 2021; Itani et al., 2016). Another prominent mechanism for RAAS-mediated benefits is via improvement in insulin resistance, which is a combination of several sub-mechanisms including the above mechanisms (Sarafidis et al., 2006; El-Atat et al., 2004; Narrative Review, 2009). Animal studies showed that blockade of RAAS with enalapril reduced GFR or hyperfiltration (Remuzzi et al., 1990). Aldosterone inhibition with eplerenone attenuated hyperfiltration and slowed progression of CKD in obese dogs (de Paula et al., 2004). Recently, there has been some discussion on the sustainability of kidney benefits with RAAS inhibition and a meta analysis failed to reveal long term renal benefits in obese, hypertensive patients (Cohen et al., 2016). Currently, the role of RAAS inhibition in ORKD can be best understood as agents that protect the kidneys from hyperfiltration, proteinuria and histological damage but newer agents such as SLGT2 inhibitors, GLP-1 agonists and other weight loss agents are additionally needed for the full benefit.

5.3. SGLT2 inhibitors

A class of drugs that were traditionally used to treat T2DM and that are useful in treating ORKD are sodium-glucose cotransporter-2 (SGLT2) inhibitors (Musso et al., 2016; Heerspink et al., 2016; Thomas and Cherney, 2018). They block the reabsorption of glucose in the proximal renal tubule, inducing glucosuria and reducing plasma glucose levels (Musso et al., 2016; Heerspink et al., 2016; Thomas and Cherney, 2018). The increased delivery of glucose and sodium to the macula densa triggers tubuloglomerular feedback and reduction in GFR (Musso et al., 2016; Heerspink et al., 2016; Thomas and Cherney, 2018). The resulting effect is the inhibition of glomerular hyperfiltration which is the initial step in the development and progression of ORKD (Musso et al., 2016; Heerspink et al., 2016; Thomas and Cherney, 2018; Kidokoro et al., 2019). SGLT2 inhibitors are not currently approved for weight loss and their effects on weight loss are modest (Kreiner et al., 2023). However, dual SGLT1 and SGLT2 inhibitors may produce more significant weight loss (Kreiner et al., 2023). SLGT2 inhibitors work very well with RAAS inhibitors in the protection of kidney function and are currently recommended as treatment in diabetic and non-diabetic CKD with eGFR ≥20 ml/min (Committee ADAPP. Addendum, 2022). An important fact to note is that SGLT2 inhibitors have their greatest benefits in obese hyperfiltrating patients than those with normal or reduced BMI and reduced GFR, emphasizing that their mechanism of renal benefits is primarily through reduction in hyperfiltration (Jimba et al., 2025).

5.4. GLP-1 agonists (incretin mimetics)

Glucagon like Peptide (GLP-1) agonists such as Semaglutide have historically been used to treat T2DM but have gained popularity in recent years due to their ability to promote weight loss in obese patients (Henao-Carrillo et al., 2024; Zheng et al., 2024; Heerspink et al., 2023; Colhoun et al., 2024b; Badve et al., 2025; Michos et al., 2023). GLP-1 agonists are incretin mimetics that work to stimulate additional insulin secretion (additional to insulin secreted by food intake) from the pancreas in the presence of glucose, a process that is diminished or completely absent in T2DM (Nauck et al., 2021). As a result, gastric emptying is delayed and glucagon production is inhibited in pancreatic alpha cells when blood glucose is elevated (Nauck et al., 2021). In the kidney, GLP-1 agonists have been shown to inhibit NHE3 in the proximal tubule, thereby inducing natriuresis and inhibit RAAS, blocking hyperfiltration at the glomerulus, thereby preventing the development and progression of ORKD (Musso et al., 2016; Carraro-Lacroix et al., 2009; Crajoinas et al., 2011; Rieg et al., 2012; Vallon and Docherty, 2014). GLP-1 plays an important role in renal hemodynamics. Generally, in obese and diabetic hypertensive patients with CKD, the drugs decrease GFR initially (i.e. reduce hyperfiltration) and also decrease BP, (albeit by small numbers), ultimately resulting in slowing down of CKD progression (Wajdlich and Nowicki, 2024). Acute administration of GLP-1 in rats and/or humans has shown that GLP-1 can increase BP primarily through alteration in afferent arteriole autoregulation (Wajdlich and Nowicki, 2024; Jensen et al., 2015). In obese patients, this drug can offer an opportunity for significant weight loss while also being renally protective against CKD progression (Colhoun et al., 2024a; Apperloo et al., 2025).

5.5. DPP4 inhibitors

Dipeptidyl peptidase-4 (DPP4) inhibitors, commonly referred to as “gliptins,” are a class of pharmacologic agents that target DPP4 enzyme, which is highly expressed in the proximal tubules of the kidney and other parts of the nephron (Nistala and Savin, 2017). These agents are primarily used in the management of type 2 diabetes mellitus (T2DM) due to their ability to inhibit the degradation of incretin hormones, including GLP-1, GLP-2, and glucose-dependent insulinotropic polypeptide (GIP) (Nistala and Savin, 2017). By prolonging the activity of these peptides, DPP4 inhibitors enhance glucose-dependent insulin secretion and contribute to improved glycemic control. Another activity of DPP4 inhibitors that has received substantial attention is the blockade of NHE3 leading to decreased Na reabsorption, blood pressure and preservation of GFR (Rieg et al., 2012; Girardi et al., 2001, 2008; Martins et al., 2024). Similar to GLP-1 agonists, inhibition of the exchanger can alleviate glomerular hyperfiltration and slow progression of ORKD although the effect on hyperfiltration is fairly weak (unpublished data) (Rieg et al., 2012; Nistala and Savin, 2017). When DPP4 inhibitors are used alone, they have been shown to reduce BP in smaller cohort studies (Alter et al., 2012; Aroor et al., 2013; Zhang et al., 2019) although several large studies have shown no BP effect (Scirica et al., 2013; Udell et al., 2015; Zhang and Zhao, 2016). Moreover, a large body of evidence exists in support of DPP4 inhibitors reducing proteinuria, which is another hallmark of CKD progression (Nistala et al., 2014a, 2014b; Scirica et al., 2013; Udell et al., 2015; Groop et al., 2013). In summary, these inhibitors have largely had neutral effects on reducing hyperfiltration or CKD progression in large clinical trials likely due to the concurrent use of high dose RAAS inhibition, in particular angiotensin converting enzyme inhibitors (ACEi) and other effects resulting from its enzymatic action (Udell et al., 2015; Jackson et al., 2015; Marney et al., 2010).

6. Summary

Obesity remains highly prevalent in modern society and is closely associated with a wide range of comorbidities. Among these, chronic kidney disease (CKD) has emerged as a condition increasingly linked to obesity, both independently and through overlapping risk factors. Evidence from preclinical and clinical trials supports a strong association between obesity and CKD, suggesting that obesity contributes directly to kidney dysfunction. Interventions such as lifestyle modifications, pharmacologic therapies, and bariatric surgery not only facilitate weight reduction but also show promise in decreasing the incidence and progression of ORKD. Despite these findings, further long-term, prospective studies are needed to clarify the extent to which obesity serves as an independent risk factor for CKD and to determine the efficacy and durability of these interventions. This review highlights the importance of recognizing obesity as a modifiable contributor to CKD and underscores the potential for targeted strategies aimed at preventing and managing ORKD.

Credit author statement

Austin Dada – Conceptualization, Writing – original draft, Writing – review & editing.

Jing Ren - Data curation, Methodology, Validation.

Yao Shi - Data curation, Investigation, Methodology, Validation.

Ravi Nistala - Conceptualization, Data curation, Formal analysis, Funding acquisition, Project administration, Resources, Supervision, Writing – original draft, Writing – review & editing.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Data availability

Data will be made available on request.