Cardiometabolic comorbidities and complications of obesity and chronic kidney disease (CKD)

Highlights

• •Obesity related Chronic Disease (ORCKD) is highly prevalent.
• •Primary ORCKD includes Obesity related glomerulopathy (ORG) and focal segmental glomerulosclerosis.
• •ORCKD is associated with a multiplicity of comorbidities and complications especially in the cardio-metabolic domain.
• •Strategies for CKD modulation in non-obese patients are also effective in ORCKD.
• •Evidence suggests that weight loss and management strategies provide added benefit to renal function and cardio-metabolic risk reduction in ORCKD.

Abstract

Obesity and chronic kidney disease are two ongoing progressive clinical pandemics of major public health and clinical care significance. Because of their growing prevalence, chronic indolent course and consequent complications both these conditions place significant burden on the health care delivery system especially in developed countries like the United States. Beyond the chance coexistence of both of these conditions in the same patient based on high prevalence it is now apparent that obesity is associated with and likely has a direct causal role in the onset, progression and severity of chronic kidney disease. The causes and underlying pathophysiology of this are myriad, complicated and multi-faceted. In this review, continuing the theme of this special edition of the journal on “ The Cross roads between Endocrinology and Nephrology” we review the epidemiology of obesity related chronic kidney disease (ORCKD), and its various underlying causes and pathophysiology. In addition, we delve into the consequent comorbidities and complications associated with ORCKD with particular emphasis on the cardio metabolic consequences and then review the current body of evidence for available strategies for chronic kidney disease modulation in ORCKD as well as the potential unique role of weight reduction and management strategies in its improvement and risk reduction.

Introduction

Obesity represents a major ongoing world-wide epidemic with increasing global prevalence [1], [2]. The GBD 2015 obesity collaborators review of over 65 million subjects worldwide spanning ∼ 195 countries and including both adults and children from 1980 to 2015 demonstrate that the prevalence of obesity doubled in more than 70 of these countries (including the United States). Furthermore, while the prevalence of childhood obesity is obviously less than in adults, the rate of increase of childhood obesity prevalence outpaces adult obesity with potentially grave public health and clinical consequences for the near future [1], [2], [3], [4].

The disease morbidity and mortality associated with obesity has been exhaustively documented [1], [2], [3], [4]. This is known to be consequent upon the direct effects of obesity itself as well as its associated comorbidities and complications which are protean. Conservative estimates suggest that obesity accounts for at least 4 million deaths annually worldwide and > two thirds of these deaths are due to cardiovascular mortality which is one of the many complications obesity brings in its wake [1], [2], [3], [4], [5].

It is generally less appreciated that beyond the scope and impact of obesity on public health and clinical morbidity and mortality there is a second (often silent) tandem global epidemic of chronic kidney disease (CKD) [6], [7], [8], [9], [10], [11], [12]. Current conservative estimates suggest that CKD afflicts > 1in 7 adults in the United States with an estimated prevalence of at least ∼ 37 million. Among “enriched” populations this CKD risk is even greater. Among the dominant known risk factors for CKD are diabetes mellitus (with ∼ 30 % CKD disease risk), essential hypertension(∼20 % disease risk), atherosclerotic vascular disease (AVD), family history of CKD and geriatric populations (>65 years old) [6], [7], [8], [9], [10], [11], [12]. Available cross sectional and cohort study data also indicate a distinct racial discrepancy in CKD prevalence with African American and Black subjects have a greater prevalence (∼20 %) compared to Hispanic (14 %) non-Hispanic Asian (∼14 %) and Non-Hispanic Caucasians (∼12 %) subjects [6], [7], [8], [9], [10], [11], [12]. As with obesity but to an even greater extent, CKD portends major associated morbidity and mortality risk with the greatest mortality risk being due to the associated accelerated AVD and acute coronary syndromes (ACS) [6], [7], [11]. Conservative estimates ascribe ∼ 1.5million deaths to CKD between 1990 and 2017, but more tellingly, the CKD mortality rate has increased by > 40 % over this period despite advances in standards of care and resources. The mortality rate from CKD is ∼ 1.28–1.3 times higher in males than females overall. In addition, conservative estimates suggest that ∼ 7.3 million years aggregate of living with disability (YLDs), ∼ 28.5 million aggregate years of life lost (YLLs) and ∼ 35.8 million disability adjusted life years (DALYs) are attributable to CKD.

While just based on the high prevalence of the twin epidemics of obesity and CKD it would be anticipated that there would be a sizeable degree of overlap between the populations and patients burdened by obesity and CKD it is now very apparent that the cohabitation of obesity and CKD in large populations of patients is not simply from statistical happenstance. It is now well established that obesity is an independent risk factor for CKD onset and progression with growing body of evidence suggesting even more provocatively that it is an independent etio-pathogenic cause for CKD like essential hypertension, diabetes and chronic nonsteroidal anti-inflammatory drug (NSAID) use [6], [11], [12]. The recognition of the distinct entity of obesity related chronic kidney disease (ORCKD) has spurred growing interest in this unique subgroup of the CKD disease burden population both to better understand its underlying pathophysiology, management strategies and to contrast its clinical course and prognosis to the more commonly known forms of CKD. Conceptually CKD identified in obese patients can be sub-stratified into primary (where obesity appears to be the only identifiable clinical etiology) and secondary ORCKD. Included in the subset of secondary ORCKD are Hypertensive CKD, Diabetic Nephropathy with CKD and Renal stone associated CKD all of which are seen with significantly greater prevalence in obese patients than in the general population [8], [9], [11], [13]. For the sake of clarity, secondary ORCKD can also be referred to as Obesity associated CKD and is not the focus of this review.

Primary ORCKD which is the main focus of this review is a complex multifaceted condition which on closer review may be better described as a syndrome with possibly several different etiopathogenetic pathways, presentations and clinical manifestations [14], [15], [16], [17], [18].

Among the identified pathophysiologic mechanisms that drive the development of primary ORCKD are altered renal and glomerular hemodynamics with hyperfiltration, chronic renal inflammation, oxidative stress and activation of the renin-angiotensin-aldosterone-Kallikrein system (RAAKS) [17], [19].

Upon microscopic evaluation, patients with primary ORCKD often display glomerulomegaly and focal segmental glomerulosclerosis often referred to as Obesity related glomerulopathy (ORG) [17], [19]. These patients are generally asymptomatic or with non-specific atypical symptoms early in the evolution of this disease. The main clinical feature to screen for prior to onset of functional renal decline is proteinuria which can range from microalbuminuria through sub-nephrotic to nephrotic range proteinuria [17], [19].

Other contributory factors to the onset and progression of primary ORCKD include lipotoxicity, adipocytokine dysregulation, glomerular hypertension and ectopic fat accumulation in the kidneys resulting in pathologic evidence of renal steatosis (fatty kidney) [14], [15], [17], [19], [20], [21], [22].

It is now apparent that well before the onset/development of diabetes in obese patients there is a continuum of progressive decline in beta cell function along with insulin resistance. This “prediabetic” state is often associated with the dysmetabolic syndrome and is now known to be an independent risk factor for ORCKD [15], [17], [19]. Even among obese patients with little to no dysmetabolic derangements (so called metabolically healthy obese patients) there is evidence a distinct, independent CKD risk and ORCKD cohort still persists [20], [23].

To provide an in-depth review of primary ORCKD we discuss in depth the epidemiology of obesity, CKD and their coexistence. Furthermore, we review the pathophysiology of ORCKD and its consequent cardiometabolic comorbidities and complications as well as review the body of evidence for CKD management in ORCKD. In addition, we also explore the unique role that weight loss and management can play in the management of ORCKD and its comorbidities and complications.

Epidemiology of obesity and CKD

In clinical practice, the widely accepted definition for overweight is a BMI of 25 – 29.9 kg/m², obesity being defined a BMI > 30 kg/m² and severe obesity classified as BMI at or above 40.0 kg/m².

Although BMI is widely used as a measure of body fat, it fails to account for factors like muscle mass, bone mass or fat distribution. At a given BMI level, body fat may vary by sex, age, and race. Additionally, the validity of some of the existing BMI cutoffs have been questioned, as they were not developed using diverse populations. The relationship between BMI and mortality is likely to be similar for all races and ethnicities, but the threshold BMI where excess risk begins may differ.

Results from the 2017–2018 National Health and Nutrition Examination Survey (NHANES), using measured heights and weights, indicate that an estimated 42.5 % of U.S. adults aged 20 and over have obesity, including 9.0 % with severe obesity, and another 31.1 % are overweight. This is detailed below in Fig. 1 [24].

Fig. 1.

NHANES Time Course Trends in Obesity and Overweight Prevalence by Gender Strata.

Non-Hispanic blacks have the highest age-adjusted rates of obesity (48.1 %) followed by Hispanics (42.5 %), non-Hispanic whites (34.5 %), and non-Hispanic Asians (11.7 %) [25].

Obesity is higher among middle-aged adults (age 40–59 years; 40.2 %) and older adults (age 60 and over; 37.0 %) than among younger adults (age 20–39; 32.3 %) [25].

The estimates presented in the 5th annual World Obesity Atlas displayed above (Fig. 2 above) suggest that, on current trends, overweight and obesity will cost the global economy over US$4 trillion of potential income in 2035, nearly 3 % of current global gross domestic product (GDP) [26].

Fig. 2.

World Obesity Prevalence Distribution.

The estimates for global levels of overweight and obesity (BMI ≥ 25 kg/m2), suggest that over 4 billion people may be affected by 2035, compared with over 2.6 billion in 2020. This reflects an increase from 38 % of the world’s population in 2020 to over 50 % by 2035.

The prevalence of obesity (BMI ≥ 30 kg/m²) alone is anticipated to rise from 14 % to 24 % of the population over the same period, affecting nearly 2 billion adults, children and adolescents by 2035 [26].

In some but certainly not all higher income countries, the rate at which obesity prevalence levels are rising appears to be slowing down. In lower income countries there are many reasons to expect rising obesity prevalence, including (a) trends in dietary preferences towards more highly processed foods, (b) trends towards greater levels of sedentary behavior, (c) weaker policies to control the food supply and food marketing and (d) less well-resourced healthcare services to assist in weight management and in health education in the population – all of which can continue to stimulate an increase in obesity prevalence.

CKD is associated with age-related renal functional decline and is accelerated in settings of hypertension, diabetes, obesity and primary renal disorders [27].

According to current estimates from NHANES data from 2017 to 2020, more than 1 in 7 US adults–about 35.5 million people, or 14 %–are estimated to have CKD [12], [28]. Fig. 3 details the breakdown from the NHANES cohort regarding CKD prevalence percentages based on age, sex and race/ethnicity strata [12].

Fig. 3.

NHANES CKD Prevalence percentages by age and Race + Ethnicity Strata.

A systematic review and meta-analysis estimating global CKD prevalence measured by all 5 stages of CKD between 11 and 13 %, with the majority being stage 3 [29]. In 2017, in the Global Burdan of disease study, 697·5 million cases of all-stage CKD were recorded, for a global prevalence of 9·1% [30], [31].

A meta-analysis of 25 cohorts, 3 cross-sectional and 19 case-control studies that met inclusion criteria confirmed that obesity increases the risk of CKD in the general population [32], suggesting a pathogenic association between both conditions. This systemic disease can affect the kidneys by at least two mechanisms: Indirectly through diabetes mellitus (DM) and hypertension and directly through adipokine secretion. Excessive adipose tissue is associated with insulin resistance, oxidative stress (OS) and visceral adiposity promotes hyper filtration and hyperperfusion, decreased podocyte density, increased foot processes which may lead to glomerular hypertrophy, and the appearance of microalbuminuria, activates the renin-angiotensin-aldosterone system and is associated with high levels of pro-inflammatory cytokines [33], [34].

The Framingham Offspring study cohort consisted of 1223 males and 1362 females who were initially free of preexisting kidney disease. After a mean follow-up of 18.5 years, 244 participants (9.4 %) had developed kidney disease (defined as Modification of Diet in Renal Disease [MDRD] estimated glomerular filtration rate [eGFR] of < 64 and 59 mL/min/1.73 m² for males and females, respectively). The development of CKD was associated with increased age, diabetes, hypertension, smoking, obesity, and lower baseline glomerular filtration rate [35].

Ejerblad et al, [36] showed that patients without diabetes or hypertension still had a threefold increased risk for CKD if they were overweight at age 20 years. Hsu et al, [37] showed that higher baseline BMI remained an independent predictor for ESRD after adjustments for BP and diabetes mellitus.

Using the Global Burden of Disease study data and methods the health effects of overweight and obesity in 195 countries over 25 years showed that CKD was the second leading cause of BMI-related disability-adjusted life-years in 2015; 18.0 % of disability-adjusted life-years occurred at a BMI of 30 or more and 7.2 % at a BMI of less than 30 [2].

Simply from the high population prevalence of both obesity and CKD the confluence of both in individual patients and subpopulations is expected, anticipated and inevitable. Beyond that though, the commonalities of etiologic causes and contributors to the ongoing twin global pandemics of both obesity and CKD result in a prevalence of ORCKD that far exceeds just statistical coexistence of both conditions [6], [10], [11], [12], [17], [28], [38], [39], [40].

It is now apparent that the association of obesity and CKD can be subdivided into primary (or so called idiopathic ORCKD) where the exact etio-pathogenic are still somewhat unclear and subject to speculation and likely multiple possibly co-interacting mechanisms (some of which are detailed below) and secondary ORCKD where well established known secondary diseases known to be associated with CKD coexist in patients with obesity. As a group secondary ORCKD is more prevalent and thus has greater public health import but this does not diminish the importance of the need for a better understanding of the both the pathophysiologic basis and long term management strategies for primary ORCKD [13], [19], [34], [36], [37], [41]. Prominent among the entities embodied in secondary ORCKD (which wont be further discussed in this review) are Hypertensive Obesity related CKD, Diabetic related Obesity related CKD, Renal stone disease related Obesity CKD, NSAID and other medication related Obesity CKD and acquired cystic Obesity related kidney disease [6], [13], [39], [41], [42], [43], [44], [45], [46], [47], [48], [49], [50].

Pathophysiology and pathobiology of Primary Obesity related chronic kidney disease

The exact etiopathogenesis of primary ORCKD is unknown but accumulating evidence from cellular basic, translational, animal model and various forms of human clinical studies and observations are progressively increasing the accumulated body of evidence in this regard and paint a complex multifaceted tapestry with different degrees of contributory factors in individual patients and subpopulation groups. To varying degrees it is now apparent that ORCKD involves elements of glomerular, tubular and renal parenchymal injury [18], [20], [51].

Among the main established pathophysiologic mechanisms involved in the development of ORCKD are the following that are discussed below.

Renal fat excess and ectopic accumulation

As Fig. 4, Fig. 5 illustrate, the kidney is associated with multiple distinct fat depots in and around them. There is now evidence that excessive amounts of fat in any of these locations with or without ectopic parenchymal renal fat accumulation akin to that seen in states of metabolic associated fatty liver disease can result in the renal dysfunction associated with ORCKD [14], [20], [22]. Ectopic fatty disease accumulation in the kidney is now well demonstrated to be pathogenic and is variously referred to as fatty kidney disease, renal steatosis and renal fatty infiltration [14], [15], [20], [21], [22]. There is some evidence from both human studies and animal models that renal sinus/hilum ectopic fat by sheer mechanical effects and compression can impair renal tissue perfusion as this is the entry point to the rest of the renal parenchyma for the renal artery, vein and lymphatics as well as the ureter and renal pelvis. The elevated hydrostatic pressure can also result in a degree of renal outflow obstruction [52], [53], [54], [55], [56]. The increased renal hilum/sinus fat accumulation and resultant intra-renal hypertension has also been demonstrated to be associated with local renal hypoxia indicated by increased production of hypoxia inducible factor 1 alpha and consequent ischemic renal tissue damage [57]. Both peri and pararenal fat depots have been shown to positively correlate with degree of blood pressure elevation, degree of insulin resistance, Hemoglobin A1C, albuminuria and presence of the dysmetabolic syndrome [58], [59]. Fig. 6 provides illustrative examples of renal parenchymal and tubular fatty infiltration.

Fig. 4.

Longitudinal Section of Kidney showing fat depots.

Fig. 5.

Transverse abdominal section at level of Kidneys showing fat depots.

Fig. 6.

Renal Steatosis/Fatty renal infiltration; A; Renal parenchymal steatosis, B; Renal tubular steatosis.

Among the established imaging modalities by which renal adiposity can be visualized and semi quantified are targeted abdominal sonography, Computed tomography (including renal tissue density measurements using Hounsfield unit scores), magnetic resonance imaging (MRI), nuclear magnetic resonance spectroscopy (NMRS) and renal elastography [14], [15], [20], [21], [22]. These methods provide in-vivo means of renal adipose tissue visualization, localization and semi-quantification that have substantively reduced the need for percutaneous renal biopsies which while being the gold standard for renal adiposity documentation is seldom performed because of its invasive nature. Just as has been recognized with fatty liver disease which can have alcohol and non-alcohol related etiologies that is now described as metabolic associated fatty liver disease (MAFLD) a subset of patients with ORCKD with demonstrable ectopic and excess intrarenal fat accumulation can be described as having metabolic associated fatty kidney disease (MAFKD).

Altered renal hemodynamics

Weisinger and colleagues were among the earliest to document the association between marked obesity and intra-renal venous hypertension which is associated with reversible proteinuria and which is one of the first pathophysiological steps in the onset of ORCKD [21], [60]. Intra-renal venous hypertension is known to result in glomerular hyperfiltration as has been demonstrated in both diabetic and hypertensive nephrosclerosis. This sustained over time results in a sustained glomerulopathy that ultimately leads to renal functional decline and CKD with end stage glomerular hypofiltration and chronic renal failure requiring renal replacement therapy [33], [61], [62], [63].

Obesity Related Glomerulopathy (ORG)

Subsequent studies have demonstrated the association of obesity with the development of a distinctive glomerulopathy characterized by glomerulomegaly and focal segmental glomerulosclerosis now commonly referred to as ORG [18], [21], [61], [64], [65].

The degree of proteinuria associated with ORG is variable and can range from mild to nephrotic range depending on various other factors and variables [21], [40], [48], [60]. The evolution of ORG also includes glomerular basement membrane expansion, podocyte hypertrophy and detachment with ultimate consequent renal functional decline accompanied with progressively worsening proteinuria [33], [34], [36], [61], [62], [63], [64].

Renin Angiotensin Aldosterone Kallikrein System (RAAKS) Activation

Consequent upon the renal hemodynamic pertubations detailed above, ORCKD has been demonstrated to be associated with both systemic and local intra-renal paracrine activation the RAASK system. The glomerular hyperfiltration in particular results in elevated proximal tubular reabsorption of sodium and water with consequent reduced sodium delivery to the macular densa, reduced afferent arteriolar vascular resistance and inhibited tubuloglomerular feedback. The fact that several components of the RAASK system (including renin and aldosterone) are known adipokines provides an additional accelerant source of these hemodynamic changes in ORCKD [45], [64], [66], [67].

Tissue inflammation and oxidative stress

The Adipocyte excess and ectopic expression associated with fatty kidneys are associated with a local and systemic pro inflammatory state also associated with oxidative stress. This is mediated at least in part with the various inflammatory adipokines produced by these adipocytes [21], [68], [69]. Among the putative pro inflammatory mediators produced from the adipocytes are leptin, resistin, free fatty acids, TNF alpha, interleukin-6 and several other pro inflammatory interleukins as well as reduced production of the anti-inflammatory, insulin sensitizing adipokine, adiponectin [21], [68], [69], [70]. The diseased adipocyte tissue depots in ORCKD (sometimes referred to as adiposopathy is also associated with cellular endoplasmic reticular stress (ER stress) and over expression of TGF-beta which is partially mediated by leptin [14], [34], [64], [71], [72], [73], [74]. Chronic inflammation with ongoing oxidative and ER stress eventually leads to progressive renal fibrosis which appears to be at least TGF-beta mediated and can involve the entirety of the renal parenchyma including the glomeruli, renal tubules and renal interstitium resulting in permanent renal dysfunction and potentially end stage renal disease (ESRD).

Renal sympathetic nervous system activation

ORCKD is also known to be associated with activation and overactivity of the local renal sympathetic nervous system. While the full details of the cause for this is unclear, leptin does appear to be contributory [21], [22], [75].

Role of lipotoxicity and myriad CKD risk mediators

Beyond the induction of local and systemic inflammation as previously detailed, ectopic renal fat can also induce direct nephrotoxicity due to specific nephrotoxicity of ectopic fat and their expressed adipokines [14], [21], [22], [73], [74], [75], [76], [77], [78], [79]. It has also been shown that the presence of certain apolipoprotein L1 (APOL1) genetic variants in patients appears to be associated with development of ORCKD as has already been demonstrated in the development of both HIV associated nephropathy and idiopathic focal segmental glomerulosclerosis (FSGS) [80], [81]. These APOL1 gene polymorphisms may impair reverse cholesterol transfer and downregulate cholesterol efflux transporters resulting in toxic tissue cholesterol accumulation in renal tissue especially within the podocytes [20], [80], [81].

As with most other forms of CKD, ORCKD is typically indolent in its natural history of progression over time. About ∼ 10–33 % of ORCKD patients in the absence of d interventions typically progress to ESRD requiring renal transplant therapy [61], [64], [82], [83].

Hyperinsulinemia and insulin resistance

Insulin resistance and the compensatory hyperinsulinemia associated with it are common in obese patients. This is known to be associated with preglomerular vasodilatation and intraglomerular hypertension. This is also consequently associated with albuminuria and possible renal functional decline. Insulin has also been demonstrated to play a role in normal podocyte function, morphology and function. Insulin resistance is consequently associated with podocyte apoptosis and hypertrophy [84], [85], [86], [87].There is some suggestion that Fetuin A may also be an intermediary mediating the transition from insulin resistance to ectopic fat accumulation in the liver (resulting in metabolically associated fatty liver disease) as well as potentially fatty kidney with possible progression to ORCKD [88], [89], [90], [91], [92], [93].

Early markers of renal injury and functional deficits

Well before the onset of measurable proteinuria and renal functional decline shown by elevated serum creatinine, Cystatin C and/or creatinine clearance decline, hypoxemic renal tissue damage which early on is predominantly in the proximal convoluted tubules is characterized by increased production of kidney injury molecule −1 (KIM 1) and fibroblast growth factor 21 (FGF-21). Chronic renal expression of both these markers over time ultimately leads to renal fibrosis [94]. Urine neutrophil gelatinase associated lipocalin, urinary Cystatin C, urinary N-acetyl Beta D aminoglucosidase and serum interleukin 18 levels have also been reported to be elevated in subjects with early ORCKD [17], [19], [95], [96], [97], [98]. Other potentially useful markers for use as biomarkers of early kidney disease in ORCKD are podocin, nephrin, podocin/nephrin ratio, podocalyxin, urinary alanyl aminopeptidase, urinary glutamyl aminopeptidase, urinary klotho, urinary osteopontin and netrin-1 [99], [100], [101], [102], [103], [104]. There is also increasing evidence suggesting a potential role and place for proteomics and metabolomic indices as early markers of renal injury in ORCKD [17]. Controversies and contention still exist regarding the accuracy of clinical prediction equations of creatinine clearance based on serum creatinine and/or cystatin C levels in patients with ORCKD compared to the general population [17], [105], [106], [107], [108].

Dysbiosis of gut microbiota and ORCKD

Derangements of normal gut microbiota profiles have recently emerged as an important factor in the onset and development of several chronic metabolic disease. The extent to which gut microbiota changes observed in obesity are etiologic as opposed to correlative, associative or consequent complications of obesity is the subject of ongoing research [109], [110], [111], [112]. Beyond the known changes in microbiota associated with obesity however, it is also now apparent that patients with CKD and ESRD have demonstrable quantitative and qualitative changes in gut microbiota compared to controls. It is also apparent that toxic products of this dysbiosis can aggravate CKD and CKD related complications [113], [114]. In particular, with ESRD serum urea levels increase and is secreted into the intestines where the urease expressed by several gut microbes increase local ammonia production resulting in elevation of the local bowel Ph. This environmental change can inhibit the normal growth and proliferation of normal bowel commensals resulting in both qualitative and quantitative changes to the bowel microbiota including significantly increase aerobic and anaerobic bacteria in the duodenum and jejunum which are not significantly colonized by bacteria In normal healthy subjects [115], [116]. Altered microbiota, low grade endotoxemia and “leaky gut syndrome” associated with uremia can initiate a systemic inflammatory state which can both initiate and/or aggravate the cascade leading to ORCKD development in obese subjects [117], [118], [119].

Histopathologic features of ORCKD

Among the myriad potential findings associated with ORCKD on histologic examination of renal biopsy tissue include glomerulomegaly, global or FSGS, reduced glomerular density, podocyte injury and loss (on Electron microscopy), glomerulosclerosis/fibrosis, mesangial and/or glomerular basement membrane expansion (on Electron microscopy), tubule-interstitial fibrosis, tubular atrophy, proximal tubular epithelial hypertrophy, and tubular cell apoptosis [17], [120], [121], [122], [123]. Fig. 7 illustrates some of these findings while Fig. 8 illustrates the salient findings of obesity related glomerulopathy (ORG). Fig. 9 summarizes the salient aspects of the known pathophysiology and pathobiology of ORCKD.

Fig. 7.

Renal Glomerular and interstitial fibrosis.

Fig. 8.

ORG showing glomerulomegaly and focal segmental glomerulosclerosis.

Fig. 9.

Summary Schema of the pathophysiology of ORCKD.

The comorbidities and complications of obesity and CKD with emphasis on cardiometabolic aspects

Both CKD and obesity are associated with myriad endocrine and metabolic comorbidities are complications of which the cardiovascular consequences are arguably the most impactful as far as chronic morbidity and mortality potential [124], [125], [126], [127], [128]. As numerous and complex as the associated endocrine and cardiometabolic comorbidities associated with CKD and obesity are separately, it is now well established that the coexistence of both in ORCKD exacerbates both in prevalence and intensity the consequent litany of endocrine, hormonal and cardiometabolic complications and comorbidities [6], [17], [33], [34], [38], [39], [124], [125], [126], [127], [128], [129]. Table 1 below summarizes the major established comorbidities associated with CKD and by extension ORCKD [6], [17], [33], [34], [38], [39], [124], [125], [126], [127], [128], [129], [130], [131], [132], [133], [134], [135], [136], [137], [138]. Even more protean are the various comorbidities and complications known to be associated with obesity. There are > 200 distinct complications and comorbidities associated with obesity and while this review wont be discussing them in depth as related to ORCKD the cardiometabolic and endocrine are of particular interest and importance [139], [140], [141], [142], [143], [144], [145], [146], [147], [148], [149], [150], [151], [152], [153], [154], [155]. Fig. 10 provides a panoramic view of the most common comorbidities and complications of obesity which affect virtually every organ system of the body [139], [140], [141], [142], [143], [144], [145], [146], [147], [148], [149], [150], [151], [152], [153], [154], [155]. Of particular note and interest as well is the growing body of evidence demonstrating the association of obesity with increased cancer risk, prevalence and consequent morbidity and mortality [1], [2], [140], [144], [146], [147], [150], [154], [155], [156]. In relation to ORCKD in particular the associated increased risk for renal cell carcinoma among other increased cancer risks and it is also notable to appreciate that from a modifiable risk perspective, obesity is now the second most prevalent risk factor for oncogenesis in humans exceeded only by tobacco abuse and exposure [1], [2], [140], [144], [146], [147], [150], [154], [155], [156]. Figs. 11 shows the cancers and benign tumors with the most robust available data to date of being obesity related and enabled.

Table 1.

Endocrine and Cardiometabolic comorbidities and complications of CKD and ORCKD.

Organ/System	Manifestations	Suggested Pathophysiologic Mechanisms	Other Comments
Hypothalamic Pituitary Axis	Hyperprolactinemia, Growth hormone deficiency and/or Growth hormone resistance, Short Stature + growth retardation on children, secondary hypogonadism.	?? Mediated by uremia and other Accumulated renal excretory metabolites
Calcium/Phosphate, Mineral Balance + Skeletal System	Hypovitaminosis D, Secondary hyperparathyroidism, renal Osteodystrophy, Osteomalacia, Osteoporosis, Hyperuricemia, Gouty arthropathy	Reduced renal clearance
Skeletal Muscle System	Sarcopenia Deconditioning Asthenia, Malaise, Chronic fatigue etc	Altered and impaired myokine Balance including irisin, Electrolyte Derangements including hypokalemia, Hypophosphatemia, hypocalcemia etc
Adipocyte tissue Depots	Obesity, Visceral fat Accumulation, Cachexia, Protein energy Malnutrition	?? Mediated by uremia and other Accumulated renal excretory metabolites
Thyroid	Subclinical hypothyroidism, Low T3 syndrome	Altered Deiodinase function and distribution, Cytokine mediated non thyroidal illness effect on TSH secretion and action.
FGF - 21 and FGF- 23	FGF - 21 involved in modulation of dysglycemia, insulin resistance and dyslipidemia, FGF- 23 (Phosphatonin) involved in phosphaturia + hypophosphatemia	Impaired renal clearance and elevated serum levels of both FGF- 21 and FGF- 23 as well other pro- inflammatory cytokines
Hematopoietic system + Bone Marrow	Normocytic anemia	Ineffective erythropoiesis and reduced erythropoietin production.
Cardiovascular System	Atherosclerotic Cardiovascular disease (ASCVD) ; Chronic disease, acute vascular events, hypertension, RAAKS activation	Vascular calcification, reduced endothelial reactivity, effects of dysglycemia, dyslipidemia and insulin resistance on vascular function.
Reproductive System	Menstrual irregularities, premature menopause, Male and female hypogonadism (primary, secondary or mixed), erectile dysfunction	?? Mediated by uremia and other Accumulated renal excretory metabolites
Multi - functional / Multi - System	Chronic Fatigue, Malaise, Asthenia, deconditioning, Depression etc	?? Mediated by uremia and other Accumulated renal excretory metabolites. ?? inflammatory cytokine mediated.
Dermatologic	Acanthosis Nigricans, Xerosis, Chronic pruritus	?? Mediated by uremia and other Accumulated renal excretory metabolites. Insulin resistance.
Endocrine Pancreas	Insulin resistance, hyperinsulinemia, Dysglycemia, Nephrogenic and Transplant associated Diabetes	?? Mediated by uremia and other Accumulated renal excretory metabolites. In Transplant patients; effects of transplant related medications.
Adrenal	Secondary adrenal insufficiency, ?? Primary Adrenal insufficiency, Hyporeninemic hypoaldosteronism	Potential roles for Renal, Adrenal and Systemic RAAKS activation, Adrenomedullin and renal prostaglandins.	Problems with measurement and assays of adrenal medullary and Adreno - cortical hormones and Metabolites

Fig. 10.

Complications and Comorbidities of Obesity.

Fig. 11.

Obesity associated cancers and benign tumors.

Cardiometabolic burden of ORCKD

Disease burden and complications of obesity

Obesity is a medical disorder that leads to many comorbidities. This association is profoundly important for the affected individuals, but the associated morbidity is also economically damaging for society. Detailed estimates of the years of ill health and lives lost between the ages of 30 years and 75 years because of excess weight are shown for the subregions of the world in Fig. 12.

Fig. 12.

Disability-adjusted life-years (DALYs) lost as a result of obesity in men and women world-wide. Derived from James and colleagues [174].

Obesity causes cardiovascular and renal diseases through several mechanisms including hypertension, hyperglycemia, dyslipidemia, inflammation, and atherosclerosis. These disorders often coexist, especially when there is excess visceral fat, and have often been referred to as the “metabolic syndrome.” However, there is substantial evidence that excess visceral fat is the main driving force for almost all of the disorders associated with the metabolic syndrome, including CKD [157], [158].

• 1)Hypertension: Obesity is an important cause of hypertension as evident by multiple studies. Although the mechanisms responsible for obesity-induced hypertension are not fully understood, there is considerable evidence that abnormal kidney function plays a key role. Obesity causes excess renal sodium reabsorption, impaired renal-pressure natriuresis, and expansion of extracellular fluid volume, which lead to increased arterial blood pressure [159], [160]. Chronically elevated blood pressure coupled with renal vasodilation and glomerular hyperfiltration, SNS and RAAS activation, inflammation and metabolic derangements eventually causes renal injury which, in turn, further impairs renal-pressure natriuresis and exacerbates hypertension and kidney injury. Structural changes in the kidneys occur within a few weeks after rapid weight gain. These glomerular changes, if progressive, could eventually impinge on the glomerular lumen and reduce filtration surface area, initiating positive feedback that further increases blood pressure [161].
• 2)Coronary artery disease and stroke: Cardiovascular disease (CVD) is a major cause of morbidity and mortality among patients with obesity as well as patients with CKD [162]. In the general population, obesity is associated with cardiovascular morbidity, and abdominal fat content predicts cardiovascular risk and CV death. The presence of overt metabolic syndrome further intensifies the CV risks. Metabolic syndrome is present in 30.5 % of stage 4 or 5 CKD patients and is an independent predictor of cardiovascular death, acute coronary syndrome, revascularization, non-fatal stroke and amputation [163], [164]. Obesity itself probably imposes a small additional cardiovascular risk to patients with mild to moderate CKD, but the effect of obesity on the cardiovascular risk of patients with advanced CKD is probably the result of the concomitant metabolic syndrome and coexisting cardiovascular risk factors [165].
• 3)Type 2 Diabetes Mellitus: Excess body weight and obesity are significant risk factors for type 2 diabetes mellitus (T2DM). The lifetime diabetes risk in men older than 18 years increases from 7 % to 70 % when BMI increases from less than 18.5 kg/m to more than 35 kg/m. Similarly, the lifetime diabetes risk in females increases from 12 % to 74 % with the same BMI values [166]. Diabetes mellitus is among the leading causes of chronic kidney disease and end-stage kidney disease in the western world. Control of diabetes mellitus is more challenging in patient with CKD and the risk for severe hypoglycemic episodes increases when GFR falls below 45 mL/min. Hypoglycemic episodes may develop due to reduced gluconeogenesis and counter-regulation in the kidneys [167], [168].
• 4)Non-alcoholic fatty liver disease (NAFLD): NAFLD is characterized by excessive fat accumulation in hepatocytes and may progress to non-alcoholic steatohepatitis (NASH), ultimately leading to advanced fibrosis and cirrhosis [169]. Experimental and epidemiological data reveal some pathophysiological links between them and support the assertion that NAFLD may be a pathogenic factor of CKD, wherein CKD accelerates the progression of NAFLD [170], [171]. Generation of lipotoxic metabolites of fatty acids typically occurred in parallel with lipid accumulation, which plays a critical role in the pathogenesis of NAFLD and CKD [171].
• 5)Cancers and reproduction: Obesity is one of the most important known preventable causes of cancer [172]. About 10 % of all cancer deaths among non-smokers are related to obesity including renal cancer. Obesity has been associated with an increased risk of kidney malignancy. Several studies have concluded the increment of risk associated with obesity and it has been estimated that 20 % of renal cancer patients were obese [173].

In addition, both Obesity and CKD can cause disruption of the hypothalamic-pituitary-ovarian axis resulting in an abnormal reproductive hormone profile, where the degree of disruption increases with CKD progression [173].

The impact of weight loss interventions in modulating obesity and CKD cardiometabolic comorbidities and complications

Dietary changes with calorie restriction have long been the cornerstone for weight loss interventions, but use of dietary changes alone typically only results in modest weight loss and is frequently associated with weight regain [175], [176], [177], [178], [179]. There are few studies of the effect of calorie restriction on improvements in kidney function and proteinuria with mixed results. One study by Praga, et al. achieved an 86 % reduction in proteinuria via a 12 % reduction in BMI using a low-calorie diet, which was similar to the reduction in proteinuria seen in the control group who was treated with captopril [180]. A meta-analysis by Navaneethan, et al. showed that caloric restricted diets were associated with a BMI reduction of 3.67 kg/m² as well as a reduction in proteinuria [181]. However, no difference has been seen in glomerular filtration rate, creatinine clearance, or rate in progression of CKD across multiple studies [51], [180], [181], [182], [183].

Dietary interventions that achieve short-term weight loss consistently show improvement in multiple cardiometabolic comorbidities and complications. In the Diabetes Prevention Program, achieving a weight loss of about 7 % resulted in about 55 % lower risk of developing type 2 diabetes mellitus after 3 years [184]. The data on weight loss through dietary interventions appears mixed, with some studies showing weight loss reduces both systolic and diastolic blood pressures independently and other studies showing that the blood pressure reduction is only associated with dietary sodium restriction [185], [186], [187], [188], [189], [190]. There does not appear to be any studies showing weight loss intervention through caloric restriction and reduction in risk of atherosclerotic cardiovascular diseases [191], [192], [193]. However, a post-hoc analysis of the Look Ahead trial showed a reduction in risk of coronary artery disease events of about 20 % in the population of participants who achieved at least a 10 % weight loss during the trial [194]. However, this was in a trial of participants with type 2 diabetes mellitus and only a small percentage of patients with CKD [194]. In addition, there are a few studies that suggest that cardiometabolic parameters worsen as weight is regained (which is common with dietary interventions alone), including insulin sensitivity and blood pressure [177], [180], [182], [195], [196].

The current recommendation is to start medication to assist with weight loss in people with a BMI greater than 30 kg/m², or a BMI greater than 27 kg/m² with associated comorbidities related to obesity [197], [198]. There are multiple different classes of medications that are FDA-approved to be used for long-term medical management of obesity, including orlistat, naltrexone-bupropion, phentermine-topiramate, and incretin mimetics. The trials for orlistat, naltrexone-bupropion, and phentermine-topiramate concluded that these medications did not significantly increase cardiovascular events, but none of these studies showed reduction in event rates [199], [200], [201]. These medications are associated with modest weight loss benefit of about 3–8 % [202], [203], [204], [205], [206], [207], [208]. Orlistat and phentermine-topiramate were consistently associated with reduction in systolic blood pressure without change in diastolic blood pressure as well as reduce the risk of developing type 2 diabetes mellitus [200], [202], [203], [204], [205], [208], [209], [210]. Only orlistat was consistently shown to reduce total and LDL cholesterol levels and improve metabolic-associated fatty liver disease, with limited data for naltrexone-bupropion [200], [202], [203], [204], [205], [208], [209], [210]. In addition, orlistat was able to achieve these cardiometabolic benefits independent of weight loss [205], [210]. However, there is not enough data published to determine the effect of these medications on progression of CKD and proteinuria in participants without type 2 diabetes mellitus [51], [183].

There are currently three FDA-approved incretin mimetics for treatment of obesity: liraglutide, semaglutide, and tirzepatide. These medications are helpful in achieving and maintaining significant weight loss while being taken, especially semaglutide and tirzepatide, which helped at least 70 % of participants achieve at least 10 % weight loss from baseline during the trial periods [211], [212], [213], [214]. Each of these medications is consistently associated with reduction in systolic blood pressure, total cholesterol, LDL cholesterol, and impaired glucose tolerance [209], [211], [212], [213]. Recent studies with semaglutide showed about a 20 % reduction in composite MACE endpoint over placebo, which appears to have mainly be driven by reductions in nonfatal myocardial infarction [214]. The findings of the study also showed about a 20 % reduction in the composite nephropathy endpoint, which included death from renal causes, initiation of renal replacement therapy, or onset of persistent macroalbuminuria, but only about 20 % of the participants had an eGFR below 60 mL/min/1.73 m² [214], [215]. Unfortunately, most of the studies of incretin mimetic therapy as regards improved renal outcomes in a CKD population have so far been exclusively in participants with type 2 diabetes [216], [217], [218]. In addition, discontinuation of these medications results in mostly complete reversal of both the weight loss and the prior noted improvements in cardiometabolic parameters [219].

The current recommendation to qualify for bariatric surgery is a BMI greater than 40 kg/m², or a BMI greater than 35 kg/m² with at least one associated comorbidity related to obesity [197], [220]. A meta-analysis by Navaneethan, et al. showed that bariatric surgery was associated with a BMI reduction of 16.53 kg/m² and showed a significant improvement in glomerular filtration rate with the majority of patients included achieving normalization of their glomerular filtration rate [181]. However, there was heterogeneity between the studies due to different types of bariatric surgery approaches being studied, but the findings for kidney function were consistent across all studies included [181]. Multiple more recent studies continue to show the benefit of bariatric surgery at improving proteinuria, improving glomerular filtration rate, and slowing the progression of CKD by about 40 % [183], [221], [222], [223], [224], [225].

Bariatric surgery consistently shows significant improvements in multiple cardiometabolic complications and comorbidities, including hypertension, hyperlipidemia, ASCVD, and impaired glucose tolerance [181], [183], [221], [226]. Multiple studies have shown significant reduction in systolic blood pressures, with the meta-analysis by Navaneethan, et al. showing an average reduction of about 22 mmHg [181], [226]. Multiple studies have shown significant reduction in cardiovascular events in patients undergoing bariatric surgery, compared to those who were receiving medical therapy for weight loss [227], [228], [229], [230], [231]. In addition, the Swedish Obese Subjects study showed a reduction in all-cause mortality by about 29 % [232]. These benefits are potentially due to rapid changes in weight loss which promotes significant improvement in inflammation, insulin sensitivity, gut microbiome, and activation of renin-angiotensin-aldosterone system [233], [234], [235], [236], [237].

Weight loss thus appears to consistently improve kidney function and reduce proteinuria in direct proportion to the amount of weight loss achieved [181], [183], [214], [215], [221], [222], [223], [224], [225]. However, the improvement in other cardiometabolic diseases associated with CKD and obesity appear to be only with the use of certain weight loss medications and bariatric surgery, which may be due to higher likelihood of achieving and maintaining significant weight loss [230]. However, there are no prospective randomized studies that specifically look at the effects of weight loss on cardiometabolic comorbidities in an obese population with chronic kidney disease (that is specifically for an ORCKD population). Most of the studies included obese patients with chronic kidney disease, but these patients made up a very small portion of the overall population, so it makes it difficult to be able to make definitive inferences about the interaction and to enable firm evidence based clinical practice recommendations in this regard [183].

Strategies for CKD modulation in patients with ORCKD

Beyond the propensity of data described above that suggest the utility of interventions geared at significant weight loss in positively modulating kidney function and its cardiometabolic consequences in patients with ORCKD, other medical and surgical interventions already established for management of CKD are equally applicable to patients with ORCKD [19], [32], [39], [182], [183], [238], [239], [240], [241], [242], [243], [244], [245], [246], [247], [248], [249].

Among the well established strategies in this regard are use of RAAKS inhibitor medications including ACE inhibitors, Angiotensin receptor blockers (ARBs), direct renin inhibitors and potentially Kallikrein inhibitors [32], [67], [250], [251], [252].

It is evident that early recognition and detection of ORCKD using various biomarkers by enabling early multi-pronged interventions offers the best prognosis for prevention of CKD progression and the potential for CKD reversal [14], [22], [34], [35], [72], [76], [79], [95], [96], [101], [117], [120], [122], [253], [254], [255], [256], [257].

There is some available data mostly from post hoc data analyses suggesting the potential utility of PPAR alpha agonists (particularly fenofibrate) in positively modulating ORCKD. The suggested putative mechanism for this effect is the ability of PPAR alpha agonists to inhibit lipolysis and beta oxidation with the potential of thus positively impacting renal lipotoxicity [258], [259], [260], [261].

There is also some evidence that suggests mineralocorticoid receptor blockers like spironolactone, eplerenone and in particular the non steroidal mineralocorticoid receptor antagonist (MRA) finerenone can also have positive modulating capacity in ORCKD management especially among patients with secondary ORCKD in the setting of coexisting diabetes mellitus [262], [263], [264].

In addition, a growing body of evidence suggests that vasopressin receptor antagonists (aka aquaretics) especially tolvaptan which is already FDA approved for modulating CKD due to autosomal dominant polycystic kidney disease (ADPKD) may also have utility in management of ORCKD [265], [266], [267], [268], [269].

The rapidly expanding body of evidence for the utility of SGLT-2 inhibitor’s positive impact in modulating CKD beyond their antidiabetic utility and the fact that these effects have been consistently demonstrated in both diabetic and non-diabetic patient populations now make them another important tool in the armamentarium of ORCKD management [39], [69], [270], [271], [272]. Beyond their glycosuric capacity, SGLT-2 inhibitors have been shown to inhibit the expression of Hypoxia inducible factor alpha (HIF-1 alpha) in both murine and human kidney tissue samples. This is of significance as HIF-1 alpha is established as the metabolic switch responsible for transition from lipid beta oxidation to glycolysis thus reducing intra-renal lipid accumulation [273], [274], [275], [276]. Furthermore, SGLT-2 inhibitors are known to reduce systemic and local tissue insulin to glucagon ratios resulting in a consequent renal tissue metabolic flux towards lipolysis as opposed to lipogenesis and of glycolysis as opposed to gluconeogenesis with the consequent reduction in renal tissue lipid and glucose accumulation as well as potentially of associated renal lipo and glucotoxicity [277], [278], [279], [280].

Among the growing list of potential therapeutic options and targets suggested for positive modulation and management of ORCKD are CD-36 inhibitors. Though human studies are still pending, the observation that CD −36 is involved in renal cholesterol and lipoprotein uptake into the renal parenchyma suggests that its modulation may have therapeutic utility [281], [282]. This is further bolstered by the finding of CD-36 inhibitors in mice having positive effects on the development of renal inflammation and fibrosis [281], [282].

The potential utility of statins for the specific management of ORCKD is still somewhat controversial as the body of evidence available has yielded somewhat conflicting and non-definitive results to firmly establish independent protective effects [283], [284], [285]. This however doesn’t in anyway preclude their use in patients with ORCKD and dyslipidemia and/or ASCVD for which they would be otherwise indicated [283], [284], [285].

As has been the case with SGLT-2 inhibitors, GLP-1 agonists have been shown with a broad range of studies to have positive effects in CKD as a whole as well as ORCKD in particular that extend beyond their effects as antidiabetic medications. While some of these effects are clearly related to the significant weight loss they induce in patients, there is also accumulating evidence suggesting that this is also related to other pleotropic effects including redistribution of renal adipose tissue, reduced renal triglyceride, free fatty acid and cholesterol accumulation with consequent reduction in renal fat infiltration, and improved mitochondrial function via modulation of the Sirt1/AMPK/PGC1 alpha cascade pathway [286], [287], [288], [289], [290], [291], [292], [293], [294]. Their capacity to improve insulin sensitivity both systemically and intrinsic to the kidney also likely plays a role in this observed reno-protective effect.

Based on the known pathophysiology and pathobiology of ORCKD the potential utility of insulin sensitizers to counteract the associated insulin resistance in ORCKD as well as anti-inflammatory agents to inhibit the systemic and local intra-renal inflammatory state in ORCKD may have utility but it is difficult to distinguish these effects independent of the various weight reduction strategies known to positively impact these pathogenic mechanisms.

The potential role of gut microbiota modulation as a strategy for positively impacting ORCKD is still preliminary but a recent meta-analysis suggests that it may have a unique niche especially in non diabetic ORCKD patients as well as ORCKD patients with ESRD on dialysis [295], [296].

Another area of clinical investigation with potential clinical utility for ORCKD management that has recently emerged is melatonin supplementation and melatonin receptor modulation. While the majority of the available data on this at the moment is animal derived it does raise appealing prospects because of the relative ease and safety of its modulation and the suggested multifaceted effects it seems to have on improving ORCKD including inhibition of the NF-kappa B pathway (with consequent reduction of expression of inflammatory cytokines like IL-1β, IL-6 and TNF-α), downregulation of the RAAKS cascade and reduction of reactive oxygen species (ROS) expression resulting in reduction of systemic and local renal oxidative stress as well as reduced expression of the fibrogenic fibronectin (Transforming growth factor beta −1; TGF-β1) [297], [298], [299], [300], [301], [302], [303]. Melatonin has pleotropic effects including circadian modulating effects, anti-inflammatory, anti-apoptotic and myriad lipid and adipocyte modulating effects including enhancing brown adipocyte tissue growth and beigeing of white adipose tissue. Via its effects of adipocyte distribution and typing it can influence energy expenditure and has been shown in murine models as well as obese diabetic and Zucker diabetic rats to increase expression of glutathione peroxidase, super oxide dismutase (SOD) and catalase (all of which have anti-oxidant effects) [297], [298], [299], [300], [301], [302], [303], [304], [305], [306], [307].

Among the other numerous potential target pathways and systems involved in renal adiposogenesis, lipid metabolism, lipid accumulation, disposition and signal transduction that offer other potential therapeutic options for ORCKD management are farnesoid X receptor (FXR) activators, anti-oxidants, endothelin receptor blockade, vitamin D receptor modulators such as doxecalciferol, M−Tor inhibitors and Sterol regulatory element binding protein 1 (SREBP-1) modulators [88], [250], [308], [309], [310], [311], [312], [313], [314], [315]. These various targets which are the subject of various ongoing in vitro and in vivo studies and trials offer considerable promise to improving the prognosis and clinical course of ORCKD and its complications in the near future. Table 2 provides a global summary of the established and putative management strategies for management of ORCKD in clinical practice.

Table 2.

Established and future Management strategies for ORCKD.

	Antilpidemics; Triglyceride lowering medications	Particularly in ORCKD patients with known persistent hypertriglyceridemia and/or confirmed renal steatosis on imaging/renal biopsy; Fibrates, niacin, fish oil analogs and derivatives, icosapent ethyl etc
	Uric acid modulators; Xanthine oxidase inhibitors and uricosurics	Particularly in ORCKD patients with known nephrolithiasis, nephrocalcinois, known hyperuricemia and/or hyperuricosuria; Allopurinol, febuxostat, probenecid etc.
Putative and Experimental adjuncts
	Anti-inflammatory agents	Limited human clinical data; No FDA approved options;?? Colchine utility based on small case series
	Endothelin Receptor blockers	Clinical trials; No clinically available nor FDA approved options
	CD-36 inhibitors	Pre-Clinical and animal model trials
	Vasopressin Receptor antagonists (V1a, V1b and V2 receptor blockers)	May have potential utility in ORCKD patients with associated polycystic kidney disease and particularly in ADPKD patients with superimposed ORCKD; tolvaptan, satavaptan, lixivaptan and conivaptan
	Fecal microbiota modulation	Limited clinical data and no clinical practice guidelines; use of pre-pro and post biotic supplements, potential of fecal transplantation in select patients. Clinical trial stage.
	Melatonin supplementation and Melatonin receptor modulation	Limited human clinical data and no clinical practice guideline. Not FDA approved?? utility of low to mid dose melatonin replacement therapy. Early clinical trial stage.
	FXR receptor activation	Preclinical trial stage; experimental
	Anti-oxidants	Limited clinical data. No clinical practice guidelines and no FDA approved options.
	SREBP-1 modulators	Preclinical trial stage; experimental
	M−Tor inhibitors	Preclinical trial stage; experimental
	Aldosterone Synthase inhibitors	Limited available human clinical data. No FDA approved options; early stages of clinical development. May have particular utility in ORCKD patients with coexisting primary aldosteronism. Osilodrostat, Baxdrostat, Lorundrostat etc.
	Vitamin D receptor agonists and modulators	Limited available clinical trial data. In early stages of clinical development. May unique niche of utility in ORCKD patients with coexisting secondary or tertiary hyperparathyroidism. Calcitriol, paricalcitol, doxercalciferol, alfacalcidol etc.
Patients with ORCKD and ESRD	Renal Replacement therapy	Hemo and/or peritoneal dialysis with the unique difficulties and challenges of the obese ORCKD patient. Renal transplant.

Concluding remarks

The ongoing epidemics of obesity and CKD has resulted in the increased prevalence of ORCKD which is a multifactorial disease entity associated with multiple comorbidities and complications. The cardiometabolic complications of ORCKD in particular, have considerable morbidity and mortality consequence with implications for both individual patient and public health care.

The growing range and effectiveness of medical and other management options for obesity add an important therapeutic option to the management strategies for effective ORCKD management. Prevention of obesity, early recognition of ORCKD before it can progress to ESRD and aggressive multi-pronged clinical interventions can ameliorate the clinical course and prognosis of this increasingly prevalent cause of CKD. Ongoing studies offer the promise for greater range of therapeutic options with greater treatment efficacy both for obesity and for renal functional preservation in patients with ORCKD.

CRediT authorship contribution statement

Mariam M. Ali: Writing – review & editing, Writing – original draft. Sanober Parveen: Writing – review & editing, Writing – original draft. Vanessa Williams: Writing – review & editing, Writing – original draft. Robert Dons: Writing – original draft, Visualization, Conceptualization. Gabriel I. Uwaifo: Writing – review & editing, Writing – original draft, Visualization, Supervision, Investigation, Conceptualization.

Declaration of competing interest

The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: There are no relevant relationships to declare. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.