Obesity and Its Impact on Kidney Stone Formation

Disease State Review

Disease State Review Obesity and Its Impact on Kidney Stone Formation William Poore, BS,1 Carter J. Boyd, BS,1 Nikhi P. Singh, BS,2 Kyle Wood, MD,2 Barbara Gower, PhD,3 Dean G. Assimos, MD2 1University of Alabama-Birmingham School of Medicine, Birmingham, AL;1Department of Urology, University of Alabama-Birmingham, Birmingham, AL; 3Department of Nutrition, University of Alabama-Birmingham, Birmingham, AL The prevalence of obesity is rising and places this cohort at risk for developing kidney stones. Some of the pathophysiologic responses that link obesity and kidney stone formation have been identified. Herein, we review the involved mechanisms driving this relationship and the impact of various weight loss strategies on kidney stone risk. [Rev Urol. 2020;22(1):17–23] © 2020 MedReviews®, LLC KEY WORDS Kidney stones • Hypertension • Obesity • Diabetes • Metabolic syndrome • Weight management • Obese animal models O besity is a disease with far-reaching effects, and many people across the United States and around the world are impacted. Although the World Health Organization (WHO) defines obesity as an abnormal fat accumulation, it is commonly defined by body mass index (BMI).1 BMI (weight in kilograms divided by height in meters squared) provides a definition based on habitus. In adults, a BMI of 25.0 kg/m2 to 29.9 kg/m2 is defined as overweight and a BMI of 30 kg/m2 is the threshold for obesity.2 In Asians, lower thresholds are proposed to define obesity due to the higher percentage of body fat and elevated prevalence of cardiovascular disease (CVD) even at lower BMI (,25 kg/m2) in this cohort. Thus, BMI serves as a suggestive surrogate for obesity and exact definitions may be nuanced by race or other factors.1 Waist has been used to estimate visceral obesity, but BMI is the preferred metric used for classification.3 Between 1980 and 2013, the prevalence of overweight or obese individuals increased 27.5% for adults and 47.1% for children worldwide. In 2013, the prevalence of overweight and obese individuals was higher in developed countries than in developing countries at all ages. Obesity rates were 12.4% for boys younger than 20 years, 31.7% for men age 20 years or older, 13.4% for girls younger than 20 years, and 33.9% for women age 20 years or older in the United States.2 Visscher and colleagues report that in the United States the prevalence rates for overweight individuals are over 50%, a rate also now observed in several other countries.4 Vol. 22 No. 1 • 2020 • Reviews in Urology • 17 4170020_05_RIU0846_V1_rev03.indd 17 5/12/20 9:27 PM Obesity and Its Impact on Kidney Stone Formation continued Compared with non-obese adults, adults with a BMI of 40 kg/m2 or higher had an increased risk of diabetes, hypertension, and hyperlipidemia. These co-morbidities have been shown to have some association with kidney stone formation and can elicit specific changes not only in systemic effects of the body but also particular body organs, ultimately contributing to kidney stone formation. The precipitants of obesity are complex and can be attributed to a variety of factors, including primary causes such as genetic disposition and a myriad of secondary causes including dietary indiscretions, lack of physical activity, and utilization of certain pharmacologic agents.2 Obesity is linked to multiple co-morbidities associated with an increased kidney stone risk. Compared with non-obese adults, adults with a BMI of 40 kg/m2 or higher had an increased risk of diabetes, hypertension, and hyperlipidemia.2 These co-morbidities have been shown to have some association with kidney stone formation and can elicit specific changes not only in systemic effects of the body but also particular body organs, ultimately contributing to kidney stone formation.3 Obesity and Kidney Stone Formation Taylor and colleagues have shown that BMI, waist circumference, and weight are positively associated with the risk of developing incident kidney stones.5 Inci and associates found that BMI was significantly higher in stone formers and may be associated with different types of urinary stone formation.6 In a study of 84,225 postmenopausal women, multivariate analyses showed an elevated BMI is associated with a 1.30-fold increased risk of incident kidney stones compared with women with a BMI in the normal range.7 In a study of 1021 patients, 140 of which were obese with BMIs ranging from 30 to 64, Ekeruo and associates found that obesity appears to be associated with metabolic changes in patients with nephrolithiasis. They reported that gouty diathesis, hypocitraturia, hyperoxaluria, hypercalciuria, and hyperuricosuria were most prevalent in obese stone formers.8 In a retrospective review of 1698 stone-forming patients by Trinchieri and colleagues, it was found that in overweight and obese patients urinary risk factors for stone formation such as calcium, oxalate, and urate excretions were much higher than in non-obese patients. However, they noted that citrate excretion was higher in this cohort.9 In a study by Eisner and associates, increasing BMI was related to several risk factors for urinary stone disease including an increase in urine sodium and decrease in pH in men and increasing urine uric acid and sodium and decreasing urine citrate in women.10 A highly significant, positive correlation between body weight/surface area and oxalate excretion was reported by Lemann and associates.11 In a study analyzing data from a national database using body weight to define obesity (men .120 kg and women .100 kg), it was found that obese women had increased concentrations of sodium, uric acid, sulfate, and phosphate, relative to non-obese women.12 In obese men, there was an increase in concentration of urinary sodium, oxalate, uric acid, sulfate, and phosphate.12 Visceral obesity can be quantified with imaging and such studies have demonstrated a correlation with this and kidney stone risk.13-16 Visceral obesity as defined with imaging may be more predictive of kidney stone risk than BMI. Kim and associates reported that there was a positive correlation with the risk of developing uric acid stones and or calcium oxalate stones, but not for BMI.17 Comorbidities commonly seen in obese subjects include hypertension and diabetes. Bidirectional associations have been demonstrated between hypertension and diabetes and the development of kidney stones.18-28 Metabolic syndrome is a constellation of systemic disorders that is associated with cardiovascular risk. 3 The components include hypertension, obesity, insulin resistance, and high lowdensity lipoprotein cholesterol (LDL-C) and low high-density lipoprotein cholesterol (HDLC) levels. An individual who has three or more of these entities is considered to have metabolic syndrome (MetS). MetS has been associated with the development of kidney stones.3,29 In a cross-sectional analysis using MetS as defined by the American Heart Association and National Heart, Lung, and Blood Institute statement, selfreported history of kidney stones in patients with three MetS traits increased by 4.5% when compared with those with no traits.30 This association has also been linked to kidney stones identified by ultrasonography in a screening study. In a longitudinal study of 2132 patients in Southern Italy, Rendina and associates noted that 50.9% of patients with ultrasonographic evidence of nephrolithiasis met the requirements for MetS. Obesity and hypertension were 18 • Vol. 22 No. 1 • 2020 • Reviews in Urology 4170020_05_RIU0846_V1_rev03.indd 18 5/12/20 9:27 PM Obesity and Its Impact on Kidney Stone Formation most frequently associated with presence of stones in this study, 50.9% and 63.2%, respectively.31 Kidney Stones Composition and Prevalence Obese patients develop more calcium oxalate stones than uric acid stones.8 Trinchieri and associates have also demonstrated that patients with uric acid stones have higher rates of obesity than patients with other types of stones.9 In addition, Li and associates found that the uric acid stone formers were, in general, more obese than other stone formers, with 53.1% of the uric acid stone formers and with 42.7 % of calcium oxalate stone formers being obese.32 Similar relationships have been reported by others.33 The formation of uric acid stones is associated with a low urinary pH, low urinary volume, and hyperuricosuria.34 Low urine pH has a larger impact on stone formation than urate excretion.34 Low urinary pH is thought to be due to a defect in the generation of ammonia excretion in the nephron that would normally buffer the H+ in the urine by creating ammonium.33,36 It has been suggested that insulin resistance may impair the transport of ammonia into the proximal tubular lumen as a consequence of attenuation of the Na1/H1 exchanger (NHE3). A defect in mitochondrial metabolism of glutamine to glutamate and subsequent conversion to alpha-ketoglutarate that generates ammonia in the proximal tubule cells may be contributory. This could have a dual effect, causing an increase in uric acid via recycling extra glutamine into the production of purines.37,38 Decreased urine volume can result in an increased concentration of substances that predispose patients to uric acid kidney stone formation. High urinary concentrations of solutes, such as urate, can result in uric acid precipitation. This is supported by the observed trend that uric acid stones are more prevalent in hotter and more tropical environments where there may not be access to clean water, resulting in dehydration from diarrhea. In these climates, loss of fluid from the skin due to heat can ultimately result in low urine volumes as well.34,39,40 Although hyperuricosuria is not a primary factor in the development of kidney stones, it has been shown that patients with hyperuricosuria but normal pH also tend to develop mixed stones of calcium oxalate and urate.34 There is ample evidence that obesity is associated with low urine pH. In a study of 4883 patients, Maalouf and associates reported that urine pH was inversely associated with body weight even when adjusting for age and markers of dietary indiscretion.41 A large epidemiologic cohort study demonstrated an inverse relationship between BMI and urine pH while also observing a positive correlation with supersaturation of uric acid and BMI.42 Pigna and associates reported that both body fat content and truncal fat distribution, as measured with dual-energy x-ray absorptiometry (DEXA), were negatively correlated with urine pH.43 Furthermore, it was also found that greater truncal fat was associated with blunted ammonium excretion.43 In general, as BMI increases so does visceral obesity and hepatic steatosis, which have both been shown to be associated with lower urinary pH.44 A similar trend corroborating the inverse relationship between urine pH and BMI was reported by Ekeruo and associates.8 Uric acid is the metabolic end product of purine compounds that are derived from the diet or endogenous sources such as cellular breakdown.45,46 Hyperuricosuria is primarily thought to be a result of nutritional indiscretion, with mutations in the URAT1 channel in congenital renal hypouricemia hyperuricosuria being another less common cause.35,47,48 The dietary habits of patients that consume high amounts of meat (commonly seen in obesity) put them at increased risk of developing uric acid stones as a consequence of an increased purine load as well as acid-ash substances of animal protein, the latter promoting a reduction in urine pH.48 In a study of two large epidemiological cohorts, Curhan and associates found that as BMI increased there was also a slight increase in age-adjusted mean daily intake of total fluid.49 Powell and colleagues also observed an increase in urine volumes but higher urine osmolality in obese stone patients as compared with a non-obese cohort.12 However, although fluid intake may be higher, urine volume may not correspondingly increase due to increased insensible losses. In a study analyzing fluid intake and hydration status as assessed by free water reserve, Maffeis and associates found that obese children were less hydrated.50 In another study using the National Health and Nutrition Examination Survey (NHANES), a multivariate analysis demonstrated a negative correlation between inadequate hydration as assessed by urine osmolity and BMI.51 A risk factor for the most common type of stone, calcium oxalate, is increased urinary oxalate excretion.45 Increased oxalate excretion may be a risk factor for the development of calcium oxalate stones in the obese cohort.52 A positive correlation between urinary oxalate excretion and body weight and body surface area was reported Vol. 22 No. 1 • 2020 • Reviews in Urology • 19 4170020_05_RIU0846_V1_rev03.indd 19 5/12/20 9:27 PM Obesity and Its Impact on Kidney Stone Formation continued by Lemann and associates. These investigators hypothesized that this is due to increased endogenous oxalate synthesis.11 Animal and Human Studies on the Pathophysiology of Stone Formation Inflammation and oxidative stress, both known to be associated with obesity, have also been reported to play a role in kidney stone inflammation. A number of animal studies have been undertaken to investigate these relationships.53 In a study of Ob/Ob (Ob) mice with leptin gene deficiencies and MetS-related characteristics, it was observed that Ob mice fed a high-fat diet plus 1% ethylene glycol (an oxalate precursor) had markedly increased expression of osteopontin, monocyte chemoattractant protein-1, interleukin-6, and tumor necrosis factor-α. These Ob mice had a considerably elevated number of proinflammatory macrophages. In these mice the increases in luminal mineral and lipid density and proinflammatory adipocytokines and macrophages facilitated renal crystal formation.54 Fatty tissue, which is abundant in obesity, is an endocrine organ that is a source of adipokines and inflammatory cytokines that contribute to the insulin resistant, proinflammatory, prothrombic, and a prohypertensive state.55 Amir and associates have shown that obese Ob mice have significantly higher urinary oxalate excretion (3.3fold) when compared with control mice.56 They proposed that an increase in inflammatory cytokines in obese mice reduced the secretion of oxalate in the intestine, resulting in increased net gastrointestinal oxalate absorption and augmented urinary oxalate excretion ultimately leading to stone formation.56 Enhanced systemic inflammation and increased inflammatory cytokines in the small intestine have been reported in murine models of obesity which might augment oxalate absorption.53 The factors that modulate intestinal oxalate secretion have not been defined. Recent studies in mice and rats have shown that the presence of Oxalobacter formigenes or its lysate within the gastrointestinal tract can promote oxalate secretion.57 Exposure to high concentrations of oxalate as well as calcium oxalate and calcium phosphate crystals for extended periods of time can cause injury to renal epithelial cells.58 Crystals bind rapidly to the surface of epithelial cells and are internalized.58 Lower levels of oxalate promote cell growth whereas higher oxalate levels induce cell damage and death.58 In rat and mouse models, calcium oxalate nephrolithiasis is produced by inducing hyperoxaluria via administration of oxalate or its precursors.58 This results in calcium oxalate crystal deposition causing inflammation and attracting many inflammatory cells including leukocytes, monocytes, macrophages, and multinucleated giant cells. This induces further crystal deposition via production of reactive oxygen species.58 Calcification and plaque formation in the body is triggered by reactive oxygen species and the development of oxidative stress.58 The mechanism whereby inflammatory cells enter the renal interstitium is not known but it is apparent that chemotactic factors and adhesion molecules are involved.58 These chemotactic factors made by renal cells can be found in the kidney and urine during inflammation, possibly explaining the increased incidence of kidney stones in obese patients who are chronically in an inflammatory state and are thus producing increased levels of reactive oxygen species. Fatty acid overload may result in the accumulation of triglycerides in non-adipose tissue, including the kidney. The latter could promote a reduction in urine pH. Bobulescu and colleagues analyzing triglyceride accumulation in the kidneys of Zucker diabetic fatty rats (ZDF; an established animal model of metabolic syndrome and multiple organ lipotoxicity) observed an increase in the renal triglyceride content, decreased urinary ammonium and pH, and lower levels of brush border membrane Na1/H1 exchanger-3 (NHE3), which is a mediator of ammonium excretion. They also noted a transient decrease in urinary ammonium and pH in Sprague-Dawley rats undergoing high-fat feeding. In these SpragueDawley rats the levels returned to normal upon being fed a regular diet. Using opossum kidney cells exposed to long-chain fatty acids to pinpoint the direct effect of lipid accumulation, they noted dosedependent decreases in NHE3 activity, surface biotin-accessible NHE3 protein, and ammonium excretion. This implies that renal lipid accumulation decreases the excretion of ammonium in the proximal tubule which, as mentioned above, is an important urinary buffer and is partially reliant on NHE3 activity and its regulation by NHE3 agonists.59 In the case of renal lipid accumulation, the subsequent decrease in pH due to defective ammonium secretion may be associated with an increased risk for uric acid stone formation. In human studies, a positive correlation between BMI and renal cortex triglyceride levels as well as lipid accumulation has been shown. Bobulescu and 20 • Vol. 22 No. 1 • 2020 • Reviews in Urology 4170020_05_RIU0846_V1_rev03.indd 20 5/12/20 9:27 PM Obesity and Its Impact on Kidney Stone Formation associates analyzed kidney cortex samples from 54 patients undergoing radical nephrectomy and found that triglyceride content in the kidneys positively correlated with BMI. Lipid accumulation was most prominent in renal proximal tubular cells.60 Response of Obese Patients to Medical Therapy for Stone Prevention Obese stone patients may be more resistant to standard medication dosing regimens for kidney stone prevention. Astroza and associ- for uric acid stones. Thus, more frequent adjustments in dosage or the addition of other agents may be necessary in this cohort.61 Weight Management and Treatment Obese patients may derive benefits from weight reduction. However, several approaches used to promote weight loss may increase kidney stone risk, including orlistat, a lipase inhibitor used for weight loss.62-65 This results in accumulation of fat in the intestine that binds calcium by saponification that may augment intestinal oxalate absorp- Obese stone patients may be more resistant to standard medication dosing regimens for kidney stone prevention. Astroza and associates reported that there was a lower incremental increase in urine pH and urinary citrate excretion in individuals with higher BMI receiving a similar dose of potassium citrate for management of hypocitraturia and urinary pH manipulation therapy for uric acid stones. Thus, more frequent adjustments in dosage or the addition of other agents may be necessary in this cohort. ates reported that there was a lower incremental increase in urine pH and urinary citrate excretion in individuals with higher BMI receiving a similar dose of potassium citrate for management of hypocitraturia and urinary pH manipulation therapy tion, resulting in increased urinary oxalate excretion, the latter increasing stone risk.62-67 Another drug, phentermine-topiramate, has been approved by the US Food and Drug Administration (FDA) for weight loss. Topiramate is a carbonic anhydrase inhibitor that promotes a reduction in urinary citrate excretion and increased urine pH, a favorable milieu for the generation of calcium phosphate stones.68-70 In a retrospective study, Maalouf and associates reported that the prevalence of symptomatic kidney stone formation among long-term topiramate users is 10.7% and many others having asymptomatic kidney calculi.70 There is an increasing number of morbidly obese patients that are having bariatric surgery.71 Malabsorptive bariatric procedures (Roux-en-Y gastric bypass, duodenal switch) have been reported to increase the risk of developing kidney stones whereas restrictive bariatric operations have not.57,72 Kidney stones typically develop 2 years after malabsorptive procedures and this has been attributed to increased urinary oxalate excretion.57,72 These patients have been demonstrated to have increased gastrointestinal oxalate absorption associated with fat malabsorption, the latter increasing urinary oxalate excretion.57,73,74 This patient cohort is also at risk of developing oxalate nephropathy.57,73 Other urinary stone risk parameters have been reported in this patient group Main Points • Large numbers of people are obese and thus more at risk for developing kidney stones. • Because obesity is associated with numerous co-morbidities, it is somewhat difficult to attribute its total impact on stone risk. However, there have been studies indicating an independent association between visceral obesity and kidney stone formation. • Calcium oxalate and uric acid stones are the most common stone found in obese patients, with calcium oxalate stones still being the most prevalent in obese and non-obese populations. The increased levels of uric acid stones, however, are enriched amongst obese stone formers. • The inflammation and oxidative stress that are known to be associated with obesity may play a role in stone risk. • One must also be aware that certain approaches to weight reduction may promote kidney stone formation. Vol. 22 No. 1 • 2020 • Reviews in Urology • 21 4170020_05_RIU0846_V1_rev03.indd 21 5/12/20 9:27 PM Obesity and Its Impact on Kidney Stone Formation continued including hypocitraturia, reduced volume, and heightened supersaturation of calcium oxalate.57,73 Conclusions Large numbers of people are obese and thus more at risk for developing kidney stones. Because obesity is associated with numerous comorbidities, it is somewhat difficult to attribute its total impact on stone risk. However, there have been studies indicating an independent association between visceral obesity and kidney stone formation. Calcium oxalate and uric acid stones are the most common stone found in obese patients, with calcium oxalate stones still being the most prevalent in obese and non-obese populations. The increased levels of uric acid stones, however, are enriched amongst obese stone formers. The low urine pH associated with obesity is the major driver in this relationship. The inflammation and oxidative stress that are known to be associated with obesity may play a part in stone risk. However, further studies are needed to better define the actual mechanisms involved. One must also be aware that certain approaches to weight reduction may promote kidney stone formation. 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