Scandinavian Journal of Urology. 2014; 48: 414–419
REVIEW ARTICLE
Metabolic syndrome: A multifaceted risk factor for kidney stones
Scandinavian Journal of Urology Downloaded from informahealthcare.com by University of Victoria on 04/09/15 For personal use only.
FERNANDO DOMINGOS1,2 & ADELAIDE SERRA2,3 1 3
Institute of Physiology, Faculty of Medicine, University of Lisbon, Lisbon, Portugal, 2Nephrology Service, and Outpatient Kidney Stone Clinic, Hospital Fernando Fonseca, Amadora, Portugal
Abstract Kidney stones and metabolic syndrome (MetS) are common conditions in industrialized countries. There is growing evidence of associations between kidney stone disease and MetS or some of its components. The link between uric acid stones and MetS is well understood, but the link with calcium oxalate (CaOx) stones, the most common kidney stone composition, is more complex, and MetS is frequently overlooked as a risk factor for calcium nephrolithiasis. The physiopathological mechanisms of kidney stone disease in MetS are reviewed in this article. Uric acid stones are a consequence of the excessively acidic urine that results from insulin resistance. The pathophysiology of CaOx stones may include: increased excretion of lithogenesis promoters and decreased excretion of inhibitors; increased risk of Randall’s plaque development; and inflammatory damage to renal epithelia by oxidative stress, as a consequence of the insulin-resistant milieu that characterizes MetS. The last mechanism contributes to the adhesion of CaOx crystals to subepithelial calcium deposits working as anchor sites where stones can grow. The predominant MetS features could determine the chemical composition of the stones in each patient. Kidney stones may be a renal manifestation of MetS and features of this syndrome should be looked for in patients with idiopathic nephrolithiasis.
Key Words: hypertension, insulin resistance, metabolic syndrome, nephrolithiasis, obesity
Introduction The metabolic syndrome (MetS) is an association of several metabolic disorders including obesity, mainly abdominal obesity, fasting or postprandial hyperglycaemia, essential hypertension, high plasma triglycerides and low plasma high-density lipoprotein cholesterol [1]. These conditions are linked by a common mechanism: insulin resistance. Although there are currently several definitions of MetS, the coexistence of three or more of the above-cited features makes the diagnosis [1] and is associated with an increased risk of cardiovascular disease [2]. The prevalence of MetS varies according to age, gender, ethnicity and definition used. Worldwide, MetS affects 24–42% of the adult population [3] and up to 66.4% of the older population [4].
An association between kidney stone disease and MetS has been documented in several cross-sectional studies. The third US National Health and Nutrition Examination Survey (NHANES III) showed that the odds ratio for kidney stones increased with the number of features of MetS, being twice the normal in patients with three or more features of this syndrome [5]. Associations with kidney stones have been documented in several individual features of MetS. The Fourth Portuguese National Health Survey found significant associations between kidney stone disease and obesity, hypertension and diabetes [6]. Despite noteworthy improvements in the treatment to remove kidney stones during the past few decades, the optimization of preventive measures to reduce the risk of stone recurrence remains a significant problem [7]. The association between MetS and
Correspondence: F. Domingos, Serviço de Nefrologia, Hospital Prof. Doutor Fernando Fonseca, Estrada IC 19, 2720-276 Amadora, Portugal. E-mail: [email protected]
(Received 16 November 2013; accepted 27 February 2014) ISSN 2168-1805 print/ISSN 2168-1813 online 2014 Informa Healthcare DOI: 10.3109/21681805.2014.903513
Metabolic syndrome and kidney stones kidney stones may have clinical relevance. If the pathophysiological mechanisms underlying MetS increase the risk of stone formation, MetS should be considered as a risk factor for nephrolithiasis, and treatment of the metabolic disorders should be part of the measures taken to prevent stone recurrence.
Scandinavian Journal of Urology Downloaded from informahealthcare.com by University of Victoria on 04/09/15 For personal use only.
Physiopathology of kidney stones in metabolic syndrome The epidemiological studies showing the association between MetS and kidney stones provided little information about the pathophysiology of kidney stone formation because stone composition and known urinary risk factors were not investigated. However, there are studies documenting the association with kidney stones in some individual manifestations of MetS. The link between uric acid kidney stones and central obesity was reported more than 50 years ago [8]. Later, high body mass index (BMI) and obesity were associated with abnormalities of the urinary profile that increase the risk of kidney stone disease [9]. Insulin resistance provides a possible link between MetS and lithogenesis. Studies showed lower citrate excretion in calcium stone formers with insulin resistance assessed by homeostasis model assessment of insulin resistance (HOMA-IR) [10]. HOMA-IR was significantly higher in women with than without kidney stones and was correlated with BMI [11], reinforcing the possible role of insulin resistance in the lithogenic process. Poor glycaemic control and the need for insulin therapy increase the risk of kidney stones in patients with type 2 diabetes [12]. Uric acid stones Studies in which stone composition has been analysed show an increased prevalence of uric stones in diabetic, obese and hypertensive patients [13,14]. Patients with features of MetS usually have overly acidic urine. Undissociated uric acid (H2U) is a week acid, with two protons in positions 3 and 9; it is poorly soluble in urine and tends to precipitate in low urinary pH. The dissociation constant (pKa) of the first proton is 5.47, meaning that when urinary pH is above 5.5 uric acid loses the first proton and turns into dissociated urate (HU–), which is much more soluble in urine. The pKa of the second proton is 10.3 and has no physiological relevance to uric acid solubility in human urine. Therefore, when urine becomes excessively acidic, most uric acid will be in the undissociated form and precipitates, causing uric acid stones. Different factors may contribute to urine acidity in MetS. Using the euglycaemic clamp test, Abate et al. [15] showed that healthy volunteers respond to acute
415
insulin administration by increasing ammonium production, urinary pH and urinary citrate. Healthy individuals resistant to insulin activity had lower urinary pH, and patients with uric acid stones had lower insulin sensitivity, urinary pH and urine citrate. The pathophysiology of the acidic urine in insulin resistance is multifactorial, and includes lower ammonium (NH4+) excretion and, therefore, increased elimination of the daily acid as titratable acid. Insulin promotes ammonia (NH3) production from glutamine mainly at the proximal tubule. This is a very important mechanism to prevent decrease of urinary pH to very low levels. Insulin resistance could decrease ammonium production by competitive mechanisms, direct lipotoxicity and interference with the transport mechanisms in the tubular cell membrane [16]. Renal steatosis and accumulation of free fatty acids in the interstitium surrounding the proximal convoluted tubule promote the competition between free fatty acids and glutamine as oxidizable substrates and, therefore, decrease ammonia production from glutamine. Recent findings showed that the accumulation of intracellular non-esterified fatty acids and their toxic metabolites may have direct lipotoxic effects within the proximal tubular cells and this could also contribute to decreased ammonium production [16]. It was demonstrated in cell cultures that insulin increases the activity of the sodium/ hydrogen antiport (NHE3) [17]. In insulin resistance, dysfunction of NHE3 may contribute to lower ammonium excretion since secretion of ammonium ions (NH4+) and protons (H+) is necessary to trap the ammonia within the tubule lumen. Recurrent uric acid stone formers with manifestations of MetS had lower urinary pH than healthy individuals despite insulin sensitivity, suggesting the existence of additional mechanisms to explain the excessively acidic urine [15]. There are at least two possible explanations for this observation. First, patients with MetS may have an increased protein intake. In a cross-sectional study, Strohmaier et al. [13] reported overly acidic urine and hyperuricosuria in two-thirds of patients with idiopathic uric acid nephrolithiasis, but decreased ammonium production was found in less than 25% of them. Urinary urea, another marker of protein intake, was higher in stone formers. Secondly, patients with MetS may have an overproduction of organic acids because of increased BMI [15]. However, the latter mechanism is largely speculative. Calcium stones The prevalence of kidney stones almost doubles when four components of MetS are present [5].
416
F. Domingos & A. Serra
Metabolic syndrome
Urinary risk factors
Systemic risk factors
pH
Obesity
Inhibitors (citrate) Promoters (oxalate, uric acid, calcium)
Scandinavian Journal of Urology Downloaded from informahealthcare.com by University of Victoria on 04/09/15 For personal use only.
Inflammation
IL-6
ROS
TNF-α
C-Reactive protein
Insulin signalling
Insulin resistance
Crystallization Oxidative stress
Cell damage
Yes
Kidney stones
No
No kidney stones Figure 1. Main pathways contributing to calcium nephrolithiasis in metabolic syndrome, including urinary and systemic risk factors. ROS = reactive oxygen species; IL-6 = interleukin-6; TNF-a = tumour necrosis factor-a.
Kadlec et al. showed that the prevalence of uric acid calculi was 14.0% in obese patients with MetS and 8.9% in non-obese patients [14]. CaOx was the most frequent kidney stone composition, found in almost 70% of patients with MetS, a prevalence similar to CaOx calculi identified in the normal population with idiopathic kidney stones. Calcium phosphate stones were reported less frequently in obese patients [14]. The overall increase in nephrolithiasis associated with MetS can only be explained by an increase in CaOx stones. A higher HOMA-IR was documented in 61 idiopathic calcium stone formers [10]. As discussed above, the low urinary citrate is a consequence of low ammonium production and the low urinary pH that characterizes the insulin-resistant milieu [15]. These results suggest that many cases of apparently idiopathic CaOx nephrolithiasis may in fact be associated with an increased prevalence of manifestations of MetS. Supersaturation hypothesis. The increased risk of CaOx in MetS has been associated with increased excretion of oxalate, uric acid and calcium, and decreased citrate excretion [18]. This risk is related not to MetS as a whole, but to some of its features. High BMI increases the excretion of uric acid, oxalate and phosphate [9]. Calcium excretion was reported to be higher in obese men [9].
Other components of MetS that have been associated with CaOx stones involve hypertension. In a prospective study, the relative risk of kidney stones was raised 5.5-fold in patients with essential hypertension compared with normotensive controls, and CaOx was the most common stone composition [19]. The pathophysiology of kidney stones in hypertension is not entirely understood. Untreated hypertension was associated with hypercalciuria. Hypertensive patients presented with higher urinary calcium, oxalate and phosphate [19], and decreased urinary citrate [20]. The imbalance between promoters and inhibitors of lithogenesis in MetS promotes CaOx supersaturation and crystallization; however, there are doubts that the retention of free crystalline particles in the kidney is sufficient to cause CaOx nephrolithiasis in humans [21]. In fact, it was documented in cell cultures that normal cells of the human distal tubule and collecting duct are resistant to crystal adhesion [22]. Randall’s plaques. Studies including endoscopic examinations from kidney stone formers support the hypothesis that a large percentage of cases of human idiopathic CaOx nephrolithiasis may be associated with subepithelial calcium phosphate deposits known as Randall’s plaques. Histological studies of
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Metabolic syndrome and kidney stones the renal tissues from idiopathic calcium stone formers showed that the plaques start as small, round apatite deposits beneath the basement membrane of the thin segment of the loop of Henle. The deposits are associated with collagen and membrane-bound vesicles, and slowly grow and migrate until they reach the subepithelial surface of the renal papilla [23]. Despite the evidence linking MetS to idiopathic calcium nephrolithiasis, there are no studies documenting the presence of Randall’s plaques in patients with MetS or suitable animal models to investigate this cause of nephrolithiasis. Patients with plaques exhibited a higher incidence of metabolic and urinary risk factors; specifically, high calcium excretion is a major cause of Randall’s plaque formation and was correlated with plaque extension [24]. Hyperinsulinaemia increases calcium excretion and delivery to the thin segment of the loop of Henle. The hyperinsulinism that accompanies insulin resistance may elicit calcium deposition in the loop of Henle. The blood flow in the vasa recta in the inner medulla has important specificities, namely the turbulent blood flow at the tip of the papilla because of the 180o angle, the lower oxygen-carrying capacity of the blood in the inner medulla compared with the renal cortex, and the hyperosmolar microenvironment. These characteristics of the blood flow are worsened by the vascular lesions related to MetS, and support a vascular theory for Randall’s plaque formation. It was documented that Randall’s plaques per se may not cause interstitial inflammation and can be covered by normal urothelium [25]. Therefore, although CaOx crystals may be present in normal urine in the absence of urothelial damage, they do not have access to Randall’s plaques, and kidney stones do not form.
Oxidative stress and inflammation. When human kidney cells become damaged or express inflammatory molecules on their membrane, crystal binding to their surface is facilitated [25]. This could explain CaOx stone formation (Figure 1), allowing the adhesion of crystals to collecting ducts and the formation of intraluminal crystal aggregates prolapsing to the papilla, as proposed by the fixed particles theory. Inflammation could also explain the growth of CaOx aggregates on damaged Randall’s plaques. Crystal adhesion becomes facilitated when the urothelium is damaged or the cells have been sloughed; under these conditions, urinary macromolecules such as osteopontin and Tamm–Horsfall protein gain access to the subepithelial apatite deposits and create a suitable interface for CaOx crystal adhesion [21].
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MetS is a profound pro-oxidant inflammatory state, and inflammatory mediators have been implicated in the vascular lesions associated with MetS. In brief, obesity increases several inflammatory markers and cytokines; interleukin-6 increases C-reactive protein, which increases the production of reactive oxygen species (ROS) [26]; and tumour necrosis factor-a directly increases the production of ROS and also decreases insulin sensitivity, contributing to the development of type 2 diabetes [27]. Diabetes further increases oxidative stress by several mechanisms. Studies based on NHANES III showed low levels of the antioxidants a-carotenes, b-carotenes and b-cryptoxanthin in individuals with kidney stones [28]. Increased inflammatory renal enzymes were found in the urine of calcium stone formers and in the matrix of kidney stones [29]. These results support the possibility that oxidatively damaged cells may be involved in the pathogenesis of kidney stones in MetS. Inflammatory enzymes have been associated with the presence of by-products of ROS in the urine. In rat models, crystals damaged renal tubular cells and led to increased levels of ROS, involvement of inflammatory markers, release of lactate dehydrogenase (LDH) and apoptosis. Exposure of tubular cells to oxalate and oxalate crystals in cell culture also elicited markers of oxidative stress, including increased hydrogen peroxide (H2O2) and lipid peroxidation by-products, and decreased glutathione and increased LDH in the culture medium [30]. The rennin–angiotensin system (RAS) may be involved in ROS production by NADPH oxidase. CaOx crystal deposition increased renin expression in rat kidneys, and activated the RAS and osteopontin expression; inhibiting the angiotensin receptor reduced CaOx crystal deposition and osteopontin expression in hyperoxaluric rats [31]. Experimental models showed that antioxidants provided protection against CaOx nephrolithiasis. Adding citrate, a substance with antioxidant properties, to the culture medium increased cell viability. When renal cells were exposed to CaOx crystals in cell cultures, the increase in LDH, H2O2 and lipid peroxidation by-products, and the decrease in glutathione were lower when citrate was added to the culture medium [30]. Rats treated with ethylene glycol (a crystal formation promoter) and pioglitazone, another known antioxidant, had less crystal deposition and fewer markers of oxidative stress compared with rats treated only with ethylene glycol [32]. Limitation of the review The authors found no studies documenting Randall’s plaque formation in patients with MetS.
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Conclusions Several studies have shown an increased prevalence of nephrolithiasis in MetS. MetS is a concept created to group several disease manifestations that share a common physiopathological mechanism: insulin resistance. The changes in urinary composition associated with MetS increase both uric acid and CaOx supersaturation. Inflammation related to insulin resistance facilitates the adhesion of urine-borne crystals to the epithelia of the distal tubule and collecting duct, or to denuded Randall’s plaques, increasing the risk of growing kidney stones. Manifestations of MetS have been documented in many patients with apparent idiopathic kidney stone disease. One or more of these manifestations may be present, and should always be considered as risk factors in kidney stone disease. The chemical composition of the calculi is dependent on the urine risk factors associated with the individual features of MetS: (i) uric acid calculi predominate in obese patients; and (ii) CaOx stones have been associated with hypertension, hyperglycaemia and dyslipidaemia.
Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
References [1] Grundy SM, Brewer HB Jr, Cleeman JI, Smith SC Jr, Lenfant C. Definition of metabolic syndrome: report of the National Heart, Lung, and Blood Institute/American Heart Association conference on scientific issues related to definition. Circulation 2004;109:433–8. [2] Lakka HM, Laaksonen DE, Lakka TA, Niskanen LK, Kumpusalo E, Tuomilehto J, et al. The metabolic syndrome and total and cardiovascular disease mortality in middle-aged men. JAMA 2002;288:2709–16. [3] Hari P, Nerusu K, Veeranna V, Sudhakar R, Zalawadiya S, Ramesh K, et al. A gender-stratified comparative analysis of various definitions of metabolic syndrome and cardiovascular risk in a multiethnic US population. Metab Syndr Relat Disord 2012;10:47–55. [4] Wang J, Ruotsalainen S, Moilanen L, Lepisto P, Laakso M, Kuusisto J. The metabolic syndrome predicts cardiovascular mortality: a 13-year follow-up study in elderly non-diabetic Finns. Eur Heart J 2007;28:857–64. [5] West B, Luke A, Durazo-Arvizu RA, Cao G, Shoham D, Kramer H. Metabolic syndrome and self-reported history of kidney stones: the National Health and Nutrition Examination Survey (NHANES III) 1988–1994. Am J Kidney Dis 2008;51:741–7. [6] Domingos F, Serra A. Nephrolithiasis is associated with an increased prevalence of cardiovascular disease. Nephrol Dial Transplant 2011;26:864–8.
[7] Tiselius HG. Urinary tract stone disease: are all problems solved? Scand J Urol 2013;47:4–9. [8] Vague J. The degree of masculine differentiation of obesities: a factor determining predisposition to diabetes, atherosclerosis, gout, and uric calculous disease. Am J Clin Nutr 1956; 4:20–34. [9] Siener R, Glatz S, Nicolay C, Hesse A. The role of overweight and obesity in calcium oxalate stone formation. Obes Res 2004;12:106–13. [10] Cupisti A, Meola M, D’Alessandro C, Bernabini G, Pasquali E, Carpi A, et al. Insulin resistance and low urinary citrate excretion in calcium stone formers. Biomed Pharmacother 2007;61:86–90. [11] Ando R, Suzuki S, Nagaya T, Yamada T, Okada A, Yasui T, et al. Impact of insulin resistance, insulin and adiponectin on kidney stones in the Japanese population. Int J Urol 2011;18:131–8. [12] Weinberg AE, Patel CJ, Chertow GM, Leppert JT. Diabetic severity and risk of kidney stone disease. Eur Urol 2014;65: 242–7. [13] Strohmaier WL, Wrobel BM, Schubert G. Overweight, insulin resistance and blood pressure (parameters of the metabolic syndrome) in uric acid urolithiasis. Urol Res 2012;40:171–5. [14] Kadlec AO, Greco K, Fridirici ZC, Hart ST, Vellos T, Turk TM. Metabolic syndrome and urinary stone composition: what factors matter most? Urology 2012;80: 805–10. [15] Abate N, Chandalia M, Cabo-Chan AV Jr, Moe OW, Sakhaee K. The metabolic syndrome and uric acid nephrolithiasis: novel features of renal manifestation of insulin resistance. Kidney Int 2004;65:386–92. [16] Bobulescu IA. Renal lipid metabolism and lipotoxicity. Curr Opin Nephrol Hypertens 2010;19:393–402. [17] Fuster DG, Bobulescu IA, Zhang J, Wade J, Moe OW. Characterization of the regulation of renal Na+/H+ exchanger NHE3 by insulin. Am J Physiol Renal Physiol 2007;292: F577–85. [18] Kohjimoto Y, Sasaki Y, Iguchi M, Matsumura N, Inagaki T, Hara I. Association of metabolic syndrome traits and severity of kidney stones: results from a nationwide survey on urolithiasis in Japan. Am J Kidney Dis 2013;61: 923–9. [19] Borghi L, Meschi T, Guerra A, Briganti A, Schianchi T, Allegri F, et al. Essential arterial hypertension and stone disease. Kidney Int 1999;55:2397–406. [20] Taylor EN, Mount DB, Forman JP, Curhan GC. Association of prevalent hypertension with 24-hour urinary excretion of calcium, citrate, and other factors. Am J Kidney Dis 2006;47: 780–9. [21] Coe FL, Evan AP, Worcester EM, Lingeman JE. Three pathways for human kidney stone formation. Urol Res 2010;38:147–60. [22] Schepers MS, van Ballegooijen ES, Bangma CH, Verkoelen CF. Crystals cause acute necrotic cell death in renal proximal tubule cells, but not in collecting tubule cells. Kidney Int 2005;68:1543–53. [23] Khan SR, Rodriguez DE, Gower LB, Monga M. Association of Randall plaque with collagen fibers and membrane vesicles. J Urol 2012;187:1094–100. [24] Low RK, Stoller ML, Schreiber CK. Metabolic and urinary risk factors associated with Randall’s papillary plaques. J Endourol 2000;14:507–10. [25] Sakhaee K. Recent advances in the pathophysiology of nephrolithiasis. Kidney Int 2009;75:585–95.
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[26] Stapleton PA, James ME, Goodwill AG, Frisbee JC. Obesity and vascular dysfunction. Pathophysiology 2008;15:79–89. [27] Li G, Barrett EJ, Barrett MO, Cao W, Liu Z. Tumor necrosis factor-alpha induces insulin resistance in endothelial cells via a p38 mitogen-activated protein kinase-dependent pathway. Endocrinology 2007;148:3356–63. [28] Holoch PA, Tracy CR. Antioxidants and self-reported history of kidney stones: the National Health and Nutrition Examination Survey. J Endourol 2011;25:1903–8. [29] Canales BK, Anderson L, Higgins L, Ensrud-Bowlin K, Roberts KP, Wu B, et al. Proteome of human calcium kidney stones. Urology 2010;76:1017.e13–20.
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[30] Byer K, Khan SR. Citrate provides protection against oxalate and calcium oxalate crystal induced oxidative damage to renal epithelium. J Urol 2005;173:640–6. [31] Umekawa T, Hatanaka Y, Kurita T, Khan SR. Effect of angiotensin II receptor blockage on osteopontin expression and calcium oxalate crystal deposition in rat kidneys. J Am Soc Nephrol 2004;15:635–44. [32] Taguchi K, Okada A, Yasui T, Kobayashi T, Ando R, Tozawa K, et al. Pioglitazone, a peroxisome proliferator activated receptor gamma agonist, decreases renal crystal deposition, oxidative stress and inflammation in hyperoxaluric rats. J Urol 2012;188:1002–11.
REVIEW ARTICLE
Metabolic syndrome: A multifaceted risk factor for kidney stones
Scandinavian Journal of Urology Downloaded from informahealthcare.com by University of Victoria on 04/09/15 For personal use only.
FERNANDO DOMINGOS1,2 & ADELAIDE SERRA2,3 1 3
Institute of Physiology, Faculty of Medicine, University of Lisbon, Lisbon, Portugal, 2Nephrology Service, and Outpatient Kidney Stone Clinic, Hospital Fernando Fonseca, Amadora, Portugal
Abstract Kidney stones and metabolic syndrome (MetS) are common conditions in industrialized countries. There is growing evidence of associations between kidney stone disease and MetS or some of its components. The link between uric acid stones and MetS is well understood, but the link with calcium oxalate (CaOx) stones, the most common kidney stone composition, is more complex, and MetS is frequently overlooked as a risk factor for calcium nephrolithiasis. The physiopathological mechanisms of kidney stone disease in MetS are reviewed in this article. Uric acid stones are a consequence of the excessively acidic urine that results from insulin resistance. The pathophysiology of CaOx stones may include: increased excretion of lithogenesis promoters and decreased excretion of inhibitors; increased risk of Randall’s plaque development; and inflammatory damage to renal epithelia by oxidative stress, as a consequence of the insulin-resistant milieu that characterizes MetS. The last mechanism contributes to the adhesion of CaOx crystals to subepithelial calcium deposits working as anchor sites where stones can grow. The predominant MetS features could determine the chemical composition of the stones in each patient. Kidney stones may be a renal manifestation of MetS and features of this syndrome should be looked for in patients with idiopathic nephrolithiasis.
Key Words: hypertension, insulin resistance, metabolic syndrome, nephrolithiasis, obesity
Introduction The metabolic syndrome (MetS) is an association of several metabolic disorders including obesity, mainly abdominal obesity, fasting or postprandial hyperglycaemia, essential hypertension, high plasma triglycerides and low plasma high-density lipoprotein cholesterol [1]. These conditions are linked by a common mechanism: insulin resistance. Although there are currently several definitions of MetS, the coexistence of three or more of the above-cited features makes the diagnosis [1] and is associated with an increased risk of cardiovascular disease [2]. The prevalence of MetS varies according to age, gender, ethnicity and definition used. Worldwide, MetS affects 24–42% of the adult population [3] and up to 66.4% of the older population [4].
An association between kidney stone disease and MetS has been documented in several cross-sectional studies. The third US National Health and Nutrition Examination Survey (NHANES III) showed that the odds ratio for kidney stones increased with the number of features of MetS, being twice the normal in patients with three or more features of this syndrome [5]. Associations with kidney stones have been documented in several individual features of MetS. The Fourth Portuguese National Health Survey found significant associations between kidney stone disease and obesity, hypertension and diabetes [6]. Despite noteworthy improvements in the treatment to remove kidney stones during the past few decades, the optimization of preventive measures to reduce the risk of stone recurrence remains a significant problem [7]. The association between MetS and
Correspondence: F. Domingos, Serviço de Nefrologia, Hospital Prof. Doutor Fernando Fonseca, Estrada IC 19, 2720-276 Amadora, Portugal. E-mail: [email protected]
(Received 16 November 2013; accepted 27 February 2014) ISSN 2168-1805 print/ISSN 2168-1813 online 2014 Informa Healthcare DOI: 10.3109/21681805.2014.903513
Metabolic syndrome and kidney stones kidney stones may have clinical relevance. If the pathophysiological mechanisms underlying MetS increase the risk of stone formation, MetS should be considered as a risk factor for nephrolithiasis, and treatment of the metabolic disorders should be part of the measures taken to prevent stone recurrence.
Scandinavian Journal of Urology Downloaded from informahealthcare.com by University of Victoria on 04/09/15 For personal use only.
Physiopathology of kidney stones in metabolic syndrome The epidemiological studies showing the association between MetS and kidney stones provided little information about the pathophysiology of kidney stone formation because stone composition and known urinary risk factors were not investigated. However, there are studies documenting the association with kidney stones in some individual manifestations of MetS. The link between uric acid kidney stones and central obesity was reported more than 50 years ago [8]. Later, high body mass index (BMI) and obesity were associated with abnormalities of the urinary profile that increase the risk of kidney stone disease [9]. Insulin resistance provides a possible link between MetS and lithogenesis. Studies showed lower citrate excretion in calcium stone formers with insulin resistance assessed by homeostasis model assessment of insulin resistance (HOMA-IR) [10]. HOMA-IR was significantly higher in women with than without kidney stones and was correlated with BMI [11], reinforcing the possible role of insulin resistance in the lithogenic process. Poor glycaemic control and the need for insulin therapy increase the risk of kidney stones in patients with type 2 diabetes [12]. Uric acid stones Studies in which stone composition has been analysed show an increased prevalence of uric stones in diabetic, obese and hypertensive patients [13,14]. Patients with features of MetS usually have overly acidic urine. Undissociated uric acid (H2U) is a week acid, with two protons in positions 3 and 9; it is poorly soluble in urine and tends to precipitate in low urinary pH. The dissociation constant (pKa) of the first proton is 5.47, meaning that when urinary pH is above 5.5 uric acid loses the first proton and turns into dissociated urate (HU–), which is much more soluble in urine. The pKa of the second proton is 10.3 and has no physiological relevance to uric acid solubility in human urine. Therefore, when urine becomes excessively acidic, most uric acid will be in the undissociated form and precipitates, causing uric acid stones. Different factors may contribute to urine acidity in MetS. Using the euglycaemic clamp test, Abate et al. [15] showed that healthy volunteers respond to acute
415
insulin administration by increasing ammonium production, urinary pH and urinary citrate. Healthy individuals resistant to insulin activity had lower urinary pH, and patients with uric acid stones had lower insulin sensitivity, urinary pH and urine citrate. The pathophysiology of the acidic urine in insulin resistance is multifactorial, and includes lower ammonium (NH4+) excretion and, therefore, increased elimination of the daily acid as titratable acid. Insulin promotes ammonia (NH3) production from glutamine mainly at the proximal tubule. This is a very important mechanism to prevent decrease of urinary pH to very low levels. Insulin resistance could decrease ammonium production by competitive mechanisms, direct lipotoxicity and interference with the transport mechanisms in the tubular cell membrane [16]. Renal steatosis and accumulation of free fatty acids in the interstitium surrounding the proximal convoluted tubule promote the competition between free fatty acids and glutamine as oxidizable substrates and, therefore, decrease ammonia production from glutamine. Recent findings showed that the accumulation of intracellular non-esterified fatty acids and their toxic metabolites may have direct lipotoxic effects within the proximal tubular cells and this could also contribute to decreased ammonium production [16]. It was demonstrated in cell cultures that insulin increases the activity of the sodium/ hydrogen antiport (NHE3) [17]. In insulin resistance, dysfunction of NHE3 may contribute to lower ammonium excretion since secretion of ammonium ions (NH4+) and protons (H+) is necessary to trap the ammonia within the tubule lumen. Recurrent uric acid stone formers with manifestations of MetS had lower urinary pH than healthy individuals despite insulin sensitivity, suggesting the existence of additional mechanisms to explain the excessively acidic urine [15]. There are at least two possible explanations for this observation. First, patients with MetS may have an increased protein intake. In a cross-sectional study, Strohmaier et al. [13] reported overly acidic urine and hyperuricosuria in two-thirds of patients with idiopathic uric acid nephrolithiasis, but decreased ammonium production was found in less than 25% of them. Urinary urea, another marker of protein intake, was higher in stone formers. Secondly, patients with MetS may have an overproduction of organic acids because of increased BMI [15]. However, the latter mechanism is largely speculative. Calcium stones The prevalence of kidney stones almost doubles when four components of MetS are present [5].
416
F. Domingos & A. Serra
Metabolic syndrome
Urinary risk factors
Systemic risk factors
pH
Obesity
Inhibitors (citrate) Promoters (oxalate, uric acid, calcium)
Scandinavian Journal of Urology Downloaded from informahealthcare.com by University of Victoria on 04/09/15 For personal use only.
Inflammation
IL-6
ROS
TNF-α
C-Reactive protein
Insulin signalling
Insulin resistance
Crystallization Oxidative stress
Cell damage
Yes
Kidney stones
No
No kidney stones Figure 1. Main pathways contributing to calcium nephrolithiasis in metabolic syndrome, including urinary and systemic risk factors. ROS = reactive oxygen species; IL-6 = interleukin-6; TNF-a = tumour necrosis factor-a.
Kadlec et al. showed that the prevalence of uric acid calculi was 14.0% in obese patients with MetS and 8.9% in non-obese patients [14]. CaOx was the most frequent kidney stone composition, found in almost 70% of patients with MetS, a prevalence similar to CaOx calculi identified in the normal population with idiopathic kidney stones. Calcium phosphate stones were reported less frequently in obese patients [14]. The overall increase in nephrolithiasis associated with MetS can only be explained by an increase in CaOx stones. A higher HOMA-IR was documented in 61 idiopathic calcium stone formers [10]. As discussed above, the low urinary citrate is a consequence of low ammonium production and the low urinary pH that characterizes the insulin-resistant milieu [15]. These results suggest that many cases of apparently idiopathic CaOx nephrolithiasis may in fact be associated with an increased prevalence of manifestations of MetS. Supersaturation hypothesis. The increased risk of CaOx in MetS has been associated with increased excretion of oxalate, uric acid and calcium, and decreased citrate excretion [18]. This risk is related not to MetS as a whole, but to some of its features. High BMI increases the excretion of uric acid, oxalate and phosphate [9]. Calcium excretion was reported to be higher in obese men [9].
Other components of MetS that have been associated with CaOx stones involve hypertension. In a prospective study, the relative risk of kidney stones was raised 5.5-fold in patients with essential hypertension compared with normotensive controls, and CaOx was the most common stone composition [19]. The pathophysiology of kidney stones in hypertension is not entirely understood. Untreated hypertension was associated with hypercalciuria. Hypertensive patients presented with higher urinary calcium, oxalate and phosphate [19], and decreased urinary citrate [20]. The imbalance between promoters and inhibitors of lithogenesis in MetS promotes CaOx supersaturation and crystallization; however, there are doubts that the retention of free crystalline particles in the kidney is sufficient to cause CaOx nephrolithiasis in humans [21]. In fact, it was documented in cell cultures that normal cells of the human distal tubule and collecting duct are resistant to crystal adhesion [22]. Randall’s plaques. Studies including endoscopic examinations from kidney stone formers support the hypothesis that a large percentage of cases of human idiopathic CaOx nephrolithiasis may be associated with subepithelial calcium phosphate deposits known as Randall’s plaques. Histological studies of
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Metabolic syndrome and kidney stones the renal tissues from idiopathic calcium stone formers showed that the plaques start as small, round apatite deposits beneath the basement membrane of the thin segment of the loop of Henle. The deposits are associated with collagen and membrane-bound vesicles, and slowly grow and migrate until they reach the subepithelial surface of the renal papilla [23]. Despite the evidence linking MetS to idiopathic calcium nephrolithiasis, there are no studies documenting the presence of Randall’s plaques in patients with MetS or suitable animal models to investigate this cause of nephrolithiasis. Patients with plaques exhibited a higher incidence of metabolic and urinary risk factors; specifically, high calcium excretion is a major cause of Randall’s plaque formation and was correlated with plaque extension [24]. Hyperinsulinaemia increases calcium excretion and delivery to the thin segment of the loop of Henle. The hyperinsulinism that accompanies insulin resistance may elicit calcium deposition in the loop of Henle. The blood flow in the vasa recta in the inner medulla has important specificities, namely the turbulent blood flow at the tip of the papilla because of the 180o angle, the lower oxygen-carrying capacity of the blood in the inner medulla compared with the renal cortex, and the hyperosmolar microenvironment. These characteristics of the blood flow are worsened by the vascular lesions related to MetS, and support a vascular theory for Randall’s plaque formation. It was documented that Randall’s plaques per se may not cause interstitial inflammation and can be covered by normal urothelium [25]. Therefore, although CaOx crystals may be present in normal urine in the absence of urothelial damage, they do not have access to Randall’s plaques, and kidney stones do not form.
Oxidative stress and inflammation. When human kidney cells become damaged or express inflammatory molecules on their membrane, crystal binding to their surface is facilitated [25]. This could explain CaOx stone formation (Figure 1), allowing the adhesion of crystals to collecting ducts and the formation of intraluminal crystal aggregates prolapsing to the papilla, as proposed by the fixed particles theory. Inflammation could also explain the growth of CaOx aggregates on damaged Randall’s plaques. Crystal adhesion becomes facilitated when the urothelium is damaged or the cells have been sloughed; under these conditions, urinary macromolecules such as osteopontin and Tamm–Horsfall protein gain access to the subepithelial apatite deposits and create a suitable interface for CaOx crystal adhesion [21].
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MetS is a profound pro-oxidant inflammatory state, and inflammatory mediators have been implicated in the vascular lesions associated with MetS. In brief, obesity increases several inflammatory markers and cytokines; interleukin-6 increases C-reactive protein, which increases the production of reactive oxygen species (ROS) [26]; and tumour necrosis factor-a directly increases the production of ROS and also decreases insulin sensitivity, contributing to the development of type 2 diabetes [27]. Diabetes further increases oxidative stress by several mechanisms. Studies based on NHANES III showed low levels of the antioxidants a-carotenes, b-carotenes and b-cryptoxanthin in individuals with kidney stones [28]. Increased inflammatory renal enzymes were found in the urine of calcium stone formers and in the matrix of kidney stones [29]. These results support the possibility that oxidatively damaged cells may be involved in the pathogenesis of kidney stones in MetS. Inflammatory enzymes have been associated with the presence of by-products of ROS in the urine. In rat models, crystals damaged renal tubular cells and led to increased levels of ROS, involvement of inflammatory markers, release of lactate dehydrogenase (LDH) and apoptosis. Exposure of tubular cells to oxalate and oxalate crystals in cell culture also elicited markers of oxidative stress, including increased hydrogen peroxide (H2O2) and lipid peroxidation by-products, and decreased glutathione and increased LDH in the culture medium [30]. The rennin–angiotensin system (RAS) may be involved in ROS production by NADPH oxidase. CaOx crystal deposition increased renin expression in rat kidneys, and activated the RAS and osteopontin expression; inhibiting the angiotensin receptor reduced CaOx crystal deposition and osteopontin expression in hyperoxaluric rats [31]. Experimental models showed that antioxidants provided protection against CaOx nephrolithiasis. Adding citrate, a substance with antioxidant properties, to the culture medium increased cell viability. When renal cells were exposed to CaOx crystals in cell cultures, the increase in LDH, H2O2 and lipid peroxidation by-products, and the decrease in glutathione were lower when citrate was added to the culture medium [30]. Rats treated with ethylene glycol (a crystal formation promoter) and pioglitazone, another known antioxidant, had less crystal deposition and fewer markers of oxidative stress compared with rats treated only with ethylene glycol [32]. Limitation of the review The authors found no studies documenting Randall’s plaque formation in patients with MetS.
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F. Domingos & A. Serra
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Conclusions Several studies have shown an increased prevalence of nephrolithiasis in MetS. MetS is a concept created to group several disease manifestations that share a common physiopathological mechanism: insulin resistance. The changes in urinary composition associated with MetS increase both uric acid and CaOx supersaturation. Inflammation related to insulin resistance facilitates the adhesion of urine-borne crystals to the epithelia of the distal tubule and collecting duct, or to denuded Randall’s plaques, increasing the risk of growing kidney stones. Manifestations of MetS have been documented in many patients with apparent idiopathic kidney stone disease. One or more of these manifestations may be present, and should always be considered as risk factors in kidney stone disease. The chemical composition of the calculi is dependent on the urine risk factors associated with the individual features of MetS: (i) uric acid calculi predominate in obese patients; and (ii) CaOx stones have been associated with hypertension, hyperglycaemia and dyslipidaemia.
Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
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