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Epidemiology, Pathogenesis, and Pathophysiology of Urolithiasis

  • Thomas Knoll
    Correspondence
    Tel. +49 7031 98 12501; Fax: +49 7031 815307.
    Affiliations
    Department of Urology, Sindelfingen-Boeblingen Medical Center, University of Tübingen, Arthur-Gruber-Str. 70, 71065 Sindelfingen, Germany
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      Abstract

      Context

      Urolithiasis (UL) is one of the most common diseases, with worldwide increasing incidence and prevalence. The pathogenesis of calcium oxalate (CaOx) UL, which accounts for >80% of all urinary stones, is only incompletely understood.

      Objective

      Our aim was to review trends in epidemiology and current concepts for the pathogenesis and pathophysiology of urinary stone disease.

      Evidence acquisition

      We reviewed data from the literature and our own series.

      Evidence synthesis

      Urinary stone formation is a result of different mechanisms. Completely different pathomechanisms lead to CaOx stone formation, with Randall plaques playing a key role in the pathogenesis.

      Conclusions

      The lithogenesis of key stones is multifactorial. Lifestyle and dietary choices are important contributing factors. The pathogenesis and pathophysiology of CaOx stones is still incompletely understood. Recent evidence suggests a primary interstitial apatite crystal formation that secondarily leads to CaOx stone formation.

      Keywords

      1. Introduction

      Urolithiasis (UL) is one of the most common diseases, with approximately 750 000 cases per year in Germany [
      • Strohmaier W.L.
      Socioeconomic aspects of urinary calculi and metaphylaxis of urinary calculi [in German].
      ]. Although most patients have only one stone episode, 25% of patients experience recurrent stone formation [
      • Hesse A.
      • Brändle E.
      • Wilbert D.
      • Köhrmann K.-U.
      • Alken P.
      Study on the prevalence and incidence of urolithiasis in Germany comparing the years 1979 vs. 2000.
      ]. UL therefore has a significant impact on quality of life and socioeconomic factors [
      • Lotan Y.
      • Cadeddu J.A.
      • Roerhborn C.G.
      • Pak C.Y.
      • Pearle M.S.
      Cost-effectiveness of medical management strategies for nephrolithiasis.
      ]. The pathogenesis of calcium oxalate (CaOx) UL, which accounts for >80% of all stones, is only incompletely understood. This paper reviews trends in epidemiology and current concepts regarding the pathogenesis and pathophysiology of urinary stone disease.

      2. Evidence acquisition

      Urinary stone formation is a common disease with an increasing incidence and prevalence worldwide that appears even more pronounced in industrialized countries [
      • Hesse A.
      • Brändle E.
      • Wilbert D.
      • Köhrmann K.-U.
      • Alken P.
      Study on the prevalence and incidence of urolithiasis in Germany comparing the years 1979 vs. 2000.
      ,
      • Taylor E.N.
      • Stampfer M.J.
      • Curhan G.C.
      Diabetes mellitus and the risk of nephrolithiasis.
      ,
      • Shekarriz B.
      • Stoller M.L.
      Uric acid nephrolithiasis: current concepts and controversies.
      ,
      • Boyce C.J.
      • Pickhardt P.J.
      • Lawrence E.M.
      • Kim D.H.
      • Bruce R.J.
      Prevalence of urolithiasis in asymptomatic adults: objective determination using low dose noncontrast computerized tomography.
      ,
      • Marickar Y.M.
      • Vijay A.
      Female stone disease: the changing trend.
      ,
      • Novak T.E.
      • Lakshmanan Y.
      • Trock B.J.
      • Gearhart J.P.
      • Matlaga B.R.
      Sex prevalence of pediatric kidney stone disease in the United States: an epidemiologic investigation.
      ,
      • Bartoletti R.
      • Cai T.
      • Mondaini N.
      • et al.
      Epidemiology and risk factors in urolithiasis.
      ,
      • Coward R.J.
      • Peters C.J.
      • Duffy P.G.
      • et al.
      Epidemiology of paediatric renal stone disease in the UK.
      ]. Such observations seem to underscore the impact of lifestyle and dietary choices as well as access to better medical care for urinary stone formation.
      Renal stone formation and the predominant chemical stone composition are age and gender dependent [
      • Daudon M.
      • Dore J.C.
      • Jungers P.
      • Lacour B.
      Changes in stone composition according to age and gender of patients: a multivariate epidemiological approach.
      ]. Most stones are formed in older patients. However, clinical observations have indicated not only a changing frequency and composition of urinary calculi but also a shift in gender- and age-related incidences [
      • Daudon M.
      • Dore J.C.
      • Jungers P.
      • Lacour B.
      Changes in stone composition according to age and gender of patients: a multivariate epidemiological approach.
      ,
      • Strope S.A.
      • Wolf Jr., J.S.
      • Hollenbeck B.K.
      Changes in gender distribution of urinary stone disease.
      ,
      • Scales Jr., C.D.
      • Curtis L.H.
      • Norris R.D.
      • et al.
      Changing gender prevalence of stone disease.
      ]. Urinary stone disease remains rare in children with a stable overall incidence in most series [
      • Rizvi S.A.
      • Naqvi S.A.
      • Hussain Z.
      • et al.
      Pediatric urolithiasis: developing nation perspectives.
      ]. As in adults, factors implicated in the metabolic syndrome complex such as obesity pose risks for urinary stone formation in children [
      • Sarica K.
      • Eryildirim B.
      • Yencilek F.
      • Kuyumcuoglu U.
      Role of overweight status on stone-forming risk factors in children: a prospective study.
      ].
      Although some authors have suggested the impact of climate change [
      • Chen Y.K.
      • Lin H.C.
      • Chen C.S.
      • Yeh S.D.
      Seasonal variations in urinary calculi attacks and their association with climate: a population based study.
      ,
      • Brikowski T.H.
      • Lotan Y.
      • Pearle M.S.
      Climate-related increase in the prevalence of urolithiasis in the United States.
      ], changing lifestyle and dietary choices are the more probable cause of the increasing incidence and prevalence of UL. Taylor and Curhan demonstrated a correlation of body weight and urinary calcium excretion [
      • Taylor E.N.
      • Curhan G.C.
      Body size and 24-hour urine composition.
      ]. In two large epidemiologic series, they also reported diabetes as an independent risk factor for the development of kidney stones [
      • Taylor E.N.
      • Stampfer M.J.
      • Curhan G.C.
      Diabetes mellitus and the risk of nephrolithiasis.
      ,
      • Ramey S.L.
      • Franke W.D.
      • Shelley II, M.C.
      Relationship among risk factors for nephrolithiasis, cardiovascular disease, and ethnicity: focus on a law enforcement cohort.
      ,
      • Siener R.
      • Glatz S.
      • Nicolay C.
      • Hesse A.
      Prospective study on the efficacy of a selective treatment and risk factors for relapse in recurrent calcium oxalate stone patients.
      ]. Siener confirmed such findings in studies on recurrent stone formers [
      • Siener R.
      Impact of dietary habits on stone incidence.
      ]. Changing chemical stone compositions have been reported, possibly as results of the described changes of lifestyle [
      • Donsimoni R.
      • Hennequin C.
      • Fellahi S.
      • et al.
      New aspects of urolithiasis in France. GERBAP: Groupe d’Evaluation et de Recherche des Biologistes de l’Assistance Publique des Hôpitaux de Paris.
      ,
      • Daudon M.
      • Donsimoni R.
      • Hennequin C.
      • et al.
      Sex- and age-related composition of 10 617 calculi analyzed by infrared spectroscopy.
      ].
      Calcium-containing calculi are predominant in males and females [
      • Daudon M.
      • Dore J.C.
      • Jungers P.
      • Lacour B.
      Changes in stone composition according to age and gender of patients: a multivariate epidemiological approach.
      ,
      • Munoz-Velez D.
      • Garcia-Montes F.
      • Costa-Bauza A.
      • Grases F.
      Analysis of spontaneously passed urinary tract stones.
      ,
      • da Silva S.F.
      • Silva S.L.
      • Daher E.F.
      • Silva Junior G.B.
      • Mota R.M.
      • Bruno da Silva C.A.
      Determination of urinary stone composition based on stone morphology: a prospective study of 325 consecutive patients in an emerging country.
      ]. However, UL remains a disease with a clear predominance in males for all stone compositions except for infection stones. In our own series, including >200 000 stone analyses, this difference increased over the observation period with a 2.7:1 male-to-female ratio for the most common calcium-containing calculi [

      Knoll T, Leusmann DB, Fahlenkamp D, Wendt-Nordahl G, Schubert G. Urolithiasis through the ages—data from more than 200,000 stone analyses. J Urol. In press.

      ]. Daudon et al showed a male predominance for CaOx and uric acid, and a female predominance for calcium phosphate (CaPh) and struvite stones [
      • Daudon M.
      • Dore J.C.
      • Jungers P.
      • Lacour B.
      Changes in stone composition according to age and gender of patients: a multivariate epidemiological approach.
      ]. Approximately 15% of all stone formers produce CaPh stones [
      • Krambeck A.E.
      • Handa S.E.
      • Evan A.P.
      • Lingeman J.E.
      Profile of the brushite stone former.
      ]. Up to a quarter of those CaPh stones contain calcium monohydrogen phosphate (brushite), which is difficult both to treat and to prevent [
      • Klee L.W.
      • Brito C.G.
      • Lingeman J.E.
      The clinical implications of brushite calculi.
      ]. Our own series demonstrated an increased prevalence of brushite [

      Knoll T, Leusmann DB, Fahlenkamp D, Wendt-Nordahl G, Schubert G. Urolithiasis through the ages—data from more than 200,000 stone analyses. J Urol. In press.

      ] (Fig. 1).
      Figure thumbnail gr1
      Fig. 1Frequency of hydroxyapatite, brushite, and calcium oxalate components in urinary stones, 1980–2004 (n = 111 196).
      Currently, uric acid composition seems to be the second most common stone in both genders. Daudon et al reported a significant increase in uric acid stone frequency, whereas in our own series the rate remained stable [
      • Daudon M.
      • Dore J.C.
      • Jungers P.
      • Lacour B.
      Changes in stone composition according to age and gender of patients: a multivariate epidemiological approach.
      ,

      Knoll T, Leusmann DB, Fahlenkamp D, Wendt-Nordahl G, Schubert G. Urolithiasis through the ages—data from more than 200,000 stone analyses. J Urol. In press.

      ].
      Stones due to infection have clearly declined over the years, attributable to improved medical care. Trinchieri et al reported a 15-yr series from Italy of stone analyses with a low number of infection stones [
      • Trinchieri A.
      • Rovera F.
      • Nespoli R.
      • Curro A.
      Clinical observations on 2086 patients with upper urinary tract stone.
      ]. Marickar and Vijay reported a decrease of infection stones in females despite an overall increase of urinary stone formation [
      • Marickar Y.M.
      • Vijay A.
      Female stone disease: the changing trend.
      ]. The decreasing number of staghorn stones in Europe supports this observation because urinary tract infections are the most common cause of such large renal calculi [
      • Preminger G.M.
      • Assimos D.G.
      • Lingeman J.E.
      • Nakada S.Y.
      • Pearle M.S.
      • Wolf Jr., J.S.
      Chapter 1: AUA guideline on management of staghorn calculi: diagnosis and treatment recommendations.
      ].
      Cystine stones, formed by patients with cystinuria, account for only a small percentage of all urinary stones [

      Knoll T, Leusmann DB, Fahlenkamp D, Wendt-Nordahl G, Schubert G. Urolithiasis through the ages—data from more than 200,000 stone analyses. J Urol. In press.

      ]. The higher peak in younger ages is in accordance with the first stone event, which typically occurs in the 2nd decade of life, whereas the lower frequency at older ages may be a result of preventive measures [
      • Knoll T.
      • Zollner A.
      • Wendt-Nordahl G.
      • Michel M.S.
      • Alken P.
      Cystinuria in childhood and adolescence: recommendations for diagnosis, treatment, and follow-up.
      ].
      Interestingly, our German series demonstrated significant regional differences [

      Knoll T, Leusmann DB, Fahlenkamp D, Wendt-Nordahl G, Schubert G. Urolithiasis through the ages—data from more than 200,000 stone analyses. J Urol. In press.

      ]. Although calculi containing uric acid were more prevalent in southern Germany, we observed a significantly higher frequency of stones due to infection in eastern Germany. We can only hypothesize an explanation for these findings. A diet based more heavily on red meat may explain the higher rate of uric acid calculi in southern Germany. The higher frequency of infection stones in the eastern part of the country (formerly the socialist German Democratic Republic) is surprising and cannot be adequately explained. However, this finding suggests that differences in medical care do exist.

      3. Evidence synthesis

      3.1 Pathogenesis and pathophysiology

      Urinary stone formation is a result of different mechanisms. Whereas exceeding supersaturation (ie, free stone formation) is the cause of uric acid or cystine calculi, infection stones result from bacterial metabolism [
      • Moe O.W.
      Kidney stones: pathophysiology and medical management.
      ]. The formation of the most common fraction, the calcium-containing calculi, is more complex and, surprisingly, is not yet completely understood. Recent evidence suggests that both free and fixed stone formation is possible [
      • Wendt-Nordahl G.
      • Evan A.P.
      • Spahn M.
      • Knoll T.
      Calcium oxalate stone formation. New pathogenetic aspects of an old disease [in German].
      ]. The long accepted simple explanation of exceeding the solubility product of lithogenic substances in the urine cannot describe these complex processes sufficiently [
      • Wendt-Nordahl G.
      • Evan A.P.
      • Spahn M.
      • Knoll T.
      Calcium oxalate stone formation. New pathogenetic aspects of an old disease [in German].
      ]. Deviating from the hypothesis that claims the initial crystal deposition takes place in the lumens of renal tubules [
      • Verkoelen C.F.
      • van der Boom B.G.
      • Houtsmuller A.B.
      • Schroder F.H.
      • Romijn J.C.
      Increased calcium oxalate monohydrate crystal binding to injured renal tubular epithelial cells in culture.
      ,
      • Khan S.R.
      • Byer K.J.
      • Thamilselvan S.
      • et al.
      Crystal-cell interaction and apoptosis in oxalate-associated injury of renal epithelial cells.
      ,
      • Kok D.J.
      Crystallization and stone formation inside the nephron.
      ], new insights suggest a primary plaque formation in the interstitial space of the renal papilla [
      • Lieske J.C.
      • Spargo B.H.
      • Toback F.G.
      Endocytosis of calcium oxalate crystals and proliferation of renal tubular epithelial cells in a patient with type 1 primary hyperoxaluria.
      ,
      • Evan A.P.
      • Lingeman J.E.
      • Coe F.L.
      • et al.
      Randall's plaque of patients with nephrolithiasis begins in basement membranes of thin loops of Henle.
      ]. CaPh crystals and organic matrix initially are deposited along the basement membranes of the thin loops of Henle and extend further into the interstitial space to the urothelium, constituting the so-called Randall plaques, which are regularly found during endoscopy of patients who form CaOx stones (Fig. 2). These CaPh crystals seem to be the origin for the development of future CaOx stones, which form by the attachment of further matrix molecules and CaOx from the urine to the plaque [
      • de Water R.
      • Noordermeer C.
      • Houtsmuller A.B.
      • et al.
      Role of macrophages in nephrolithiasis in rats: an analysis of the renal interstitium.
      ]. The driving forces, the exact pathogenetic mechanisms, and the involved matrix molecules are still largely unknown. Completely different pathomechanisms obviously lead to the common clinical diagnosis of “CaOx stone former.”
      Figure thumbnail gr2
      Fig. 2Microcalcifications on renal papilla are thought to be precursors of calcium oxalate stones (Randall plaques).
      Stoller et al raised another interesting hypothesis. They suggested an even closer participation of the vasa recta in the lithogenesis of kidney stones [
      • Stoller M.L.
      • Meng M.V.
      • Abrahams H.M.
      • Kane J.P.
      The primary stone event: a new hypothesis involving a vascular etiology.
      ]. The descending and ascending vasa recta are vulnerable because of the hypoxic and hyperosmolar environment in the papillary tip and because the blood flow in the papillary tip changes from a laminar to a turbulent flow as the ascending vasa recta repeatedly bifurcates [
      • Sampaio F.J.
      • Aragao A.H.
      Anatomical relationship between the intrarenal arteries and the kidney collecting system.
      ]. They proposed this could lead to atherosclerotic-like lesions and calcifications in the wall of the vasa recta. These calcifications could then erode to papillary interstitium and grow there, supported by cellular promotors [
      • Bushinsky D.A.
      • Monk R.D.
      Electrolyte quintet: calcium.
      ]. The close participation of the vasa recta has led to a new hypothesis regarding the role of vascular phenomena in the lithogenesis of kidney stones.

      3.2 Key role of Randall plaques

      Randall plaques are thought to be involved in idiopathic CaOx stone formation. Seventy years ago, Randall described calcifications within the renal papilla that he found in 20% of autopsies [
      • Randall A.
      The origin and growth of renal calculi.
      ]. These calcifications were made of CaPh (apatite). Randall proposed that the plaques are precursors of urinary stones. His idea was lost for decades until Evan et al were able to show that such plaques are present in all idiopathic CaOx stone formers but not in healthy controls [
      • Evan A.P.
      • Lingeman J.E.
      • Coe F.L.
      • et al.
      Randall's plaque of patients with nephrolithiasis begins in basement membranes of thin loops of Henle.
      ,
      • Kim S.C.
      • Coe F.L.
      • Tinmouth W.W.
      • et al.
      Stone formation is proportional to papillary surface coverage by Randall's plaque.
      ,
      • Matlaga B.R.
      • Williams Jr., J.C.
      • Kim S.C.
      • et al.
      Endoscopic evidence of calculus attachment to Randall's plaque.
      ]. When attached stones were removed from the renal papilla, they had the impression that the plaques were the connection of the stones to the papilla. Microscopic computed tomography examinations of CaOx stones confirmed this hypothesis by demonstrating the presence of apatite at the former attachment side [
      • Williams Jr., J.C.
      • Matlaga B.R.
      • Kim S.C.
      • et al.
      Calcium oxalate calculi found attached to the renal papilla: preliminary evidence for early mechanisms in stone formation.
      ]. Matlaga et al demonstrated a positive correlation of the frequency of stone recurrences and the total papillary surface covered by plaques [
      • Matlaga B.R.
      • Williams Jr., J.C.
      • Kim S.C.
      • et al.
      Endoscopic evidence of calculus attachment to Randall's plaque.
      ]. Scanning microscopy of these plaques confirmed that the initial site of crystal deposit is within the base membrane of the thin loop of Henle, as hypothesized by Evan et al [
      • Evan A.P.
      • Lingeman J.E.
      • Coe F.L.
      • et al.
      Randall's plaque of patients with nephrolithiasis begins in basement membranes of thin loops of Henle.
      ,
      • Evan A.P.
      • Lingeman J.E.
      • Coe F.L.
      • Worcester E.M.
      Role of interstitial apatite plaque in the pathogenesis of the common calcium oxalate stone.
      ]. Intratubular crystallization was not found within the renal tubules or collecting ducts in idiopathic CaOx stone formers.
      Although the site of stone formation has become clear, the initial trigger for crystallization remains under discussion. A multifactorial process seems to be the most probable. An increased urinary calcium excretion appears to play an important role because the measured papillary coverage correlates with urinary calcium and urine pH [
      • Kuo R.L.
      • Lingeman J.E.
      • Evan A.P.
      • et al.
      Urine calcium and volume predict coverage of renal papilla by Randall's plaque.
      ]. Earlier examinations showed higher calcium and oxalate concentrations within the renal papilla than within the renal cortex, medulla, or urine [
      • Hautmann R.
      • Lehmann A.
      • Komor S.
      Calcium and oxalate concentrations in human renal tissue: the key to the pathogenesis of stone formation?.
      ]. An acidic urinary pH leads to an increased bicarbonate resorption into the renal medulla and a consecutive increasing interstitial pH that may promote apatite depletion [
      • Matlaga B.R.
      • Williams Jr., J.C.
      • Kim S.C.
      • et al.
      Endoscopic evidence of calculus attachment to Randall's plaque.
      ].
      Recent findings have helped us understand the mechanism of CaOx stone formation on the Randall plaques (which are separated from the urine by the urothelial layer) [
      • Evan A.P.
      • Lingeman J.E.
      • Coe F.L.
      • Worcester E.M.
      Role of interstitial apatite plaque in the pathogenesis of the common calcium oxalate stone.
      ,
      • Matlaga B.R.
      • Coe F.L.
      • Evan A.P.
      • Lingeman J.E.
      The role of Randall's plaques in the pathogenesis of calcium stones.
      ]. Stones derived from biopsies of renal papillae were evaluated by immunohistochemistry, scanning microscopy, and infrared spectroscopy. These examinations demonstrated that the urothelium was lost at the attachment side. Organic matrix (mainly Tamm-Horsfall protein and osteopontin) and crystals formed belts that are obviously required to allow further crystal depletion and consequently CaOx stone formation.

      4. Conclusions

      UL is a common disease with an increasing incidence and prevalence worldwide. Lifestyle and dietary choices implicated in the complex of the metabolic syndrome are important factors contributing to such developments. The pathogenesis and pathophysiology of CaOx stones, the most common urinary stones, is still incompletely understood. Recent evidence suggests a primary interstitial apatite crystal formation (Randall plaque) that secondarily leads to CaOx stone formation.

      Conflicts of interest

      In recent years, the author has received consultancy or lecturer honoraria from Rowa Pharmaceuticals.

      Funding support

      None.

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