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结石 病生过程
结石 病生过程

Recent advances in the pathophysiology of nephrolithiasis

Khashayar Sakhaee 1

1

Department of Internal Medicine,Charles and Jane Pak Center for Mineral Metabolism and Clinical Research,University of Texas Southwestern Medical Center at Dallas,Dallas,Texas,USA

Over the past 10years,major progress has been made in the pathogenesis of uric acid and calcium stones.These advances have led to our further understanding of a pathogenetic link between uric acid nephrolithiasis and the metabolic syndrome,the role of Oxalobacter formigenes in calcium oxalate stone formation,oxalate transport in Slc26a6-null mice,the potential pathogenetic role of Randall’s plaque as a precursor for calcium oxalate nephrolithiasis,and the role of renal tubular crystal retention.With these advances,we may target the development of novel drugs including (1)insulin sensitizers;(2)probiotic therapy with O.formigenes ,

recombinant enzymes,or engineered bacteria;(3)treatments that involve the upregulation of intestinal luminal oxalate secretion by increasing anion transporter activity (Slc26a6),luminally active nonabsorbed agents,or oxalate binders;and (4)drugs that prevent the formation of Randall’s plaque and/or renal tubular crystal adhesions.

Kidney International (2009)75,585–595;doi:10.1038/ki.2008.626;published online 10December 2008

KEYWORDS:calcium oxalate;kidney stone;metabolic syndrome;nephrolithiasis;uric acid

Calcium oxalate is the most prevalent type of kidney stone disease in the United States and has been shown to occur in 70–80%of the kidney stone population.1The prevalence of recurrent calcium oxalate stones has progressively increased in untreated subjects,approaching a 50%recurrence rate over 10years.2The lifetime risk for kidney stone disease currently exceeds 6–12%in the general population.3,4In the ?nal quarter of the twenty-?rst century,the prevalence of kidney stone disease increased in both gender and ethnicity.4Although kidney stone nephrolithiasis is perceived as an acute illness,there has been growing evidence that nephro-lithiasis is a systemic disorder that leads to end-stage renal disease.5–7It is also associated with an increased risk of hypertension,8–12coronary artery disease,13,14the metabolic syndrome (MS),15–20and diabetes mellitus.19–24Nephro-lithiasis without medical treatment is a recurrent illness with a prevalence of 50%over 10years.2Nephrolithiasis has remained a prominent issue that imposes a signi?cant burden on human health and is a considerable ?nancial expenditure for the nation.In 2005,based on inpatient and outpatient claims,this condition was estimated to cost over $2.1billion.25A novel strategy for the development of new drugs has been hampered largely by the complexity of this disease’s pathogenetic mechanism and its molecular genetic basis.Our further understanding of these underlying pathophysiologic mechanisms will be the key step in developing more effective preventive and therapeutic measures.

ETIOLOGIC MECHANISMS OF URIC ACID STONE FORMATION

Three major factors for the development of uric acid (UA)stones are low urine volume,acidic urine pH,and hyperuricosuria.However,abnormally acidic urine is the principal determinate in UA crystallization.The etiologic mechanisms for UA stone formation are diverse,and include congenital,acquired,and idiopathic causes.26The most prevalent cause of UA nephrolithiasis is idiopathic.In its initial description,the term ‘gouty diathesis’was coined.27The clinical and biochemical presentation of idiopathic UA nephrolithiasis (IUAN)cannot be attributed to an inborn error of metabolism 26,28,29or secondary causes such as chronic diarrhea,30strenuous physical exercise,31and a high purine diet.32

https://www.sodocs.net/doc/2c14234046.html, r e v i e w

&2009International Society of Nephrology

Received 15August 2008;revised 14October 2008;accepted 21October 2008;published online 10December 2008

Correspondence:Khashayar Sakhaee,Department of Internal Medicine,Charles and Jane Pak Center for Mineral Metabolism and Clinical Research,University of Texas Southwestern Medical Center at Dallas,3523Harry Hines Blvd,Dallas,Texas 75390-8885,USA.

E-mail:Khashayar.Sakhaee@https://www.sodocs.net/doc/2c14234046.html,

PHYSICOCHEMICAL CHARACTERISTICS OF URIC ACID

In humans and higher primates,UA is an end product of purine metabolism.Owing to their lack of the hepatic enzyme,uricase,which converts UA to soluble allantoin,their serum and urinary levels of UA are considerably higher than in other mammals.33Normally,urinary UA solubility is limited to96mg/l.In humans with a urinary UA excretion of 600mg/day,this should generally exceed the limit of solubility and susceptibility to precipitation.34Moreover, urine pH is another important factor in UA solubility.UA is a weak organic acid with an ionization constant(pKa)of 5.5.35,36Therefore,at a urine pH less than5.5,the urinary environment becomes supersaturated with sparingly soluble, undissociated UA that precipitates to form UA stones21,37,38 (Figure1).

EPIDEMIOLOGY OF URIC ACID NEPHROLITHIASIS AND THE METABOLIC SYNDROME

The MS is an aggregate of features that increase the risk of type2diabetes mellitus(T2DM)and atherosclerotic cardiovascular disease.15–17In a retrospective analysis a stone registry in Dallas initially showed a high prevalence of features of the MS in IUAN patients,leading to the determination that patients with IUAN share characteristics similar to those of the MS.Numerous epidemiologic studies have shown that obesity,weight gain,and T2DM are associated with an increased risk of nephrolithiasis.39,40 Despite the large sample size,stone composition was not reported among these studies.This center?rst reported the high prevalence of UA stones as the main stone constitute found in T2DM.In addition,recent retrospective and cross-sectional studies have noted an increased prevalence of UA stones among obese and T2DM patients.23,41–44However, T2DM and a greater body mass index were shown to be independent risk factors for nephrolithiasis.44PATHOPHYSIOLOGY OF LOW URINE pH IN IDIOPATHIC URIC

ACID NEPHROLITHIASIS

The metabolic defect suspected for low urinary pH in UA

stone formation was described almost four decades ago.45

Defective ammoniagenesis or excretion was attributed as a

possible pathogenetic mechanism.Initial studies showing

abnormalities in glutamine metabolism,which resulted in the

impaired conversion of glutamine to a-ketoglutarate and

consequently resulted in reduced renal ammonium(NH4t) excretion,were not supported by further investigation.46–49

Mechanistic studies,however,have shown that the two major

factors responsible for abnormally low urine pH are a

combination of defective NH4texcretion and increased net acid excretion(NAE).

Defective ammonium excretion

Under normal circumstances,a tight acid–base balance is maintained with a high capacity buffer,ammonia,(pKa9.2), which effectively buffers most protons while the remaining protons are buffered by titratable acids.This process works to sustain a normal urinary pH.In contrast,the defective NH4texcretion in IUAN requires the urine to be buffered mainly by titratable acids to maintain this equilibrium,thus promoting an acidic urinary pH and providing an environment highly conducive for UA precipitation(Figure2).

Increased acid production alone may not be suf?cient in causing abnormally acidic urine,as the excreted acid is neutralized by urinary buffers.Evidence of defective NH4texcretion was provided in IUAN patients under a?xed, metabolic diet.21,23Therefore,an unduly acidic urine pH in the IUAN population is not related to environmental factors but it is,in part,related to the higher body weight in these subjects.50The defective NH4tproduction in these subjects was further explored by the administration of an acute acid load,which ampli?ed the ammoniagenic effect21(Figure3). Similar?ndings were also demonstrated in IUAN patients on a random diet.22Furthermore,it has been shown that in normal persons,urinary pH and NH4t/NAE ratio falls with increasing features of the MS,indicating that renal

H+ + Urate Uric acid

pKa = 5.5

pH < 5.5

Undissociated uric acid

Uric acid or uric

acid/CaOx stones

Figure1|Physicochemical scheme for the development of uric acid stones.

Renal tubule lumen

NH3

NH4+

A–

HA

H+H+

NH3

NH4+

Normal UA nephrolithiasis

A–

HA Figure2|Mechanisms of urinary acidification.

ammoniagenesis and low urine pH may be features of the general MS and not IUAN speci?c.51

Several studies have provided evidence supporting a relationship between UA nephrolithiasis,obesity,and insulin resistance.21,23,41–44The mechanistic connection between

peripheral insulin resistance,urinary pH,and NH 4t

,was ?rst demonstrated using the hyperinsulinemic-euglycemic clamp technique in patients with IUAN.24These studies support the potential role of insulin resistance in an impaired

urinary NH 4t

excretion and low urinary pH.Insulin receptors are expressed in various portions of the ne-phron.52,53Furthermore,in vitro studies have shown that insulin has a stimulatory function in renal ammoniagen-esis.54,55In addition,NH 4t

secretion is regulated by the sodium–hydrogen exchanger NHE3.56As NHE3has a key

function in the transport or trapping of NH 4t

in the renal

tubular lumen,56

insulin resistance may potentially lead to

defective renal NH 4t

excretion.One other plausible mechan-ism may be substrate competition by substituting circulating free fatty acid for glutamine,which is increased in the MS,thereby reducing the proximal renal tubular cell utilization of glutamine and renal ammoniagenesis.57

Increased net acid excretion

An elevated NAE may occur due to increased endogenous acid production or because of dietary in?uences such as low dietary alkali or the increased consumption of acid-rich foods.36Metabolic studies comparing subjects on ?xed,low-acid ash diets showed a higher NAE in IUAN patients compared to control subjects,suggesting that endogenous acid production may increase in IUAN 34(Figure 4).In addition,the urinary NAE for any given urinary sulfate

(a surrogate marker of acid intake)tended to be higher in patients with T2DM.22These studies also implied that the pathophysiologic mechanism accounting for increased NAE is related to obesity/insulin resistance.Supporting this correlation,additional studies have shown increased organic acid excretion with higher body weight and higher body surface area.58,59The nature of these putative organic anions and their link to obesity and/or UA stones has not been fully studied.

POTENTIAL ROLE OF RENAL LIPOTOXICITY

Under standard metabolic conditions,when caloric intake and caloric utilization are well balanced,triglycerides accumulate in adipocytes.60,61A disequilibrium in this tight balance leads to the accumulation of fat to non-adipocyte tissues.61This process of fat redistribution,termed lipotoxi-city,typically affects tissues such as cardiac myocardial cells,pancreatic b -cells,skeletal muscle cells,and parenchymal liver cells.61–66

Cellular injury is primarily due to the accumulation of nonesteri?ed fatty acids and their toxic metabolites including fatty acyl CoA,diacylglycerol,and ceramide.60,67,68It has been shown that fat redistribution is accompanied with impaired insulin sensitivity,63cardiac dysfunction,65and steatohepatitis.62,69There is an emerging interest in the role of renal lipotoxicity in the pathogenesis of renal disease.67,70,71A few studies have revealed a mechanistic link between obesity,obesity-initiated MS,and chronic kidney disease.70,71Additional studies have shown a possible role of sterol-regulating element-binding proteins in renal fat accumulation and injury.72–74At the present time,there is insuf?cient data available to suggest whether renal lipotoxi-city in?uences endogenous acid production and reduces renal ammoniagenesis,consequently leading to abnormally acidic urine.

From the above information,one may propose a three-hit mechanism for the development of low urinary pH and the propensity for UA stone formation.The ?rst mechanism is related to excessive dietary acid intake and/or increased endogenous acid production.However,this alone may not be suf?cient in lowering urinary pH.Therefore,the second

mechanism is associated with defective NH 4t

excretion.Together,these two defects lower urinary pH adequately enough to convert urate salt into undissociated UA.This is necessary but not suf?cient for the formation of UA stones.Finally,the possible absence of inhibitors or presence of promoters of UA precipitation is operative in triggering UA stone formation.

CALCIUM OXALATE NEPHROLITHIASIS

Although it affects both genders,calcium oxalate nephro-lithiasis generally tends to occur in more men than women.In the calcium oxalate stone former,urinary oxalate and urinary calcium are equally conducive in raising urinary calcium oxalate supersaturation.75Hyperoxaluria is encoun-tered in 8–50%of kidney stone formers.76–78The main

N H 3/C r m o l /m g (p r e a n d p o s t )

N H 4+/C r m o l /m g (p r e a n d p o s t )

U r i n a r y p H (p r e a n d p o s t )

0.001

0.0020.0030.0040.00510

20

30

40

NH

3/Cr mol/mg (pre and post)NH 4+/Cr mol/mg (pre and post)Normal subjects

Urinary pH (pre and post)

6.5

6.0

5.5

5.0

Uric acid stone formers

NH 3 + H +

NH 4+

Figure 3|Acute acid loading.Previously published in Sakhaee et al .21

etiologic causes of hyperoxaluria can be classi?ed into three groups:(1)increased oxalate production as a result of an inborn error in metabolism of the oxalate synthetic pathway,(2)increased substrate provision from dietary oxalate-rich foods or other oxalate precursors,and (3)increased intestinal oxalate absorption.1With the study of Oxalobacter formigenes (OF)79,80and the role of putative anion transporter Slc26a681as potential tools in the treatment of primary hyperoxaluria,our knowledge of the pathophysiologic mechanisms of oxalate metabolism has advanced signi?cantly over the past decade.82

PHYSICOCHEMICAL PROPERTIES OF OXALATE

The human serum oxalate concentration ranges between 1and 5m M ,however,due to water reabsorption in the kidney,its concentration is 100times higher in the urine.1,83At a physiologic pH,oxalate will form an insoluble salt with calcium.As the solubility of calcium oxalate in an aqueous solution is limited to approximately 5mg/l at a pH of 7.0,assuming that normal urine volume ranges between 1and 2l/day and normal urinary oxalate excretion is less than 40mg/day,normal urine is often supersaturated with calcium oxalate.However,under normal conditions,the blood is undersaturated with respect to calcium oxalate.As seen in patients with primary hyperoxaluria and renal insuf?ciency,when the serum oxalate concentration increases to above 30m M ,the blood becomes supersaturated with calcium oxalate.84In the plasma,oxalate is not signi?cantly bound to protein and is freely ?ltered by the kidneys.A recent study reported that urinary calcium is as important as urinary oxalate in raising calcium oxalate supersaturation.75

OXALATE HOMEOSTASIS Hepatic production

In mammals,oxalate is an end product of hepatic metabolism.79The major precursor for hepatic oxalate production is glyoxalate metabolism within hepatic peroxi-somes.This metabolic conversion is mediated by enzyme alanine–glyoxalate aminotransferase.Under normal circum-stances,the metabolism of glyoxalate to glycolate and glycine determines the conversion of glyoxalate to oxalate.Glyoxalate is also metabolized to glycolate by enzyme D -glycerate dehydrogenase,which has both glyoxalate/hydroxypyruvate reductase activity.85An inborn error in metabolism with alanine–glyoxalate aminotransferase and glyoxalate/hydroxy-pyruvate reductase de?ciency leads to oxalate overproduc-tion,which results in type 1and type 2primary hyperoxaluria.79,81,85Several other metabolic precursors of oxalate metabolism,including the breakdown of ascorbic acid,fructose,xylose,and hydroxyproline,have also been incriminated.However,their in?uences on oxalate produc-tion,under normal physiologic circumstances,have not been fully accepted.86–88

Intestinal absorption

Dietary oxalate intake is important in urinary oxalate excretion.The estimated intake of oxalate ranges between 50and 1000mg/day.77,78,89Oxalate-rich foods primarily include seeds,such as chocolate that is derived from tropical cacao tree,and leafy vegetation,including spinach,rhubarb,and tea.Approaching approximately 45%,the contribution of dietary oxalate to urinary oxalate excretion has been shown to be much higher than previously described.90In addition,with intestinal oxalate absorption ranging between 10and

m E q /d a y

Normal subjects Net acid excretion 32 mEq

NH 4

+

NH 4+

NH 4+

TA

Net acid excretion 61 mEq

HCO 3

Cit

Type 2 diabetics

TA

Cit

HCO 3–HCO 3–

UA Stone formers

Net acid excretion 61 mEq

T A

Cit

*P <0.001 vs NV

*

*

*

–20

–100102030405060708090Figure 4|Inpatient net acid https://www.sodocs.net/doc/2c14234046.html, acid excretion ?NH 4ttTA–(HCO 3àtCit).

72%,this relationship between oxalate absorption and dietary oxalate intake has not been shown to be linear.90 In humans,the exact intestinal segment participating in oxalate absorption has not been determined.Indirect evidence suggests that oxalate absorption occurs throughout a large segment of the small intestine.This has been proposed as the main percentage of absorption occurs during the?rst 4–8h after the ingestion of oxalate-rich foods.91–93This inference has been made based on the reported5-h intestinal transit time from the stomach to the colon.However,it has also been suggested that the colon may also participate in oxalate absorption,but to a lesser extent.93In addition,the paracellular intestinal oxalate?ux has been suggested to occur in the early segment of the small intestine largely due to the negative intestinal luminal potential and higher luminal oxalate concentration compared to the blood.94

Role of the putative anion exchange transporter Slc26a6 Recently,the putative anion exchange transporter Slc26a6has been shown to be involved in intestinal oxalate transport.82 The Slc26a6is expressed in the apical portion of various segments of the small intestine such as the duodenum, jejunum,and ileum.It can also be found in the large

intestine,but to a smaller percentage.95In vitro studies using the Ussing chamber technique demonstrated defective net oxalate secretion in mice with a targeted inactivation of the Slc26a6.96Moreover,in vivo studies in the Slc26a6-null mice on a controlled oxalate diet reported high urinary oxalate excretion,increased plasma oxalate concentration,and decreased fecal oxalate excretion.96The differences in urinary oxalate excretion,plasma oxalate concentration,and fecal oxalate excretion were abolished following a7-day equilibra-tion on an oxalate-free diet.These?ndings suggest that the reduction of net oxalate secretion in Slc26a6-null mice increases net oxalate absorption,raising plasma oxalate concentrations and consequently raising urinary oxalate excretion.This study concluded that the Slc26a6anion exchanger has a key function in urinary oxalate excretion.96 These results were also associated with bladder stones and Yasue-positive crystals in the kidney.Staining of the kidney specimen with Yasue stain demonstrated evidence of birefringent crystal deposits in the luminal cortical collecting ducts and,to a minimal extent,in the inner medullary collecting ducts(IMCD).Calcium oxalate stones were found in the renal pelvis and bladder.The renal tubular epithelial cells were surrounded by lymphocytic in?ltration and distorted morphology.However,unlike with the kidneys in idiopathic calcium oxalate stone formers,no abnormality was found in the medullary interstitial space.

Role of O.formigenes

Among many other bacteria including Eubacterium lentum,Enterococcus faecalis,Lactobacillus,Streptococcus thermophilus,and Bi?dobacterium infantis,OF have been reported to degrade oxalate.94OF was?rst isolated in ruminates97and has since been found in many animal species as well as in humans.98However,OF is not found in infancy.The bowel becomes colonized with this bacterium at approximately6–8years of age.It decreases in later years and may only be found in the feces of60–80%of the adult population.99

OF is a Gram-negative obligate anaerobe microorganism that primary utilizes oxalate as a source of energy for cellular biosynthesis.100Through this electrogenic process,oxalate enters the oxalobacter through an oxalate–formate antiporter. It then utilizes its own enzymes,formyl CoA transferase and oxalyl-CoA decarboxylase,to convert oxalate into formate and CO2.101In this process,one proton is utilized and creates a chemical gradiant due to the cell alkalinity.The electro-chemical gradients created by these processes facilitate proton entry and ATP synthesis101(Figure5).

The clinical importance of OF colonization is primarily suggested for patients with recurrent calcium oxalate nephro-lithiasis,102–104in patients with enteric hyperoxaluria,105,106and in those with cystic?brosis.107Studies in patients with urolithiasis and cystic?brosis have shown that the prolonged use of antibiotics may abrogate the bowel colonization of OF and may irreversibly destroy these bacteria.Very recently,a case–control study of274patients with recurrent calcium oxalate stones and259normal subjects matched for age and gender displayed that the prevalence of OF was signi?cantly lower in the stone formers.In this study,17%of stone formers were positive for OF vs38%of normal subjects.This relationship persisted with age,gender,race,ethnic back-ground,region,and antibiotic use108(Figure6).

The colonization of OF may be regulated by dietary oxalate intake.This has been shown in animal models where a signi?cant decrease in urinary oxalate resulted from the administration or in the upregulation of OF coloniza-

Formyl-CoA transferase

Oxalyl-CoA decarboxylase

+ + + + + + + +

––––––––

O–O–

O–

O

O

O O

O O

O

H

H+

H

Oxalate2–Formate1–

F0 F1

3H+

ADP

CO2

A TP

1

SCoA SCoA

Formyl-CoA

Oxalyl-CoA

2

Figure5|Oxalate catabolism and energy conservation in Oxalobacter formigenes.

tion.102,109It has been recently shown in rodents, ex vivo using the Ussing chamber method,that the role of OF in oxalate metabolism is not solely dependent on its capacity to degrade intestinal luminal oxalate or to lower mucosal to serosal oxalate?ux,but also on its capacity to stimulate the net intestinal oxalate secretion.110Given this experimental design,increased net oxalate secretion cannot be explained by transepithelial oxalate gradients.One may speculate that OF interacts with mucosal epithelial cells, enhancing luminal oxalate secretion.

The result of these animal experiments has been recently conveyed into human diseases.80One such study conducted in patients with type1primary hyperoxaluria,in subjects with normal renal function,and in patients with chronic renal insuf?ciency,reported the reduction of urinary oxalate that ensued following the oral administration of OF.80The major drawbacks of the use of OF are(1)the lack of large, long-term,controlled studies in calcium oxalate kidney stone formers and in subjects with enteric hyperoxaluria,such as patients with cystic?brosis or those following a gastro-intestinal bypass procedure;(2)the variable response to OF administration;and(C)OF’s short life span on the complete utilization of its primary nutrient source,oxalate.Future long-term studies and the development of target drugs to either upregulate the intestinal secretion of oxalate by stimulating Slc26a6provide the enzyme products of OF to allow for its persistent oxalate-degrading capacity,provide engineered bacteria that are not entirely dependent on oxalate as a substrate for nutrients,or contain a luminally active agent that binds intestinal luminal oxalate content are necessary in overcoming these de?ciencies.

Renal excretion

The kidney has an important function in oxalate excretion. With impaired kidney function,plasma oxalate concentra-tions progressively rise and result in kidney damage. Eventually,with further impairment,there is a robust spike in plasma oxalate concentration that exceeds its saturation in the blood and thereby increases the risk of systemic tissue oxalate deposition.It has been recently demonstrated that Slc26a6is also expressed in the apical portion of the proximal renal tubule111and in?uences the activity of various apical anion exchangers.112In Slc26a6-null mice,it has been shown that Cl–oxalate exchange activity is completely inhibited,and the activity of Clà/OHàand Clà/HCO3is signi?cantly diminished.However,the signi?cance of this putative anion transporter in calcium oxalate stone formation has not been fully elucidated.

RANDALL’S PLAQUE IN THE PATHOGENESIS OF CALCIUM OXALATE STONES

Several mechanisms have been proposed for the formation of calcium stones.First,it has been suggested that the increased supersaturation of stone-forming salts are responsible for the process of homogenous nucleation in the lumen of the nephron.This process,followed by crystal growth,ultimately results in an obstruction in the distal nephron.Second,it has been suggested that crystal forms in the renal tubular lumen adhere to the luminal renal tubular cells.This adhesion then induces renal cell injury resulting in the formation of a?xed nuclei that interacts with the supersaturated urinary environment and results in crystal growth.These processes both lead to nephron obstruction and consequently result in intratubular calci?cation.113However,the theory of?xed and free crystal growth attachments in the nephron has not been fully described as a mechanism of kidney stone formation.As occurs in intestinal bypass and cystine patients,if an intraluminal crystal plug attachment occurs at the opening of the Bellini duct,it is possible that this mineral plug can protrude to the minor calyx,resulting in stone growth.

Dr Alexander Randall was the?rst to argue that intraluminal plugging is an infrequent occurrence in kidney stone formers.114Conversely,he suggested that interstitial calcium phosphate deposits are initial niduses that anchor urinary crystals beneath the normal uroepithelial cells of the renal papilla.The erosion of the overlying uroepithelium exposes these deposits,referred to as plaques,to the supersaturated urine that then propagate calcium oxalate stones.He found these lesions to be interstitial as opposed to intraluminal,and without any in?ammatory reactions.He also showed these deposits to be mainly found beneath the tubular basement membrane and in the interstitial collagen. Randall’s hypothesis was primarily disputed since it was carried out in cadaveric kidney specimens and not in a targeted kidney stone-forming population.114His major discovery,however,was a small stone propagated in the renal pelvis that was attached to a calcium plaque found in the papillae of the kidney.

Characteristics of the interstitial plaques

Randall’s initial observations were recently followed with the development of modern techniques for determining mineral composition.These techniques have been used to

Positive

(17%)

Oxalobacter formigenes status

Negative (83%)

Positive

(38%) Negative

(62%)

Recurrent CaOx stone formers

(n = 247)Non-stone formers

(n = 259)

Figure6|Oxalobacter formigenes in stool among patients with recurrent calcium oxalate kidney stones and non-stone formers.Previously published as a modification of information obtained from Kaufman et al.108

characterize the nature of crystals attached to these plaques and to develop novel techniques to visualize Randall’s plaque in vivo in patients with nephrolithiasis.115,116An analysis of over5000stones showed the main mineral composition of interstitial plaque to be mainly carbapatite.However, amorphous carbonated calcium phosphate,dosium hydrogen urate,and UA were found to a smaller extent.117Another study utilizing m-CT determined that apatite crystal surrounded by calcium oxalate was the main mineral composition of Randall’s plaque.118

It was?rst shown that Randall’s plaques occur more frequently in patients with kidney stones as compared to non-stone formers undergoing an endoscopic evaluation.119 Furthermore,a relationship was found between metabolic abnormalities in patients with calcium stones and the number of plaques.120The result of this study was reached using digital video and endoscopic techniques to estimate accurately the extent of Randall’s plaque in both calcium stone-forming and non-stone-forming subjects.121In this study,the main biochemical pro?les correlating with the formation of interstitial plaque were urinary volume,urinary pH,and urinary calcium excretion.Higher urinary calcium and lower urinary volume showed an increased coverage of the renal papilla with plaque.This study supports a mechanistic relationship between water reabsorption in the renal medulla and papilla with plaque formation.In addition, a separate retrospective study,using nephroscopic papillary

mapping with representative still images and Moving Pictures Expert Group movies in13calcium oxalate kidney stone formers,determined the percent of plaque coverage to be directly correlated with the number of kidney stones formed.122

LOCALIZATION OF RANDALL’S PLAQUE

The basement membrane of thin descending loops of Henle is the principal site of Randall’s plaque localization.115The thin descending limb basement membrane is made up of collagen and mucopolysaccharides,which attract calcium and phosphate ions.123Once attracted to this protein matrix,the crystallization processes begins.In the interaction following, calcium phosphate crystals grow and propagate to the surrounding collagen and mucopolysaccharide-rich renal interstitium.124This complex then makes its way through the urothelium and serves as a nidus for calcium oxalate deposition,ultimately resulting in calcium oxalate kidney stone formation.Randall’s plaque has only been localized in the basement membranes and in the interstitium.It has never been found in the tubular lumen within epithelial cells or vessels.Within the basement membrane,this plaque consists of coated particles of overlying regions of crystalline material and organic matrix116(Figure7).

MECHANISM OF PLAQUE FORMATION

The mechanism of interstitial plaque formation has not been fully elucidated.Our limitations in this area are based on the lack of availability of an animal model that mimics this human disease.A few clinical studies have suggested a correlation between urine volume,urinary calcium,and severity of stone disease with the fraction of papillary interstitium covered by Randall’s plaque.119–122Although this link is not causal,however,it indicates some correlation between plaque formation and kidney stone disease in idiopathic hypercalciuric patients.It is plausible to propose that plaque formation in the thin descending limb of Henle occurs because of an increase in interstitial calcium and phosphate concentration as well as an increase in renal papillary osmolality as a result of water reabsorption in this nephron segmet.125Moreover,whether increasing interstitial ?uid pH affects the abundance of plaque formation has been suggested but has never been fully explored.116

ABSENCE OF RANDALL’S PLAQUE

Following gastric bypass surgery

Hyperoxaluria and calcium oxalate stones are a common occurrence in patients following intestinal bypass surgery due to morbid obesity.116,126In these subjects,there is no plaque observed in the renal papilla.However,crystal aggregates are found in the IMCD.Moreover,in contrast to conditions in idiopathic calcium oxalate stone formers,there is evidence of renal IMCD cell injury,interstitial?brosis,and in?ammation adjacent to the crystal aggregates.The IMCD crystal aggregates are usually composed of apatite crystals.The deposition of these apatite crystals occurs despite an acidic urinary environment,implying that tubular pH may be different from the?nal urinary pH.

116,126

Figure7|Sites and characteristics of crystal deposition.A transmission electron micrograph showing a crystalline structure composed of concentric layers of crystalline material(light)and matrix protein(dark).Previously published in Evan et al.127

Brushite stone formers

In brushite stone formers,similar to calcium oxalate stone formers following gastric bypass surgery,there is evidence of cell injury and interstitial?brosis in the IMCD adjacent to apatite crystal deposits.Although brushite stone formers, much like idiopathic calcium oxalate stone formers,have plaque in the renal papilla,the stones have not been shown to attach to the plaque.127This may be,in part,due to clinical and technical dif?culties as the high burden of brushite stones may affect the structural integrity of the renal papillae, making it dif?cult to detect smaller stones that may be attached to the plaque.In addition,the extent of Randall’s plaque is minimal in brushite stone formers so attached stones are not commonly anticipated.One important predisposition to distortion of structural integrity of the renal papillae in these subjects may be acquired and is related to the number of shockwave lithotripsy in this popula-tion.127,128

THE ROLE OF RENAL TUBULAR CRYSTAL RETENTION Although the crystallization process is necessary,it alone is not suf?cient for the formation of kidney stones.Three decades ago,it was initially proposed that the accumulation of crystals in the renal calices are involved in the pathogenesis of nephrolithiasis.129It was further hypothesized that tubular nephrocalcinosis is preceded by renal stone formation.This scheme does not refute Randall’s theory that interstitial nephrocalcinosis and plaque formation are precursors for the development of kidney stones.114However,it has become increasingly recognized that both mechanisms may be signi?cant in the formation of kidney stones.130,131The further elaboration of these two pathogenic pathways is important as stone formation may occur in the absence of plaque in the kidney.132Furthermore,experimental evidence has suggested that crystal binding to the surface of the regenerating/redifferentiating renal tubular cell is regulated by the expression of a number of luminal membrane molecules,including hyaluronic acid,osteopontin,their transmembrane receptor protein CD44,and p38mitogen-activated protein kinase.130,133–137In addition,several other molecules expressed in the renal tubular apical membrane such as Annexin-II138and an acidic fragment of nucleolin-related protein139have been proposed as active binding protein regions for calcium oxalate crystals.The clinical implications of this experimental evidence are progressively emerging in the?eld.

In addition,the increased incidence of tubular nephro-calcinosis in preterm infants may possibly occur from exposure of differentiating renal tubular epithelial cells following crystalluria caused by furosemide treatment.140,141 Moreover,tubular nephrocalcinosis has been seen in a large number of renal allografts,suggesting that ischemic injury resulting in increased expression of hyaluronic acid and osteopontin precedes crystal retention.142,143From the above discussion,one can conclude that under normal conditions, crystals do not adhere to renal tubular epithelial cells and are readily excreted in the urine.However,with antecedent renal tubular epithelial damage and during the process of renal tubular repair,144–146speci?c crystal-binding proteins are expressed at the apical surface of the renal epithelial cell, predisposing crystal adhesion and possibly stone formation. Whether this process has a pathogenic function in many clinical conditions associated with tubular nephrocalcinosis and nephrolithiasis deserves intense future investigation.130 CONCLUSION

Kidney stone disease remains a major public health burden. Its pathophysiologic mechanisms are complex,mainly because it is a polygenic disorder,and it involves an intricate interaction between the gut,kidney,and bone.In addition, an exact animal model to recapitulate the human disease has not yet been de?ned.Despite these limitations,our comprehension of UA stone formation’s link to insulin resistance and renal lipotoxicity,the underlying mechanisms of intestinal oxalate transport,the role of renal papillary plaque in idiopathic calcium oxalate stone formation and renal tubular crystal bindings,has advanced signi?cantly over the past decade.These elucidations can potentially lead us to the development of novel drugs targeting basic metabolic abnormalities that abrogate stone formation. DISCLOSURE

The author declared no competing interest. ACKNOWLEDGMENTS

This work was supported by the National Institutes of Health grants (P01-DK20543and M01-RR00633).We acknowledge Hadley Armstrong for her primary role in the preparation and editorial review of this paper.

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