kidney stone journal

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Kidney Stones 2012: Pathogenesis, Diagnosis,

and Management

Khashayar Sakhaee, Naim M. Maalouf, and Bridget Sinnott

Department of Internal Medicine, Charles and Jane Pak Center for Mineral Metabolism and Clinical

Research, University of Texas Southwestern Medical Center, Dallas, Texas 75390

Context:The pathogenetic mechanisms of kidney stone formation are complex and involve both

metabolic and environmental risk factors. Over the past decade, major advances have been made

in the understanding of the pathogenesis, diagnosis, and treatment of kidney stone disease.

Evidence Acquisition and Synthesis:Both original and review articles were found via PubMed

search reporting on pathophysiology, diagnosis, and management of kidney stones. These re-

sources were integrated with the authors knowledge of the field.

Conclusion: Nephrolithiasis remains a major economic and health burden worldwide. Nephroli-thiasis is considered a systemic disorder associated with chronic kidney disease, bone loss and

fractures, increased risk of coronaryartery disease, hypertension, type 2 diabetes mellitus, and the

metabolic syndrome. Further understanding of the pathophysiological link between nephrolithi-

asis and these systemic disorders is necessary for the development of new therapeutic options.

(J Clin Endocrinol Metab97: 18471860, 2012)

The increased prevalence of kidney stone disease is pan-demic (1). The lifetime risk of kidney stones is cur-rently at 6 12% in the general U.S. population (2). Neph-

rolithiasis has become increasingly recognized as a

systemic disorder (3) that is associated with chronic kid-

ney disease, nephrolithiasis-induced bone disease (4), in-

creased risk of coronary artery disease, hypertension, type

2 diabetes mellitus, and the metabolic syndrome (MS) (5).

Without medical treatment, nephrolithiasis is a chronic

illness with a recurrence rate greater than 50% over 10 yr

(6). Given that the annual expenditure in the United States

exceeds $5 billion, the economic and social burden of

nephrolithiasis is immense (7).

Epidemiology

The prevalence of nephrolithiasis in the United States

has doubled over the past three decades. This increase

has also been noted in most European countries and

Southeast Asia (1). Racial and ethnic differences are

seen in kidney stone disease, primarily occurring in

Caucasian males and least prevalent in young African-

American females. The prevalence in Asian and His-

panic ethnicities is intermediate (1).

The incidence of nephrolithiasis is highest in Caucasian

males (2), where the incidence of kidney stones rises after

age 20, peaks between 40 and 60 yr of age (at approxi-

mately 3 per 1000 per year), and then declines (8). In

females, the incidence rate is higher in the late 20s, de-

creases by age 50, and remains relatively constant there-

after (2, 8).

Pathophysiological Mechanism(s) of

Calcium StonesApproximately 80% of calcium kidney stones are calcium

oxalate (CaOx) (9), with a small percentage (15%) of cal-

cium phosphate (CaP) (10). The pathophysiological

mechanisms for calcium kidney stone formation are com-

plex and diverse and include low urine volume, hypercal-

ISSN Print 0021-972X ISSN Online 1945-7197

Printed in U.S.A.

Copyright 2012 by The Endocrine Society

doi: 10.1210/jc.2011-3492 Received December 29, 2011. Accepted March 6, 2012.

First Published Online March 30, 2012

Abbreviations: Ca:Cr, Calcium:creatinine (ratio); CaOx, calcium oxalate; CaP, calcium

phosphate; dRTA, distal renal tubular acidosis; MS, metabolic syndrome; 1,25(OH)2D,

1,25-dihydroxyvitamin D; PBMC, peripheral blood mononuclear cells; RS, relative super-

saturation; UA, uric acid; VDR, vitamin D receptor.

S P E C I A L F E A T U R E

C l i n i c a l R e v i e w

J Clin Endocrinol Metab, June 2012, 97(6):18471860 jcem.endojournals.org 1847

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TABLE 1. Causes and treatment of kidney stone formation

Etiology Prevalence Physiological mechanism(s) Pharmacological treatment Potential side effects

Calcium kidney stonesHypercalciur ia 3060% 1,25(OH)

2D-dependent Hydrochlorothiazide (50 mg/d) Hypokalemia1,25(OH)2D-independent Chlorthal idone (2550 mg/d) Glucose intoleranceIntrinsic renal calcium leak Indapamide (1.22.5 mg/d) HypomagnesemiaIntrinsic renal phosphorus leak

Resorptive hypercalciuria: PTH-dependent(primary hyperparathyroidism); PTH-

independent

Amiloride

hydrochlorothiazide (5 mg/d 50 mg/d)

Hypertriglyceridemia

Hyperuricosuria 10 40% Exogenous: diet-induced (purine-rich

food)

Allopurinol (100300 mg/d) Rare, severe skin hypersensitivity

Endogenous: urate overproductionHypocitraturia 2060% Low extracellular fluid pH: chronic

diarrhea; exercise-induced lactic

acidosis; dRTA; drug-induced

(acetazolamide, topiramate)

Alkali treatment (30 60 mEq/d) Alkali treatment is generally safe

Normal extracellular fluid pH: potassium

deficiency; excess dietary protein;

urinary tract infection

Potassium alkali is preferred to avert complications

with calcium stone formation

Although it has not been proven, high doses of

alkali may increase the risk of CaP stonesHyperoxaluria 1050% Intestinal hyperabsorption of oxalate:

imbalance between intestinal calcium

and oxalate content; diet-induced highoxalate intake (chocolate, brewed

tea, spinach, nuts; vitamin C, 2 g/d);

role ofOxalobacter formigenes

Alkali treatment (30 60 mEq/d)

to avert metabolic acidosis

Both alkali and pyridoxine treatments are generally

safe

Primary hyperoxaluria: enzymatic

disturbances (types I, II, or undefined

primary hyperoxaluria)

Pyridoxine (2550 mg/d) in type

I primary hyperoxaluria




alkali may increase the risk of CaP stonesUrine pH Unknown Acidic urine: diet, diarrhea, low urine

ammonium

Alkali treatment (30 60 mEq/d) Alkali treatment is generally safe

Alkaline urine: infection; drug-induced

(alkali overtreatment, topiramate,

acetazolamide); defective renal acid

excretion




alkali may increase the risk of CaP stonesNon-calcium kidney

stonesUA 510% Low urine volume Alkali treatment (30 60 mEq/d) Alkali treatment is generally safe

Hyperuricosuria Allopurinol (100300 mg/d) Potassium alkali is preferred to avert complicat ionswith calcium stone formation

Unduly acidic urine Although it has not been proven, high doses of

alkali may increase the risk of CaP stonesAllopurinol rarely causes severe skin

hypersensitivityCystine 5% Renal tubular defect in dibasic amino acid

transport

Alkali treatment (30 60 mEq/d) Alkali treatment is generally safed-Penicillamine (10002000

mg/d)



-Mercaptopropionylglycine

(4001200 mg/d)


alkali may increase the risk of CaP stonesBoth d-penicillamine and -

mercaptopropionylglycine may cause nausea,

vomiting, diarrhea, fever, skin rashes,

arthralgia, lupus-like syndrome, dysgeusia,

insomnia, leukopenia, thrombocytopenia, and

proteinuria-Mercaptopropionylglycine has generally less

frequent severe side effects than d-

penicillamineInfection Unknown Urease-producing bacteria Acetohydroxamic acid (10 15

mg/kg/d)

This treatment should only be used if surgical

removal of infectious stone followed by

eradication of infection with antibiotics is

ineffectiveSevere side effects of acetohydroxamic acid

include intractable headache, hemolytic

anemia, and thrombophlebitis

1848 Sakhaeeet al. Kidney Stones 2012 J Clin Endocrinol Metab, June 2012, 97(6):18471860



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ciuria, hyperuricosuria, hypocitraturia, hyperoxaluria,

and abnormalities in urine pH (Table 1) (11).

Hypercalciuria

Hypercalciuria is the most prevalent abnormality in cal-

cium kidney stone formers. It is detected in 3060% of

adultswith nephrolithiasis(12).In1939, Flocks(13)initiallydescribed the link between hypercalciuria and nephrolithia-

sis. In 1958, Albright and Henneman (14, 15) applied the

term idiopathic hypercalciuria. The pathophysiological

mechanisms for hypercalciuria are numerous and may in-

volve increased intestinal calcium absorption, decreased

renal calcium reabsorption, and enhanced calcium mobi-

lization from bone (4, 1618). However, intestinal cal-

cium hyperabsorptionis themost commonabnormality in

this population (19). Hence, some have adopted the term

absorptive hypercalciuria (19). Nevertheless, all the

aforementioned physiological defects may coexist in in-dividual patients, leading to decreased bone mineral den-

sity and bone fracture (4).

Hypercalciuria is a heterogeneous disorder in which

intestinal calcium hyperabsorption may be dependent (20,

21) or independent(19, 2225) of 1,25-dihydroxyvitamin

D [1,25(OH)2D]. Classically, hypercalciuria is classified

into two different groups. The most severe variant is char-

acterized by normocalcemia, hypercalciuria, intestinalhy-

perabsorption of calcium, and normal or suppressed se-

rum PTH and/or urinary cAMP. However, a less severe

form shares many of the same biochemical characteristics,but hypercalciuria normalizes after a restricted calcium

diet (400 mg/d) (26).

1,25(OH)2D-dependent hypercalciuria

In two studies, increased serum 1,25(OH)2D concentra-

tion was reported in the majority of kidney stone formers

with hypercalciuria (20, 21). Insogna et al. (21) demon-

strated increased 1,25(OH)2D production rather than dis-

turbed clearance in well-characterized patients with hyper-

calciuria. The underlying mechanism(s) of enhanced

1,25(OH)2Dproductionhaveyettobeelucidated.However,in the majority of well-defined hypercalciuric stone formers,

the main regulators of 1,25(OH)2D production, namely se-

rum PTH, phosphorus, and tubular maximum renal phos-

phorus reabsorption, were all at comparable levels to those

of normal non-stone-forming subjects(24). Fewstudieshave

suggested a link between renal tubular phosphorus abnor-

malities and serum 1,25(OH)2D levels (20, 27). Further sup-

porting the role of 1,25(OH)2D-mediated hypercalciuria,

several studies have shown excessive urinary calcium excre-

tion in normal subjects challenged with a large dose of

1,25(OH)2D (20, 28). However, a disagreement has arisenbetween the origin of hypercalciuria in which onestudy sup-

ports theintestinalorigin (20)and theother suggestscalcium

mobilization from bone (28).

1,25(OH)2D-independent hypercalciuria

Despite reports of high circulating 1,25(OH)2D in hyper-

calciuric stone formers (20, 21), several studies have shown

thathyperabsorptionofcalciumisindependentofvitaminD,with over two thirds of idiopathic hypercalciuric patients

exhibiting increased intestinal calcium absorption with nor-

mal prevailing serum 1,25(OH)2D concentration (19, 22

25). To probe this possibility, short-term administration

of ketoconazole, an antimycotic agent known to reduce

serum 1,25(OH)2D, was shown to significantly lower se-

rum 1,25(OH)2D concentration without a significant al-

teration in intestinal calcium absorption in hypercalciuric

subjects (29). Similarly, treatment with thiazide, gluco-

corticoids, and phosphate was not shown to influence in-

testinal calcium absorption in this population, suggestingthat calcitriol has a limited pathophysiological role in hy-

percalciuria (25, 30, 31).

Several studies have exhibited similar phenotypic char-

acteristics in a model of hypercalciuric stone-forming rat

(GHS rat). These studies demonstrated normal serum cal-

cium and calcitriol concentrations, increased intestinal

calcium absorption with the presence of CaP and CaOx

stones (32, 33), enhanced bone resorption, and dimin-

ished renal tubular calcium reabsorption (32, 34, 35). In

this rat model, an increased abundance of vitamin D re-

ceptor (VDR) was shown with normal circulating cal-citriol levels and increased VDR protein in the intestine,

kidney, and bone that was attributed to increased VDR

half-life (34, 36). These results support the notion that

prolonged VDR half-life increases VDR tissue expression,

resulting in hypercalciuria mediated via VDR-regulated

genes controlling vitamin D-regulated calcium transport

mechanisms (36). The biological action of the VDR-

1,25(OH)2D complex wassupportedby increased expres-

sion of both 9- and 28-kDa calbindin levels in the duode-

num and renal cortical tissue of the GHS rat (36).

In human subjects with hypercalciuria, peripheral

blood mononuclear cells (PBMC) were used as an organ

model to further explore the functionality of the VDR-

1,25(OH)2D complex (37). When the PBMC were acti-

vated with phytohemagglutinin, these patients showed a

significantly greater concentration of VDR in the presence

of normal serum calcitriol levels, suggesting 1,25(OH)2D-

independent VDR up-regulation (37). In addition, higher

VDR levels were detected in hypercalciuric subjects in

PBMC without stimulation (38).

Renal leak hypercalciuria

Renal leak hypercalciuria is a second, less common va-riety of hypercalciuria in which defective renal tubular




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calcium reabsorption is accompanied by enhanced PTH,

calcitriol, and net intestinalcalciumabsorption(39).Stud-

ies using a single dose of hydrochlorothiazide in both un-

selected andselected groupsof calcium stone formers have

linked defective renal calcium reabsorption to a proximal

renal tubular defect (16, 17).

Resorptive hypercalciuria

The most common prototype of resorptive hypercalci-

uria is primary hyperparathyroidism. However, dueto the

more frequent early diagnosis of primary hyperparathy-

roidism, the prevalence of nephrolithiasis in thiscondition

is nowadays approximately 28% (11). Hypercalciuria is

perceived as a cause of kidney stones in this population.

Nevertheless, the exact relationship between hypercalci-

uria and the risk of nephrolithiasis with primary hyper-

parathyroidism is not fully agreed upon (40, 41). It has

been disputed whether hypercalciuria originates from in-creasedcalciummobilization fromboneor reflectsincreased

intestinal calciumabsorption (40,42, 43). It issuggested that

kidney stones are more prevalent in younger populations

with primary hyperparathyroidism due to enhanced synthe-

sis of 1,25(OH)2D with intact kidney function, and conse-

quent increased intestinalcalciumabsorption (42). Bone dis-

ease may occur in older subjects due to their lower serum

1,25(OH)2D levels and consequently diminished intestinal

calcium absorption.

HyperuricosuriaHyperuricosuria as an isolated abnormality is detected

in 10% of calcium stone formers. However, in combina-

tion with other metabolic abnormalities it may be present

in 40% of this population (44). The pathophysiological

mechanism underlying hyperuricosuria is attributed to a

high purine diet (45). However, in approximately one

third of patients, endogenous uric acid (UA) overproduc-

tion prevails, and dietary restriction does not significantly

alter urinary UA excretion (46). The physicochemical ba-

sis involved in this process has not been well established.

Although one study has attributed the physicochemicalprocess to urinary supersaturation with colloidal mono-

sodium urate-induced CaOx crystallization (47), another

study has shown a lack of effect of monosodium urate and

attributesCaOx stoneformationto decreased solubility of

CaOx in solution, a process described as salting out

(48).Additionally,a retrospective population-based study

in a large number of patients has not shown a relationship

between urinary UA and CaOx stone formation (49).

Hypocitraturia

Citrate is an endogenous inhibitor of calcium stone for-mation, and low urine citrate excretion (hypocitraturia) is

encountered in 20 60% of calcium nephrolithiasis (50).

Themajor determinant of urinary citrate excretion is acid-

base balance (51). Hypocitraturia commonly occurs with

metabolic acidosis or acid loading mediated through up-

regulation of proximal renal tubular reabsorption of ci-

trate(52).Themainconditionsincludedistalrenaltubular

acidosis (dRTA) (53), carbonic anhydrase inhibitors (54,

55), and normal bicarbonatemic states (56), including in-

complete dRTA (57), thiazide treatment with hypokale-

mia (58), primary aldosteronism (59), high protein con-

sumption (60), excessive salt intake (61), and converting

enzyme inhibitors (62). The physicochemical basis for the

inhibitory role of citrate involves the formation of soluble

complexes and reduction of urinary saturation with re-

spect to calcium salts in addition to direct inhibition of

CaOx crystallization processes (63).

HyperoxaluriaUrinary oxalate and calcium are equally important in

raising urinary CaOx supersaturation (5). Hyperoxaluria

is detected in 10 50% of calcium stone formers (5). The

underlying mechanisms of hyperoxaluria can be divided

into: 1) oxalate overproduction as a result of an inborn

error in metabolism; 2) increased dietary intake and bio-

availability (64); and 3) increased intestinal oxalate ab-

sorption. Inborn errors in metabolism include type I hy-

peroxaluria resulting from a deficiency or mistargeting of

hepatic alanine glyoxylate transferase, type II primary hy-

peroxaluria due to a deficiency in glyoxylate reductase/hydroxypyruvate reductase, and the rare type III hyper-

oxaluria as a result of the gain of function of hepatic or

renal mitochondrial 4-hydroxy-2-oxoglutarate aldolase

(6567). Subsequent investigation substantiated such a

mutation; however, it remains unknown how changes in

enzyme activity result in hyperoxaluria (68). Recently,

Oxalobacterformigenes inhumanshavebeenproposedto

participate in intestinal oxalate metabolism (69). Al-

though a putative anion exchange transporter SLC26A6

has been shown to play a key role in intestinal oxalate

absorption in mice, phenotypic and functional analysishas excluded a significant effect of identified variants in

the corresponding human gene on oxalate excretion in

humans (70, 71).

The most important circumstances in clinical practice

are intestinal malabsorptive disorders including chronic

diarrhea, inflammatory bowel diseases, and intestinal re-

section as occurs post-gastric bypass surgery (72) leading

to enteric hyperoxaluria.Normally, oxalate absorption

takes place throughout the small intestineand, to a certain

extent, in the colon (73). In enteric hyperoxaluria, the

underlying mechanisms are purported to be increased per-meability to oxalate with unabsorbed bile acid and fatty




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acids interacting with divalent cations in the lumen of the

intestine, thereby raising intestinal luminal oxalate con-

tent and resulting in excessive urinary oxalate excretion

(74). In addition to hyperoxaluria, these disorders are as-

sociated with multiple other kidney stone risk factors in-

cluding low urine volume, hypocitraturia, hypomagnes-

uria, and highly acidic urine.

Disturbances in urinary pH

Both highly acidic urine (pH 5.5) and highly alkaline

urine (pH 6.7) predispose patients to calcium kidney

stone formation. With unduly acidic pH, urine becomes

supersaturated with undissociated UA that participates in

CaOx crystallization (47). Significantly alkaline urine in-

creases the abundance of monohydrogen phosphate [dis-

sociation constant (pKa) 6.7], which, in combination

with calcium, transforms to thermodynamically unstable

brushite (CaHPO4.2H2O) and finally to hydroxyapatite[Ca10(PO4)6(OH)2]. In clinical practice, conditions asso-

ciated with CaP stone formation include dRTA, primary

hyperparathyroidism, and use of carbonic anhydrase in-

hibitors (75, 76).

Histopathological mechanisms of calcium kidney

stone formation

Onesuggestedmechanismfor theformationof calcium

stones is increased urinary supersaturation of stone-form-

ing salts, which leads to homogeneous nucleation in the

lumen of the nephron, followed by crystal growth andconsequent obstruction in the distal nephron (5). How-

ever, over the past decade it has become apparent that

CaOx stone formation differs histologically from that of

CaP (77). CaOx stones have been shown to anchor on and

growfrom an interstitial apatite plaque (Randalls plaque)

that covers the renal papillary surface (77). The extent of

plaque in the renal papilla has been positively correlated

with urinary calcium excretion and negatively correlated

withurinary volume (77).The decreased proximaltubular

reabsorption of calcium and enhanced renal tubular cal-

cium reabsorption at the thick ascending limb have beenpurported as the potential pathophysiological mechanism

resulting in interstitial plaque formation. Unlike CaOx, in

CaP stone formers there is apatite crystal deposition in the

inner medullary collecting duct, producing plugs associ-

ated with interstitial scarring (77).

Genetic basis of calcium stone formation

A higher percentage of kidney stones has been reported

in first-degree relatives and family members with kidney

stones (78). This genetic link was further documented in a

study showing a greater concordance with renal stone in-cidence in monozygotic than dizygotic twins (79). How-

ever, due to the complex nature of idiopathic hypercalci-

uria, many putative candidate genes have been identified

that participate in this polygenic illness. Genome-wide

linkage approach in three families with absorptive hyper-

calciuria discovered polymorphisms in the putativesolu-

ble adenylyl cyclase (ADCY10) gene on chromosome

1q23.41q24 (80). Another genome-wide screening in a

large population from Iceland and The Netherlands with

documented radio-opaque kidney stones found polymor-

phisms in sequence variants in the Claudin 14 (CLDN14)

gene, which encodes for the tight junction protein in the

kidney, liver, and inner ear (81). Another study has sug-

gested an association between the calcium sensor receptor

(CASR) gene polymorphism and recurrent nephrolithiasis

(82). However, none of these instances established the

functional significance of these polymorphisms. Future

phenotype-genotype studies are needed to identify the as-

sociated gene defect.

Pathophysiological Mechanism(s) ofNon-Calcium Stones

UA stone formation and its link to the MS

The etiological causes of UA stone formation are ge-

netic, acquired, or a combination of both (60, 83). Over

the past decade, the MS has been characterizedas the most

prevalent cause of UA stone formation (Fig. 1A) (84, 85).

The underlying pathophysiological mechanisms respon-sible for UA nephrolithiasis are: 1) low urine volume; 2)

hyperuricosuria; and 3) unduly acidic urine.

Unduly acidic urine (urinary pH 5.5) is an invariable

feature in UA nephrolithiasis (5). In such an acidic milieu,

the urinary environment becomes supersaturated with

sparingly soluble undissociated UA (84). The two princi-

pal causes for acidic urine are: 1) impaired ammonium

(NH4) excretion; and 2) increased endogenous acid pro-

duction (84, 85). Impaired NH4 excretion in this popu-

lation is shared with patients with the MS and type II

diabetes mellitus without kidney stones (85). Recent ex-perimental evidence using an established rodent model of

obesity (Zucher diabetic fatty rat) and a renal proximal

tubular cell line have demonstrated a causal role of renal

steatosis in the pathogenesis of disturbed urinary acidifi-

cation (86,87).Increased endogenousacidproductionhas

been shown in both UA stone formers and diabetic non-

stone formers (84, 85). However, the nature and source of

this putative organic anion has not been fully elucidated.

Hyperuricosuria may be encountered in certain clinical

circumstances and/or rare genetic disorders linked to the

UA syntheticpathway andas a result of a genetic mutationin renal UA transporters (83, 88).




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Genetic basis of UA stone formation

Many monogenic mutations are associated with hype-

ruricosuria, hyperuricemia, gout,renal failure, and kidney

stone formation (83, 88). However, most UA stone form-

ers have a low fractional excretion of urate and low uri-

nary pH (84). In one study conducted in a Sardinian co-

hort, most subjects exhibited low urinary pH with high

urinary titratable acidity, with only one third showing

elevated urinary UA excretion (89). In this study, genetic

analysis identified a locus on chromosome 10q21-22 as-

sociated with increased propensity to UA nephrolithiasis.

A subsequent study identified the putative gene as zinc

finger protein 365 (ZNF365) (90). However, the func-

tionalimportanceofthisfindingandtheroleoftheprotein

encoded by this gene have not been fully established.

Cystinuria

Cystinenephrolithiasis comprises only a small fraction of

kidney stones inadults but ismore prevalentamongchildren

and adolescents with stones (91). Cystinuria is either auto-somal recessive (obligate heterozygotes withnormal urinary

cystine excretion) or autosomal dominant with incomplete

penetrance (obligate heterozygotes with increased urinary

cystine excretion but typically not enough to cause cystine

stones). It is characterized by an inherited defect in renal

cystine reabsorption expressed as b0, (SLC3A1 and

SLC7A9). Although thedefective renal tubularreabsorption

affects other dibasic amino acids including arginine, lysine,

and ornithine, cystine stones are the main complication of

this genetic defect due to the low solubility of cystine in the

urinary environment (Fig. 1B) (92). In a recent genetic clas-sification, cystinuria is defined as type A if mutations are

found in bothSLC3A1alleles, type B if

mutations are found in both SLC7A9 al-

leles, and type AB if one mutation is

found in each gene (93). With digenic in-

heritance, one would expect 50% of AB

individuals to be affected by nephrolithi-

asis. However, cystine stones are rarelyencountered in this genotype (94).

Infection and rare stones

The most important factors for the

formation of infectious stones are

highly alkaline urine pH (7.2) in the

presence of urease-producing organ-

isms and supersaturated urinary envi-

ronment with respect to magnesium,

ammonium, and phosphate ions (Fig.

1C) (95). Rare forms of kidney stonessuch as dihydroxyadanine, ammonium

urate, and stones resulting from pro-

tease inhibitor drugs may also occur.

Diagnosis

Medical history

In the diagnosis of these patients, systemic and environ-

mental influences must be carefully identified. Systemic ab-

normalities include intestinal disease, disorders of calciumhomeostasis such as primary hyperparathyroidism, condi-

tions accompanied by extra renal 1,25(OH)2D production

such as granulomatous diseases, obesity, type II diabetes,

recurrenturinarytractinfection,bariatricsurgery,medullary

sponge kidney, and various drug treatments.

Diet plays a crucial role in the formation of kidney

stones. High dietary salt and protein consumption are the

two most common dietary aberrations that increase the

risk of nephrolithiasis (61, 96). Epidemiological studies

have shown an association between a higherrisk of kidney

stone formationand lower dietary calcium intake(97, 98).Although the exact pathophysiological mechanism has

not been established, it has been suggested to be due to

lowered urinary oxalate excretion or possibly a rise in

urinary antilithogenic factors with a high-calcium diet. In

contrast, increased calcium and vitamin D supplementa-

tion is reportedly accompanied by a higher risk of neph-

rolithiasis (99). Aside from dietary risk factors, it has been

suggested that kidney stone risk increases in hot climates

aswellaswithfrequentand/orintenseexercise,largelydue

to extra renal fluid loss as a resultof perspiration, resulting

in a significant fall in urine volume (83). It has also beensuggested that certain professions associated with de-

FIG. 1. Causes of non-calcium kidney stone formation. A, UA stones; B, cystine stones; C,infectious stones.

1852 Sakhaeeet al


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creased fluid intake and/or increased perspiration are at

high risk for kidney stones.

Although hypercalciuric nephrolithiasis is typically a

polygenetic complex trait, in rare instances it may be a

monogenetic disorder. The occurrence of hypercalci-

uric nephrolithiasis among male subjects accompanied

by renal impairment and low-molecular-weight pro-

teinuria is suggestive of x-linked recessive disorder de-

tected in patients with Dents disease (100). The occur-

rence of kidney stones and nephrocalcinosis in male

subjects with early cataracts, glaucoma, and neurolog-

ical deficit is suggestive of Lowe syndrome (101). Ag-

gressive nephrolithiasis, nephrocalcinosis, retarded

growth, and deafness can be seen in patients with dRTA

presenting with both autosomal dominant and auto-

somal recessive inheritance (102).

Laboratory diagnosisLaboratory diagnosis includes stone analysis, imaging

studies, blood profiles, and a urine metabolic evaluation

(Table 2). Stone analysis plays a valuable role in the di-

agnosis of kidney stone patients, specifically in infre-

quently encountered kidney stones such as UA, cystine,

infection-induced, drug-induced, and NH4 urate stones.

Imaging studies are valuable in the diagnosis of kidney

stone disease. Despite numerous imaging methodologies,

computed tomography is the most sensitive and specific

mode of diagnosis (103). High fasting blood calcium, low

phosphorus, and elevated PTH are suggestive of primaryhyperparathyroidism. In that case, the patient must be

considered for a noninvasive localization study followed

by parathyroidectomy. Normal serumcalcium, low serum

phosphorus, elevated 1,25(OH)2D, and normal PTH are

suggestive of renal phosphorus leak. The finding of low

serum potassium and low CO2 is suggestive of dRTA.

Hyperuricemia and high serum triglycerides are encoun-

tered in patients with UA stones.

Metabolic evaluation

A simplified metabolic evaluation starts with a random24-h urinary profile (Table 2). However, there is disagree-

ment whether a singlecollection or duplicaterandom 24-h

urine collections are necessary to document kidney stone

risk (104, 105). In some optional instances, 2-h fasting

urinary calcium:creatinine ratio (Ca:Cr) and fasting uri-

nary phosphorus are obtained to establish the diagnosisof

renal leak calcium, excessive calcium mobilization from

bone, and renal phosphorus leak. A 4-h urinary Ca:Cr

after 1 g oral calcium load may follow the 2-h fasting

Ca:Cr for indirect assessmentof intestinalcalcium absorp-

tion (19). An extensive metabolic evaluation may also in-clude bone density analysis becausetheprevalence of bone

fracture hasbeen shown to be higherin kidney stone form-

ers than in the general population (4). Although it is opin-

ion-based, extensive metabolic evaluation may be per-

formed in recurrent kidney stone formers, those with a

familyhistoryofkidneystones,ahistoryofbonefractures,

dRTA, and chronic diarrheal state.

Urinary supersaturation

The utility of urinary supersaturation measurement as

a surrogate of kidney stone incidence has not been fully

studied. To date, only a singlestudy hasprovided evidence

that a reduction in CaOx supersaturation is associated

with a fall in stone incidence (106). However, urinary su-

persaturation is reported in stone risk profiles by most

commercial laboratories. Two methods applied for uri-

nary supersaturation measurements are relative supersat-

uration (RS) ratio and urinary RS (106, 107). With RS

ratio, values greater than 1 indicate supersaturation forallstone types. With RS, the upper limit of normal for ox-

alate, brushite,monosodium urate,and UA is defined as 2.

Treatment

Acute treatment for symptomatic stone passage is beyond

the scope of this review and has previously been exten-

sively described (108).

Conservative management

High oral fluid intake must be considered in all stone

formers. A prospective controlled study has shown that

increasing water intake to ensure a urinary volume of ap-

proximately 2.5 liters/d was associated with reduced uri-

nary supersaturation with CaOx and a significant reduc-

tion in stone recurrence (109).Another study suggests that

fluid intake as fruit juice, specifically orange juice, is also

effective in reducing urinary CaOxsaturationand increas-

ing urinary citrate excretion(110). Thiseffectiveness is not

shared with apple juice, grapefruit juice, cola, and some

sport drinks due to their elevated oxalate and fructose

content(110112).BasedononestudyinItalianmenwithhypercalciuria, great emphasis has been placed on low

dietary sodium (100 mEq/d) and animal protein con-

sumption (5060 g/d) as well as normal calcium intake

(1200 mg/d) in the reduction of calcium stone recurrence

(113). However, another study using only a low-fiber,

low-protein diet in a cohort in the United States did not

show decreased stone recurrence (114). Dietary oxalate

restriction (100 mg/d) is also useful in lowering urinary

oxalate excretion. Foods that are known to raise urinary

oxalate excretion include fruits such as raspberries, figs,

andplums; vegetables such as spinach, rhubarb, andbeets;and most nuts, tea, wheat bran, chocolate, and high




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TABLE 2. Diagnostic evaluation and interpretation of laboratory profiles

Simplified ambulatory

metabolic evaluation

Extensive ambulatory

metabolic evaluation Expected daily values Results interpretation

Random 24-h urinary profile Random 24-h urine profile and

24-h urine profile after 1 wk

of dietary restrictionsTotal volume Total volume 2.5 liter Indicative of daily fluid intake. This value diminishes with low fluid

intake, sweating, and diarrheapH pH 5.9 6.2 Values 5.5 increase UA precipitation. Commonly found in UA

stone patients, subjects with intestinal disease and diarrhea,

and in those with intestinal bypass surgery. Values 6.7

increase CaP precipitation. Commonly found in patients with

dRTA, primary hyperparathyroidism, alkali overtreatment, and

carbonic anhydrase treatment. Values 7.07.5 indicate a

urinary tract infection as a result of urease-producing bacteriaCreatinine Creatinine 1525 mg/kg body weight 1520 mg/kg body weight in females; 20 25 mg/kg body weight

in malesSodium Sodium 100 mEq Reflective of dietary sodium intake, given a lack of excessive

sweating and/or diarrheaPotassium Potassium 40 60 mEq Reflective of dietary potassium intake, given a lack of diarrheaCalcium Calcium 250300 mg There may be differences in male and female subjects. A higher

value is expected in malesMagnesium Magnesium 30 120 mg Low urinary magnesium is detected with low magnesium intake,

intestinal malabsorption (small bowel disease), and afterbariatric surgery

Oxalate Oxalate 45 mg Commonly encountered with intestinal fat malabsorption and

after bariatric surgery. Values 100 mg/d may indicate

primary hyperoxaluriaPhosphorus Phosphorus 1100 mg Indicative of dietary phosphorus intake and absorption. A higher

excretion may increase the risk of CaP stone formationUA UA 600 800 mg Hyperuricosuria is encountered with the overindulgence of

purine-rich foods such as red meat, poultry, and fishSulfate Sulfate 2530 mmol Sulfate is a marker of an acid-rich diet that occurs as a result of

increased oxidation of sulfur-rich amino acids (methionine)

found in meat and meat productsCitrate Citrate 320 mg An inhibitor of calcium stone formation. Hypocitraturia is

commonly encountered in metabolic acidosis, dRTA, chronic

diarrhea, excessive protein ingestion, strenuous physical

exercise, hypokalemia, intracellular acidosis, with carbonic

anhydrase inhibitor drugs (acetazolamide, topiramate, and

zonisamide), and rarely with ACE-inhibitorsAmmonium Ammonium 30 40 mEq Ammonium is a major buffer that neutralizes hydrogen protons

secreted by the kidney. Its excretion corresponds with urinary

sulfate (acid load). A higher ammonium:sulfate ratio indicates

gastrointestinal alkali lossChloride Chloride 100 mEq Chloride values also correspond with sodium intakeCystine Cystine 3060 mg Cystine has a l imited urinary solubil ity at 250 mg/li ter

2-h fasting Ca:Cr ratio 0.11 mg/100 ml glomerular

filtrate

Elevated fasting Ca:Cr, high serum calcium, and elevated PTH are

suggestive of primary hyperparathyroidism. Elevated fasting

Ca:Cr, normal serum calcium, and normal or suppressed PTH

are suggestive of resorptive hypercalciuria. Elevated fasting Ca:

Cr, normal serum calcium, and elevated PTH are suggestive of

renal hypercalciuria4-h Ca:Cr ratio after a 1-g oral

calcium load

0.20 mg/mg Cr Elevated Ca:Cr after a 1-g oral calcium load is suggestive of

absorptive hypercalciuriaSimplified fasting blood

chemistries

Extensive fasting blood

chemistriesComplete metabolic panel Complete metabolic panel Variablea Low serum potassium, high serum chloride, and low serum total

CO2content are suggestive of a diarrheal state of dRTA

PTH PTH 10 65 pg/mla High serum calcium, low serum phosphorus, and high PTH are

suggestive of primary hyperparathyroidism1,25(OH)2D Variable

a Normal serum calcium, normal PTH, and elevated 1,25(OH)2D are

suggestive of absorptive hypercalciuria. Normal serum calcium,

normal PTH, low serum phosphorus, and elevated 1,25(OH)2D

are suggestive of renal phosphorus leakOther evaluationsBone mineral density

measurements (DXA)

Z-score 2; T-score 2.5 Z-score 2 or T-score 2.5 indicates bone loss. This finding

may be more prevalent in hypercalciuric kidney stone formers

These limits are mean 2 SD (for calcium, oxalate, UA, pH, sodium, sulfate, and phosphorus) or mean 2 SD (for citrate, pH, and magnesium)

from normal. ACE, Angiotensin-converting enzyme; DXA, dual-energy x-ray absorptiometry.a Expected values should be cross-checked with reference laboratory recommendations because these values may differ.




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amounts of vitamin C (115, 116). There is no specific

report detailing the amount of vitamin D intake for these

subjects. However, 800 IU/d is generally recommended.

Pharmacological treatment

Pharmacological treatment is needed in most recurrentcalcium kidney stone formers as well as in specific stone-

forming populations such as UA, cystine, and infection-

induced stones due to the lack of availability and/or con-

sensus regarding the effectiveness of dietary restrictions

(Tables 1 and 3) (113, 114).

Thiazide diuretic treatment

Thiazidediureticsandtheiranalogsare commonlyused

medical treatments for lowering calcium excretion in re-

current calcium stone formers (108). In several random-

ized controlled trials, thiazide diuretics were effective insignificantly reducing kidney stone recurrence (117120).

These results were consistent with a number of open stud-

ies showing reduced kidney stone formation with thia-

zides (121127). Thiazides are effective in treating hyper-

calciuria and reducing stone recurrence regardless of the

underlying pathophysiological mechanism (127). The op-

timaleffectofthiazidesisachievedwithalow-saltdietthat

attenuates urinary calcium excretion and the provision of

sufficient potassium supplementation to avoid hypocitra-

turia (58). Potassium citrate holds an advantage over po-

tassium chloride (128).

Alkali treatment

Potassium citrate is used either alone or in combination

with thiazide treatment in recurrent calcium or UA stone

formers. In four randomized controlled trials, three non-

randomized nonplacebo controlled studies, and one non-randomized controlled trial, this treatment was shown to

TABLE 3. Major clinical trials in pharmacotherapy of calcium and non-calcium nephrolithiasis

First author (Ref.) Treatment

No. of

patients Design Outcome

Thiazide diureticsLaerum (117) Hydrochlorothiazidevs. placebo 50 RCT Decreased new stone formation and prolonged

stone-free intervalEtt inger (118) Chlorthal idonevs. Mg hydroxidevs. placebo 124 RCT Chlorthalidone more effective than Mg

hydroxide or placebo in reducing stone eventsOhkawa (119) Trichlormethiazidevs. no treatment 175 RCT Decreased calciuria and stone formation rateBorghi (120) Dietvs. diet indapamidevs.

diet indapamide allopurinol

75 RCT Diet pharmacotherapy better than diet alone

Yendt (121) Hydrodiuril 33 NNT Decreased number of stone events or invasive

and noninvasive proceduresCoe (122) Trichlormethiazide 37 NNT Decreased new stone formationCoe (123) Trichlormethiazidevs. allopurinolvs. both 222 NNT Decreased new stone formationYendt (124) Hydrochlorothiazide 139 NNT Decreased new stone formation or stone growthBackman (125) Bendroflumethiazide 44 NNT Decreased new stone formationMaschio (126) Hydrochlorothiazide amiloridevs.

both allopurinol

519 NNT Decreased new stone formation

Pak (127) Hydrochlorothiazide 37 NNT Decreased new stone formationAlkali treatment

Pak (129) Potassium citratevs. pretreatment in calcium and UA

stone formers

89 NNT Decreased stone events

Preminger (57) Potassium citrate 9 NNT Decreased new stone formationPak (130) Potassium citrate 18 NNT Decreased stone eventsBarcelo (131) Potassium citratevs. placebo 57 RCT Decreased new stone formation and increased

urinary citrateHofbauer (132) Diet sodium potassium citratevs. diet 50 RCT No difference in stone formationEttinger (133) Potassium magnesium citratevs. placebo 64 RCT Decreased new stone formationSoygr (134) Potassium citratevs. no treatment after shock wave

lithotripsy

110 RCT Decreased stone recurrence

Kang (135) Mix of potassium citrate, thiazide, allopurinolvs. no

treatment after percutaneous nephrolithotomy

226 NCT Decreased stone recurrence

Allopurinol treatmentEttinger (137) Allopurinolvs. placebo 60 RCT Decreased stone eventsCoe (123) Thiazidevs. allopurinolvs. both 202 RCT Decreased stone eventsvs. pretreatment

Other treatmentDahlberg (139) d-Penicillamine 89 R Decreased stone event and dissolution of stonesPak (140) d-Penicillamine or -mercaptopropionylglycinevs.

conservative Rx

66 R Both drug s equally effective in reducing stone

eventsChow (141) d-Penicillamine or -mercaptopropionylglycinevs.

conservative Rx

16 NNT Decreased stone event

Barbey (138) d-Penicillamine or -mercaptopropionylglycinevs.

conservative Rx

27 R Decreased stone events

Williams (142) Acetohydroxemic acidvs. placebo 18 RCT Decreased stone sizeGriff ith (143) Acetohydroxemic acidvs. placebo 210 RCT Decreased stone growthGriff ith (144) Acetohydroxemic acidvs. placebo 94 RCT Decreased stone growth

R, Retrospective; RCT, randomized controlled trial; NCT, nonrandomized controlled trial; NNT, nonrandomized, non-placebo controlled trial.




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reduce the risk of kidney stone events (57, 129135). Al-

kali treatment is effective in lowering urinary calcium ex-

cretion, raising urinary citrate, and reducing urinary

CaOx, CaP, and undissociated UA supersaturation (136).

Because bone loss and fracture are prevalent in patients

with nephrolithiasis, both alkali and thiazide treatments

have been shown to increase bone mineral density in thekidney stone-forming population (4). However, no ran-

domized data have been obtained showing decreased frac-

ture rate.

Allopurinol treatment

In a randomized controlled trial in hyperuricosuric cal-

cium stone formers, treatment with allopurinol was

shown to reduce urinary UA excretion as well as stone

recurrence (137). Because multiple metabolic abnormal-

ities maycoexist in hyperuricosuricpatients, onestudy has

shown that combined thiazide and allopurinol treatmentis more effective in reducing stone events compared with

either treatment alone (123).

Other drug treatment for stone prevention

Although urinary cystine solubility is pH dependent, al-

kali treatment alone has limited effectiveness in the manage-

ment of cystine stone formers. This is due to the high pKa of

cystine at 8.0, requiring a large dose of alkali that is difficult

toachieve.Furthermore, highlyalkalineurinecanpredispose

thepatient to CaP stones. The main treatments used in those

who suffer from severe cystinuria (

500 mg/d) are thiol-derivativesthat split cystinemolecules intotwo cysteines and

producea highlysolubledisulfide compound(92). Twosuch

drugs are d-penicillamine and -mercaptopropionylglycine.

In four retrospective, nonrandomized, nonplacebo, con-

trolledtrials,bothdrugswereshown todecreasestone events

(138141). Both drugs share many side effects; however,

-mercaptopropionylglycine may have lower incidence of

side effects compared with d-penicillamine (92).

Acetohydroxamic acid is the only drug approved for

the treatment of infectious kidney stones. This treatment

should only be used if surgical removal of an infectious

stone followed by eradication of infection with antibiotics

is ineffective. This medication causes an irreversible inhi-

bition of the enzyme urease, therefore attenuating the rise

in both urinary pH and NH4. Three randomized con-

trolled studies have found reduced stone growth with this

treatment (142144). However, compliance is very poor

due to severe side effects.

Clinical Follow-Up

Follow-up treatment is typically indicated with an annualclinical visit. This evaluation includes medical history,

physical examination, andlaboratoryexaminationfor full

serum chemistries and urine profiles.

Future Directions

Thecurrentmanagementofnephrolithiasislacksareliablesurrogate marker of kidney stone formation to correlate

with stone incidence. The development of practical and

novel techniques to easily assess the physicochemical pro-

cesses involved in crystal growth, aggregation, agglomer-

ation, and attachment will immensely benefit the field.

Further effort must also be aimed at understanding the

molecular and genetic basis of both calcium and non-cal-

cium kidney stones. Such an effort is necessary for the

development of targeted therapy based on the underlying

pathophysiological mechanisms of nephrolithiasis. To ac-

complish these goals, a close interaction between bed andbench investigation is crucial.

Acknowledgments

The authors acknowledge Ms. Hadley Palmer for her primary

role in the preparation and review of this manuscript.

Address all correspondence and requests for reprints to: Kha-shayar Sakhaee, M.D., 5323 Harry Hines Boulevard, Dallas,Texas 75390. E-mail: [email protected].

The authors were supported by the National Institutes of

Health (R01 DK081423, P01 DK20543, K23 RR021710).Disclosure Summary: The authors have nothing to disclose.

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