CHAPTER 111 Nephrolithiasis 803
GENERAL REFERENCES
For the General References and other additional features, please visit Elsevier eBooks+
at https://ebooks.health.elsevier.com.
Grade A References
A1. Piaggio D, Bracale U, Pecchia L, et al. Endovascular treatment versus medical therapy for hyper-
tensive patients with renal artery stenosis: an updated systematic review. Ann Vasc Surg. 2019;61:
445-454.
A2. R aman G, Adam GP, Halladay CW, et al. Comparative effectiveness of management strategies for
renal artery stenosis: an updated systematic review. Ann Intern Med. 2016;165:635-649.
111
NEPHROLITHIASIS
DAVID A. BUSHINSKY
Kidney stones are composed of crystals in a protein matrix. Most crystals contain
calcium, which is generally complexed with oxalate, phosphate, or both, whereas
other stones are composed of uric acid, magnesium ammonium phosphate
(struvite), or cystine, alone or in combination. Kidney stones form when the
saturation of their components exceeds the solubility of the solid phase in urine.
EPIDEMIOLOGY
The annual incidence of kidney stones in industrialized nations exceeds 1 per
1000 persons, with a lifetime risk of about 10% in women and about 15% in
men. The incidence of stone formation peaks in the fourth and fifth decades, and
prevalence increases with age until approximately 70 years in men and 60 years
in women. In the United States, the prevalence of nephrolithiasis has increased
from 3% in the late 1970s to more than 5%, an increase that is likely due to
changes to diet and lifestyle, as well as more accurate diagnosis.1 The estimated
yearly economic cost of kidney stones exceeds $5 billion in the United States.
In the United States, Whites are more likely to develop renal stones than are
other ethnic groups. Stones are more common in hot, dry climates, perhaps
because greater fluid loss through the skin and respiratory epithelium leads to
more concentrated urine. Many occupations make it inconvenient to utilize a
restroom, and these individuals often avoid fluids in an effort to avoid urination,
thereby leading to excretion of concentrated urine. Insufficient rehydration
among people who engage in physical activity and have large insensible losses
also leads to concentrated urine.
Obesity is correlated with the risk for kidney stone formation. Individuals
weighing more than 220 pounds or having a body mass index greater than 30
are significantly more likely to form stones than are individuals who weigh less
than 150 pounds or have a body mass index between 21 and 22.9.
The types of stones vary around the world,2 but in the United States, the
majority of stones are calcium oxalate and/or calcium phosphate (>80%), and
less than 10% are pure uric acid stones. By comparison, about 70% of stones
in the Mediterranean and Middle East are composed of uric acid. Magnesium
ammonium phosphate (struvite) stones account for 1 to 25% of stones, whereas
cystine stones comprise 1 to 2% of stones.3
PATHOBIOLOGY
Human bone is composed of calcium and phosphate, principally in the form
of apatite. Once humans reach their adult height and their skeleton is fully
mineralized, the net amount of calcium that is absorbed by nonpregnant indi-
viduals must be excreted in the urine. Similarly absorbed phosphate that is not
needed for bone mineralization or cell growth must be excreted. Oxalate is
an end product of metabolism, and it too must be excreted in the urine. The
need for water conservation by terrestrial humans often leads to excretion of
these ions in relatively scant amounts of urine, thereby promoting increased
saturation with respect to the solid phases of calcium oxalate and/or calcium
phosphate. Increasing saturation drives the formation of the solid crystal phase
and is expressed as the ratio of calcium oxalate (or phosphate) ion activity to
its solubility. At ratios of greater than 1, termed supersaturation, a solid phase
can form, whereas the substances remain in solution at ratios less than 1. When
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urine is supersaturated, ions can bond to form the more stable, solid phase,
which is termed nucleation. Homogeneous nucleation refers to the bonding of
similar ions into crystals. The more common and thermodynamically favored
heterogeneous nucleation occurs when crystals grow on dissimilar crystals or
substances as cellular debris in the urine. Although humans produce inhibitors
of stone formation, such as osteopontin and Tamm-Horsfall protein, super-
saturation can overwhelm this inhibition, and a solid phase will form.
Calcium Stones
About 70 to 80% of kidney stones contain calcium, which is often complexed with
oxalate or phosphate. Calcium-containing kidney stones are most often caused
by excessive excretion of calcium (hypercalciuria), oxalate (hyperoxaluria), or
urate (hyperuricosuria) or insufficient excretion of citrate (hypocitraturia).4
Calcium-containing stone formation has a strong genetic component.5
Idiopathic hypercalciuria is thought to be a polygenic disorder in which a
generalized dysregulation of calcium transport in the kidney, intestine, and
bone leads to increased urinary calcium. A number of single-nucleotide poly-
morphisms, in genes coding for the calcium-sensing receptor, the vitamin D
receptor, and osteopontin, and others, have been associated with calcium
nephrolithiasis. Overall, 14 monogenic mutations account for 15% of neph-
rolithiasis/nephrocalcinosis, and genetic factors appear to explain about 20
to 35% of the interindividual variation in excretion of ions critical to stone
formation.
Urinary oxalate is derived from endogenous metabolism of glyoxylate and
ascorbic acid or from dietary sources, such as cocoa, nuts, tea, and certain leafy
green vegetables such as spinach. The three main causes of hyperoxaluria are
excessive oxalate ingestion (dietary oxaluria), excessive intestinal absorption
of oxalate (enteric oxaluria) that is paradoxically observed in malabsorptive
gastrointestinal disorders, and excessive endogenous oxalate production seen
in certain hepatic enzyme deficiencies (primary hyperoxaluria; Chapter 189).
Additionally, ethylene glycol, a common automobile antifreeze, is metabolized
to oxalate and can cause excessive urinary oxalate excretion in conjunction
with severe metabolic acidosis and renal failure (Chapter 96).
Enteric oxaluria results in elevated urinary oxalate levels (60 to 100 mg/day).6
In gastrointestinal malabsorptive conditions such as Crohn disease (Chapter
127), celiac sprue (Chapter 126), jejunoileal bypass (Chapter 201), and chronic
pancreatitis (Chapter 130), malabsorbed fatty acids bind dietary calcium,
thereby leaving oxalate free to pass into the colon, where it is more likely to
be absorbed owing to the presence of bile acids; this excess oxalate is then
subsequently filtered by the glomerulus and excreted in the urine. Intestinal
bacteria also can influence oxalate levels by degrading it, preventing its absorp-
tion, or even stimulating its secretion from the circulation into the intestine.
Primary hyperoxaluria (Chapter 189) results from defects in hepatic
enzymes in the liver glyoxylate pathway; the results are substantial endog-
enous oxalate production and a marked elevation of urinary oxalate (80 to
300 mg/day).7 Oxalate deposits in numerous organs, including the heart,
bone marrow, muscle, and renal parenchyma, where they lead to renal failure,
cardiomyopathy, and bone marrow suppression at an early age. In type 1
primary hyperoxaluria, which accounts for about 80% of cases, the hepatic
enzyme alanine glyoxylate aminotransferase, which converts glyoxylate to
glycine, is deficient because of one of a large number of mutations in the
AGXT gene. With deficient alanine glyoxylate aminotransferase, the glyoxylate
is converted to oxalate. In the milder type 2 primary hyperoxaluria, which
represents approximately 10% of cases, patients lack d-glycerate reductase and
glyoxylate reductase owing to mutations in the GRHPR gene. Type 3 primary
hyperoxaluria, which accounts for about 5% of cases, is a result of mutations
in the HOGA1 gene that catalyzes the cleavage of 4-hydroxy-2-oxoglutarate
to pyruvate and glyoxylate.
Nephrolithiasis and nephrocalcinosis can also result from a variety of
monogenic disorders, such as Dent disease (X-linked recessive nephrolithi-
asis; Chapter 113), McCune-Albright syndrome (Chapters 212 and 229),
osteogenesis imperfecta type 1 (Chapter 239), and congenital lactase defi-
ciency (Chapter 126).
Citrate inhibits stone formation by combining with calcium to form a soluble
complex that reduces the availability of calcium to bind with oxalate or phos-
phate. The principal risk factor for hypocitraturia is a high protein intake. Men
often have lower urinary citrate concentrations than women. Distal renal tubular
acidosis (Chapter 104) promotes the formation of calcium phosphate stones
owing to bone demineralization and an alkaline tubular pH.
Calcium oxalate kidney stones form on calcium phosphate deposits, termed
Randall plaques, which are located in the renal papillae. Randall plaque for-
mation is positively correlated with urine calcium excretion and negatively
803.e2 CHAPTER 111 NEPHROLITHIASIS
ABSTRACT KEYWORDS
The prevalence of kidney stones has increased over the last several decades, nephrolithiasis
almost certainly due to changes in diet and the increased prevalence of obesity. kidney stone
Most kidney stones consist of calcium complexed with oxalate and/or phos- hypercalciuria
phate. The most common metabolic abnormality found in kidney stone formers hyperoxaluria
is idiopathic hypercalciuria, which is due to a systemic dysregulation of calcium calcium stones
transport at all major calcium transporting sites and has a strong genetic com-
ponent. Stones form when the saturation of the major components of the
stone exceeds the solubility of the associated solid phase. Stones often present
as acute colic, and their spontaneous passage is directly correlated with their
size. Alpha blockers such as tamsulosin can promote passage of smaller stones.
Every patient who forms a kidney stone should undergo a metabolic evaluation
to prevent recurrent stones. The depth of the evaluation is dependent on a
number of factors, including the age when the first stone is diagnosed and the
frequency of recurrent stones. Treatment for recurrent calcium stones rests on
the 4 pillars of increased hydration (goal urine volume >2 liters per day), mod-
eration of sodium intake (goal <2000 mg/day), moderation of protein intake
(~1 g/kg/day), and an age- and gender-appropriate calcium intake derived
mainly from dairy products and not from supplements. If these measures do
not lower urinary supersaturation adequately, then thiazide diuretics and/
or potassium citrate may be required. The recurrence rate of calcium oxalate
nephrolithiasis is about 25% at 3 to 5 years.

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804 CHAPTER 111 Nephrolithiasis
correlated with urine volume and pH. These calcium phosphate crystals, in
the form of apatite, originate around the thin loop of Henle and then extend
into the interstitium without eroding into the tubular lumen or damaging the
tubular cells. The crystals move toward the urinary space, where they form
Randall plaques, which are visible on cystoscopy and also may be seen as
medullary calcifications on computed tomography (CT). In the presence of
urine that is supersaturated with respect to calcium oxalate, these ions may
form a crystal that increases in size to several millimeters or even a centimeter.
The stone can break off from the Randall plaque and then migrate to, irritate,
and possibly obstruct the ureter.
Uric Acid Stones
The incidence of uric acid stones appears to be rising in the United States in
parallel with the increase in obesity, which leads to renal insulin resistance
and a very low urine pH.8 Over 5 times as much uric acid is soluble in a urine
with a pH of 6.5 compared with a pH of 5.3. Diarrhea and diets high in animal
protein can contribute to an acidic urinary pH. Most patients with uric acid
stones have a reduced urine pH, and some have low urine volumes or elevated
urinary uric acid levels. Uric acid stone formers have greater body weight and
a higher incidence of insulin resistance and type 2 diabetes mellitus. Insulin
resistance also leads to impaired urinary ammonium excretion, thereby result-
ing in the excretion of more hydrogen ions as titratable acids and lower urine
pH, which reduces the solubility of ammonium.
Hyperuricosuria may be seen in patients who ingest large quantities of
dietary purine, such as organ meats, shellfish, certain fish (e.g., anchovies,
sardines, herring, and mackerel), meat extracts (e.g., bouillon and con-
sommé), and protein. Hyperuricemic disorders, including gout (Chapter 252),
myeloproliferative disorders, tumor lysis syndrome, and certain inborn errors of
metabolism, can also contribute to an increased urinary uric acid. Medications
such as salicylates and probenecid can be hyperuricosuric.
Struvite Stones
Struvite stones, sometimes called triple phosphate stones, magnesium ammonium
phosphate stones, and infection stones, comprise only about 10 to 25% of all
stones but constitute the majority of staghorn calculi, which are large stones
that extend beyond a single renal calyx.9 Struvite stones are far more common
in women than in men, in large part owing to women’s increased susceptibility
to upper urinary tract infections (Chapter 263). Similarly, any patient with
urinary stasis, such as patients with neurogenic bladders, indwelling urinary
catheters, or spinal cord lesions, is susceptible to struvite stones.
Struvite stones form only in the presence of both increased production of
ammonium and an alkaline urine (pH ≥ 7), which occur only with urease-
producing bacteria. Proteus mirabilis (Chapter 281) is a common urease-pro-
ducing bacterium, but other gram-negative and gram-positive bacteria, such
as Klebsiella spp. and Staphylococcus epidermidis, as well as Mycoplasma spp.
(Chapter 293) and yeast species, have been implicated in urease production.
By comparison, Escherichia coli does not produce urease.
Cystine Stones
Cystinuria (Chapter 113), which is an autosomal dominant disorder with
incomplete penetrance or an autosomal recessive disorder caused by mutations
of the SLC3A1 gene or the SLC7A9 gene, results in decreased renal tubular
reabsorption and excessive urinary excretion of the dibasic amino acids cystine,
ornithine, lysine, and arginine.10 The resulting urinary excretion of cystine

Ultrasound or helical computed tomography of the abdomen and pelvis

No evidence of nephrolithiasis Ureteral stone or secondary signs

Investigate nonurologic causes Pain control

Urgent intervention Nonurgent

required intervention

Insert stent or Assess likelihood of

nephrostomy tube stone passage
High Low

Conservative Urologic
management intervention to
remove stone
(e.g., ESWL,
Stone passed? No percutaneous
nephrolithotomy)
Yes

Prevention:
1. Stone analysis
2. Metabolic evaluation

Preventive
recommendations

Monitor response to
recommendations

  FIGURE 111-1.    Algorithm for evaluation of suspected renal colic. ESWL = extracorporeal shock wave lithotripsy. (From Curhan GC. Nephrolithiasis. In: Goldman L, Schafer AI, eds.
Goldman’s Cecil Textbook of Medicine. 24th ed. Philadelphia: Elsevier Saunders; 2012.)

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in the typical volume of urine exceeds its solubility of about 250 mg/L and
enables stone formation. Although normal people excrete about 30 to 50 mg
of cystine per day, heterozygotes for cystinuria excrete about 400 mg/day,
and homozygotes often excrete about 600 mg/day. Thus, homozygotes must
continually excrete more than 2 L of urine each day to avoid stone formation.
Cystinuria is unrelated to the much more severe disorder cystinosis (Chapter
113), which results in extensive intracellular cystine accumulation.
CLINICAL MANIFESTATIONS
Patients with kidney stones often present with pain and/or hematuria, and
less often present with urinary tract infections (Chapter 263) or acute kidney
injury (Chapter 106), either owing to bilateral obstruction or unilateral obstruc-
tion in a single functioning kidney (Fig. 111-1). Patients often complain of
severe ureteral colic. The pain is of abrupt onset and can intensify into severe,
excruciating flank pain. The pain may migrate anteriorly along the abdomen
and inferiorly to the groin, testicles, or labia majora as the stone moves down
the ureter toward the ureterovesical junction. The pain resolves only after the
stone passes or is removed. Microscopic or gross hematuria is common, and
patients occasionally present with painless hematuria (see Fig. 100-3). The
finding of a stone on radiographic examination does not preclude another
cause. Conversely, even large calculi may be asymptomatic and be discov-
ered during the investigation of unrelated symptoms. Obstruction caused by
calculi may also be painless, and nephrolithiasis should always be considered
in the differential diagnosis of unexplained acute or chronic kidney disease
(Chapters 106 and 116).
DIAGNOSIS
The physical examination can provide clues to the diagnosis of kidney stones
but is not diagnostic. Some patients have demonstrable flank tenderness, and
a rare patient with hyperuricemia will have tophi (Chapter 252). However, the
physical examination is most helpful for not showing other potential causes of
pain. The suspicion of a kidney stone generally obligates radiographic evalua-
tion. Radiographic studies can be deferred, however, in patients in whom the
clinical diagnosis is clear, who have no evidence of infection, who are able to
eat and drink, and who can be managed on oral analgesics.
Ultrasonography is an easy and rapid way to detect possible urinary obstruc-
tion without exposing the patient to ionizing radiation. Ultrasound can detect
clinically significant renal calculi, with about an 85% sensitivity for detecting
the ureteral stones that cause acute symptoms. Among emergency department
patients with suspected nephrolithiasis, those who undergo ultrasonography
have a lower cumulative radiation exposure than those randomized to CT
without any significant differences in high-risk diagnoses, serious adverse
events, pain scores, or subsequent rehospitalizations or emergency department
visits.A1 A helical CT scan or a low radiation CT scan without radiographic
contrast can detect kidney stones with both a sensitivity and a specificity
exceeding 95% (Fig. 111-2).11 Based on the density of the stone, it also can
  FIGURE 111-2.    High-resolution helical computed tomographic (CT) scan of the upper
part of the abdomen demonstrating a stone in the right renal pelvis (arrow). There is no
hydronephrosis. (From Curhan GC. Clinical crossroads: a 44-year-old woman with kidney
stones. JAMA. 2005;293:1107-1114.)
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CHAPTER 111 Nephrolithiasis 805
often differentiate a calcium-containing stone from a cystine or uric acid stone.
An added benefit is that helical CT is often helpful in determining the cause
of nonstone abdominal pain (Chapter 119). In certain situations, such as in
human immunodeficiency virus (HIV)–infected patients thought to have
stones induced by a protease inhibitor, a helical CT scan with contrast is often
required because the stones are not radiopaque and do not obstruct the ureter.
Approximately 90% of kidney stones are radiopaque and may be detected
on a simple abdominal radiograph. Unfortunately, however, the stone is often
obscured by stool, vertebrae, or abdominal gas, so the sensitivity of a plain
abdominal radiograph is about 55%, and its specificity is only about 75%. Uric
acid stones are radiolucent and cannot be detected radiographically without
contrast.
Intravenous pyelography has a sensitivity of about 75% and a specificity
of more than 90% for detecting renal calculi. Intravenous pyelography is also
useful for identifying structural abnormalities of the urinary tract, such as a
medullary sponge kidney (Chapter 112), that predisposes to stone formation.
However, an intravenous pyelogram often does not detect nonobstructing
radiolucent stones because they do not create a filling defect. An intravenous
pyelogram exposes the patient to more radiation than a plain radiograph but
less than a CT scan. It also carries the risk of radiographic contrast material,
which is greater in individuals with underlying renal compromise. With the
widespread availability of ultrasonography and helical CT scans, an intravenous
pyelogram is rarely indicated.
TREATMENT
Medical Therapy
Because the pain of renal colic can be excruciating, pain control is critical after
the definitive diagnosis has been made. If nausea and vomiting prevent the use
of oral medication, parenteral medication is typically required. Nonsteroidal
anti-inflammatory drugs (NSAIDs; Table 26-4) are as or more effective compared
with opiates for renal colic and are preferred because they have fewer side
effects.A2,A3 An intravenous or intramuscular option is ketorolac (15 to 30 mg),
and an oral option is ibuprofen (200 to 400 mg/dose every 4 to 6 hours with
a maximum daily dose of 1.2 g) in patients who can tolerate oral medication.
Because NSAIDs can cause acute kidney injury, especially in patients who are
dehydrated or have pre-existing kidney injury, adequate hydration (e.g., normal
saline at 75 to 150 mL/hour) is essential, but neither high-volume fluid therapy
nor diuretics promote the passage of the stone. If necessary, oral oxycodone (5
to 15 mg every 4 to 6 hours as needed) may be added to ibuprofen for outpatient
pain control. The dose and frequency of administration of oxycodone should
be reduced in patients who have renal impairment.
Medical Expulsive Therapy
Kidney stones 5 mm or smaller have about a 70% probability of passing spon-
taneously, whereas stones between 5 and 7 mm have a 60% chance, stones 7
to 9 mm have a 48% chance, and stones 9 mm or larger have a 25% chance of
passing spontaneously. Stones located more distally in the ureter are more likely
to pass spontaneously. Medical expulsive therapy may be cautiously attempted
with ureteral stones smaller than 10 mm diameter for 4 to 6 weeks if pain is
controlled, kidney function is normal, and there is no evidence of urinary tract
infection or significant obstruction.12 The patient must be followed closely, gen-
erally with repeat ultrasound examinations every week or 2 weeks.
Expulsive therapy can reduce ureteral spasm and increase spontaneous
passage rates by about 50%. Meta-analyses demonstrate an overall benefit for
the α-blocker tamsulosin (0.4 mg orally daily), A4,A5 which appears to promote
the passage of the stone more quickly and effectively than the calcium-chan­
nel blocker nifedipine (nifedipine XL 30 mg daily or twice daily). Other options
include a phosphodiesterase type 5 inhibitor (e.g., tadalafil 10 mg/day for 10
days) or a selective α1a-receptor blocker (e.g., silodosin 4 mg/day). Silodosin
appears more effective than tamsulosin for promoting the passage of large,
distal ureteral stones.A6
Initial Surgical Treatment
Stones that cause obstruction, infection, acute kidney injury, or intractable pain
must be removed expeditiously.12b In general, larger and more proximal stones
are less likely to pass spontaneously, even with medical expulsive therapy, and
are often an indicator for earlier intervention. Approximately 15% of all kidney
stones require an intervention to remove them. For example, removal of small,
asymptomatic kidney stones at the time of surgery to remove a ureteral or
contralateral stone reduces the rate of relapse.A7
The approach to stone removal depends on its size, location, and com-
position, as well as on urinary tract anatomy. The major options for ureteral
stone removal include percutaneous nephrolithotomy, extracorporeal shock
wave lithotripsy, and ureteroscopy; open surgical extraction is rarely required.
Percutaneous nephrolithotomy involves the passage of a flexible scope through
the kidney and into the urinary space. Extracorporeal shock wave lithotripsy
focuses external sound waves onto the kidney stone, thereby causing it to
806 CHAPTER 111 Nephrolithiasis
fragment into smaller stones that can more easily be passed spontaneously.
Ureteroscopy involves the passage of a ureteroscope into the ureter with
removal or laser fragmentation of the stone. Meta-analyses suggest that ureteral
stones should be treated with ureteroscopy or shock wave lithotripsy rather
than percutaneous nephrolithotomy and that percutaneous nephrolithotomy
is the treatment of choice for lower pole renal stones and the majority of large
kidney stones (≥15 mm),A8,A8b because it results in longer stone-free rates and
a lower need for retreatment, even though it is associated with more complica-
tions, usually minor, and a longer hospitalization compared with shock wave
lithotripsy.
Medical Evaluation
After an initial stone episode, the recurrence rate in nontreated patients is esti-
mated to be about 25% at 3 to 5 years and about 50% at 5 to 10 years. As a result,
every patient who forms an initial stone should undergo evaluation with the
goal of preventing recurrent stones. The history should focus on uncovering
factors that predispose to stone formation. All stones should be analyzed to
assist in defining the underlying metabolic abnormality and to guide therapy.13
A careful dietary history, including an estimate of fluid intake, is essential.
Many stone formers are erroneously instructed to eliminate all calcium from
their diet, a practice that not only increases stone formation but also may induce
bone demineralization. Sodium intake should be estimated because sodium
excretion obligates calcium excretion, thereby potentially leading to urinary
supersaturation. Excessive animal protein intake increases metabolic acid pro-
duction, which increases bone demineralization and calciuria.
Hypercalcemic disorders—including malignancy (Chapter 227), hyper-
parathyroidism (Chapter 227), and sarcoidosis (Chapter 83)—often result in
hypercalciuria, increased urinary supersaturation, and calcium stone formation.
Malabsorptive gastrointestinal disorders, such as Crohn disease (Chapter 127)
and celiac disease (Chapter 126), or weight reduction surgery (Chapter 201),
such as ileal resection or jejunoileal bypass, will often result in calcium oxalate
stone formation from increased oxalate absorption and excretion as well as
volume depletion.
Medications that can cause calcium stone formation include loop diuretics,
which increase urinary calcium excretion, as well as salicylates and proben-
ecid, which increase urinary uric acid excretion. Various medications that can
themselves precipitate into stones include intravenous acyclovir, high-dose
sulfadiazine, triamterene, and the antiretroviral agents indinavir and nelfinavir.
Other medications that inhibit renal tubular carbonic anhydrase activity, such
as acetazolamide and topiramate, can lead to metabolic acidosis, bone resorp-
tion, hypercalciuria, lower urinary citrate excretion, and higher urinary pH, all
of which promote the formation of calcium phosphate stones.
The number and frequency of stones formed, the patient’s age at the time of
the first stone, the size of the stone, and an analysis of the composition of the
stone are also important clues. Stones that develop at a young age suggest a
genetic disorder, such as primary hyperoxaluria or cystinuria. Large staghorn
calculi in elderly patients are consistent with struvite stones. A stone’s response
to intervention is also helpful: cystine stones do not fragment well with litho-
tripsy, and stones that recur frequently in a single kidney suggest a unilateral
anatomic abnormality.
Basic laboratory testing should include levels of serum electrolytes (sodium,
potassium, chloride, and bicarbonate), creatinine, calcium, phosphorus, uric
acid, 25-hydroxyvitamin D, and thyroid-stimulating hormone. If the serum
calcium is above and the serum phosphorus is below the midrange of normal,
a serum parathyroid hormone level should be obtained.
An elevated urine specific gravity suggests inadequate fluid intake. Hematuria
may indicate irritation to the urothelial lining by a stone. Characteristic crystals
(see Fig. 100-10) are more common than in nonstone formers. The presence
of hexagonal crystals (see Fig. 100-9) mandates that cystinuria be excluded.
Patients with struvite stones generally have an elevated urine pH (>7.4) owing
to the splitting of urea into ammonia and bicarbonate, whereas a low urinary pH
(<5.5) raises the suspicion of uric acid stones. An elevated urine pH combined
with bacteriuria (Chapter 263) suggests struvite stones. Because urease produc-
tion may stimulate struvite stone formation despite low bacterial colony counts,
the laboratory must identify all bacteria and determine antibiotic sensitivities
even with low colony counts. If no bacteria are isolated, cultures for Ureaplasma
urealyticum should be requested. The combination of an elevated urinary pH
(6.5 to 7.2) with a low serum potassium and serum bicarbonate level strongly
suggests distal renal tubular acidosis (Chapter 104).
In patients with recurrent stones and/or high-risk characteristics for recur-
rence, a 24-hour urine collection can determine the levels of calcium, oxalate,
citrate, sodium, urate, phosphorus, and creatinine, as well as the calculation of
supersaturation with respect to calcium oxalate, calcium phosphate, and uric
acid (Table 111-1). Increased ion excretion of the components of a stone leads
to increased rates of forming recurrent stones. An elevated supersaturation
should lead the clinician to determine the individual components of the urine
that are causing the increased supersaturation, and efforts can then be made
to rectify these abnormalities. Cystine should also be measured at least once
in every stone former to exclude cystinuria and regularly in patients who form
cystine stones. Multivitamins should be discontinued about 5 days before the
collection to prevent any antioxidant effect on the urine sample.
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TABLE 111-1 OPTIMAL 24-HOUR URINE VALUES IN
PATIENTS WITH NEPHROLITHIASIS
PARAMETER VALUE
Volume >2-2.5 L
pH >5.5 and <7.0 (24-hr
specimen not required)
Calcium <250 mg
Oxalate <40 mg
Sodium <2000 mg
Uric acid <750 mg
Phosphorus <1100 mg
Citrate >320 mg
Supersaturation with respect to calcium oxalate <5
Supersaturation with respect to calcium phosphate 0.5-2
Supersaturation with respect to uric acid 0-1
Urine creatinine should be measured to ensure the adequacy of collection and should be >15 mg/kg
in men and >10 mg/kg in women. Supersaturation is the ratio of the ion activity product and its
solubility product.
PREVENTION
Preventive treatment (Fig. 111-3)13b emphasizes advising the patient to increase
oral fluid intake to produce a urine volume greater than 2 L per day, an oral
intake that will reduce recurrent stone formation by about 50%.A9,A10
Calcium Stones
Because urine calcium excretion is directly correlated with urine sodium
excretion, decreasing sodium intake will decrease urine calcium excretion
and reduce supersaturation.14 Patients with calcium stones should limit daily
sodium intake to no more than 2 g per day and reduce animal protein intake
to 0.8 to 1.0 g/kg per day.
The recommended calcium intake for a 19- to 50-year-old man or woman
is 1000 mg of elemental calcium per day, and a number of studies demonstrate
decreased formation of calcium stones when people consume diets adequate in
calcium, presumably because appropriate calcium intake is needed for intestinal
binding of dietary oxalate to prevent its absorption. Dairy products are preferred
over calcium supplements because clinical studies indicate that women taking sup-
plemental vitamin D and calcium have a significant increase in stone formation.
Patients with persistent hypercalciuria often benefit from longer-acting
thiazide diuretics (e.g., chlorthalidone 12.5 to 25 mg/day), which directly
lower urinary calcium and reduce recurrent stone formation by about 50%.A11
However, a short-acting thiazide diuretic given once daily does not reduce
symptomatic recurrences.A12 Thiazides are effective only if patients restrict
dietary sodium. In patients with hypercholesterolemia or hyperglycemia, inda-
pamide (1.25 to 5 mg/day) can be used because it has less effect on these
parameters. If patients develop hypokalemia, dietary potassium intake should
be increased, or a potassium supplement can be administered. Allopurinol
should be prescribed as for gout (300 mg daily; see Chapter 252). Potassium
citrate (10 to 40 mEq/day) will increase urinary citrate excretion, bind urinary
calcium, and further decrease recurrent stone formation.A13 Potassium citrate
is available as a wax-matrix tablet. A 24-hour urine collection can be repeated
in a month or two to assess the response to therapy. Sodium-glucose cotrans-
porter-2 (SGLT2) inhibitors appear to reduce the risk of nephrolithiasis by
50%A14 but are not currently recommended for routine prophylactic use.
Patients with diet-related hyperoxaluria should be instructed to limit or
avoid foods with high oxalate content such as cocoa, nuts, tea, and green
leafy vegetables such as spinach. Because dietary calcium and oxalate bind
in the gut, patients should consume these foods with calcium-containing
foods. For enteric hyperoxaluria, treatment is first directed at the underly-
ing disorder and then at instituting therapy for the cause of the steatorrhea
(Chapter 126). Dietary oxalate should be restricted, and dietary calcium
and oxalate should be ingested at the same meal. A diet that is low in fat;
that is high in fruits, vegetables, and low-fat dairy products; that is rich in
grains, fish, poultry, beans, seeds, and nuts; and that contains fewer sweets
and less added sugar and red meat appears to be a reasonable alternative to
a low-oxalate diet. Additional fluid intake and potassium citrate are often
beneficial. Reloxaliase, which is an oral nonabsorbable oxalate-degrading
enzyme,15 is currently in clinical trials.
 CHAPTER 111 Nephrolithiasis 807
Approach to a Patient with Calcium Oxalate Nephrolithiasis

Patient with first stone

Basic evaluation and treatment

Exclude metabolic cause such as primary hyperparathyroidism, primary hyperoxaluria, etc.
General stone treatment:
Increased fluid intake to increase urine volume to 2.0 to 2.5 L/day
Sodium moderation to lower urinary sodium to <2000 mg/day
Protein moderation to about 1 g/kg/day
Appropriate calcium intake for age and gender preferably from dairy products and not supplements

Recurrent stones, all children, noncalcium

All others (i.e., single calcium-containing stone)
stone formers and nontypical demographics

Follow, reinforce general stone treatment advice

Complete evaluation
if recurrent stone

Obtain 24-hr urine ion excretion and supersaturation

If supersaturation is elevated determine if:

Idiopathic Dietary hyperoxaluria: Hypocitraturia: Hyperuricosuria: Excess Low

hypercalciuria: Decrease dietary Decrease animal protein Decrease dietary purine urinary sodium: urinary volume:
Decrease sodium oxalate intake Potassium citrate Allopurinol Decrease sodium intake Increase fluid intake
intake Increase calcium
Thiazide diuretic with meals
(e.g., chlorthalidone)
If potassium is low,
then potassium citrate Repeat 24-hr urine ion excretion and supersaturation every 6 to 12 months and treat as indicated
+/– amiloride Avoid radiographs unless results are likely to change management significantly

  FIGURE 111-3.    Approach to a patient with calcium oxalate nephrolithiasis.

In some patients with type 1 primary hyperoxaluria, pyridoxine (vitamin
B6) can increase enzyme activity and reduce oxalate production. These
patients should also be treated with measures that reduce the precipita-
tion of calcium oxalate, such as ample fluid intake and potassium citrate
(10 to 40 mEq/day). Lumasiran, which is a small interfering RNA that
decreases the levels of glycolate oxidase thereby resulting in less production
of oxalate, reduces urinary oxalate levels by approximately 50% and reduces
plasma oxalate levels into the normal range in patients who have type 1
primary hyperoxaluria.A15 Lumasiran has the potential to eliminate the clinical
manifestations, such as renal failure, of type 1 primary hyperoxaluria and to
prevent the need for curative liver transplantation. All patients with type 1
primary hyperoxaluria should be seen by specialists and be considered for
treatment with this therapy.
Calcium stones may be found in patients with hyperuricosuria. These
patients often excrete excess amounts of urinary uric acid but normal amounts
of urinary calcium and oxalate. Compared with patients with pure uric acid
stones, they generally have a higher urinary pH (about 5.5). The mechanism
by which uric acid promotes calcium stone formation is unclear. Therapy
generally consists of dietary purine restriction, increased fluid intake, and the
addition of allopurinol (300 mg daily) if necessary.
If moderation of dietary protein is not successful in patients with hypoci-
traturia, oral potassium citrate is given (10 to 40 mEq/day). Serum levels of
potassium and bicarbonate must be closely monitored, especially in patients
with chronic kidney disease.
Uric Acid Stones
Uric acid stones are radiolucent and are thus most often visualized with CT.
Therapy for patients with uric acid stones begins with nonspecific measures
such as increasing fluid intake, a low purine diet, and lowering animal protein
intake to increase urinary pH. Ideally, the urinary pH should be elevated to
approximately 6.5 to 7.0, a level that not only prevents new stone formation
but also can dissolve existing uric acid stones without promoting calcium
phosphate deposition. Potassium citrate (10 to 40 mEq/day) may be required
to raise the urinary pH sufficiently. If all else fails, the carbonic anhydrase
inhibitor acetazolamide (250 to 500 mg/day) may be initiated to raise urine
pH. Because concomitant hyperuricemia may be present, allopurinol (100 to
300 mg daily) may be indicated to lower the serum uric acid level.
Struvite Stones
Struvite stones rapidly grow to a large size and may promptly recur if not com-
pletely removed. Therapy requires complete surgical stone removal coupled
with appropriate long-term antibiotics (Chapter 263), selected on the basis of
cultures of stone fragments retrieved from surgery. Antibiotics should be con-
tinued at full doses until the urine is sterile and then continued at a lower dose.
Monthly surveillance cultures should be performed until the urine remains
sterile for 3 consecutive months. Antibiotics can then be discontinued with
monthly surveillance urine cultures for another year.
Cystine Stones
Cystine kidney stones, which usually develop by the second or third decade of
life, are radiopaque and may appear as staghorn calculi or multiple stones. The
disease should be suspected in any patient with an early onset of stones, fre-
quently recurrent nephrolithiasis, and a family history of the disease. Although
the presence of the classic hexagonal cystine crystals in the urine (see Fig. 100-9
in Chapter 100) may suggest the diagnosis, anyone suspected of the disorder
should have a quantitative cystine measurement on a 24-hour urine sample.16
The goal of treatment is to lower the urinary cystine concentration below
the limits of solubility.17 Patients are advised to drink sufficient quantities
of water to maintain excreted cystine in solution. Patients should moderate
intake of sodium and animal protein foods, which contain large amounts of
methionine, which is a precursor of cystine. Because cystine is more soluble
at a higher pH, urinary alkalinization with potassium citrate (10 to 40 mEq/
day) can be used to maintain a urinary pH ≥ 7.0. Chelating agents reduce the
free cystine concentration by forming more soluble compounds and should
be prescribed by a specialist owing to their high incidence of side effects.

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808 CHAPTER 112 Cystic Kidney Diseases
PROGNOSIS
The recurrence rate of calcium oxalate nephrolithiasis is about 25% at 3 to 5
years and about 50% at 5 to 10 years, and the rate is higher for cystine, uric
acid, and struvite stones.18 For stones that have not yet caused symptoms, the
risk of developing symptoms varies widely among studies, but the size of the
stone is not predictive of future symptomatic nephrolithiasis.19 Patients with
kidney stones often have an increase in aortic calcification and a decrease in
bone mineral density, thereby supporting the concept that there is dysregula-
tion in calcium homeostasis in patients who form calcium-containing stones.
Patients with nephrolithiasis have a higher risk of losing kidney function20 and
also have an increased risk for coronary heart disease and stroke.
GENERAL REFERENCES
For the General References and other additional features, please visit Elsevier eBooks+
at https://ebooks.health.elsevier.com.
Grade A References
A1. Wang RC, Fahimi J, Dillon D, et al. Effect of an ultrasound-first clinical decision tool in emer-
gency department patients with suspected nephrolithiasis: a randomized trial. Am J Emerg Med.
2022;60:164-170.
A2. Pathan SA, Mitra B, Straney LD, et al. Delivering safe and effective analgesia for management of
renal colic in the emergency department: a double-blind, multigroup, randomised controlled trial.
Lancet. 2016;387:1999-2007.
A3. Pathan SA, Mitra B, Cameron PA. A systematic review and meta-analysis comparing the efficacy
of nonsteroidal anti-inflammatory drugs, opioids, and paracetamol in the treatment of acute renal
colic. Eur Urol. 2018;73:583-595.
A4. Hollingsworth JM, Canales BK, Rogers MA, et al. Alpha blockers for treatment of ureteric stones:
systematic review and meta-analysis. BMJ. 2016;355:1-11.
A5. Campschroer T, Zhu X, Vernooij RW, et al. Alpha-blockers as medical expulsive therapy for ure-
teral stones. Cochrane Database Syst Rev. 2018;4:CD008509.
A6. Liu XJ, Wen JG, Wan YD, et al. Role of silodosin as medical expulsive therapy in ureteral calculi:
a meta-analysis of randomized controlled trials. Urolithiasis. 2018;46:212-218.
A7. Sorensen MD, Harper JD, Borofsky MS, et al. Removal of small, asymptomatic kidney stones and
incidence of relapse. N Engl J Med. 2022;387:506-513.
A8. Tsai SH, Chung HJ, Tseng PT, et al. Comparison of the efficacy and safety of shockwave lithotripsy,
retrograde intrarenal surgery, percutaneous nephrolithotomy, and minimally invasive percutane-
ous nephrolithotomy for lower-pole renal stones: a systematic review and network meta-analysis.
Medicine (Baltimore). 2020;99:e19403.
A8b. Soderberg L, Ergun O, Ding M, et al. Percutaneous nephrolithotomy versus retrograde intrarenal
surgery for treatment of renal stones in adults. Cochrane Database Syst Rev. 2023;11:CD013445.
A9. Bao Y, Tu X, Wei Q. Water for preventing urinary stones. Cochrane Database Syst Rev.
2020;2:CD004292.
A10. Wang Z, Zhang Y, Wei W. Effect of dietary treatment and fluid intake on the prevention of recurrent
calcium stones and changes in urine composition: a meta-analysis and systematic review. PLoS
One. 2021;16:e0250257.
A11. Li DF, Gao YL, Liu HC, et al. Use of thiazide diuretics for the prevention of recurrent kidney
calculi: a systematic review and meta-analysis. J Transl Med. 2020;18:106.
A12. Dhayat NA, Bonny O, Roth B, et al. Hydrochlorothiazide and prevention of kidney-stone recur-
rence. N Engl J Med. 2023;388:781-791.
A13. Phillips R, Hanchanale VS, Myatt A, et al. Citrate salts for preventing and treating calcium contain-
ing kidney stones in adults. Cochrane Database Syst Rev. 2015;10:CD010057.
A14. Balasubramanian P, Wanner C, Ferreira JP, et al. Empagliflozin and decreased risk of nephrolithi-
asis: a potential new role for SGLT2 inhibition? J Clin Endocrinol Metab. 2022;107:e3003-e3007.
A15. Garrelfs SF, Frishberg Y, Hulton SA, et al. Lumasiran, an RNAi therapeutic for primary hyperox-
aluria type 1. N Engl J Med. 2021;384:1216-1226.
112
CYSTIC KIDNEY DISEASES
M. AMIN ARNAOUT
DEFINITION AND EPIDEMIOLOGY
The term cystic kidney diseases refers to a heterogeneous group of hereditary
and acquired disorders characterized by the presence of unilateral or bilateral
renal cysts.1 When acquired singly or in small numbers and in the absence of
any other pathology, renal cysts are termed simple cysts, which are present in
approximately 50% of individuals older than 40 years, are usually not loculated,
and tend to bulge out from the renal surface (Fig. 112-1). The polycystic
kidney diseases (PKDs), by comparison, constitute a clinically important
group of genetically mediated disorders characterized by prominent, expand-
ing, typically bilateral renal cysts. PKDs are classified as dominant, recessive,
or X-linked, based on their pattern of inheritance. Autosomal dominant PKD,
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Elsevier on February 25, 2024. For personal use only. No other uses without permission. Copyright ©2024. Elsevier Inc. All rights reserved.
A Simple cysts B ADPKD C ARPKD
  FIGURE 112-1.    Gross pathology of selected cystic kidney diseases. A, Photograph
of a kidney with multiple simple cysts. The cysts bulge out from the surface of a normal-
sized kidney. B, Sagittal cross section of a kidney from an adult with autosomal domi-
nant polycystic kidney disease (ADPKD). Multiple macroscopic cysts have resulted in an
enlarged but still reniform kidney (note the evidence of prior hemorrhage within some of
the cysts). (Courtesy Dr. Robert Colvin, Massachusetts General Hospital.) C, Sagittal cross
section of a kidney segment from a patient with autosomal recessive polycystic kidney
disease (ARPKD). It shows multiple, small, slit-like radially oriented cysts (ranging from
0.2 cm up to 1.8 cm in greatest dimension) that replace the entire cortex and medulla and
are arranged perpendicular to the external surface. Patchy foci of hemorrhage are also
present. (Courtesy Dr. Alyaa Al-Ibraheemi, Boston Children’s Hospital.)
with a prevalence rate between 1 in 400 and 1 in 2000,2 is among the most
common monogenic diseases in humans and accounts for about 8 to 10% of
all end-stage renal disease in the United States. Autosomal dominant PKD
develops in an age-dependent manner and affects mainly adults. Autosomal
recessive PKD, by contrast, is a relatively rare childhood disorder that appears
in 1 in every 6000 to 50,000 live births. Renal cysts are also seen in several
other rare hereditary kidney diseases and in several syndromic PKDs (Table
112-1). Collectively, the hereditary PKDs generally affect both sexes and all
races equally and cost more than $1 billion annually to manage in the United
States alone. Acquired cystic kidney disease refers to the multiple bilateral renal
cysts that occur in 90% of patients who have received renal replacement therapy
for 8 years or longer. Acquired cystic kidney disease is associated with increased
rates of renal cell carcinoma.
AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY
DISEASE
PATHOBIOLOGY
Autosomal dominant PKD is a systemic disorder characterized by cyst for-
mation in multiple organs, including the kidneys, other ductal organs, and
the cardiovascular system. Renal cysts originate as outpouchings of tubules
and may arise from any portion of the nephron, with up to 1% of nephrons
involved. The outpouchings expand and eventually separate from the parent
tubules, yielding cysts (Fig. 112-2). Cyst growth is caused by proliferation
of the cyst lining cells and by abnormal fluid accumulation that results when
chloride-driven fluid secretion outpaces absorption. Cyst expansion and
fibrosis (induced by cystic epithelium-derived chemokines, cytokines, and
growth factors that attract macrophages and fibroblasts) cause compression
and obstruction of noncystic normal tubules, thereby resulting in upstream
tubular dilation. The kidneys become massively enlarged, and kidney function
progressively declines.
Genetics
Heterogeneous mutations in PKD1 and PKD2 cause ADPKD and account for
approximately 80% and 15% of the cases, respectively. Mutations in GANAB,
DNAJB11,3 and ALG9, which code for endoplasmic reticulum enzymes
involved in the protein biosynthetic pathway, account for fewer than 1% of cases.
Carriers of loss-of-function mutations in GANAB, which encodes GIIα, have
mild autosomal dominant PKD and variable degrees of polycystic liver disease.
Carriers of inactivating mutations in DNAJB11, which encodes the chaperon
protein ERdj3, have a phenotypic hybrid of autosomal dominant PKD and
autosomal dominant tubulointerstitial kidney disease (TKD), characterized

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