Marshall L. Stoller, Maxwell V. Meng-Urinary Stone Disease
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338 Shekarriz
MANAGEMENT
Acute management of cystinuria includes measures to resolve the acute stone crisis,
which is identical to other stone types. Pain management and hydration are the initial
steps. In the chronic phase, the goal of treatment is to decrease the urinary concentration
of cystine to below 150 mg/L. This goal can be achieved by non-specific measures or
more specific medications designed for cystinuria.
Medical Management of Cystinuria
The goal of medical management is prevention of new stone formation. This can be
achieved by the reduction of the cystine concentration in urine or increasing the urinary
cystine solubility (Table 2).
Dietary modification is an integral part of treatment. Previous studies have reported
that high methionine intake may contribute to increased cystine excretion. Methionine
is a precursor of cystine and is contained in essentially all meat products and other high
protein foods such as eggs, soy, and wheat. Clearly, a dietary restriction of all methion-
ine-containing products is not practical and patient compliance is a limiting factor.
Moreover, only a small proportion of methionine is excreted as cystine and the majority
is incorporated into proteins. In current medical practice, therefore, patients are advised
to maintain a balanced diet and avoid high protein intake. Cystine excretion is influenced
by dietary salt intake (54). A reduction in dietary sodium of 150 mEq/d results in a
decrease in urinary cystine concentration of 650 mmol/d (55).
The effect of sodium restriction is, however, limited. Furthermore, similar to methion-
ine restriction, a rigid dietary sodium restriction is difficult (25). A reduction in salt
intake to <2g/d has been recommended (47).
Fig. 4. (Continued) Ultrasonographic diagnosis of bladder (C) cystine calculi.
Chapter 18 / Cystine Stone Disease 339
The most important, general dietary measure to reduce urinary cystine concentration
is hydration. The upper limit of cystine solubility is 400 mg/L. Adequate hydration to
keep the urinary cystine concentration below this limit is effective. Hydration has been
shown to decrease urinary stone formation in as many as 67% of patients with cystinuria.
Adequate hydration can be monitored by checking the specific gravity of urine. A spe-
cific gravity of 1.010 has been recommended (16). In a recent study from France, a daily
urinary volume of >3.1 liters was recommended (56). This urinary volume was associ-
ated with a significant decrease in new stone formation over a long period of time.
Furthermore, the appearance of crystalluria in the first morning urine associated with a
specific gravity of 1.010 or greater was predictive of stone formation and growth (56).
Nocturnal hydration is important to decrease urinary supersaturation during sleeping
hours. A bedtime fluid intake of 500 mL has been suggested (50). Various types of fluid
can be used. The use of fruit juice, such as orange, is beneficial since they increase the
alkali load and subsequently the urinary pH (25).
Urinary alkalinization increases cystine solubility. Although theoretically simple, a
limitation of oral alkali therapy is the relative high cystine pKa of 8.5. Therefore, in order
to achieve a clinically significant increase in cystine solubility, a urinary pH of >7.5 is
desirable. There are two limitations for oral alkali therapy. First, to achieve and maintain
a urinary pH above 7.5 is difficult and not practical. Secondly, a high urinary pH will
predispose to calcium phosphate stone formation. Considering these limitations, the
goal of alkali therapy is to maintain a pH in the 6.5–7.0 range.
Various agents have been used for urinary alkalinization. Sodium bicarbonate is
effective but associated with a sodium load, which may not be desired in patients with
associated medical conditions, such as hypertension. Furthermore, sodium has the ad-
verse effect of promoting cystine excretion. Potassium citrate is currently the medication
of choice for urinary alkalinization. The starting dose is 60–80 mEq/d in divided doses
to maintain a constant pH level (15). Patients should be given pH paper to monitor their
urinary pH and to titrate their medication dose as needed.
Unfortunately, general measures with hydration and urinary alkalinization are com-
monly ineffective to control recurrent stone formation and more specific treatment is
required. Glutamine intake was once reported to reduce the cystine excretion rate (57).
Table 2
Medical Management of Cystine Calculi
Dietary • Moderate protein intake
• Low salt intake (<2 g/d)
• Hydration (specific gravity <1.010
Urinary alkalinization • PH 6.5–7
• Sodium bicarbonate
• Potassium citrate
Thiol derivatives •
D-Penicillamine
• Alpha mercaptoproprionylglycine
• Bucillamine
ACE inhibitor • Captopril
ACE, angiotensin-converting enzyme.
340 Shekarriz
However, others could not duplicate this finding and currently there is no role for this
treatment.
Thiol derivatives are chelating agents. They contain a sulfhydryl group, which can
undergo a thio-disulfide exchange with cystine; the disulfide bond of cystine therefore
is challenged resulting in more soluble complexes incorporating cystine monomers.
Therefore, these medications may result in dissolution of existing stones when other
general measures have failed and help prevent stone recurrences.
D-Peniciliamine was the first chelating agent (9). It can produce complexes 50 times
more soluble than cystine.
D-Penicillamine has been associated with frequent side effects
including gastrointestinal disturbances, allergic reactions with fever and rash, arthralgia,
leukopenia, thrombocytopenia, proteinuria with nephrotic syndrome, and polymyositis
(58). Frequent side effects may occur in as many as 50% of patients after long-term
therapy.
D-Penicillamine may result in pyridoxine (vitamin B6) deficiency. Therefore,
prophylactic medication with vitamin B6 (50 mg/d) is recommended (50) and this com-
bination is frequently responsible for discontinuation of the medication.
Alphamercaptopropionylglycine (αMPG) is a second generation chelating agent,
which is structurally related to
D-penicillamine and has a similar mechanism of action
with significantly reduced side effects. In an early report, after long-term treatment with
αMPG, one third of stones were dissolved and new stone formation was prevented in
85% of patients. αMPG was found to be 50% more effective than
D-penicillamine in
reducing free cystine levels and increasing the amount of cystine disulfide in the urine
(59). In a multicenter trial, 67% of patients discontinued
D-penicillamine due to signifi-
cant side effect compared to 31% of those taking αMPG (60). This treatment reduced the
stone formation rate by 81–94% with a remission rate of 63–71% in 66 patients (60).
It appears that αMPG is a more effective agent for cystinuric patients with reduced
severity of side effects compared to
D-penicillamine. Therefore, αMPG is currently the
medication of choice in most centers. The starting dose is 400 mg/d in divided doses.
This dose can be increased to 800–1200 mg/d. Bucillamine (Rimatil) is a third generation
chelating agent; Rimatil is theoretically more effective since it is a dithiol compound.
Clinical experience with Rimatil is limited. However, a lower toxicity with similar
efficacy has been reported (25).
Captopril, an angiotensin-converting enzyme inhibitor, has been reported to decrease
the urinary cystine concentration (61). The mechanism of action is similar to thiols.
Captopril contains a free sulfhydryl group, which can compete the disulfide bond in
cystine and result in formation of cystine-captopril complex, which is 200 times more
soluble than cystine. However, studies on the efficacy of captopril have been inconclu-
sive. Some centers have reported a role for captopril especially in patients with hyper-
tension who require antihypertensive medications or those patients who failed standard
treatment for cystinuria (62). Conversely, others did not find a significant effect from
captopril treatment (56,63,64).
Surgical Management of Cystine Stones
Patients with cystinuria typically have frequent recurrences of multiple stones despite
medical management. Management of large volume calculi requires surgical interven-
tion. Due to the natural history of the disease, current surgical management is directed
by means of minimally invasive endourological techniques. This includes extracorpo-
real and intracorporeal lithotripsy using ureteroscopic or percutaneous approaches.
Chapter 18 / Cystine Stone Disease 341
A limitation of extracorporeal shock wave lithotripsy (SWL) is the fact that cystine
stones are recalcitrant to cracking and relatively hard to break. This modality is usually
reserved for stones smaller than 1.5 cm in diameter (47). Based on the results with SWL,
two different crystal structures for cystine stones have been proposed (65). In this study,
the rough calculi were composed of large, organized hexagonal crystals that form good
cleavage planes for fragmentation. Smooth calculi, however, were made of smaller,
disorganized poorly formed crystals and were much more difficult to fragment. Another
study reported that SWL of cystine calculi resulted in large fragments compared to other
stone types (53). Medical treatment before SWL may result in easier fragmentation by
promoting the formation of apatite in cystine calculi (66). Conversely, SWL may be used
initially to improve the results of medical chemolysis by increasing the exposed stone
surface (67).
The principles of ureteroscopic management are similar to other stone types. The best
available modalities of intracorporeal lithotripsy include the lithoclast and holmium-
yttrium-aluminum-garnet laser. The Swiss Lithoclast delivers mechanical pneumatic
fragmentation generated by compressed air similar to the jackhammer principle (68).
Holmium-yttrium-aluminum-garnet laser generated pulsed light at a wavelength of 2100
nm to induce both fragmentation and vaporization (69). In our experience, laser litho-
tripsy of cystine stones produces a sulfur odor during the procedure, which is harmless
and likely related to release of sulfur gas from the stone surface. The introduction of these
two modalities have facilitated stone fragmentation and improve stone free rate after
ureteroscopic procedures. Both modalities have the advantage of fragmenting all stone
types and are equally effective (68,69). However, laser produces smaller fragments and
less retrograde stone migration (47).
Larger renal stones or proximal ureteral stones are best managed with percutaneous
nephrolithotomy. This modality offers the advantage of large endoscopes and the use of
ultrasonic lithotripsy, which can easily fragment cystine stones. Other modalities such
as the use of lithoclast and laser can also be employed (70). Another advantage of the
percutaneous approach is the direct access for stone chemolysis. If residual fragments
persist after the percutaneous approach, chemo-dissolution of residual fragments can
be attempted. Various solutions including N-acetylcysteine, tris-hydroxymethyl
aninomethane (THAM-E), and alkali agents have been successfully utilized (16).
We utilize the percutaneous tube and an indwelling ureteral access catheter for con-
tinuous irrigation with alkali solutions. A limitation of percutaneous chemolysis is the
need for hospital admission, careful monitoring of intrapelvic pressure, and hence an
associated high cost. Therefore, direct chemolysis is mainly used in conjunction with
other modalities when ureteroscopic and percutaneous procedures remain unsuccessful
in eradicating all stone fragments.
Acceptable stone free rates can be achieved using these modalities. In a recent study
of 61 renal units, a stone free rate of 87% has been reported using various modalities,
which was not influenced by the initial stone burden or the type of initial management
selected (71).
It is important to keep in mind that patients with cystinuria present with early and
frequent recurrences after surgical procedures despite medical treatment. Therefore,
contrary to other stone types, the primary goals of surgical treatment are relief of symp-
toms associated with renal obstruction and preservation of renal function rather than
achieving a complete stone free status.
342 Shekarriz
FUTURE PERSPECTIVES
Recent advances in molecular biology have provided new insights into the patho-
physiology and genetics of cystinuria. However, the new knowledge has not translated
into a more effective medical treatment for cystinuria to date. Current modalities for
medical treatment of cystinuria with urinary alkalinization and chelating agents have
limited effectiveness for prevention of frustrating recurrent calculi. It is expected that
future development will be based on molecular and gene therapy. Until that time, the
treatment of cystinuric patients remains a difficult task and the goal should be prevention
of recurrences and the use of minimally invasive surgery to preserve renal function.
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Chapter 19 / Urinary Stones of Unusual Etiology 345
345
From: Current Clinical Urology, Urinary Stone Disease:
A Practical Guide to Medical and Surgical Management
Edited by: M. L. Stoller and M. V. Meng © Humana Press Inc., Totowa, NJ
19
Urinary Stones of Unusual Etiology
Patrick S. Lowry, MD and Stephen Y. Nakada, MD
CONTENTS
INTRODUCTION
METABOLIC STONES
MEDICATION RELATED STONES
PEDIATRIC STONES
REFERENCES
Key Words: Nephrolithiasis; xanthine; antiretroviral medication; ammo-
nium.
INTRODUCTION
The vast majority of urinary stones are composed of calcium oxalate, calcium phos-
phate, struvite, uric acid, or cystine. Enumerable studies analyzing over 45,000 total
calculi have shown urinary stones to be composed of “other” constituents only 0.5–3.5%
of the time. Although uncommon, these stones can be challenging to both diagnose and
to treat. In many cases, accurate diagnosis is necessary for proper treatment. This chal-
lenge begins with routine stone analysis, especially in the case of radiolucent stones that
do not clinically fit the uric acid picture, or that recur despite appropriate therapy with
strict urinary alkalinization and xanthine oxidase inhibition.
Some types of rare stones are caused by ingestion of inappropriately large doses of
medications, and treatment requires merely cessation of the medication to prevent fur-
ther stone episodes. Other stones are genetic disorders of metabolism, which require a
more complex medical decision-making process. Although commonly a fortuitous dis-
covery made through stone analysis, good knowledge of the patient history and an
increased awareness of the conditions that predispose to formation of unusual stones will
heighten clinical suspicion which may lead to the diagnosis of an unusual stone. Only
by understanding the metabolic pathways leading to the formation of these stones, and
346 Lowry and Nakada
applying this knowledge to clinical practice, can we avoid confusing rare calculi with
more common stone entities, avoid needless recurrence of stone episodes, and prevent
deterioration of renal function.
The goal of this chapter is to present information that will help urologists diagnose and
treat unusual urinary stones (Table 1).
METABOLIC STONES
2, 8-Dihydroxyadenine Stones
In purine metabolism, the breakdown of adenine into adenine monophosphate involves
the enzyme adenine phosphoribosyl transferase (APRT). Deficiency of the APRT enzyme
prevents adenine from entering the salvage pathway, and consequently, adenine is con-
verted by xanthine oxidase into 2, 8-dihydroxyadenine (2,8-DHA) (Fig. 1) (1). 2,8-DHA
is highly insoluble in the urine and patients have resulting crystalluria, often with neph-
rolithiasis (2). APRT deficiency is inherited as an autosomal recessive trait (3), and
patients must be homozygotes or compound heterozygotes with a null allele for the
patient to have APRT deficiency (1).
Two types of APRT deficiency have been described. Type I predominantly affects
Caucasians, and has almost no APRT activity, as measured by the level of enzyme
activity in erythrocytes (4). Until recently, type II APRT deficiency was found only in
Japan, but is now described in patients of Polish ancestry (5). In type II disease, mutations
exist in both genes, yet residual APRT activity (10–25% activity) remains (1).
Table 1
Types of Unusual Stones
Metabolic stones
2,8-Dihydroxyadenine stones
Ammonium acid urate steones
Primary xanthine stones
Medication-related stones
Ephedrine stones
Guaifenesin stones
Indinavir stones
Nelfinavir stones
Oxypurinol stones
Silicate stones
Sulfa stones
Topimarate-induced stones
Triamterene stones
Xanthine stones
a
Ammonium acid urate stones
a
Pediatric stones
Stones in low-birth-weight premature infants
Stones in children and adolescents/endemic bladder stones
a
Caused by both medications and metabolic abnormalities.
Chapter 19 / Urinary Stones of Unusual Etiology 347
2,8-DHA excretion into the urine follows a circadian rhythm, with increased elevation
during the late night and early morning (6). Owing to usual sleeping habits, this is the
time when most people have the lowest fluid intake, and the most concentrated urine,
resulting in a circadian dependent risk of 2,8-DHA stone formation.
2,8-DHA urinary stones were first described in 1974 (7), yet likely went misdiag-
nosed before that as uric acid stones. Interestingly, deposition of 2,8-DHA crystals in
renal tubular lumen were reported by Joost et al in 1898 (8). Like uric acid stones, 2,8-
DHA calculi are radiolucent, although they can be seen on CT scans. 2,8-DHA stones
are also difficult to distinguish from uric acid stones from an analysis standpoint. 2,8-
DHA appears indistinguishable from uric acid in biochemical analysis (murexide test for
urate; phosphotungstate or phosphomolybdate for uric acid) (1,3). Ultraviolet testing
may also fail to distinguish the two, if performed in alkaline solution (2). Only infrared
spectroscopy, X-ray diffraction, and properly performed UV testing will distinguish the
two(1,2,6). Gross appearances should suggest a difference between the two when closely
examined; uric acid stones have a smooth, yellow, hard surface, whereas dried 2,8-DHA
calculi are rough, gray, and friable (1).
Another confounder to prevent recognition of 2,8-DHA stones is the treatment. To
prevent crystallization of 2,8-DHA in the urine, the production must be stopped. Allopu-
rinol inhibits xanthine oxidase, preventing the conversion of adenine to 2,8-DHA, and
is very effective for stone prophylaxis (1). The patients misdiagnosed with uric acid
stones will likely be placed on allopurinol at some point as their stones recur. This will
aid in the prevention of further stone formation from either uric acid or 2,8-DHA.
Early recognition of APRT deficiency and proper diagnosis of stone type is necessary
to prevent decline of renal function. In a series of 17 APRT deficient patients, 8 presented
with renal insufficiency, 25% of which progressed to renal failure or died from uremic
complications (1). Renal damage occurs because of deposition of crystalline material in
tubular lumen and within epithelial cells (9). Failure of transplanted kidneys in patients
with undiagnosed, and consequently, untreated 2,8-DHA lithiasis has been reported
(10,11). In one report, the patient presented with renal failure, and after appropriate acute
Fig. 1. Pathway of purine metabolism leading to 2,8-dihydroxyadenine.