Editing Stones: Evaluation and Medical Management

== Diagnosis and Evaluation ==

* Any evaluation for recurrent stone disease should be able to identify associated metabolic disorders such as distal renal tubular acidosis (RTA), primary hyperparathyroidism, enteric hyperoxaluria, cystinuria, and gouty diathesis
* First-time stone formers have been estimated to have a 50% risk for recurrence within the subsequent 10 years
** Patients at higher risk for repeat episodes:
*** Family history of stones
*** Intestinal disease (particularly when causing chronic diarrheal states)
*** Pathologic skeletal fractures
*** Osteoporosis
*** UTI
*** Gout
* Indications for a metabolic stone evaluation
*# Recurrent stone formers
*# Strong family history of stones
*# Intestinal disease
*# Pathological skeletal fractures
*# Osteoporosis
*# History of UTI with calculi
*# Personal history of gout
*# Infirm health (unable to tolerate repeat stone episodes)
*# Solitary kidney
*# Anatomic abnormalities
*# Stones composed of cystine, uric acid, and struvite
*# Children should generally be evaluated because of concerns about renal damage and long-term sequelae of stone recurrence
* Abbreviated protocol for low-risk single-stone formers
** History
*** Screen for factors that predispose to calculi
**** Chronic diarrhea that could be caused by inflammatory bowel disease (Crohn disease, ulcerative colitis) or irritable bowel syndrome
**** Gout may predispose the patient to hyperuricosuria or gouty diathesis with either uric acid calculi or calcium oxalate stone formers
**** Surgical history should be obtained focusing particularly on bariatric surgery and surgeries of the intestinal tract. '''In contrast to gastric bypass surgery, restrictive bariatric surgeries such as gastric sleeve or gastric band do not seem to increase the risk for kidney stones'''
** Laboratory
*** Serum metabolic panel
**** Preoperative serum chemistries are important because they may provide clues to underlying serious diseases such as renal tubular acidosis or hypoparathyroidism or other metabolic derangements
**** '''Assessment of underlying renal function is necessary'''
*** Urinalysis +/- culture
**** '''Urinalysis should include pH'''
***** '''pH > 7.0 is suggestive of infection lithiasis or RTA'''
***** '''pH < 5.5 suggests uric acid lithiasis secondary to gouty diathesis'''
**** Urine culture
***** Many infected calculi will harbour bacteria even after treatment with broad-spectrum antibiotics
***** Half of infected calculi grow bacterial cultures that are different from the preoperative urine specimen
*** Urine microscopy for crystals may provide clues to diagnosis


Insert table

** '''Imaging'''
*** '''Plain abdominal film'''
**** Can identify nephrocalcinosis, suggestive of RTA
**** '''Radiolucent stones (6):'''
***** '''Uric acid'''
***** '''Matrix'''
***** '''Medication stones (xanthine, triamterene, 2,8-dihydroxyadenine, indivir)'''
**** '''Radioopaque stones: calcium oxalate, calcium phosphate, magnesium ammonium phosphate (struvite) and cystine stones'''
***** '''Although magnesium ammonium phosphate and cystine stones are often radioopaque, they are not as dense as calcium oxalate or calcium phosphate stones'''
***** Campbell’s says '''cystine stones''' radioopaque but other source (<nowiki>https://radiopaedia.org/articles/urolithiasis</nowiki>) says usually radiolucent. European Guidelines say they '''are''' '''poorly radioopaque'''§
**** Underestimates >90% of stones >10mm
*** '''Ultrasound'''
**** '''Limitations (2):'''
***** '''Inability to visualize most ureteral stones'''
***** '''Poor correlation between measured and actual stone size and location'''
****** '''US and CT measurements correlate 2/3 of the time'''
******* '''With stone <10mm, US underestimates size of stone 1/3 of the time'''
******* '''With stone >10mm, US overestimates size of stone 1/3 of the time'''
*** '''CT'''
**** '''Pure uric acid stones have much lower Hounsfield units than calcium types'''
*** '''Forniceal extravasation'''
**** Usually associated with a small distal ureteral calculus.
**** '''Should be similarly to other ureteral stones:''' intervention should be undertaken when there is an associated fever, nausea/vomiting, or unrelenting pain. Otherwise, conservative observation is appropriate.
** '''Stone composition'''
*** Can direct metabolic investigation or potentially obviate the need for a complete metabolic evaluation

* '''Extensive diagnostic evaluation'''
** Includes one or two 24-hour urine collections
** '''Significant aberrations in total creatinine excretion from estimated volumes (males 20-25mg/kg and females 15-20mg/kg in 24 hours) imply incomplete collection, overcollection, greater than expected muscle mass, or less than expected muscle mass'''
*** For abnormally collected 24 hour urine collections, can divide metabolite excretion by creatinine excretion to compare collections
** The urinary constituents most commonly assayed in a 24 hours urine collection include calcium, oxalate, citrate, total volume, sodium, magnesium, potassium, pH, uric acid, and sulfate.
*** Sulfate is added to assess the volume of protein loading from animal meat.

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* Toradol 30 mg IV
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* Acetaminophen 1000 mg PO
* 1 L 0.9% NS bolus

===== '''Conservative management''' =====

* '''Fluid recommendations'''
** '''Increase fluid intake to achieve a daily urine output of ≥2 liters'''
*** '''Overall, most evidence suggests that it is not the type of fluid ingested that is important for stone prevention but rather the absolute amount of fluid volume taken in per day'''
**** Water hardness should be a minor concern with respect to stone formation
**** Carbonated water may provide some protective benefit
**** Citrus juices (particularly lemon and orange juices) may be a useful adjunct to stone prevention
**** '''Soda flavored with phosphoric acid may increase stone risk, whereas those with citric acid may decrease risk'''
***** Several sodas are acidified by citric acid and contain an amount of citrate equal to or greater than that of lemonade, including Diet Sunkist Orange, Diet 7Up, Sprite Zero, Diet Canada Dry Ginger Ale, Sierra Mist Free, Diet Orange Crush, Fresca, and Diet Mountain Dew. All of the aforementioned sodas have the potential to decrease the risk of kidney stones similar to or greater than lemonade.
***** In contrast, colas, including Caffeine Free Diet Coke, Diet Coke, Diet Coke with Lime, Coke Zero, Caffeine Free Diet Pepsi and Pepsi, are acidified by phosphoric acid, not by citric acid and contain low citrate levels.
****** One randomized study of recurrent stone formers with baseline soda consumption > 160 ml per day, found that over a 3-year period those who abstained from any soft drink consumption had a lower risk of symptomatic stone events (34%) compared to those who continued to drink sodas acidified by phosphoric acid (41%; RR, 0.83).§
**** '''Performance sports drinks'''
***** '''May increase urinary citrate and pH''' thereby reducing risk of stones.
****** However, these drinks have a high fructose and total carbohydrate content so they should not be recommended as the primary means of hydration for stone formers.
***** Do not lead to hypernatriuria, even though sodium content may be high
***** No effect on urinary calcium, oxalate, and uric acid. 
* '''Dietary recommendations'''
** '''Protein restriction'''
*** '''Protein intake increases urinary calcium, oxalate, and uric acid excretion'''
*** RCTs have demonstrated a benefit of a diet with reduced animal protein (meat) intake
** '''Sodium restriction'''
*** '''High sodium intake is associated with:'''
***# '''Increases calcium excretion'''
***# '''Increases urinary pH'''
***# '''Decreases citrate excretion'''
*** RCTs have demonstrated a benefit of dietary sodium restriction
** Weight-loss diets
*** The consumption of a low-carbohydrate, high-protein diet delivers a marked acid load to the kidney, increases the risk for stone formation, and may increase the risk of bone loss
* '''Obesity'''
** '''Increased BMI, larger waist size, and weight gain are correlated with an increased risk for stone episodes'''

*** '''The association of obesity and uric acid stone formation is primarily due to change in urinary pH'''
*** '''The association of obesity with calcium oxalate stone formation is primarily due to increased excretion of promoters of stone formation''' (oxalate, uric acid, sodium, and phosphorus)

** '''Metabolic syndrome is associated with lower urinary pH'''
** Roux-en-Y-gastric bypass surgery may significantly increase the overall risk for stone formation
* '''Dietary calcium'''
** '''Moderate calcium intake is preferred'''
*** '''Restricted calcium intake leads to an increase in available intestinal oxalate, which subsequently increases oxalate absorption,''' thereby raising the supersaturation of calcium oxalate;
** '''Calcium supplements are safe if attention is paid to preparation (calcium citrate appears to be a more stone-friendly calcium supplement because of the additional inhibitory action of citrate) and especially timing (should be taken with meals)'''
* '''Vitamin D'''
** '''Controversy exists over the role of vitamin D supplementation and kidney stone formation'''
** '''Patients who undergo vitamin D repletion should have their 24-hour urine calcium monitored'''
* '''Dietary oxalate'''
** Although dietary oxalate clearly plays a role in increased urinary oxalate, it is difficult to restrict its intake because oxalate is ubiquitous and found in most vegetable matter. However, it is important to avoid large portions of foodstuffs that are rich in oxalate, such as spinach, beets, chocolate, nuts, and tea.
** Whereas general advice on a restricted-oxalate intake might be given to patients with recurrent nephrolithiasis, '''a low-oxalate diet would be most useful in patients with enteric hyperoxaluria, such as those with underlying bowel abnormalities or previous gastric bypass surgery'''
* Follow-up
** If the patient’s metabolic or environmental abnormalities have been corrected, the conservative therapy can be continued and the patient followed every 6-12 months with repeat 24-hour urine testing as indicated.
*** Follow-up is essential not only to monitor the efficiency of treatment but also to encourage patient compliance. If, however, a metabolic defect persists, a more selective medical therapy may be instituted.

===== '''Selective medical therapy for nephrolithiasis''' =====

* See Tables 52-9 and 52-10 for dosages and side effects
* '''Hypercalcuria'''
** '''In patients with renal or absorptive type I hypercalciuria, thiazide is the first choice.'''
*** Recall, in absorptive hypercalciuria I, increased absorption will occur regardless of the amount of calcium in the patient’s diet (these patients will demonstrate an hypercalcuria on both the fasting and the loading specimens). In contrast, patients with absorptive hypercalciuria II will have a normal amount of urinary calcium excretion during calcium restriction, but will show elevations during their regular diet
*** Currently, no treatment is capable of correcting the basic abnormality of type I absorptive hypercalcuria
*** Thiazides may have a limited long-term effectiveness in type I absorptive hypercalcuria
*** In type II absorptive hypercalciuria, no specific drug treatment may be necessary because the physiologic defect is not as severe as in type I.
** '''Thiazides'''
*** '''MOA'''
***# '''Directly stimulate calcium reabsorption in the distal nephron'''
***# '''Promotes excretion of sodium causing extracellular volume depletion'''
***** '''Long-term thiazide therapy results in volume depletion, extracellular volume contraction, and proximal tubular resorption of sodium and calcium.'''
*** Chlorthalidone (25-50 mg/day) or indapamide (2.5 mg/day) are preferred to hydrochlorothiazide since they are long-acting and are once a day dosing.
**** Indapamide is technically not a thiazide but does share a successful hypocalciuric effect with the other agents.
*** '''Patients placed on thiazide diuretics for management of hypercalciuria should also be placed on dietary sodium restriction'''
**** An excess sodium load will inhibit reabsorption of calcium in the proximal tubule, thereby causing hypercalciuria.
*** '''Adverse events'''
**** '''Lassitude and sleepiness'''
***** '''Most common side effects of thiazides'''
***** Can occur in the absence of hypokalemia
***** Usually seen on initiation of treatment but resolves with continued therapy.
**** '''Metabolic/electrolyte abnormalities''' ('''3 hypers, 3 hypos + metabolic alkalosis''')
****# '''Hyperglycemia'''
****# '''Hyperlipidemia'''
****# '''Hyperuricemia'''
****# '''Hypokalemia'''
****# '''Hypomagnesemia'''
****# '''Hypocitraturia'''
****# '''Metabolic alkalosis'''

* '''Hypokalemia and hyperglycemia'''
** '''The degree of diuretic-induced hypokalemia correlates with level of hyperglycemia.'''
*** Mechanism: hypokalemia impairs insulin secretion, thereby increasing plasma glucose.
** '''Potassium supplementations should always be considered at either the onset of thiazide therapy or upon the discovery of glucose intolerance'''
*** '''Can prevent or significantly lessens the degree of hypokalemia or glucose intolerance'''
*** '''Can be administered as potassium citrate, potassium-sparing agents (triamterene), or with dietary supplements such as a banana per day'''
**** '''Citrates are generally well tolerated, with only a small risk for GI upset'''
***** A liquid preparation of potassium citrate, rather than the slow-release tablet preparation, is recommended in patients with rapid intestinal transit time (i.e. chronic diarrhea); the slow-release medication may be poorly absorbed
**** Conflicting evidence of an increased risk of calcium phosphate stone formation with the long-term use of potassium citrate therapy
*** Particularly important in patients with evident potassium deficiency, patients on digitalis therapy, and those individuals who develop hypocitraturia
* '''Hypocitraturia'''
** '''Result of hypokalemia with intracellular acidosis'''
**** '''Patients with undiagnosed primary hyperparathyroidism may develop hypercalcemia after initiation of thiazide therapy'''
***** Although most patients with primary hyperparathyroidism demonstrate hypercalcemia and hypercalciuria, a normal serum calcium level in the presence of an inappropriately high serum PTH value may be seen in some cases, making the diagnosis more difficult. Administration of a thiazide diuretic will enhance renal calcium reabsorption and exacerbate the hypercalcemia, thereby facilitating the diagnosis (“thiazide challenge”)
****** In the thiazide challenge, cessation of thiazide should reduce PTH and serum calcium. However, in primary hyperparathyroidism, PTH and serum calcium remain persistently elevated with cessation of thiazide.
**** '''Bisphosphonates combined with thiazide diuretics appear to reduce hypercalciuria while protecting the bone'''
*** '''Thiazide diuretics lose their effectiveness in the treatment of hypercalciuria in up to 25% of patients on long-term management.'''
**** '''Loss of effectiveness is due to increased serum calcium levels which stimulate the C cells in the thyroid to produce more calcitonin.''' Increased calcitonin leads to increased urinary calcium excretion.
** '''Fish oil'''
*** '''An effective, first-line therapy for mild-moderate hypercalciuria'''
**** Thought to have a protective role in preventing nephrolithiasis by decreasing urinary calcium and oxalate excretion through alteration of prostaglandin metabolism
** '''Hyperparathyroidism complicated by stone disease is best treated with surgical excision of the adenoma'''

* '''Hyperuricosuric Calcium Oxalate Nephrolithiasis'''
** '''Patients with hyperuricosuria should be instructed to decrease dietary purine intake'''
** '''Pharmacologic approaches to the management of hyperuricosuric calcium nephrolithiasis (2):'''
**# '''Alkalinizing the urine so that uric acid remains in a dissolved state'''
**#* '''Potassium citrate may be used'''
**#** CUA Guidelines only discuss allopurinol for hyperuricosuric calcium oxalate nephrolithiasis, not potassium citrate
**# '''Decreasing the production of uric acid'''
**** '''Allopurinol (300 mg/day) may be used'''
***** MOA: blocks the ability of xanthine oxidase to convert xanthine to uric acid.
****** The resultant decrease in serum uric acid will ultimately lead to a decrease in urinary uric acid as well.
***** Allopurinol’s use in hyperuricosuria associated with dietary purine overindulgence also may be reasonable if patients are unable or unwilling to comply with dietary purine restriction.

* '''Enteric hyperoxaluria'''
** '''Fluid intake should be strongly encouraged to correct the relative state of dehydration'''
** '''Dietary/supplemental calcium may help bind intestinal oxalate and decrease its absorption'''
** '''Treatment with potassium citrate (60 to 120 mEq/day) may correct the hypokalemia and metabolic acidosis in patients with enteric hyperoxaluria''' and, in some individuals, increase urinary citrate toward normal.

* '''Hypocitraturic Calcium Oxalate Nephrolithiasis'''
** '''Citrates are first-line therapy for the management of RTA, thiazide-induced hypocitraturia, and idiopathic hypocitraturia'''
*** Potassium citrate therapy is able to correct the metabolic acidosis and hypokalemia found in patients with distal RTA



* '''Hypomagnesuric Calcium Nephrolithiasis'''
** Magnesium oxide or magnesium hydroxide can be used to restore urinary magnesium; hypocitraturia can be corrected with potassium citrate
*** Use of magnesium has been limited by the risk for diarrhea
*** Potassium-magnesium may restore urinary magnesium and citrate levels with minimal GI side effects

* '''Uric acid stones'''
** '''Goal is to increase the urinary pH > 5.5, preferably between 6.0-6.5, through an alkalinizing agent such as potassium citrate'''
*** With adequate alkali therapy, patient's can raise the urine pH above the dissociation constant of uric acid.
**** '''Attempts at alkalinizing the urine to a pH > 7.0 should be avoided. At a higher pH, there is a danger of increasing the risk for calcium phosphate stone formation.'''
*** Patients may initially present with low/normal 24-hour urinary uric acid levels because the uric acid will precipitate out of solution in the acid urinary environment. Once the urine has been alkalized, all of the uric acid will come back into solution, causing a significant increase in the measured urinary uric acid.
** '''Patient's treated with sodium alkali will occasionally begin forming calcium oxalate stones due to an excess sodium load that will inhibit reabsorption of calcium in the proximal tubule, thereby causing hypercalciuria'''
*** Potassium citrate is advantageous because it is not only a good alkalinizing agent, but it appears to be devoid of the complication of calcium stones.
** '''Acetazolamide is effective in increasing the urinary pH in patients with uric acid and cystine stone formation who are already taking potassium citrate.'''
*** Acetazolamide, a carbonic anhydrase inhibitor, leads to an increase in urinary bicarbonate and increased H+ reabsorption.
*** Up to 50% of patients may discontinue acetazolamide due to adverse effects.

* '''Cystinuria'''
** '''First-line: aggressive fluid intake, urinary alkalinization, and salt avoidance''' (excess dietary sodium can lead to increases in cystine excretion)
** '''Second line: cystine-binding agents'''
*** '''MOA: increase cystine solubility in urine by formation of a more soluble mixed-disulfide bond (i.e., cystine to drug, rather than cystine to cystine).'''
*** '''Options include α-mercaptopropionylglycine (tiopronin [Thiola]),''' D-penicillamine (Cuprimine), and captopril
**** d-Penicillamine and α-MPG are equally effective in their ability to decrease urinary cystine levels. However, α-mercaptopropionylglycine is significantly less toxic than d-penicillamine.
**** Side effects of '''D-penicillamine''' include gastrointestinal disturbances, fever and rash, arthralgia, leukopenia, thrombocytopenia, proteinuria with nephrotic syndrome, polymyositis, and '''pyridoxine (Vitamin B6) deficiency'''
***** '''Pyridoxine (vitamin B6) deficiency supplementation is recommended'''

* '''Infection stones'''
** '''The preferred management of struvite calculi involves aggressive surgical approaches'''
** '''The medical management of infection calculi centers on the prevention of recurrence, rather than medical dissolution.'''
*** Long-standing effective control of infection with urea-splitting organisms should be achieved if at all possible with improved bladder health, adequate urinary drainage, and suppressive antibiotics
*** '''Acetohydroxamic acid (AHA)'''
**** '''MOA: urease inhibitor; may reduce the urinary saturation of struvite and therefore delay stone formation'''
**** '''Adverse effects'''
***** Minor side effects common (up to 30% of patients)
***** '''Deep venous thrombosis''' (15%)
***** '''Hemolytic anemia'''
****** '''Most serious side effect'''
****** '''Occurs in up to 15% of the patients; more prevalent in patients with renal insufficiency'''
**** '''Frequently reserved for patients deemed too ill for surgical management.'''
*** '''Phosphate therapy is contraindicated in cases of infection calculi because this medication may promote further stone formation.'''

===== '''Medical management of pediatric calculi''' =====

* '''Neonates can develop furosemide-induced nephrolithiasis.'''
** Neonates treated with loop diuretics should be screened for the development of nephrocalcinosis.
** '''Cessation of furosemide diuresis is considered helpful and standard therapy'''.
*** Although switching to a thiazide diuretic may not actively cause the dissolution of calculi, it at least removes the causative agent and allows the kidney an opportunity to heal and clear the calcium deposits.
* '''The appearance of urinary calculi during childhood should raise the distinct possibility of an inherited genetic disorder, such as cystinuria, distal RTA, or primary hyperoxaluria'''
* There is a lack of consensus regarding normal laboratory values during 24-hour urine collections in children. Clinicians have relied on ratios to correct for the wide variation of weight
* '''The medical management of nephrolithiasis and the prevention of subsequent recurrences in children do not differ that dramatically from the approaches undertaken for adults'''


===== Questions =====

# What is the risk of stone recurrence at 10 years in first-time stone formers?
# What is the microscopic appearance of common urinary calculi?

===== Answers =====
1. 50%

===== References =====

* Wein AJ, Kavoussi LR, Partin AW, Peters CA (eds): CAMPBELL-WALSH UROLOGY, ed 11. Philadelphia, Elsevier, 2015, chap 52