Editing Stones: Evaluation and Medical Management (section)

== Pharmacologic Therapies ==
===Calcium or calcium phosphate stones===

==== <span style="color:#ff0000">Thiazide diuretics</span> ====

*'''<span style="color:#ff0000">Indications</span>'''
**'''<span style="color:#ff0000">Should be offered to patients with (2):</span>'''
***'''<span style="color:#ff0000">Hypercalcuria AND</span>'''
***'''<span style="color:#ff0000">Recurrent calcium or calcium phosphate stones</span>'''
* '''Mechanism of Action'''
*# '''Directly stimulate calcium reabsorption in the distal nephron''' (hypocalcuric effect)
*# '''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.'''
* '''<span style="color:#ff0000">Drugs and dosages'''
*#'''<span style="color:#ff0000">Hydrochlorothiazide</span> (50mg orally, once daily;''' 25mg orally, twice daily''')'''
*#'''<span style="color:#ff0000">Chlorthalidone</span>''' (25mg orally, once daily)
*#'''<span style="color:#ff0000">Indapamide</span> (2.5mg orally, once daily)'''
*#*Chlorthalidone or indapamide 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.
* '''<span style="color:#ff0000">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.'''
* '''<span style="color:#ff0000">Adverse events'''
** '''<span style="color:#ff0000">Sleepiness and lassitude'''
*** '''<span style="color:#ff0000">Most common side effects of thiazides'''
*** Can occur in the absence of hypokalemia
*** Usually seen on initiation of treatment but resolves with continued therapy.
** '''<span style="color:#ff0000">Metabolic/electrolyte abnormalities''' ('''3 hypers, 3 hypos + metabolic alkalosis''')
**# '''<span style="color:#ff0000">Hyperglycemia'''
**# '''<span style="color:#ff0000">Hyperlipidemia'''
**# '''<span style="color:#ff0000">Hyperuricemia'''
**# '''<span style="color:#ff0000">Hypokalemia'''
**# '''<span style="color:#ff0000">Hypomagnesemia'''
**# '''<span style="color:#ff0000">Hypocitraturia'''
**# '''<span style="color:#ff0000">Metabolic alkalosis'''
**'''<span style="color:#ff0000">Hypokalemia and glucose intolerance'''
*** '''The degree of diuretic-induced hypokalemia correlates with level of hyperglycemia.'''
**** Mechanism: hypokalemia impairs insulin secretion, thereby increasing plasma glucose.
***'''<span style="color:#ff0000">Potassium supplementation (either potassium citrate or potassium chloride)</span>''' 
****'''<span style="color:#ff0000">May be needed when thiazide therapy is employed because of the hypokalemic effects of these medications</span>'''
****'''<span style="color:#ff0000">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 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
****'''The addition of amiloride or spironolactone may avoid the need for potassium supplementation'''.
****Triamterene, although it is potassium-sparing, should be avoided as stones of this compound have been reported
**'''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.

==== <span style="color:#ff0000">Potassium citrate</span> ====
*'''<span style="color:#ff0000">Indications</span>'''
**'''<span style="color:#ff0000">Should be offered to patients with (2)</span>'''
**#'''<span style="color:#ff0000">Hypocitraturia AND</span>'''
**#'''<span style="color:#ff0000">Recurrent calcium or calcium phosphate stones</span>'''
**#*'''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
**#*'''Calcium stone-forming patients with normal citrate excretion but low urinary pH may also benefit from citrate therapy'''
**#**There is also a risk that higher urine pH can promote calcium phosphate stone formation, or change calcium oxalate stone formers to calcium phosphate stone formers.
**#* '''Potassium citrate is preferred over sodium citrate'''
**#**'''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'''
**#**'''If the patient is at risk for hyperkalemia, other agents such as sodium bicarbonate or sodium citrate should be considered.'''
*'''<span style="color:#ff0000">Adverse Events (2)</span>'''
**'''<span style="color:#ff0000">Hyperkalemia</span>'''
**'''<span style="color:#ff0000">GI upset</span>'''

===Recurrent calcium stones===
*'''<span style="color:#ff0000">Allopurinol should be offered to patients with recurrent calcium oxalate stones who have hyperuricosuria and normal urinary calcium</span>'''
**'''Hyperuricemia is not a required criterion for allopurinol therapy'''
**'''In addition to medication, patients with hyperuricosuria should be instructed to limit non-dairy animal protein, which also may maximize the efficacy of allopurinol.'''
***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.
*'''<span style="color:#ff0000">Thiazide diuretics and/or potassium citrate should be offered to patients with recurrent calcium stones in whom other metabolic abnormalities are absent or have been appropriately addressed and stone formation persists</span>'''
**Both thiazides and potassium citrate therapy have been shown to prevent recurrent stones in patients with normal range urinary calcium and citrate, respectively
**'''For patients with no identified risk factors for nephrolithiasis, potassium citrate may be the preferred first-line therapy, given its relatively low side effect profile.'''
===Uric acid stones===
*'''<span style="color:#ff0000">First-line therapy for patients with uric acid stones is alkalinization of the urine with potassium citrate to raise urinary pH to an optimal level so that uric acid remains in a dissolved state.</span>'''
**'''<span style="color:#ff0000">Allopurinol should not be routinely offered as first-line therapy to patients with uric acid stones</span>'''
***'''Most patients with uric acid stones have low urinary pH rather than hyperuricosuria as the predominant risk factor'''
***'''<span style="color:#ff0000">Goal is to increase the urinary pH > 5.5 (AUA targets 6.0 and CUA targets 6.5), through an alkalinizing agent such as potassium citrate'''
**** With adequate alkali therapy, patient's can raise the urine pH to an optimal level so that uric acid remains in a dissolved state.
***** '''<span style="color:#ff0000">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.
*'''<span style="color:#ff0000">Allopurinol may be considered as an adjunct when alkalinization is not successful or for patients who continue to form uric acid stones despite adequate alkalinization of the urine.</span>'''
**'''Allopurinol (300 mg/day) may be used'''
*** MOA: blocks the ability of xanthine oxidase to convert xanthine to uric acid, resulting in decreased production of uric acid
**** The resultant decrease in serum uric acid will ultimately lead to a decrease in urinary uric acid as well.
* '''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.

===Uric acid and cystine stones===
* '''<span style="color:#ff0000">Potassium citrate should be offered to patients with uric acid and cystine stones to raise urinary pH to an optimal level</span>'''
**'''For uric acid stone formers, a urine pH of 6.0 (CUA targets 6.5)''' '''should be achieved'''
**'''For cystine stone formers, a urine pH of 7.0 (CUA targets >7.0) should be achieved'''
===Cystine stones===
*'''<span style="color:#ff0000">First-line therapy for patients with cystine stones:</span>'''
*#'''<span style="color:#ff0000">Increased fluid intake</span>'''
*#'''<span style="color:#ff0000">Urinary alkalinization</span>'''
*#'''<span style="color:#ff0000">Restriction of sodium and protein intake</span>'''
*##Excess dietary sodium can lead to increases in cystine excretion
*'''<span style="color:#ff0000">Potassium citrate should be offered to patients with cystine stones to raise urinary pH to an optimal level</span>'''
**'''AUA: Urine pH of 7.0 (CUA targets >7.0) should be achieved'''
*'''<span style="color:#ff0000">Cystine-binding thiol drugs, such as alpha-mercaptopropionylglycine (tiopronin), should be offered to patients with cystine stones who are unresponsive to dietary modifications and urinary alkalinization, or have large recurrent stone burdens.</span>'''
** '''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
*** '''Tiopronin is possibly more effective and associated with fewer adverse events than d-penicillamine and should be considered first.'''
***'''Captopril, another thiol agent, has not been shown to be effective for the prevention of recurrent cystine stones'''
***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/Struvite stones===
*'''<span style="color:#ff0000">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.'''
*'''<span style="color:#ff0000">Acetohydroxamic acid (AHA) may be offered to patients with residual or recurrent struvite stones only after surgical options have been exhausted.</span>'''
** '''Patients treated for struvite stones may still be at risk for recurrent UTIs after stone removal, and in some patients surgical stone removal is not feasible.'''
**'''The use of a urease inhibitor, AHA, may be beneficial in these patients, although the extensive side effect profile may limit its use. In particular, patients taking this medication should be closely monitored for phlebitis and hypercoagulable phenomena'''
**'''<span style="color:#ff0000">Acetohydroxamic acid (AHA)'''
*** '''MOA: urease inhibitor; may reduce the urinary saturation of struvite and therefore delay stone formation'''
*** '''<span style="color:#ff0000">Adverse effects'''
**** Minor side effects common (up to 30% of patients)
**** '''<span style="color:#ff0000">Deep venous thrombosis</span>''' (15%)
**** '''<span style="color:#ff0000">Hemolytic anemia'''
***** '''Most serious side effect'''
***** '''Occurs in up to 15% of the patients; more prevalent in patients with renal insufficiency'''
****'''<span style="color:#ff0000">Phlebitis'''
*** '''Frequently reserved for patients deemed too ill for surgical management.'''
*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
*'''Phosphate therapy is contraindicated in cases of infection calculi because this medication may promote further stone formation.'''

=== Other ===
* '''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'''
**'''Best treated with surgical excision of the adenoma'''

* '''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.

* '''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

=== 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'''