Editing Stones: Epidemiology and Pathogenesis (section)

== Calcium stones ==

* '''Urinary calcium and oxalate are both important and equal contributors to calcium oxalate stone formation'''

=== Hypercalcuria ===
* '''<span style="color:#ff0000">Most common abnormality identified in calcium stone formers</span>'''
** '''Recall, hypercalcuria is the most common cause of microscopic hematuria in children'''
* '''<span style="color:#ff0000">Classification:</span>'''
*# '''<span style="color:#ff0000">Absorptive hypercalcuria</span>'''
*#* '''Characterized by'''
*#*# '''Normal serum calcium'''
*#*# '''Normal or suppressed PTH'''
*#*# '''Hypercalcuria'''
*#** '''Increased intestinal absorption of calcium results''' '''in''' a transient increase in serum calcium, which suppresses serum PTH and results in increased renal filtration of calcium, ultimately leading to hypercalcuria.
*#** Serum calcium level remains normal because the increase in intestinal absorption of calcium is matched by enhanced renal calcium excretion
*#* '''Calcium fasting and load tests can discriminate between the various types of absorptive hypercalcuria'''; however, routine performance of these tests is not required
*#** '''Absorptive hypercalciuria type I: increased absorption will occur regardless of the amount of calcium in the diet'''. Therefore, these subjects will demonstrate an increased urinary excretion of calcium on both the fasting and the loading specimens.
*#** '''Absorptive hypercalciuria type II: normal amount of urinary calcium excretion during calcium restriction''', but will show elevations during their regular diet
*# '''<span style="color:#ff0000">Renal (leak) hypercalcuria</span>'''
*#* '''Characterized by'''
*#*# '''Normal serum calcium'''
*#*# '''Elevated PTH'''
*#*# '''High fasting urinary calcium levels'''
*#** '''Impaired renal reabsorption of calcium results in elevated urinary calcium levels leading to secondary hyperparathyroidism (elevated PTH).'''
*#*** '''Other causes of secondary hyperparathyroidism: rickets, osteopenia, CKD'''
*#*** Patients may have low or low/normal radial bone density due to secondary hyperparathyroidism
*#** Serum calcium levels remain normal because the renal loss of calcium is compensated by enhanced intestinal absorption of calcium and bone resorption as a result of increased secretion of PTH
*#** '''The elevated serum PTH and elevated fasting urinary calcium (except if absorptive hypercalciuria I) levels differentiate renal from absorptive hypercalciuria'''
*# '''<span style="color:#ff0000">Resorptive hypercalcuria</span>'''
*#* Infrequent abnormality; '''most commonly associated with primary hyperparathyroidism'''
*#* '''Characterized by:'''
*#*# '''Elevated serum calcium'''
*#*# '''Elevated PTH'''
*#*# '''Hypercalcuria'''
*#*# '''Hypophosphatemia'''
*#** '''Excessive PTH secretion from a parathyroid adenoma results in''' excessive bone resorption and increased renal synthesis of 1,25(OH)2D3, which in turn enhances intestinal absorption of calcium. The net effect is elevated serum and urine calcium levels and reduced serum phosphorus levels.
*#* '''Recurrent calcium phosphate (100%) brushite stones are unusual and should raise suspicion for primary hyperparathyroidism (resorptive hypercalciuria)'''
*#** Mechanism: elevated PTH increases phosphate excretion
*#* '''Additional, rare causes of resorptive hypercalciuria include hypercalcemia of malignancy, sarcoidosis''', '''thyrotoxicosis, and vitamin D toxicity'''. Many granulomatous diseases, including tuberculosis, histoplasmosis, leprosy, and silicosis, have been reported to produce hypercalcemia.
*#** The hypercalcemia in sarcoidosis is due to the production of 1,25(OH)2D3 from 1α-hydroxylase present in macrophages of the sarcoid granuloma
*# '''<span style="color:#ff0000">Idiopathic (unclassified) hypercalcuria</span>'''
*#* Often refers to unevaluated or unknown cause
*#* Patients may demonstrate hypercalcuria in all phases of the dietary calcium manipulation, but will not demonstrate serum abnormalities
*# '''<span style="color:#ff0000">Malignancy-associated hypercalemia</span>'''
*#* An assay for intact PTH can help distinguish patients with hyperparathyroidism from those with other causes of hypercalcuria. Tumours in patients with humoral hypercalcemia produce a PTH-related protein (PTHrP)
*# '''<span style="color:#ff0000">Glucocorticoid-induced hypercalemia</span>'''

=== Hyperoxaluria ===
* '''<span style="color:#ff0000">Classification (4):</span>'''
*# '''<span style="color:#ff0000">Primary hyperoxaluria</span>'''
*#* Due to '''rare autosomal recessive inherited disorders in glyoxylate metabolism''', '''leading to preferential oxidative conversion of glyoxylate to oxalate''', an end product of metabolism
*# '''<span style="color:#ff0000">Enteric hyperoxaluria</span>'''
*#* '''In patients with enteric hyperoxaluria, intestinal hyperabsorption of oxalate is the most significant risk factor leading to recurrent calculus formation'''
*#** '''<span style="color:#ff0000">Fat malabsorption results in increased intestinal oxalate absorption</span>'''
*#*** '''In fat malabsorption, saponification of fatty acids occurs with divalent cations such as calcium''' and magnesium, '''which reduces calcium available for complexation with oxalate''' thereby resulting in an increased amount of oxalate available for reabsorption.
*#*** '''The poorly absorbed fatty acids and bile salts may increase colonic permeability to oxalate, further enhancing intestinal oxalate absorption'''
*#*** '''<span style="color:#ff0000">Patients with enteric hyperoxaluria are more likely to form calcium oxalate stones,</span>''' due to increased urinary excretion of oxalate and decreased inhibitory activity from hypocitraturia, secondary to chronic metabolic acidosis and hypomagnesuria.
*#** '''<span style="color:#ff0000">Malabsorption of any cause (chronic diarrheal states, inflammatory bowel disease, celiac sprue, or intestinal resection)</span> can lead to increased intestinal absorption of oxalate and hyperoxaluria; as a result of intestinal fluid loss, patients will often exhibit dehydration, bicarbonate losses, low urine volume'''
*#*** '''Hyperoxaluria has been described in''' both stone-forming and non-stone-forming patients who have undergone '''Roux-en-Y gastric bypass surgery,''' with urinary oxalate levels in some patients exceeding 100 mg/day
*#**** '''<span style="color:#ff0000">Bariatric surgery patients typically develop enteric hyperoxaluria, which should be managed with calcium supplementation</span>'''
*#***** '''Iron deficiency is the most common cause of anemia following bariatric surgery,''' particularly in premenopausal women.
*#*** '''<span style="color:#ff0000">Chronic diarrheal syndromes</span> promote intestinal loss of alkali and dehydration, resulting in metabolic acidosis and reduced urinary citrate levels.'''
*#**** '''Chronic metabolic acidosis can lead to low urine pH, hypercalciuria, and hypocitraturia.'''
*#* '''Restricting oxalate is generally insufficient as the cause is not an overabundance of oxalate'''
*# '''<span style="color:#ff0000">Dietary hyperoxaluria</span>'''
*#* '''<span style="color:#ff0000">Overindulgence in oxalate-rich foods such as (Oxalate Rich Chocolate, Pepper, Nuts): Okra, Rhubarb, Chocolate, Pepper, Nuts, Tea (black), cocoa, spinach, mustard greens, pokeweed, swiss chard, beets, berries, wheat germ, and soy crackers can result in hyperoxaluria in otherwise normal individuals.</span>'''
*#** Compliance is difficult for regimens intending to eliminate all oxalate sources
*#* '''<span style="color:#ff0000">Severe calcium restriction may result in reduced intestinal binding of oxalate and increased intestinal oxalate absorption, hence calcium intake should be moderate, rather than restricted</span>'''
*#** '''<span style="color:#ff0000">Increasing calcium intake, which may include supplements, specifically timed with meals, may reduce hyperoxaluria</span>'''
*#* '''<span style="color:#ff0000">High substrate levels (vitamin C) can also cause hyperoxaluria;</span>''' doses should be limited to 2 g/day
*# '''<span style="color:#ff0000">Idiopathic hyperoxaluria</span>'''

=== Hyperuricosuria ===
* '''<span style="color:#ff0000">May be associated with pure uric acid calculi or calcium oxalate calculi through heterogenous nucleation</span>'''
** '''Patients with hyperuricosuric calcium nephrolithiasis who form calcium oxalate stones present with normal urinary pH and hyperuricosuria, accompanied sometimes by hypercalciuria'''
** In contrast, those with gouty diathesis, who can form either uric acid or calcium oxalate calculi, have a low fractional excretion of urate (that contributes to hyperuricemia) and low urinary pH (that leads to increased amount of undissociated uric acid)
* '''<span style="color:#ff0000">Causes:</span>'''
*# '''<span style="color:#ff0000">Increased dietary purine intake (most common cause)</span>'''
*# '''<span style="color:#ff0000">Gout</span>'''
*# '''<span style="color:#ff0000">Myeloproliferative and lymphoproliferative disorders</span>'''
*# '''<span style="color:#ff0000">Multiple myeloma</span>'''
*# '''<span style="color:#ff0000">Thalassemia</span>'''
*# '''<span style="color:#ff0000">Hemolytic disorders</span>'''
*# '''<span style="color:#ff0000">Pernicious anemia</span>'''
*# '''<span style="color:#ff0000">Hemoglobinopathies</span>'''
*# '''<span style="color:#ff0000">Secondary polycythemia</span>'''
*# '''<span style="color:#ff0000">Complete or partial hypoxanthine-guanine phosphoribosyltransferase (HGPRT) deficiency</span>'''
*#* Lesch-Nyhan syndrome is an inherited deficiency of the purine salvage enzyme hypoxanthine-guanine phosphoribosyltransferase, which leads to the accumulation of hypoxanthine, which is ultimately converted to uric acid
*# '''<span style="color:#ff0000">Overactivity of phosphoribosylpyrophosphate synthetase</span>'''
*# '''<span style="color:#ff0000">Hereditary renal hypouricemia</span>'''

=== Renal tubular acidosis (RTA) ===
* '''RTA is a clinical syndrome characterized by metabolic acidosis'''
* '''Classified: acquired vs. inherited'''
** '''Causes of acquired RTA: A CASH POT'''
*# '''Analgesic nephropathy'''
*# '''Idiopathic hyperCalciuria'''
*# '''Acute tubular necrosis (ATN)'''
*# '''Sarcoidosis'''
*# '''Hyperparathyroidism (primary)'''
*# '''Pyelonephritis, recurrent'''
*# '''Obstructive uropathy'''
*# '''Transplant (renal)'''
* '''<span style="color:#ff0000">3 types: type 1 (distal), type 2 (proximal), and type 4 (distal)</span>'''
*# '''<span style="color:#ff0000">Type 1 (distal) RTA</span>'''
*#* '''<span style="color:#ff0000">Most common form of RTA and most commonly associated with kidney stones</span>''' (up to 70% of adults with type 1 RTA have kidney stones)
*#* '''<span style="color:#ff0000">Characterized by (5):</span>'''
*#*# '''<span style="color:#ff0000">Increased urinary pH''' (>6.0)
*#*#'''Hyperchloremic, non-anion gap metabolic acidosis'''
*#*# </span>'''Hypercalcuria'''
*#*# '''Hypocitraturia'''
*#*# '''Hypokalemia'''
*#** '''<span style="color:#ff0000">Due to impaired acid (H+, hydrogen is first element in periodic table so type 1 ) excretion into the urine in the presence of systemic acidosis, from dysfunction of the alpha-type intercalated cells</span>''', which secrete protons into the urine via an apical H+-ATPase
*#*** Metabolic acidosis may cause a negative calcium balance as a result of impaired renal tubular reabsorption of calcium in the proximal tubule, leading to excessive renal loss of calcium. In addition, intestinal calcium absorption is diminished in patients with persistent acidosis. Slow dissolution of bone mineral can also be identified as calcium and phosphate act as buffering mechanisms to correct the acidosis. Chronic acidosis has been cited as a major factor in the genesis of bone disease.
*#** Patients with the incomplete form of distal RTA are not persistently acidemic despite their inability to lower urinary pH with an acid load. '''The diagnosis of incomplete distal RTA can be confirmed by inadequate urinary acidification''' after an ammonium chloride loading test.
*#* '''Potassium citrate therapy is able to correct the metabolic acidosis and hypokalemia'''
*#* '''<span style="color:#ff0000">Most common stone composition associated with Type 1/distal RTA is calcium phosphate</span>''' as a result of increased urinary pH, hypercalciuria, and hypocitraturia
*#*'''<span style="color:#ff0000">Associated with nephrocalcinosis on imaging</span>'''
*# '''<span style="color:#ff0000">Type 2 (proximal) RTA</span>'''
*#* '''<span style="color:#ff0000">Due to impaired bicarbonate (bi=2, type 2) reabsorption</span>'''
*#* Proximal RTA is characterized by a defect in HCO3− reabsorption associated with initial high urine pH that normalizes as plasma HCO3– decreases and the amount of filtered HCO3– falls.  With reduced capacity of the proximal tubule to reclaim filtered HCO3−, more HCO3− is delivered to the distal tubule, which has a limited capacity for bicarbonate reabsorption. Consequently, bicarbonaturia ensues, resulting in reduced net acid excretion and metabolic acidosis. As the filtered HCO3- load declines with progressive metabolic acidosis, less bicarbonate reaches the distal tubule until eventually the capacity of the distal tubule is sufficient to handle the load and no further bicarbonate is lost. '''At steady state, serum HCO3− is low (15 to 18 mEq/L) and urine pH is acidic (<5.5).'''
*#* '''Nephrolithiasis is uncommon in this disorder as urinary citrate levels are not decreased, in contrast to type 1 RTA'''
*# '''Type 4 (distal) RTA'''
*#* '''Usually seen in patients with chronic renal damage''' (obstructive uropathy, interstitial renal disease, diabetic nephropathy, multicystic dysplasia)
*#* '''Pathophysiology results from impaired response to mineralocorticoid''' caused by damage to the cortical collecting duct
*#* Associated with hyperkalemia
*#* '''Nephrolithiasis is uncommon in this disorder'''

=== Hypomagnesiuria ===
* Rare cause of nephrolithiasis
* '''Most common cause is inflammatory bowel disease associated with malabsorption'''
* '''Frequently associated with chronic thiazide therapy'''
* Magnesium complexes with oxalate and calcium salts, and therefore low magnesium levels result in reduced inhibitory activity. '''Low urinary magnesium is also associated with decreased urinary citrate levels'''

=== Hypocitraturia ===
* '''Acid-base state is the primary determinant of urinary citrate excretion'''
** '''Metabolic acidosis reduces urinary citrate levels''' by augmenting citrate reabsorption and mitochondrial oxidation
** Metabolic alkalosis enhances citrate excretion
* '''Causes (4) DIRT:'''
*# '''Chronic Diarrhea'''
*# '''Idiopathic'''
*# '''Type 1 (distal) RTA:''' '''laboratory hallmark is low urine citrate with an inappropriately high urine pH'''; '''Severe hypocitraturia should immediately raise suspicious for RTA.'''
*# '''Thiazide-induced (side effects of thiazide therapy)'''

=== Urine pH ===
* '''<span style="color:#ff0000">At low urine pH (<5.5), the undissociated form of uric acid predominates, leading to uric acid and/or calcium stone formation.</span>'''
** '''Any disorder leading to low urine pH may predispose to stone formation.'''
** '''Calcium oxalate stones can form in low urine pH as a result of heterogeneous nucleation with uric acid crystals'''.
** '''Chronic metabolic acidosis can lead to low urine pH, hypercalciuria, and hypocitraturia.'''