Stones: Epidemiology and Pathogenesis: Difference between revisions

== Physiochemistry and Pathogenesis ==

** The state of saturation of the urine with respect to particular stone-forming salts indicates the stone-forming propensity of the urine. The state of saturation is determined by pH and the ionic strength of the major ions in solution.

** The solubility product refers to the point of saturation where dissolved and crystalline components in solution are in equilibrium. Addition of more crystals to the solution will result in precipitation of crystals. In this supersaturated urine (metastable state), crystallization can occur on preexisting crystals, but spontaneous crystallization occurs only when the concentration product exceeds the formation product. In the supersaturated state, the presence of inhibitors prevents or delays crystallization.

*** The process by which nuclei form in pure solutions is called homogeneous nucleation.

*** Heterogeneous nucleation occurs when microscopic impurities or other constituents in the urine promote nucleation by providing a surface on which the crystal components can grow.

**#* Inhibitory activity derived from its complexation with oxalate, which reduces ionic oxalate concentration and calcium oxalate supersaturation

**#*# '''Complexes calcium''', thereby lowering urinary saturation of calcium oxalate

**#*# Inhibits spontaneous precipitation of calcium oxalate and agglomeration of calcium oxalate crystals

**#*# Inhibits calcium oxalate and calcium phosphate crystal growth, with effect on calcium phosphate crystal growth more pronounced than on calcium oxalate crystal growth

**#*# Prevents heterogeneous nucleation of calcium oxalate by monosodium urate

**#* '''Most abundant protein in the urine'''

** '''No known inhibitors affect uric acid crystallization'''

*** '''Typically accounts for 2.5% of the weight of the stone.'''

== Mineral metabolism ==

=== Calcium ===

* '''Absorption of calcium varies with calcium intake by a process of intestinal adaptation''' - at times of low calcium intake, fractional calcium absorption is enhanced; during high calcium intake, fractional calcium absorption is reduced

*** '''Functions (3):'''

***# '''Increases renal reabsorption of calcium and reduces reabsorption of phosphate from distal tubule (primary effect)'''

== Classification of nephrolithiasis ==

== Calcium stones ==

=== Hypercalcuria ===

** '''Recall, hypercalcuria is the most common cause of microscopic hematuria in children'''

*#* '''Characterized by'''

*#*# '''Normal serum calcium'''

*#** '''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

*#* '''Characterized by'''

*#*# '''Normal serum calcium'''

*#** 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'''

*#* Infrequent abnormality; '''most commonly associated with primary hyperparathyroidism'''

*#* '''Characterized by:'''

*#* '''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

*#* 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

*#* 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)

=== Hyperoxaluria ===

*#* Due to '''rare autosomal recessive inherited disorders in glyoxylate metabolism''', '''leading to preferential oxidative conversion of glyoxylate to oxalate''', an end product of metabolism

*#* '''In patients with enteric hyperoxaluria, intestinal hyperabsorption of oxalate is the most significant risk factor leading to recurrent calculus formation'''

*#*** '''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'''

*#*** '''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

*#***** '''Iron deficiency is the most common cause of anemia following bariatric surgery,''' particularly in premenopausal women.

*#**** '''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'''

*#** Compliance is difficult for regimens intending to eliminate all oxalate sources

=== Hyperuricosuria ===

** '''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)

*#* 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

=== Renal tubular acidosis (RTA) ===

* '''RTA is a clinical syndrome characterized by metabolic acidosis'''

*# '''Analgesic nephropathy'''

*# '''Idiopathic hyperCalciuria'''

*# '''Obstructive uropathy'''

*# '''Transplant (renal)'''

*#*# '''Hypocitraturia'''

*#*# '''Hypokalemia'''

*#*** 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'''

*#* 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'''

*#* Associated with hyperkalemia

*#* '''Nephrolithiasis is uncommon in this disorder'''

=== Hypomagnesiuria ===

=== Urine pH ===

** '''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'''.

== Uric acid stones ==

#* Urine pH remains the most cost-effective means of screening for this condition and monitoring therapy.

=== Causes ===

==== Acquired ====

#* '''Diabetic stone formers have a lower urine pH''' compared with non-diabetic stone formers '''due to insulin resistance'''

#** In normal individuals, insulin stimulates ammoniagenesis in renal tubule cells by promoting gluconeogenesis from glutamine and by stimulating ammonium excretion by the proximal tubular sodium/hydrogen exchanger. Failure of the renal tubule cells to respond to insulin '''results in defective ammonia production and/or excretion, thereby leading to a reduction in urinary pH and uric acid stone formation'''.

#* '''Diabetic stone formers are approximately 6x more likely to develop a uric acid stone'''.

#** Uric acid stones are found in 34% of stone-forming patients with diabetes mellitus compared to 6% of non-diabetic stone formers

=== Causes ===

*** '''Used for screening purposes to identify patients with cystine stone disease''' who are undergoing a 24 hour urine collection for evaluation.

** '''Urease hydrolyzes urea, forming ammonium and carbon dioxide, which increases urinary pH.'''

*** Alkaline urine promotes supersaturation and precipitation of crystals of magnesium ammonium phosphate and carbonate apatite.

** '''Some yeasts and mycoplasma species have the capacity to synthesize urease'''

* '''Pathogenesis'''

** '''Occur more often in females''' than males by a ratio of 2:1 '''because infection stones occur most commonly in those prone to frequent UTIs.'''

** '''Spinal cord–injured patients are at particular risk for both infection and metabolic stones owing to neurogenic urinary tract dysfunction and hypercalciuria related to immobility'''

* '''Commonly produce staghorn stones; however, other crystals, including cystine, calcium oxalate monohydrate, and uric acid, can assume a staghorn configuration'''

== Other stones ==

* '''Predominately composed (65%) of organic proteins''', sugars, and glucosaminses, unlike other stones that have minimal organic material (2.5%)

** Among the proteins incorporated into the matrix substance are Tamm-Horsfall protein, nephrocalcin, a γ-carboxyglutamic acid–rich protein, renal lithostathine, albumin, glycosaminoglycans, free carbohydrates, and a mucoprotein called matrix substance A

=== Xanthine stones ===

** Subjects who abuse laxatives are chronically dehydrated, resulting in intracellular acidosis. In addition, urinary sodium is low from sodium loss as a result of the laxatives. In this environment, urate preferentially complexes with the abundant ammonium rather than sodium and produces ammonium acid urate stones.

*#* '''Thiazides''' cause intracellular acidosis and '''subsequent hypocitraturia'''

*#* '''MOA: protease inhibitor'''

*#* '''Used in patients with HIV/AIDS.'''

*#* '''Now infrequently used''', replaced with newer generation agents. Kidney stone formation has been associated with a number of newer anti-retroviral agents.

*#* '''Radiolucent on plain film and may not be seen on CT'''

*#* Creates a chronic intracellular acidosis resulting '''in a urinary milieu similar to distal RTA''' with hyperchloremic acidosis, high urine pH, extremely low urinary citrate, and hypercalciuria.

*#* '''Treatment may be potassium citrate''' or cessation of the medication if possible.

*#* Used for the treatment of hypertension

*#* '''Radiolucent'''

== Anatomic predisposition to stones ==