Editing Kidney stone disease (section)

== Pathophysiology ==
[[File:Staghorn Kidney Stone Progression.png|thumb|Small crystals formed in the kidney. The most common crystals are made of calcium oxalate and they are generally 4–5&nbsp;mm. Staghorn kidney stones are considerably larger. 1. Calcium and oxalate come together to make the crystal nucleus. Supersaturation promotes their combination (as does inhibition.) 2. Continued deposition at the renal papillae leads to the growth of the kidney stones. 3. Kidney stones grow and collect debris. In the case where the kidney stones block all routes to the renal papillae, this can cause extreme discomfort and pain. 4. The complete staghorn stone forms and retention occurs. Smaller solids that break off can become trapped in the urinary glands causing discomfort. 5. Displaced stones travel through the ureter. If they cannot be broken down, they must be physically removed by a surgeon.]]

=== Supersaturation of urine ===
Kidney stones are primarily composed of calcium salts, with the most common being calcium oxalate (70-80%), followed by calcium phosphate and uric acid. When urine contains high concentrations of these ions, they can form crystals and eventually stones.<ref name="pmid26439475">{{cite journal |vauthors=Phillips R, Hanchanale VS, Myatt A, Somani B, Nabi G, Biyani CS |title=Citrate salts for preventing and treating calcium containing kidney stones in adults |journal=Cochrane Database Syst Rev |volume=2015 |issue=10 |pages=CD010057 |date=October 2015 |pmid=26439475 |pmc=9578669 |doi=10.1002/14651858.CD010057.pub2 |url=}}</ref>

The formation of kidney stones occurs in three main phases:<ref name="pmid26439475"/>
# [[nucleation]] (initial crystal formation)
# growth (expansion of single crystals)
# aggregation (clumping together of multiple crystals)<ref name="pmid26439475"/>

When the urine becomes [[Supersaturation|supersaturated]] (when the urine [[solvent]] contains more [[wikt:Special:Search/solute|solutes]] than it can hold in [[Solution (chemistry)|solution]]) with one or more calculogenic (crystal-forming) substances, initial [[seed crystal]]s may form through the process of [[nucleation]].<ref name=Reilly2005Ch13 /> Heterogeneous nucleation (where there is a solid surface present on which a crystal can grow) proceeds more rapidly than homogeneous nucleation (where a crystal must grow in a liquid medium with no such surface), because it requires less energy. Adhering to cells on the surface of a [[renal papilla]], a seed crystal can grow and aggregate into an organized mass. Depending on the chemical composition of the crystal, the stone-forming process may proceed more rapidly when the urine pH is unusually high or low.<ref name=Reilly2005Ch14 />

Supersaturation of the urine with respect to a calculogenic compound is pH-dependent. For example, at a pH of 7.0, the solubility of uric acid in urine is 158&nbsp;mg/100&nbsp;mL. Reducing the pH to 5.0 decreases the [[solubility]] of [[uric acid]] to less than 8&nbsp;mg/100&nbsp;mL. The formation of uric-acid stones requires a combination of [[hyperuricosuria]] (high urine uric-acid levels) and low urine pH; hyperuricosuria alone is not associated with uric-acid stone formation if the urine pH is alkaline.<ref name=Knudsen2007 /> Supersaturation of the urine is a necessary, but not a sufficient, condition for the development of any urinary calculus.<ref name=Reilly2005Ch13 /> Supersaturation is likely the underlying cause of uric acid and [[cystine]] stones, but calcium-based stones (especially [[calcium oxalate]] stones) may have a more complex cause.<ref name=Wolf2011p />

=== Randall's plaque ===
While supersaturation of urine may lead to [[crystalluria]], it does not necessarily promote the formation of a kidney stone because the particle may not reach the sufficient size needed for renal attachment.<ref>{{cite journal | vauthors = Robertson WG, Peacock M, Nordin BE | title = Calcium crystalluria in recurrent renal-stone formers | journal = Lancet | volume = 2 | issue = 7610 | pages = 21–24 | date = July 1969 | pmid = 4182793 | doi = 10.1016/S0140-6736(69)92598-7 }}</ref><ref>{{cite journal | vauthors = Elliot JS, Rabinowitz IN | title = Calcium oxalate crystalluria: crystal size in urine | journal = The Journal of Urology | volume = 123 | issue = 3 | pages = 324–327 | date = March 1980 | pmid = 7359628 | doi = 10.1016/S0022-5347(17)55918-2 }}</ref> On the other hand, Randall's plaques, which were first identified by Alexander Randall in 1937,<ref>{{cite journal | vauthors = Randall A | title = The Origin and Growth of Renal Calculi | journal = Annals of Surgery | volume = 105 | issue = 6 | pages = 1009–1027 | date = June 1937 | pmid = 17856988 | pmc = 1390483 | doi = 10.1097/00000658-193706000-00014 }}</ref> are [[calcium phosphate]] deposits that form in the papillary interstitium and are thought to be the nidus required for stone development.<ref>{{cite journal | vauthors = Ratkalkar VN, Kleinman JG | title = Mechanisms of Stone Formation | journal = Clinical Reviews in Bone and Mineral Metabolism | volume = 9 | issue = 3–4 | pages = 187–197 | date = December 2011 | pmid = 22229020 | pmc = 3252394 | doi = 10.1007/s12018-011-9104-8 }}</ref> In addition to Randall's plugs, which form in the [[Duct of Bellini]], these structures can generate reactive oxygen species that further enhance stone formation.<ref>{{cite journal | vauthors = Khan SR | title = Reactive oxygen species, inflammation and calcium oxalate nephrolithiasis | journal = Translational Andrology and Urology | volume = 3 | issue = 3 | pages = 256–276 | date = September 2014 | pmid = 25383321 | pmc = 4220551 | doi = 10.3978/j.issn.2223-4683.2014.06.04 }}</ref>

=== Pathogenic bacteria ===
Some [[bacteria]] have roles in promoting stone formation. Specifically, [[urease-positive]] bacteria, such as ''[[Proteus mirabilis]]'' can produce the [[enzyme]] [[urease]], which converts [[urea]] to [[ammonia]] and [[carbon dioxide]].<ref>{{cite journal | vauthors = Jones BD, Mobley HL | title = Proteus mirabilis urease: genetic organization, regulation, and expression of structural genes | journal = Journal of Bacteriology | volume = 170 | issue = 8 | pages = 3342–3349 | date = August 1988 | pmid = 2841283 | pmc = 211300 | doi = 10.1128/jb.170.8.3342-3349.1988 }}</ref> This increases the urinary [[pH]] and promotes [[struvite]] stone formation. Additionally, non-urease producing bacteria can provide bacterial components that promote [[calcium oxalate]] crystallization, though this mechanism is poorly understood.<ref>{{cite journal | vauthors = Chmiel JA, Stuivenberg GA, Alathel A, Gorla J, Grohe B, Razvi H, Burton JP, Bjazevic J | title = High-Throughput in vitro Gel-Based Plate Assay to Screen for Calcium Oxalate Stone Inhibitors | journal = Urologia Internationalis | pages = 616–622 | date = December 2021 | volume = 106 | issue = 6 | pmid = 34883484 | doi = 10.1159/000519842 | s2cid = 245012979 }}</ref><ref>{{cite journal | vauthors = Kanlaya R, Naruepantawart O, Thongboonkerd V | title = Flagellum Is Responsible for Promoting Effects of Viable ''Escherichia coli'' on Calcium Oxalate Crystallization, Crystal Growth, and Crystal Aggregation | journal = Frontiers in Microbiology | volume = 10 | pages = 2507 | date = 2019-11-05 | pmid = 31749785 | pmc = 6848068 | doi = 10.3389/fmicb.2019.02507 | doi-access = free }}</ref>

=== Inhibitors of stone formation ===
Normal [[urine]] contains [[Chelation|chelating]] agents, such as [[Citric acid|citrate]], that inhibit the [[nucleation]], [[Crystal growth|growth]], and aggregation of calcium-containing crystals. Other [[endogenous]] inhibitors include [[calgranulin]] (an [[S-100 protein|S-100 calcium-binding protein]]), [[Tamm–Horsfall protein]], [[glycosaminoglycan]]s, uropontin (a form of [[osteopontin]]), [[nephrocalcin]] (an acidic [[glycoprotein]]), pro[[thrombin]] F1 peptide, and [[Alpha-1-microglobulin/bikunin precursor|bikunin]] ([[uronic acid]]-rich protein). The biochemical mechanisms of action of these substances have not yet been thoroughly elucidated. However, when these substances fall below their normal proportions, stones can form from an aggregation of crystals.<ref name=Coe2005 />

Sufficient dietary intake of [[magnesium]] and [[citrate]] inhibits the formation of calcium oxalate and calcium phosphate stones; in addition, magnesium and citrate operate synergistically to inhibit kidney stones. The efficacy of magnesium in subduing stone formation and growth is [[dose-dependent]].<ref name=Johri2010 /><ref name="Riley-2013" /><ref name="del Valle-2013">{{cite journal | vauthors = del Valle EE, Spivacow FR, Negri AL | title = [Citrate and renal stones] | journal = Medicina | volume = 73 | issue = 4 | pages = 363–8 | year = 2013 | pmid = 23924538 }}</ref>

=== Hypocitraturia ===
Hypocitraturia or low urinary-citrate excretion (variably defined as less than 320&nbsp;mg/day) can be a contributing cause of kidney stones in up to 2/3 of cases. The protective role of citrate is linked to several mechanisms; citrate reduces urinary supersaturation of calcium salts by forming soluble complexes with calcium ions and by inhibiting crystal growth and aggregation. Therapy with [[potassium citrate]]  is commonly prescribed in clinical practice to increase urinary citrate and to reduce stone formation rates. [[Alkali citrate]] is also used to increase urine citrate levels. It can be prescribed or found over-the-counter in pill, liquid or powder form.<ref>{{cite web |title=Educate Your Patients about Kidney Stones |url=https://www.kidney.org/sites/default/files/moonstone-professional-education-teaching-card-final.pdf |archive-url=https://web.archive.org/web/20201026133550/https://www.kidney.org/sites/default/files/moonstone-professional-education-teaching-card-final.pdf |archive-date=2020-10-26 |url-status=live |website=kidney.org}}</ref><ref>{{cite journal | vauthors = Caudarella R, Vescini F | title = Urinary citrate and renal stone disease: the preventive role of alkali citrate treatment | journal = Archivio Italiano di Urologia, Andrologia | volume = 81 | issue = 3 | pages = 182–7 | date = September 2009 | pmid = 19911682 |url=https://www.researchgate.net/publication/38087757 }}</ref>