Ciężka niedobór hormonu antydiuretycznego

Ciężka niedobór hormonu antydiuretycznego
Patofizjologia i mechanizm

Ciężka niedobór hormonu antydiuretycznego (ADH, wazopresyny) manifestuje się jako moczówka prosta, z podziałem na typ centralny (AVP-D) i nerkowy (AVP-R). AVP-D wynika z uszkodzenia podwzgórza lub tylnego płata przysadki, prowadząc do niewystarczającej syntezy lub uwalniania ADH, co skutkuje brakiem wbudowywania akwaporyn-2 w kanaliki zbiorcze nerek i poliurią z hipernatremią (>145 mEq/L) oraz wzrostem osmolalności osocza. Przyczyny obejmują idiopatyczne (autoimmunologiczne), nowotwory, urazy, zapalenia i mutacje genetyczne (ponad 55 mutacji w prohormonie AVP). AVP-R charakteryzuje się prawidłowym poziomem ADH, ale opornością nerek na jego działanie, spowodowaną mutacjami receptorów V2 (AVPR2) lub akwaporyn-2 (AQP2) oraz czynnikami nabytymi, takimi jak toksyczność litem, hiperkalcemia, hipokaliemia i leki nefrotoksyczne. Mutacje AVPR2 najczęściej są klasy II, prowadząc do zatrzymania receptorów w retikulum endoplazmatycznym i degradacji proteasomalnej, natomiast mutacje AQP2 mogą mieć dziedziczenie autosomalne dominujące lub recesywne, wpływając na syntezę i lokalizację kanałów wodnych.

Patogeneza ciężkiej niedoboru hormonu antydiuretycznego

Centralny niedobór wazopresyny (AVP-D)
Nerkowa oporność na wazopresynę (AVP-R)

Mechanizmy molekularne moczówki prostej

Fizjologia działania wazopresyny
Mechanizmy patogenetyczne w centralnym niedoborze wazopresyny
Mechanizmy patogenetyczne w nerkowej oporności na wazopresynę
Molekularne klasyfikacje mutacji

Mechanizmy specyficzne dla różnych form moczówki prostej

Moczówka prosta związana z litem
Moczówka prosta ciążowa
Moczówka prosta dipsogenna

Konsekwencje patofizjologiczne moczówki prostej
Podsumowanie mechanizmów patogenetycznych

Kolejne rozdziały

Patogeneza ciężkiej niedoboru hormonu antydiuretycznego

Ciężka niedobór hormonu antydiuretycznego, wcześniej znana jako moczówka prosta (diabetes insipidus), to zaburzenie charakteryzujące się nieprawidłową regulacją gospodarki wodnej w organizmie, prowadzące do zwiększonego wydalania wody z moczem i nasilonego pragnienia. Jest to następstwo nieprawidłowości w działaniu lub poziomie hormonu antydiuretycznego (ADH), nazywanego również wazopresyną (AVP). W zależności od miejsca patologii, można wyróżnić dwa główne typy tego zaburzenia: centralny (niedobór wazopresyny, AVP-D) oraz nerkowy (oporność na wazopresynę, AVP-R).

Centralny niedobór wazopresyny (AVP-D)

Centralny niedobór wazopresyny (AVP-D) jest spowodowany niewystarczającą produkcją lub wydzielaniem hormonu antydiuretycznego przez podwzgórze lub przysadkę mózgową¹. Hormon ten jest syntetyzowany w jądrach nadwzrokowych i przykomorowych podwzgórza, a następnie transportowany aksonami do tylnego płata przysadki, gdzie jest magazynowany i uwalniany w odpowiedzi na bodźce osmotyczne i zmniejszenie objętości krwi²³.

Uszkodzenie lub dysfunkcja którejkolwiek części tego systemu neurohormanalnego może prowadzić do AVP-D. Uszkodzenia mogą dotyczyć:⁴
– Osmoreceptorów podwzgórza
– Jąder nadwzrokowych lub przykomorowych
– Górnej części drogi podwzgórzowo-przysadkowej

W wyniku tych uszkodzeń, poziomy wazopresyny (i kopeptyny, która jest produktem rozszczepienia prohormonu AVP) są niewykrywalne w całkowitym AVP-D lub niewspółmiernie niskie w stosunku do osmolalności osocza w częściowym AVP-D⁵.

Etiologia centralnego niedoboru wazopresyny

Przyczyny centralnego niedoboru wazopresyny mogą być różnorodne:⁶⁷
– Idiopatyczne (prawdopodobnie na tle autoimmunologicznym) – najczęstsza przyczyna
– Nowotwory (germinoma, przerzuty, czaszkogardlak)
– Przysadowe zapalenie (zapalenie przysadki)
– Choroby naciekowe (sarkoidoza, histiocytoza z komórek Langerhansa)
– Encefalopatia niedotlenieniowa
– Urazy głowy
– Zabiegi neurochirurgiczne (najczęstsza przyczyna pooperacyjnej poliurii)
– Choroby genetyczne (rodzinna moczówka prosta, zespół Wolframa, wrodzona niedoczynność przysadki)

W przypadku rodzinnej moczówki prostej centralnej, zidentyfikowano ponad 55 różnych mutacji genetycznych powodujących defekt w prohormonie i niedobór AVP⁸. Mutacje te mogą prowadzić do toksyczności dla komórek syntetyzujących ADH poprzez akumulację nieprawidłowego prekursora⁹.

Nerkowa oporność na wazopresynę (AVP-R)

Nerkowa oporność na wazopresynę (AVP-R), wcześniej znana jako moczówka prosta nerkowa, charakteryzuje się zmniejszoną zdolnością nerek do koncentracji moczu w wyniku oporności na działanie wazopresyny¹⁰. W przeciwieństwie do AVP-D, poziomy wazopresyny są prawidłowe, ale nerki nie reagują odpowiednio na ten hormon¹¹.

Oporność może być spowodowana:¹²¹³
– Defektem w receptorach V2 wazopresyny
– Zaburzeniami w sygnalizacji wewnątrzkomórkowej
– Nieprawidłowościami w kanałach wodnych akwaporyny-2 (AQP2)
– Zaburzeniami w mechanizmie przeciwprądowym w rdzeniu nerki

Etiologia nerkowej oporności na wazopresynę

Nerkowa oporność na wazopresynę może być wrodzona lub nabyta:¹⁴¹⁵
– Wrodzona (genetyczna):
– Mutacje genu receptora V2 wazopresyny (AVPR2) na chromosomie Xq28 (dziedziczenie sprzężone z płcią, najczęstsza forma)
– Mutacje genu akwaporyny-2 (AQP2) na chromosomie 12 (dziedziczenie autosomalne)
– Nabyta:
– Toksyczność litem (najczęstsza przyczyna nabyta)
– Hiperkalcemia
– Hipokaliemia
– Choroby nerek (obustronna niedrożność dróg moczowych, wielotorbielowatość nerek)
– Leki (amfoterycyna B, cidofowir, foskarnet)

Mechanizmy molekularne moczówki prostej

Fizjologia działania wazopresyny

Wazopresyna jest kluczowym hormonem w regulacji gospodarki wodnej organizmu. Działa głównie na nerki, gdzie modyfikuje przepuszczalność dla wody w kanalikach zbiorczych¹⁶. Mechanizm działania wazopresyny obejmuje kilka etapów:¹⁷¹⁸

1. Wazopresyna wiąże się z receptorami V2 na błonie podstawno-bocznej komórek głównych kanalików zbiorczych

2. To wiązanie inicjuje kaskadę wewnątrzkomórkową:
– Aktywacja cyklazy adenylanowej
– Wzrost poziomu cyklicznego AMP (cAMP)
– Aktywacja kinazy białkowej A (PKA)
– Fosforylacja białek

3. W wyniku tej kaskady dochodzi do:
– Przemieszczenia pęcherzyków zawierających akwaporyny-2 z cytoplazmy do błony szczytowej komórek
– Wbudowania kanałów akwaporyny-2 w błonę komórkową
– Zwiększenia przepuszczalności dla wody w kanalikach zbiorczych

4. Woda jest resorbowana zgodnie z gradientem osmotycznym do hipertonicznego śródmiąższu, a następnie powraca do krwiobiegu¹⁹

Mechanizmy patogenetyczne w centralnym niedoborze wazopresyny

W centralnym niedoborze wazopresyny, zaburzony jest proces syntezy, transportu lub uwalniania wazopresyny. Niedobór wazopresyny prowadzi do zmniejszonego wbudowywania kanałów akwaporyny-2 do błony szczytowej komórek kanalików zbiorczych²⁰. To z kolei upośledza zdolność nerek do zagęszczania moczu i prowadzi do wydalania dużej objętości rozcieńczonego moczu, zwiększając tym samym osmolalność osocza. Wzrost osmolalności osocza stymuluje pragnienie i polidypsję²¹.

Centralny niedobór wazopresyny może być również skutkiem dysfunkcji osmoreceptorów. W takich przypadkach neurohipofiza jest nienaruszona, ale osmoreceptory w przednim podwzgórzu, odpowiedzialne za wykrywanie wzrostu osmolalności osocza, są uszkodzone. W rezultacie stymulacja wydzielania AVP jest zmniejszona, a pacjent staje się objawowy z powodu niedoboru wydzielania AVP, mimo normalnej produkcji AVP²².

Mechanizmy patogenetyczne w nerkowej oporności na wazopresynę

W nerkowej oporności na wazopresynę, nerki nie reagują prawidłowo na wazopresynę, mimo jej normalnych poziomów w krwiobiegu. Możliwe mechanizmy obejmują:²³²⁴

1. Mutacje genetyczne:
– Mutacje genu AVPR2 prowadzące do nieprawidłowych lub nieczynnych receptorów V2
– Mutacje genu AQP2 prowadzące do nieprawidłowej syntezy, transportu lub funkcji kanałów akwaporyny-2

2. Zaburzenia nabyte:
– Toksyczność litem: Lit wchodzi do komórek głównych kanalików zbiorczych przez kanały sodowe (ENaC) i gromadzi się, zaburzając normalną odpowiedź na ADH. Lit hamuje aktywność cyklazy adenylanowej, zmniejszając produkcję cAMP i fosforylację zależną od cAMP akwaporyny-2²⁵²⁶
– Hiperkalcemia: Aktywacja receptora wapniowego (CaSR) w grubej części wstępującej pętli Henlego, zmniejszająca reabsorpcję NaCl i osłabiająca gradient osmotyczny w rdzeniu nerki²⁷
– Hipokaliemia: Degradacja kanałów akwaporyny-2 w kanalikach zbiorczych. Wykazano, że hipokaliemia prowadzi do autofagicznej degradacji białek, w szczególności AQP2, co jest wczesnym zdarzeniem w moczówce prostej wywołanej hipokaliemią²⁸

Molekularne klasyfikacje mutacji

Mutacje prowadzące do nerkowej oporności na wazopresynę można sklasyfikować w kilka kategorii w oparciu o różnice w transporcie do powierzchni komórki oraz wiązaniu i stymulacji cyklazy adenylanowej przez AVP²⁹. W przypadku receptora AVPR2, najczęstsze są mutacje klasy II, będące mutacjami missense lub insercyjno-delecyjnymi, produkującymi nieprawidłowo sfałdowane białka pełnej długości, które są zatrzymywane w retikulum endoplazmatycznym przez mechanizm kontroli jakości i kierowane do degradacji przez proteasom³⁰.

W przypadku akwaporyny-2, większość mutacji powodujących autosomalną moczówkę prostą nerkową wykazuje dziedziczenie recesywne. Mutacje te mogą wpływać na prawidłową syntezę, przetwarzanie lub lokalizację w błonie komórkowej produktu genu, uniemożliwiając antydiuretyczne działanie AVP w komórkach głównych kanalików zbiorczych³¹.

Interesujące jest, że w przypadku większości mutacji AQP2 powodujących autosomalną dominującą moczówkę prostą nerkową, mutanty AQP2 zachowują resztkową zdolność do przemieszczania się do błony szczytowej w odpowiedzi na AVP, co skutkuje mniej nasilonym defektem koncentracji moczu (częściowa moczówka prosta nerkowa)³².

Mechanizmy specyficzne dla różnych form moczówki prostej

Moczówka prosta związana z litem

Toksyczność litem jest najczęstszą przyczyną nabytej moczówki prostej nerkowej. Mechanizmy, przez które przewlekła terapia litem może zmniejszać antydiuretyczne działanie wazopresyny, obejmują:³³

1. Zwiększenie produkcji prostaglandyny E2 (PGE2), która zmniejsza syntezę cAMP indukowaną przez wazopresynę

2. Hamowanie kinazy-3 syntazy glikogenu (GSK-3), co prowadzi do zwiększonej ekspresji cyklooksygenazy-2 (COX-2) i syntezy PGE2, czego wynikiem jest zmniejszona aktywność wazopresyny i zwiększone wydalanie moczu

3. Zmniejszenie stosunku między komórkami głównymi a wstawkowymi w kanalikach zbiorczych u myszy z powodu zatrzymania cyklu komórkowego G2 w komórkach głównych

4. Zahamowanie aktywności cyklazy adenylanowej w kanalikach zbiorczych, co zmniejsza zdolność do generowania i gromadzenia cAMP w odpowiedzi na stymulację przez AVP³⁴

5. Niższa osmolalność tkanki rdzeniowej nerki, głównie z powodu wyczerpania mocznika, co zmniejsza siłę napędową osmozy dla reabsorpcji wody w kanalikach zbiorczych³⁵

Moczówka prosta ciążowa

Moczówka prosta ciążowa jest rzadkim powikłaniem ciąży, zwykle rozwijającym się w trzecim trymestrze i ustępującym samoistnie 4-6 tygodni po porodzie. Jest spowodowana głównie nadmierną aktywnością wazopresynazy, enzymu wydzielanego przez trofoblasty łożyskowe, który metabolizuje argininę wazopresynę (AVP)³⁶.

Aktywność wazopresynazy jest proporcjonalna do masy łożyska, co wyjaśnia wyższą aktywność wazopresynazy w trzecim trymestrze lub w ciążach mnogich. Wazopresynaza jest metabolizowana w wątrobie, co wyjaśnia wyższe stężenia tego enzymu u pacjentek z dysfunkcją wątroby³⁷.

Przejściowe (ostre stłuszczenie wątroby w ciąży, zespół HELLP i stan przedrzucawkowy) lub przewlekłe (zapalenie wątroby, alkoholowe zapalenie wątroby i marskość) choroby/uszkodzenia wątroby zmniejszają wątrobową degradację wazopresynazy, co z kolei sprzyja metabolicznej degradacji AVP³⁸.

Moczówka prosta dipsogenna

Dipsogenna moczówka prosta, znana również jako pierwotna polidypsja, jest spowodowana dysfunkcją mechanizmu pragnienia w podwzgórzu³⁹. Uszkodzenie to powoduje, że osoba stale odczuwa pragnienie i pije duże ilości płynów. Może ono wystąpić częściej u osób z pewnymi zaburzeniami psychicznymi lub przyjmujących określone leki⁴⁰.

W przeciwieństwie do innych form moczówki prostej, dipsogenna moczówka prosta nie występuje z powodu problemów związanych z wazopresyną⁴¹. Zamiast tego, uszkodzenie podwzgórza zakłóca normalny mechanizm pragnienia, prowadząc do nadmiernego pragnienia i spożycia płynów.

Konsekwencje patofizjologiczne moczówki prostej

Bez względu na przyczynę, konsekwencje patofizjologiczne moczówki prostej są podobne i prowadzą do charakterystycznych objawów klinicznych:⁴²⁴³

1. Zmniejszona zdolność nerek do zagęszczania moczu

2. Zwiększone wydalanie wody przez nerki, prowadzące do poliurii (wydalanie dużej ilości rozcieńczonego moczu)

3. Odwodnienie i zwiększona osmolalność krwi

4. Hipernatremia (podwyższone stężenie sodu w surowicy > 145 mEq/L)

5. Nasilone pragnienie (polidypsja) jako mechanizm kompensacyjny

Moczówka prosta, niezależnie od typu, charakteryzuje się zwiększonym wydalaniem moczu (poliuria) i zwiększonym pragnieniem (polidypsja). Ilość produkowanego moczu może wynosić prawie 20 litrów dziennie. Ograniczenie spożycia płynów ma niewielki wpływ na stężenie moczu⁴⁴.

Głównym powikłaniem zaburzeń wazopresyny argininowej jest odwodnienie. Ma to miejsce, gdy organizm traci zbyt dużo płynów i elektrolitów, aby funkcjonować zgodnie z przeznaczeniem⁴⁵.

Podsumowanie mechanizmów patogenetycznych

Ciężka niedobór hormonu antydiuretycznego (moczówka prosta) jest wynikiem zaburzeń w syntezie, uwalnianiu lub działaniu wazopresyny. W zależności od miejsca patologii, można ją podzielić na dwie główne kategorie: centralną (niedobór wazopresyny, AVP-D) i nerkową (oporność na wazopresynę, AVP-R).

W centralnej moczówce prostej, uszkodzenie podwzgórza lub przysadki mózgowej prowadzi do niewystarczającej produkcji lub uwalniania wazopresyny. To z kolei powoduje zmniejszone wbudowywanie kanałów akwaporyny-2 do błony szczytowej komórek kanalików zbiorczych, co uniemożliwia reabsorpcję wody i prowadzi do poliurii.

W nerkowej moczówce prostej, mimo normalnych poziomów wazopresyny, nerki nie reagują na ten hormon. Może to być spowodowane mutacjami genetycznymi wpływającymi na receptory V2 lub kanały akwaporyny-2, lub czynnikami nabytymi, takimi jak toksyczność litem, hiperkalcemia czy hipokaliemia. Te zaburzenia prowadzą do upośledzonej reabsorpcji wody w kanalikach zbiorczych i zwiększonego wydalania moczu.

Zrozumienie mechanizmów patogenetycznych moczówki prostej ma kluczowe znaczenie dla właściwego diagnozowania i leczenia tego zaburzenia, które, choć rzadkie, może powodować poważne problemy zdrowotne, jeśli nie jest odpowiednio leczone.

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Materiały źródłowe

#1 Arginine vasopressin deficiency (central diabetes insipidus): Etiology, clinical manifestations, and postdiagnostic evaluation – UpToDate
https://www.uptodate.com/contents/arginine-vasopressin-deficiency-central-diabetes-insipidus-etiology-clinical-manifestations-and-postdiagnostic-evaluation
Arginine vasopressin deficiency (AVP-D), previously called central diabetes insipidus, is characterized by decreased release of arginine vasopressin (AVP), also known as antidiuretic hormone (ADH), resulting in variable degrees of polyuria. Lack of AVP can be caused by disorders that act at one or more of the sites involved in AVP synthesis and secretion: the hypothalamic osmoreceptors, the supraoptic or paraventricular nuclei, or the superior portion of the supraopticohypophyseal tract. […] AVP-D is caused by the inability of the neurohypophysis to synthesize and/or secrete AVP in response to increased plasma osmolality. Although AVP-D can be inherited as an autosomal dominant disease or caused by developmental abnormalities, most cases are acquired. […] Damage or dysfunction of any part of the neurohypophysis, if sufficiently severe, can cause AVP-D. Plasma levels of AVP (and of copeptin, which is a cleavage product of the AVP prohormone) are undetectable in complete AVP-D and inappropriately low for the plasma osmolality in partial AVP-D.
#2 Diabetes insipidus pathophysiology – wikidoc
https://www.wikidoc.org/index.php/Diabetes_insipidus_pathophysiology
The posterior pituitary consists of the paraventricular and supraoptic nuclei, which synthesize oxytocin and arginine vasopressin, respectively. In cases of central DI, there is an absence of vasopressin, which is responsive to the exogenous administration of desmopressin. […] More than 55 different genetic mutations resulting in a defective prohormone and a deficiency of AVP have been implicated in the development of familial central diabetes. […] In cases of nephrogenic DI, solute excretion and all filtration functions of the kidney are normal, but urine is hypotonic and there is a characteristic resistance to the antidiuretic effects of endogenous vasopressin. Abnormalities in the medullary osmotic gradient, directed by antidiuretic hormone (ADH) or arginine vasopressin (AVP) and inhibition of the action of ADH on the renal tubules, are both thought to be mechanisms by which nephrogenic DI develops.
#3 Diabetes insipidus – Wikipedia
https://en.wikipedia.org/wiki/Diabetes_insipidus
Despite the name, diabetes insipidus is unrelated to diabetes mellitus and the conditions have a distinct mechanism, though both can result in the production of large amounts of urine. […] Neurogenic/central DI results from a lack of ADH; occasionally it can present with decreased thirst as regulation of thirst and ADH production occur in close proximity in the hypothalamus. It is encountered as a result of hypoxic encephalopathy, neurosurgery, autoimmunity or cancer, or sometimes without an underlying cause (idiopathic). […] The main effector organ for fluid homeostasis is the kidney. ADH acts by increasing water permeability in the collecting ducts and distal convoluted tubules; specifically, it acts on proteins called aquaporins and more specifically aquaporin 2 in the following cascade. When released, ADH binds to V2 G-protein coupled receptors within the distal convoluted tubules, increasing cyclic AMP, which couples with protein kinase A, stimulating translocation of the aquaporin 2 channel stored in the cytoplasm of the distal convoluted tubules and collecting ducts into the apical membrane. These transcribed channels allow water into the collecting duct cells. The increase in permeability allows for the reabsorption of water into the bloodstream, thus concentrating the urine.
#4 Arginine vasopressin deficiency (central diabetes insipidus): Etiology, clinical manifestations, and postdiagnostic evaluation – UpToDate
https://www.uptodate.com/contents/arginine-vasopressin-deficiency-central-diabetes-insipidus-etiology-clinical-manifestations-and-postdiagnostic-evaluation
Arginine vasopressin deficiency (AVP-D), previously called central diabetes insipidus, is characterized by decreased release of arginine vasopressin (AVP), also known as antidiuretic hormone (ADH), resulting in variable degrees of polyuria. Lack of AVP can be caused by disorders that act at one or more of the sites involved in AVP synthesis and secretion: the hypothalamic osmoreceptors, the supraoptic or paraventricular nuclei, or the superior portion of the supraopticohypophyseal tract. […] AVP-D is caused by the inability of the neurohypophysis to synthesize and/or secrete AVP in response to increased plasma osmolality. Although AVP-D can be inherited as an autosomal dominant disease or caused by developmental abnormalities, most cases are acquired. […] Damage or dysfunction of any part of the neurohypophysis, if sufficiently severe, can cause AVP-D. Plasma levels of AVP (and of copeptin, which is a cleavage product of the AVP prohormone) are undetectable in complete AVP-D and inappropriately low for the plasma osmolality in partial AVP-D.
#5 Arginine vasopressin deficiency (central diabetes insipidus): Etiology, clinical manifestations, and postdiagnostic evaluation – UpToDate
https://www.uptodate.com/contents/arginine-vasopressin-deficiency-central-diabetes-insipidus-etiology-clinical-manifestations-and-postdiagnostic-evaluation
Arginine vasopressin deficiency (AVP-D), previously called central diabetes insipidus, is characterized by decreased release of arginine vasopressin (AVP), also known as antidiuretic hormone (ADH), resulting in variable degrees of polyuria. Lack of AVP can be caused by disorders that act at one or more of the sites involved in AVP synthesis and secretion: the hypothalamic osmoreceptors, the supraoptic or paraventricular nuclei, or the superior portion of the supraopticohypophyseal tract. […] AVP-D is caused by the inability of the neurohypophysis to synthesize and/or secrete AVP in response to increased plasma osmolality. Although AVP-D can be inherited as an autosomal dominant disease or caused by developmental abnormalities, most cases are acquired. […] Damage or dysfunction of any part of the neurohypophysis, if sufficiently severe, can cause AVP-D. Plasma levels of AVP (and of copeptin, which is a cleavage product of the AVP prohormone) are undetectable in complete AVP-D and inappropriately low for the plasma osmolality in partial AVP-D.
#6 Diabetes Insipidus: Practice Essentials, Background, Etiology
https://emedicine.medscape.com/article/117648-overview
AVP is the primary determinant of free water excretion in the body. Its main target is the kidney, where it acts by altering the water permeability of the cortical and medullary collecting tubules. Water is reabsorbed by osmotic equilibration with the hypertonic interstitium and returned to the systemic circulation. […] Diminished or absent ADH production can be the result of a defect in 1 or more sites in the neurohypophysis. These include the hypothalamic osmoreceptors, the supraoptic or paraventricular nuclei, and the supraopticohypophyseal tract. […] Central DI has many possible causes. […] Idiopathic central DI presumably develops when cells in the hypothalamus are damaged or destroyed. […] Increasingly, the role of inflammation and autoimmunity in DI is being recognized. […] The role of human chorionic gonadotropin (hCG) in the early diagnosis of germinoma is not fully established.
#7 Diabetes Insipidus (DI) – Hypothalamus and Pituitary Diseases – Endocrinology – Diseases – McMaster Textbook of Internal Medicine
https://empendium.com/mcmtextbook/chapter/B31.II.8.1.
Diabetes insipidus (DI) is a condition characterized by increased water loss (polyuria 50 mL/kg/d) resulting from excretion of a large volume of diluted urine and usually by compensatory increased thirst (polydipsia) due to: […] Central DI (neurohypophyseal): Arginine vasopressin (antidiuretic hormone) (ADH) deficiency. This may result from: […] Damage to the vasopressin-secreting neurons located in the supraoptic and paraventricular nuclei in the hypothalamus or to the pituitary stalk or posterior pituitary gland (vasopressin transport and storage sites, respectively). The most common cause of central DI is idiopathic (autoimmune process) followed by tumors (germinoma, metastatic lesions, craniopharyngioma), hypophysitis (inflammation of the pituitary gland), infiltrative diseases (sarcoidosis, Langerhans cell histiocytosis), hypoxic encephalopathy, and head trauma.
#8 Diabetes insipidus pathophysiology – wikidoc
https://www.wikidoc.org/index.php/Diabetes_insipidus_pathophysiology
The posterior pituitary consists of the paraventricular and supraoptic nuclei, which synthesize oxytocin and arginine vasopressin, respectively. In cases of central DI, there is an absence of vasopressin, which is responsive to the exogenous administration of desmopressin. […] More than 55 different genetic mutations resulting in a defective prohormone and a deficiency of AVP have been implicated in the development of familial central diabetes. […] In cases of nephrogenic DI, solute excretion and all filtration functions of the kidney are normal, but urine is hypotonic and there is a characteristic resistance to the antidiuretic effects of endogenous vasopressin. Abnormalities in the medullary osmotic gradient, directed by antidiuretic hormone (ADH) or arginine vasopressin (AVP) and inhibition of the action of ADH on the renal tubules, are both thought to be mechanisms by which nephrogenic DI develops.
#9 Central Diabetes Insipidus
https://mobile.fpnotebook.com/Renal/Endo/CntrlDbtsInspds.htm
Central Diabetes Insipidus, Central DI […] Mechanism […] Antidiuretic Hormone (ADH) deficiency […] Contrast with Nephrogenic Diabetes Insipidus (deficient renal response to ADH) […] Polyuria […] Decreased ADH release […] Permanent Polyuria […] Central lesion above median eminence […] Transient Polyuria […] Central lesion below median eminence […] ADH passes via Hypothalamus to portal capillaries […] Results in ADH release below the median eminence […] Etiology […] Idiopathic (30%) […] Autoimmune Disease (common) […] Lymphocyte inflammation […] Pituitary stalk (thickened stalk on MRI) […] Posterior pituitary […] Familial Diabetes Insipidus (very rare) […] Point mutation in ADH precursor gene […] Precursor accumulates […] Toxicity to ADH synthesizing cells
#10 Arginine vasopressin resistance (nephrogenic diabetes insipidus): Etiology, clinical manifestations, and postdiagnostic evaluation – UpToDate
https://www.uptodate.com/contents/clinical-manifestations-and-causes-of-nephrogenic-diabetes-insipidus
Arginine vasopressin V2 resistance (AVP-R), previously called nephrogenic diabetes insipidus, refers to a decrease in urinary concentrating ability that results from resistance to the action of arginine vasopressin (AVP, also known as antidiuretic hormone [ADH]). This problem can reflect resistance at the AVP site of action in the collecting tubules, or interference with the countercurrent mechanism due, for example, to medullary injury or to decreased sodium chloride reabsorption in the medullary aspect of the thick ascending limb of the loop of Henle. […] The etiologies, clinical manifestations, and postdiagnostic evaluation of AVP-R are reviewed in this topic. […] Mechanisms of arginine vasopressin resistance due to hypercalcemia, hypokalemia, and lithium toxicity.
#11 Arginine Vasopressin Disorders (Diabetes Insipidus)
https://my.clevelandclinic.org/health/diseases/16618-diabetes-insipidus
Arginine vasopressin disorder, formerly known as diabetes insipidus, represents two conditions that happen when your body lets go of too much urine (pee). It cant keep (retain) water properly. These conditions are rare but treatable. […] An issue with arginine vasopressin (AVP) a hormone mainly causes these conditions: AVP deficiency (AVP-D) happens when your body doesnt make enough AVP. […] AVP resistance (AVP-R) happens because your kidneys dont use AVP properly. […] The causes vary based on the type: Arginine vasopressin deficiency (AVP-D). Formerly known as central diabetes insipidus, AVP-D happens when your body doesnt have enough arginine vasopressin (a deficiency). Its the most common type. […] Arginine vasopressin resistance (AVP-R). This type was formerly known as nephrogenic diabetes insipidus. AVP-R happens when your pituitary gland releases enough AVP, but your kidneys dont respond to it properly (resistance).
#12 Nephrogenic diabetes insipidus – Wikipedia
https://en.wikipedia.org/wiki/Nephrogenic_diabetes_insipidus
Nephrogenic diabetes insipidus, recently renamed arginine vasopressin resistance (AVP-R) and previously known as renal diabetes insipidus, is a form of diabetes insipidus primarily due to pathology of the kidney. This is in contrast to central or neurogenic diabetes insipidus, which is caused by insufficient levels of vasopressin (also called antidiuretic hormone, ADH). Nephrogenic diabetes insipidus is caused by an improper response of the kidney to vasopressin, leading to a decrease in the ability of the kidney to concentrate the urine by removing free water. […] The major causes of acquired nephrogenic diabetes insipidus that produce clinical symptoms (e.g., polyuria) in the adult are lithium toxicity and high blood calcium. About 80% of lithium ingested appears to affect the proximal tubules by entering the collecting tubule cells through sodium channels, accumulating and interfering with the normal response to antidiuretic hormone in a mechanism that is not yet fully understood.
#13 Diabetes insipidus – Wikipedia
https://en.wikipedia.org/wiki/Diabetes_insipidus
Despite the name, diabetes insipidus is unrelated to diabetes mellitus and the conditions have a distinct mechanism, though both can result in the production of large amounts of urine. […] Neurogenic/central DI results from a lack of ADH; occasionally it can present with decreased thirst as regulation of thirst and ADH production occur in close proximity in the hypothalamus. It is encountered as a result of hypoxic encephalopathy, neurosurgery, autoimmunity or cancer, or sometimes without an underlying cause (idiopathic). […] The main effector organ for fluid homeostasis is the kidney. ADH acts by increasing water permeability in the collecting ducts and distal convoluted tubules; specifically, it acts on proteins called aquaporins and more specifically aquaporin 2 in the following cascade. When released, ADH binds to V2 G-protein coupled receptors within the distal convoluted tubules, increasing cyclic AMP, which couples with protein kinase A, stimulating translocation of the aquaporin 2 channel stored in the cytoplasm of the distal convoluted tubules and collecting ducts into the apical membrane. These transcribed channels allow water into the collecting duct cells. The increase in permeability allows for the reabsorption of water into the bloodstream, thus concentrating the urine.
#14 Diabetes Insipidus: Practice Essentials, Background, Etiology
https://emedicine.medscape.com/article/117648-overview
Other causes of central DI include cancer, hypoxic encephalopathy, granulomatous disease, anorexia nervosa, and vascular lesions. […] In adults, nephrogenic DI most often develops as a result of lithium toxicity or hypercalcemia. […] Hereditary nephrogenic DI is relatively rare. […] The most common inherited form results from mutations in the AVP receptor 2 gene (AVPR2) on chromosome Xq28. […] Defects in the AVP receptor cause resistance to the antidiuretic effect of vasopressin.
#15 Diabetes Insipidus (DI) – Hypothalamus and Pituitary Diseases – Endocrinology – Diseases – McMaster Textbook of Internal Medicine
https://empendium.com/mcmtextbook/chapter/B31.II.8.1.
Genetic defects, such as familial central DI (autosomal dominant gene defect encoding ADH), Wolfram syndrome (DIDMOAD syndrome [diabetes insipidus, diabetes mellitus, optic atrophy, and deafness]), congenital hypopituitarism, and septo-optic dysplasia. […] Nephrogenic DI: Loss of sensitivity of the renal tubules to ADH (ADH resistance), which may result from mutations in the vasopressin V2-receptor gene (X-linked inheritance with males mostly affected; heterozygous females may be asymptomatic but at risk of polyuria during pregnancy) and in the aquaporin 2 (AQP2) gene (encodes the ADH-sensitive water channels in the collecting tubule cells). Nephrogenic DI may also occur in hypercalcemia, hypokalemia, renal diseases (eg, bilateral urinary tract obstruction, polycystic kidney disease, renal amyloidosis), and it can be caused by drugs (eg, lithium [most common], amphotericin B, cidofovir, and foscarnet).
#16 Diabetes Insipidus: Practice Essentials, Background, Etiology
https://emedicine.medscape.com/article/117648-overview
AVP is the primary determinant of free water excretion in the body. Its main target is the kidney, where it acts by altering the water permeability of the cortical and medullary collecting tubules. Water is reabsorbed by osmotic equilibration with the hypertonic interstitium and returned to the systemic circulation. […] Diminished or absent ADH production can be the result of a defect in 1 or more sites in the neurohypophysis. These include the hypothalamic osmoreceptors, the supraoptic or paraventricular nuclei, and the supraopticohypophyseal tract. […] Central DI has many possible causes. […] Idiopathic central DI presumably develops when cells in the hypothalamus are damaged or destroyed. […] Increasingly, the role of inflammation and autoimmunity in DI is being recognized. […] The role of human chorionic gonadotropin (hCG) in the early diagnosis of germinoma is not fully established.
#17 Diabetes insipidus – Wikipedia
https://en.wikipedia.org/wiki/Diabetes_insipidus
Despite the name, diabetes insipidus is unrelated to diabetes mellitus and the conditions have a distinct mechanism, though both can result in the production of large amounts of urine. […] Neurogenic/central DI results from a lack of ADH; occasionally it can present with decreased thirst as regulation of thirst and ADH production occur in close proximity in the hypothalamus. It is encountered as a result of hypoxic encephalopathy, neurosurgery, autoimmunity or cancer, or sometimes without an underlying cause (idiopathic). […] The main effector organ for fluid homeostasis is the kidney. ADH acts by increasing water permeability in the collecting ducts and distal convoluted tubules; specifically, it acts on proteins called aquaporins and more specifically aquaporin 2 in the following cascade. When released, ADH binds to V2 G-protein coupled receptors within the distal convoluted tubules, increasing cyclic AMP, which couples with protein kinase A, stimulating translocation of the aquaporin 2 channel stored in the cytoplasm of the distal convoluted tubules and collecting ducts into the apical membrane. These transcribed channels allow water into the collecting duct cells. The increase in permeability allows for the reabsorption of water into the bloodstream, thus concentrating the urine.
#18 Hereditary Nephrogenic Diabetes Insipidus: Pathophysiology and Possible Treatment. An Update
https://www.mdpi.com/1422-0067/18/11/2385
Hereditary Nephrogenic Diabetes Insipidus: Pathophysiology and Possible Treatment. An Update […] Under physiological conditions, excessive loss of water through the urine is prevented by the release of the antidiuretic hormone arginine-vasopressin (AVP) from the posterior pituitary. In the kidney, AVP elicits a number of cellular responses, which converge on increasing the osmotic reabsorption of water in the collecting duct. One of the key events triggered by the binding of AVP to its type-2 receptor (AVPR2) is the exocytosis of the water channel aquaporin 2 (AQP2) at the apical membrane the principal cells of the collecting duct. Mutations of either AVPR2 or AQP2 result in a genetic disease known as nephrogenic diabetes insipidus, which is characterized by the lack of responsiveness of the collecting duct to the antidiuretic action of AVP. […] The congenital form of nephrogenic diabetes insipidus (NDI) is a rare inherited disorder, characterized by insensitivity of the distal nephron to the antidiuretic action of AVP and the reduced ability of the kidney to concentrate the urine, leading to severe dehydration and electrolyte imbalance (hypernatremia and hyperchloremia). In most cases, NDI is caused by a non-functional AVPR2 receptor (X-linked NDI). Mutations of the AQP2 gene also lead to congenital NDI. […] The clinical diagnosis of NDI relies on the demonstration of a reduced ability to concentrate the urine, despite the presence of high plasma AVP or the parenteral administration of AVP or desmopressin (DDAVP). To confirm/establish the diagnosis in a proband, male or female, genetic testing is performed on the AVPR2 gene by sequencing and deletion/duplication analysis. AQP2 gene sequencing is performed first in cases of affected children from consanguineous parents. Only if pathogenic variants of AQP2 are not identified, AVPR2 sequencing is performed. Congenital NDI is caused by mutations in the AVPR2 or the AQP2 genes. […] The AVPR2 is a typical seven membrane-spanning helices G protein-coupled receptor (GPCR). Mutations in the AVPR2 gene lead to X-linked NDI (X-NDI). […] The number of identified AVPR2 mutations leading to X-NDI is constantly increasing. As of September 2017, according to the Human Gene Mutation Database, 274 identified mutations of AVPR2 gene are classified as âloss of functionâ. […] Class II mutations, the most common, are missense or insertion/deletion producing full-length misfolded proteins, mostly retained in the endoplasmic reticulum (ER) by the ER quality-control machinery and targeted for proteasome degradation. […] Conversely, AVPR2 can also be affected by âgain of functionâ mutations. These mutant receptors have increased binding affinity to AVP or are constitutively activated, causing the nephrogenic syndrome of inappropriate antidiuresis (NSIAD). […] The AQP2 gene is located on chromosome 12q13 and codes for the 271 amino acid AQP2 protein, a type IV-A transmembrane protein characterized by six transmembrane domains connected by five loops and intracellular N- and C-termini. […] About 10% of NDI patients are affected by an autosomal form of NDI. Similar to the AVPR2 inactivating mutations, those on AQP2 can affect the proper synthesis, processing, or plasma membrane localization of the gene product, thus preventing the antidiuretic action of AVP in the collecting duct principal cells. […] Currently, 65 mutations of the AQP2 gene have been described as causative of autosomal NDI, most of which show a recessive inheritance. […] The majority of patients with X-NDI display little or no rise in urine osmolality in response to fluid deprivation tests or large doses of AVP or desmopressin (DDAVP). […] Interestingly, in the majority of AQP2 mutations causing autosomal dominant NDI, AQP2 mutants retain residual trafficking to the apical membrane in response to AVP, thus resulting in a less severe concentrating defect (partial NDI). […] In addition to genetic defects, partial NDI may be also attributable to aging.
#19 Diabetes Insipidus: Practice Essentials, Background, Etiology
https://emedicine.medscape.com/article/117648-overview
AVP is the primary determinant of free water excretion in the body. Its main target is the kidney, where it acts by altering the water permeability of the cortical and medullary collecting tubules. Water is reabsorbed by osmotic equilibration with the hypertonic interstitium and returned to the systemic circulation. […] Diminished or absent ADH production can be the result of a defect in 1 or more sites in the neurohypophysis. These include the hypothalamic osmoreceptors, the supraoptic or paraventricular nuclei, and the supraopticohypophyseal tract. […] Central DI has many possible causes. […] Idiopathic central DI presumably develops when cells in the hypothalamus are damaged or destroyed. […] Increasingly, the role of inflammation and autoimmunity in DI is being recognized. […] The role of human chorionic gonadotropin (hCG) in the early diagnosis of germinoma is not fully established.
#20 Arginine vasopressin deficiency (central diabetes insipidus): Etiology, clinical manifestations, and postdiagnostic evaluation – UpToDate
https://www.uptodate.com/contents/arginine-vasopressin-deficiency-central-diabetes-insipidus-etiology-clinical-manifestations-and-postdiagnostic-evaluation
Deficient AVP release leads to diminished insertion of aquaporin 2 water channels into the luminal membrane of the collecting duct. This in turn impairs the ability of the kidney to concentrate the urine and leads to excretion of a large volume of hypotonic urine, thereby increasing the plasma osmolality. The increase in plasma osmolality stimulates thirst and polydipsia. […] AVP-D may also result from osmoreceptor dysfunction. In such patients, the neurohypophysis is intact, but the osmoreceptors in the anterior hypothalamus that are responsible for detecting a rise in plasma osmolality are damaged. As a result, stimulation of AVP secretion is diminished, and the patient becomes symptomatic due to deficient AVP secretion despite normal amounts of AVP production.
#21 Arginine vasopressin deficiency (central diabetes insipidus): Etiology, clinical manifestations, and postdiagnostic evaluation – UpToDate
https://www.uptodate.com/contents/arginine-vasopressin-deficiency-central-diabetes-insipidus-etiology-clinical-manifestations-and-postdiagnostic-evaluation
Deficient AVP release leads to diminished insertion of aquaporin 2 water channels into the luminal membrane of the collecting duct. This in turn impairs the ability of the kidney to concentrate the urine and leads to excretion of a large volume of hypotonic urine, thereby increasing the plasma osmolality. The increase in plasma osmolality stimulates thirst and polydipsia. […] AVP-D may also result from osmoreceptor dysfunction. In such patients, the neurohypophysis is intact, but the osmoreceptors in the anterior hypothalamus that are responsible for detecting a rise in plasma osmolality are damaged. As a result, stimulation of AVP secretion is diminished, and the patient becomes symptomatic due to deficient AVP secretion despite normal amounts of AVP production.
#22 Arginine vasopressin deficiency (central diabetes insipidus): Etiology, clinical manifestations, and postdiagnostic evaluation – UpToDate
https://www.uptodate.com/contents/arginine-vasopressin-deficiency-central-diabetes-insipidus-etiology-clinical-manifestations-and-postdiagnostic-evaluation
Deficient AVP release leads to diminished insertion of aquaporin 2 water channels into the luminal membrane of the collecting duct. This in turn impairs the ability of the kidney to concentrate the urine and leads to excretion of a large volume of hypotonic urine, thereby increasing the plasma osmolality. The increase in plasma osmolality stimulates thirst and polydipsia. […] AVP-D may also result from osmoreceptor dysfunction. In such patients, the neurohypophysis is intact, but the osmoreceptors in the anterior hypothalamus that are responsible for detecting a rise in plasma osmolality are damaged. As a result, stimulation of AVP secretion is diminished, and the patient becomes symptomatic due to deficient AVP secretion despite normal amounts of AVP production.
#23 Diabetes insipidus pathophysiology – wikidoc
https://www.wikidoc.org/index.php/Diabetes_insipidus_pathophysiology
The posterior pituitary consists of the paraventricular and supraoptic nuclei, which synthesize oxytocin and arginine vasopressin, respectively. In cases of central DI, there is an absence of vasopressin, which is responsive to the exogenous administration of desmopressin. […] More than 55 different genetic mutations resulting in a defective prohormone and a deficiency of AVP have been implicated in the development of familial central diabetes. […] In cases of nephrogenic DI, solute excretion and all filtration functions of the kidney are normal, but urine is hypotonic and there is a characteristic resistance to the antidiuretic effects of endogenous vasopressin. Abnormalities in the medullary osmotic gradient, directed by antidiuretic hormone (ADH) or arginine vasopressin (AVP) and inhibition of the action of ADH on the renal tubules, are both thought to be mechanisms by which nephrogenic DI develops.
#24 Diabetes insipidus – Wikipedia
https://en.wikipedia.org/wiki/Diabetes_insipidus
Nephrogenic DI results from a lack of aquaporin channels in the distal collecting duct (decreased surface expression and transcription). It is seen in lithium toxicity, hypercalcemia, hypokalemia, or the release of ureteral obstruction. Therefore, a lack of ADH prevents water reabsorption and the osmolarity of the blood increases. With increased osmolarity, the osmoreceptors in the hypothalamus detect this change and stimulate thirst. With increased thirst, the person now experiences a polydipsia and polyuria cycle. […] Hereditary forms of diabetes insipidus account for less than 10% of the cases of diabetes insipidus seen in clinical practice.
#25 diabetes-insipidus-pathogenesis-and-clinical-findings | Calgary Guide
https://calgaryguide.ucalgary.ca/diabetes-insipidus-pathogenesis-and-clinical-findings/diabetes-insipidus/
Diabetes Insipidus: Pathogenesis and clinical findings Hereditary Autoimmune/ Idiopathic Auto-antibodies destroy neurons that release antidiuretic hormone (ADH) […] Mass Effect/ Tumor Invasion Mass pressing on hypothalamus or pituitary […] Electrolyte Imbalance (mechanism unclear) […] Hereditary Lithium (Li) (mechanism unclear) Li enters principal cells of collecting ducts via ENaCs […] Li inhibits GSK3, reducing adenylyl cyclase activity cAMP- dependent phosphorylation of aquaporin-2 […] Serum [Ca2+] Activation of CaSR in thick ascending limb of Loop of Henle […] NaCl reabsorption in thick ascending limb Generation of medullary osmotic gradient […] Serum [K+] Degradation of aquaporin-2 channels in collecting duct […] Aquaporin- 2 channels transporting water across apical membrane of collecting duct
#26 Accelerated-Onset Diabetes Insipidus Secondary to Lithium Use
https://www.psychiatrist.com/pcc/accelerated-onset-diabetes-insipidus-secondary-to-lithium-use/
Nephrogenic diabetes insipidus is characterized by the inability of distal nephrons of renal tubules to sense and respond to antidiuretic hormone (ADH), leading to increased frequency and amount of urine excretion and excessive thirst. […] Lithium has been shown to induce desensitization of the renal cells toward the ADH signal, particularly with chronic use. […] Lithium-induced diabetes insipidus is characterized by decreased urinary concentrating ability in the kidneys. Prior studies have shown that lithium inhibits expression of aquaporin-2 in the renal collecting duct, likely due to inhibition of adenylate cyclase activity. […] We hypothesize that the antipsychotics used in our patient modulated the inhibition of adenylate cyclase activity, decreasing sensitivity to ADH and leading to nephrogenic diabetes insipidus.
#27 diabetes-insipidus-pathogenesis-and-clinical-findings | Calgary Guide
https://calgaryguide.ucalgary.ca/diabetes-insipidus-pathogenesis-and-clinical-findings/diabetes-insipidus/
Diabetes Insipidus: Pathogenesis and clinical findings Hereditary Autoimmune/ Idiopathic Auto-antibodies destroy neurons that release antidiuretic hormone (ADH) […] Mass Effect/ Tumor Invasion Mass pressing on hypothalamus or pituitary […] Electrolyte Imbalance (mechanism unclear) […] Hereditary Lithium (Li) (mechanism unclear) Li enters principal cells of collecting ducts via ENaCs […] Li inhibits GSK3, reducing adenylyl cyclase activity cAMP- dependent phosphorylation of aquaporin-2 […] Serum [Ca2+] Activation of CaSR in thick ascending limb of Loop of Henle […] NaCl reabsorption in thick ascending limb Generation of medullary osmotic gradient […] Serum [K+] Degradation of aquaporin-2 channels in collecting duct […] Aquaporin- 2 channels transporting water across apical membrane of collecting duct
#28 Autophagic degradation of aquaporin-2 is an early event in hypokalemia-induced nephrogenic diabetes insipidus | Scientific Reports
https://www.nature.com/articles/srep18311
Hypokalemia (low serum potassium level) is a common electrolyte imbalance that can cause a defect in urinary concentrating ability, i.e., nephrogenic diabetes insipidus (NDI), but the molecular mechanism is unknown. […] Thus, enhanced autophagic degradation of proteins, most notably including AQP2, is an early event in hypokalemia-induced NDI. […] Potassium deprivation has been reported to induce urinary concentrating defects through alterations in abundances of various proteins, including NKCC2 in thick ascending limb cells as well as AQP2 and/or urea transporter proteins in inner medullary collecting duct cells. […] The present study is the first to demonstrate that AQP2 in IMCD cells is sequestered in autophagosomes/autolysosomes as an early event following potassium deprivation. […] Our data indicate that potassium deprivation lead to autophagic degradation of a specific subset of cellular proteins, including AQP2 and the other proteins mentioned above.
#29 Arginine Vasopressin Disorder (Diabetes Insipidus) – StatPearls – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK470458/
Arginine vasopressin disorder, formerly known as diabetes insipidus (DI), is a disease process that results in either decreased release of antidiuretic hormone (ADH, also known as vasopressin or AVP) or reduced response to ADH, causing electrolyte imbalances. […] Arginine vasopressin disorder is caused by a problem with vasopressin production in the pituitary gland (deficiency) or the action of vasopressin in the kidneys (resistance). […] Arginine vasopressin disorder (AVP-D), based on the site of pathology, can be caused by two different defects, ie, central and peripheral (nephrogenic) types. […] AVP-D is secondary to inadequate or impaired secretion of AVP from the posterior pituitary gland in response to osmotic stimulation and a decrease in blood pressure. […] In AVP-R, the site of action of AVP at the levels of kidneys is at defective V2 receptors. […] Various mutations cause several different defects in cellular processing and function of the receptor but can be classified into four general categories based on differences in transport to the cell surface and AVP binding and stimulation of adenylyl cyclase.
#30 Hereditary Nephrogenic Diabetes Insipidus: Pathophysiology and Possible Treatment. An Update
https://www.mdpi.com/1422-0067/18/11/2385
Hereditary Nephrogenic Diabetes Insipidus: Pathophysiology and Possible Treatment. An Update […] Under physiological conditions, excessive loss of water through the urine is prevented by the release of the antidiuretic hormone arginine-vasopressin (AVP) from the posterior pituitary. In the kidney, AVP elicits a number of cellular responses, which converge on increasing the osmotic reabsorption of water in the collecting duct. One of the key events triggered by the binding of AVP to its type-2 receptor (AVPR2) is the exocytosis of the water channel aquaporin 2 (AQP2) at the apical membrane the principal cells of the collecting duct. Mutations of either AVPR2 or AQP2 result in a genetic disease known as nephrogenic diabetes insipidus, which is characterized by the lack of responsiveness of the collecting duct to the antidiuretic action of AVP. […] The congenital form of nephrogenic diabetes insipidus (NDI) is a rare inherited disorder, characterized by insensitivity of the distal nephron to the antidiuretic action of AVP and the reduced ability of the kidney to concentrate the urine, leading to severe dehydration and electrolyte imbalance (hypernatremia and hyperchloremia). In most cases, NDI is caused by a non-functional AVPR2 receptor (X-linked NDI). Mutations of the AQP2 gene also lead to congenital NDI. […] The clinical diagnosis of NDI relies on the demonstration of a reduced ability to concentrate the urine, despite the presence of high plasma AVP or the parenteral administration of AVP or desmopressin (DDAVP). To confirm/establish the diagnosis in a proband, male or female, genetic testing is performed on the AVPR2 gene by sequencing and deletion/duplication analysis. AQP2 gene sequencing is performed first in cases of affected children from consanguineous parents. Only if pathogenic variants of AQP2 are not identified, AVPR2 sequencing is performed. Congenital NDI is caused by mutations in the AVPR2 or the AQP2 genes. […] The AVPR2 is a typical seven membrane-spanning helices G protein-coupled receptor (GPCR). Mutations in the AVPR2 gene lead to X-linked NDI (X-NDI). […] The number of identified AVPR2 mutations leading to X-NDI is constantly increasing. As of September 2017, according to the Human Gene Mutation Database, 274 identified mutations of AVPR2 gene are classified as âloss of functionâ. […] Class II mutations, the most common, are missense or insertion/deletion producing full-length misfolded proteins, mostly retained in the endoplasmic reticulum (ER) by the ER quality-control machinery and targeted for proteasome degradation. […] Conversely, AVPR2 can also be affected by âgain of functionâ mutations. These mutant receptors have increased binding affinity to AVP or are constitutively activated, causing the nephrogenic syndrome of inappropriate antidiuresis (NSIAD). […] The AQP2 gene is located on chromosome 12q13 and codes for the 271 amino acid AQP2 protein, a type IV-A transmembrane protein characterized by six transmembrane domains connected by five loops and intracellular N- and C-termini. […] About 10% of NDI patients are affected by an autosomal form of NDI. Similar to the AVPR2 inactivating mutations, those on AQP2 can affect the proper synthesis, processing, or plasma membrane localization of the gene product, thus preventing the antidiuretic action of AVP in the collecting duct principal cells. […] Currently, 65 mutations of the AQP2 gene have been described as causative of autosomal NDI, most of which show a recessive inheritance. […] The majority of patients with X-NDI display little or no rise in urine osmolality in response to fluid deprivation tests or large doses of AVP or desmopressin (DDAVP). […] Interestingly, in the majority of AQP2 mutations causing autosomal dominant NDI, AQP2 mutants retain residual trafficking to the apical membrane in response to AVP, thus resulting in a less severe concentrating defect (partial NDI). […] In addition to genetic defects, partial NDI may be also attributable to aging.
#31 Hereditary Nephrogenic Diabetes Insipidus: Pathophysiology and Possible Treatment. An Update
https://www.mdpi.com/1422-0067/18/11/2385
Hereditary Nephrogenic Diabetes Insipidus: Pathophysiology and Possible Treatment. An Update […] Under physiological conditions, excessive loss of water through the urine is prevented by the release of the antidiuretic hormone arginine-vasopressin (AVP) from the posterior pituitary. In the kidney, AVP elicits a number of cellular responses, which converge on increasing the osmotic reabsorption of water in the collecting duct. One of the key events triggered by the binding of AVP to its type-2 receptor (AVPR2) is the exocytosis of the water channel aquaporin 2 (AQP2) at the apical membrane the principal cells of the collecting duct. Mutations of either AVPR2 or AQP2 result in a genetic disease known as nephrogenic diabetes insipidus, which is characterized by the lack of responsiveness of the collecting duct to the antidiuretic action of AVP. […] The congenital form of nephrogenic diabetes insipidus (NDI) is a rare inherited disorder, characterized by insensitivity of the distal nephron to the antidiuretic action of AVP and the reduced ability of the kidney to concentrate the urine, leading to severe dehydration and electrolyte imbalance (hypernatremia and hyperchloremia). In most cases, NDI is caused by a non-functional AVPR2 receptor (X-linked NDI). Mutations of the AQP2 gene also lead to congenital NDI. […] The clinical diagnosis of NDI relies on the demonstration of a reduced ability to concentrate the urine, despite the presence of high plasma AVP or the parenteral administration of AVP or desmopressin (DDAVP). To confirm/establish the diagnosis in a proband, male or female, genetic testing is performed on the AVPR2 gene by sequencing and deletion/duplication analysis. AQP2 gene sequencing is performed first in cases of affected children from consanguineous parents. Only if pathogenic variants of AQP2 are not identified, AVPR2 sequencing is performed. Congenital NDI is caused by mutations in the AVPR2 or the AQP2 genes. […] The AVPR2 is a typical seven membrane-spanning helices G protein-coupled receptor (GPCR). Mutations in the AVPR2 gene lead to X-linked NDI (X-NDI). […] The number of identified AVPR2 mutations leading to X-NDI is constantly increasing. As of September 2017, according to the Human Gene Mutation Database, 274 identified mutations of AVPR2 gene are classified as âloss of functionâ. […] Class II mutations, the most common, are missense or insertion/deletion producing full-length misfolded proteins, mostly retained in the endoplasmic reticulum (ER) by the ER quality-control machinery and targeted for proteasome degradation. […] Conversely, AVPR2 can also be affected by âgain of functionâ mutations. These mutant receptors have increased binding affinity to AVP or are constitutively activated, causing the nephrogenic syndrome of inappropriate antidiuresis (NSIAD). […] The AQP2 gene is located on chromosome 12q13 and codes for the 271 amino acid AQP2 protein, a type IV-A transmembrane protein characterized by six transmembrane domains connected by five loops and intracellular N- and C-termini. […] About 10% of NDI patients are affected by an autosomal form of NDI. Similar to the AVPR2 inactivating mutations, those on AQP2 can affect the proper synthesis, processing, or plasma membrane localization of the gene product, thus preventing the antidiuretic action of AVP in the collecting duct principal cells. […] Currently, 65 mutations of the AQP2 gene have been described as causative of autosomal NDI, most of which show a recessive inheritance. […] The majority of patients with X-NDI display little or no rise in urine osmolality in response to fluid deprivation tests or large doses of AVP or desmopressin (DDAVP). […] Interestingly, in the majority of AQP2 mutations causing autosomal dominant NDI, AQP2 mutants retain residual trafficking to the apical membrane in response to AVP, thus resulting in a less severe concentrating defect (partial NDI). […] In addition to genetic defects, partial NDI may be also attributable to aging.
#32 Hereditary Nephrogenic Diabetes Insipidus: Pathophysiology and Possible Treatment. An Update
https://www.mdpi.com/1422-0067/18/11/2385
Hereditary Nephrogenic Diabetes Insipidus: Pathophysiology and Possible Treatment. An Update […] Under physiological conditions, excessive loss of water through the urine is prevented by the release of the antidiuretic hormone arginine-vasopressin (AVP) from the posterior pituitary. In the kidney, AVP elicits a number of cellular responses, which converge on increasing the osmotic reabsorption of water in the collecting duct. One of the key events triggered by the binding of AVP to its type-2 receptor (AVPR2) is the exocytosis of the water channel aquaporin 2 (AQP2) at the apical membrane the principal cells of the collecting duct. Mutations of either AVPR2 or AQP2 result in a genetic disease known as nephrogenic diabetes insipidus, which is characterized by the lack of responsiveness of the collecting duct to the antidiuretic action of AVP. […] The congenital form of nephrogenic diabetes insipidus (NDI) is a rare inherited disorder, characterized by insensitivity of the distal nephron to the antidiuretic action of AVP and the reduced ability of the kidney to concentrate the urine, leading to severe dehydration and electrolyte imbalance (hypernatremia and hyperchloremia). In most cases, NDI is caused by a non-functional AVPR2 receptor (X-linked NDI). Mutations of the AQP2 gene also lead to congenital NDI. […] The clinical diagnosis of NDI relies on the demonstration of a reduced ability to concentrate the urine, despite the presence of high plasma AVP or the parenteral administration of AVP or desmopressin (DDAVP). To confirm/establish the diagnosis in a proband, male or female, genetic testing is performed on the AVPR2 gene by sequencing and deletion/duplication analysis. AQP2 gene sequencing is performed first in cases of affected children from consanguineous parents. Only if pathogenic variants of AQP2 are not identified, AVPR2 sequencing is performed. Congenital NDI is caused by mutations in the AVPR2 or the AQP2 genes. […] The AVPR2 is a typical seven membrane-spanning helices G protein-coupled receptor (GPCR). Mutations in the AVPR2 gene lead to X-linked NDI (X-NDI). […] The number of identified AVPR2 mutations leading to X-NDI is constantly increasing. As of September 2017, according to the Human Gene Mutation Database, 274 identified mutations of AVPR2 gene are classified as âloss of functionâ. […] Class II mutations, the most common, are missense or insertion/deletion producing full-length misfolded proteins, mostly retained in the endoplasmic reticulum (ER) by the ER quality-control machinery and targeted for proteasome degradation. […] Conversely, AVPR2 can also be affected by âgain of functionâ mutations. These mutant receptors have increased binding affinity to AVP or are constitutively activated, causing the nephrogenic syndrome of inappropriate antidiuresis (NSIAD). […] The AQP2 gene is located on chromosome 12q13 and codes for the 271 amino acid AQP2 protein, a type IV-A transmembrane protein characterized by six transmembrane domains connected by five loops and intracellular N- and C-termini. […] About 10% of NDI patients are affected by an autosomal form of NDI. Similar to the AVPR2 inactivating mutations, those on AQP2 can affect the proper synthesis, processing, or plasma membrane localization of the gene product, thus preventing the antidiuretic action of AVP in the collecting duct principal cells. […] Currently, 65 mutations of the AQP2 gene have been described as causative of autosomal NDI, most of which show a recessive inheritance. […] The majority of patients with X-NDI display little or no rise in urine osmolality in response to fluid deprivation tests or large doses of AVP or desmopressin (DDAVP). […] Interestingly, in the majority of AQP2 mutations causing autosomal dominant NDI, AQP2 mutants retain residual trafficking to the apical membrane in response to AVP, thus resulting in a less severe concentrating defect (partial NDI). […] In addition to genetic defects, partial NDI may be also attributable to aging.
#33 Lithium-induced Nephrogenic Diabetes InsipidusâA Case Report and Discussion on the Pathophysiological Mechanism
https://sciforschenonline.org/journals/nephrology-kidney/IJNKF-1-113.php
Lithium decreases the antidiuretic effect of vasopressin after short as well as long-term treatment duration. […] The mechanisms by which chronic lithium therapy may reduce the antidiuretic effect of vasopressin are: First, lithium enhances PGE2 production, which decreases vasopressin-induced cAMP synthesis. […] Thus, the regulation of renal sodium and water homeostasis by the GSK-3-COX-2 pathway may be summarized as follows: (i) PGE2 increases urination by attenuating the antidiuretic action of vasopressin; (ii) GSK-3 enhances the antidiuretic action of vasopressin by decreasing COX-2 expression and reducing PGE2 synthesis; (iii) lithium inhibits GSK-3 leading to increased COX-2 expression and PGE2 synthesis the result of which is diminished vasopressin activity and increased urination. […] Fourth, lithium was found to decrease the ratio between principal and intercalated cells in mice collecting duct due to G2 (cell cycle) arrest in principal cells. The decrease in principal/intercalated cell ratio was accompanied with features of NDI.
#34
https://www.jci.org/articles/view/111901
A polyuric syndrome with nephrogenic diabetes insipidus (NDI) is a frequent consequence of prolonged administration of lithium (Li) salts. […] However, the pathogenesis of the NDI due to chronic oral administration of low therapeutic doses of Li salts is not yet clarified. […] Based on these results, we conclude that at least two factors play an important role in the pathogenesis of NDI consequent to chronic oral administration of Li: (a) decreased ability of MCT and PCD to generate and accumulate cAMP in response to stimulation by AVP; this defect is primarily due to diminished activity of AdC in these tubular segments caused by prolonged exposure to Li; and (b) lower osmolality of renal papillary tissue, due to primarily to depletion of urea, which decreases osmotic driving force for water reabsorption in collecting tubules.
#35
https://www.jci.org/articles/view/111901
A polyuric syndrome with nephrogenic diabetes insipidus (NDI) is a frequent consequence of prolonged administration of lithium (Li) salts. […] However, the pathogenesis of the NDI due to chronic oral administration of low therapeutic doses of Li salts is not yet clarified. […] Based on these results, we conclude that at least two factors play an important role in the pathogenesis of NDI consequent to chronic oral administration of Li: (a) decreased ability of MCT and PCD to generate and accumulate cAMP in response to stimulation by AVP; this defect is primarily due to diminished activity of AdC in these tubular segments caused by prolonged exposure to Li; and (b) lower osmolality of renal papillary tissue, due to primarily to depletion of urea, which decreases osmotic driving force for water reabsorption in collecting tubules.
#36 Transient diabetes insipidus in pregnancy in: Endocrinology, Diabetes & Metabolism Case Reports Volume 2015 Issue 1 (2015)
https://edm.bioscientifica.com/view/journals/edm/2015/1/EDM15-0078.xml
Gestational diabetes insipidus (DI) is a rare complication of pregnancy, usually developing in the third trimester and remitting spontaneously 46 weeks post-partum. It is mainly caused by excessive vasopressinase activity, an enzyme expressed by placental trophoblasts which metabolises arginine vasopressin (AVP). […] Gestational DI occurrence is related to excessive vasopressinase activity, an enzyme expressed by placental trophoblasts during pregnancy, which metabolises AVP. Its activity is proportional to the placental weight, explaining the higher vasopressinase activity in third trimester or in multiple pregnancies. […] Vasopressinase is metabolised in the liver, explaining the higher concentrations of this enzyme in patients with hepatic dysfunction. Transient (acute fatty liver of pregnancy, HELLP syndrome and preeclampsia) or chronic (hepatitis, alcoholic hepatitis and cirrhosis) liver disease/damage decreases the hepatic degradation of vasopressinase, which in turn favours the metabolic AVP degradation.
#37 Transient diabetes insipidus in pregnancy in: Endocrinology, Diabetes & Metabolism Case Reports Volume 2015 Issue 1 (2015)
https://edm.bioscientifica.com/view/journals/edm/2015/1/EDM15-0078.xml
Gestational diabetes insipidus (DI) is a rare complication of pregnancy, usually developing in the third trimester and remitting spontaneously 46 weeks post-partum. It is mainly caused by excessive vasopressinase activity, an enzyme expressed by placental trophoblasts which metabolises arginine vasopressin (AVP). […] Gestational DI occurrence is related to excessive vasopressinase activity, an enzyme expressed by placental trophoblasts during pregnancy, which metabolises AVP. Its activity is proportional to the placental weight, explaining the higher vasopressinase activity in third trimester or in multiple pregnancies. […] Vasopressinase is metabolised in the liver, explaining the higher concentrations of this enzyme in patients with hepatic dysfunction. Transient (acute fatty liver of pregnancy, HELLP syndrome and preeclampsia) or chronic (hepatitis, alcoholic hepatitis and cirrhosis) liver disease/damage decreases the hepatic degradation of vasopressinase, which in turn favours the metabolic AVP degradation.
#38 Transient diabetes insipidus in pregnancy in: Endocrinology, Diabetes & Metabolism Case Reports Volume 2015 Issue 1 (2015)
https://edm.bioscientifica.com/view/journals/edm/2015/1/EDM15-0078.xml
Gestational diabetes insipidus (DI) is a rare complication of pregnancy, usually developing in the third trimester and remitting spontaneously 46 weeks post-partum. It is mainly caused by excessive vasopressinase activity, an enzyme expressed by placental trophoblasts which metabolises arginine vasopressin (AVP). […] Gestational DI occurrence is related to excessive vasopressinase activity, an enzyme expressed by placental trophoblasts during pregnancy, which metabolises AVP. Its activity is proportional to the placental weight, explaining the higher vasopressinase activity in third trimester or in multiple pregnancies. […] Vasopressinase is metabolised in the liver, explaining the higher concentrations of this enzyme in patients with hepatic dysfunction. Transient (acute fatty liver of pregnancy, HELLP syndrome and preeclampsia) or chronic (hepatitis, alcoholic hepatitis and cirrhosis) liver disease/damage decreases the hepatic degradation of vasopressinase, which in turn favours the metabolic AVP degradation.
#39 Diabetes insipidus – Symptoms and causes – Mayo Clinic
https://www.mayoclinic.org/diseases-conditions/diabetes-insipidus/symptoms-causes/syc-20351269
This happens when there’s a problem with the kidneys that makes them unable to properly respond to ADH. That problem may be due to an inherited disorder. […] This rare form of diabetes insipidus only happens during pregnancy. It develops when an enzyme made by the placenta destroys ADH in a pregnant person. […] People who have this disorder constantly feel thirsty and drink lots of fluids. It can be caused by damage to the thirst-regulating mechanism in the hypothalamus.
#40 Diabetes insipidus – Wikipedia
https://en.wikipedia.org/wiki/Diabetes_insipidus
Diabetes insipidus (DI) is a condition characterized by large amounts of dilute urine and increased thirst. The amount of urine produced can be nearly 20 liters per day. Reduction of fluid has little effect on the concentration of the urine. Complications may include dehydration or seizures. […] There are four types of DI, each with a different set of causes. Central DI (CDI), now known as arginine vasopressin deficiency (AVP-D), is due to a lack of vasopressin (antidiuretic hormone) production. This can be due to injury to the hypothalamus or pituitary gland or due to genetics. Nephrogenic DI (NDI), also known as arginine vasopressin resistance (AVP-R), occurs when the kidneys do not respond properly to vasopressin. Dipsogenic DI is a result of excessive fluid intake due to damage to the hypothalamic thirst mechanism. It occurs more often in those with certain psychiatric disorders or on certain medications. Gestational DI occurs only during pregnancy.
#41 Diabetes Insipidus Types, Causes, and Symptoms
https://www.healthline.com/health/diabetes-insipidus-types
There are four types of diabetes insipidus. Each type occurs due to a different mechanism and has a variety of potential causes. The type of diabetes insipidus determines its treatment. […] Most of the time, DI happens due to issues with a hormone called vasopressin. You may also see vasopressin called antidiuretic hormone. […] In central DI, or cranial DI, your hypothalamus doesn’t make enough vasopressin. When there’s not enough vasopressin, your kidneys cannot pull fluid back into the bloodstream. Instead, fluid is flushed out in the urine. […] In nephrogenic DI, your hypothalamus makes typical levels of vasopressin. However, your kidneys don’t respond well to it. […] Dipsogenic DI, also known as primary polydipsia, is a rarer type of DI. It’s also a type that doesn’t occur due to issues related to vasopressin.
#42 Diabetes insipidus – Wikipedia
https://en.wikipedia.org/wiki/Diabetes_insipidus
Diabetes insipidus (DI) is a condition characterized by large amounts of dilute urine and increased thirst. The amount of urine produced can be nearly 20 liters per day. Reduction of fluid has little effect on the concentration of the urine. Complications may include dehydration or seizures. […] There are four types of DI, each with a different set of causes. Central DI (CDI), now known as arginine vasopressin deficiency (AVP-D), is due to a lack of vasopressin (antidiuretic hormone) production. This can be due to injury to the hypothalamus or pituitary gland or due to genetics. Nephrogenic DI (NDI), also known as arginine vasopressin resistance (AVP-R), occurs when the kidneys do not respond properly to vasopressin. Dipsogenic DI is a result of excessive fluid intake due to damage to the hypothalamic thirst mechanism. It occurs more often in those with certain psychiatric disorders or on certain medications. Gestational DI occurs only during pregnancy.
#43 diabetes-insipidus-pathogenesis-and-clinical-findings | Calgary Guide
https://calgaryguide.ucalgary.ca/diabetes-insipidus-pathogenesis-and-clinical-findings/diabetes-insipidus/
Central Diabetes Insipidus Nephrogenic Diabetes Insipidus […] Diabetes Insipidus Decreased ability of kidneys to concentrate urine […] Reabsorption of water from collecting duct into vasculature […] Urine becomes more dilute […] Urine output […] Blood becomes more concentrated […] Hypernatremia (Serum [Na+] 145 mEq/L) […] Polydipsia.
#44 Diabetes insipidus – Wikipedia
https://en.wikipedia.org/wiki/Diabetes_insipidus
Diabetes insipidus (DI) is a condition characterized by large amounts of dilute urine and increased thirst. The amount of urine produced can be nearly 20 liters per day. Reduction of fluid has little effect on the concentration of the urine. Complications may include dehydration or seizures. […] There are four types of DI, each with a different set of causes. Central DI (CDI), now known as arginine vasopressin deficiency (AVP-D), is due to a lack of vasopressin (antidiuretic hormone) production. This can be due to injury to the hypothalamus or pituitary gland or due to genetics. Nephrogenic DI (NDI), also known as arginine vasopressin resistance (AVP-R), occurs when the kidneys do not respond properly to vasopressin. Dipsogenic DI is a result of excessive fluid intake due to damage to the hypothalamic thirst mechanism. It occurs more often in those with certain psychiatric disorders or on certain medications. Gestational DI occurs only during pregnancy.
#45 Arginine Vasopressin Disorders (Diabetes Insipidus)
https://my.clevelandclinic.org/health/diseases/16618-diabetes-insipidus
Specific causes of AVP-R include: A blocked urinary tract, An inherited gene variation, Certain medications, Hypercalcemia, Hypokalemia, Lithium toxicity. […] The main complication of arginine vasopressin disorders is dehydration. This happens when your body loses too much fluid and electrolytes to function as its meant to. […] A water deprivation test is the most reliable way to diagnose either AVP-D or AVP-R. […] Treatment depends on whether you have AVP-D or AVP-R. Even with medical treatment, its important to drink water regularly to make sure you dont get dehydrated. […] Desmopressin is the first-line treatment for arginine vasopressin deficiency (AVP-D). Its a medication that works like AVP. […] Treatment for arginine vasopressin resistance (AVP-R) is more complicated. It sometimes involves a combination of approaches, like taking the following medications: Thiazide diuretics, Nonsteroidal anti-inflammatory drugs (NSAIDs). […] The outlook (prognosis) for AVP-D and AVP-R is generally good. It usually doesnt cause serious problems as long as you get treatment and drink enough water.