Ostre uszkodzenie nerek – Patofizjologia i mechanizm

Ostre uszkodzenie nerek
Patofizjologia i mechanizm

Ostre uszkodzenie nerek (AKI) to zespół kliniczny charakteryzujący się nagłym spadkiem funkcji nerek, manifestującym się wzrostem stężenia kreatyniny i zmniejszeniem diurezy w ciągu godzin do dni. Etiologia AKI dzieli się na trzy główne kategorie: przednerkową (55% przypadków, związana z hipoperfuzją nerek i aktywacją układu RAAS, wazopresyny oraz układu współczulnego), śródnerkową (uszkodzenie miąższu nerek, najczęściej ostra martwica cewek nerkowych – ATN, wywołana niedokrwieniem, sepsą lub nefrotoksynami) oraz zanerkową (obstrukcja odpływu moczu prowadząca do wzrostu ciśnienia wewnątrzcewkowego i zmniejszenia GFR). Patofizjologia obejmuje uszkodzenie rąbka szczoteczkowego, depolimeryzację cytoszkieletu aktynowego, aktywację układu dopełniacza, oraz różne formy śmierci komórkowej (apoptoza, nekroptoza, ferroptoza, piroptoza). Odpowiedź immunologiczna z udziałem neutrofili, makrofagów, komórek dendrytycznych i limfocytów T CD4+ odgrywa kluczową rolę w progresji uszkodzenia. Stres oksydacyjny i dysfunkcja śródbłonka nasilają proces zapalny i uszkodzenie nerek, a autofagia pełni funkcję nefroprotekcyjną, chroniąc komórki przed apoptozą.

Patofizjologia ostrego uszkodzenia nerek

Ostre uszkodzenie nerek (AKI – acute kidney injury) to zespół kliniczny charakteryzujący się nagłym spadkiem funkcji nerek, objawiającym się zwiększeniem stężenia kreatyniny lub zmniejszeniem objętości moczu w ciągu godzin do dni. Patogeneza AKI jest zależna od etiologii, a wspólnym punktem końcowym w ostrej martwicy cewek nerkowych jest uszkodzenie komórkowe w wyniku niedokrwienia lub bezpośredniego działania toksyn, co prowadzi do zniszczenia rąbka szczoteczkowego, śmierci komórek i zmniejszenia funkcji komórek cewkowych¹. Zrozumienie złożonych mechanizmów patofizjologicznych leżących u podstaw AKI jest niezbędne do opracowania skutecznych strategii profilaktycznych i terapeutycznych²³.

Klasyfikacja etiologiczna

Etiologię AKI koncepcyjnie klasyfikuje się do trzech głównych kategorii⁴⁵:

Przednerkowa – spowodowana zmniejszoną perfuzją nerek (55% przypadków)
Śródnerkowa (wewnątrznerkowa) – spowodowana uszkodzeniem miąższu nerek
Zanerkowa – spowodowana obstrukcją odpływu moczu

Patofizjologia przednerkowego AKI

Przednerkowe AKI, znane również jako azotemia przednerkowa, jest najczęstszą przyczyną ostrego uszkodzenia nerek, stanowiącą 30-50% wszystkich przypadków¹. Głównym mechanizmem jest hipoperfuzja nerek, która może być częścią ogólnego zmniejszenia perfuzji tkankowej lub selektywnego niedokrwienia nerek¹.

Hipoperfuzja nerek prowadzi do zmniejszenia ciśnienia hydrostatycznego w kłębuszkach, co jest wymagane do prawidłowej filtracji kłębuszkowej. Spadek przepływu osocza przez nerki poza zdolność autoregulacji, osłabiona lub nieadekwatna kompensacja nerkowa w odpowiedzi na zmiany perfuzji, lub kombinacja obu tych czynników prowadzi do uszkodzenia przednerkowego¹.

W odpowiedzi na zmniejszoną perfuzję nerek dochodzi do aktywacji mechanizmów kompensacyjnych, w tym¹:

Aktywacja układu renina-angiotensyna-aldosteron (RAAS)
Zwiększone uwalnianie wazopresyny
Aktywacja układu współczulnego
Zmiana przepływu krwi wewnątrz nerek

Nerki w normalnej odpowiedzi na zmniejszoną perfuzję nerkową maksymalnie zagęszczają mocz i reabsorbują sód, aby utrzymać lub zwiększyć objętość wewnątrznaczyniową i znormalizować perfuzję nerek¹. Jednak zmniejszony przepływ krwi przez nerki ostatecznie prowadzi do niedokrwienia i śmierci komórek².

Zespół wątrobowo-nerkowy

Patofizjologia zespołu wątrobowo-nerkowego (HRS) nie jest w pełni zrozumiała, ale obejmuje złożoną interakcję między kilkoma różnymi czynnikami³³. Mechanizm ten wiąże się z wazodylatacją tętniczą w krążeniu trzewnym, która jest kompensowana przez aktywację endogennych układów wazoaktywnych, prowadząc ostatecznie do skurczu naczyń nerkowych i zmniejszenia GFR.

Patofizjologia śródnerkowego AKI

Śródnerkowe AKI jest spowodowane bezpośrednim uszkodzeniem miąższu nerek. Może być klasyfikowane zgodnie z miejscem uszkodzenia na²:

Kłębuszkowe
Cewkowe
Śródmiąższowe
Naczyniowe

Ostra martwica cewek nerkowych

Ostra martwica cewek nerkowych (ATN) jest najczęstszą przyczyną śródnerkowego AKI u pacjentów hospitalizowanych⁴. Główne przyczyny ATN to niedokrwienie nerek, sepsa i działanie nefrotoksyn⁵.

Uszkodzenie komórek śródbłonka i nabłonka są głównymi czynnikami przyczyniającymi się do patogenezy ATN⁴⁶. Podstawowe mechanizmy obejmują również uwalnianie cytokin, stan zapalny nerek i obrzęk tkanek⁵.

Klasyczny objaw ATN to utrata rąbka szczoteczkowego w komórkach cewek proksymalnych. Obecne są również płaciste oddzielanie się i następowa utrata komórek cewkowych, odsłaniające obszary obnażonej błony podstawnej cewek oraz ogniskowe obszary rozszerzenia cewek proksymalnych wraz z obecnością wałeczków w cewkach dystalnych¹.

Mechanizmy uszkodzenia cewek nerkowych

Struktura i funkcja komórek nabłonkowych są częściowo zależne od cytoszkieletu aktynowego. W komórkach cewek proksymalnych cytoszkielet aktynowy tworzy warstwę sieci końcowej tuż pod błoną plazmatyczną wierzchołkową. Głównym mechanizmem uszkodzenia jest depolimeryzacja pośredniczona przez białko wiążące aktynę znane jako czynnik depolimeryzujący aktynę (ADF) lub kofilina².

Uszkodzenie niedokrwienne powoduje wyczerpanie komórkowego ATP, co z kolei prowadzi do szybkiego zakłócenia wierzchołkowej aktyny i przerwania oraz redystrybucji rdzenia cytoszkieletu F-aktyny, powodując tworzenie pęcherzyków zewnątrzkomórkowych związanych z błoną³.

Innym ważnym następstwem przerwania cytoszkieletu aktynowego jest utrata połączeń ścisłych i adherentnych. Aktyna obecna w sieci końcowej jest połączona z zonula occludens, więc każde zakłócenie sieci końcowej powoduje przerwanie połączeń ścisłych¹.

Wczesne uszkodzenie niedokrwienne powoduje otwarcie tych połączeń ścisłych, co prowadzi do zwiększonej przepuszczalności parakomórkowej, powodując dalszy wyciek filtratu kłębuszkowego do śródmiąższu².

Rola układu dopełniacza

Układ dopełniacza może być aktywowany bezpośrednio lub pośrednio u pacjentów z sepsą i przyczynia się do patogenezy AKI⁶⁴. Nieodpowiednia aktywacja dopełniacza przyczynia się do patogenezy AKI poprzez różne mechanizmy zidentyfikowane w badaniach eksperymentalnych⁷.

Mechanizmy śmierci komórek

W AKI występuje kilka mechanizmów śmierci komórek¹:

Apoptoza – programowana śmierć komórki charakteryzująca się skurczeniem komórki i jądra, kondensacją chromatyny i fragmentacją DNA¹
Nekroptoza – forma programowanej lub regulowanej nekrozy lub zapalnej śmierci komórki²
Ferroptoza – forma śmierci komórki zależna od żelaza
Nekroza zależna od MPT (mitochondrial permeability transition regulated necrosis)
Piroptoza – forma śmierci komórki związana z aktywacją zapalasomów

Główną siłą napędową AKI jest przede wszystkim uszkodzenie cewek i hipoperfuzja w naczyniach włosowatych okołocewkowych. Kombinacja uszkodzenia cewek i hipoperfuzji może powodować trwałą utratę nefronów u pacjentów, którzy nie mogą wyzdrowieć po ATN, ostatecznie prowadząc do zwłóknienia tkanek i przewlekłej choroby nerek po ostrym uszkodzeniu¹.

Rola stanu zapalnego i komórek odpornościowych

Odpowiedź immunologiczna w AKI obejmuje komórki zarówno wrodzonego, jak i adaptacyjnego układu odpornościowego¹. Badania na modelach zwierzęcych AKI wykazały, że komórki odporności wrodzonej, takie jak neutrofile, makrofagi, komórki dendrytyczne, komórki NK i komórki NKT, oraz adaptacyjne limfocyty CD4+ promują uszkodzenie nerek.

Stan zapalny nerek jest typową cechą AKI u ludzi, a szczegółowa analiza próbek biopsji od pacjentów z AKI wykazała obecność jednojądrowych leukocytów (niektóre limfocyty CD3+) i neutrofili².

Neutrofile

Neutrofile usuwają patogeny inwazyjne poprzez fagocytozę lub uwalnianie toksycznych ziarnistości zawierających proteazy i inne enzymy oraz reaktywne formy tlenu (ROS). Z tego powodu degranulacja neutrofili może prowadzić do uszkodzenia komórek gospodarza w zapalnej tkance¹.

W kilku mysich modelach AKI (np. uszkodzenie spowodowane niedokrwieniem/reperfuzją i uszkodzenie nerek wywołane cisplatyną) akumulacja neutrofili w uszkodzonej nerce jest spójnym i wczesnym zjawiskiem, a deplecja neutrofili lub zapobieganie przemieszczaniu się neutrofili do nerki zmniejsza uszkodzenie nerki².

Makrofagi

Makrofagi to komórki fagocytujące, które powstają z monocytów we krwi. Liczba makrofagów wzrasta wcześnie w uszkodzonej nerce (w ciągu 1 godziny od reperfuzji w modelu niedokrwienia/reperfuzji), a ta infiltracja jest mediowana przez szlaki sygnalizacyjne CCR2 i CX3CR1¹.

Deplecja makrofagów za pomocą liposomalnego klodronatu przed niedokrwieniem/reperfuzją nerek zmniejszała uszkodzenie nerek, a adoptywny transfer makrofagów przywracał AKI².

Komórki dendrytyczne

Komórki dendrytyczne migrują do nerkowych węzłów chłonnych po uszkodzeniu niedokrwienno-reperfuzyjnym i indukują proliferację limfocytów T, co sugeruje, że nerkowe komórki dendrytyczne są istotne dla adaptacyjnej odpowiedzi immunologicznej na uszkodzenie niedokrwienno-reperfuzyjne¹.

Komórki dendrytyczne są również ważne w odpowiedzi immunologicznej wrodzonej poprzez kilka mechanizmów: uwalnianie czynników prozapalnych, interakcję z komórkami NKT poprzez cząsteczkę kostymulującą CD40 i prezentację glikolipidów komórkom NKT za pośrednictwem cząsteczki CD1d².

Limfocyty T

Udział limfocytów T w patogenezie uszkodzenia niedokrwienno-reperfuzyjnego nerek został ustalony w różnych modelach mysich pozbawionych pewnych typów limfocytów. U myszy pozbawionych limfocytów T CD4 i CD8 (myszy nu/nu) uszkodzenie i dysfunkcja nerek były znacznie zmniejszone w porównaniu z kontrolami typu dzikiego po uszkodzeniu niedokrwienno-reperfuzyjnym i uszkodzeniu wywołanym cisplatyną¹.

Rekonstytucja myszy nu/nu samymi limfocytami T CD4+, ale nie samymi limfocytami T CD8+, przywracała uszkodzenie nerek po uszkodzeniu niedokrwienno-reperfuzyjnym, a myszy pozbawione samych limfocytów T CD8 lub CD4 cierpiały na mniejszą dysfunkcję nerek po podaniu cisplatyny².

Regulatorowe limfocyty T

Regulatorowe limfocyty T (Treg) stanowią niezbędną przeciwwagę dla prozapalnych komórek układu odpornościowego. Główne mechanizmy supresyjne stosowane przez Treg obejmują produkcję cytokin przeciwzapalnych, takich jak IL-10 i transformujący czynnik wzrostu (TGF)-β, wytwarzanie zewnątrzkomórkowej adenozyny, bezpośrednie hamowanie komórek dendrytycznych poprzez kontakt za pośrednictwem cząsteczek powierzchniowych, takich jak LAG-3 i CTLA-4, oraz kilka innych³.

W przeciwieństwie do komórek prozapalnych, limfocyty CD4+FoxP3+ Treg mogą chronić nerkę przed uszkodzeniem niedokrwiennym i nefrotoksycznym w modelach zwierzęcych³.

Rola stresu oksydacyjnego

Procesy stresu oksydacyjnego w AKI obejmują głównie produkcję ROS, deplecję tlenku azotu, tworzenie wzorców molekularnych związanych z uszkodzeniem (DAMPs), aktywację receptorów toll-podobnych (TLRs), autofagię i dysfunkcję mikronaczyniową¹.

Długotrwała ekspozycja na bodźce stresu oksydacyjnego w tkance nerkowej powoduje początkową fazę zapalną, co następnie prowadzi do nadmiernej produkcji tkanki włóknistej, która zaburza funkcję narządu i może prowadzić do przewlekłej choroby nerek².

Szlak sygnalizacyjny kinazy MAPK aktywowany przez ROS ze stresu oksydacyjnego promuje aktywację białka aktywującego-1, które reguluje modulację prozapalnych cytokin i chemokin¹.

Rola autofagii

Autofagia to proces zachodzący we wszystkich komórkach eukariotycznych, który utrzymuje komórki przy życiu w warunkach stresowych¹¹.

Indukcja autofagii w cewkach proksymalnych podczas ostrego śródmiąższowego zapalenia nerek wykazała, że autofagia pełni funkcję nefroprotekcyjną w AKI, niemniej jednak nadmierna autofagia ostatecznie prowadzi do śmierci komórek².

Hamowanie autofagii za pomocą siRNA dla ATG5 zwiększa apoptozę podczas ponownego ogrzewania po przechowywaniu w niskiej temperaturze w komórkach nabłonkowych cewek nerkowych. Badania te sugerują, że autofagia jest mechanizmem nefroprotekcyjnym, który chroni przed apoptozą, umożliwiając przeżycie komórek²².

Rola zmian epigenetycznych

Przejście od ostrego uszkodzenia nerek do przewlekłej choroby nerek jest spowodowane modyfikacjami epigenetycznymi, szczególnie mikroRNA¹. Te zmiany epigenetyczne mogą wpływać na szereg procesów komórkowych i molekularnych zaangażowanych w patogenezę AKI.

Patofizjologia zanerkowego AKI

Zanerkowe AKI (nefropatia obstrukcyjna) jest spowodowane różnymi rodzajami przeszkód w układzie odprowadzającym mocz¹. Obstrukcja może również wystąpić na poziomie mikroskopowym w cewkach, gdy materiał krystaliczny lub białkowy ulega wytrąceniu.

Zablokowany ultrafiltrat w cewkach lub dalszych częściach układu moczowego zwiększa ciśnienie w przestrzeni moczowej kłębuszka, zmniejszając GFR. Obstrukcja wpływa również na przepływ krwi w nerkach, początkowo zwiększając przepływ i ciśnienie w naczyniach włosowatych kłębuszka przez zmniejszenie oporu tętniczek doprowadzających².

Jednak w ciągu 3-4 godzin przepływ krwi przez nerki ulega zmniejszeniu, a po 24 godzinach spada do 50% wartości prawidłowej ze względu na zwiększony opór naczyń nerkowych³.

Zmiany hemodynamiczne są wyzwalane przez nagły wzrost ciśnienia wewnątrzcewkowego. Początkowo następuje okres przekrwienia z rozszerzeniem tętniczek doprowadzających, a następnie skurcz naczyń wewnątrznerkowych w wyniku wytwarzania angiotensyny II, tromboksanu A2 i wazopresyny oraz zmniejszenia produkcji tlenku azotu, co prowadzi do zmniejszenia GFR¹.

W celu wywołania znaczącego AKI, obstrukcja na poziomie moczowodu wymaga zajęcia obu moczowodów, chyba że pacjent ma tylko jedną funkcjonującą nerkę⁴.

Rola angiotensyny II

Centralna rola angiotensyny II może być wykazana przez zdolność inhibitorów enzymu konwertującego angiotensynę i innych inhibitorów układu renina-angiotensyna do minimalizowania spadku przepływu osocza przez nerki i GFR. Zwiększony poziom angiotensyny II stymuluje również wydzielanie TNF-α, co powoduje zwłóknienie i apoptozę komórek cewkowych¹.

Fazy AKI

Przebieg AKI, szczególnie ostrej martwicy cewek nerkowych, można podzielić na cztery fazy¹:

Faza inicjacji

Charakteryzuje się ostrym spadkiem GFR, z odpowiadającym nagłym wzrostem stężenia kreatyniny i azotu mocznikowego we krwi. W tej fazie dochodzi do bezpośredniego uszkodzenia komórek cewkowych i śródbłonkowych².

Faza rozszerzenia

Charakteryzuje się utrzymującym się niedotlenieniem prowadzącym do przedłużającego się niedokrwienia tkanek, które wyzwala odpowiedź zapalną. Biorąc pod uwagę ograniczone zaopatrzenie w krew, granica korowo-rdzeniowa nerki jest najbardziej podatna na uraz nerkowy. Ciągłe uwalnianie cytokin i chemokin z uszkodzonej granicy korowo-rdzeniowej wzmacnia kaskadę zapalną, a ta ciągła aktywacja kaskady zapalnej skutkuje spadkiem GFR³.

Faza podtrzymania

W tej fazie mechanizmy opisane powyżej mogą przyczyniać się do kontynuacji dysfunkcji nefronów, ale sprzężenie zwrotne cewkowo-kłębuszkowe również odgrywa rolę. Sprzężenie zwrotne cewkowo-kłębuszkowe w tym ustawieniu prowadzi do zwężenia tętniczek doprowadzających przez komórki plamki gęstej, które wykrywają zwiększone obciążenie solą w cewkach dystalnych. Wynikające stąd zmniejszone perfuzja nefronów może utrwalać uszkodzenie nerek¹.

Faza zdrowienia

Faza zdrowienia ATN charakteryzuje się regeneracją komórek nabłonkowych cewek. Podczas zdrowienia czasami występuje nieprawidłowa diureza, powodująca utratę soli i wody oraz zmniejszenie objętości. Mechanizm diurezy nie jest do końca zrozumiały, ale może być częściowo spowodowany opóźnionym przywróceniem funkcji komórek cewkowych w warunkach zwiększonej filtracji kłębuszkowej. Ponadto, ciągłe stosowanie diuretyków (często podawanych podczas fazy inicjacji i podtrzymania) może również pogłębiać problem¹.

Powrót do zdrowia po AKI zależy przede wszystkim od przywrócenia przepływu krwi przez nerki (RBF). Wczesna normalizacja RBF przewiduje lepsze rokowanie dla powrotu funkcji nerek. Po przywróceniu RBF, pozostałe funkcjonalne nefrony zwiększają swoją filtrację i ostatecznie ulegają hipertrofii. Powrót GFR zależy od wielkości puli pozostałych nefronów¹.

Powstaje błędne koło: kontynuowana utrata nefronów powoduje więcej hiperfiltracji, aż do wystąpienia całkowitej niewydolności nerek. Zostało to nazwane teorią hiperfiltracji niewydolności nerek i wyjaśnia scenariusz, w którym często obserwuje się postępującą niewydolność po pozornym wyzdrowieniu z AKI².

Konsekwencje molekularne i biochemiczne AKI

W przypadku ostrego uszkodzenia nerek kreatynina i mocznik gromadzą się we krwi w ciągu kilku dni, a zaburzenia płynów i elektrolitów się rozwijają. Najpoważniejszymi z tych zaburzeń są hiperkaliemia i przewodnienie (mogące powodować obrzęk płuc)¹.

Retencja fosforanów prowadzi do hiperfosfatemii. Uważa się, że hipokaliemia występuje, ponieważ uszkodzona nerka nie produkuje już kalcytriolu (zmniejszając wchłanianie wapnia z przewodu pokarmowego) i ponieważ hiperfosfatemia powoduje wytrącanie fosforanu wapnia w tkankach. Rozwija się kwasica, ponieważ jony wodorowe nie mogą być wydalane².

Przejście z AKI do CKD

Długoterminowe konsekwencje AKI obejmują przewlekłą chorobę nerek (CKD) i chorobowość sercowo-naczyniową¹. Dlatego zapobieganie i wczesne wykrywanie AKI są niezbędne.

Przejście z ostrego uszkodzenia nerek do przewlekłej choroby nerek jest spowodowane nieprawidłową naprawą komórkową lub nieprawidłowym procesem gojenia, co jest powszechnie określane jako nieprawidłowy proces naprawy¹.

Nieprawidłowa naprawa może wystąpić w przedziale cewkowym, naczyniowym i śródmiąższowym po AKI, prowadząc do zwiększonego ryzyka zwłóknienia śródmiąższowego¹.

Nieprawidłowa i nieefektywna naprawa cewek nerkowych, znana jako nieprawidłowa naprawa, jest związana z utrzymującym się stanem zapalnym, odkładaniem macierzy zewnątrzkomórkowej oraz rozwojem stanu profibrogennego i starzenia się w komórkach nabłonkowych cewek².

Naprawa po uszkodzeniu cewek nerkowych indukująca postępujące zwłóknienie nerek i zniszczenie normalnej architektury nerki jest uważana za kluczowy mechanizm patologiczny przyczyniający się do CKD¹.

Szlaki sygnalizacyjne Wnt/β-katenina, TGF-β1/SMAD i Hippo są istotne w tym przejściu, promując zwłóknienie i wpływając na funkcję nerek. Dysfunkcja mitochondrialna, starzenie się komórek, hipoksja i RAAS są również kluczowymi czynnikami przyczyniającymi się do progresji AKI i przejścia do CKD, przy czym RAAS odgrywa szczególną rolę w przebudowie nerek i zwłóknieniu².

Podsumowanie

Ostre uszkodzenie nerek to złożony zespół kliniczny o różnorodnej etiologii i patofizjologii. Mechanizmy leżące u podstaw AKI różnią się w zależności od przyczyny (przednerkowa, śródnerkowa lub zanerkowa), ale często nakładają się na siebie. Zrozumienie tych mechanizmów jest kluczowe dla opracowania skutecznych strategii zapobiegania i leczenia AKI oraz zapobiegania jego progresji do przewlekłej choroby nerek.

Głównymi elementami patofizjologii AKI są: hipoperfuzja nerkowa, bezpośrednie uszkodzenie komórek cewkowych, stan zapalny, stres oksydacyjny, dysfunkcja śródbłonka, aktywacja układu dopełniacza oraz nieprawidłowe mechanizmy naprawcze. Każdy z tych elementów stanowi potencjalny cel terapeutyczny w opracowywaniu nowych strategii leczenia AKI.

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Materiały źródłowe

#1 Acute Kidney Injury – StatPearls – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK441896/
Acute kidney injury (AKI), previously known as acute renal failure, denotes a sudden and often reversible reduction in kidney function, as measured by increased creatinine or decreased urine volume. […] The pathogenesis of AKI is etiology-driven. The common endpoint in acute tubular necrosis is a cellular insult secondary to ischemia or direct toxins, which results in effacement of the brush border, cell death, and decreased function of tubular cells. One intrarenal cause is intratubular obstruction such as by pigments such as myoglobin, crystals such as uric acid in tumor lysis syndrome, or immunoglobulin light chains, as seen in monoclonal gammopathy which can also lead to the same result. Other intrarenal mechanisms of injury are glomerulonephritis or acute interstitial nephritis, which can be due to immune-mediated injury of the vasculature, inflammatory responses, and immune complex deposition leading to glomerular and tubular damage. […] Postrenal pathophysiology is usually related to urinary reflux, causing decreased renal perfusion, tubular atrophy, and interstitial inflammation.
#1 Acute kidney injury pathophysiology – wikidoc
https://www.wikidoc.org/index.php/Acute_kidney_injury_pathophysiology
Acute kidney injury is defined as spontaneous deficit in kidney functions leading to urea retention and electrolyte imbalance. Etiologies of AKI can be divided based on pathophysiologic mechanisms into 3 broad categories: prerenal, intrinsic renal, and postrenal causes. Pre-renal AKI is most common and typically results from hypovolemia. Intrinsic renal is due to damage to renal paranchyma. Post-renal AKI is usually result of an obstruction, may be due to stones or strictures. […] Etiologies of AKI can be divided based on pathophysiologic mechanisms into 3 broad categories: prerenal, intrinsic renal, and postrenal causes. […] Prerenal AKI, known as prerenal azotemia, is by far the most common cause of AKI representing 30-50% of all cases. It is provoked by inadequate renal blood flow commonly due to decreased effective circulating blood flow. This causes a decrease in the intraglomerular hydrostatic pressure required to achieve proper glomerular filtration.
#1 Acute Kidney Injury: Medical Causes and Pathogenesis
https://pmc.ncbi.nlm.nih.gov/articles/PMC9821234/
Renal hypoperfusion can be a part of a generalized decrease in tissue perfusion or selective renal ischemia and plays a critical role in the pathogenesis of prerenal AKI. […] The pathophysiology of HRS is not fully understood, but the complex interaction between several different factors is implicated. […] Endothelial and epithelial cell injuries are main factors that contribute to the pathogenesis of ATN. […] The underlying mechanisms also include the release of cytokines, kidney inflammation, and tissue edema. […] The complement system can be directly or indirectly activated in patients with sepsis and contributes to the pathogenesis. […] Inappropriate complement activation contributes to the pathogenesis of AKI. […] Various mechanisms have been identified in experimental studies.
#1 Acute kidney injury pathophysiology – wikidoc
https://www.wikidoc.org/index.php/Acute_kidney_injury_pathophysiology
As such, the pathophysiology of prerenal azotemia entails a drop in renal plasma flow beyond the capacity of autoregulation, a blunted or inadequate renal compensation for an otherwise tolerable change in perfusion, or a combination of both. This eventually leads to ischemic renal injury particularly to the medulla which is maintained in hypoxic conditions at baseline. Causes of prerenal injury are summarized in the figure below. To note, as prerenal AKI progresses with further ischemia, it transforms into acute tubular necrosis (ATN) crossing into the realm of intrinsic AKI. […] Intrinsic renal AKI generally occurs due to renal parenchymal injury and may be classified according to the site of injury into: glomerular, tubular, interstitial, and vascular. […] The most common form of intrinsic renal AKI involves damage to the renal tubules. In this context, the most common etiologies are sepsis, nephrotoxins, and ischemia. Ischemic AKI is part of a disease continuum involving prerenal AKI and manifests in states of prolonged renal blood flow compromise or renal hypoperfusion with other pre-existing or concomitant renal insults.
#1 Pathophysiology of acute kidney injury | PPT
https://www.slideshare.net/slideshow/pathophysiology-of-acute-kidney-injury/54810091
More severe hypoperfusion may lead to ischemic injury of renal parenchyma and intrinsic renal AKI. Thus, prerenal AKI and intrinsic renal AKI due to ischemia are part of a spectrum of manifestations of renal hypoperfusion. […] Pathophysiology: Hypovolemia leads to glomerular hypoperfusion, but filtration rate are preserved during mild hypoperfusion through several compensatory mechanisms. During states of more severe hypoperfusion, these compensatory responses are overwhelmed and GFR falls, leading to prerenal AKI. […] The major and most commonly injured epithelial cell involved in AKI from ischemia, sepsis, or other nephrotoxins is the proximal tubular cell(S3 segment of PT in outer stripe of medulla) The S1 and S2 segments are most commonly involved in toxic nephropathy because of their high rates of endocytosis, which leads to increased cellular uptake of the toxin.
#1 Acute Kidney Injury: Medical Causes and Pathogenesis
https://www.mdpi.com/2077-0383/12/1/375
The pathophysiology of HRS is not fully understood, but the complex interaction between several different factors is implicated. […] The complement system can be directly or indirectly activated in patients with sepsis and contributes to the pathogenesis. […] The increase in biomarkers as NGAL and KIM-1 is associated with an increased risk of subsequent renal replacement therapy and/or mortality. […] The normal response of the kidney to decreased renal perfusion is to maximally concentrate the urine and reabsorb sodium to maintain or to increase intravascular volume and normalize renal perfusion. […] However, reduced RBF eventually leads to ischemia and cell death. […] The timely and accurate identification of AKI and a better understanding of the pathophysiological mechanisms that cause kidney dysfunction are essential.
#1 Pathophysiology of acute kidney injury | PPT
https://www.slideshare.net/slideshow/pathophysiology-of-acute-kidney-injury/54810091
The classical hallmark of ATN is the loss of the apical brush border of the proximal tubular cells. Patchy detachment and subsequent loss of tubular cells exposing areas of denuded tubular basement and focal areas of proximal tubular dilatation along with the presence of distal tubular casts. […] Epithelial cell structure and function are mediated in part by the actin cytoskeleton. In proximal tubule cells the actin cytoskeleton forms a terminal web layer just below the apical plasma membrane. The core mechanism of disruption is the depolymerization mediated by the actin-binding protein known as actin depolymerizing factor (ADF) or cofilin. […] Ischemic insult results in cellular ATP depletion, which in turn leads to a rapid disruption of the apical actin and disruption and redistribution of the cytoskeleton F-actin core, resulting in formation of membrane-bound extracellular vesicles or blebs.
#1 Pathophysiology of acute kidney injury | PPT
https://www.slideshare.net/slideshow/pathophysiology-of-acute-kidney-injury/54810091
Another important consequence of disruption of the actin cytoskeleton is the loss of tight junctions and adherens junctions. The actin present in the terminal web is linked to zonula occludens, and hence any disruption of the terminal web results in disruption of the tight junctions. […] Early ischemic injury causes opening of these tight junctions, which leads to increased paracellular permeability producing further backleak of the glomerular filtrate into the interstitium. […] The complex heat shock protein (hsp) system is induced to exceptionally high levels during stress conditions. Overexpression of hsp25 has been shown to be protective against actin-cytoskeleton disruption. […] Endothelial cells control vascular tone, regulation of blood flow to local tissue beds, modulation of coagulation and inflammation, and permeability. Both ischemia and sepsis have profound effects on the endothelium.
#1
https://journals.lww.com/mgmj/fulltext/2022/09040/pathophysiology_of_acute_kidney_injury_on_a.21.aspx
Acute Kidney Injury (AKI) is a clinical condition with various etiologies. […] The pathophysiology of various types of AKI is different. […] This review attempts to identify changes on a molecular level during different stages of the disease and further discussed understanding the pathophysiology of AKI to find important molecules involved in various metabolic pathways, various phases and types of AKI, and the effect of drugs on kidneys and cellular level changes. […] The mechanisms of tubular injury may be glomerular hypo perfusion, oxidative stress, inflammation, and immune dysregulation. […] The main site where AKI causes mutilation is the membrane enclosing the contents of the cells. […] The cholesterol composition of the lipid bilayer gets altered after AKI. […] Key proteins involved in the signaling pathway of necroptosis or inflammatory cell death are necrostatin-1, receptor-interacting protein kinase 3, and mixed lineage kinase domain-like protein.
#1 Mechanisms and therapeutic targets of ischemic acute kidney injury
https://www.krcp-ksn.org/journal/view.php?doi=10.23876/j.krcp.19.062
Mild (sublethal) injury induces loss of cell polarity, such as mislocalization of adhesion molecules/membrane proteins and disruption of cytoskeletal integrity, and cells could recover if the insult is interrupted, whereas more severe (lethal) injury induces irreversible renal tubular cell death by apoptosis or necrosis, resulting in renal dysfunction observed in AKI. […] Apoptosis is a programmed cell death characterized by energy-dependent biochemical mechanisms and morphologic changes, including shrinkage of the cell and nucleus, chromatin condensation, and deoxyribonucleic acid (DNA) fragmentation, followed by rapid engulfment of the cellular corpse by macrophages and neighboring viable epithelial cells. […] The ischemic insult induces severe and rapid ATP depletion, resulting in mitochondrial injury preferentially with subsequent breakdown of oxidative phosphorylation, further energy depletion, and massive formation of reactive oxidative species (ROS) during reperfusion, which mediates further cellular injury.
#1 Acute Tubular Necrosis (ATN): Practice Essentials, Pathophysiology, Etiology
https://emedicine.medscape.com/article/238064-overview
The mechanisms of injury described above may contribute to continued nephron dysfunction, but tubuloglomerular feedback also plays a role. Tubuloglomerular feedback in this setting leads to constriction of afferent arterioles by the macula densa cells, which detect an increased salt load in the distal tubules. The resulting decreased perfusion of the nephrons can perpetuate the kidney injury. […] The driving force of ATN is primarily tubular injury and hypoperfusion in peritubular capillaries. The combination of tubular injury and hypoperfusion could cause permanent nephron loss in those patients who cannot recover from ATN, eventually tissue fibrosis and CKD after acute injury. […] Further, at molecular levels, regulated cell death through tubular cell apoptosis, necrosis, and cell loss drive AKI development upon a renal insult. Apoptosis, necroptosis, ferroptosis, MPT-RN (mitochondrial permeability transition regulated necrosis), and possible pyroptosis are potential molecular mechanisms of AKI induced by ischemic-reperfusion injury, toxin, cytokine storm, and crystals.
#1 Role of leukocytes in the pathogenesis of acute kidney injury | Critical Care | Full Text
https://ccforum.biomedcentral.com/articles/10.1186/cc11228
Acute kidney injury (AKI) is a significant cause of morbidity and mortality in hospitalized patients, especially those who are critically ill. Numerous factors contribute to the development of AKI, including reductions in renal blood flow, actions of nephrotoxic drugs, cellular injury/death of proximal tubule epithelial cells, pro-inflammatory responses of renal endothelial cells, influx and activation of inflammatory leukocytes that further reduces renal blood flow through vascular congestion and promotes and extends injury to kidney parenchymal cells. The immune response in AKI involves cells of both the innate and adaptive immune systems. Studies in animal models of AKI have revealed that innate immune cells, such as neutrophils, macrophages, dendritic cells, natural killer (NK) cells and natural killer T (NKT) cells, and adaptive CD4+ T cells promote renal injury. Indeed, renal inflammation is a common feature of human AKI and detailed analyses of biopsy samples from patients with AKI demonstrated the presence of mononuclear leukocytes (some CD3+ T cells) and neutrophils. In contrast, CD4+FoxP3+ regulatory T cells (Tregs) can protect the kidney from ischemic and nephrotoxic injury in animal models. Understanding the immune mechanisms of renal injury and protection should yield new approaches to prevention and treatment of AKI.
#1 Role of leukocytes in the pathogenesis of acute kidney injury | Critical Care | Full Text
https://ccforum.biomedcentral.com/articles/10.1186/cc11228
Neutrophils clear invading pathogens by phagocytosis or by releasing toxic granules containing proteases and other enzymes and reactive oxygen species (ROS). For this reason, neutrophil degranulation can lead to damage of host cells in the inflamed tissue. In several mouse models of AKI (e.g., ischemia/reperfusion injury and cisplatin-induced kidney injury), neutrophil accumulation in the injured kidney is a consistent and early finding and depletion of neutrophils or prevention of neutrophil tracking to the kidney reduces kidney injury. In addition to releasing granules, neutrophils have been shown to produce the pro-inflammatory cytokines, interferon (IFN)- and interleukin (IL)-17, and the chemokine CXCL1, in the injured kidney. These findings demonstrate the involvement of neutrophils in the pathogenesis of kidney injury in the commonly used murine model of ischemia/reperfusion-induced AKI.
#1 Role of leukocytes in the pathogenesis of acute kidney injury | Critical Care | Full Text
https://ccforum.biomedcentral.com/articles/10.1186/cc11228
Macrophages are phagocytic cells that arise from monocytes in the blood. Macrophage numbers increase early in the injured kidney (within 1 hour of reperfusion in an ischemia/reperfusion model), and this infiltration is mediated by CCR2 and CX3CR1 signaling pathways. Depletion of macrophages, using liposomal clodronate, prior to kidney ischemia/reperfusion injury, reduced renal injury and adoptive transfer of macrophages reconstituted AKI. Although macrophage infiltration is observed in cisplatin-induced experimental AKI, blockade of macrophage trafficking to the kidney did not prevent renal injury. Analysis of post-ischemic kidney infiltrating macrophages by flow cytometry demonstrated that they are significant producers of many pro-inflammatory cytokines, including IL-6 and tumor necrosis factor (TNF)-.
#1 Role of leukocytes in the pathogenesis of acute kidney injury | Critical Care | Full Text
https://ccforum.biomedcentral.com/articles/10.1186/cc11228
During experimental AKI, the proximal tubule epithelial cells (TECs) upregulate the expression of an NK cell activating ligand, Rae-1, which promotes TEC killing by activating the NKG2D receptor on NK cells. The NK cells utilize perforins to kill the TECs in this model and their numbers in the kidney are elevated as early as 4 h after ischemic insult. […] Dendritic cells migrate to the renal draining lymph nodes after ischemia/reperfusion injury and induce T cell proliferation suggesting that kidney dendritic cells are vital to the adaptive immune response to ischemia/reperfusion injury. Dendritic cells are also important in the innate immune response through several mechanisms. These include releasing pro-inflammatory factors, interacting with NKT cells via the co-stimulatory molecule, CD40, and presenting glycolipid to NKT cells via the CD1d molecule.
#1 Role of leukocytes in the pathogenesis of acute kidney injury | Critical Care | Full Text
https://ccforum.biomedcentral.com/articles/10.1186/cc11228
T cell contribution to the pathogenesis of kidney ischemia/reperfusion injury has been established in different mouse models lacking certain types of lymphocytes. In mice which lack CD4 and CD8 T cells (nu/nu mice), kidney injury and dysfunction were significantly reduced compared to wild-type controls after ischemia/reperfusion injury and cisplatin induced injury. Reconstitution of nu/nu mice with CD4+ T cells alone but not with CD8+ T cells alone restored kidney injury after ischemia/reperfusion injury and mice lacking CD8 or CD4 T cells alone suffered less kidney dysfunction after cisplatin administration. […] Tregs make up an indispensible counter-balance to the pro-inflammatory cells of the immune system. The main mechanisms of suppression employed by Tregs include production of anti-inflammatory cytokines, such as IL-10 and transforming-growth factor (TGF)-, generation of extracellular adenosine, direct contact-mediated inhibition of dendritic cells through cell surface molecules such as lymphocyte activation gene (LAG)-3 and cytotoxic T-lymphocyte antigen (CTLA)-4 and several others. Based on the important contribution of the pro-inflammatory immune cells to AKI discussed above we hypothesized that Tregs would serve to protect the kidney from inflammation and injury.
#1 Molecular mechanisms and therapeutic interventions in acute kidney injury: a literature review | BMC Nephrology | Full Text
https://bmcnephrol.biomedcentral.com/articles/10.1186/s12882-025-04077-4
Diverse molecular mechanisms have been reported to contribute to the parenchymal damage of kidneys in AKI, including complement activation, oxidative stress, and inflammation. Delving into these molecular mechanisms underlying the pathological processes of AKI is an important approach to identify specific biomarkers and potential therapeutic targets. […] The oxidative stress processes of AKI primarily encompass ROS production, nitric oxide depletion, damage-associated molecular patterns (DAMPs) formation, toll-like receptors (TLRs) activation, autophagy, and microvascular dysfunction. […] Prolonged exposure to oxidative stress stimuli in kidney tissue results in an initial inflammatory phase, subsequently leading to the excessive production of fibrous tissue, which compromises organ function and may result in CKD.
#1 Molecular mechanisms and therapeutic interventions in acute kidney injury: a literature review | BMC Nephrology | Full Text
https://bmcnephrol.biomedcentral.com/articles/10.1186/s12882-025-04077-4
The MAPK kinase signaling pathway activated by ROS from oxidative stress promotes the activation of activator protein-1, which regulates the modulation of pro-inflammatory cytokines and chemokines. […] The induction of autophagy in proximal tubules during acute tubulointerstitial nephritis demonstrated that autophagy serves a nephroprotective function in AKI, nevertheless, excessive autophagy ultimately results in cellular demise. […] In AKI, renal interstitial cells generate significant quantities of inflammatory mediators, initiating sustained inflammatory responses that result in renal interstitial fibrosis and subsequently impair the recovery of kidney function.
#1 Acute Kidney Injury: Pathogenesis, Diagnosis, and Management | Abdominal Key
https://abdominalkey.com/acute-kidney-injury-pathogenesis-diagnosis-and-management/
Autophagy is a process that takes place in all eukaryotic cells that keeps cells alive under stressful conditions. […] Inhibition of autophagy using an ATG5 siRNA increases apoptosis during rewarming after cold storage in renal tubular epithelial cells. […] Together, these studies suggest that autophagy is a renoprotective mechanism that protects against apoptosis to enable cell survival. […] Potential mediators/mechanisms of AKI cause tubular injury, inflammation, or vascular injury. […] Ca2+ overload is characteristic of tissues with lethally injured cells, since the breakdown of the plasma membrane barrier to Ca2+ causes a large increase in cytosolic Ca2+. […] The administration of Ca2+ channel blockers reduces the intensity of renal vasoconstriction and provides better delivery of nutrients to renal tissues.
#1 Acute Kidney Injury: Pathogenesis, Diagnosis, and Management | Basicmedical Key
https://basicmedicalkey.com/acute-kidney-injury-pathogenesis-diagnosis-and-management/
Autophagy is a process that takes place in all eukaryotic cells that keeps cells alive under stressful conditions. […] Together, these studies suggest that autophagy is a renoprotective mechanism that protects against apoptosis to enable cell survival. […] The cytotoxicity of crystals of calcium oxalate, monosodium urate, calcium pyrophosphate dihydrate and cystine trigger caspase-independent necroptosis in five different cell types. […] These studies demonstrated that necroptosis is a major mechanism of proximal tubular cell death in AKI. […] The role of caspases and calpain in cisplatin-induced endothelial cell death was investigated. […] In summary, I/R injury is accompanied by dramatic changes in basal and reactive vascular function of the organ involved. […] The role of caspases and calpain in cisplatin-induced endothelial cell death was investigated. […] In AKI, impaired endothelial proliferation and mesenchymal transition contribute to vascular rarefaction and may contribute to the development of chronic kidney disease (CKD).
#1
https://journals.lww.com/mgmj/fulltext/2022/09040/pathophysiology_of_acute_kidney_injury_on_a.21.aspx
The important transcription factors that are responsible for the pathogenesis of AKI via the regulation of genes include Nuclear Factor Erythroid 2Related Factor 2 (Nrf2), the Activator Protein 1(AP-1) family, Nuclear factor kappa B (NF-B), hypoxia-inducible factors, and Specificity Protein 1 (Sp1). […] The transition from acute kidney injury to chronic kidney disease is due to epigenetic modifications importantly the microRNAs. […] The changes in actin composition changes in polarity of the cells, cell-cell interactions, and cell-matrix integrity which in turn affects the function of the tubules changing the glomerular filtration rate. […] The accumulation of unfolded proteins can cause ER stress during AKI. […] Mitochondrial pathology is common to all forms of AKI including renal ischemia, sepsis, and nephrotoxic injury.
#1 Acute Kidney Injury (AKI) – Genitourinary Disorders – Merck Manual Professional Edition
https://www.merckmanuals.com/professional/genitourinary-disorders/acute-kidney-injury/acute-kidney-injury-aki
Postrenal AKI (obstructive nephropathy) is due to various types of obstruction in the voiding and collecting parts of the urinary system. Obstruction can also occur on the microscopic level within the tubules when crystalline or proteinaceous material precipitates. Obstructed ultrafiltrate, in tubules or more distally, increases pressure in the urinary space of the glomerulus, reducing GFR. Obstruction also affects renal blood flow, initially increasing the flow and pressure in the glomerular capillary by reducing afferent arteriolar resistance. However, within 3 to 4 hours, the renal blood flow is reduced, and by 24 hours, it has fallen to 50% of normal because of increased resistance of the renal vasculature. […] To produce significant AKI, obstruction at the level of the ureter requires involvement of both ureters unless the patient has only a single functioning kidney.
#1 Pathophysiology of acute kidney injury | PPT
https://www.slideshare.net/slideshow/pathophysiology-of-acute-kidney-injury/54810091
Nephrotoxins associated AKI High blood perfusion, medullary concentrating property. Risk factors- Older age, CKD, prerenal azotemia, hypoalbuminemia. […] Acute Tubular Necrosis Ischaemic ATN Toxic ATN. […] The normally unidirectional flow of urine is acutely blocked either partially or totally, leading to increased retrograde hydrostatic pressure and interference with glomerular filtration. […] Hemodynamic alterations are triggered by an abrupt increase in intratubular pressure. Initial period of hyperaemia from afferent arteriolar dilation- followed by intrarenal vasoconstriction from the generation of angiotensin II, thromboxane A2, and vasopressin, and a reduction in NO production- decreased GFR.
#1
https://journals.lww.com/cjasn/fulltext/2022/07000/low_flow_acute_kidney_injury__the_pathophysiology.16.aspx
The pathophysiology of abdominal compartment syndrome includes all intra-abdominal organs, and its consequences reach outside the abdomen to affect cardiac, pulmonary, and central nervous system function. Many of these extra-abdominal effects result in part from the pathophysiology of AKI during abdominal compartment syndrome. Increasing intra-abdominal hypertension reduces cardiac function in several ways. […] Therefore, the pathophysiology of AKI from abdominal compartment syndrome is multidimensional, primarily involving increased renal venous resistance and a reduction in cardiac output, both leading to reduced kidney perfusion and a prerenal state. […] Obstructive uropathy is a frequent cause of AKI, accounting for up to 10% of all AKI cases in the general population and an even higher percentage in the elderly. The degree of injury resulting from obstructive uropathy depends on the extent of the obstruction and its duration. […] The central role of angiotensin II can be demonstrated by the ability of angiotensin-converting enzyme and other renin-angiotensin system inhibitors to minimize the decline in renal plasma flow and GFR. The increased level of angiotensin II also stimulates secretion of TNF-, resulting in fibrosis and tubular cell apoptosis.
#1 Acute Tubular Necrosis (ATN): Practice Essentials, Pathophysiology, Etiology
https://emedicine.medscape.com/article/238064-overview
Acute tubular necrosis (ATN) is the most common cause of acute kidney injury (AKI) in the renal category (that is, AKI in which the pathology lies within the kidney itself). The term ATN is actually a misnomer, as there is minimal cell necrosis and the damage is not limited to tubules. […] ATN follows a well-defined four-part sequence of initiation, extension, maintenance, and recovery, as follows: The initiation phase is characterized by an acute decrease in glomerular filtration rate (GFR), with a corresponding sudden increase in serum creatinine (Cr) and blood urea nitrogen (BUN) concentrations. The extension phase is characterized by ongoing hypoxia leading to sustained tissue ischemia, which triggers an inflammatory response. Given its limited blood supply, the corticomedullary junction of the kidney is most susceptible to a renal insult. A continuous release of cytokines and chemokines from impaired corticomedullary junction enhances the inflammatory cascade and this ongoing activation of the inflammatory cascade results in the drop of GFR. The tubule cell damage and cell death that characterize ATN usually result from an acute ischemic or toxic event. Nephrotoxic mechanisms of ATN include direct drug toxicity, intrarenal vasoconstriction, and intratubular obstruction. Whether the cause is ischemia or nephrotoxicity, most of the pathophysiologic features of ATN are the same.
#1 Acute Tubular Necrosis (ATN): Practice Essentials, Pathophysiology, Etiology
https://emedicine.medscape.com/article/238064-overview
The recovery phase of ATN is characterized by regeneration of tubular epithelial cells. During recovery, abnormal diuresis sometimes occurs, causing salt and water loss and volume depletion. The mechanism of the diuresis is not entirely understood. Still, it may, in part, be due to the delayed recovery of tubular cell function in the setting of increased glomerular filtration. In addition, continued use of diuretics (often administered during initiation and maintenance phases) may also add to the problem.
#1 Acute Kidney Injury (AKI): Practice Essentials, Background, Pathophysiology
https://emedicine.medscape.com/article/243492-overview
During this period of depressed RBF, the kidneys are particularly vulnerable to additional insults; this is when iatrogenic kidney injury is most common. […] Intrarenal vasoconstriction is the dominant mechanism for reduced GFR in patients with ATN. […] The importance of this mechanism is highlighted by the improvement in kidney function that follows the relief of such intratubular obstruction. […] A physiologic hallmark of ATN is a failure to dilute or concentrate urine (isosthenuria) maximally. […] Recovery from AKI is first dependent upon the restoration of RBF. Early RBF normalization predicts a better prognosis for recovery of kidney function. […] Once RBF is restored, the remaining functional nephrons increase their filtration and eventually undergo hypertrophy. GFR recovery depends on the size of this remnant nephron pool. […] A vicious cycle ensues: continued nephron loss causes more hyperfiltration until complete kidney failure results. This has been termed the hyperfiltration theory of kidney failure and explains the scenario in which progressive failure is frequently observed after apparent recovery from AKI.
#1 Acute Kidney Injury (AKI) – Genitourinary Disorders – Merck Manual Professional Edition
https://www.merckmanuals.com/professional/genitourinary-disorders/acute-kidney-injury/acute-kidney-injury-aki
Acute kidney injury is a rapid decrease in renal function over days to weeks, causing an accumulation of nitrogenous products in the blood (azotemia) with or without reduction in amount of urine output. […] In all cases of acute kidney injury (AKI), creatinine and urea build up in the blood over several days, and fluid and electrolyte disorders develop. The most serious of these disorders are hyperkalemia and fluid overload (possibly causing pulmonary edema). Phosphate retention leads to hyperphosphatemia. Hypocalcemia is thought to occur because the impaired kidney no longer produces calcitriol (reducing calcium absorption from the gastrointestinal tract) and because hyperphosphatemia causes calcium phosphate precipitation in the tissues. Acidosis develops because hydrogen ions cannot be excreted.
#1 Acute kidney injury | Nature Reviews Disease Primers
https://www.nature.com/articles/s41572-021-00284-z
Acute kidney injury (AKI) is defined by a sudden loss of excretory kidney function. […] The large spectrum of AKI implies diverse pathophysiological mechanisms. […] AKI management in critical care settings is challenging, including appropriate volume control, nephrotoxic drug management, and the timing and type of kidney support. […] Long-term consequences of AKI and AKD include CKD and cardiovascular morbidity. […] Thus, prevention and early detection of AKI are essential. […] The pathophysiology of ischemic acute kidney injury. […] Study demonstrating the occurrence of regulated necrosis and synchronized death of upon AKI, with consequent triggering of a detrimental immune response. […] Mechanisms and mediators of lung injury after acute kidney injury. […] The substantial loss of nephrons in healthy human kidneys with aging. […] The contrasting characteristics of acute kidney injury in developed and developing countries.
#1 :: YMJ :: Yonsei Medical Journal
https://eymj.org/DOIx.php?id=10.3349/ymj.2023.0306
Therefore, the importance of defining the concept of acute kidney disease (AKD) as a transition stage between AKI and CKD, or as a separate disease entity, is gaining attention. […] The KDIGO definition of CKD is based on both functional and structural abnormalities, whereas AKI is defined solely based on serum creatinine levels and urine output without considering the duration of AKI, recovery, or markers of kidney damage. […] AKD is currently defined as kidney functional or structural impairment lasting for a period of less than 3 months. […] AKD encompasses a spectrum of kidney conditions, ranging from mild and self-limiting to severe and persistent, and it can also develop gradually, unlike the rapid onset typically seen in AKI. […] While our understanding of the mechanisms driving AKI-to-CKD transition in humans remains incomplete, decades of experimental data have indicated that such transition may stem from an inappropriate cellular reaction or incorrect healing process, commonly referred to as a maladaptive repair process.
#1 :: YMJ :: Yonsei Medical Journal
https://eymj.org/DOIx.php?id=10.3349/ymj.2023.0306
Maladaptive repair can occur in tubular, vascular, and interstitial compartments after AKI, leading to an increased risk of interstitial fibrosis. […] Dysregulated and inefficient repair of kidney tubules, known as maladaptive repair, is associated with persistent inflammation, ECM deposition, and the development of a pro-fibrotic and senescent state in TECs. […] Overall, while favorable cell cycle events can contribute to tissue repair, cell cycle arrest plays a crucial role in determining the progression of injury. […] These findings suggest that inhibiting the excessive activity of PCAF can alleviate kidney fibrosis by restoring imbalanced inflammatory signaling and antioxidant response by modulating NF-B and Nrf2. […] The so-called capillary rarefaction phenomenon occurs during the early stages of AKI.
#1 From Acute to Chronic: Unraveling the Pathophysiological Mechanisms of the Progression from Acute Kidney Injury to Acute Kidney Disease to Chronic Kidney Disease
https://www.mdpi.com/1422-0067/25/3/1755
Prolonged and overactivation of RAAS after AKI can lead to CKD progression through various mechanisms. […] The transformation of various local stromal cells in the kidney to myofibroblasts plays important roles in the progressive kidney fibrosis, including effects on resident fibroblasts and pericytes/perivascular fibroblasts, EMT, endothelial to mesenchymal transition (EndMT), and macrophage (bone-marrow-derived) to myofibroblast transition (MMT). […] Maladaptive repair after renal tubule injury inducing progressive renal fibrosis and destruction of the normal architecture of the kidney is thought to be the key pathological mechanism contributing to CKD. […] The Wnt/Î²-catenin, TGF-Î²1/SMAD, and Hippo signaling pathways are critical in this transition, promoting fibrosis and affecting renal function. […] Mitochondrial dysfunction, cellular senescence, hypoxia, and the RAAS are also key contributors to AKI progression and CKD transition, with the RAAS in particular playing a role in renal remodeling and fibrosis.
#2 Acute Kidney Injury: Medical Causes and Pathogenesis
https://pmc.ncbi.nlm.nih.gov/articles/PMC9821234/
Acute kidney injury (AKI) is a common clinical syndrome characterized by a sudden decline in or loss of kidney function. […] The timely and accurate identification of AKI and a better understanding of the pathophysiological mechanisms that cause kidney dysfunction are essential. […] The etiology of AKI is conceptually classified into three general categories: prerenal, intrarenal, and postrenal. […] AKI may develop more commonly after exposure to certain insults or in susceptible groups and many common pathophysiological factors play into the pathogenesis of AKI. […] The main focus of this review is to summarize the various medical causes of AKI. Furthermore, we summarize the most recent research updates in the pathogenesis of AKI. […] Prerenal disease and acute tubular necrosis are two major causes of AKI in hospitalized patients.
#2 Acute Kidney Injury: Medical Causes and Pathogenesis
https://www.mdpi.com/2077-0383/12/1/375
The pathophysiology of HRS is not fully understood, but the complex interaction between several different factors is implicated. […] The complement system can be directly or indirectly activated in patients with sepsis and contributes to the pathogenesis. […] The increase in biomarkers as NGAL and KIM-1 is associated with an increased risk of subsequent renal replacement therapy and/or mortality. […] The normal response of the kidney to decreased renal perfusion is to maximally concentrate the urine and reabsorb sodium to maintain or to increase intravascular volume and normalize renal perfusion. […] However, reduced RBF eventually leads to ischemia and cell death. […] The timely and accurate identification of AKI and a better understanding of the pathophysiological mechanisms that cause kidney dysfunction are essential.
#2 Acute kidney injury pathophysiology – wikidoc
https://www.wikidoc.org/index.php/Acute_kidney_injury_pathophysiology
As such, the pathophysiology of prerenal azotemia entails a drop in renal plasma flow beyond the capacity of autoregulation, a blunted or inadequate renal compensation for an otherwise tolerable change in perfusion, or a combination of both. This eventually leads to ischemic renal injury particularly to the medulla which is maintained in hypoxic conditions at baseline. Causes of prerenal injury are summarized in the figure below. To note, as prerenal AKI progresses with further ischemia, it transforms into acute tubular necrosis (ATN) crossing into the realm of intrinsic AKI. […] Intrinsic renal AKI generally occurs due to renal parenchymal injury and may be classified according to the site of injury into: glomerular, tubular, interstitial, and vascular. […] The most common form of intrinsic renal AKI involves damage to the renal tubules. In this context, the most common etiologies are sepsis, nephrotoxins, and ischemia. Ischemic AKI is part of a disease continuum involving prerenal AKI and manifests in states of prolonged renal blood flow compromise or renal hypoperfusion with other pre-existing or concomitant renal insults.
#2 Pathophysiology of acute kidney injury | PPT
https://www.slideshare.net/slideshow/pathophysiology-of-acute-kidney-injury/54810091
The classical hallmark of ATN is the loss of the apical brush border of the proximal tubular cells. Patchy detachment and subsequent loss of tubular cells exposing areas of denuded tubular basement and focal areas of proximal tubular dilatation along with the presence of distal tubular casts. […] Epithelial cell structure and function are mediated in part by the actin cytoskeleton. In proximal tubule cells the actin cytoskeleton forms a terminal web layer just below the apical plasma membrane. The core mechanism of disruption is the depolymerization mediated by the actin-binding protein known as actin depolymerizing factor (ADF) or cofilin. […] Ischemic insult results in cellular ATP depletion, which in turn leads to a rapid disruption of the apical actin and disruption and redistribution of the cytoskeleton F-actin core, resulting in formation of membrane-bound extracellular vesicles or blebs.
#2 Pathophysiology of acute kidney injury | PPT
https://www.slideshare.net/slideshow/pathophysiology-of-acute-kidney-injury/54810091
Another important consequence of disruption of the actin cytoskeleton is the loss of tight junctions and adherens junctions. The actin present in the terminal web is linked to zonula occludens, and hence any disruption of the terminal web results in disruption of the tight junctions. […] Early ischemic injury causes opening of these tight junctions, which leads to increased paracellular permeability producing further backleak of the glomerular filtrate into the interstitium. […] The complex heat shock protein (hsp) system is induced to exceptionally high levels during stress conditions. Overexpression of hsp25 has been shown to be protective against actin-cytoskeleton disruption. […] Endothelial cells control vascular tone, regulation of blood flow to local tissue beds, modulation of coagulation and inflammation, and permeability. Both ischemia and sepsis have profound effects on the endothelium.
#2 Acute Kidney Injury: Pathogenesis, Diagnosis, and Management | Abdominal Key
https://abdominalkey.com/acute-kidney-injury-pathogenesis-diagnosis-and-management/
Acute kidney injury (AKI) is defined as a sudden decrease in the glomerular filtration rate (GFR) occurring over a period of hours to days. […] The nature of proximal tubular injury in ischemic AKI includes reversible sublethal dysfunction (loss of polarity, swelling, loss of the apical brush border), lethal injury (necrosis necroptosis and apoptosis) and autophagy, a normal physiologic process that tries to rescue the destruction of cells in the body. […] Proximal tubular cell death due to ischemic AKI in vivo in rodents and hypoxia in vitro results predominantly in necrosis, hence the term acute tubular necrosis, or ATN. […] The loss of polarity is also associated with redistribution of integrins. […] Necroptosis is a form of programmed or regulated necrosis or inflammatory cell death.
#2 Role of leukocytes in the pathogenesis of acute kidney injury | Critical Care | Full Text
https://ccforum.biomedcentral.com/articles/10.1186/cc11228
Acute kidney injury (AKI) is a significant cause of morbidity and mortality in hospitalized patients, especially those who are critically ill. Numerous factors contribute to the development of AKI, including reductions in renal blood flow, actions of nephrotoxic drugs, cellular injury/death of proximal tubule epithelial cells, pro-inflammatory responses of renal endothelial cells, influx and activation of inflammatory leukocytes that further reduces renal blood flow through vascular congestion and promotes and extends injury to kidney parenchymal cells. The immune response in AKI involves cells of both the innate and adaptive immune systems. Studies in animal models of AKI have revealed that innate immune cells, such as neutrophils, macrophages, dendritic cells, natural killer (NK) cells and natural killer T (NKT) cells, and adaptive CD4+ T cells promote renal injury. Indeed, renal inflammation is a common feature of human AKI and detailed analyses of biopsy samples from patients with AKI demonstrated the presence of mononuclear leukocytes (some CD3+ T cells) and neutrophils. In contrast, CD4+FoxP3+ regulatory T cells (Tregs) can protect the kidney from ischemic and nephrotoxic injury in animal models. Understanding the immune mechanisms of renal injury and protection should yield new approaches to prevention and treatment of AKI.
#2 Role of leukocytes in the pathogenesis of acute kidney injury | Critical Care | Full Text
https://ccforum.biomedcentral.com/articles/10.1186/cc11228
Neutrophils clear invading pathogens by phagocytosis or by releasing toxic granules containing proteases and other enzymes and reactive oxygen species (ROS). For this reason, neutrophil degranulation can lead to damage of host cells in the inflamed tissue. In several mouse models of AKI (e.g., ischemia/reperfusion injury and cisplatin-induced kidney injury), neutrophil accumulation in the injured kidney is a consistent and early finding and depletion of neutrophils or prevention of neutrophil tracking to the kidney reduces kidney injury. In addition to releasing granules, neutrophils have been shown to produce the pro-inflammatory cytokines, interferon (IFN)- and interleukin (IL)-17, and the chemokine CXCL1, in the injured kidney. These findings demonstrate the involvement of neutrophils in the pathogenesis of kidney injury in the commonly used murine model of ischemia/reperfusion-induced AKI.
#2 Role of leukocytes in the pathogenesis of acute kidney injury | Critical Care | Full Text
https://ccforum.biomedcentral.com/articles/10.1186/cc11228
Macrophages are phagocytic cells that arise from monocytes in the blood. Macrophage numbers increase early in the injured kidney (within 1 hour of reperfusion in an ischemia/reperfusion model), and this infiltration is mediated by CCR2 and CX3CR1 signaling pathways. Depletion of macrophages, using liposomal clodronate, prior to kidney ischemia/reperfusion injury, reduced renal injury and adoptive transfer of macrophages reconstituted AKI. Although macrophage infiltration is observed in cisplatin-induced experimental AKI, blockade of macrophage trafficking to the kidney did not prevent renal injury. Analysis of post-ischemic kidney infiltrating macrophages by flow cytometry demonstrated that they are significant producers of many pro-inflammatory cytokines, including IL-6 and tumor necrosis factor (TNF)-.
#2 Role of leukocytes in the pathogenesis of acute kidney injury | Critical Care | Full Text
https://ccforum.biomedcentral.com/articles/10.1186/cc11228
During experimental AKI, the proximal tubule epithelial cells (TECs) upregulate the expression of an NK cell activating ligand, Rae-1, which promotes TEC killing by activating the NKG2D receptor on NK cells. The NK cells utilize perforins to kill the TECs in this model and their numbers in the kidney are elevated as early as 4 h after ischemic insult. […] Dendritic cells migrate to the renal draining lymph nodes after ischemia/reperfusion injury and induce T cell proliferation suggesting that kidney dendritic cells are vital to the adaptive immune response to ischemia/reperfusion injury. Dendritic cells are also important in the innate immune response through several mechanisms. These include releasing pro-inflammatory factors, interacting with NKT cells via the co-stimulatory molecule, CD40, and presenting glycolipid to NKT cells via the CD1d molecule.
#2 Role of leukocytes in the pathogenesis of acute kidney injury | Critical Care | Full Text
https://ccforum.biomedcentral.com/articles/10.1186/cc11228
T cell contribution to the pathogenesis of kidney ischemia/reperfusion injury has been established in different mouse models lacking certain types of lymphocytes. In mice which lack CD4 and CD8 T cells (nu/nu mice), kidney injury and dysfunction were significantly reduced compared to wild-type controls after ischemia/reperfusion injury and cisplatin induced injury. Reconstitution of nu/nu mice with CD4+ T cells alone but not with CD8+ T cells alone restored kidney injury after ischemia/reperfusion injury and mice lacking CD8 or CD4 T cells alone suffered less kidney dysfunction after cisplatin administration. […] Tregs make up an indispensible counter-balance to the pro-inflammatory cells of the immune system. The main mechanisms of suppression employed by Tregs include production of anti-inflammatory cytokines, such as IL-10 and transforming-growth factor (TGF)-, generation of extracellular adenosine, direct contact-mediated inhibition of dendritic cells through cell surface molecules such as lymphocyte activation gene (LAG)-3 and cytotoxic T-lymphocyte antigen (CTLA)-4 and several others. Based on the important contribution of the pro-inflammatory immune cells to AKI discussed above we hypothesized that Tregs would serve to protect the kidney from inflammation and injury.
#2 Molecular mechanisms and therapeutic interventions in acute kidney injury: a literature review | BMC Nephrology | Full Text
https://bmcnephrol.biomedcentral.com/articles/10.1186/s12882-025-04077-4
Diverse molecular mechanisms have been reported to contribute to the parenchymal damage of kidneys in AKI, including complement activation, oxidative stress, and inflammation. Delving into these molecular mechanisms underlying the pathological processes of AKI is an important approach to identify specific biomarkers and potential therapeutic targets. […] The oxidative stress processes of AKI primarily encompass ROS production, nitric oxide depletion, damage-associated molecular patterns (DAMPs) formation, toll-like receptors (TLRs) activation, autophagy, and microvascular dysfunction. […] Prolonged exposure to oxidative stress stimuli in kidney tissue results in an initial inflammatory phase, subsequently leading to the excessive production of fibrous tissue, which compromises organ function and may result in CKD.
#2 Molecular mechanisms and therapeutic interventions in acute kidney injury: a literature review | BMC Nephrology | Full Text
https://bmcnephrol.biomedcentral.com/articles/10.1186/s12882-025-04077-4
The MAPK kinase signaling pathway activated by ROS from oxidative stress promotes the activation of activator protein-1, which regulates the modulation of pro-inflammatory cytokines and chemokines. […] The induction of autophagy in proximal tubules during acute tubulointerstitial nephritis demonstrated that autophagy serves a nephroprotective function in AKI, nevertheless, excessive autophagy ultimately results in cellular demise. […] In AKI, renal interstitial cells generate significant quantities of inflammatory mediators, initiating sustained inflammatory responses that result in renal interstitial fibrosis and subsequently impair the recovery of kidney function.
#2 Acute Kidney Injury: Pathogenesis, Diagnosis, and Management | Abdominal Key
https://abdominalkey.com/acute-kidney-injury-pathogenesis-diagnosis-and-management/
Autophagy is a process that takes place in all eukaryotic cells that keeps cells alive under stressful conditions. […] Inhibition of autophagy using an ATG5 siRNA increases apoptosis during rewarming after cold storage in renal tubular epithelial cells. […] Together, these studies suggest that autophagy is a renoprotective mechanism that protects against apoptosis to enable cell survival. […] Potential mediators/mechanisms of AKI cause tubular injury, inflammation, or vascular injury. […] Ca2+ overload is characteristic of tissues with lethally injured cells, since the breakdown of the plasma membrane barrier to Ca2+ causes a large increase in cytosolic Ca2+. […] The administration of Ca2+ channel blockers reduces the intensity of renal vasoconstriction and provides better delivery of nutrients to renal tissues.
#2 Acute Kidney Injury: Pathogenesis, Diagnosis, and Management | Basicmedical Key
https://basicmedicalkey.com/acute-kidney-injury-pathogenesis-diagnosis-and-management/
Autophagy is a process that takes place in all eukaryotic cells that keeps cells alive under stressful conditions. […] Together, these studies suggest that autophagy is a renoprotective mechanism that protects against apoptosis to enable cell survival. […] The cytotoxicity of crystals of calcium oxalate, monosodium urate, calcium pyrophosphate dihydrate and cystine trigger caspase-independent necroptosis in five different cell types. […] These studies demonstrated that necroptosis is a major mechanism of proximal tubular cell death in AKI. […] The role of caspases and calpain in cisplatin-induced endothelial cell death was investigated. […] In summary, I/R injury is accompanied by dramatic changes in basal and reactive vascular function of the organ involved. […] The role of caspases and calpain in cisplatin-induced endothelial cell death was investigated. […] In AKI, impaired endothelial proliferation and mesenchymal transition contribute to vascular rarefaction and may contribute to the development of chronic kidney disease (CKD).
#2 Acute Kidney Injury (AKI) – Genitourinary Disorders – Merck Manual Professional Edition
https://www.merckmanuals.com/professional/genitourinary-disorders/acute-kidney-injury/acute-kidney-injury-aki
Postrenal AKI (obstructive nephropathy) is due to various types of obstruction in the voiding and collecting parts of the urinary system. Obstruction can also occur on the microscopic level within the tubules when crystalline or proteinaceous material precipitates. Obstructed ultrafiltrate, in tubules or more distally, increases pressure in the urinary space of the glomerulus, reducing GFR. Obstruction also affects renal blood flow, initially increasing the flow and pressure in the glomerular capillary by reducing afferent arteriolar resistance. However, within 3 to 4 hours, the renal blood flow is reduced, and by 24 hours, it has fallen to 50% of normal because of increased resistance of the renal vasculature. […] To produce significant AKI, obstruction at the level of the ureter requires involvement of both ureters unless the patient has only a single functioning kidney.
#2 Acute Tubular Necrosis (ATN): Practice Essentials, Pathophysiology, Etiology
https://emedicine.medscape.com/article/238064-overview
Acute tubular necrosis (ATN) is the most common cause of acute kidney injury (AKI) in the renal category (that is, AKI in which the pathology lies within the kidney itself). The term ATN is actually a misnomer, as there is minimal cell necrosis and the damage is not limited to tubules. […] ATN follows a well-defined four-part sequence of initiation, extension, maintenance, and recovery, as follows: The initiation phase is characterized by an acute decrease in glomerular filtration rate (GFR), with a corresponding sudden increase in serum creatinine (Cr) and blood urea nitrogen (BUN) concentrations. The extension phase is characterized by ongoing hypoxia leading to sustained tissue ischemia, which triggers an inflammatory response. Given its limited blood supply, the corticomedullary junction of the kidney is most susceptible to a renal insult. A continuous release of cytokines and chemokines from impaired corticomedullary junction enhances the inflammatory cascade and this ongoing activation of the inflammatory cascade results in the drop of GFR. The tubule cell damage and cell death that characterize ATN usually result from an acute ischemic or toxic event. Nephrotoxic mechanisms of ATN include direct drug toxicity, intrarenal vasoconstriction, and intratubular obstruction. Whether the cause is ischemia or nephrotoxicity, most of the pathophysiologic features of ATN are the same.
#2 Acute Kidney Injury (AKI): Practice Essentials, Background, Pathophysiology
https://emedicine.medscape.com/article/243492-overview
During this period of depressed RBF, the kidneys are particularly vulnerable to additional insults; this is when iatrogenic kidney injury is most common. […] Intrarenal vasoconstriction is the dominant mechanism for reduced GFR in patients with ATN. […] The importance of this mechanism is highlighted by the improvement in kidney function that follows the relief of such intratubular obstruction. […] A physiologic hallmark of ATN is a failure to dilute or concentrate urine (isosthenuria) maximally. […] Recovery from AKI is first dependent upon the restoration of RBF. Early RBF normalization predicts a better prognosis for recovery of kidney function. […] Once RBF is restored, the remaining functional nephrons increase their filtration and eventually undergo hypertrophy. GFR recovery depends on the size of this remnant nephron pool. […] A vicious cycle ensues: continued nephron loss causes more hyperfiltration until complete kidney failure results. This has been termed the hyperfiltration theory of kidney failure and explains the scenario in which progressive failure is frequently observed after apparent recovery from AKI.
#2 Acute Kidney Injury (AKI) – Genitourinary Disorders – Merck Manual Professional Edition
https://www.merckmanuals.com/professional/genitourinary-disorders/acute-kidney-injury/acute-kidney-injury-aki
Acute kidney injury is a rapid decrease in renal function over days to weeks, causing an accumulation of nitrogenous products in the blood (azotemia) with or without reduction in amount of urine output. […] In all cases of acute kidney injury (AKI), creatinine and urea build up in the blood over several days, and fluid and electrolyte disorders develop. The most serious of these disorders are hyperkalemia and fluid overload (possibly causing pulmonary edema). Phosphate retention leads to hyperphosphatemia. Hypocalcemia is thought to occur because the impaired kidney no longer produces calcitriol (reducing calcium absorption from the gastrointestinal tract) and because hyperphosphatemia causes calcium phosphate precipitation in the tissues. Acidosis develops because hydrogen ions cannot be excreted.
#2 :: YMJ :: Yonsei Medical Journal
https://eymj.org/DOIx.php?id=10.3349/ymj.2023.0306
Maladaptive repair can occur in tubular, vascular, and interstitial compartments after AKI, leading to an increased risk of interstitial fibrosis. […] Dysregulated and inefficient repair of kidney tubules, known as maladaptive repair, is associated with persistent inflammation, ECM deposition, and the development of a pro-fibrotic and senescent state in TECs. […] Overall, while favorable cell cycle events can contribute to tissue repair, cell cycle arrest plays a crucial role in determining the progression of injury. […] These findings suggest that inhibiting the excessive activity of PCAF can alleviate kidney fibrosis by restoring imbalanced inflammatory signaling and antioxidant response by modulating NF-B and Nrf2. […] The so-called capillary rarefaction phenomenon occurs during the early stages of AKI.
#2 From Acute to Chronic: Unraveling the Pathophysiological Mechanisms of the Progression from Acute Kidney Injury to Acute Kidney Disease to Chronic Kidney Disease
https://www.mdpi.com/1422-0067/25/3/1755
Prolonged and overactivation of RAAS after AKI can lead to CKD progression through various mechanisms. […] The transformation of various local stromal cells in the kidney to myofibroblasts plays important roles in the progressive kidney fibrosis, including effects on resident fibroblasts and pericytes/perivascular fibroblasts, EMT, endothelial to mesenchymal transition (EndMT), and macrophage (bone-marrow-derived) to myofibroblast transition (MMT). […] Maladaptive repair after renal tubule injury inducing progressive renal fibrosis and destruction of the normal architecture of the kidney is thought to be the key pathological mechanism contributing to CKD. […] The Wnt/Î²-catenin, TGF-Î²1/SMAD, and Hippo signaling pathways are critical in this transition, promoting fibrosis and affecting renal function. […] Mitochondrial dysfunction, cellular senescence, hypoxia, and the RAAS are also key contributors to AKI progression and CKD transition, with the RAAS in particular playing a role in renal remodeling and fibrosis.
#3 Acute Kidney Injury: Medical Causes and Pathogenesis
https://www.mdpi.com/2077-0383/12/1/375
Acute kidney injury (AKI) is a common clinical syndrome characterized by a sudden decline in or loss of kidney function. […] The etiology of AKI is conceptually classified into three general categories: prerenal, intrarenal, and postrenal. […] AKI may develop more commonly after exposure to certain insults or in susceptible groups and many common pathophysiological factors play into the pathogenesis of AKI. […] The main focus of this review is to summarize the various medical causes of AKI. Furthermore, we summarize the most recent research updates in the pathogenesis of AKI. […] Acute tubular necrosis (ATN) is the most common cause of intrarenal AKI in hospitalized patients. Renal ischemia, sepsis, and nephrotoxins are major causes of ATN. […] Endothelial and epithelial cell injuries are main factors that contribute to the pathogenesis of ATN.
#3 Acute Kidney Injury: Medical Causes and Pathogenesis
https://pmc.ncbi.nlm.nih.gov/articles/PMC9821234/
Renal hypoperfusion can be a part of a generalized decrease in tissue perfusion or selective renal ischemia and plays a critical role in the pathogenesis of prerenal AKI. […] The pathophysiology of HRS is not fully understood, but the complex interaction between several different factors is implicated. […] Endothelial and epithelial cell injuries are main factors that contribute to the pathogenesis of ATN. […] The underlying mechanisms also include the release of cytokines, kidney inflammation, and tissue edema. […] The complement system can be directly or indirectly activated in patients with sepsis and contributes to the pathogenesis. […] Inappropriate complement activation contributes to the pathogenesis of AKI. […] Various mechanisms have been identified in experimental studies.
#3 Acute Kidney Injury: Medical Causes and Pathogenesis
https://www.mdpi.com/2077-0383/12/1/375
The pathophysiology of HRS is not fully understood, but the complex interaction between several different factors is implicated. […] The complement system can be directly or indirectly activated in patients with sepsis and contributes to the pathogenesis. […] The increase in biomarkers as NGAL and KIM-1 is associated with an increased risk of subsequent renal replacement therapy and/or mortality. […] The normal response of the kidney to decreased renal perfusion is to maximally concentrate the urine and reabsorb sodium to maintain or to increase intravascular volume and normalize renal perfusion. […] However, reduced RBF eventually leads to ischemia and cell death. […] The timely and accurate identification of AKI and a better understanding of the pathophysiological mechanisms that cause kidney dysfunction are essential.
#3 Pathophysiology of acute kidney injury | PPT
https://www.slideshare.net/slideshow/pathophysiology-of-acute-kidney-injury/54810091
The classical hallmark of ATN is the loss of the apical brush border of the proximal tubular cells. Patchy detachment and subsequent loss of tubular cells exposing areas of denuded tubular basement and focal areas of proximal tubular dilatation along with the presence of distal tubular casts. […] Epithelial cell structure and function are mediated in part by the actin cytoskeleton. In proximal tubule cells the actin cytoskeleton forms a terminal web layer just below the apical plasma membrane. The core mechanism of disruption is the depolymerization mediated by the actin-binding protein known as actin depolymerizing factor (ADF) or cofilin. […] Ischemic insult results in cellular ATP depletion, which in turn leads to a rapid disruption of the apical actin and disruption and redistribution of the cytoskeleton F-actin core, resulting in formation of membrane-bound extracellular vesicles or blebs.
#3 Role of leukocytes in the pathogenesis of acute kidney injury | Critical Care | Full Text
https://ccforum.biomedcentral.com/articles/10.1186/cc11228
T cell contribution to the pathogenesis of kidney ischemia/reperfusion injury has been established in different mouse models lacking certain types of lymphocytes. In mice which lack CD4 and CD8 T cells (nu/nu mice), kidney injury and dysfunction were significantly reduced compared to wild-type controls after ischemia/reperfusion injury and cisplatin induced injury. Reconstitution of nu/nu mice with CD4+ T cells alone but not with CD8+ T cells alone restored kidney injury after ischemia/reperfusion injury and mice lacking CD8 or CD4 T cells alone suffered less kidney dysfunction after cisplatin administration. […] Tregs make up an indispensible counter-balance to the pro-inflammatory cells of the immune system. The main mechanisms of suppression employed by Tregs include production of anti-inflammatory cytokines, such as IL-10 and transforming-growth factor (TGF)-, generation of extracellular adenosine, direct contact-mediated inhibition of dendritic cells through cell surface molecules such as lymphocyte activation gene (LAG)-3 and cytotoxic T-lymphocyte antigen (CTLA)-4 and several others. Based on the important contribution of the pro-inflammatory immune cells to AKI discussed above we hypothesized that Tregs would serve to protect the kidney from inflammation and injury.
#3 Role of leukocytes in the pathogenesis of acute kidney injury | Critical Care | Full Text
https://ccforum.biomedcentral.com/articles/10.1186/cc11228
Acute kidney injury (AKI) is a significant cause of morbidity and mortality in hospitalized patients, especially those who are critically ill. Numerous factors contribute to the development of AKI, including reductions in renal blood flow, actions of nephrotoxic drugs, cellular injury/death of proximal tubule epithelial cells, pro-inflammatory responses of renal endothelial cells, influx and activation of inflammatory leukocytes that further reduces renal blood flow through vascular congestion and promotes and extends injury to kidney parenchymal cells. The immune response in AKI involves cells of both the innate and adaptive immune systems. Studies in animal models of AKI have revealed that innate immune cells, such as neutrophils, macrophages, dendritic cells, natural killer (NK) cells and natural killer T (NKT) cells, and adaptive CD4+ T cells promote renal injury. Indeed, renal inflammation is a common feature of human AKI and detailed analyses of biopsy samples from patients with AKI demonstrated the presence of mononuclear leukocytes (some CD3+ T cells) and neutrophils. In contrast, CD4+FoxP3+ regulatory T cells (Tregs) can protect the kidney from ischemic and nephrotoxic injury in animal models. Understanding the immune mechanisms of renal injury and protection should yield new approaches to prevention and treatment of AKI.
#3 Acute Kidney Injury (AKI) – Genitourinary Disorders – Merck Manual Professional Edition
https://www.merckmanuals.com/professional/genitourinary-disorders/acute-kidney-injury/acute-kidney-injury-aki
Postrenal AKI (obstructive nephropathy) is due to various types of obstruction in the voiding and collecting parts of the urinary system. Obstruction can also occur on the microscopic level within the tubules when crystalline or proteinaceous material precipitates. Obstructed ultrafiltrate, in tubules or more distally, increases pressure in the urinary space of the glomerulus, reducing GFR. Obstruction also affects renal blood flow, initially increasing the flow and pressure in the glomerular capillary by reducing afferent arteriolar resistance. However, within 3 to 4 hours, the renal blood flow is reduced, and by 24 hours, it has fallen to 50% of normal because of increased resistance of the renal vasculature. […] To produce significant AKI, obstruction at the level of the ureter requires involvement of both ureters unless the patient has only a single functioning kidney.
#3 Acute Tubular Necrosis (ATN): Practice Essentials, Pathophysiology, Etiology
https://emedicine.medscape.com/article/238064-overview
Acute tubular necrosis (ATN) is the most common cause of acute kidney injury (AKI) in the renal category (that is, AKI in which the pathology lies within the kidney itself). The term ATN is actually a misnomer, as there is minimal cell necrosis and the damage is not limited to tubules. […] ATN follows a well-defined four-part sequence of initiation, extension, maintenance, and recovery, as follows: The initiation phase is characterized by an acute decrease in glomerular filtration rate (GFR), with a corresponding sudden increase in serum creatinine (Cr) and blood urea nitrogen (BUN) concentrations. The extension phase is characterized by ongoing hypoxia leading to sustained tissue ischemia, which triggers an inflammatory response. Given its limited blood supply, the corticomedullary junction of the kidney is most susceptible to a renal insult. A continuous release of cytokines and chemokines from impaired corticomedullary junction enhances the inflammatory cascade and this ongoing activation of the inflammatory cascade results in the drop of GFR. The tubule cell damage and cell death that characterize ATN usually result from an acute ischemic or toxic event. Nephrotoxic mechanisms of ATN include direct drug toxicity, intrarenal vasoconstriction, and intratubular obstruction. Whether the cause is ischemia or nephrotoxicity, most of the pathophysiologic features of ATN are the same.
#4 Acute Kidney Injury: Medical Causes and Pathogenesis
https://pmc.ncbi.nlm.nih.gov/articles/PMC9821234/
Acute kidney injury (AKI) is a common clinical syndrome characterized by a sudden decline in or loss of kidney function. […] The timely and accurate identification of AKI and a better understanding of the pathophysiological mechanisms that cause kidney dysfunction are essential. […] The etiology of AKI is conceptually classified into three general categories: prerenal, intrarenal, and postrenal. […] AKI may develop more commonly after exposure to certain insults or in susceptible groups and many common pathophysiological factors play into the pathogenesis of AKI. […] The main focus of this review is to summarize the various medical causes of AKI. Furthermore, we summarize the most recent research updates in the pathogenesis of AKI. […] Prerenal disease and acute tubular necrosis are two major causes of AKI in hospitalized patients.
#4 Acute Kidney Injury: Medical Causes and Pathogenesis
https://www.mdpi.com/2077-0383/12/1/375
Acute kidney injury (AKI) is a common clinical syndrome characterized by a sudden decline in or loss of kidney function. […] The etiology of AKI is conceptually classified into three general categories: prerenal, intrarenal, and postrenal. […] AKI may develop more commonly after exposure to certain insults or in susceptible groups and many common pathophysiological factors play into the pathogenesis of AKI. […] The main focus of this review is to summarize the various medical causes of AKI. Furthermore, we summarize the most recent research updates in the pathogenesis of AKI. […] Acute tubular necrosis (ATN) is the most common cause of intrarenal AKI in hospitalized patients. Renal ischemia, sepsis, and nephrotoxins are major causes of ATN. […] Endothelial and epithelial cell injuries are main factors that contribute to the pathogenesis of ATN.
#4 Acute Kidney Injury: Medical Causes and Pathogenesis
https://pmc.ncbi.nlm.nih.gov/articles/PMC9821234/
Renal hypoperfusion can be a part of a generalized decrease in tissue perfusion or selective renal ischemia and plays a critical role in the pathogenesis of prerenal AKI. […] The pathophysiology of HRS is not fully understood, but the complex interaction between several different factors is implicated. […] Endothelial and epithelial cell injuries are main factors that contribute to the pathogenesis of ATN. […] The underlying mechanisms also include the release of cytokines, kidney inflammation, and tissue edema. […] The complement system can be directly or indirectly activated in patients with sepsis and contributes to the pathogenesis. […] Inappropriate complement activation contributes to the pathogenesis of AKI. […] Various mechanisms have been identified in experimental studies.
#4 Acute Kidney Injury: Medical Causes and Pathogenesis
https://www.mdpi.com/2077-0383/12/1/375
The pathophysiology of HRS is not fully understood, but the complex interaction between several different factors is implicated. […] The complement system can be directly or indirectly activated in patients with sepsis and contributes to the pathogenesis. […] The increase in biomarkers as NGAL and KIM-1 is associated with an increased risk of subsequent renal replacement therapy and/or mortality. […] The normal response of the kidney to decreased renal perfusion is to maximally concentrate the urine and reabsorb sodium to maintain or to increase intravascular volume and normalize renal perfusion. […] However, reduced RBF eventually leads to ischemia and cell death. […] The timely and accurate identification of AKI and a better understanding of the pathophysiological mechanisms that cause kidney dysfunction are essential.
#4 Acute Kidney Injury (AKI) – Genitourinary Disorders – Merck Manual Professional Edition
https://www.merckmanuals.com/professional/genitourinary-disorders/acute-kidney-injury/acute-kidney-injury-aki
Postrenal AKI (obstructive nephropathy) is due to various types of obstruction in the voiding and collecting parts of the urinary system. Obstruction can also occur on the microscopic level within the tubules when crystalline or proteinaceous material precipitates. Obstructed ultrafiltrate, in tubules or more distally, increases pressure in the urinary space of the glomerulus, reducing GFR. Obstruction also affects renal blood flow, initially increasing the flow and pressure in the glomerular capillary by reducing afferent arteriolar resistance. However, within 3 to 4 hours, the renal blood flow is reduced, and by 24 hours, it has fallen to 50% of normal because of increased resistance of the renal vasculature. […] To produce significant AKI, obstruction at the level of the ureter requires involvement of both ureters unless the patient has only a single functioning kidney.
#5 Acute Kidney Injury: Medical Causes and Pathogenesis
https://www.mdpi.com/2077-0383/12/1/375
Acute kidney injury (AKI) is a common clinical syndrome characterized by a sudden decline in or loss of kidney function. […] The etiology of AKI is conceptually classified into three general categories: prerenal, intrarenal, and postrenal. […] AKI may develop more commonly after exposure to certain insults or in susceptible groups and many common pathophysiological factors play into the pathogenesis of AKI. […] The main focus of this review is to summarize the various medical causes of AKI. Furthermore, we summarize the most recent research updates in the pathogenesis of AKI. […] Acute tubular necrosis (ATN) is the most common cause of intrarenal AKI in hospitalized patients. Renal ischemia, sepsis, and nephrotoxins are major causes of ATN. […] Endothelial and epithelial cell injuries are main factors that contribute to the pathogenesis of ATN.
#5 Acute Kidney Injury: Medical Causes and Pathogenesis
https://pmc.ncbi.nlm.nih.gov/articles/PMC9821234/
Renal hypoperfusion can be a part of a generalized decrease in tissue perfusion or selective renal ischemia and plays a critical role in the pathogenesis of prerenal AKI. […] The pathophysiology of HRS is not fully understood, but the complex interaction between several different factors is implicated. […] Endothelial and epithelial cell injuries are main factors that contribute to the pathogenesis of ATN. […] The underlying mechanisms also include the release of cytokines, kidney inflammation, and tissue edema. […] The complement system can be directly or indirectly activated in patients with sepsis and contributes to the pathogenesis. […] Inappropriate complement activation contributes to the pathogenesis of AKI. […] Various mechanisms have been identified in experimental studies.
#6 Acute Kidney Injury: Medical Causes and Pathogenesis
https://www.mdpi.com/2077-0383/12/1/375
Acute kidney injury (AKI) is a common clinical syndrome characterized by a sudden decline in or loss of kidney function. […] The etiology of AKI is conceptually classified into three general categories: prerenal, intrarenal, and postrenal. […] AKI may develop more commonly after exposure to certain insults or in susceptible groups and many common pathophysiological factors play into the pathogenesis of AKI. […] The main focus of this review is to summarize the various medical causes of AKI. Furthermore, we summarize the most recent research updates in the pathogenesis of AKI. […] Acute tubular necrosis (ATN) is the most common cause of intrarenal AKI in hospitalized patients. Renal ischemia, sepsis, and nephrotoxins are major causes of ATN. […] Endothelial and epithelial cell injuries are main factors that contribute to the pathogenesis of ATN.
#6 Acute Kidney Injury: Medical Causes and Pathogenesis
https://pmc.ncbi.nlm.nih.gov/articles/PMC9821234/
Renal hypoperfusion can be a part of a generalized decrease in tissue perfusion or selective renal ischemia and plays a critical role in the pathogenesis of prerenal AKI. […] The pathophysiology of HRS is not fully understood, but the complex interaction between several different factors is implicated. […] Endothelial and epithelial cell injuries are main factors that contribute to the pathogenesis of ATN. […] The underlying mechanisms also include the release of cytokines, kidney inflammation, and tissue edema. […] The complement system can be directly or indirectly activated in patients with sepsis and contributes to the pathogenesis. […] Inappropriate complement activation contributes to the pathogenesis of AKI. […] Various mechanisms have been identified in experimental studies.
#7 Acute Kidney Injury: Medical Causes and Pathogenesis
https://pmc.ncbi.nlm.nih.gov/articles/PMC9821234/
Renal hypoperfusion can be a part of a generalized decrease in tissue perfusion or selective renal ischemia and plays a critical role in the pathogenesis of prerenal AKI. […] The pathophysiology of HRS is not fully understood, but the complex interaction between several different factors is implicated. […] Endothelial and epithelial cell injuries are main factors that contribute to the pathogenesis of ATN. […] The underlying mechanisms also include the release of cytokines, kidney inflammation, and tissue edema. […] The complement system can be directly or indirectly activated in patients with sepsis and contributes to the pathogenesis. […] Inappropriate complement activation contributes to the pathogenesis of AKI. […] Various mechanisms have been identified in experimental studies.