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Bonvini, Stefano (2009) Temporary renal reperfusion to increase safe ischemic time. [Tesi di dottorato]

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Abstract (inglese)

The reported rate of acute renal failure from large series of patients undergoing Thoraco Abdominal Aortic Aneurysms (TAAA) repair ranges from 5% to 40% and is associated with mortality rates of 70%. Patients who develop acute renal failure also more frequently present a worse outcome and sustain non renal complications, such as respiratory failure, central nervous system dysfunction, sepsis, and gastrointestinal haemorrhage.
The factors contributing to renal dysfunction after TAAA repair include ischemia reperfusion injury, nonpulsatile flow in perfusion systems, transfusion of blood products, pre-operatory renal impairment etc.
Ischemia (cessation of blood flow), followed by reperfusion (re-establishment of blood flow), causes characteristic injury to organs and tissues. Ischemia compromises the continuous supply of oxygen required by tissues and organs to survive and maintain normal physiological function. A rapid return of oxygenated blood (reperfusion) is therefore essential for preventing ischemic and apoptotic cell death. However, reperfusion itself also contributes to cellular injury and death by the production of free oxygen radicals and the activation of a cytokine mediated inflammatory response that, on one side, through a pro-inflammatory component expression (IL1?, IL1?, IL,2, IL6, GM-CSF, TNF?, INF?) sustain cellular damage, and on the other side, through an anti inflammatory component expression (IL4, IL10) tends to limit it being therefore the prelude of the reestablishment of normal conditions.
The short term arterial blood reperfusion of renal arteries is one of the surgical techniques applied at the Vascular and Endovascular division of the University of Padova to prevent renal impairment. Renal blood reperfusion is obtained, once the proximal anastomosis between the proximal aorta and the Dacron graft is performed, by re-establishing pulsatile normothermic blood flow through a Pruitt-Inahara shunt. Application of the shunt may change in different surgical procedure. When the procedure requires more than 30 min to re-establish a normal flow in the renal artery, the proximal end of the shunt is distally inserted in the vascular graft. The proximal aortic clamp is released; the shunt is blood perfused and its distal end is inserted into the open end of the renal artery. After 3 min of blood reperfusion, the aorta and the renal artery are reclamped, the shunt is promptly removed and the renal artery reconstruction completed. The reperfusion is repeated every 30 min if necessary.
Aim of my PhD thesis was to evaluate on an animal model the possibility to increase the total time of clamping ischaemia by re-establishing blood flow into renal artery for 3 or 6 minutes leading to a total ischemic period of 90 minutes, evaluating functional, morphological damage and molecular processes involved in the pathophysiology of ischemia reperfusion injury.
27 Male Sprague-Dawley rats weighing 200 to 250 g, were used for the experiment. Through a midline laparotomy both renal arteries were dissected and clamped to obtain a bilateral ischemia followed by reperfusion in selected group of animals.The rats were allocated into one of the 4 experimental groups; control group, 18 rats with ischemia alone (with progressive clamping time of both renal arteries to assess organ damage at 30-45-60-90 min); group A, 4 rats (30 min of renal ischaemia followed by 3 min of reperfusion followed by other 30 min of ischemia for a total ischaemic time of 60 min), group B,4 rats (45 min of renal ischaemia followed by 3 min of reperfusion plus 45 minutes of ischemia for a total ischemic time of 90 min) and group C, 3 rats (30 min of renal ischaemia followed by 3 min of reperfusion repeated 3 times for a total ischemic time of 90min). A blood sample from inferior vena cava was drawn to evaluate serum creatinine level before the renal clamping. After 48 hours from the procedure the rats were sacrificed for kidney harvesting. Before kidney removal a blood sample from inferior vena cava was drawn to evaluate serum creatinine level.
Renal injury was assessed through evaluation of: a) renal functional parameters (serum level of creatinine at 0 and 48 hours after ischemia), b) morphological parameters on histological samples ( tubular necrosis, tubular dilatation, mitosis, apoptosis, haemorrhage infiltration interstitial leukocyte infiltration, and the proliferative index (Ki67), c) pro-inflammatory (IL1?, IL1?, IL,2, IL6, GM-CSF, TNF?, INF?) and anti-inflammatory (IL4, IL10) cytokine expression on tissue samples.
Results
Animals that underwent renal ischemia with no reperfusion exhibited increase in the serum concentrations of creatinine when the clamping ischemia was more than 45 min, and this difference becomes statistically significant when the clamping time is more than 60 minutes suggesting glomerular dysfunction. In revascularized groups creatinine serum level demonstrates no significant changes compared to the base pre-ischemic value regardless the pattern of revascularization performed suggesting the lack of glomerular dysfunction also in these groups of animals.
Morphological damages were absent in the revascularized group if the total ischemic time is less than 60 minutes. When the total ischemic time was prolonged up to 90 minutes even if no functional alteration was present histopathological analysis demonstrated a moderate renal injury in terms of necrosis and apoptosis. However a higher proliferative index is present at 90 minutes in all revascularized group with the highest increase in double reperfusion. Pro inflammatory (IL-1?, IL-2, IL-6, GM-CSF, IFM-? ,TNF-?: ) and anti-inflammatory(IL-10, IL-4) cytokines are expressed in all the different groups of animals after ischemia and after ischemia and reperfusion. Both pro and anti inflammatory cytokines are over-expressed in animals that underwent a total ischemic time of 60 minutes with a single reperfusion (30+3+30 ), compared to the group without reperfusion and with those with ischemia of 90 min (30+3+30+3+30; 45+3+45). The cytokine evaluation showed a prevalence of anti-inflammatory cytokine expression in the revascularized group with a statistically significant difference for IL10 over-expression.
In the reperfusion at 90 minutes we observed a decrease in both pro-inflammatory and anti inflammatory cytokines. However with double reperfusion the decrease was more pronounced for the proinflammatory cytokines (TNF?) allowing the biological effect of IL10 to be more powerful (higher proliferative index).
Discussion
The results of my PhD thesis showed that the functional, morphological and molecular results are congruent. At 60 min of ischemia there is an irreversible damage to the kidney with an increased creatinine level, necrosis and apoptosis, low proliferative response and increase in cytokines expression especially of pro-inflammatory cytokines (IL1?, IL2, IL6, TNF? and INF?). With ischemia-reperfusion (30-3-30) we obtain a less ischemic damage, a more pronounced proliferative response and anti-inflammatory cytokines over-expression (IL-10, IL-4) compared to ischemia alone. The balance was in favour of the protective role of reperfusion. With the ischemic-reperfusion model of 90 min of ischemia and 6 minutes reperfusion (30-3-30-3-30) we still observed the beneficial role of reperfusion since there is a reduction of necrosis, apoptosis and increasing in proliferation activity and at the end a positive ratio in favour of anti-inflammatory cytokines (IL-10). In the setting of 90 min ischemia and 3 min reperfusion, (45-3-45) we observed a similar ischemic damage in term of necrosis and less proliferative index and the ratio between pro and anti inflammatory was still in favour of anti inflammatory cytokines. However the decrease of pro inflammatory cytokine TNF? was less evident, thus counterbalancing more actively the protective role of anti inflammatory cytokine IL10.
We can state that according to our results the best model would be that of 30-3-30-3-30 which means less ischemic damage and more reperfusion benefits.

Abstract (italiano)

SOMMARIO

Introduzione
L’incidenza di insufficienza renale (i.r.) post-operatoria in pazienti sottoposti a chirurgia dell’aorta toraco-addominale è riportata essere dal 5 al 40 % a seconda delle casistiche associata ad un tasso di mortalità intorno al 70%. I pazienti che sviluppano una insufficienza renale acuta post-operatoria sviluppano più frequentemente complicanze non renali come ad esempio insufficienza respiratoria, disfunzioni del sistema nervoso centrale, sepsi ed emorragie gastrointestinali.
I fattori che contribuiscono al danno renale dopo chirurgia aortica includono il danno da ischemia e riperfusione, il flusso non pulsato di alcuni sistemi di riperfusione, condizione renale preoperatoria, perdite ematiche etc.
L’ischemia (interruzione del flusso ematico a livello del parenchima renale), seguita dalla riperfusione (ripristino del flusso), provocano dei danni caratteristici ad organi e tessuti. L’ischemia compromette il continuo rifornimento di ossigeno ai tessuti necessario per il mantenimento delle normali funzioni fisiologiche. La riperfusione però, necessaria per il mantenimento della vitalità cellulare, è essa stessa causa di danno cellulare attraverso la produzione di radicali liberi dell’ossigeno e attivazione di una risposta infiammatoria mediata dalle citochine che da un lato, attraverso l’espressione della componente pro-infiammatoria (IL1?, IL1?, IL,2, IL6, GM-CSF, TNF?, INF?) sostiene il danno e dall’altro, attraverso l’espressione della sua componente anti-infiammatoria (IL4, IL10) tende ad arginarlo costituendo il preludio al ritorno alla condizione di normalità.
Attualmente la metodica chirurgica utilizzata presso la Clinica di Chirurgia Vascolare ed Endovascolare dell’Università degli studi di Padova nella prevenzione dell’insufficienza renale è rappresentata dall’utilizzo della riperfusione breve delle arterie renali che consiste nel riperfondere le arterie renali per 3 minuti, una volta completata l’anastomosi prossimale della ricostruzione aortica, attraverso degli shunt temporanei inseriti nella protesi. Tale riperfusione permette di poter clampare per ulteriori 30 minuti di ischemia le arterie renali permettendo di poter completare l’intervento. Qualora necessario è possibile inoltre riperfondere per ulteriori 3 minuti le arterie renali per ottenere ulteriori 30 minuti di ischemia.

Scopo di questo studio è dimostrare nel modello animale che è possibile incrementare il tempo di ischemia totale renale ristabilendo per 3 minuti un flusso pulsato all’interno dell’arteria renale, valutando i danni funzionali, morfologici ed i processi molecolari legati ad essi. La riperfusione breve delle arterie renali può essere ripetuta più volte raggiungendo un tempo di ischemia totale di 90 minuti.
Materiali e metodi
Lo studio è stato condotto su 27 ratti albini del ceppo Sprague-Dawley di sesso maschile e del peso di 250 gr circa .Dopo aver praticato una laparotomia mediana si è proceduto all’isolamento e al clampaggio dell’arteria renale bilateralmente ottenendo l’ischemia completa dei reni seguita da riperfusione secondo il protocollo. Gli animali sono stati suddivisi in 4 gruppi sperimentali; un gruppo di controllo, 18 ratti, (sottoposti ad un clampaggio di tempo crescente delle arterie renali per valutare la gravità del danno ischemico a tempi differenti pari a 30-35-40-45-50-55-60-75-90 minuti. Un gruppo A, 4 ratti (sottoposti a 30 minuti di ischemia seguiti da 3 minuti di riperfusione e successivi 30 minuti di ischemia per un totale di 60 minuti), un gruppo B, 4 ratti, (sottoposti a due periodi di ischemia di 45 minuti intervallati da 3 min di riperfusione per un totale di 90 minuti di ischemia); un gruppo C, 3 ratti, (sottoposti a tre periodi di ischemia di 30 minuti ognuno interrotti da 3 min di riperfusione per un totale di 90 minuti di ischemia). Prima dell’ischemia è stato eseguito un prelievo venoso dalla cava per il dosaggio della creatinina sierica. In seconda giornata post-operatoria i ratti sono stati sottoposti a riapertura della ferita chirurgica, con espianto di entrambi i reni e sacrificio dell’animale previo prelievo venoso dalla cava. Il materiale prelevato è stato inviato presso i laboratori di Anatomia Patologica per una valutazione mediante microscopia ottica.
La valutazione del danno renale è stata eseguita controllando i parametri di funzionalità renale (creatininemia a 0 e 48 ore dall’evento ischemico), i parametri morfologici di danno sugli esami istologici (la necrosi, la dilatazione tubuale, le mitosi, apoptosi, dimorfismi, stravasi ematici, infiltrato infiammatorio) e l’indice proliferativo (Ki67).
Inoltre è stata valutata l’espressione delle interleuchine pro-infiammatorie (IL1?, IL1?, IL,2, IL6, GM-CSF, TNF?, INF?) ed anti-infiammatorie (IL4, IL10)
Risultati
La valutazione della creatinine mia a 0 e 48 ore ha evidenziato come la riperfusione temporanea sia in grado di proteggere funzionalmente il parenchima renale. A 90 minuti i ratti riperfusi mostrano valori di creatininemia sovrapponibili ai valori di base preischemici mentre i ratti non riperfusi a 90 minuti hanno un aumento significativo della creatininemia.
Da un punto di vista morfologico la valutazione a 60 minuti documenta l’assenza di lesioni. Quando il tempo di ischemia è prolungato a 90 minuti, anche se da un punto di vista funzionale non vi è evidenza di alterazioni, l’analisi istopatologica ha dimostrato un danno seppur lieve sia in termini di necrosi che di apoptosi. Tuttavia a 90 minuti si osserva un alto indice proliferativi in tutti gli animali sottoposti a riperfusione con il più alto valore che si riscontra nei ratti sottoposti a doppia riperfusione. Le citofhine pro-infiammatorie (IL-1?, IL-2, IL-6, GM-CSF, IFM-? ,TNF-?: ) ed antiinfiammatorie (IL-10, IL-4) sono espresse dai vari gruppi di animali dopo ischemia e dopo ischemia e riperfusione. Sia le citochine pro che antiinfiammatorie sono sovra espresse negli animali sottoposti ad una ischemia totale di 60 minuti con singola riperfusione confrontati con il gruppo senza riperfusione e con quelli con ischemia di 90 minuti. La valutazione delle citochine dimostra una prevalenza di citochine antinfiammatorie nel gruppo rivascolarizzato con una differenza statisticamente significativa per IL10.
Nelle riperfusioni a 90 minuti si è osservato un decremento sia per quel che riguarda le citochine pro che antinfiammatoria . Tuttavia con la doppia riperfusione il decremento era più marcato per le citochine proinfiammatorie (TNF?) permettendo l’esplicarsi dell’attività biologica della IL10.
Discussione
I risultati della mia tesi di dottorato dimostrano come i risultati funzionali, morfologici e molecolari siano congrui. A 60 minuti di ischemia vi è la comparsa di un donno parenchimale irreversibile con incremento del dosaggio della creatininemia sierica, dei processi di apoptosi e necrosi cellulare, basso indice proliferatici ed un incremento del livello di espressione delle citochine. A tale riguardo tale incremento riguarda in particolar modo l’espressione delle citochine pro-infiammatorie (IL1?, IL1?, IL,2, IL6, GM-CSF, TNF?, INF?). Nel caso di ischemia e riperfusione con pattern 30-3-30 è stato osservato un minor danno ischemico accompagnato ad una risposta proliferativa pronunciata ed a una sovraespressione di citochine anti-infiammatorie (IL10, IL4). Il bilancio finale è in favore del ruolo protettivo della riperfusione. Con il modello di riperfusione di 90 minuti di ischemia e 6 di riperfusione (30-3-30-3-30) si osservano ancora i risultati positivi della riperfusione con una riduzione della necrosi, ed un incremento dell’attività proliferativi con un rapporto favorevole verso la produzione di citochine antinfiammatorie (IL10). Nel pattern dei 90 minuti di ischemia e 3 di riperfusione (45-3-45), abbiamo osservato un danno ischemico simile in termini di necrosi ed apoptosi ed un indice proliferativo più basso ed un rapporto tra citochine pro ed anti infiammatorie a favore di quelle antinfiammatorie. Tuttavia il decremento delle citochine pro-infiammatorie TNF è risultato essere meno evidente, contrastando così in maniera più attiva il ruolo antinfiammatorio di IL10.
Si può concludere,in accordo con i risultati presentati, che il miglior modello di riperfusione risulta essere quello di ischemia / riperfusione 30-3-30-3-30 accompagnato da meno danno ischemico associato ai benefici della riperfusione.

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Tipo di EPrint:Tesi di dottorato
Relatore:Deriu, Giovanni
Correlatore:Angelini , Annalisa
Dottorato (corsi e scuole):Ciclo 20 > Scuole per il 20simo ciclo > SCIENZE MEDICHE, CLINICHE E SPERIMENTALI > SCIENZE CARDIOVASCOLARI
Data di deposito della tesi:02 Febbraio 2009
Anno di Pubblicazione:2009
Parole chiave (italiano / inglese):Renal, surgery, cytokine, aortic surgery, reperfusion
Settori scientifico-disciplinari MIUR:Area 06 - Scienze mediche > MED/22 Chirurgia vascolare
Struttura di riferimento:Dipartimenti > Dipartimento di Scienze Cardiologiche, Toraciche e Vascolari
Codice ID:1954
Depositato il:02 Feb 2009
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