Dissertation (MD)--Stellenbosch University, 2000. / ENGLISH ABSTRACT: Acute renal failure still is, with the exception of cardiac deaths, the most important
pathological process associated with perioperative mortality in patients operated for
abdominal aortic aneurysms. The intraoperative change in renal blood flow (RBF) and
glomerular function have been investigated in human and animal models, particularly
over the past 15 years. Despite large variation in study populations, measurement
techniques and study designs in general, a significant body of evidence has developed
which suggests infrarenal aortic clamp-induced renal ischemia to be the cause of
postoperative acute renal failure when this complication does occur.
It is rather surprizing then that, despite some recent studies which have reported on
various pharmacological interventions to prevent intraoperative renal ischemia (with
variable success), very little has apparently been done to unravel the pathogenesis
and exact pathophysiology of this potentially lethal complication. Although a number of
investigators suggest the possibility of hormonal involvement (particularly reninangiotensin,
antidiuretic hormone (ADH) and catecholamines) in the process, the exact
role of these mediators have not been explored (or reported) in a structured fashion.
In an initial human study, renal hemodynamics and function were measured from the
preoperative period, during the intraoperative phase and at least until 4 hours after
aortic unclamping. To investigate the possibility of a temporal relationship between
renal changes and fluctuations in hormonal concentrations, plasma concentrations of
relevant hormones were determined at every sampling period where renal parameters
were measured.
The decrease in RBF and glomerular filtration rate (GFR) which we demonstrated to
coincide with infrarenal aortic cross clamping, is consistent with results previously
published. We demonstrated persistence of the impairment of these parameters as
long as 4 hours into the postoperative phase; which has previously only been reported
for the period until immediately after aortic unclamping with the abdomen still open.
The persistence of a depressed GFR until the time of discharge of patients is cause for
concern, particularly in patients with compromised renal function prior to surgery. Of the measured hormones with a potential influence on RBF and nephron function,
renin was the only mediator where changes in plasma concentrations coincided with
the depression of RBF and GFR after aortic cross clamping. The design of our study
did not allow us to conclude whether the concomitant increase in angiotensin II was
primarily responsible for the change in renal hemodynamics, or whether the raised
renin (and angiotensin) levels were stimulated by the decrease in RBF induced by
another mechanism.
In another patient group, we demonstrated that the combination of mannitol and
dopamine provided no protection against the deleterious effects of aortic cross
clamping. In fact, the high urine volumes produced under the influence of these
agents (which did not correlate with RBF at the corresponding periods), is likely to
prompt a false sense of security. Given the lack of any objective benefit afforded by
these agents, their use in these clinical circumstances should be discouraged.
The animal studies were aimed at elucidation of the exact role of angiotensin in the
pathogenesis and pathophysiology of the renal changes associated with infrarenal
aortic clamping, as well as the interaction of angiotensin with other modulators for
which an interactive relationship had been described previously under other
experimental and/or clinical circumstances.
The first study showed that, although renin (and thus angiotensin) concentrations were
high after aortic unclamping, the hormone had no pathogenic or pathophysiological
role of significance in the observed renal changes during this period (since blocking
angiotensin II activation by the prevention of renin release, or by inhibiting the
conversion enzyme, did not prevent a substantial decrease in RBF or GFR during that
period). Preventing angiotensin II activation did, however, prevent renal changes
during aortic clamping. This beneficial effect did not establish a primary role for
angiotensin during that period, since the favourable influence could also (at least
partially) be explained by prevention of the permissive influence of angiotensin on
other vasoconstrictors and/or other vasodilatory influences of ACE inhibition and [1-
blockade which are unrelated to angiotensin. This study did indicate that (at least
partially) different mechanisms are responsible for the renal changes seen during
aortic clamping, and after aortic unclamping. The second study explored the role of calcium in the renal pathophysiological changes
during aortic clamping and after unclamping. The protective influence effected by
the administration of a Ca2
+ -blocker suggest the dependence of the renal
vasoconstrictive and glomerular pathophysiological process( es) on the cellular influx of
Ca2
+ through voltage-gated channels. It unfortunately provides no definitive insight
into the primary instigators of these processes. However, it does offer a clinically
useful method of preventing these changes and protecting the kidney against ischemic
injury during abdominal aortic surgery.
The third component of the animal studies demonstrates the importance of the
protective effect of renal prostaglandins during the specific experimental (and probably
also the clinical) circumstances. Again, it does not provide definitive information on the
mediators responsible for the renal changes, since the deleterious effects of numerous
endogenous substances have previously been shown to be counterbalanced by
intrarenal synthesis of prostaglandins under various experimental and clinical
circumstances. The extent of the pathophysiological and ultrastructural changes which
occurred under the influence of a NSAID does, however, suggest that these drugs
should not be used under these clinical circumstances.
The last component of the study provides evidence that angiotensin only plays a
secondary/supplementary role in the renal pathophysiological process even during
aortic clamping. This may explain the contradictory evidence regarding the potential
beneficial effect of ACE inhibition (on renal hemodynamics and glomerular function)
during abdominal aortic surgery (Licker et al. 1996, Colson et al. 1992a). Based on
our studies, ACE inhibition can not be supported for this purpose. / AFRIKAANSE OPSOMMING: Akute nierversaking is met die uitsondering van kardiale sterftes, steeds die
belangrikste patologiese proses wat geassosieer is met perioperatiewe mortaliteit in
pasiënte wat opereer word vir abdominale aorta aneurismes. Die intraoperatiewe
veranderinge in renale bloedvloei (NBV) en glomerulêre funksie is die afgelope 15 jaar
ondersoek en gerapporteer in pasiënte- sowel as diere-modelle. Ten spyte van groot
variasies in studie-populasies, meettegnieke en ontwerp van studies in die algemeen,
dui 'n wesenlike hoeveelheid getuienis daarop dat infrarenale klemming van die aorta
renale isgemie induseer, wat die oorsaak is van postoperatiewe akute nierversaking
wanneer hierdie komplikasie voorkom.
Dit is verbasend dat, ten spyte van sommige onlangse studies wat rapporteer oor 'n
verskeidenheid farmakologiese ingrepe om intraoperatiewe renale isgemie te voorkom
(met wisselende sukses), baie min oënskynlik gedoen is om die patogenese en die
presiese patofisiologie van hierdie potensieel dodelike komplikasie te ontrafel. Hoewel
verskeie outeurs die moontlikheid van hormonale betrokkenheid (veral renienangiotensien,
antidiuretiese hormoon en katekolamiene) in hierdie proses suggereer, is
die presiese rol van hierdie mediators nog nie op 'n gestruktureerde wyse ondersoek
(of rapporteer) nie.
In ons aanvanklike pasiënte-studie is renale hemodinamika en -funksie gemeet vanaf
die preoperatiewe periode, gedurende die intra-operatiewe fase en tot minstens vier
uur na ontklemming van die aorta. Serumkonsentrasies van relevante hormone is
bepaal tydens elke metingsperiode waar renale parameters gemeet is, ten einde die
moontlikheid van 'n temporale verwantskap tussen renale veranderinge en variasies in
hormoonkonsentrasies te ondersoek.
Die vermindering in NBV en glomerulêre filtrasiespoed (GFS) wat ons aangetoon het
om saam te val met infrarenale aortaklemming, stem ooreen met resultate wat tevore
deur ander navorsers publiseer is. Ons het aangetoon dat die inkorting van hierdie
parameters voortduur tot minstens vier uur na aorta-ontklemming. Hierdie
veranderinge is tevore slegs rapporteer vir periodes tot kort na aorta-ontklemming voor
sluiting van die buikwond. Die feit dat die GFS steeds verlaag is met ontslag van hierdie pasiënte, skep rede tot kommer, veral in pasiënte wat alreeds ingekorte
nierfunksie het voor die chirurgiese prosedure.
Van die gemete hormone wat moontlik 'n invloed sou kon uitoefen op NBV eh
nefronfunksie, was renien die enigste waarvan verandering in plasmakonsentrasies
saamgeval het met die onderdrukking van NBV en GFS na aortaklemming. Die
ontwerp van ons studie het ons nie toegelaat om 'n besliste uitspraak te maak of die
geassosieerde verhoging in angiotensien II primêr verantwoordelik was vir die
verandering in renale hemodinamika, of dat die verhoogde renien (en angiotensien)
bloedvlakke moontlik sekondêr stimuleer is deur die verandering in NBV wat deur 'n
ander meganisme induseer is.
In 'n ander pasiëntegroep het ons aangetoon dat die kombinasie van mannitol en
dopamien geen beskerming verleen het teen die nadelige effekte van aorta-klemming
nie. Die groot volumes uriene wat uitgeskei is onder die invloed van hierdie middels
(wat nie korreleer het met NBV tydens ooreenstemmende periodes nie), het
inderwaarheid 'n ontoepaslike gerustheid uitgelok. Weens die ooglopende gebrek aan
objektiewe voordeel wat verleen word deur hierdie middels, behoort hulle gebruik
tydens hierdie kliniese omstandighede ontmoedig te word.
Die doel van die diere studies was die identifisering van die presiese rol van
angiotensien in die patogenese en patofisiologie van die renale veranderinge
geassosieer met infrarenale aortaklemming, sowel as die interaksie van angiotensien
met ander modulators waarvoor 'n interaktiewe verwantskap voorheen beskryf is onder
eksperimentele en/of kliniese omstandighede.
Die eerste studie het getoon dat alhoewel renien (en dus angiotensien) konsentrasies
hoog was na aorta-ontklemming, die hormone geen betekenisvolle patogenetiese of
patofisiologiese rol in die waargenome renale veranderinge gedurende hierdie
periode het nie (aangesien blokkade van angiotensien aktivering deur voorkoming van
renien vrystelling, of deur inhibisie van angiotensien omsettingsensiem (AOE), nie 'n
daling in NBV of GFS kon voorkom nie). Voorkoming van angiotensien II aktivering het
egter wel renale verandering voorkom gedurende aortaklemming. Dié voordelige
effek het nie 'n primêre rol vir angiotensien gedurende die periode bevestig nie,
aangesien die gunstige invloed ook (ten minste gedeeltelik) verduidelik kon word deur
die voorkoming van die fassiliterende invloed van angiotensien op ander vasokonstriktore en/of ander vasodilator-invloede van die onderdrukking van AOE en
ïs-blokkers (wat geen verband het met angiotensien of die blokkade daarvan nie). Die
studie het aangetoon dat (ten minste gedeeltelik) verskillende meganismes
verantwoordelik is vir renale veranderinge wat gesien is gedurende aortaklemming
en na -ontklemming.
Die tweede studie het die rol van kalsium in die renale patofisiologiese veranderinge
gedurende aortaklemming en na ontklemming ondersoek. Die beskermende
invloed wat deur die toediening van Ca2
+ -blokkers bewerkstellig is, het bevestig dat die
renale vasokonstriktoriese en glomerulêre patofisiologiese prosesse afhanklik is van
sellulêre influks van kalsium deur spannings-afhanklike kannale. Dit het ongelukkig
geen definitiewe insig verleen ten opsigte van die primêre inisieerders van die proses
nie. Dit verskaf nogtans 'n bruikbare kliniese metode om daardie veranderinge te
voorkom en die niere teen isgemiese besering gedurende abdominale aorta-chirurgie
te beskerm.
Die derde komponent van die diere-studies demonstreer die belangrikheid van die
beskermende effek van renale prostaglandiene tydens die spesifieke eksperimentele
(en waarskynlik ook die kliniese) omstandighede. Weereens gee dit nie definitiewe
inligting oor die bemiddelaars wat verantwoordelik is vir die renale veranderinge nie,
aangesien die skadelike effekte van verskeie endogene stowwe voorheen aangetoon
is om beperk of voorkom te word deur die intrarenale vrystelling van prostaglandiene.
Die omvang van die patofisiologiese en ultrastrukturele veranderinge wat ontstaan het
onder die invloed van nie-steroïed anti-inflammatoriese middels (wat gebruik is om
prostaglandien sintese te inhibeer), dui aan dat hierdie middels vermy moet word
onder soortelyke kliniese omstandighede.
Die laaste komponent van die studie verskaf 'n sterk aanduiding dat angiotensien slegs
'n sekondêre/aanvullende rol speel in die renale patofisiologiese proses, selfs
gedurende aortaklemming. Dit mag die weersprekende getuienis oor die potensiële
voordeel van AOE onderdrukking (op renale hemodinamika en glomerulêre funksie)
gedurende abdominale aortachirurgie (Licker et al. 1996, Colson et al. 1992a) verklaar.
Gebaseer op ons studies, kan AOE onderdrukking nie ondersteun word vir hierdie doel
nie.
| Identifer | oai:union.ndltd.org:netd.ac.za/oai:union.ndltd.org:sun/oai:scholar.sun.ac.za:10019.1/51895 |
| Date | 03 1900 |
| Creators | Van der Merwe, Wynand Louw |
| Contributors | Coetzee, A. R., Stellenbosch University. Faculty of Medicine & Health Sciences. Dept. of Anaesthesiology & Critical Care. |
| Publisher | Stellenbosch : Stellenbosch University |
| Source Sets | South African National ETD Portal |
| Language | en_ZA |
| Detected Language | English |
| Type | Thesis |
| Format | 235 p. : ill. |
| Rights | Stellenbosch University |
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