The increase in intra-abdominal pressure (IAP) above specific levels (i.e., intra-abdominal
hypertension, IAH) may lead to organ dysfunction in abdominal and extra-abdominal
systems (Kirkpatrick and Roberts, 2013). Possible etiologies or risk factors for IAH
development comprehend diminished abdominal compliance, increased intraluminal or
intra-abdominal contents and capillary leak/fluid resuscitation (Kirkpatrick and Roberts,
2013). In this conditions, formally known as abdominal compartment syndrome, acute
kidney injury (AKI) frequently develops and further worsens the patients outcome (Dalfino
et al., 2008).
Pathophysiological mechanisms leading to AKI during IAH are not completely known;
nevertheless, evidence from the literature recognize the decrease in renal perfusion
as the main factor responsible for development of AKI in this condition (De Waele
et al., 2011). In particular, renal hypoperfusion might occur during an acute or progressive
increase in IAP, mainly due to the reduction of both arterial inflow and venous outflow,
leading to glomerular hemodynamic alterations.
Beyond the subsequent activation of neuro-hormonal pathways (e.g., noradrenergic response
and Renin-Angiotensin-Aldosteron system), the intrarenal hemodynamic alteration may
be itself the responsible for an acute decrease of glomerular filtration gradient
(FG; De Waele et al., 2011). The FG reflects the balance among hydrostatic and oncotic
forces that support the ultrafiltration through the glomerular barrier. During IAH,
the decrease of glomerular hydrostatic pressure (due to hypoperfusion) and the increase
of Bowman's space hydrostatic pressure (due to IAH) may lead to acute reduction in
FG (De Waele et al., 2011). Data from literature confirm an inverse correlation between
IAP and FG (Harman et al., 1982).
Physiologically, an acute increase in IAP narrows renal arteries and veins, reduces
renal blood flow, leading to the activation of autoregulatory mechanisms. These cause
a vasodilation of afferent arterioles, ensuring glomerular filtration also during
the early stage of acute increase in IAP (Just, 2007). Probably, the activation of
these mechanisms may determine an acute increase in glomerular filtration during stressful
events and we hypothesized that it might be related to the patient's renal functional
reserve. Moreover, the same IAP value may produce different levels of decreased renal
function related to different levels of myogenic response influencing the efficiency
of autoregulatory mechanisms.
According to experimental data showed by Harman et al., Figure 1 represents the correlation
between current renal function (x axis) and IAP (y-right axis) (Harman et al., 1982).
In patients with effective myogenic response (patient n°1, dashed line), an acute
increase in IAP is associated to a slight decrease in renal function. Whereas, in
patients with a compromised myogenic response (patient n°2, solid line), and lower
renal functional reserve, an acute increase in IAP is associated with a strong reduction
in renal function.
Figure 1
Correlation between current renal function, intra-abdominal pressure (IAP), and biomarkers
of acute kidney injury (AKI). Patient n° 1 (dashed line): in presence of effective
myogenic response, an acute increase in IAP is associated to a slight decrease in
renal function (tract 0–C). A further increase of IAP may lead to biomarkers increase
(subclinical AKI, tract C–D). When IAP overcomes the intrarenal autoregulation, glomerular
hypoperfusion occurs and a picture of clinical AKI becomes manifest (above point D).
Patient n° 2 (solid line): in presence of compromised myogenic response, an acute
increase in IAP is associated with a strong reduction in renal function until the
development of clinical functional AKI (tract A–B). If IAP further increases, the
inflammatory and ischemic insults may lead to the kidney parenchymal damage detectable
by biomarkers (above point B).
Although the hemodynamic issue is certainly quintessential to explain the pathophysiology
of AKI during IAH, other mechanisms may further affect the kidney function (e.g.,
the direct parenchyma compression or the inflammatory damage; Doty et al., 2000; Kösüm
et al., 2013).
Beyond the etiological conditions leading to the acute increase in IAP, the IAH itself
may induce systemic inflammation (Rezende-Neto et al., 2002). Indeed, it is well known
as systemic inflammation can widely sustain AKI through circulating biochemical factors
inducing apoptotic/necrotic damages to the renal parenchyma (Honore et al., 2011).
Furthermore, also metabolic alterations induced locally may be recognized in the kidney
during IAH. In particular, during IAP elevation a widely range of genes are up- and
down-regulated in the kidney, leading to a dynamic and constantly changing metabolic
response (Edil et al., 2003). In experimental models of IAH, high levels of locally-produced
inflammatory mediators (e.g., TNF-a or IL-6) have been demonstrated in the kidney
during the IAP elevation as well as their association with histopathological and cytoarchitectural
alterations (Akbulut et al., 2010; Kösüm et al., 2013).
The susceptibility to kidney damage due to hemodynamic or biological insults during
“IAH exposure” might be theoretical detectable through the use of biomarkers of AKI
(Li et al., 2014). Several biomarkers have been proposed to identify the kidney damage
during clinical scenarios at risk for AKI, for example the perioperative urinary liver-type
fatty-acid-binding protein during endovascular abdominal repair (Obata et al., 2016).
Although most of literature provides information on specific molecules, such as neutrophil
gelatinase-associated lipocalin or Kidney injury molecule-1, biomarkers of cell-cycle
arrest have been recently identified as the most sensitive and specific biomarkers
for AKI in most clinical settings (Kashani et al., 2013). According to ADQI classifications
(McCullough et al., 2013), biomarkers of AKI might identify the parenchyma kidney
damage occurred after a metabolic insult, whereas the clinical classifications based
on urinary output or serum creatinine (aimed to quantify the glomerular filtration
rate) might identify the kidney dysfunction (Ronco et al., 2012). As demonstrated
in literature, clinical AKI is widely correlated with an increased patients' mortality;
in these conditions the use of biomarkers of kidney damage might inform about severity,
prognosis, and recovery from AKI (Endre et al., 2011). Nevertheless, also conditions
characterized by an increase of biomarkers of kidney damage, but in which clinical
scoring systems fail to identify a kidney dysfunction (i.e., “subclinical AKI”) are
associated to patients' mortality (Ronco et al., 2012).
The identification of the pathophysiological mechanisms for AKI, as well as the quantification
of specific patient's responses to pathological stimuli (as myogenic activation and
renal functional reserve) and the evaluation of the kidney damage/dysfunction, should
be achieved during IAH-induced AKI. This may allow a personalized treatment for that
specific patient and a target-directed therapy for AKI (Joannidis et al., 2010) even
during IAH.
In particular, in patient n°2 (with low myogenic response) renal function rapidly
falls during IAP elevation until the development of clinical AKI (from point A). In
this situation, the ineffective response of the patient to the reduced glomerular
perfusion might produce a clinical “functional” AKI even if the parenchymal kidney
damage (biological or ischemic) does not actually occurred (tract A–B). In this phase
the optimization of cardiac output and/or volume replacement might increase the renal
perfusion restoring glomerular function. If IAP further increases, the biological
inflammatory insult, as well as the ischemic insult deriving from hypoperfusion, may
lead to the kidney parenchymal damage detectable by biomarkers (above point B).
On the other hand, in patient n°1 (with an effective myogenic response) renal function
slightly decreases during the IAP elevation (from point 0 to C). The patient's effective
intrarenal autoregulation allows him to maintain the glomerular filtration pressure
in this early phase, avoiding the “functional” AKI (deriving from hypoperfusion or
hypovolemia). However, the progression of IAH and the subsequent biological inflammatory
insult may lead to kidney damage clinically detectable through the biomarkers increase
(point C). In this specific condition, the reduction of renal function occurs in a
picture of subclinical AKI (from point C to D), in which the patient's parenchymal
damage is associated to a normal glomerular function sustained by intrarenal autoregulation.
If IAH progresses, the IAP overcomes the intrarenal autoregulation, glomerular hypoperfusion
occurs meanwhile the biological insult progresses and a picture of clinical AKI becomes
manifest (above point D).
In conclusion, although pathophysiological mechanisms responsible to AKI during IAH
are not completely understood, the decrease in renal perfusion is one of the most
important causative factor (De Waele et al., 2011). The acute increase of intra-abdominal
pressure reduces the renal blood flow and triggers the autoregulatory mechanisms,
acutely rising glomerular filtration. The integrity of myogenic response might be
related to the patient's capability to maintain an adequate glomerular filtration
rate during stressful conditions (e.g., metabolic load or hemodynamic insult leading
to kidney hypoperfusion). Other etiological stimuli such as inflammatory end/or toxic
exposures may also induce kidney impairment and/or kidney dysfunction during IAH,
thus leading to clinical or subclinical AKI. In a comprehensive approach to the kidney
function during IAH, the evaluation of myogenic response with the clinical and biochemical
parameters of AKI may have a role to personalizing the treatment for each specific
patient.
Author contributions
GV, SS, and SD have substantially contributed to the conception of the work, drafting
the work or revising it critically for important intellectual content. CR has finally
approved the version to be published.
Conflict of interest statement
The authors declare that the research was conducted in the absence of any commercial
or financial relationships that could be construed as a potential conflict of interest.