Pathophysiology of Acute Kidney Injury: History
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Csaba Kopitkó
,
Tibor Fülöp
,
Mihály Tapolyai
,
Tibor Gondos

In clinical practice, one of the most common interventions is volume expansion in those with perceived hypovolemia. Intravenous fluid administration is easily performable with crystalloid and colloid infusions or with various blood products. In the era, the isotonic but non-physiologic 0.9% saline and balanced solutions are available as crystalloid infusions, whereas the 6% hydroxyethyl starch (HES) (130/0.4 or 0.42) and the 5% or 20% human albumin are available as colloids, respectively.

  • hydroxyethyl starch
  • acute kidney injury
  • hemodynamic monitoring

1. Introduction

In clinical practice, one of the most common interventions is volume expansion in those with perceived hypovolemia. Intravenous fluid administration is easily performable with crystalloid and colloid infusions or with various blood products. In the current era, the isotonic but non-physiologic 0.9% saline and balanced solutions are available as crystalloid infusions, whereas the 6% hydroxyethyl starch (HES) (130/0.4 or 0.42) and the 5% or 20% human albumin are available as colloids, respectively.
Formerly, dextrans, gelatin and early generations of HES were also available as well. Dextran products are high (40–200 kDa) molecular weight polymers of glucose produced by bacteria (Leuconostoc mesenteroides) in sucrose-rich environments [1]. Their volume expansive effect is quite significant. Unfortunately, the risk of life-threatening allergic reactions to dextran products is prohibitively high. While these reactions are preventable by the administration of hapten (1 kDa dextran) a few minutes before the infusion, this property of dextran makes it unsuitable for use in acute situations. An alternative, gelatin infusion was manufactured by partial hydrolysis and chemical modifications after extraction from animal (pig, calf, fish) bones, skin and tendon (molecular weight: 30–35 kDa, concentration: 3–5%) [2]. Their volume-expanding effect is limited and their administration carries the risk of prion-mediated disease transmission. HES preparations are plant-derived products featured at various concentrations (6%, 10%), molecular weights (450 kDa, 200 kDa, 130 kDa) and molar substitutions (0.7, 0.6, 0.5, 0.42, 0.4) [3][4]. This latter property needs some explanation for further interpretation. A molar substitution of 0.7 means that on average there are 7 hydroxyethyl groups for 10 glucose molecules. The evolution of HES generations is as follows: (1) hetastarch–6% HES 450/0.7, (2) hexastarch–6% HES 200/0.6, (3) pentastarch–6%/10% HES 200/0.5 and (4) tetrastarch–6% HES 130/0.4. Other properties such as the C2:C6 hydroxylation ratio, or whether it is made from potato or waxy maize, are generally not labeled on the infusion bottle. The C2:C6 hydroxylation ratio—which potentially affects the elimination of the molecule or its blood coagulation compromising effect—has shown an increasing tendency in commercial products over the years (9:1 in currently available solutions) [5][6]. All dextrans, gelatins and older generation HESs are now removed from the market for various reasons [3][4]. More recently, the use of 6% HES (130/0.4 or 0.42) has been restricted by the European Medicines Agency and the U.S. Food and Drug Administration as its deleterious effects on kidney function came to light [3][7]. On 24 May 2022, the European Commission issued a suspension of the marketing authorizations of HES solutions for infusion in the EU (https://www.ema.europa.eu/en/news/hydroxyethyl-starch-solutions-infusion-recommended-suspension-market (accessed on 11 February 2022, updated on 26 July 2022). The opportunity was given for the individual EU Member States to delay the suspension for no longer than 18 months and keep HES solutions on the market. However, conclusions derived from resource-rich environments, such the EU is, should not be extended to more resource-scarce environments without proper qualifiers. Albumin, the ideal “volume expander”, remains expensive and its supply is ultimately limited. While current methods are safe for preventing the transmission of prion-like illnesses with human albumin preparations, all these are contingent on resource investment and societal wealth to support them [8][9].
Early hemodynamic stabilization can be crucial in the prevention of AKI regarding the short warm ischemic time of the kidneys [10][11]. A promising tool to discriminate between hypovolemic and normovolemic patients is the hypovolemic index (values between 0 and 1) [12]. This parameter is capable of separating these groups of patients (threshold: 0.5), but its validation is still in progress. The first step for hemodynamic stabilization is to achieve euvolemia, which is a wide gray zone without clear boundaries between the volume-sensitive and volume-resistive circulatory states [13][14]. Interstitial accumulation of intravenously administered fluids can increase the renal parenchymal pressure dramatically, and therefore the fluid resuscitation with crystalloids is only a question under debate [15]. The evaluation of kidney perfusion by ultrasound can aid in finding the right balance between fluids and vasoactive drug therapy.
At the same time and over the past several years, the definition of acute kidney failure has become increasingly precise, fostering earlier diagnosis and standardization across the world. The first systematic, universal definition of acute kidney injury (AKI) was accepted in 2002 (RIFLE criteria) and has been followed by three other generally established ones (AKIN, KDIGO, KDIGO with biomarkers) [16][17][18][19]. The studies conducted with third-generation HES show wide differences in the definition of deteriorating renal function, as discussed further below. The severity stages of AKI do not correspond equivocally between the AKI definitions, making it harder to generate a robust comparison [20]. AKI itself has multiple possible causes and is featured by different microhemodynamics and humoral/cellular changes depending on the underlying pathological processes [21]. Two meta-analyses on this topic were performed in 2013, which also included a few studies conducted with the older generation of HES culminating in harmful renal consequences [22][23]. Two other meta-analyses were conducted in recent years to demonstrate the advantages and disadvantages of the administration of 6% 130/0.4–0.42 HES in surgical and trauma patients, proving it safe and favorable in terms of hemodynamic properties [24][25].
It is important, however, to recognize that modern HES products may have value due to their low cost, easy storage and represent a meaningful potential alternative in resource-scare environments. Albumin, although an ideal volume expander, remains expensive and its supply is ultimately limited. While current methods are safe for preventing the transmission of prion-like illnesses with human albumin preparations, all these are contingent on resource investment and societal wealth to support them [8][9]. To further complicate the scenario, researchers also recognize that the use of plasma expanders may not entirely come from the expansion of plasma volume. A quantity of 250 milliliters of 5% albumin is really 12.5 mL of albumin, which is a syringeful; it is unlikely to only work by expansion of the intravascular space [26]. Shimizu K. et al. have shown in an elegant study that the injection of 20 mL of “plasma expander” hypertonic saline or hypertonic glucose increased blood pressure by suddenly increasing endogenous vasopressin even though plasma volume only increased by 2.3%. The injection of 200 mL of isotonic saline, while expanding plasma volume by 12.7%, did not increase vasopressin levels.

2. The Brief Pathophysiology of AKI

In high-income countries, the three main forms of AKI are the postoperative, the septic and the AKI of cardiac origin, except for forms caused by nephrotoxic agents [21][27]. After noncardiac surgeries, the leading cause of renal dysfunction is the ischemic-reperfusion injury due to general or local hemodynamic instability, transport hypoxia due to blood loss and increased intraabdominal pressure [27]. In cardiology patients, venous congestion and with on-pump cardiac surgery, the activation of the immune system is added to these confounders as a significant contributing factor [28]. Hypovolemia and congestive cardiac insufficiency are accompanied by the high activity of the renin-angiotensin-aldosterone system (RAAS) in contrast to the low activity of the RAAS due to hypervolemia, resulting in absolutely different renal microcirculation. Given the presence of renal capsules in in situ kidneys, with venous congestion, fluid overload and third-spacing, the interstitial pressure can exponentially rise within the kidney parenchyma [29]. It is to be understood that from an evolutionary biological standpoint, one would expect fewer escape mechanisms to evolve for surviving fluid overload than coping with hypovolemia. However, septic AKI is characterized by a different intrarenal hemodynamics: the dilatation of the efferent glomerular arteries and the increased patency of shunt vessels produce a low-pressure-high-flow state, consequently dropping the filtration rate in the glomeruli [30]. Besides circulatory changes, several inflammatory mediators play a crucial role in the progression of septic AKI. However, the main contributor of AKI is hemodynamic instability with a potential contribution of nephrotoxic agents, as described recently [31].

3. The Diagnostic Uncertainties of AKI

The worsening of kidney function represents a continuum. Since no clear boundaries can be observed between physiological and pathological conditions, it is difficult to define infliction points. Despite several known pitfalls, most generally accepted diagnostic systems employ the rise of serum creatinine and the amount of urine output as the basis for detecting AKI [16][17][18][19]. However, serum creatinine concentration is considered a ‘slow-reacting parameter’: serum creatinine levels follow clinical changes with an outstanding delay. Moreover, the definition of the perceived “baseline” serum creatinine level further qualifies the perceived frequency and severity of AKI [32]. Using eGFR (as suggested by the Acute Dialysis Quality Initiative [ADQI]) or minimum inpatient serum creatinine levels as the baseline inflated the incidence of AKI in comparison to the most recent outpatient serum creatinine levels between 7 and 365 days prior to admission (38.3%, 35.9% vs. 25.5%, p < 0.001, respectively) [33]. However, the first admission serum creatinine level underestimated the incidence of AKI compared to the most recent outpatient serum creatinine concentration (13.7% vs. 25.5%, p < 0.001) [33]. The main differences (both false positive and negative) were in the AKIN 1 stage. Based on data from the Beginning and Ending Supportive Therapy for the Kidney (BEST Kidney) study, the estimated serum creatinine (Modification of Diet in Renal Disease [MDRD]) leads to a bidirectional misclassification of patients at enrollment (false negative for Risk: 7.3%; false positive for Failure: 18.7%, false positive for all AKI: 11.7%) and at admission to ICU (false positive for Injury, Failure, all AKI: 5.5%, 14%, 18.8%, respectively) [34]. Muscle wasting, sarcopenia, racial differences and fluid overload are important qualifier to interpret serum creatinine values in the ICU settings [32]. In an attempt to overcome these difficulties, newer markers (e.g., cystatin C, NGAL, TIMP2 × IGFBP7) are implemented, but their general usefulness is debated [21][27]. Urine output is an important parameter contributing to the diagnostic frequency and severity of AKI, but administering diuretics blurs the diagnostic reliability [35].

This entry is adapted from the peer-reviewed paper 10.3390/jcm12165262

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