**8. Role of the gut microbiota in acute kidney injury and inflammation**

In AKI, the inflammatory response of the parenchyma determines a remote signal that is expressed in the activation of neutrophils in the lamina propria of the intestine; this leads to the dedifferentiation of circulating monocytes and generates a proinflammatory macrophage phenotype at the intestinal level; this is accompanied by of inflammation, increased permeability of the intestinal wall, and bacterial or endotoxin translocation; a dysbiosis is generated with a decrease in Lactobacillus and an increase in Escherichia and Enterobacter, and this imbalance leads to the loss of short-chain fatty acids (SCFAs).) that under normal conditions fulfills pleiotropic functions in the integrity of the intestinal barrier, T-reg activation mediating immunomodulation and under dysbiosis conditions; it facilitates the activation of the innate immune response [108].

Through the increase of TGF-β and IL-6 and *E. coli*, Th17 lymphocytes are activated in the small and large intestine; it is also mentioned that the intestinal inflammatory response is expressed with increases in the mRNA of renal tumor necrosis factor (TNFα) and interferon (IFN-γ) and IL17, which is related to inflammatory amplification and greater severity of AKI [109]. TNFα, IFN, and IL-6 are elevated after ischemic and non-ischemic AKI these cytokines generate liver damage, which in turn amplifies the inflammatory response that impacts intestinal damage and induces IL-17A release [110].

The marker used to assess uremia for many years has been urea/BUN; the cut-off value of blood urea nitrogen (BUN) for CKRT onset originates from retrospective cohort studies of several studies in which high values or values considered as "late" onset for CKRT as values >94.5 mg/dl were related to higher mortality (p < 0.0001) *Timing of Initiation of Kidney Replacement Therapy in Acute Kidney Injury… DOI: http://dx.doi.org/10.5772/intechopen.112156*

[110]. In another retrospective cohort study of patients with sepsis and AKI, those requiring KRT were defined as "early" onset with BUN <100 mg/dl and "late" onset with BUN values ≥100 mg/dl. In logistic regression analysis, those in the "late" group mortality at 14 days (OR 3.6, P = 0.001), 28 days (OR 2.6, P = 0.01), and 365 days (OR 3.5, P = 0.02) was higher [111]. Vin-Cent Wu et al. in another retrospective cohort study of critically ill patients with acute liver injury and AKI who required CKRT after major surgery, it was observed that those in the "late" dialysis group with BUN >80 mg/dl had higher mortality rate (P = 0.02) and lower rate of recovery of renal function (P = 0.02) compared to the "early" dialysis group [112].

In the PICARD study, a multicenter observational study of 243 patients, it was observed that in the group with high azotemia (BUN >76 mg/dl) adjusted by variables, the relative risk (RR) of death associated with the start of dialysis at a high BUN was of 1.85 (95% confidence interval: 1.16 to 2.96) [113].

In the RCTs, the urea values for the start of CKRT were taken from the reference values of retrospective cohort studies; in the ELAIN study, in the "late" start group, BUN >46.67 mg/dl had an outcome of higher mortality at 90 days, when compared to the "early" start (P = 0.03.). In the AKIKI study, the development of uremia was defined as a BUN >112 mg/dl, criteria for starting KRT in the late group; 60-day mortality did not have significant differences with the early start group (AKI KDIGO3). The AKIKI 2 study defines a limit of very late when BUN >112 mg/dl or oliguria is >72 hours. In the multivariable analysis, the risk of mortality is 65%. If we wait a long time for the decision to start KRT, this study gives us the waiting limit [48, 49, 114].

Future studies on risk assessment of AKI development, prevention measures, use of biomarkers or modulation of the inflammatory response, management of dysbiosis, and timely initiation of KRT will be important to make better decisions on AKI management in critically ill patients.

### **9. Evidence at the START of kidney replacement therapy**

#### **9.1 Randomized controlled trials (RCTs)**

Controversy has been generated for many years at the start of KRT in AKI, with the desire to answer this question; from 2016, several RCTs were carried out in order to make better decisions and with better outcomes, then will describe the most relevant studies.

The ELAIN is a French study, with a single-center RCTs design, which included patients aged 18–90 years, with severe Sepsis with catecholamines (noradrenaline/ adrenaline) at a dose >0.1 mcg/kg/min, with refractory fluid overload data (PaO2/ FiO2 < 300 mgHg, FO >10% of body weight), with SOFA ≥2 and with Acute Kidney Injury - KDIGO stage 2 and NGAL >150 ng/dl. Two groups were randomized, when the "early" KRT onset (n = 112) was within 8 hours of AKI - KDIGO2 diagnosis and the "late" onset group (n = 119) within 12 hours of AKI-KDIGO3 diagnosis or when they met any of the absolute indications (Urea >100 mg/dl, oliguria <200 ml/12 hours or anuria, K > 6 and/or ECG abnormalities, magnesium >4 mmol, pH <7. 15, organ edema in the presence of AKI, resistance to diuretics). The primary outcome was mortality at 90 days showing lower mortality in the "early" group (39.3) vs. "late" (54.7%) with HR 0.66, and p = 0.03, in relation to secondary outcomes median duration of KRT, was lower in the "early" group (9 days) vs. "late" (25 days)

(p = 0. 04); improved recovery of renal function at day 90 in the "early" group was 53.6% (p = 0.02) vs. 38.7% in the "late" group; median duration of mechanical ventilation was shorter in the early group (p = 0.02); the same group had shorter hospital stay (p = <0.001); in the rest of outcomes, there were no significant statistical differences. This is a single-center study with our patients mostly surgical; not all treatments were standardized, and it generates bias in internal validity. On a positive note, it is worth noting that CKRT was performed and then transitioned to SLED and intermittent haemodialysis. These results of the benefit in the "early" start are related to other similar results in patients operated on cardiac surgery, where the temporality is different with respect to other etiologies of AKI [55].

The AKIKI Trail, a French study, is a multicenter, unblinded, RCTs design, which included critically ill patients >18 years with invasive ventilation and/or catecholamine infusion, with AKI within 6 hours after validation of KDIGO stage 3 renal injury (defined by creatinine >354 μmol/liter or 3 times baseline, Anuria (<100 ml/day for >12 hours) and Oliguria (diuresis <0.3 ml/kg/h or < 500 ml/day for >24 hours) compatible with tubular necrosis. Two groups were randomized; the "early" KRT initiation group (n = 312) was within 6 hours after AKI-KDIGO3 diagnosis and the "late" KRT initiation group (n = 308) when they developed absolute indications (urea >40 mmol/L, K > 6 mmol/L, pH < 7.15; acute pulmonary edema with severe hypoxemia and oliguria/anuria >72 hours). The primary outcome was mortality at 60 days and there was no statistical difference between groups (p = 49); in the secondary outcome, the "early" group received KRT in 98% of patients unlike the other group (51%); there were more catheter-associated infections in the "early" group (10%) vs. 5% in the late group; in other outcomes analyzed, there were no significant statistical differences. A strength is that 49% of patients in the "late" group did not require KRT and recovered renal function (50). This work was not blinded, and this generates bias. It is noteworthy that 50% of the critical patients performed KRT in intermittent modality, and this is not a common practice in the clinical condition where 80% of the patients required vasoactive agents, and it is not a common practice in the country where the study was carried out. This study is not comparable to ELAIN, because a greater number of patients who were included in the AKIKI were medical causes of hospital admission and the most frequent cause of AKI was sepsis, which has a different pathophysiological context than the cardiac surgery patients in the ELAIN Trail [56].

In the IDEAL-ICU is another French study with a multicenter, unblinded RCTs design, which included adult patients with septic shock within 48 hours of vasopressor initiation and AKI defined and classified according to RIFLE criteria in grade F; randomization was performed in two branches: those who initiated KRT "early" (n = 239) within 12 hours of AKI-RIFLE(F) diagnosis and those who initiated KRT "late" (n = 238) was within 48 hours of AKI-RIFLE(F) diagnosis or in the presence of absolute indications (K > 6. 5 mmol/L, pH < 7.15, fluid overload refractory to diuretics). In mortality outcomes at 28 and 90 days, there were no significant statistical differences (p = 048 and p = 38, respectively), median days free of KRT, mechanical ventilation, vasopressors, and positive cumulative balance at 7th day; there were no differences between groups, but a higher incidence of hyperkalemia was identified in 4% (p = 0.03) in the "late" start group. Delayed onset allowed time for spontaneous recovery, and only 29% of this group did not require KRT [57].

STARRT-AKI Trail is a multinational RCTs with larger number of patients enrolled (n = 2927); participants were randomized 1:1 for accelerated versus standard KRT initiation. >18 years of age, admitted to an ICU with AKI defined as Cr > 100 umol/l in women and Cr > 130 umol/l in men and who have not decreased Cr by >27 umol/l

#### *Timing of Initiation of Kidney Replacement Therapy in Acute Kidney Injury… DOI: http://dx.doi.org/10.5772/intechopen.112156*

in 48 hours and with evidence of severe AKI with at least 1 of the following 3 cases: >2-fold increase in creatinine from baseline, Cr > 354 umol/l and >27 umol/l above baseline creatinine and with urine output < 6 ml/kg in 12 hours. Two groups were randomized: "accelerated" (n = 1462) was termed when starting KRT within 12 hours after AKI-KDIGO3 diagnosis and the standard group(n = 1465), when AKI persists >72 hours from randomization and one or more of the classic indications: K > 6 mmol/ L, pH < 7.2 or HCO3 < 12 mmol/L, acute pulmonary edema (P/F < 200). In the analysis of the outcomes, it is evident that in mortality at 90 days, there were no differences between both groups (p = 0.92); KRT dependence at 90 days was higher in the accelerated group (10.4%) vs. 6% (RR1.74), and adverse events such as hypotension and hypophosphatemia were higher in the accelerated group, all-cause mortality, KRT dependence at 90 days, MAKE, glomerular filtration, albuminuria, mechanical ventilation, and vasoactive-free days, no significant differences were found between the two groups. This study recruited the largest number of patients of all the RCTs and has internal and external validity, which is applicable to real-world life and has significant results at the time of decision making [58].

The AKIKI2 study is from the group of S. Gaudry et al. and is an unblinded, multicenter, prospective, randomized, and controlled trial. It included patients hospitalized in ICU who received mechanical ventilation and/or catecholamine infusion with AKI according to KDIGO definition. Randomization was performed in two groups, "delayed" group (n = 137) when KRT onset occurs with AKI-KDIGO3 with KDIGO with oliguria: diuresis <0.3 ml/kg/h or < 500 ml/d) or anuria (diuresis <100 ml/d) for >72 hours or azotemia: BUN >112 mg/dl (40 mmol/l) and 140 mg/dl (50 mmol/l) and the "more delayed" group (n = 141), those with absolute indications mentioned in the AKIKI or urea >140 mg/dl (50 mmol/l). In the primary outcome was number of days without KRT from randomization to day 28; there were no differences between groups (p = 0.93); in terms of ICU, in hospital mortality at 28 and 60 days, there were no statistical differences (p = 0.26, p = 0.71, respectively), the number of patients with renal recovery, days free mechanical ventilation, vasoactive agents, ICU-hospital stay time, dialysis dependency time, infection rates, and positive cumulative balance was similar in the two groups. In the multivariate analysis, the risk factors associated with 60-day mortality were more delayed initiation of KRT (HR 1.65), mechanical ventilation (HR 3.44), and SAPS III (HR 1.03). The strength of this study is that it places an "upper limit" for dialysis initiation as a mortality risk point [114].

#### **9.2 Meta-analysis**

In a systematic review and meta-analysis, they included 56 studies, and of these, 10 were RCTs; 4753 critically ill patients with severe AKI were included, where all-cause mortality was 45.5% in the accelerated group vs. 46.6% in the standard group (p = 0.46), without differences in mortality at 28 and 90 days; there were no differences in dependence between both groups (p = 0.08). In the analysis by subgroups, there was a greater dependence on KRT in early-onset patients with SOFA >11 and in mixed dialysis modality (CKRT and intermittent hemodialysis). The subgroup of surgical patients had lower mortality when receiving CKRT and less dialysis dependence than the subgroup of nonsurgical patients; the risk of dialysis dependence was increased in the accelerated KRT group when those patients used non-CKRT modality or had high SOFA scores. This meta-analysis was methodologically flawless and low in publication bias [115].

Another meta-analysis includes 18 RCTs with 2856 patients and focused on the timing of KRT initiation (accelerated vs. standard), and there were no differences in mortality (p = 0.9). In the subgroup of high-quality RCTs, there were no statistical differences (p = 0.7) and there were no differences in mortality at 28 and 90 days, mortality was similar in the CKRT and intermittent hemodialysis modalities, and mortality was similar in the AKI groups. In the community and in the ICU, it is reported that there was greater dependence on KRT in the accelerated start group and in four studies catheter-associated complications and infections were observed [116].

Wei-Ting Lin et al. report a meta-analysis of 11 RCTs assigned to early (n = 1131) and late (1111) groups; mortality at 28, 60, and 90 days was similar in both groups; in ICU and hospital mortality, there were no statistical differences. In four studies of surgical patients, mortality was lower in the early-onset group and is supported by other studies with similar results in the same population, but the dependence of KRT at 28 and 90 days was similar between groups and did not improve renal recovery either. Regarding adverse events, infections and hypophosphatemia were more frequent in the early-onset group. In this study, the heterogeneity of the studies was high [117]. In another meta-analysis of 15 RCTs, they included 5395 patients who showed similar results in that there were no significant differences in mortality at 28, 60, and 90 days, without differences in terms of ICU and hospital stay, with more episodes of hypotension and infections in the early-onset group [118].

Another meta-analysis of 14 RCTs where 5234 patients were recruited and compared early vs. late initiation of KRT, no differences were found in mortality at 30 (RR 1.0) and 90 days (RR 1.0); there was greater dependence on KRT; hypotension and hypophosphatemia in the early-onset group [119].

The current evidence supports the conservative approach of waiting for classic indications, considering a time limit of more than 3 days of anuria/oliguria or urea >240 mg/dl for the start of KRT, given that a longer delay increases the risk of mortality [114, 119].
