**10. Other non-classic indicators that should be considered when decisión making at the START of KRT**

#### **10.1 Patient severity**

Patient severity influences the risk of developing AKI, as evidenced in a prospective cohort study of 33 surgical patients admitted to the ICU, 22 of whom had sepsis and AKI at different stages. The biomarkers SOFA, APACHE III and serum and urinary NGAL these last two biomarkers had an area under the curve (AUROC) of 0.98, AUROC of 0.885 respectively, the SOFA score together with serum and urinary NGAL reach an AUROC 0.963 to predict AKI and mortality [120].

It is a retrospective cohort of 90 patients who are divided into two groups: the survivors and the non-survivor group. In the non-survivor group at the start of KRT, the APACHE III value, vasoactive-inotropic score (VIS), and lactate were higher than in the survivor group; the APACHE III scores had an AUROC of 0.866 and the VIS AUROC of 0.796; the SOFA had an AUROC of 0.732, as predictors of mortality. In the multivariate analysis at the beginning of KRT, APACHE III had an OR 1.22, VIS an OR1.147, low MAP before KRT had OR 1.17, lactate before KRT had OR 1.55; time from diagnosis to "late" start of KRT reached OR 1.014; all were independent risk factors for mortality in AKI with KRT. Variables other than the classical ones are

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

#### **Figure 5.**

*Classic and severity criteria in the critically ill patient for initiation of KRT. Classically known indications for KRT are when complications are generated in severe AKI. We mention that AKI is a pathology with systemic impact and it is important to observe other severity factors in the critically ill patient that allow us to make the best decision on when to initiate KRT [120–122, 124–127].*

possible (uremia, pH, bicarbonate and K) and should be considered and help to choose the moment to start KRT in critically ill patients [121]. Regarding VIS, a retrospective cohort showed in the multivariable logistic regression analysis that VIS was associated with postoperative AKI (OR 1.19) (P < 0.001) and with the need for KRT (OR: 1.29, P = 0.007). The VIS AUROC is a good predictor of postoperative AKI (AUROC: 0.84, P < 0.001) and predictor of the need for KRT (AUROC: 0.91, P < 0.001) [122]. Further studies are required to validate these data.

Lactate is a good biomarker to assess tissue perfusion and energetic-metabolic status; in different clinical circumstances, production may be normal or increased with defective or close to normal clearance. The increase in lactate has been widely studied as a predictor of mortality in sepsis and septic patients receiving KRT [123].

It is important to mention that lactate clearance is 1379 ml/min under normal conditions and the clearance capacity for a hemofilter is on average 24.2 ml/min, and the hemofilter represents <3% of lactate clearance, which is not sufficient in patients critical and should focus on treating the primary cause of decompensation (**Figure 5**) [128].

In a prospective cohort of 186 patients with sepsis and septic AKI (S-AKI) who received CKRT-CVVHDF, serum lactate value was assessed before initiation, 24 hours after CKRT, and percentage lactate clearance. They were divided into a group of survivors and non-survivors; in this last group lactate at the beginning, at 24 hours, it was significantly higher (p = <0–001), and lactate clearance was <10% (p = 0.004). The lactate value 24 hours after starting the CKRT is associated with early mortality (48 hours) with OR 1.72 and late mortality (28 days) with OR 2.35; in those in which clearance is >10%, it is associated with lower early mortality (OR 0.114) and late (OR 0.235); the AUROC values for lactate at 24 hours predict early mortality 0.87 and late mortality 0.82; the AUROC for lactate clearance as a predictor of early mortality was 0.72 and late mortality 0.70, respectively [124].

In a retrospective cohort of 342 patients divided into three groups: early recovery, early death group, and control group, the multivariate logistic regression analysis

identified factors that can predict the recovery of renal function in the first 48 hours, such as the presence of diuresis. (AUROC 0.64), SOFA <10 (AUROC 0.67), and short duration (0.3 days) between ICU admission and initiation of CKRT (AUROC 0.68); all three factors predict recovery of renal function with AUROC 0.78. In the group with early mortality, they presented SOFA values >13, SAPSIII>74 points, neurological disease (OR 9.64), use of vasopressors (OR 3.68), lactate >3.6 mmol/L with a sensitivity of 88%, and a specificity of 67% (OR 1.19).), albumin <2.2 g/dl (OR 0.52) as predictors of mortality and capable of predicting a group of very seriously ill people who do not benefit from KRT [129]. In the post hoc study of the AKIKI and IDEAL-ICU clinical trials in the stratified analysis of thirds of the SOFA score, those with SOFA >10, the CKRT did not show a decrease in mortality at 60 days [125].

In a prospective cohort of 999 patients with S-AKI requiring dialysis, three patient phenotypes were identified through the Manhattan plot of the standardized differences of the clinical characteristics evaluated. Phenotype 1 is characterized by young patients, low Charlson comorbidity index (CCI), normal renal function, low Glasgow, low Po2, low PaO2/FiO2, high lactate and SOFA, APACHE III, unlike phenotype 2 with intermediate characteristics and phenotype 3 with older patients, altered renal function, and less severe acute disease with low lactate and SOFA. Phenotype 1 presented a higher risk of mortality 73.86% and when compared with group 2 (56.57%) and group 3 (46.22%) (p < 0.001); also, a lactate >3.3 mmol/L at the start of KRT is associated with mortality (HR 1. 34), and KRT-dependent (HR 0.69) could be a predictive biomarker for dialysis initiation or SA-AKI severity, and further research is required to confirm this hypothesis [126].

In a prospective cohort of 500 patients with type 1 cardiorenal syndrome (type 1 CRS) who required KRT, serum lactate measurement may be a marker of hemodialysis withdrawal and 90-day mortality. qSOFA values were higher (>1) in the mortality group and hemodialysis dependence group; lactate values >4.2 mmol/L were associated with higher 90-day mortality (p = <0.001) and lower probability of withdrawal of dialysis (p = <0.001) in the presence or absence of sepsis [127].

In relation to what has been reviewed, it should be considered that patients with diuresis, SOFA <10, and lactate <4.2 mmol/L, are likely to have early renal recovery and do not require KRT.

#### **10.2 Furosemide stress test (FST)**

Diuretic use has been controversial in AKI; Chawa et al. show in a retrospective, prospective cohort that administering a furosemide bolus of 1 mg/kg or 1.5 mg/kg in those receiving diuretics is one way to assess functional reserve.. In the presence of AKI, the use of FST with a value of <200 ml of diuresis in 2 hours is a predictive marker of AKI-AKIN III progression with AUC 0.87 (p = 0.001) with a sensitivity of 87.1% and a specificity of 84. 1% and as a predictor of the need for KRT with AUROC 0.86 and mortality with AUROC 0.70. Koyner et al. compare the use of FST and biomarkers or biomarkers alone to assess AKI progression; the combination of FST and biomarkers predicts progression to AKI-AKIN III with AUROC 0.90 and predicts the need for KRT with AUROC 0.91. This furosemide challenge is useful to differentiate those without functional reserve and consider initiation of KRT [52, 130].

In a randomized, multicenter, and controlled trial of 162 patients with ARF at any KDIGO stage without emergency indications and without contraindications, the use of FST allowed the evaluation of two groups, responders and nonresponders; the latter *Timing of Initiation of Kidney Replacement Therapy in Acute Kidney Injury… DOI: http://dx.doi.org/10.5772/intechopen.112156*

group was divided according to the time of KRT initiation into two groups: the earlyonset group within 6 hours of ARF-KDIGO diagnosis 1,2,3 and the late-onset group when initiation is due to absolute indications. FST discriminates patients with AKI who may potentially require KRT; in nonresponders, early or late onset of KRT did not affect mortality [131].

The diagnostic accuracy of FST for AKI progression had an AUROC of 0.88 (sensitivity 0.81 and specificity 0.88); as a predictor for KRT initiation, it has an AUROC of 0.86 (sensitivity 0.84 and specificity 0.77); FST performs better as a predictor of need for KRT in AKI-KDIGO 1–2 compared to AKI-KDIGO 3 with a pooled diagnostic accuracy of 0.86 [132].

In a prospective, double-blind, and interventional cohort study of 187 patients admitted to the ICU with AKI undergoing FST, 37.5% of patients who responded to FST received CKRT, while 89.2% of patients who did not respond to FST received CKRT. On univariate analysis, platelet count was lower in the CKRT group (p = 0.04); more patients with acidosis were identified in the CKRT group (p = < 0. 05); there were more patients with AKI-KDIGO 2 and 3 in the CKRT group and a higher number of stage 1 patients in the non-KRT group; urinary volume was lower in the CKRT group (35 ml, IQR 5–143. 75 vs. 400 ml, IQR 210–890; P = 0. 000), SOFA and APACHE II were lower in the non-KRT group (p = 0.000); SOFA and APACHE II scores were higher in the CKRT group (P < 0. 05); in multivariate analysis, negative FST (diuresis <200 ml in 2 hours) was a predictor of CKRT initiation (P = 0. 032). Patients who did not respond to FST were 2.379 times more likely to initiate CKRT (P = 0. 000). Post-STF urine volume of 156 ml had an AUROC of 0.966 (sensitivity 94.85%, specificity 98.04%, p < 0.001), and SOFA (>8) had an AUROC of 0.846 predictors of CKRT initiation [133].

In a prospective, observational study of 312 patients in a medical ICU, those who developed AKI according to KDIGO diuresis criteria were subjected to receive Sequential Nephron Blockade (SBN) with initial use of Furosemide at 1 mg/kg (maximum 60 mg), followed by a maintenance dose of 10 to 20 mg/hour; adequate diuretic response was termed >0.5 ml/kg/h or > 300 ml in 6 hours and 5 ml/kg/h or > 300 ml in 6 hours, if adequate diuretic response was not achieved (<0.5 ml/kg/h or < 300 ml in 6 hours). Metolazone 10 mg was administered; those nonresponders to SBN started KRT [134]. In multivariate logistic regression analysis, those with SOFA >9 (OR 4.5), those who achieved a positive cumulative balance of 4.2 L (OR 2.82), those who required KRT (OR 1.78), and those with negative diuresis (OR 0.45) had higher mortality [134].

It is important to mention that the SOFA score is a good predictor of AKI severity, poor diuretic response, and the need for KRT. More prospective studies with larger numbers of patients are required to confirm these data.

The combination of FST and elevated urine levels of the chemokine biomarker (C-C motif) ligand 14 (CCL14) had a high predictive value (AUC ROC 0.87) as a predictor of the need for CKRT, compared to FST alone (AUC ROC 0.79) or CCL14 (AUC 0.83), P = <0.001 [135].

I believe that negative FST and the use of biomarkers along with factors determining increased demands for critical illness may be useful at the time of decision making.

#### **10.3 Kinetic eFG**

It is known that creatinine is a late marker in AKI, and its value is influenced by various variables that underestimate (fluid overload, hyperbilirubinemia,

malnutrition) or overestimate the value (cimetidine, fibrates, and sulfamethoxazole and trimethoprim). Determination of eGFR in the patient with AKI with the classic eGFR formulas in CKD requires a steady state of creatinine values, a condition that is not met in AKI.

The eFG kinetic (KeFG) is a formula proposed by Chen [136] incorporates the mass equilibrium principles (generation, distribution, excretion) together with an "elapsed time" factor to assign an eGFR to each value of Cr as long as the time elapsed since the last value is known. The KeFG evaluates sudden and rapid changes in eGFR, unlike the eGFR measured by Clearance calculated, where the decrease in GFR is gradual by the Crocoft, MDRD, and CKD-EPI formulas (**Figure 6**).

In a retrospective cohort of 2492 patients, the KeGFR was incorporated with or without UO criteria (diuresis) and added to the KDIGO classification with three modified stages:

Stage 1: KeGFR 45 to 60 mL/min/1.73 m<sup>2</sup> or urine output <0.5 mL/kg/h for 6 h.

$$KeGFR = \frac{baseline \, SCr \, X \, eGFR}{Mean \, SCr} \qquad \propto \left[1 \cdot \frac{24 \text{\AA} \, \Delta \text{SCr}}{\Delta Time(h) \, \text{\AA} \, \text{mA} \, \Delta \text{SCr}/day} \right]$$

#### **Figure 6.**

*Modified see end of document. KeGFR. SSPCR is steady-state plasma creatinine; crcl is MDRD creatinine clearance. Mean PCR refers to the difference in plasma creatinine concentration. Δ time(h) is the interval in hours between two consecutive creatinine measurements and max delta pcr/day is the theoretical maximum change in plasma creatinine that can occur per day if renal function ceases completely. ΔPCr is defined as the initial creatinine subtracted from the final creatinine. MaxΔPCr/day, addresses the principle of creatinine mass balance by incorporating the volume of distribution factor (V d) [136]*.

**Figure 7.** *Kidney replacement therapy initiation algorithm [137].*

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

Stage 2: KeGFR 30 to 45 mL/min/1.73 m2 or urine output <0.5 mL/kg/h for 12 hours.

Stage 3: KeGFR <30 ml/min/1.73 m<sup>2</sup> or diuresis <0.3 ml/kg/h for 12 h or anuria for 12 h.

In this study, the degree of agreement between KDIGO and KeGFR was very good (Cohen's kappa with square weights = 0.77). The sensitivity of the combined KeGFR and urine criteria compared to the KDIGO criteria was 93.2%, specificity 73.0%, and accuracy 85.7%, also allowing faster AKI recognition, where a time difference in recognition between KDIGO and KeGFR at stage 1 is 5.9 hours, stage 2 is 7.2 hours, and stage 3 is 4 hours. In the logistic regression model, the prediction of mortality at 28 days by KDIGO was AUROC 0.57 and for KeGFR, an AUROC 0.60; as a predictor of the need for KRT, the KDIGO had an AUROC 0.81 and for KeGFR, an AUROC 0.80. We see that the KeGFR allows a faster diagnosis of AKI using serial creatinine determinations at time intervals and with good ability to predict the severity of AKI, with the ability to predict the need for KRT and mortality. It is possible that the use of KeGFR, FST, and biomarkers provides complementary tools for the early diagnosis of AKI and allows better decisions to be made in choosing the right moment to start KRT (**Figure 7**) [138].
