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Non-recovery of renal function is a strong independent risk factor associated with mortality in AKI patients

ABSTRACT

Introduction:

Acute kidney injury (AKI) is a recurrent complication in the intensive care unit (ICU) and is associated with negative outcomes.

Objective:

To investigate factors associated with mortality in critically ill AKI patients in a South Brazilian ICU.

Methods:

The study was observational retrospective involving AKI patients admitted to the ICU between January 2011 and December 2016 of at least 18 years old upon admission and who remained in the ICU at least 48 hours. Comparisons between selected characteristics of survivor and non-survivor groups were done using univariate analysis; multivariate logistic regression was applied to determine factors associated with patient mortality.

Results:

Of 838 eligible patients, 613 participated in the study. Men represented the majority (61.2%) of the patients, the median age was 53 years, and the global mortality rate was 39.6% (n= 243). Non-recovery of renal function after AKI (OR= 92.7 [38.43 - 223.62]; p <0.001), major surgery-associated AKI diagnosis (OR= 16.22 [3.49 - 75.38]; p <0.001), and the use of vasoactive drugs during the ICU stay (OR = 11.49 [2.46 - 53.70]; p <0.002) were the main factors independently associated with patient mortality.

Conclusion:

The mortality rate observed in this study was similar to that verified in other centers. Non-recovery of renal function was the variable most strongly associated with patient mortality, suggesting that the prevention of factors that aggravate or maintain the AKI episode should be actively identified and mitigated, possibly constituting an important strategy to reduce mortality in AKI patients.

Keywords:
Acute Kidney Injury; Mortality; Risk Factors; Epidemiology; Intensive Care Units

RESUMO

Introdução:

A lesão renal aguda (LRA) é uma complicação recorrente na unidade de terapia intensiva (UTI), e está associada a desfechos desfavoráveis.

Objetivo:

Investigar fatores associados à mortalidade em pacientes com LRA, criticamente enfermos em uma UTI do Sul do Brasil.

Métodos:

O estudo foi retrospectivo observacional, envolvendo pacientes com LRA internados na UTI entre janeiro de 2011 e dezembro de 2016, com pelo menos 18 anos de idade na admissão e que permaneceram na UTI por pelo menos 48 horas. Comparações entre características selecionadas de grupos sobreviventes e não sobreviventes foram feitas usando análise univariada; regressão logística multivariada foi aplicada para determinar fatores associados à mortalidade dos pacientes.

Resultados:

Dos 838 pacientes elegíveis, 613 participaram do estudo. Os homens representaram a maioria (61,2%) dos pacientes, a idade média foi de 53 anos e a taxa de mortalidade global foi de 39,6% (n = 243). Não recuperação da função renal após LRA (OR = 92,7 [38,43 - 223,62]; p <0,001), diagnóstico de LRA associado à cirurgia (OR = 16,22 [3,49 - 75,38]; p <0,001) e uso de drogas vasoativas durante a internação na UTI (OR = 11,49 [2,46 - 53,70]; p <0,002) foram os principais fatores independentemente associados à mortalidade dos pacientes.

Conclusão:

A taxa de mortalidade observada neste estudo foi semelhante à verificada em outros centros. A não recuperação da função renal foi a variável mais fortemente associada à mortalidade dos pacientes, sugerindo que a prevenção de fatores que agravam ou mantêm o episódio de LRA deve ser ativamente buscada e incentivada, possivelmente constituindo uma estratégia importante para reduzir a mortalidade em pacientes com LRA.

Descritores:
Lesão Renal Aguda; Mortalidade; Fatores de Risco; Epidemiologia; Unidades de Terapia Intensiva

Introduction

Acute kidney injury (AKI) is a clinical syndrome, whose main defining characteristic is related to the abrupt and sustained decline of the glomerular filtration rate.11 Kidney Disease: Improving Global Outcomes (KDIGO). Acute Kidney Injury Work Group (2012). KDIGO clinical practice guideline for acute kidney injury. Kidney Int. 2:1-138.-22 Koza Y. Acute kidney injury: current concepts and new insights. J Inj Violence Res. 2014 Oct;8(1):58-62. DOI: https://doi.org/10.5249/jivr.v8i1.610
https://doi.org/10.5249/jivr.v8i1.610...
In association with this characteristic, oliguria, water and electrolyte imbalance, and instability of blood pH are also observed.33 Rossaint J, Zarbock A. Acute kidney injury: definition, diagnosis, and epidemiology. Minerva Urol Nefrol. 2016 Feb;68(1):49-57. Also, the complex clinical disorder caused by AKI results in the retention of nitrogenous wastes and increase in extracellular volume.44 Bellomo R, Kellum JA, Ronco C. Acute kidney injury. Lancet. 2012 Aug;380(9843):756-66. DOI: https://doi.org/10.1016/S0140-6736(11)61454-2
https://doi.org/10.1016/S0140-6736(11)61...

AKI is a recurrent complication in the intensive care unit (ICU), and is associated with several negative outcomes, including increased length of ICU and hospital stay, greater need for professional care, and a higher mortality rate.55 Hoste EAJ, Bagshaw SM, Bellomo R, Cely CM, Colman RC, Cruz DN, et al. Epidemiology of acute kidney injury in critically ill patients: the multinational AKI-EPI study. Intensive Care Med. 2015 Jul;41:1411-23. DOI: https://doi.org/10.1007/s00134-015-3934-7
https://doi.org/10.1007/s00134-015-3934-...

6 Bouchard J, Acharya A, Cerdá J, Maccariello ER, Madarasu RC, Tolwani AJ, et al. A prospective international multicenter study of AKI in the intensive care unit. Clin J Am Soc Nephrol. 2015 Aug;10(8):1324-31. DOI: https://doi.org/10.2215/CJN.04360514
https://doi.org/10.2215/CJN.04360514...
-77 Mehta RL, Burdmann EA, Cerdá J, Feehally J, Finkelstein F, García-García G, et al. Recognition and management of acute kidney injury in the International Society of Nephrology 0by25 Global Snapshot: a multinational cross-sectional study. Lancet. 2016 May;387(10032):2017-25. DOI: https://doi.org/10.1016/S0140-6736(16)30240-9
https://doi.org/10.1016/S0140-6736(16)30...
Many aspects influence the variation in the AKI incidence rate, with critically ill patients from developing countries showing worse outcomes.66 Bouchard J, Acharya A, Cerdá J, Maccariello ER, Madarasu RC, Tolwani AJ, et al. A prospective international multicenter study of AKI in the intensive care unit. Clin J Am Soc Nephrol. 2015 Aug;10(8):1324-31. DOI: https://doi.org/10.2215/CJN.04360514
https://doi.org/10.2215/CJN.04360514...

7 Mehta RL, Burdmann EA, Cerdá J, Feehally J, Finkelstein F, García-García G, et al. Recognition and management of acute kidney injury in the International Society of Nephrology 0by25 Global Snapshot: a multinational cross-sectional study. Lancet. 2016 May;387(10032):2017-25. DOI: https://doi.org/10.1016/S0140-6736(16)30240-9
https://doi.org/10.1016/S0140-6736(16)30...
-88 Bouchard J, Mehta RL. Acute kidney injury in Western countries. Kidney Dis (Basel). 2016;2(3):103-10. DOI: https://doi.org/10.1159/000445091
https://doi.org/10.1159/000445091...
In a recent international multicenter study, AKI episodes occurred in 44.6% of ICU patients, whereas the incidence of these events was 12.7% in South America.55 Hoste EAJ, Bagshaw SM, Bellomo R, Cely CM, Colman RC, Cruz DN, et al. Epidemiology of acute kidney injury in critically ill patients: the multinational AKI-EPI study. Intensive Care Med. 2015 Jul;41:1411-23. DOI: https://doi.org/10.1007/s00134-015-3934-7
https://doi.org/10.1007/s00134-015-3934-...

According to the available literature, in Brazil, the mortality of critically ill AKI patients varies from 15.3% (in the Northeast)99 Daher EF, Silva Junior GB, Santos SQ, Bezerra CCR, Diniz EJB, Lima RSA, et al. Differences in community, hospital and intensive care unit-acquired acute kidney injury: observational study in a nephrology service of a developing country. Clin Nephrol. 2012 Dec;78(6):449-55. DOI: https://doi.org/10.5414/CN107167
https://doi.org/10.5414/CN107167...
to 53.2% (in the South).1010 Peres LAB, Wandeur V, Matsuo T. Predictors of acute kidney injury and mortality in an intensive care unit. J Bras Nefrol. 2015 Mar;37(1):38-46. DOI: https://doi.org/10.5935/0101-2800.20150007
https://doi.org/10.5935/0101-2800.201500...
This variation in mortality can be understood in the context of the continental dimensions of Brazil and the great diversity in the allocation of (economic-financial, human, etc.) resources for health care amongst the different Brazilian regions. Therefore, this study aimed to investigate factors associated with mortality in critically ill AKI patients in a South Brazilian ICU.

Methods

The study report was elaborated following the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines.1111 Von Elm E, Altman DG, Eggeer M, Pocock SJ, Gotzsche PC, Vandenbroucke JP. Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. BMJ. 2007 Oct;335(7624):806-8. DOI: https://doi.org/10.1136/bmj.39335.541782.AD
https://doi.org/10.1136/bmj.39335.541782...

Design, Setting, and Patients

We carried out an observational retrospective study in a single ICU in Brazil. The unit is in a university hospital, has fifteen beds, and provides care to clinical and surgical patients of various medical specialties. All patients admitted between January 2011 and December 2016 were included in this research, with ICU-acquired AKI defined and classified according to the Kidney Disease: Improving Global Outcomes (KDIGO)11 Kidney Disease: Improving Global Outcomes (KDIGO). Acute Kidney Injury Work Group (2012). KDIGO clinical practice guideline for acute kidney injury. Kidney Int. 2:1-138. criteria, who were at least 18 years old upon admission, and remained in the unit at least 48 hours. Patients with AKI acquired outside the ICU, those with serum creatinine >4.0 mg/dL upon admission, and with chronic kidney disease were excluded.

Variables

Data collection occurred between October 2016 and January 2018, and included variables of clinical-epidemiological features (age; gender; race; comorbidities; diagnosis and clinical conditions at ICU admission (ICU-ad), serum creatine and oliguria at ICU-ad; urine output in the first 24 hours; scores of the second version of the mortality prognostic system Acute Physiology and Chronic Health Evaluation (APACHE II),1212 Knaus WA, Draper EA, Wagner DP, Zimmerman JE. APACHE II: a severity of disease classification system. Crit Care Med. 1985 Oct;13(10):818-29. and length of ICU and hospital stay).

Furthermore, data were collected on occurrences during the ICU stay, including general occurrences (need for mechanical ventilation, intravenous contrast, blood transfusion, surgeries, infection, and sepsis), biochemical imbalance (hyponatremia - sodium serum concentration <135 mEq/L; hypernatremia - sodium serum concentration >145 mEq/L; hypokalemia - potassium serum concentration <3.5 mEq/L, hyperkalemia - potassium serum concentration >5.5 mEq/L; hypoglycemia - glucose serum concentration <70 mg/dL; hyperglycemia - glucose serum concentration >140 mg/dL; metabolic acidosis - arterial blood pH <7.35 and bicarbonate serum concentration <22 mEq/L), need for drugs (vasoactive drugs, diuretics, nonsteroidal anti-inflammatory drugs, vancomycin, amphotericin B, polymyxin B, and aminoglycosides); and fluid balance (days of oliguria, positive and negative fluid balance, as well as accumulated fluid balance). Oliguria was defined as urine output below 400 mL/day. Fluid balance was considered as the difference between fluid gains and losses by the patient over 24 hours. Thus, we considered that patients with positive fluid balance (or water overload) presented fluid gains greater than losses (in 24 h). Accumulated fluid balance was considered as the result of the patient’s general water balance at the end of the ICU stay.

Organ dysfunction (hematological, cardiovascular, hepatology, respiratory, and multiple) was analyzed considering the current definitions.1313 Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, et al. The third international consensus definitions for sepsis and septic shock (sepsis-3). JAMA. 2016 Feb;315(8):801-10. DOI: https://doi.org/10.1001/jama.2016.0287
https://doi.org/10.1001/jama.2016.0287...
Additionally, we collected variables related to the timing of the AKI diagnosis (KDIGO criteria for diagnosis and stage, main associated etiology, and need for renal replacement therapy (RRT)). Finally, we evaluated the recovery of renal function at ICU discharge, classifying the recovery in three levels: 1) full recovery - absence of AKI criteria; 2) partial recovery - drop in the AKI stage; 3) non-recovery - maintenance of the AKI stage.1414 Forni LG, Darmon M, Oudemans-van Straaten HM, Pettilä V, Prowle JR, Schetz M, et al. Renal recovery after acute kidney injury. Intensive Care Med. 2017 May;43(6):855-66. DOI: https://doi.org/10.1007/s00134-017-4809-x
https://doi.org/10.1007/s00134-017-4809-...

Statistical Analysis

We determined the mortality rate by the number of patients with AKI who died in the ICU. The mortality risk factors were determined by performing comparative analysis between groups of survivor and non-survivor patients. Categorical variables are presented as absolute and relative frequency and continuous variables as medians and interquartile range (IQR 25% - 75%). Comparisons between groups were carried out applying Chi-square or Fisher’s exact test and Mann-Whitney’s U-test, for categorical and continuous variables, respectively.

Variables that in the bivariate analysis presented p-value <0.20 were selected for the multivariate logistic regression model using the stepwise method. In the final model, variables with variance inflation factor greater than ten were excluded to avoid multicollinearity problems. The Hosmer-Lemeshow test and area under the receiver operating characteristic curve were used to assess the discrimination and calibration of the final model, respectively. Also, we constructed a Kaplan-Meier curve with log-rank test to determine survival rates for the different subgroups of recovery of renal function post-AKI in ICU. We considered p-values <0.05 as statistically significant. All analyses were performed in the XLSTAT version 2018.

Ethical Aspects

The study received approval from the Ethics Committee of the authors’ institution, under approval number 1.622.962. There was no need for informed consent. Nonetheless, we declare that all local and international ethical precepts have been respected, including those contained in the Declaration of Helsinki.

Results

Of 838 eligible patients, we excluded 64 with AKI acquired before ICU-ad, 52 with serum creatinine >4.0 mg/dL, and 109 with chronic kidney disease. Thus, in this study, 613 AKI patients were included. The median age was 53 (38-67) years, and non-survivors were older. In the mortality rate analysis, we could determine that the global mortality continued at 39.6% (n= 243) and that, among those with KDIGO stage 3, the mortality amounted to 74.4% (Fig. 1).

Figure 1
Mortality rate global and according the KDIGO stage.

KDIGO - Kidney Disease Improving Global Outcomes.


When comparing the data collected in the ICU-ad, there was no difference between the groups for serum creatinine (survivors: 1.1 [0.7-1.7] mg/dL vs. nonsurvivors: 1.1 [0.8-1.6] mg/dL; p-value 0.547), but oliguria upon admission was more frequent among non-survivors (n= 25; 10.3% vs. survivors group: n= 11; 3.0%; p-value <0.001). Similarly, APACHE II score was also significantly higher among those who died (median 28 [23-31] points vs. survivors group: median 24 [19-29] points; p-value <0.001) (Table 1).

Table 1
Clinical-epidemiological features of patients.

During the ICU stay, the need for mechanical ventilation was greater among non-survivors (median 10 [5-20] days vs. survivor group: median 9 [4-17] days; p-value <0.001), as well as the occurrence of sepsis (n= 61, 16.5% vs. survivor group: n= 102, 40.2%; p-value <0.001) and metabolic acidosis (n= 252, 68.1% vs. survivor group: n= 217, 89.3%; p-value <0.001). Non-survivors had less need for NSAIDs (n= 98, 40.3% vs. survivor group: n= 216, 58.4%, p-value <0.001), but higher fluid balance alterations and higher frequency of organ dysfunction (Table 2).

Table 2
Occurrences during the length of ICU stay.

The non-survivor group had AKI diagnosis carried out mainly by KDIGO criteria (n= 134, 55.2% vs. survivor group: n= 63, 17%; p-value <0.001), more sepsis-associated AKI (n= 69, 28.4% vs. survivor group: n= 59, 15.9%; p-value <0.001), RRT need (n= 47, 19.3% vs. survivor group: n= 29, 7.8%; p-value <0.001), and higher frequency of non-recovery of renal function (n= 221, 90.9% vs. survivor group: n= 54, 14.6%; p-value <0.001) (Table 3).

Table 3
Data of AKI diagnosis.

The multivariate logistic regression results showed that the independent factors associated with mortality were the need for vasoactive drugs during the ICU stay (odds ratio (OR) = 11.49 [2.46-53.70]; p-value 0.002), diagnosis of major surgery-associated AKI (OR= 16.22 [3.49-75.38]; p-value <0.001), and non-recovery of renal function (OR= 92.7 [38.43-223.62]; p-value = <0.001) (Table 4).

Table 4
Mortality risk factors by multivariate logistic regression.

Figure 2 shows the patient’s survival rate by Kaplan-Meier curves according to the recovery of renal function after AKI in ICU.

Figure 2
Kaplan-Meier curves stratified by recovery of renal function post-AKI in ICU.

Discussion

In Brazil, epidemiologic studies about AKI are still incipient, but the event is frequent among critically ill patients in the ICUs and the negative outcome rate is high.99 Daher EF, Silva Junior GB, Santos SQ, Bezerra CCR, Diniz EJB, Lima RSA, et al. Differences in community, hospital and intensive care unit-acquired acute kidney injury: observational study in a nephrology service of a developing country. Clin Nephrol. 2012 Dec;78(6):449-55. DOI: https://doi.org/10.5414/CN107167
https://doi.org/10.5414/CN107167...
-1010 Peres LAB, Wandeur V, Matsuo T. Predictors of acute kidney injury and mortality in an intensive care unit. J Bras Nefrol. 2015 Mar;37(1):38-46. DOI: https://doi.org/10.5935/0101-2800.20150007
https://doi.org/10.5935/0101-2800.201500...
,1515 Barros LCN, Silveira FS, Silveira MS, Morais TC, Nunes MAP, Bastos KA. Acute kidney injury in hospitalized patients with descompensated heart failure. J Bras Nefrol. 2012 Jun;34(2):122-9. DOI: https://doi.org/10.1590/S0101-28002012000200004
https://doi.org/10.1590/S0101-2800201200...

16 Ponce D, Zorzenon CPF, Santos NY, Teixeira UA, Balbi AL. Acute kidney injury in intensive care unit patients: a prospective study on incidence, risk factors and mortality. Rev Bras Ter Intensiva. 2011 Sep;23(3):321-6. DOI: https://doi.org/10.1590/S0103-507X2011000300010
https://doi.org/10.1590/S0103-507X201100...
-1717 Santos NY, Zorzenon CPF, Araújo MF, Balbi AL, Ponce D. Observational prospective study on the incidence of acute renal failure in the intensive care unit of a university-affiliated hospital. J Bras Nefrol. 2009 Sep;31(3):206-11. DOI: https://doi.org/10.1590/S0101-28002009000300006
https://doi.org/10.1590/S0101-2800200900...
. We carried out a comprehensive analysis of 613 AKI patients diagnosed by KDIGO11 Kidney Disease: Improving Global Outcomes (KDIGO). Acute Kidney Injury Work Group (2012). KDIGO clinical practice guideline for acute kidney injury. Kidney Int. 2:1-138. criteria, with a focus on mortality and its risk factors.

Data were analyzed from patients with general clinical-epidemiological features, who stayed in one mixed ICU from a university-affiliated hospital, the majority admitted to the ICU with a surgical diagnosis (58.6%) (Table 1). In this study, the global mortality rate was 39.6% and increased progressively according to the severity of the event (Fig. 1). In earlier research conducted in the same region as our study, the AKI mortality rate was 52% in general, and 84.2% among patients with the need for RRT. In that study, the APACHE II score median was 21 points and the median length of ICU stay was 8.5 days.1010 Peres LAB, Wandeur V, Matsuo T. Predictors of acute kidney injury and mortality in an intensive care unit. J Bras Nefrol. 2015 Mar;37(1):38-46. DOI: https://doi.org/10.5935/0101-2800.20150007
https://doi.org/10.5935/0101-2800.201500...

Other researchers carried out a prospective study of 498 patients admitted to the general ICU of a university-affiliated hospital located in the Brazilian Southeast, with clinical-epidemiological features similar to the patients included in our study. The mortality among AKI patients was 62.1%.1717 Santos NY, Zorzenon CPF, Araújo MF, Balbi AL, Ponce D. Observational prospective study on the incidence of acute renal failure in the intensive care unit of a university-affiliated hospital. J Bras Nefrol. 2009 Sep;31(3):206-11. DOI: https://doi.org/10.1590/S0101-28002009000300006
https://doi.org/10.1590/S0101-2800200900...

During the ICU stay, the non-survivor group had greater accumulated fluid balance (in liters) (+3.9 [-0.433 - +12.37] vs. +13.5 [+6.6 - +28]; p-value: <0.001) (Table 2), as well as higher sepsis-associated AKI (42% vs 16.5%; p-value: <0.001) (Table 3).

Fluid overload is not only associated with AKI but can also be its result and it is pointed out as a potential prognostic biomarker of AKI, considering that its occurrence precedes the increase in creatinine and the decrease in diuresis.1818 Ávila MON, Rocha PN, Zanetta DMT, Yu L, Burdmann EA. Water balance, acute kidney injury and mortality of intensive care unit patients. J Bras Nefrol. 2014 Sep;36(3):379-88. DOI: https://doi.org/10.5935/0101-2800.20140054
https://doi.org/10.5935/0101-2800.201400...

19 Macedo E, Bouchard J, Soroko SH, Chertow GM, Himmelfarb J, Ikizler TA, et al. Fluid accumulation, recognition and staging of acute kidney injury in critically-ill patients. Crit Care. 2010 May;14:R82. DOI: https://doi.org/10.1186/cc9004
https://doi.org/10.1186/cc9004...

20 Thongprayoon C, Cheungpasitporn W, Srivali N, Ungprasert P, Kittanamongkolchai W, Kashani K. The impact of fluid balance on diagnosis, staging and prediction of mortality in critically ill patients with acute kidney injury. J Nephrol. 2016 Apr;29(2):221-7. DOI: https://doi.org/10.1007/s40620-015-0211-3
https://doi.org/10.1007/s40620-015-0211-...
-2121 Kim IY, Kim JH, Lee DW, Lee SB, Rhee H, Seong EY, et al. Fluid overload and survival in critically ill patients with acute kidney injury receiving continuous renal replacement therapy. PloS ONE. 2017 Feb;12(2):e0172137. DOI: https://doi.org/10.1371/journal.pone.0172137
https://doi.org/10.1371/journal.pone.017...
Besides, many patients may have an underestimated creatinine level due to hemodilution caused by fluid overload, which restricts the identification of AKI through the application of current diagnostic criteria.1818 Ávila MON, Rocha PN, Zanetta DMT, Yu L, Burdmann EA. Water balance, acute kidney injury and mortality of intensive care unit patients. J Bras Nefrol. 2014 Sep;36(3):379-88. DOI: https://doi.org/10.5935/0101-2800.20140054
https://doi.org/10.5935/0101-2800.201400...
In an attempt to minimize this bias, Macedo et al.1919 Macedo E, Bouchard J, Soroko SH, Chertow GM, Himmelfarb J, Ikizler TA, et al. Fluid accumulation, recognition and staging of acute kidney injury in critically-ill patients. Crit Care. 2010 May;14:R82. DOI: https://doi.org/10.1186/cc9004
https://doi.org/10.1186/cc9004...
and, more recently, Thongprayoon et al.2020 Thongprayoon C, Cheungpasitporn W, Srivali N, Ungprasert P, Kittanamongkolchai W, Kashani K. The impact of fluid balance on diagnosis, staging and prediction of mortality in critically ill patients with acute kidney injury. J Nephrol. 2016 Apr;29(2):221-7. DOI: https://doi.org/10.1007/s40620-015-0211-3
https://doi.org/10.1007/s40620-015-0211-...
proposed the application of formulas to calculate the creatinine level adjusted for the positive fluid balance. Another way of defining fluid overload is to assess the increase in the percentage of the patient’s baseline bodyweight.2121 Kim IY, Kim JH, Lee DW, Lee SB, Rhee H, Seong EY, et al. Fluid overload and survival in critically ill patients with acute kidney injury receiving continuous renal replacement therapy. PloS ONE. 2017 Feb;12(2):e0172137. DOI: https://doi.org/10.1371/journal.pone.0172137
https://doi.org/10.1371/journal.pone.017...

Besides, it is known that there is an association between fluid overload and greater negative outcomes in AKI patients, including death.1818 Ávila MON, Rocha PN, Zanetta DMT, Yu L, Burdmann EA. Water balance, acute kidney injury and mortality of intensive care unit patients. J Bras Nefrol. 2014 Sep;36(3):379-88. DOI: https://doi.org/10.5935/0101-2800.20140054
https://doi.org/10.5935/0101-2800.201400...

19 Macedo E, Bouchard J, Soroko SH, Chertow GM, Himmelfarb J, Ikizler TA, et al. Fluid accumulation, recognition and staging of acute kidney injury in critically-ill patients. Crit Care. 2010 May;14:R82. DOI: https://doi.org/10.1186/cc9004
https://doi.org/10.1186/cc9004...

20 Thongprayoon C, Cheungpasitporn W, Srivali N, Ungprasert P, Kittanamongkolchai W, Kashani K. The impact of fluid balance on diagnosis, staging and prediction of mortality in critically ill patients with acute kidney injury. J Nephrol. 2016 Apr;29(2):221-7. DOI: https://doi.org/10.1007/s40620-015-0211-3
https://doi.org/10.1007/s40620-015-0211-...

21 Kim IY, Kim JH, Lee DW, Lee SB, Rhee H, Seong EY, et al. Fluid overload and survival in critically ill patients with acute kidney injury receiving continuous renal replacement therapy. PloS ONE. 2017 Feb;12(2):e0172137. DOI: https://doi.org/10.1371/journal.pone.0172137
https://doi.org/10.1371/journal.pone.017...
-2222 Ostermann M, Liu K, Kashani K. Fluid management in acute kidney injury. Chest. 2019 Sep;156(3):594-603. DOI: https://doi.org/10.1016/j.chest.2019.04.004
https://doi.org/10.1016/j.chest.2019.04....
Considering that septic patients can benefit from volume expansion in the early hours, it is emphasized that volume replacement should occur until the intravascular volume is restored, with minimum fluid administration.2222 Ostermann M, Liu K, Kashani K. Fluid management in acute kidney injury. Chest. 2019 Sep;156(3):594-603. DOI: https://doi.org/10.1016/j.chest.2019.04.004
https://doi.org/10.1016/j.chest.2019.04....

Sepsis is the main AKI cause,55 Hoste EAJ, Bagshaw SM, Bellomo R, Cely CM, Colman RC, Cruz DN, et al. Epidemiology of acute kidney injury in critically ill patients: the multinational AKI-EPI study. Intensive Care Med. 2015 Jul;41:1411-23. DOI: https://doi.org/10.1007/s00134-015-3934-7
https://doi.org/10.1007/s00134-015-3934-...
substantially increases the risk of death in the critically ill patients, both in adult and pediatric populations,2323 Devarajan P, Basu RK. Sepsis-associated acute kidney injury - is it possible to move the needle against this syndrome?. J Pediatr. 2017 Jan/Feb;93(1):1-3. DOI: https://doi.org/10.1016/j.jped.2016.09.001
https://doi.org/10.1016/j.jped.2016.09.0...
and contributes to the progression of chronic kidney disease after AKI.2424 Pereira BJ, Barreto S, Gentil T, Assis LS, Soeiro EMD, Castro I, et al. Risk factors for the progression of chronic kidney disease after acute kidney injury. J Bras Nefrol. 2017 Sep;39(3):239-45. DOI: https://doi.org/10.5935/0101-2800.20170041
https://doi.org/10.5935/0101-2800.201700...
We did not include sepsis occurrence and sepsis-associated AKI in the multivariate models of mortality due to multicollinearity.

In Table 4, we show that non-recovery of renal function at ICU discharge was significantly associated with death among AKI patients. The pathophysiology of renal recovery after an AKI episode involves several mechanisms, including cell cycle arrest, infiltration of inflammatory cells, stimulation of fibrocytes and myofibroblasts, as well as secretion of inflammatory cytokines.1414 Forni LG, Darmon M, Oudemans-van Straaten HM, Pettilä V, Prowle JR, Schetz M, et al. Renal recovery after acute kidney injury. Intensive Care Med. 2017 May;43(6):855-66. DOI: https://doi.org/10.1007/s00134-017-4809-x
https://doi.org/10.1007/s00134-017-4809-...

The non-recovery of renal function after AKI has been related to several negative outcomes, and the severity and duration of the AKI can influence the recovery degree.1414 Forni LG, Darmon M, Oudemans-van Straaten HM, Pettilä V, Prowle JR, Schetz M, et al. Renal recovery after acute kidney injury. Intensive Care Med. 2017 May;43(6):855-66. DOI: https://doi.org/10.1007/s00134-017-4809-x
https://doi.org/10.1007/s00134-017-4809-...
,2525 Pannu N, James M, Hemmelgarn B, Klarenbach S, Alberta Kidney Disease Network. Association between AKI, recovery of renal function, and long-term outcomes after hospital discharge. Clin J Am Soc Nephrol. 2013 Feb;8(2):194-202. DOI: https://doi.org/10.2215/CJN.06480612
https://doi.org/10.2215/CJN.06480612...
In a group of Brazilian patients with dialysis AKI, the non-recovery of renal function was associated with a higher mortality rate.2626 Lee SA, Cozzi M, Bush EL, Rabb H. Distant organ dysfunction in acute kidney injury: a review. Am J Kidney Dis. 2018 Dec;72(6):846-56. DOI: https://doi.org/10.1053/j.ajkd.2018.03.028
https://doi.org/10.1053/j.ajkd.2018.03.0...
) In another Brazilian study, after 30 days of follow-up, AKI patients who did not require dialysis showed greater recovery of renal function.2727 Hoste EAJ, Corte W. Clinical consequences of acute kidney injury. Contrib Nephrol. 2011;174:56-64. DOI: https://doi.org/10.1159/000329236
https://doi.org/10.1159/000329236...
) In a population-based study carried out in Canada, non-recovery of renal function was associated with death and other adverse renal events in the long term, including end-stage renal disease (ESRD).2828 Sampaio MC, Máximo CAG, Montenegro CM, Mota DM, Fernandes TR, Bianco ACM, et al. Comparison of diagnostic criteria for acute kidney injury in cardiac surgery. Arq Bras Cardiol. 2013 Jul;101(1):18-25. DOI: https://doi.org/10.5935/abc.20130115
https://doi.org/10.5935/abc.20130115...

Age, comorbidities, and some genetic aspects are among the risk factors for non-recovery of renal function after AKI.1414 Forni LG, Darmon M, Oudemans-van Straaten HM, Pettilä V, Prowle JR, Schetz M, et al. Renal recovery after acute kidney injury. Intensive Care Med. 2017 May;43(6):855-66. DOI: https://doi.org/10.1007/s00134-017-4809-x
https://doi.org/10.1007/s00134-017-4809-...
,2525 Pannu N, James M, Hemmelgarn B, Klarenbach S, Alberta Kidney Disease Network. Association between AKI, recovery of renal function, and long-term outcomes after hospital discharge. Clin J Am Soc Nephrol. 2013 Feb;8(2):194-202. DOI: https://doi.org/10.2215/CJN.06480612
https://doi.org/10.2215/CJN.06480612...
The impact of the event on distant organs also plays an important role, as AKI is responsible for lung (edema and acute injury), cardiac (arrhythmia, congestive heart failure, and ischemic heart disease), brain (uremic encephalopathy, dementia, and stroke), hepatic (altered hepatic metabolism), intestinal (uremic toxin accumulation and altered gut microbiota), and immune system (systemic inflammation) dysfunctions, and the non-recovery of the renal function may stress the hemodynamic, humoral, and immunologic changes.2626 Lee SA, Cozzi M, Bush EL, Rabb H. Distant organ dysfunction in acute kidney injury: a review. Am J Kidney Dis. 2018 Dec;72(6):846-56. DOI: https://doi.org/10.1053/j.ajkd.2018.03.028
https://doi.org/10.1053/j.ajkd.2018.03.0...

In this sense, delays in the recognition and treatment of clinical complications (fluid overload, inflammation/infection, acidosis, electrolyte abnormalities, and other local and distant organ complications) in combination with ineffective care (improper antimicrobial therapy, as well as improper metabolic and nutritional support) are determinants of the non-recovery of renal function and, consequently, explain the role of this condition as a strong independent risk factor associated with mortality in AKI patients.2727 Hoste EAJ, Corte W. Clinical consequences of acute kidney injury. Contrib Nephrol. 2011;174:56-64. DOI: https://doi.org/10.1159/000329236
https://doi.org/10.1159/000329236...

AKI occurrence after major surgery also showed an independent association with mortality among patients. As in other regions of the world, postoperative AKI in Brazil is described mostly after cardiac surgery, with high incidence and mortality rates.2828 Sampaio MC, Máximo CAG, Montenegro CM, Mota DM, Fernandes TR, Bianco ACM, et al. Comparison of diagnostic criteria for acute kidney injury in cardiac surgery. Arq Bras Cardiol. 2013 Jul;101(1):18-25. DOI: https://doi.org/10.5935/abc.20130115
https://doi.org/10.5935/abc.20130115...

29 Laizo A, Delgado FEF, Rocha GM. Complications that increase the time of hospitalization at ICU of patients submitted to cardiac surgery. Rev Bras Cir Cardiovasc. 2010 Jun;25(2):166-71. DOI: https://doi.org/10.1590/S0102-76382010000200007
https://doi.org/10.1590/S0102-7638201000...
-3030 Rodrigues AJ, Evora PRB, Bassetto S, Alves Júnior L, Scorzoni Filho A, Araújo WF, et al. Risk factors for acute kidney injury after cardiac surgery. Rev Bras Cir Cardiovasc. 2009 Dec;24(4):441-6. DOI: https://doi.org/10.1590/S0102-76382009000500003
https://doi.org/10.1590/S0102-7638200900...
Considering that our institution is a reference in trauma, empirically, we know that postoperative AKI is mainly associated with neurologic, abdominal, and orthopedic surgeries.

The use of vasoactive drugs during ICU stay (OR: 11.49; CI: 2.46-53.7), occurrence of hyperkalemia (OR: 3.6; CI: 1.78-7.30), and metabolic acidosis (OR: 2.8; CI: 1.13-6.92) were modifiable factors significantly associated with mortality in the patients studied. KDIGO stage 3 (OR: 3.21; CI: 1.26-8.24) and AKI diagnosis by both KDIGO criteria (OR: 2.27; CI: 1.10-4.72) (see Table 4) were also associated to death (Table 4). These results are similar to the data observed in other Brazilian studies, as well as in large international cohorts.55 Hoste EAJ, Bagshaw SM, Bellomo R, Cely CM, Colman RC, Cruz DN, et al. Epidemiology of acute kidney injury in critically ill patients: the multinational AKI-EPI study. Intensive Care Med. 2015 Jul;41:1411-23. DOI: https://doi.org/10.1007/s00134-015-3934-7
https://doi.org/10.1007/s00134-015-3934-...

6 Bouchard J, Acharya A, Cerdá J, Maccariello ER, Madarasu RC, Tolwani AJ, et al. A prospective international multicenter study of AKI in the intensive care unit. Clin J Am Soc Nephrol. 2015 Aug;10(8):1324-31. DOI: https://doi.org/10.2215/CJN.04360514
https://doi.org/10.2215/CJN.04360514...

7 Mehta RL, Burdmann EA, Cerdá J, Feehally J, Finkelstein F, García-García G, et al. Recognition and management of acute kidney injury in the International Society of Nephrology 0by25 Global Snapshot: a multinational cross-sectional study. Lancet. 2016 May;387(10032):2017-25. DOI: https://doi.org/10.1016/S0140-6736(16)30240-9
https://doi.org/10.1016/S0140-6736(16)30...

8 Bouchard J, Mehta RL. Acute kidney injury in Western countries. Kidney Dis (Basel). 2016;2(3):103-10. DOI: https://doi.org/10.1159/000445091
https://doi.org/10.1159/000445091...

9 Daher EF, Silva Junior GB, Santos SQ, Bezerra CCR, Diniz EJB, Lima RSA, et al. Differences in community, hospital and intensive care unit-acquired acute kidney injury: observational study in a nephrology service of a developing country. Clin Nephrol. 2012 Dec;78(6):449-55. DOI: https://doi.org/10.5414/CN107167
https://doi.org/10.5414/CN107167...
-1010 Peres LAB, Wandeur V, Matsuo T. Predictors of acute kidney injury and mortality in an intensive care unit. J Bras Nefrol. 2015 Mar;37(1):38-46. DOI: https://doi.org/10.5935/0101-2800.20150007
https://doi.org/10.5935/0101-2800.201500...
,1515 Barros LCN, Silveira FS, Silveira MS, Morais TC, Nunes MAP, Bastos KA. Acute kidney injury in hospitalized patients with descompensated heart failure. J Bras Nefrol. 2012 Jun;34(2):122-9. DOI: https://doi.org/10.1590/S0101-28002012000200004
https://doi.org/10.1590/S0101-2800201200...

16 Ponce D, Zorzenon CPF, Santos NY, Teixeira UA, Balbi AL. Acute kidney injury in intensive care unit patients: a prospective study on incidence, risk factors and mortality. Rev Bras Ter Intensiva. 2011 Sep;23(3):321-6. DOI: https://doi.org/10.1590/S0103-507X2011000300010
https://doi.org/10.1590/S0103-507X201100...
-1717 Santos NY, Zorzenon CPF, Araújo MF, Balbi AL, Ponce D. Observational prospective study on the incidence of acute renal failure in the intensive care unit of a university-affiliated hospital. J Bras Nefrol. 2009 Sep;31(3):206-11. DOI: https://doi.org/10.1590/S0101-28002009000300006
https://doi.org/10.1590/S0101-2800200900...
,3131 Hobson C, Ozrazgat-Baslanti T, Kuxhausen A, Thottakkara P, Efron PA, Moore FA, et al. Cost and mortality associated with postoperative acute kidney injury. Ann Surg. 2015 Jun;261(6):1207-14. DOI: https://doi.org/10.1097/SLA.0000000000000732
https://doi.org/10.1097/SLA.000000000000...
-3232 Grams ME, Sang Y, Coresh J, Ballew S, Matsushita K, Molnar MZ, et al. Acute kidney injury after major surgery: a retrospective analysis of veterans health administration data. Am J Kidney Dis. 2016 Jun;67(6):872-80. DOI: https://doi.org/10.1053/j.ajkd.2015.07.022
https://doi.org/10.1053/j.ajkd.2015.07.0...

Despite the robust and growing number of studies carried out around the world, the Brazilian literature on AKI in the ICU is still incipient and many aspects need further study in our country. We conducted a comprehensive epidemiologic study to investigate the factors associated with death in AKI patients in the ICU of a Brazilian center. Nevertheless, we recognized that our study had some limitations, including the retrospective design and data from a single center. Unfortunately, the lack of data prevented us from performing subgroup analyses and limited our ability to further reduce confounding biases. We neither assessed the AKI duration nor factors associated with renal recovery after AKI. Thus, in future studies, these aspects should be addressed.

Conclusion

The mortality rate in the AKI patients in this study was similar to other studies and the factors significantly associated with death were verified. Further research is necessary to confirm the findings through multicenter studies with a prospective design. For the appropriate management of AKI in the ICU, early recognition of determinant factors of incidence and mortality is essential. Also, it is important to eliminate risk factors for AKI in patients who are at risk for and/or have been diagnosed with AKI.

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    » https://doi.org/10.1097/SLA.0000000000000732
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    » https://doi.org/10.1053/j.ajkd.2015.07.022

Publication Dates

  • Publication in this collection
    27 July 2020
  • Date of issue
    Jul-Sep 2020

History

  • Received
    10 Feb 2019
  • Accepted
    06 May 2020
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