Acute kidney injury in coronavirus disease: a comparative study of the two waves in Brazil

ABSTRACT

Objective:

This study aimed to evaluate the incidence of acute kidney injury in hospitalized Brazilian patients with COVID-19 and identify the risk factors associated with its development and prognosis during the two waves of the disease.

Methods:

We performed a prospective cohort study of hospitalized patients with COVID-19 at a public university hospital in São Paulo from March 2020 to May 2021.

Results:

Of 887 patients hospitalized with COVID-19, 54.6% were admitted to the intensive care unit. The incidence of acute kidney injury was 48.1%, and the overall mortality rate was 38.9%. Acute kidney replacement therapy was indicated for 58.8% of the patients. The factors associated with acute kidney injury were diuretic use (odds ratio [OR] 2.2, 95%CI= 1.2-4.1, p=0.01), mechanical ventilation (OR= 12.9, 95%CI= 4.3-38.2, p<0.0001), hematuria(OR= 2.02, 95%CI= 1.1-3.5, p<0.0001), chronic kidney disease (OR= 2.6, 95%CI= 1.2-5.5, p=0.009), age (OR= 1.03, 95%CI= 1.01-1.07, p=0.02), and elevated creatine phosphokinase (OR= 1.02, 95%CI= 1.01-1.07, p=0.02) and D-dimer levels (OR= 1.01, 95%CI= 1.01-1.09, p<0.0001). Mortality was higher among those with acute kidney injury (OR= 1.12, 95%CI= 1.02-2.05, p=0.01), elevated Sequential Organ Failure Assessment Scores (OR= 1.35, 95%CI= 1.1-1.6, p=0.007), elevated Acute Tubular Necrosis-Injury Severity Score (ATN-ISS; (OR= 96.4, 95%CI= 4.8-203.1, p<0.0001), and who received mechanical ventilation (OR= 12.9, 95%CI= 4.3-38.2, p<0.0001). During the second wave, the number of cases requiring mechanical ventilation (OR= 1.57, 95%CI= 1.01-2.3, p=0.026), with proteinuria (OR= 1.44, 95%CI= 1.01-2.1, p=0.04), and with higher ATN-ISS Scores (OR= 40.9, 95%CI= 1.7-48.1, p=0.04) was higher than that during the first wave.

Conclusion:

Acute kidney injury was frequent in hospitalized patients with COVID-19, and the second wave was associated with greater severity. However, mortality rates were similar between the two periods, which may reflect both the effectiveness of vaccines and the constant learning that frontline professionals gained throughout the pandemic to provide greater support to their patients.

Registry of Clinical Trials:

RBR-62y3h7

Keywords:
Coronavirus infections; COVID-19; Prognosis; Acute kidney injury; Receptor cross-talk; Incidence; Mortality; Brazil

Highlights

• ◼

  Renal involvement was frequent in patients with COVID-19 and related to worse outcomes.

• ◼

  Diuretic use, mechanical ventilation, proteinuria, hematuria, age, and creatine phosphokinase and D-dimer levels were risk factors for acute kidney injury.

• ◼

  Acute kidney injury, mechanical ventilation, elevated SOFA Score, and elevated ATN-ISS were associated with mortality.

• ◼

  The second wave was associated with greater severity; however, the mortality rates were similar between the two periods.

• ◼

  This may reflect the effectiveness of vaccines and the constant learning that frontline professionals gained throughout the pandemic.

Highlights

• ◼

  Renal involvement was frequent in patients with COVID-19 and related to worse outcomes.

• ◼

  Diuretic use, mechanical ventilation, proteinuria, hematuria, age, and creatine phosphokinase and D-dimer levels were risk factors for acute kidney injury.

• ◼

  Acute kidney injury, mechanical ventilation, elevated SOFA Score, and elevated ATN-ISS were associated with mortality.

• ◼

  The second wave was associated with greater severity; however, the mortality rates were similar between the two periods.

• ◼

  This may reflect the effectiveness of vaccines and the constant learning that frontline professionals gained throughout the pandemic.

INTRODUCTION

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was declared a pandemic by the World Health Organization in March 2020.

The clinical spectrum of COVID-19 ranges from typical and atypical symptoms of upper respiratory tract infection to more severe complications such as pneumonia and acute respiratory distress syndrome, which usually require intensive care.(¹,²)

Other complications include circulatory shock, heart failure, and acute kidney injury (AKI). Using a pathophysiological model of cross-talk, few authors hypothesized that severe COVID-19 is associated with immune dysregulation, cytokine storm, and systemic inflammation.(²,³) Renal involvement is frequent (4-37%), especially among critically ill patients, and is a factor related to worse outcomes.(³-⁶) This incidence is associated with age, disease severity, and ethnicity.

Acute kidney injury is characterized by a rapid decline in renal function, with consequent accumulation of nitrogenous wastes and occurrence of hydroelectrolytic and acid-base disorders.(³-⁸) Besides direct virus-induced tissue damage, the involvement of organs in COVID-19 may occur secondary to inflammation, endothelial dysfunction, and hypercoagulability.

Acute kidney injury has been associated with increased mortality among hospitalized patients with COVID-19. According to a recent meta-analysis, the incidence of AKI in patients with COVID-19 was 8.9%.(⁹)However, statistical heterogeneity was observed among the included studies. Other meta-analyses have showed that male sex and diabetes are associated with a higher AKI and mortality rate among patients with COVID-19.(¹⁰,¹¹) Studies from the USA and Europe have reported pooled incidences of 28.6% and 7.7%for AKI, respectively, and AKI has been identified as a predictor of fatality and severe COVID-19.(¹²,¹³)

The pathophysiology of AKI in patients with COVID-19 is multifactorial. The effects of a SARS-CoV-2 infection on the renal tissues can be direct or indirect.(⁵,¹⁰) Direct effects include endothelial damage due to viral entry, local inflammation, and collapsing glomerulopathy, whereas indirect effects include sepsis, adverse effects due to nephrotoxic drug use, and systemic inflammation-also known as a cytokine storm.

Although there lies ample literature on the association between respiratory failure and AKI, few studies have elucidated the renal repercussions caused by the novel coronavirus in view of its recent discovery.

OBJECTIVE

To evaluate the incidence of acute kidney injury in hospitalized Brazilian patients with COVID-19 during the two waves of the disease and to identify risk factors associated with its onset and prognosis between the two periods.

METHODS

The research was performed following current regulations, and written informed consent was obtained from all participants or their legal guardians.

A prospective cohort study of hospitalized patients diagnosed with COVID-19, confirmed using real-time polymerase chain reaction for SARS-CoV-2, was performed in clinical wards and intensive care units (ICUs) of a public and tertiary university hospital in São Paulo, Brazil, from March to December 2020 (first wave) and January to May 2021 (second wave). Patients were hospitalized until the clinical outcome (discharge or mortality) was met, AKI diagnosis was assessed, and risk factors were identified through the collection of information from electronic medical records including those of their diagnosis, mortality, and indication for acute kidney replacement therapy.

Clinical and laboratory data were collected during hospitalization. Renal function was evaluated daily by measuring the serum creatinine levels and urine output. AKI was identified according to the Kidney Disease: Improving Global Outcomes (KDIGO) definition: an increase in serum creatinine level >0.3mg/dL within 48 hours or by 50% within 7 days; AKI was staged as one of the three KDIGO categories.(⁶) For the detection of proteinuria or hematuria, a semi-quantitative dipstick test was performed; data were requested at admission for all patients and during hospitalization for patients without proteinuria at admission. The indications for acute kidney replacement therapy were uremia or azotemia (blood urea nitrogen >100mg/dL), fluid overload (after diuretic use), electrolyte imbalance (K >6.5mEq/L after clinical treatment), acid-base disturbance (pH <7.1 and bicarbonate <10mEq/L after clinical treatment), and metabolic and fluid demand-to-capacity imbalance.(¹³,¹⁴) The demand is determined by the severity of the acute illness and solute and fluid burdens. The demand capacity balance is dynamic and varies with the course of critical illness. When renal capacity decreased and the patient failed to cope with the demands, acute kidney replacement therapy was initiated.

Using the study protocol, the data were entered into an electronic spreadsheet, eliminating any typographical errors. Analyses were performed using SPSS version 20 (IBM Corp., Armonk, NY) or SigmaStat 3.5 (Systat Software, San Jose, CA). The frequency or central tendency and dispersion measures were calculated for categorical and continuous variables, respectively, with AKI as the outcome variable. The χ² test was used to compare categorical variables, and the t-test was used for continuous variables.

A multivariate analysis was performed through the construction of a logistic regression model with calculations of the odds ratio (OR), including all the independent variables that showed association with the outcome in the model, with p≤0.05. A similar procedure was performed by establishing the occurrence of mortality and indication for acute kidney replacement therapy as dependent variables.

This study was approved by the local Ethics Committee of Faculdade de Medicina de Botucatu (CAAE: 30451520.6.0000.5411; #4.003.880).

RESULTS

Between 2020 and 2021, 887 patients with a confirmed diagnosis of COVID-19 were hospitalized at our hospital (Figure 1). The mean age was 58.8±15.7 years; 52.3% were men, 59.1% had hypertension, 54.6% were admitted to the ICU, and 45.4% were admitted to the ward. The overall incidence of AKI was 48.1%; AKI was more frequent among patients admitted to the ICU than among those admitted to the ward (83.8% versus 17.1%, p<0.0001). The mean time for AKI diagnosis was 6 days, and KDIGO stage 3 was most frequently diagnosed (60.2%). Acute kidney replacement therapy was indicated for 263 (58.8%) patients.

Figure 1
Classification of patients

Factors associated with AKI development were advanced age (61.5±14.4 versus 56.3±16.3 years, p<0.0001), ICU admission (83.8% versus 27.6%, p<0.0001), mechanical ventilation (81.5% versus 11.5%, p<0.0001), vasoactive drug use (VAD; 80.1% versus 12.6%, p<0.0001), proteinuria (68.2% versus 33.9%, p<0.0001), and hematuria (75% versus 40.5%, p<0.0001) (Table 1).

Table 1
Clinical and laboratory characteristics of hospitalized patients with or without acute kidney injury

Variables	General (n=887)	Without AKI (n=460)	With AKI (n=427)	p value
First wave (%)	337 (38)	180 (39.1)	157 (36.8)	0.469
Second wave (%)	550 (62)	280 (60.8)	270 (63.2)	0.469
Male sex (%)	464 (52.3)	229 (49.8)	235 (55)	0.118
Caucasian ethnicity (%)	750 (84.6)	403 (87.6)	347 (82.2)	0.025
Age (years)*	58.8±15.7	56.3±16.3	61.5±14.4	<0.0001
Arterial hypertension (%)	524 (59.1)	235 (51.1)	289 (67.7)	<0.0001
ACE inhibitor use (%)	377 (42.5)	172 (37.4)	205 (48)	0.001
Diuretic use (%)	214 (24.1)	91 (19.8)	123 (28.8)	0.002
CVD (%)	157 (17.7)	76 (16.5)	81 (19)	0.34
Diabetes (%)	229 (33.7)	131 (28.5)	168 (39.3)	0.001
Obesity (%)	288 (32.5)	118 (25.7)	170 (39.8)	<0.0001
Dyslipidemia (%)	190 (21.4)	77 (16.7)	113 (26.5)	<0.0001
Lung disease (%)	87 (9.8)	44 (9.6)	43 (10.1)	0.8
Smoking (%)	232 (26.2)	125 (27.2)	107 (25.1)	0.48
CKD (%)	118 (13.3)	48 (10.4)	70 (16.4)	0.009
GFR (mL/min/1.73 m2)	90.8±29.9	98.9±26.7	82.7±30.5	<0.0001
Dialysis (%)	263 (29.7)	12 (2.6)	251 (58.8)	<0.0001
ATN-ISS*	0.7±0.2	0.8	0.7±0.2	0.491
CPK**	117 (52.5-436)	68 (37-146)	274 (84-841)	<0.0001
D-dimer**	2509 (1133.7-10956.2)	1485 (859-3144)	7533 (2137-15527)	<0.0001
Mechanical ventilation (%)	401 (45.2)	53 (11.5)	348 (81.5)	<0.0001
Vasoactive drug use (%)	400 (45.1)	58 (12.6)	342 (80.1)	<0.0001
ICU admission (%)	484 (54.6)	126 (27.6)	358 (83.8)	<0.0001
APACHE*	16.8±6.6	12.6±5.3	18.3±6.3	<0.0001
SOFA*	7±3.8	4.8±3.1	7.7±3.7	<0.0001
Hematuria (%)	508 (57.2)	186 (40.5)	322 (75)	p<0.0001
Proteinuria (%)	447 (50.4)	155 (33.9)	292 (68.2)	p<0.0001
Mortality (%)	345 (38.9)	52 (11.3)	293 (68.6)	<0.0001

• ^*
  Mean±SD
• ^**
  Median (interquartile range).
• AKI: acute kidney injury; ACE: angiotensin-converting enzyme; CKD: chronic kidney disease; CVD: cardiovascular disease; GFR: glomerular filtration rate; CPK: creatine phosphokinase; ICU: intensive care unit; ATN-ISS: Acute Tubular Necrosis-Injury Severity Score; APACHE II: Acute Physiology and Chronic Health Evaluation; SOFA: Sequential Organ Failure Assessment.

Diuretic use (OR= 2.2, 95% confidence interval [CI]= 1.2-4.1, p=0.01), mechanical ventilation (OR= 12.9, 95%CI= 4.3-38.2, p<0.0001), hematuria (OR= 2.02, 95%CI= 1.1-3.5, p=0.01), chronic kidney disease (CKD; OR= 2.6, 95%CI= 1.2-5.5, p=0.009), older age (OR= 1.03, 95%CI= 1.01-1.07], p=0.02), and elevated creatine phosphokinase (CPK; OR= 1.02, 95%CI= 101-107, p=0.02) and D-dimer (OR= 1.01, 95%CI= 101-1.09, p<0.0001) levels were risk factors for AKI. Table 2 shows the factors associated with AKI in the multivariate analysis.

Table 2
Logistic regression of variables associated with acute kidney injury

Variables	Odds ratio	95% confidence interval	p value
Diuretic use	2.2	1.2-4.1	0.01
Dyslipidemia	0.54	0.3-1.05	0.07
Vasoactive drug use	2.7	0.9-7.7	0.06
Mechanical ventilation	12.9	4.3-38.2	<0.0001
Chronic kidney disease	2.6	1.2-5.5	0.009
Hematuria	2.02	1.1-3.5	0.01
Age	1.03	1.01-1.07	0.02
Creatine phosphokinase	1.02	1.01-1.07	0.02
D-dimer	1.01	1.01-1.09	<0.0001

The overall mortality rate was 38.9% (345 patients), which was higher among ICU patients (63.2 versus 9.6%, p<0.0001). Factors associated with mortality were advanced age (64.11±14.2 versus 55.5±15.7 years, p<0.0001), ICU admission (88.7% versus 32.8%, p<0.0001), VAD use (85.5% versus 19.4%, p<0.0001), mechanical ventilation (86.4% versus 19%, p<0.0001), kidney acute support (61.4% versus 9.4%, p<0.0001), AKI (84.9% versus 24.7%, p<0.0001), KDIGO stage 3 (59.7% versus 9.4%, p<0.0001), proteinuria (70.9% versus 38.1%, p<0.0001), and hematuria (75.3% versus 46.9%, p<0.0001) (Table 3).

Table 3
Clinical and laboratory characteristics of hospitalized patients with respect to mortality

Variables	No mortality (n=542)	Mortality (n=345)	p value
First wave (%)	216 (39.9)	121 (35.1)	0.153
Second wave (%)	326 (60.1)	224 (64.9)	0.153
Male sex (%)	270 (49.8)	194 (56.2)	0.062
Caucasian ethnicity (%)	464 (85.9)	286 (83.6)	0.351
Age (years)*	55.5±15.7	64.11±14.2	<0.0001
Arterial hypertension (%)	284 (52.4)	240 (69.5)	<0.0001
ACE inhibitor use (%)	210 (38.7)	167 (48.4)	0.005
Diuretic use (%)	122 (22.5)	92 (26.7)	0.158
CVD (%)	82 (15.1)	75 (21.7)	0.012
Diabetes (%)	164 (30.3)	135 (39.1)	0.006
Obesity (%)	155 (29.2)	130 (37.7)	0.023
Dyslipidemia (%)	106 (19.6)	84 (24.3)	0.09
Lung disease (%)	52 (9.6)	35 (10.1)	0.788
Smoking (%)	138 (25.5)	94 (27.2)	0.617
CKD (%)	65 (12)	53 (15.4)	0.15
AKI (%)	134 (24.7)	293 (84.9)	<0.0001
KDIGO stage 3 (%)	51 (9.4)	206 (59.7)	<0.0001
GFR (mL/min/1.73 m2)	97.2±27.6	81.5±30.4	<0.0001
Dialysis (%)	51 (9.4)	212 (61.4)	<0.0001
ATN-ISS*	0.54±0.28	0.78±0.14	<0.0001
CPK**	78 (40-193)	293 (86-754)	<0.0001
D-dimer**	1683 (969-5707)	7433 (2116-14931)	<0.0001
Mechanical ventilation (%)	103 (19)	298 (86.4)	<0.0001
Vasoactive drug use (%)	105 (19.4)	295 (85.5)	<0.0001
ICU admission (%)	178 (32.8)	306 (88.7)	<0.0001
APACHE*	12.6±5.7	19.3±5.8	<0.0001
SOFA*	4.7±3.2	83±3.4	<0.0001
Hematuria	252 (46.9)	261 (75.3)	<0.0001
Proteinuria	209 (38.1)	245 (70.9)	<0.0001

• ^*
  Mean±SD;
• ^**
  Median (interquartile range).
• AKI: acute kidney injury; ACE: angiotensin-converting enzyme; CKD: chronic kidney disease; CVD: cardiovascular disease; GFR: glomerular filtration rate; CPK: creatine phosphokinase; KDIGO: Kidney Disease: Improving Global Outcomes; ICU: intensive care unit; ATN-ISS: Acute Tubular Necrosis-Injury Severity Score; APACHE II: Acute Physiology and Chronic Health Evaluation; SOFA: Sequential Organ Failure Assessment.

Acute kidney injury (OR= 1.12, 95%CI= 1.02-2.05, p=0.01), mechanical ventilation (OR= 12.9, 95%CI= 4.3-38.2, p<0.0001), elevated SOFA Scores (OR= 1.35, 95%CI= 1.1-1.6, p=0.007), and elevated ATN-ISS (OR= 96.4, 95%CI= 4.8-203.1, p<0.0001) were associated with mortality (Table 4).

Table 4
Logistic regression of variables associated with death

Variables	OR	95%CI	p value
AKI	1.12	1.02-2.05	0.01
SOFA	1.35	1.1-1.6	0.007
ATN-ISS	96.4	4.8-203.1	<0.0001
Mechanical ventilation	12.9	4.3-38.2	<0.0001
Vasoactive drugs	1.06	0.96-5.5	0.09
Obesity	1.01	0.91-3.5	0.15
Age	1.02	0.99-1.54	0.11

• Failure Assessment Score.
• AKI: Acute kidney injury; ATN-ISS: Acute Tubular Necrosis-Injury Severity Score; SOFA: Sequential Organ.

Univariate analysis identified clinical and laboratory similarities and differences between patients hospitalized during the first and second waves of the pandemic (Table 5). During the first wave, the proportion of men (58.2% versus 48.7%, p=0.006) and D-dimer levels (1558-11221 versus 948-9938, p=0.009) were higher than those during the second wave. During the second wave, proteinuria (57% versus 45.2%, p=0.009), hematuria (63% versus 53.5%, p=0.033), increased use of dialysis (32.4% versus 25.2%, p=0.024), mechanical ventilation (48.4% versus 40.1%, p=0.016), VAD use (48% versus 40.4%, p=0.026), and higher ATN-ISS (0.76±0.2 versus 0.63±0.24, p<0.001) were increased than those during the first wave. During the first wave, no participants were vaccinated; in contrast 14% were vaccinated during the second wave (one dose).

Table 5
Clinical and laboratory characteristics of hospitalized patients during the first and second waves

Variables	First wave (n=337)	Second wave (n=550)	p value
Male sex (%)	196 (58.2)	268 (48.7)	0.006
Caucasian ethnicity (%)	271 (80.4)	479 (87.9)	0.002
Age (years)*	59.5±16.2	58.4±15.3	0.32
Vaccinated patients (%)	0 (0)	77 (14)	<0.001
Arterial hypertension (%)	203 (60.2)	321 (58.4)	0.58
ACE inhibitor use (%)	145 (43)	232 (42.2)	0.8
Diuretic use (%)	93 (27.6)	121 (22)	0.059
CVD (%)	60 (17.8)	97 (17.6)	0.95
Diabetes (%)	119 (35.3)	180 (32.7)	0.43
Obesity (%)	98 (29.1)	190 (34.5)	0.17
Dyslipidemia (%)	75 (22.3)	115 (20.9)	0.63
Lung disease (%)	29 (8.6)	58 (10.5)	0,34
Smoking (%)	79 (23.4)	153 (27.8)	0.25
CKD (%)	44 (13.1)	74 (13.5)	0.86
AKI (%)	157 (46.6)	270 (49.1)	0.47
KDIGO stage 3 (%)	84 (24.9)	173 (31.5)	0.13
GFR (mL/min/1.73 m2)	89±29.3	91.8±29.9	0.25
Dialysis (%)	85 (25.2)	178 (32.4)	0.024
ATN-ISS*	0.63±0.24	0.76±0.2	<0.0001
CPK**	99 (47-407)	146 (62-495)	0.083
D-dimer**	4268 (1558-11221)	1940 (948-9938)	0.009
Mechanical ventilation (%)	135 (40.1)	266 (48.4)	0.016
Vasoactive drug use (%)	136 (40.4)	264 (48)	0.026
ICU admission (%)	175 (51.9)	309 (56.2)	0.21
APACHE II*	17.8±7.5	16.2±5.9	0.02
SOFA*	7.7±4.1	6.6±3.5	0.003
Proteinuria	151 (45.2)	313 (57)	0.009
Hematuria	179 (53.5)	346 (63)	0.033
Mortality (%)	121 (35.9)	224 (40.7)	0.15

• ^*
  Mean±SD
• ^**
  Median (interquartile range).
• AKI: acute kidney injury; ACE: angiotensin-converting enzyme; CKD: chronic kidney disease; CVD: cardiovascular disease; GFR: glomerular filtration rate; CPK: creatine phosphokinase; ICU: intensive care unit; KDIGO: Kidney Disease: Improving Global Outcomes; ATN-ISS: Acute Tubular Necrosis-Injury Severity Score; APACHE II: Acute Physiology and Chronic Health Evaluation; SOFA: Sequential Organ Failure Assessment.

Table 6 shows variables with differences during the second wave of the pandemic. Male sex (OR= 0.51, 95%CI= 0.35-0.74, p<0.0001) and Caucasian ethnicity (OR= 0.47, 95%CI= 0.2-0.8, p=0.006) were less prevalent during the second wave, while mechanical ventilation (OR= 1.57, 95%CI= 101-2.3, p=0.026), proteinuria (OR= 1.44, 95%CI= 101-2.1, p=0.04), D-dimer level (OR= 1.09, 95%CI= 1.02-1.1, p=0.02), and elevated ATN-ISS (OR= 40.9, 95%CI= 1.7-48.1, p=0.04) were more prevalent during the second wave.

Table 6
Logistic regression analysis of patient variables during the second wave

Variables	Odds ratio	95%CI	p value
Male sex	0.51	0.35-0.74	<0.0001
Caucasian race	0.47	0.2-0.8	0.006
Mechanical ventilation	1.57	1.01-2.3	0.026
Proteinuria	1.44	1.01-2.1	0.04
D-dimer	1.09	1.02-1.1	0.02
Acute Tubular Necrosis-Injury Severity Score	40.9	1.7-48.1	0.04

• 95%CI: 95% confidence interval.

DISCUSSION

This study describes the first and second waves of the COVID-19 pandemic at a public university hospital in São Paulo, Brazil, which serves as a reference for 28 municipalities in the region with more than 2 million inhabitants.(¹⁴) During this period, 887 patients diagnosed with COVID-19 were hospitalized; 54.6% were admitted to the ICU and 45.4% to the ward. The overall incidence of AKI was 48.1%, with a mean diagnosis time of 6 days. This incidence was higher than that reported in the literature.

Chinese studies(¹⁵-²¹) have reported a low and variable incidence of AKI in hospitalized patients (0.5-7%) and a higher incidence in severe COVID19 cases (2.9-19%). European and North American studies(²²-²⁷) have reported an AKI incidence of 20-40% in patients hospitalized with COVID-19. In all cohorts, AKI occurred between days 7 and 14 of illness; it was associated with higher hospital mortality and was decisive in the prognosis of these patients.(²⁵) Brazil is a large country with several vulnerable groups, in addition to an emerging economy and fragile social protection, which may have contributed to the increased demand for health services and the development of serious forms of COVID-19.(²⁸)

SARS-CoV-2 comprises a spike protein that binds to the angiotensin-converting enzyme 2 (ACE2) receptor present in host cells, enabling its activation and cleavage by transmembrane proteases, culminating in the release of fusion peptides by the virus. ACE2 is highly expressed in the mouth, tongue, and alveolar epithelial cells. In the kidneys, it is highly expressed in proximal tubule cells and, to a lesser extent, in podocytes.(¹⁶,²⁵,²⁶) Thus, the higher AKI incidence in European and American countries could be associated with the higher expression of ACE2 in podocytes and proximal tubules in Western individuals than in Eastern individuals, as identified in normal kidneys and described by Pan et al.(²⁶) However, other studies did not identify SARS-CoV-2 in renal biopsy/autopsy tissue samples.(²⁷)

Acute kidney injury is a complex disorder characterized by the degradation of renal function over hours to days, resulting in a temporary decrease or interruption of renal capacity to promote the excretion of nitrogenous products and hydroelectrolytic homeostasis of the body, resulting in volume overload.(²⁹) Its incidence in hospitalized patients varies between 5 and 7%; according to other studies, it is higher in ICU patients (approximately 50%). Despite technological advances and the reduction in mortality rate in the last decade, AKI prognosis remains severe, and the mortality rate remains high, especially in patients requiring dialysis (up to 62%).(³⁰-³⁸)

Logistic regression analysis revealed that the factors associated with the development of AKI in patients hospitalized with COVID-19 were diuretic use, dyslipidemia, mechanical ventilation, VAD use, CKD, proteinuria, hematuria, older age, and elevated CPK and D-dimer levels.

In a Brazilian study, Bucuvic et al.(³⁵) reported that 62% of patients diagnosed with AKI were of male sex, 65.2% were aged >60 years, 61.9% had diabetes mellitus, 44.4% had hypertension, and 21.9% had CKD. Ponce et al.(³⁶) performed a large retrospective observational study investigating the epidemiology of AKI and its effect on patient outcomes over time. For comparison purposes, patients were divided into two groups according to the year of follow-up: 2011-2014 and 2015-2018. The authors evaluated 5,428 patients with AKI. Three (50.6%) patients had stage 3 AKI, and the mortality rate was 34.3% (1,865 patients). Dialysis was indicated for 928 patients (17.1%). Patient survival improved during the study periods, and patients treated during 2015-2018 had a relative risk mortality reduction of 0.89 (95%CI= 0.81-0.98, p=0.02). The independent risk factors for mortality were sepsis, age >65 years, ICU admission, KDIGO stage 3, recurrent AKI, no metabolic and fluid demand-to-capacity imbalance (as a dialysis indication), and treatment period.

A recent systematic review showed that 40%, 61.4%, 57.1%, and 22.2% of patients with COVID-19 and AKI had a history of diabetes mellitus, hypertension, hyperlipidemia, and CKD, respectively.(³⁷) Based on a growing consensus and evidence, factors such as older age, diabetes, hypertension, cardiovascular disease, high body mass index, CKD, immunosuppression for any reason, and smoking are potential risk factors for COVID-19-associated AKI.(³⁸-⁴⁰) Some laboratory parameters, including leukocytosis; lymphopenia; elevated levels of C-reactive protein and ferritin; hematuria; and proteinuria,(⁴¹-⁴⁴) were also associated with COVID-19-associated AKI; their incidence was 100%, 72.2%, 92.7%, 88.9%, 61.8%, and 97.4%, respectively.

Acute kidney injury is associated with worse clinical outcomes. A 2015 international multicenter study(³⁷) involving 1,032 ICU patients showed that AKI was independently associated with higher mortality at all stages, with the following ORs: 1.7 for KDIGO stage 1 and 6.9 for KDIGO stage 3. In ICU patients, AKI is associated with a longer duration of mechanical ventilation, VAD use, and an increased length of hospital stay, with acute kidney replacement therapy required in 50% of cases.

The data presented in our study revealed an overall mortality rate of 38.9%, which was higher among ICU patients (63.2% versus 9.6%, p<0.0001). Factors associated with mortality were AKI, KDIGO stage 3, arterial hypertension, VAD use, mechanical ventilation, proteinuria, high D-dimer level, elevated SOFA Scores, and elevated ATN-ISS.

In terms of prognosis, previous studies have shown that ICU hospitalization and the need for assisted ventilation are commonly reported in 86.7% and 87.5% of AKI patients, respectively. In patients with COVID-19 and AKI, the overall hospital mortality rate was approximately 84%, similar to that in early reports from developing countries.(⁴⁵,⁴⁶) AKI is an independent risk factor for increased mortality in critically ill patients with diseases, including COVID-19.(⁴⁷) Kidney involvement has also been reported as an indicator of poor prognosis, regardless of the initial COVID-19 severity,(⁴⁸) which suggests that early detection and treatment of renal abnormalities improve the vital prognosis of patients with COVID-19.

Many factors contribute to the high mortality rate of AKI in patients with COVID-19, especially the lack of identification of risk factors for the development of this pathology at the time as well as the lack of knowledge about factors associated with mortality.(⁴⁹-⁵⁵)

However, mechanical ventilation, mainly associated with renal and/or pulmonary involvement, may predispose patients to hospital infections that contribute to higher mortality. When intubated patients are receiving mechanical ventilation, lung defense mechanisms are altered by the underlying disease or by the loss of protection of the upper airways, such as the loss of an intact cough reflex, which may result in pulmonary hypersecretion or an increase in the frequency of respiratory infections with high morbidity and mortality rates.

Notably, proteinuria, as highlighted in our results, was shown to be an important risk factor associated with the development of AKI, which is the main pathophysiological basis for the hypothesis of direct damage caused by SARS-CoV-2 in tubular epithelial cells and renal podocytes. Therefore, proteinuria in patients with COVID-19 may be associated with viral cytopathic effects, which reduce filtration and protein reabsorption, resulting in tubular injury, or even have a glomerular origin, especially in patients who develop acute glomerulopathy.(⁵,⁸,²⁶)

Using logistic regression, this study identified similarities and clinical and laboratory differences between patients hospitalized during the first and second waves of the pandemic. During the first wave, a predominance of men and Caucasians was observed, while during the second wave, a predominance of cases requiring mechanical ventilation, with proteinuria, and with higher D-dimer levels and elevated ATN-ISS were observed.

Thus, it can be inferred that clinically more severely ill patients were hospitalized during the second wave, with a greater need for mechanical ventilation and greater AKI severity, despite the similar incidence of AKI and mortality between waves, which may reflect both the effectiveness of the SARS-CoV-2 vaccines and the constant learning that frontline professionals gained throughout the pandemic to provide greater support to their patients.

The limitation of this study was that data were collected from a single center using electronic medical records. However, this study represents important data regarding the epidemiological profile of AKI associated with COVID-19 in Brazil, a country with continental characteristics and a heterogeneous and vulnerable population.

CONCLUSION

Acute kidney injury associated with severe COVID-19 was more frequent than that already reported in Chinese, European, and North American studies. The risk factors for acute kidney injury were diuretic use, mechanical ventilation, vasoactive drug use, dyslipidemia, proteinuria, hematuria, chronic kidney disease, older age, and elevated creatine phosphokinase and D-dimer levels. Mortality rate was high in this population and higher in patients with hypertension; mechanical ventilation; proteinuria; acute kidney injury (mainly KDIGO stage 3); and elevated D-dimer levels, SOFA Scores, and ATN-ISS. Mortality rates were similar between waves, which may reflect both the effectiveness of vaccines against SARS-CoV-2 and the constant learning that frontline professionals gained throughout the pandemic to provide greater support to their patients.

TRANSPARENCY DECLARATION

The lead authors confirm that the manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as originally planned (and, if relevant, registered) have been explained.

DATA AVAILABILITY STATEMENT

Raw data supporting the conclusions of this study are available from the authors without undue reservation.

ACKNOWLEDGMENT

This research was funded by Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP; grant number 2020/11766-8).

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Edited by

Associate Editor:

Henrique Andrade Rodrigues da Fonseca – Hospital Israelita Albert Einstein, São Paulo, SP, Brazil ORCID: https://orcid.org/0000-0001-8360-8465

Publication Dates

• Publication in this collection
  30 Sept 2024
• Date of issue
  2024

History

• Received
  21 Aug 2023
• Accepted
  04 Jan 2024