Acute kidney disease in patients with Covid 19. A prospective, multicenter, multinational study in Latin America

doi:10.21203/rs.3.rs-3585505/v1

Introduction

Acute kidney disease (AKD) is an innovative perspective that enables a more comprehensive description of acute and subacute kidney disorders. This study aimed to evaluate the clinical characteristics of COVID-19 patients based on their AKD stage.

Methods

Observational, prospective, longitudinal, multinational cohort study conducted across five Latin American countries. Adult patients with diagnosis of Covid 19 were included. Upon hospital admission, a urinalysis or urine strip tests was performed. If protein was not detected, a follow-up search was conducted five days later. Patients were classified in four AKD categories: non-kidney disease, only proteinuria, only acute kidney injury (AKI), proteinuria and AKI.

Results

Three hundred and sixty patients were included. AKD was present in 273 patients (75.8%), of whom 142 (52.0%) had only proteinuria, 11 (4.1%) had AKI without proteinuria, and 120 (43.9%) had both proteinuria and AKI. Overall, proteinuria with or without AKI was present in 262 patients (72.8%), with 37 of them developing this condition during their hospital stay which shown a more severe condition. AKI with or without proteinuria occurred in 131 patients (36.4%). AKI was mainly severe, non-oliguric and hospital-acquired. In-hospital mortality increased with the severity of AKD stage: non-kidney disease 9.5%, only proteinuria 22.8%, only AKI 56.7%, and proteinuria plus AKI 53.0% (p = 0.001).

Conclusions

Our data endorse a novel and comprehensive approach based on the concept of AKD. This integrative approach, encompassing the structural and functional continuum of AKI, AKD, and CKD, enables timely interventions and the implementation of preventive and therapeutic strategies.

acute kidney disease

acute kidney injury

Covid 19

proteinuria

Kidney involvement in COVID-19 has been extensively documented and is frequently linked to adverse outcomes (1). Proteinuria has been reported in 28–84% of cases (2), while acute kidney injury (AKI) affects approximately 17% of patients, with a wide range of incidence from 0.5–80%, as indicated by a systematic review and meta-analysis of 20 cohorts (3). Regional disparities in the frequency of AKI have been noted (4) with a higher prevalence in the USA and Europe compared to China (28.6% vs. 5.5%), attributed to possible differences in hospital admission criteria.

Both proteinuria and impaired kidney function lasting less than 90 days, either in isolation or combination, define the condition known as acute kidney disease (AKD) (5). AKD is characterized by the presence of functional and/or structural abnormalities for less than 3 months, with significant health implications (6). This innovative perspective on kidney diseases enables a more comprehensive description of various clinical scenarios, thus enhancing the development of targeted research strategies. Accordingly, our study aimed to evaluate the clinical characteristics of COVID-19 patients based on their AKD stage.

Study protocol

This is an observational, prospective, longitudinal, multinational cohort study conducted from March 8, 2021 to April 30, 2022 across five Latin American countries (Argentine, Bolivia, Brazil, Peru and Uruguay). Participants entered their data into a dedicated online platform designed for this study, ensuring the confidentiality of information through data de-identification. Once enrolled in the platform, each patient was randomly assigned a unique identification number, which was used to access their patient-specific information. Upon hospital admission, the presence of proteinuria was assessed either through urinalysis or urine strip tests. In cases where no protein was initially detected, a follow-up search was conducted five days later. Data recording occurred for all patients, regardless of the presence or absence of proteinuria. Inclusion criteria encompassed adult patients aged ≥ 18 years, confirmed to have COVID-19 through RT-PCR of nasopharyngeal swabs or antigen tests for SARS-CoV-2 in nasopharyngeal swabs, and requiring hospitalization.

Exclusion criteria consisted of patients with chronic kidney disease (CKD) stage 5, those currently undergoing chronic dialysis, or individuals with functioning transplanted kidneys.

Definitions

The diagnosis and staging of acute kidney injury (AKI) were determined using the KDIGO 2012 criteria, which define AKI as an increase in serum creatinine (SCr) of ≥ 0.3 mg/dl within 48 hours or ≥ 50% above the baseline within the prior 7 days. The classification of acute kidney disease (AKD) was based on the KDIGO 2020 definition and classification, which considers abnormalities in kidney function and/or structure with health implications and a duration of ≤ 3 months (6). We established non-recovery in cases where SCr did not decrease or the patient remained on dialysis, full recovery when SCr decreased to the baseline level or lower, and partial recovery when SCr decreased but did not reach the baseline. We categorized AKI as community-acquired (CA-AKI) if the patient exhibited an elevated SCr within the first 24 hours of admission, and hospital-acquired (HA-AKI) when AKI developed during the hospital stay.

Data Collection

Data were obtained from the clinical record of patients. Variables included country and city of residence, demographics, comorbidities, condition at admission, process of care, risk factors and etiology of AKI, in-hospital complications, Covid-19 vaccination status, discharge condition.

Statistical analysis.

Quantitative variables are presented as median and interquartile range (IQR) according to their distribution, and the categorical variables as number and proportions. The Kolmogorov-Smirnov test was employed to assess data distribution. For bivariate comparisons between groups, the Chi-square test was applied to categorical variables, and the U Mann-Whitney test or the Kruskal-Wallis test was used for quantitative variables. Odds ratios and 95% confidence intervals (CIs) were calculated. All statistical tests were two-sided, and significance was determined by a probability of the null hypothesis ≤ 5%. Data processing and statistical analysis were conducted using IBM SPSS Statistics Base version 22 (NY, USA).

Three hundred and sixty patients from five countries participated in the study, with the following distribution: Peru (45%), Brazil (22.5%), Bolivia (14.7%), Argentina (11.1%), and Uruguay (6.7%). The median age (IQR) of the cohort was 64 (50–74) years, with a majority of male patients (57.7%). The most prevalent comorbidities included arterial hypertension (49.7%), diabetes (31.8%), and obesity (26.3%). Upon admission, the median (IQR) serum creatinine level was 0.86 (0.68–1.07) mg/dl. Regarding hospitalization, the majority of patients were admitted to the ward (73.8%), with 15.6% in the intensive care unit (ICU) and 10.6% in the emergency room. However, ICU admissions increased to 50.9% during the hospital stay, and 45.3% of patients received invasive mechanical ventilation. Complications were frequent (48.9%), with sepsis being the most common (27.6%). The median hospital length-of-stay was 15 (7–28) days, and the all-cause in-hospital mortality rate was 30.2%. Out of 185 patients (51.4%) for whom vaccination status information was available, 100 (54.1%) had received at least one dose, while 82 of the vaccinated patients received two to three vaccine doses (82%). Table 1 provides a detailed profile of patients according to their vaccination status. Vaccinated patients exhibited fewer comorbidities, less disease severity, particularly in terms of proteinuria and hematuria, a lower rate of ICU admission, and a lower mortality rate. AKI was also less frequent but didn’t reach statistical difference.

Table 1 Clinical characteristics according to vaccination status

Table 2. Clinical characteristics of patients according to AKD category

	Non AKD 87	Proteinuria 142	AKI 11	Pr + AKI 120	p
Age, years, median (IQR)	59 (42-71)	61.5 (49-76)	72 (64-79)	66 (53-74)	0.041
Hypertension %	36.8	43.7	40.0	69.0	0.000
Diabetes %	20.9	26.2	60.0	43.5	0.001
Chronic heart disease %	3.4	7.6	0	23.8	0.000
Hospital setting % Ward Emergency room ICU	87.4 2.3 10.3	73.2 10.6 16.2	72.7 18.2 9.1	64.4 16.1 19.5	0.013
Lymphocyte count mm³	1000 (678-1577)	835 (608-1170)	660 (580-1200)	1063 (652-2330)	0.005
Platelet count mm³	259 (210-311)	220 (172-292)	185 (114-287)	242 (189-308)	0.045
D-dimers ng/mL	800 (582-1000)	850 (500-1200)	695 (420-1352)	1123 (597-1477)	0.012
Ferritine ng/mL	900 (503-1200)	1141 (646-1600)	1100 (653-1680)	1500 (767-1800)	0.001
ICU admission %	27.9	42.9	72.7	70.6	0.000
Invasive mechanical ventilation %	32.4	58.7	70.0	78.8	0.000
Vasopressors %	11.1	25.0	50.0	67.6	0.000
In-hospital mortality %	5.8	24.1	36.4	55.5	0.000

Acute kidney disease (AKD) was present in 273 patients (75.8%), of whom 142 (52.0%) had only proteinuria, 11 (4.1%) had AKI without proteinuria, and 120 (43.9%) had both proteinuria and AKI. Eighty-seven patients (24.2%) did not exhibit evident kidney disease. Overall, proteinuria with or without AKI was present in 262 patients (72.8%), with 37 of them developing this condition during their hospital stay. Notably, these patients had higher D-dimer levels [1048 (900–1430) ng/mL vs. 900 (520–1250) ng/mL], worse Pa/FiO2 [80 (78–85) vs. 134 (99–180)], longer lengths of hospital stay [26 (12–45) days vs. 15 (7–25) days], and a trend toward more AKI, ICU admissions, mechanical ventilation, and mortality. On the other hand, AKI with or without proteinuria occurred in 131 patients (36.4%). The predominant pattern of AKI was severe (KDIGO 3, 47.9%), hospital-acquired (70.9%), and non-oliguric (71.4%). Kidney replacement therapy was required in 37.4% of AKI patients. Renal recovery was observed in 52.6% (full recovery in 40.2% and partial recovery in 12.4%), while non-recovery occurred in the remaining 47.4%. Table 2 presents the clinical characteristics of patients according to their AKD stage. Importantly, the mortality rate increased with the severity of AKD stage: non-kidney disease 9.5%, only proteinuria 22.8%, only AKI 56.7%, and proteinuria plus AKI 53.0% (p = 0.001).

The concept of Acute Kidney Disease was introduced by the KDIGO AKI Workgroup in 2012 (5) with the aim of providing an integrated clinical approach to patients experiencing acute abnormalities in kidney function and structure. The KDIGO Workgroup defines AKD as the occurrence of AKI, eGFR < 60 ml/min/1.73 m2, a decrease in GFR by > 35%, an increase in serum creatinine of > 50%, or any kidney damage, within 7 to 90 days following an episode of AKI. In 2016, the ADQI Workgroup published a consensus report on AKD and renal recovery (7). ADQI 16 refined the definition of AKD and introduced a stratification system for this condition. More recently, KDIGO organized a consensus conference with the goal of expanding and harmonizing existing definitions of AKD. Consequently, KDIGO guidelines now define kidney disease as functional and/or structural abnormalities of the kidneys with implications for health and a duration of ≤ 90 days, been AKI a subset of AKD. Kidney disease is further classified according to its cause, the severity of structural and functional abnormalities, and the duration of those abnormalities (11, 12). This novel perspective on acute functional and structural kidney disorders provides a broader understanding of these complex conditions.

Typically, studies addressing renal involvement in COVID-19 report data on AKI and/or proteinuria/hematuria as separate events. However, we believe that a more integrative approach is essential to identify subgroups from the perspective of AKD, as demonstrated in our study. This approach enables us to better determine the extent of renal involvement, implement preventive and therapeutic strategies, and establish a prognostic framework. As we observed, the frequency of adverse events increased in the following order: non-kidney disease, isolated proteinuria, isolated AKI, and both proteinuria and AKI. Comorbidities, the severity of the condition at admission, the need for ICU care and organ support, and laboratory abnormalities also followed a similar pattern as expected.

Our patient series exhibited the typical characteristics of individuals with COVID-19 in terms of age, gender, and comorbidities. Additionally, COVID-19 disease severity was high, with approximately half of the patients requiring ICU admission, mechanical ventilation, experiencing serious complications, and having a high in-hospital mortality rate. Overall, AKD was a prevalent condition, affecting nearly 76% of patients. The most common disturbance was proteinuria, with or without AKI (72.8%), followed by AKI with or without proteinuria (36.4%). As it was already said, for our analysis we classified patients into four groups: non-kidney disease, only proteinuria, only AKI, and proteinuria with AKI. We included as AKD without AKI those patients who had only proteinuria. This subgroup is noteworthy because, as demonstrated by James (8) and Sawhney (9), among others, AKD without AKI is a frequent and serious occurrence. James et al. reported a frequency of this subgroup that is three times the incidence of AKI, and the expected adverse outcomes were at least as severe as those of AKI. The authors concluded that AKD without AKI is common, identifies patients not recognized by AKI and CKD criteria, and is associated with an overall increased risk of long-term adverse outcomes, like us. In our series, AKD without AKI, when compared to non-kidney disease, was associated with more comorbidities, worse markers of disease severity, and an increase in in-hospital mortality from 5.8–24.1%. This time frame is critical for preventing worsening of the condition and progression to CKD.

Furthermore, in our series, AKI with or without proteinuria occurred in a third of cases, with the majority being severe, hospital-acquired, and non-oliguric. We observed a higher frequency of KDIGO 3, followed by KDIGO 1 and KDIGO 2 stages, as is common in this setting. The main causes of AKI were multiorgan dysfunction linked to COVID-19 or sepsis (47.6% and 25.0%, respectively), followed by hypovolemia or dehydration (22.6%). This pattern reflects the multifactorial nature of renal impairment in COVID-19-related AKI due to the effects of cytokine storms, hypovolemia, mechanical ventilation, and nephrotoxins (10). Approximately one-third of patients received kidney replacement therapy (KRT), primarily intermittent hemodialysis (IHD), despite being critically ill patients for whom continuous kidney replacement therapy (CKRT) or prolonged intermittent kidney replacement therapy (PIKRT) might have been more appropriate considering limited resources during the pandemic None of the patients were treated with extracorporeal blood purification. A similar profile was found in two Latin American studies conducted by our group, one of which focused on COVID-19-related AKI (11, 12) Recovery of kidney function, both complete and partial, was slightly higher in our study. However, it should be noted that follow-up was only conducted until hospital discharge or death.

Finally, we explored the association between clinical conditions and vaccination status. We obtained data for slightly more than half of the population, of which 54% received at least one dose of the vaccine. The vast majority of these patients received full vaccination (82%). Vaccinated patients had fewer comorbidities, less severity of disease at admission and during their hospital stay, less proteinuria, and better outcomes. Distribution of patients within AKD categories was similar (data not shown). These findings are likely related to the positive impact of the COVID-19 vaccine in reducing the severity of infection.

Our study has certain limitations, primarily stemming from the limited number of patients, which affected the power of the statistical analysis. Additionally, a high number of missing cases in some variables due to work overload because of the pandemic, prevented us from conducting a thorough analysis of the dynamics of the process, such as the trajectory of proteinuria and AKI, the time from AKI to ICU admission, and mechanical ventilation.

Nonetheless, the primary strength of our study lies in supporting the strategy of approaching kidney disorders from the perspective of AKD. AKD should be understood as a continuous and dynamic process that enables the timely identification of patients at the early stages of kidney injury, thereby reducing the risk of further progression.

In conclusion, our data endorse a novel and comprehensive approach to acute kidney diseases and disorders based on the concept of AKD. This integrative approach, encompassing the structural and functional continuum of AKI, AKD, and CKD, enables timely interventions and the implementation of preventive and therapeutic strategies.

Ethics approval and consent to participate. The study protocol received approval from the Ethics Committee of the Hospital de Clínicas, School of Medicine, Universidad de la República, Uruguay; the Ethics Committee, Hospital Provincial de Rosario, Sante Fe, Argentina and Ethics Committee, Hospital Nacional Arzobispo Loayza, Lima, Perú. Remaining participants were authorized to participate in the study by their Hospital authorities under approval of the aforementioned Ethic Committees. Given the observational nature of the study and the appropriate de-identification of data as mentioned above, informed consent was not deemed mandatory by the reference Ethics Committees, as stated in the Study Protocol approved.

Consent for publication. All authors have approved the submitted version.

Availability of data and materials. The datasets used and analyzed during the current study are deposited in the RedIRA site https://slanh.net/red-ira/ and available from the corresponding author on reasonable request.

Competing interests: RCDG received honoraria from Novo Biomedical, Baxter and Medtronic. MBP received support for attending 60º ERA Congress from European Renal Association. AF was Past President of SLANH. All authors declare no competing financial or non-financial interest in relation to the work described.

Funding. The Latin American Society of Nephrology and Hypertension (SLANH) provided financial support for the platform's design and maintenance during the recruitment period, as well as covering publishing fees. The funder played no role in study design, data collection and analysis, decision to publish, or manuscript preparation.

Authors’ contributions. Conception, study design, analysis and interpretation of data: RL, AF. Data acquisition, analysis and interpretation of data: YV, MP, CC, RCDG, DP, DM, AZ. Manuscript drafting: RL, RCDG. Critical revision of the manuscript: all author

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No competing interests reported.

Acute kidney disease in patients with Covid 19. A prospective, multicenter, multinational study in Latin America

Status:

Version 1

Abstract

Introduction

Methods

Results

Conclusions

INTRODUCTION

METHODS

Study protocol

Definitions

Data Collection

Statistical analysis.

Results

Discussion

Declarations

References

Additional Declarations

Status:

Version 1