key: cord-0980671-vm3bvrbw authors: Raina, Rupesh; Mahajan, Zubin A.; Vasistha, Prabhav; Chakraborty, Ronith; Mukunda, Krishna; Tibrewal, Abhishek; Neyra, Javier A. title: Incidence and Outcomes of Acute Kidney Injury in COVID-19: A Systematic Review date: 2021-06-15 journal: Blood Purif DOI: 10.1159/000514940 sha: 3f807e8f9e78feaf6417f94a316e44205a7a3cee doc_id: 980671 cord_uid: vm3bvrbw BACKGROUND AND OBJECTIVES: The recent worldwide pandemic of COVID-19 has been a serious, multidimensional problem that has left a detrimental worldwide impact on individuals of all ages and several organ systems. The typical manifestation of kidney involvement is acute kidney injury (AKI); however, there is a lack of consensus data regarding AKI epidemiology in COVID-19. This systematic literature review aims to bridge this knowledge gap. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS: MEDLINE and Cochrane library were systematically searched for the literature related to AKI in COVID-19 patients of all ages. MedRxIV was searched for relevant unpublished manuscripts. Two reviewers independently assessed the literature on the incidence of AKI and mortality, extracting the need for kidney replacement therapy (KRT). RESULTS: Sixty studies (n = 43,871 patients) were included in this review. The pooled incidence of AKI among COVID-19 patients was 19.45% (95% confidence intervals [95% CI]: 14.63–24.77%), while the pooled incidence of AKI COVID-19 patients requiring KRT was 39.04% (16.38–64.57%). The pooled proportion of COVID+ patients was significantly lower at 8.83% (5.64% to 12/66%). The overall mortality of COVID-19 patients was calculated to be 17.71% (95% CI: 11.49–24.93%), while the mortality among patients with AKI was higher at 54.24% (95% CI: 44.70–63.63%). CONCLUSION: This comprehensive systematic review summarizes the available literature pertaining to AKI epidemiology in COVID-19 patients and highlights the incidence, associated mortality, and the need for KRT in this susceptible population. The COVID-19 pandemic is a serious, multidimensional problem with tremendous detrimental consequences for healthcare, occupation, and economy [1] [2] [3] . First identified as a cluster of pneumonia cases of unknown origin in Wuhan, China in December 2019, the severe acute respiratory syndrome coronavirus 2 (SARS- The primary outcome of this systematic literature review, conducted according to the preferred reporting items for systematic reviews and meta-analyses "PRISMA" checklist (Appendix 1), was with the objective to identify evidence regarding acute kidney involvement in COVID-19, focusing on the incidence and outcomes of COVID-19 patients with AKI. A systematic search was conducted in PubMed/MEDLINE and Cochrane Center Trials databases to identify all published literature relevant to AKI in COVID-19 patients from November 1, 2019 to June 5, 2020. Search terms such as "COVID," "Coronavirus," "Betacoronavirus," "kidney," "renal," and "creatinine" were included in the search criteria (Appendix 2). The search strategy was modified as per the search engine, as appropriate. Study identification was done in 2 phases: first, all the literature retrieved from the search strategy was imported into Rayyan QCRI via End-Note and reviewed using the inclusion and exclusion criteria. Second, the reference lists of the selected studies were reviewed to identify other relevant publications. The inclusion criteria included prospective and retrospective cohort studies and case series assessing AKI in both adult and pediatric COVID-19 patients. All included studies needed to demonstrate laboratory-confirmed SARS-CoV-2 infection (including detection of SARS-CoV-2 nucleic acid via transcriptase polymerase chain reaction and CT scanning of the lung) and include demographic data, epidemiological data (incidence of AKI, severity, and comorbidities), laboratory and radiological data, treatment, and outcome. Case reports, systematic reviews, meta-analyses, randomized clinical trials, animal studies, and studies not in English were excluded. Studies exclusively on kidney transplant patients were also excluded from this analysis. The titles, abstracts, full-texts, and reference lists of the collected manuscripts were independently reviewed by 2 investigators (Z.M. and P.V.) to identify relevant studies for inclusion. Any disagreements or conflicts were resolved either via a consensus of the 2 reviewers or by the opinion of a third independent reviewer (R.C.). The schema for the selection of studies is shown in online suppl. Fig. 1 ; for all online suppl. material, see www.karger.com/ doi/10.1159/000514940. The data regarding patient demographics, presence of comorbidities, AKI incidence and severity, presence of hematuria and/or proteinuria, mortality rates, need for kidney replacement therapy (KRT), and outcomes were recorded electronically. The outcomes included the incidence of AKI among COV-ID-19 patients, the proportion of COVID-19 patients with AKI receiving KRT over the study period, and mortality among CO-VID-19 patients with incident AKI. These outcomes and their 95% confidence intervals (95% CI) were calculated for each study. A meta-analysis of these outcomes was conducted. The degree of between-study heterogeneity was assessed using the I 2 test, where I 2 ≥ 50% indicated high heterogeneity. Overall (pooled) estimates were calculated with random effects models for high heterogeneity and fixed effects models for low heterogeneity. Forest plots were used to visualize these outcomes in each study and the combined estimated outcomes with their 95% CI. Publication bias was assessed graphically using funnel plots. To determine the source of heterogeneity, sensitivity analyses and random-effects meta-regression were performed based on these parameters (criteria used for defining AKI, the study design, the geographic location of the study, age of the studied population, and the sample size of the study). A p-value ≤0.05 was considered for statistical significance. All statistical analyses were performed with R software version 3.1.0. The initial database search yielded 146 potential articles and considered 31 additional studies by searching through citation lists and unpublished manuscripts (online suppl. Fig. 1 ). A total of 177 studies were screened, of which 113 were excluded. After screening titles and abstracts, 61 full-text articles were obtained for detailed evaluation based on the inclusion criteria. One study was excluded after the full-text review, yielding a total of 60 Fig. 5 ). Visual inspection of the funnel plot showed an asymmetrical distribution, which indicated the presence of publication bias for all the above outcome measures (Fig. 1-5 ). The pooled proportion (95% CI) of proteinuria among COVID+ patients was 52 The I 2 value for sensitivity analyses was like that obtained without excluding the studies based on the previously mentioned parameters (online suppl. Table 8) . Also, the proportion (%) of the outcomes obtained from the sensitivity analyses was within the 95% CI of the overall proportion for all the parameters (except for age and geography), indicating that the results of this metaanalysis are robust enough. To further explore the impact of these parameters on the outcomes, the meta-regression analyses were conducted (online suppl. Table 9 ). The meta-regression analyses reported that the pooled incidence of AKI among COVID+ patients was significantly higher among studies from geography other than China .99]), the only significant parameter observed. None of the parameters were significantly associated with the incidence of KRT among COVID+ patients. These analyses were not conducted for other outcomes due to insufficient data. Discussion COVID-19 primarily manifests as an acute respiratory illness with interstitial or alveolar pneumonia, but can also affect multiple organs, such as the kidneys, heart, liver, blood, and nervous system [65, 66] . Recent literature suggests that kidneys are especially vulnerable in COV-ID-19 patients, with AKI being the most frequent manifestation [5] . There is a dearth of accurate consensus re-garding incidence, pathogenesis, diagnosis, management, and outcomes of AKI. This systematic literature review and meta-analysis specifically aims to address incidence and outcomes of AKI in COVID-19 patients. Our findings revealed that AKI was a frequently observed complication of COVID-19 infection, with a cumulative incidence of 19.76%. COVID-19 patients had an overall mortality rate of 17.51%. This is in line with the historical mortality estimates of the SERS and MERS epidemics (10 and 40%, respectively) [65, 66] . COVID-19 patients with AKI had a significantly higher mortality rate of 54.24% and, overall, 18 times higher risk of death when compared to COVID-19 patients without AKI. Thus, AKI is a major negative prognostic factor in COVID-19 patients with dire need of prevention and management in this susceptible population. The pathophysiology of AKI in COVID-19 is complex, suggestive of a biphasic pattern with volume responsive AKI occurring in early stages of the disease and kidney injury occurring in later stages of the disease [67] . Acute lung injury that ensues in COVID-19 patients can effectuate impairment of the kidney function through its effect on gas exchange, release of pro-inflammatory mediators (IL-2, IL-7, IL-10, IFN-γ, IP10, GCSF, and MCP1), and cardiopulmonary interactions [67, 68] . The lung-kidney crosstalk may be bidirectionally deleterious, due to a cascade of irreversible cytokine release [67, 69] . A transient febrile/illness-related proteinuria may also be seen, like the MERS CoV infection [6, 70] . The cellular entry of SARS-CoV-2 is mediated by angiotensin-converting enzyme II, which is highly expressed in the podocytes and proximal tubules (100× levels compared to the lungs) and upregulated in patients with COVID-19 [7, [71] [72] [73] . An autopsy series conducted by Puelles et al. [74] (n = 27), showed that SARS-CoV-2 has organotropism beyond the pulmonary tract. Recent postmortem kidney pathology findings in patients with COVID-19 suggests that although there are little signs of viral nephropathy, noted acute tubular injury in the setting of creatinine elevation is reversible with appropriate care such as aggressive fluid management [75] . Mechanical ventilation may be provided to patients which affects the renal and systemic hemodynamics, stimulates sympathetic pathways, and causes biotrauma [9, 76] . Recent studies in London indicate that COVID-19 may present as multisystem inflammatory syndrome; however, there is still limited information regarding this COVID-19 associated condition. In terms of management of patients with COVID-19 and AKI, discussion of goals of supportive care (e.g., KRT) among clinicians and patients/families is recommended. Standard recommendations by KDIGO include nutritional and fluid support, avoidance of nephrotoxins, maintenance of oxygenation saturation, and hemodynamic stability for the management of AKI. KRT may reduce the burden of inflammatory mediators and cytokines as supported by a study with Ghani et al. [77] [78] [79] [80] particularly to patients with AKI; however, more studies are required. Various modalities such as peritoneal dialysis, hemodialysis, CKRT, and sustained low-efficiency dialysis can be utilized for AKI management. Although CKRT is the preferred modality in most ICU settings, the choice of modality should be based on the hemodynamic status, patient characteristics and needs, available resources, and health-care expertise [81] [82] [83] . Newer modalities such as CytoSorb (an extracorporeal cytokine filter) and Oxiris (a blood purification device for cytokine clearance) have received expedited FDA approval for use in adult COVID-19 patients (≥18 years old) with AKI [84, 85] , where the provider can obtain an exploratory investigational new drug for use in the pediatric population. Evidence is actively evolving but insufficient for widespread application in COVID-19 patients with AKI. This systematic literature review is constrained due to the paucity of relevant peer reviewed studies and data. Our review excludes studies that are not in the English language. In several studies, baseline creatinine levels were unavailable and data of kidney recovery, drug exposure, or long-term kidney outcomes were not reported. Renal pathology data were sparse, and it was difficult to assess the precise etiology of AKI in COVID-19 patients. Additionally, visual inspection of the funnel plots for the incidence of AKI, need of KRT, and mortality showed an asymmetrical distribution, which indicates the possibility of publication bias (Fig. 2-5 ). The differences between this systematic review and recently published work helps address the prior lack of generalizability; this study includes data spanning Asia, Europe, and USA in addition to including a broader scope of studies as highlighted in online suppl. Table 10 . Additionally, this systematic review reports higher incidence of AKI with COVID-19 patients (results = 19.76%, range in literature = 2-11%) and delves into a possible explanation with the results on the need for KRT [83, [86] [87] [88] [89] [90] [91] [92] [93] [94] [95] . Future studies should assess risk stratification, specific management strategies, and long-term outcomes of COVID-19 patients with AKI. AKI is increasingly being recognized as a negative prognostic factor in patients with COVID-19. Its high incidence (19.76%) and mortality rate (54.24%) mandated routine and standardized monitoring of the kidney function during hospitalization. Supportive measures, fluid management, and prevention of immune dysregulation are necessary to potentially improve outcomes in these patients. Effective use of KRT should be considered with evolving multiorgan failure, especially in patients with concomitant mechanical ventilation. Therapeutic options in COVID-19 patients with AKI require further exploration with randomized controlled trials. Improved awareness among health-care providers and proactive prevention and management of AKI are key to improve the high mortality observed in these patients. World Health Organization declares global emergency: a review of the Emergence of novel coronavirus 2019-nCoV: need for rapid vaccine and biologics development The epidemiology and pathogenesis of coronavirus disease (CO-VID-19) outbreak Statement on the meeting of the International Health Regulations (2005) Emergency Committee regarding the outbreak of novel coronavirus (2019-nCoV) Clinical features of patients infected with 2019 novel coronavirus in Wuhan Renal involvement and early prognosis in patients with COVID-19 pneumonia Renal histopathological analysis of 26 postmortem findings of patients with COV-ID-19 in China Human kidney is a target for novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. med-Rxiv Kidney disease is associated with in-hospital death of patients with COV-ID-19 Clinical features, laboratory characteristics, and outcomes of patients hospitalized with coronavirus disease 2019 (COVID-19): early report from the United States Clinical characteristics and outcomes of older patients with coronavirus disease 2019 (COVID-19) in Wuhan, China (2019): a single-centered, retrospective Coronavirus disease 19 infection does not result in acute kidney injury: an analysis of 116 hospitalized patients from Wuhan, China Analysis of 92 deceased patients with COV-ID-19 Clinical course, and outcome of 107 patients infected with the novel coronavirus, SARS-CoV-2, discharged from two hospitals in Wuhan Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan Clinical features and short-term outcomes of 221 patients with COVID-19 in Wuhan Acute kidney injury in patients hospitalized with COVID-19 in Wuhan, China: a singlecenter retrospective observational study. med-Rxiv Clinical characteristics of coronavirus disease 2019 in China Characteristics and outcomes of 21 critically Ill patients with CO-VID-19 in Washington State Clinical characteristics of patients with 2019 coronavirus disease in a non-Wuhan area of Hubei Province, China: a retrospective study Anti-2019-nCoV Volunteers Caution on kidney dysfunctions of COVID-19 patients. med-Rxiv ICNARC report on COVID-19 in critical care. ICNARC COVID-19 study case mix program database Epidemiology, clinical course, and outcomes of critically ill adults with COVID-19 in New York City: a prospective cohort study Clinical characteristics of 34 COV-ID-19 patients admitted to intensive care unit in Hangzhou Clinical features of acute kidney injury in coronavirus disease 2019: a case report with review of literature Characterization and clinical course of 1000 patients with coronavirus disease 2019 in New York: retrospective case series The value of urine biochemical parameters in the prediction of the severity of coronavirus disease 2019 Clinical features of patients infected with the 2019 novel coronavirus (COVID-19 Acute kidney injury at early stage as a negative prognostic indicator of patients with COVID-19: a hospital-based retrospective analysis COVID-19 in a designated infectious diseases hospital outside Hubei Province, China Clinical findings in critical ill patients infected with SARS-Cov-2 in Guangdong Province, China: a multi-center, retrospective, observational study Clinical characteristics of 101 COV-ID-19 nonsurvivors in Wuhan, China: a retrospective study Characteristics of patients with COV-ID-19 during epidemic ongoing outbreak in Wuhan, China. medRxiv Clinical predictors of mortality due to COV-ID-19 based on an analysis of data of 150 patients from Wuhan, China Risk factors associated with clinical outcomes in 323 COVID-19 hospitalized patients in Wuhan, China Clinical features of 85 fatal cases of CO-VID-19 from Wuhan: a retrospective observational study Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China Clinical features and outcomes of 98 patients hospitalized with sarscov-2 infection in daegu, south korea: a brief descriptive study Clinical characteristics of fatal and recovered cases of coronavirus disease 2019 in Wuhan, China: a retrospective study Acute kidney injury in patients hospitalized with COVID-19 Acute kidney injury associated with coronavirus disease 2019 in Urban New Orleans Acute kidney injury in hospitalized patients with COVID-19. med-Rxiv AKI in hospitalized patients with and without COVID-19: a comparison study Fatal outcomes of COVID-19 in patients with severe acute kidney injury AKI and collapsing glomerulopathy associated with COVID-19 and APOL 1 high-risk genotype Clinical characteristics and outcomes of community-and hospital-acquired acute kidney injury with COVID-19 in a US inner city hospital system A continuous renal replacement therapy protocol for patients with acute kidney injury in intensive care unit with COVID-19 Clinical characteristics and risk factors of acute kidney injury in coronavirus disease Clinical course and predictors of 60-day mortality in 239 critically ill patients with CO-VID-19: a multicenter retrospective study from Wuhan Acute kidney injury and kidney damage in COVID-19 patients Activation of the reninangiotensin-aldosterone system is associated with acute kidney injury in COVID-19 Characterisation of acute kidney injury in critically Ill patients with severe coronavirus disease-2019 (COV-ID-19) Clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study Clinical manifestations and outcomes of critically Ill children and adolescents with COVID-19 in New York City Factors associated with death in critically Ill patients with coronavirus disease 2019 in the US Clinical characteristics of 82 death cases with COVID-19 Kidney manifestations of mild, moderate and severe coronavirus disease 2019: a retrospective cohort study Urinalysis, but not blood biochemistry, detects the early renal-impairment in patients with COVID-19 Summary of probable SARS cases with onset of illness from 1 Middle East respiratory syndrome Kidney-lung cross-talk and acute kidney injury Lungkidney cross-talk in the critically ill patient Kidney-lung pathophysiological crosstalk: its characteristics and importance Renal complications and their prognosis in korean patients with middle east respiratory syndrome-coronavirus from the Central MERS-CoV Designated Hospital A pneumonia outbreak associated with a new coronavirus of probable bat origin The novel coronavirus 2019 (2019-nCoV) uses the SARS-coronavirus receptor ACE2 and the cellular protease TMPRSS2 for entry into target cells Anti-2019-nCoV Volunteers Caution on kidney dysfunctions of 2019-nCoV patients. med-Rxiv Multiorgan and Renal Tropism of SARS-CoV-2 Postmortem kidney pathology findings in patients with COV-ID-19 Mechanical ventilation and acute renal failure Treatment for severe acute respiratory distress syndrome from COVID-19 Management of acute kidney injury in patients with COVID-19 COVID-19 and renal failure: challenges in the delivery of renal replacement therapy Serum IL-6 and IL-1-ra with sequential organ failure assessment scores in septic patients receiving high-volume haemofiltration and continuous venovenous haemofiltration Managing children with renal diseases during COV-ID-19 pandemic Ensuring sustainability of continuous kidney replacement therapy in the face of extraordinary demand: lessons from the COVID-19 pandemic Estimating shortages in capacity to deliver continuous kidney replacement therapy during the COVID-19 pandemic in the United States Management of patients on dialysis and with kidney transplant during SARS-COV-2 (COVID-19) pandemic in Brescia Continuous renal replacement therapy with the adsorbing filter oXiris in septic patients: a case series Prevalence and impact of acute renal impairment on COVID-19: a systematic review and meta-analysis Acute kidney injury in coronavirus disease 2019 infected patients: a meta-analytic study Renal complications in COVID-19: a systematic review and meta-analysis Incidence of acute kidney injury and its association with mortality in patients with COVID-19: a meta-analysis Multiorgan failure with emphasis on acute kidney injury and severity of COVID-19: systematic review and meta-analysis Acute kidney injury is associated with severe infection and fatality in patients with COV-ID-19: a systematic review and meta-analysis of 40 studies and 24,527 patients Outcomes for patients with COVID-19 and acute kidney injury: a systematic review and metaanalysis Clinical characteristics and risks of Chinàs 2019 novel coronavirus patients with AKI: a systematic review and meta-analysis Acute kidney injury and kidney replacement therapy in COVID-19: a systematic review and meta-analysis Multi-organ dysfunction in patients with COVID-19: a systematic review and meta-analysis