A review of Covid-19 and acute kidney injury: from pathophysiology to clinical results

All authors contributed substantially to the collection, analysis and interpretation of data, the writing of the article and the critical review. All authors approved the final version to be published.

Conflict of Interest

The authors declare that they have no conflict of interest related to the publication of this manuscript.

Origin of Kidney Injury	Pathophysiological Mechanism
Viral Cytopathic Effect	The strong association between SARS-CoV-2 and RAAS suggests a direct viral aggression towards the kidney parenchyma, culminating in kidney injury. SARS-CoV-2 through Spike (S) surface protein could bind with ACE-2, expressed in kidney tissue, facilitating viral entrance and direct injury to the kidney parenchyma. ACE-2 is mainly expressed in the apical brush border of proximal tubular cells and podocytes. Early studies from autopsies of post-mortem kidney tissues revealed through electronic microscopy the presence of possible spherical viral particles in tubular epithelium and podocytes, suggesting that SARS-CoV-2 viral tropism might directly affect the kidney. Nonetheless, more robust data from recent autopsy studies were not able to detect viral particles in immunohistochemistry and in situ hybridization, causing the hypothesis of viral replication in renal parenchyma controversial.
ARDS	Studies emphasize a pathological axis between AKI and ARDS. Despite unclear pathophysiology, authors hypothesize mechanical ventilation, hypoxemia, and systemic inflammation as major mechanisms. High pressure ventilation may not only cause lung injury but also systemic inflammation and organ dysfunction due to cytokine release syndrome. Moreover, higher PEEP values is associated with hypercytokinemia and AKI. Positive pressure ventilation can decrease cardiac preload and induce kidney hypoperfusion. In the context of ARDS, hypoxia and hypercapnia is also associated with inflammation leading to AKI, which can enhance inflammation leading to alveolar cells apoptosis and increased vascular permeability, diminishing pulmonary function, and characterizing an ARDS-AKI pathological axis.
Cytokine Storm/ Inflammation	SARS-CoV-2 infection, mainly in severe forms, is associated with immune hyperactivity, hypercytokinemia, and systemic inflammation. Systemic inflammation is associated with multi-organ endotheliitis. Therefore, endotheliitis leading to endothelial dysfunction and complement activation causes hypercoagulability, microangiopathy, altered renal blood flow, hypoperfusion, ischemia, and kidney injury. Therefore, hypercytokinemia associated with COVID-19 might lead to severe impairment of renal microcirculation. Moreover, authors also postulate that kidney injury induced by SARS-CoV-2 can also be indirectly associated with immune mechanisms triggered by viral renal cellular damage, as inflammatory cytokines originated from macrophages and complement-mediated mechanisms from viral cytopathic kidney cell injury can aggravate tubular and interstitial injury. Cytokine storm and immune dysregulation prompts immune-mediated kidney injury. APOL1 gene expression may possibly play an important role in the pathogenesis of AKI due to its important association with inflammation and viral infection.
Myocardium/ Acute Heart Failure/ Hemodynamic Status	Studies are also describing viral tropism of SARS-CoV-2 to ACE-2 receptors present in the myocardium, causing major left ventricular systolic function depression and consequent hemodynamic impairment which can lead to kidney hypoperfusion and AKI. Additionally, right ventricular dysfunction secondary to PTE or pulmonary hypertension associated with hypoxia and/or hypercapnia can also cause hemodynamic instability in patients with COVID-19. Volume depletion and inappropriate volume resuscitation associated with kidney hypoperfusion can aggravate kidney injury.
Rhabdomyolysis	Histopathological studies have demonstrated rhabdomyolysis with histologic evidence in patients with COVID-19. Rhabdomyolysis is associated with massive release of myoglobin into systemic circulation, with myoglobinuria, cast formation, and iron deposition in proximal tubular cells causing intratubular obstruction. Direct toxicity on kidney tubular cells causes acute tubular necrosis.

Author	N	Major Histopathology Findings
Kudose et al. 2020	17	• 15 patients (88%) developed AKI. • Collapsing glomerulopathy: 5 patients; Minimal change disease: 1 patient; Membranous glomerulopathy: 2 patients; Crescentic transformation of lupus nephritis: 1 patient; anti-GBM nephritis: 1 patient; isolated ATN: 4 patients. • Electron microscopy: Absence of definitive virions within renal cells. Immunohistochemical stains for spike and nucleocapsid proteins for SARS-CoV-2 RNA showed no definitive staining. • Authors highlight that the lack of definitive viral particles observed in kidney parenchyma argues against direct viral tropism as the major pathophysiological mechanism for AKI.
Sharma et al. 2020	10	• Severe AKI requiring RRT (80%), proteinuria (100%). • Thrombotic microangiopathy: 2 patients; Pauci-immune crescentic GN: 1 patient; Global and segmental glomerulosclerosis: 1 patient; Widespread myoglobin casts: 1 patient. All patients presented varying degrees of ATN. • Electron microscopy: Ultrastructural examination showed no evidence of viral particles and immunohistochemical staining of kidney biopsy for SARS-CoV-2 were negative • Authors conclude that ATN was the most common histopathological finding in the kidney biopsies of patients with COVID-19 studied. Similar to findings from Kudose et al., as there was no evidence of SARS-CoV-2 viral particles.
Golmai et al. 2020	12	• All patients had a pathologic diagnosis of acute tubular injury with focal ATN (varied from mild to diffuse). No histopathological evidence of GN, vasculitis, or thrombotic microangiopathy. • Electron microscopy: None of the cases demonstrated viral particles similar to coronavirus morphology. Immunohistochemical assays for SARS-CoV-2 nucleocapsid protein were negative in all cases. Additionally, in situ hybridization performed in four cases were negative. • None of the kidney biopsies evidenced viral cytopathic effects or necrotizing inflammatory changes. • As EM did not detect viral particles, authors hypothesize that COVID-19 induced AKI is more predominantly associated with ischemic ATN, resulting from systemic inflammation and hypoperfusion, resembling septic AKI, rather than viral cytopathic effect.
Santoriello et al. 2020	42	• Predominant histopathological finding: Acute tubular injury. • Glomerular fibrin thrombi: 6 patients (focal). • Electron microscopy: SARS-CoV-2 viral particles were not identified at ultrastructural level. ISH for SARS-CoV-2 RNA was not able to identify definite positivity for viral particles. • Authors observed a mild degree of ATI even in the setting of severe AKI. • Authors conclude that COVID-19 induced AKI is associated with a complex etiology involving ischemia, hypoxia, sepsis-associated factors, and nephrotoxicity.
Xia et al. 2020	81	• 41 (50.6%) patients developed AKI. • Predominant histopathological finding: Acute tubular injury. • All autopsied patients evidenced different degrees of tubular injury and cytoplasmic vacuolization in tubular epithelial cells. • Crystallizations were observed in proximal tubular cells and casts, suggesting drug-induced AKI, and glomerular lesions were not remarkable. • Electron microscopy: Few particles enclosed in vesicles were observed in the cytoplasm of renal proximal tubular epithelial cells. • SARS-CoV-2 viral particles were not detected by immunohistochemistry. • Inflammation-mediated vascular endothelial injury and immune hyperactivity might play a major role in kidney injury and critical COVID-19 disease.

Author	N	Design	Age (years)	Comorbidities	Major findings
Nimkar et al. 2020	370	Retrospective	71 (59-82)	HTN (63.9%) DM (42.5%) DLP (34.9%) CVD (29.9%)	1.Odds for AKI in hospitalized patients with COVID-19 (Multivariable analysis): • African-American race (OR 2.01 [95%CI 1.1-3.6], p=0.02); hyperlipidemia (OR 1.8 [1.04-3.01], p=0.03); History of CKD (OR 3.3 [95%CI 1.4-7.9], p=0.08).
Wang et al.2020	116	Retrospective	62 (55-69)	HTN (40.5%) DM (17.2% CAD (10.3%) CD (6.0%	1.Odds for AKI in hospitalized patients with COVID-19 (Multivariable analysis): • Procalcitonina > 0.1ng/mL (OR 4.822 [95%IC 1.095-21.228], p=0.037); TFGe <60mL/min/1.73m2 (OR= 13.451 [95%IC 1.617-111.891], p=0.016
Hirsch et al.	5.499	Cohort	64 (52-75)	HTN (55.7%) DM (33.0%) CAD (11.0%) HF (6.4%)	1. Risk factors associated with the development of AKI (Multivariate analysis): • Age (OR 1.03 [95%CI 1.03-1.04], p<0.001); Black race (OR 1.23 [95%CI 1.01-1.50], p=0.04); Diabetes (OR 1.76 [95%CI 1.49-2.07], p<0.001); CVD (OR 1.48 [95%CI 1.22-1.80], p<0.001); Mechanical ventilation (OR 10.7 [95%CI 6.81-16.70], p<0.001); Vasoactive drugs (OR 4.53 [95%CI 2.88-7.13], p<0.001).
Cheng et al. 2020	1,392	Retrospective	63 (50-71)	HTN (36.0%) DM (17.0%) CKD (2.0%)	1.Risk factors associated with the development of AKI (Multivariate analysis): • Severe disease (OR 2.25 [95%CI 1.37-3.67]); Higher baseline SCr (OR 2.19 [95%CI 1.17-4.11]); Lymphopenia (OR 1.99 [95%CI 1.12-3.53]); Elevated D-dimer level (OR 2.68 [95%CI 1.07-6.70]).
Fisher et al. 2020	3,345	Retrospective	64.4 (SD 16.4)	DM (27.1%) CKD (12.2%)	1. Risk factors associated with the development of AKI (Adjusted model): • Male (OR 1.6 [95%CI 1.4-1.8]; Non-Hispanic Black ethnicity (OR 1.7 [95%CI 1.3-2.3]). 2. Predictive Model of AKI Stage 2 or 3: • Black race (OR 1.8 [95%CI 1.2-2.8]); Male sex (OR 1.4 [95%CI 1.1-1.7]); DM (OR 1.3 [95%CI 1.0-1.7]); Nursing home resident (OR 1.6 [95%CI 1.2-2.1]); Neutrophil/lymphocyte ratio (OR 1.5 (95%CI 1.2-1.9]); LDH levels (OR 2.1 [95%CI 1.8-2.5]).
Xia et al.2020	81	Retrospective	66.6 (SD 11.4)	HTN (53.1% DM (23.6%) CAD (21.0%)	1. Risk factors associated with the development of AKI: • Age (per 10 years): (HR 1.8 [95%CI 1.2-2.7], p=0.002); Serum IL-6 (HR 1.8 [95%CI 1.2-2.7], p=0.003).

Author	N	Design	Age (years)	Comorbidities	Major finding
Thakkar et al. 2020	300	Retrospective	AKI: 60 (26-97) Non-AKI: 52 (30-89)	AKI: HTN (69%) DM (448%) Non-AKI: HTN (54%) DM (30%)	1.Admission laboratory data (Survivors x non-survivors): -Creatinine (1.1 vs. 1.3, p=0.041); Hemoglobin (13.0 vs. 13.6, p=0.025).. 2. Peak laboratory values: -Creatinine (3.8 vs. 6.2, p=0.007); Phosphate (7.1 vs. 8.3, p=0.050); Lactate (2.6 vs. 3.4, p<0.01); Procalcitonin (2.6 vs. 6.0, p=0.013); CRP (23.4 vs. 33.8, p=0.001).
Fisher et al. 2020	3.345	Retrospective	64.4 (SD 16.4)	DM (27.1%) CKD (12.2%)	1.Clinical manifestations: (AKI vs. non-AKI) -Respiratory rate, breaths/min (22.3 vs. 20.6, p<0.001); pulse oximetry (91.7 vs. 94.3%, p<0.001). 2. Initial laboratory data: -WBC (9.3 vs. 7.8, p<0.001); Neutrophil (7.3 vs. 5.8, p<0.001); neutrophil-lymphocyte ratio (6.6 vs. 4.7, p<0.001); procalcitonin (0.4 vs. 0.2, p<0.001); fibrinogen (659.1 vs. 631.8, p=0.002); CRP (13.2 vs. 7.3, p<0.001); D-dimer (2.2 vs. 1.1, p<0.001); LDH (458 vs. 350, p<0.001); Ferritin (911 vs. 610, p<0.001).
Chan et al. 2020	3.993	Retrospective	64.0 (56.0-78.0)	HTN (38%) DM (26%) CKD (11%) CHF (10%)	1. Clinical manifestations: (AKI vs. non-AKI) -Temperature (36.9 vs. 37.0); Diastolic BP (125 vs. 124); Heart rate (87 vs. 87); Respiratory rate (20 vs. 18); Oxygen saturation (96 vs. 96). 2. Initial laboratory data: -WBC (8.7 vs. 6.9); Lymphocyte % (10.6 vs. 15.5); Hemoglobin (12.3 vs. 12.8); Platelets (207 vs. 221); Creatinine (1.42 vs. 0.8); BUN (31 vs. 13).
Xia et al. 2020	3.345	Retrospective	66,6 (±11.4)	HTN (53.1%) DM (23.5%) CAD (21.0%) CD (13.6%)	1. Clinical manifestations: (AKI vs. non-AKI) -Dyspnea (70.7% vs. 65.0%); Cough (80.5% vs. 75.0%); Fever (82.9% vs. 95.0%); 2. Initial laboratory data: -Platelets (145.0 vs. 176.5, p=0.03); Lymphocytes (0.50 vs. 0.65, p=0.02); SCr (104.0 vs. 65.5, p<0.001); Elevated SCr (51.2 % vs. 7.5%, p<0.001); Cystatin C (1.74 vs. 1.06, p<0.001); BUN (12.5 vs. 7.1, p<0.001); Serum uric acid (289.5 vs. 164.0, p<0.001); IL-6 (100.4 vs. 36.8, p=0.01); PT (17.2 vs. 16.0, p=0.04); INR (1.40 vs. 1.26, p=0.02); NT-proBNP (1902.0 vs. 843.0, p=0.03).

Author	N	Design	Age (years)	Comorbidities	Major findings
Thakkar et al. 2020	300	Retrospective	AKI: 60.1 (26.0-97.0) Non-AKI: 52.1 (30.0-89.0)	AKI: HTN (68.75%) DM (44.77%) Non-AKI: HTN (53.94%) DM (30.26%)	1. Mechanical Ventilation: -AKI stage: Stage 1 (96%); Stage 2 (91%); Stage 3 (99%). 2.ARDS: -Severe ARDS: 60% -Severe ARDS and AKI: Stage 1 (21%); Stage 2 (13%); Stage 3 (66%). 3.RRT -Incidence: 50.8%.
Fisher et al. 2020	3.345	Retrospective	64.4 (SD 16.4)	DM (27.1%) CKD (12.2%)	1. AKI Incidence (COVID-19 positive, negative, and controls) AKI Stages: Stage 1 (49.5%), Stage 2 (20.3%), Stage 3 (30.2%) -RRT: (4.9% vs. 1.6% vs. 0.9%) -28.5% COVID-19 positive patients with stage 3 AKI required RRT. 2. ICU Admission and Mechanical Ventilation: 2.1) ICU admission (AKI vs. non-AKI): (20.1% vs. 3.9%, p<0.001). 2.2) Mechanical Ventilation (AKI vs. non-AKI): (29.9% vs 3.8%, p<0.001).
Chan et al. 2020	3.993	Retrospective	64.0 (56.0-78.0)	HTN (38.0%) DM (26.0%) CKD (11.0%) CHF (10.0%)	1. Clinical Outcomes (AKI vs. non-AKI); -ICU admission (41% vs. 11%); Mechanical ventilation (44% vs. 6%); Vasopressor use (43% vs. 10%). 2.Predictors Severe AKI: -Male sex (OR: 1.46 [95%CI 1.2-1.8]); Admission potassium (OR: 1.7 [95%CI 1.6-2.0]); CKD ( OR: 2.8 [95%CI 2.1-3.7]).
Xia et al. 2020	1.752	Retrospective	66.6 (±11.4)	HTN (53.1%) DM (23.5%) CAD (21.0%) CD (13.6%)	1.Clinical Characteristics ICU (AKI vs. non-AKI): - APACHE II score (16 vs. 14, p=0.02); SOFA score 7 vs. 6, p=0.03); Coagulopathy (73.2 % vs. 52.5%, p=0.05).
Hirsch et al. 2020	5.499	Cohort	64.0 (52.0-75.0)	HTN (55.7%) DM (33.0%) CAD (11.0%) HF (6.4%)	1.Mechanical Ventilation -AKI Stage: Stage 1 (24.2%); Stage 2 (22.0%); Stage 3 (43.5%); RRT (23.2%); AKI any stage (89.7%).

Author	N	Design	Age (years)	Comorbidities	Major findings
Thakkar et al. 2020	300	Retrospective	AKI: 60.1 (26.0-97.0) Non-AKI: 52.1 (30.0-89.0)	AKI: HTN (68.75%) DM (44.77%) Non-AKI: HTN (53.94%) DM (30.26%)	1.Mortality: -60-day hospital mortality: 66.5% -Mortality Rate RRT: 70.0% 2.Predictors of Risk of In-hospital Mortality:- -Advancing age, serum potassium levels on admission, and hemoglobin levels on admission.
Fisher et al. 2020	3.345	Retrospective	64.4 (SD 16.4)	DM (27.1%) CKD (12.2%)	1.Mortality: -1.1 COVID-19 Positive Cohort -Mortality Rate (AKI vs. non-AKI): (33.7% vs. 9.3%) -1.2 COVID-19 Negative Cohort -Mortality Rate (AKI vs. non-AKI): (13.4% vs. 3.7%) -1.3 Stage 3 AKI and RRT -(COVID-19 Positive vs. Negative) - (52.1% vs. 19.6%; RR 3.8 [CI95% 2.6-3.9]).
Chan et al. 2020	3.993	Retrospective	64.0 (56.0-78.0)	HTN (38.0%) DM (26.0%) CKD (11.0%) CHF (10.0%)	1.Mortality: 1.1 Mortality Rates: -In-hospital mortality (AKI vs. non-AKI): (50.0 vs. 8.0, p<0.001). -Mortality Rate AKI (ICU vs. non-ICU): (42.0% vs. 62.0%). -Mortality Rate non-AKI (ICU vs. non-ICU): (7.0% vs. 13.0%). -1.2 Kaplan-Meier Survival analysis (AKI vs. non-AKI): -Survival probability after 30 days: (51.5% vs. 91.8%, p<0.0001). 1.2 Odds for Mortality: -ICU (AKI vs. non-AKI): (OR 11.4 [95%CI 7.2-18]). -All patients (AKI vs. non-AKI): (OR 9.2 [95%CI 7.5-11.3]). -AKI stages (all patients): Stage 1 (OR 4.5 [95%CI 3.5-5.6]); Stage 2 (OR 6.6 [CI95% 4.9-8.9]); Stage 3- no dialysis (OR 20.2 [95%CI 15-27.3]); Stage 3-dialysis (OR 38.7 [95%CI 27.4-54.6]).
Xia et al. 2020	1.752	Retrospective	66,6 (±11,4)	HTN (53.1%) DM (23.5%) CAD (21.0%) CD (13.6%)	1.Independent Predictors of Mortality: -IL-6 levels (HR 2.12 [95%CI 1.27-3.53], P=0.004]); Higher levels of D-dimer (HR 1.57 [95%CI 1.13-2.18],p=0.008); SOFA score (HR 1.08 [95%CI 1.01-1.15], p=0.03); Male sex (OR 2.38 [95%CI 1.31-4.33], p=0.004); KDIGO Stage 3 AKI (HR 2.58 [95%CI 1.25-5.31], p=0.010);
Cheng et al. 2020	1.392	Retrospective	63,0 (50,0-71,0)	HTN (36.0%) DM (17.0%) CKD (2.0%)	1.Mortality: -1.1 Mortality Rates: -Overall in-hospital mortality: 14% -Overall AKI mortality: 72.0%; Stage 1: 62.0%; Stage 2: 77.0%; Stage 3: 80.0%; 21.0% died 1 day after AKI occurred. -1.2 Odds for Mortality: - AKI KDIGO (OR 5.12 [95%CI 2.70-9.72]).

Author	N	Design	Age (years)	Comorbidities	Major findings
Fisher et al.2020	3.345	Retrospective	64.4 (SD 16.4)	DM (27.1%) CKD (12.2%)	1.RRT (COVID-19 positive vs. negative vs. controls: -COVID-19 positive vs. negative: (4.9% vs. 1.6%) -COVID-19 positive vs. controls: (4.9% vs. 0.9%) 2.Renal Recovery: - (42,3% vs. 68,5% vs. 63,9%)
Wilbers et al.2020	37	Retrospective	64 (42-73)	HTN (23.0%) DM (15.0%) CKD (8.0%)	1.RRT (RRT vs. non-RRT): -1.1Incidence: 59.0% -1.2 Clinical characteristics: Younger, higher levels of SCr and BUN, Higher incidence of oliguria -1.3 Mortality Rate: (39.0% vs. 44.0%) 2.Renal Recovery: - -Renal function recovered to KDIGO stage 1 in 64.0% of patients with AKI when discharged from ICU.
Mohamed et al. 2020	575	Observational	AKI: 65 (34-96) Non-AKI 66 (23-97)	AKI: HTN (83.0%) DM (53.0%) Non-AKI HTN (70.0%) DM (47.0%)	1.RRT and AKI -1.1 Inflammatory Biomarkers: -AKI vs non-AKI: Ferritin (1016 vs. 680); D-dimer (1.57 vs. 1.13); CRP (163 vs. 93); Procalcitonin (0.37 vs. 0.12); LDH (532 vs. 428). -AKI-RRT: Higher baseline serum ferritin, CRP, procalcitonin, and LDH. Higher D-dimer median peak value (7.8 vs. 3.8, p=0.003). -1.2: Incidence: -Total cohort: 55.0% -ICU: 73.0% -1.3: Risk factors for RRT: -Younger age (61 vs. 68, p=0.0003); Higher BMI (35 vs. 33, p=0.05). -1.4 Mortality: -In-hospital mortality rate: 72.0% -AKI-RRT and MV: 74.0%
Chan et al.2020	3.993	Retrospective	64 (56-78)	HTN (38.0%) DM (26.0%) CKD (11.0%) CHF (10.0%)	1.RRT: 1.1 Incidence: -Total: 19.0% -ICU: 32.0% 2.Renal Recovery: -Hospital discharge: 65.0% had recovery of AKI; 35.0% had AKD.
Gupta et al.2020	3.099	Cohort	62(51-71)	HTN (60.3%) DMNID (26.2%) DMID (13.5%) CAD (12.6%) CHF (8.7%) COPD (8.3%)	1.RRT: -1.1 Risk Factors AKI-RRT: CKD male sex; non-White race; HTN; DM; BMI; Higher D-dimer; Hypoxemia -1.2 Incidence: -ICU: 20.6% -1.3 Mortality: -Rate: 63.3% -Predictors 28-day mortality AKI-RRT: Older age; severe oliguria. 2.Renal Recovery: - Hospital discharge (33.9%): 33.8% remained RRT dependent -60 days after ICU admission: 18.1% remained RRT dependent. 1/3 remains RRT dependent on discharge; 1/6 remains 60 days after ICU admission.

[TFN1] Abbreviations: RAAS, renin-angiotensin aldosterone system; AKI, acute kidney injury; ARDS, acute respiratory distress syndrome; PEEP, positive end-expiratory pressure.

A review of Covid-19 and acute kidney injury: from pathophysiology to clinical results

Abstract