Cause of acute kidney injury in COVID-19
The prevalence of acute kidney injury (AKI) in Covid-19 varies from 0.5% (1) of patients to 5% (2) according to Chinese studies. Cheng et al. reported that 43.9% of patients with covid-19 had proteinuria and 26.7% had hematuria on admission (2). AKI was associated with increased morbidity and mortality (2). Zhou et al reported that all of the patients with COVID-19 requiring renal replacement therapy died during their study period (3).
A Chinese study performed postmortem renal biopsies on 6 patients. Severe acute tubular injury, prominent lymphocyte infiltration, detection of viral antigen in tubular epithelial cells, macrophage infiltration and complement C5b-9 deposition were seen (B. Diao, C.H. Wang, R.S. Wang, Z.Q. Feng, Y.J. Tan, H.M. Wang, et al.: Human kidney is a target for novel severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2] infection [preprint posted online April 10, 2020]. medRxiv doi:10.1101/2020.03.04.20031120). A study investigating 26 postmortem renal biopsies in COVID-19 patients showed also acute proximal tubular injury, but, additionally, peritubular erythrocyte aggregation and glomerular fibrin thrombi with ischemic collapse and signs of pigment casts from rhabdomyolysis (4). To our knowledge, the only alive kidney biopsy performed in Covid-19 patients with AKI was an African American woman with collapsing glomerulonephritis (5).
Ronco et al proposed the following three potential pathways of kidney damage in COVID-19 (6):
1) Cytokine damage or cytokine release syndrome which leads to intra-renal inflammation. Increased vascular permeability, volume depletion and cardiomyopathy leading to cardio-renal syndrome. Cardio-renal syndrome can generally be defined as a pathophysiological disorder of the heart and kidneys, in which dysfunction of one organ may induce dysfunction in the other (7). In the following cases, various cardiac dysfunction lead to compromised circulation and, as a result, to acute kidney injury.
2) Organ crosstalk where high peak airway pressure and intra-abdominal hypertension causes renal compartment syndrome. Alveolar damage leads to renal medullary hypoxia. Cardiomyopathy and myocarditis lead to impaired circulation causing cardio-renal syndrome.
3) Systemic effects: positive fluid balance leading to renal compartment syndrome, third space loss leading to renal hypo-perfusion and endotoxins leading to septic AKI.
Rhabdomyolysis has been described as a feature in both organ crosstalk and systemic effects. CRRT has been suggested as a causal treatment to remove cytokines and treat rhabdomyolysis (6).
Batlle et al agree that AKI in COVID-19 patients appears to involve a complex process driven by virus-mediated injury and cytokine storm. However, the authors additionally propose that angiotensin II pathway activation, dysregulation of complement, hyper-coagulation, and micro-angiopathy play a role (8).
Angiotensin converting enzyme (ACE2) is expressed, among others, in brush border apical membrane of the proximal tubule and podocytes (9). SARS-CoV-2, the strain of coronavirus that causes COVID-19, can bind to renal epithelial cells and injure them. Furthermore, an association between angiotensin II and over-activity of immune and complement pathways and the coagulation systems, have been proposed to play a role in AKI in Covid-19 patients (8).
Elevated d-dimer levels have been shown to correlate with worse outcome pointing towards a hyper-coagulable state in COVID-19 patients which potentially could lead to cortical necrosis (8, 10).
Our patient presented with a d-dimer of 1.34 and only microscopic hematuria. Since cortical necrosis is causing irreversible damage (8), we suppose that, if at all, our patient only suffered from mild cortical necrosis.
Concerns have been raised regarding the safety of inhibitors of the renin-angiotensin-aldosterone system (RAAS) in COVID-19 patients. Recommendations from some medical societies suggest that RAAS inhibitors should be continued since the available data points to the benefits outweighing the risks (11). However NICE guidelines from the 21st of May state that at this stage no conclusion on the role of ACE inhibitors in COVID-19 can be drawn due to the poor quality and subject to bias and confounding of the available data (12). Although mainly based on opinions and observational data, withdrawal or reduction of RAAS inhibition is part of many guidelines for AKI to improve renal perfusion (13). At least in our case report, the cessation of ACE inhibitor had a favorable effect.
We have presented a rare case of full renal recovery after acute, anuric renal failure due to COVID-19. The weakness of the present report is the lack of a renal biopsy, creatinine kinase/myoglobin or reliable quantification of proteinuria. Since the patient was receiving critical care and was later quickly regaining his renal function, a renal biopsy was considered unnecessary in terms of treatment regimen at the time. Our patient was Caucasian and his renal function improved quickly. We, therefore, do not assume collapsing glomerulonephritis as cause for the patient’s AKI. We argue that the most plausible cause was acute tubular injury. We cannot rule out rhabdomyolysis as a contributing factor. However, since urine color was described as normal and electrolytes were unaffected, we consider rhabdomyolysis unlikely.