Proximal tubular dysfunction in patients with COVID-19: what have we learnt so far?
Authors: Fabian Braun, Tobias B. Huber, Victor G. Puelles
Journal: Kidney International (2020)

Recent studies have reported a variety of urine abnormalities in patients hospitalized due to severe acute respiratory syndrome coronavirus 2 infection. In a single-center study from Belgium, Werion et al. present a concise investigation of tubular dysfunction in patients with coronavirus disease 2019, identifying potential risk factors for increased disease severity. These data complement current evidence regarding severe acute respiratory syndrome coronavirus 2 presence and potential infection in the kidney. Recent studies have reported a variety of urine abnormalities in patients hospitalized due to severe acute respiratory syndrome coronavirus 2 infection. In a single-center study from Belgium, Werion et al. present a concise investigation of tubular dysfunction in patients with coronavirus disease 2019, identifying potential risk factors for increased disease severity. These data complement current evidence regarding severe acute respiratory syndrome coronavirus 2 presence and potential infection in the kidney. The characterization of the potential effects of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in extrapulmonary organs is a matter of great interest worldwide. It has been reported that close to 40% of hospitalized patients with severe courses of coronavirus disease 2019 (COVID-19) develop acute kidney injury during hospitalization.1Yang X. Yu Y. Xu J. et al.Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study.Lancet Respir Med. 2020; 8 ([published correction appears in Lancet Respir Med. 2020;8:e26]): 475-481Abstract Full Text Full Text PDF PubMed Scopus (7052) Google Scholar Furthermore, other studies have shown additional signs of kidney injury, including hematuria and proteinuria.2Cheng Y. Luo R. Wang K. et al.Kidney disease is associated with in-hospital death of patients with COVID-19.Kidney Int. 2020; 97: 829-838Abstract Full Text Full Text PDF PubMed Scopus (1932) Google Scholar Given the devastating nature of this pandemic and the unknown future health sequelae of COVID-19, the nephrology community has wisely turned its attention into the potential effects of SARS-CoV-2 in the kidney. Werion et al.3Werion A. Belkhir L. Perrot M. et al.SARS-CoV-2 causes a specific dysfunction of the kidney proximal tubule.Kidney Int. 2020; 98: 1296-1307Abstract Full Text Full Text PDF PubMed Scopus (167) Google Scholar provide systematic evidence of proximal tubule dysfunction in a well-characterized cohort of patients diagnosed with COVID-19 that required hospitalization. Among the features of proximal tubule dysfunction, hypouricemia with inappropriate uricosuria was independently associated with overall disease severity and with an increased risk of respiratory failure requiring invasive mechanical ventilation. These findings are certainly a step forward in our understanding of extrapulmonary manifestations of COVID-19 and also provide a unique opportunity to discuss the current evidence regarding SARS-CoV-2 infection and its role in kidney injury. While there have been several studies depicting the presence of potential SARS-CoV-2 particles by electron microscopy, and SARS-CoV-2 protein or RNA or both in kidney tubular cells,4Puelles V.G. Lütgehetmann M. Lindenmeyer M.T. et al.Multiorgan and renal tropism of SARS-CoV-2.N Engl J Med. 2020; 383: 590-592Crossref PubMed Scopus (1309) Google Scholar, 5Bradley B.T. Maioli H. Johnston R. et al.Histopathology and ultrastructural findings of fatal COVID-19 infections in Washington State: a case series.Lancet. 2020; 396 ([published correction appears in Lancet. 2020;396:312]): 320-332Abstract Full Text Full Text PDF PubMed Scopus (587) Google Scholar, 6Su H. Yang M. Wan C. et al.Renal histopathological analysis of 26 postmortem findings of patients with COVID-19 in China.Kidney Int. 2020; 98: 219-227Abstract Full Text Full Text PDF PubMed Scopus (1291) Google Scholar functional changes remained incompletely understood. Werion et al.3Werion A. Belkhir L. Perrot M. et al.SARS-CoV-2 causes a specific dysfunction of the kidney proximal tubule.Kidney Int. 2020; 98: 1296-1307Abstract Full Text Full Text PDF PubMed Scopus (167) Google Scholar provide unique evidence of a distinct tubular phenotype in a subset of patients with COVID-19 who were hospitalized at a tertiary care center in Belgium. The majority of 49 patients showed features of proximal tubular dysfunction, including low molecular weight proteinuria, deficiency in uric acid and phosphate handling, and neutral aminoaciduria in specific urine analyses. Furthermore, fractional uric acid excretion of >10% in the presence of hypouricemia was reported, postulating that this may serve as a risk factor for the need of mechanical ventilation, disease severity, and death. A strength of this study is that the patient cohort is well characterized with an extensive clinical description and a broad range of outcomes at the end of the investigation period. Thus, we believe that inadequate uric acid handling can be considered as a potential predictor of clinical outcome. However, these observations remain limited as larger and prospective studies will be required to provide further validation. Another interesting finding of this study are the similarities between proximal tubular dysfunction in patients with COVID-19 and other types of tubular injury, including Dent disease and toxic acute tubular necrosis due to tenofovir exposure, 2 entities characterized by low molecular weight proteinuria. The investigators propose a novel injury mechanism after SARS-CoV-2 entry, which is based on expression data and functional network analysis between ACE2 and solute channel genes (i.e., SLC6A19 and SLC22A12), suggesting that this could be one of the ways the virus is directly affecting tubular function. This provocative hypothesis certainly merits more in-depth analysis and careful experimental characterization. It is worth noting that dysfunctional channel activity may also be a consequence of cytokine imbalances due to systemic inflammation or hemodynamic changes (or both) leading to periods of ischemia. The investigators provide evidence of tubular damage with debris in the lumen of dilated tubules, brush border loss, and denuded basement membranes. Furthermore, thorough electron microscopy analyses were performed, identifying potential viral particles with trilaminar envelopes and projections from their surface in vacuoles or cisternae of the endoplasmic reticulum in proximal tubular cells. While this is not conclusive, it provides at least indirect evidence and suggests a potential role for viral infection in proximal tubuli. However, precisely defining the cause of tubular dysfunction may not necessarily modify a potential approach for clinical stratification in hospitalized COVID-19 cases. For example, a diagnostic strategy could involve a first step based on routine blood analysis for uric acid to identify patients at risk (i.e., with hypouricemia) and a urine analysis to determine the fractional uric acid excretion as a second step for at-risk patients. This may expand the range of diagnostic algorithms proposed for patients with COVID-19.7Gross O. Moerer O. Weber M. Huber T.B. Scheithauer S. COVID-19-associated nephritis: early warning for disease severity and complications?.Lancet. 2020; 395: e87-e88Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar The presence of SARS-CoV-2 in the kidney has been documented with multiple complementary techniques (e.g., RNA and protein detection) as highlighted by some examples from several groups around the world.4Puelles V.G. Lütgehetmann M. Lindenmeyer M.T. et al.Multiorgan and renal tropism of SARS-CoV-2.N Engl J Med. 2020; 383: 590-592Crossref PubMed Scopus (1309) Google Scholar, 5Bradley B.T. Maioli H. Johnston R. et al.Histopathology and ultrastructural findings of fatal COVID-19 infections in Washington State: a case series.Lancet. 2020; 396 ([published correction appears in Lancet. 2020;396:312]): 320-332Abstract Full Text Full Text PDF PubMed Scopus (587) Google Scholar, 6Su H. Yang M. Wan C. et al.Renal histopathological analysis of 26 postmortem findings of patients with COVID-19 in China.Kidney Int. 2020; 98: 219-227Abstract Full Text Full Text PDF PubMed Scopus (1291) Google Scholar However, identification of SARS-CoV-2 particles by electron microscopy, or the presence of viral RNA or proteins, should not be considered conclusive evidence of infection. Importantly, a recent report has documented replication-competent SARS-CoV-2 isolated from a post-mortem kidney8Braun F. Lütgehetmann M. Pfefferle S. et al.SARS-CoV-2 renal tropism associates with acute kidney injury.Lancet. 2020; 396: 597-598Abstract Full Text Full Text PDF PubMed Scopus (235) Google Scholar—a finding that cannot be explained by viral remnants or inactive virus passively up-taken in the kidney. While the cellular target of SARS-CoV-2 replication in the kidney is still unclear, the most logical target is the tubular system. The study by Werion et al.3Werion A. Belkhir L. Perrot M. et al.SARS-CoV-2 causes a specific dysfunction of the kidney proximal tubule.Kidney Int. 2020; 98: 1296-1307Abstract Full Text Full Text PDF PubMed Scopus (167) Google Scholar adds to this theory as it provides functional and clinical evidence for the pathophysiological changes triggered by SARS-CoV-2 infection. Some studies also have failed to identify SARS-CoV-2 renal tropism, for example.9Santoriello D. Khairallah P. Bomback A.S. et al.Postmortem kidney pathology findings in patients with COVID-19.J Am Soc Nephrol. 2020; 31: 2158-2167Crossref PubMed Scopus (230) Google Scholar An important caveat should be considered: All tissue-based studies attempt to identify processes based on a "snapshot," and as such, we do not know what happened before and we do not know what will happen later. This means that event frequency, timing, and location play central roles in positive detection. Unfortunately, event frequency is unknown and hard to predict. Perhaps we are assuming that proximal tubular infection should be comparable to infection of the respiratory tract. If this is an infrequent or highly dynamic process, then sample size and location within the kidney will significantly affect the sensitivity of any method. Furthermore, the clinical course at the time of sampling can also mask viral identification (i.e., extensive proximal tubular damage during episodes of acute kidney injury). Finally, it will be important to remain open to the possibility that multiple factors contribute to the same pathophysiological finding. For example, it is likely that this pattern of proximal tubular dysfunction described by Werion et al.3Werion A. Belkhir L. Perrot M. et al.SARS-CoV-2 causes a specific dysfunction of the kidney proximal tubule.Kidney Int. 2020; 98: 1296-1307Abstract Full Text Full Text PDF PubMed Scopus (167) Google Scholar is explained by a combination of viral infection, cytokine effects, and hemodynamic changes associated with critical-ill status (Figure 1). However, despite of our current level of uncertainty, the fact to the matter is that a subset of patients with COVID-19 who developed signs of proximal tubular dysfunction during their disease course, which at the very least merits open discussions regarding the need to implement precise protocols to identify at-risk patients and validation of these findings by larger prospective studies. All the authors declared no competing interests. SARS-CoV-2 causes a specific dysfunction of the kidney proximal tubuleKidney InternationalVol. 98Issue 5PreviewCoronavirus disease 2019 (COVID-19) is commonly associated with kidney damage, and the angiotensin converting enzyme 2 (ACE2) receptor for SARS-CoV-2 is highly expressed in the proximal tubule cells. Whether patients with COVID-19 present specific manifestations of proximal tubule dysfunction remains unknown. To test this, we examined a cohort of 49 patients requiring hospitalization in a large academic hospital in Brussels, Belgium. There was evidence of proximal tubule dysfunction in a subset of patients with COVID-19, as attested by low-molecular-weight proteinuria (70-80%), neutral aminoaciduria (46%), and defective handling of uric acid (46%) or phosphate (19%). Full-Text PDF