Post‑acute COVID‑19 Syndrome And Kidney Diseases: What Do We Know?

Abstract

COVID-19, a disease caused by a novel coronavirus (SARS-CoV-2), is a major global threat that has turned into a pandemic. Despite the emergence of multiple vaccination alternatives and developing therapeutic options, dramatic short- and long-term clinical outcomes have been recorded with more than 250 million infected people and over 5 million deaths as of November 2021. COVID-19 presents various respiratory, cardiovascular, neuropsychiatric, musculoskeletal, and kidney features during the acute phase; nevertheless, renal involvement in the post-infection period has recently been emphasized. The present review aims to evaluate the growing literature on kidney involvement in the SARS-CoV-2 infection along with clinical features reported both in the acute phase of the infection and in the post-acute COVID-19 period by assessing potential pathophysiological frameworks explaining such conditions. Chronic kidney disease and the development of acute kidney injury (AKI) in the course of initial hospitalization are associated with high mortality and morbidity rates. Moreover, growing evidence suggests a decline in renal function in the 6-to-12-month follow-up period even in patients without any signs of AKI during the acute phase. Despite such concerns, there are no guidelines regulating the follow-up period or therapeutic alternatives for such patient populations. In conclusion, the burden of COVID-19 on the kidney is yet to be determined. Future prospective large-scale studies are needed with long follow-up periods assessing kidney involvement via multiple parameters such as biopsy studies, urinalysis, measurement of serum creatinine and cystatin C, directly measured glomerular filtration rate, and assessment of tubular function via urinary β2-microglobulin measurements.

NEW HERBAL FORMULATION TO RELIEVE BURDEN OF COVID-19 ON THE KIDNEY

Graphical abstract

Keywords Acute kidney injury · Chronic kidney disease · COVID-19 · End-stage kidney disease · Post-acute COVID-19 syndrome

Introduction

COVID-19, a disease caused by a novel coronavirus (SARS-CoV-2), is a major global human threat that has turned into a pandemic [1, 2]. It is the second one among the latest outbreaks caused by a coronavirus family member, following the severe SARS-CoV and the Middle East respiratory syndrome (MERS)-CoV. COVID-19 presents various respiratory, cardiovascular, neuropsychiatric, musculoskeletal, and kidney features during the acute infection phase; nevertheless, renal involvement in the post-infection period has recently been highlighted. Despite the emergence of multiple vaccination alternatives and the development of therapeutic options, dramatic short- and long-term clinical outcomes have been recorded with more than 250 million infected people and over 5 million deaths as of November 2021 [3, 4]. The most common presenting symptoms include shortness of breath, fatigue, fever, and cough, all of which are commonly observed between days 4 and 5 from exposure [5]. The most common causes of mortality and morbidity among infected patients are respiratory complications followed by cardiovascular events; nevertheless, pathological investigations and autopsy studies demonstrated the involvement of almost all systems, including central and peripheral nervous, gastrointestinal, musculoskeletal, and renal systems [6]. In addition to cardiovascular and respiratory comorbidities, chronic kidney disease (CKD), diabetes mellitus, and immunocompromising disorders are associated with higher hospitalization and mortality rates [7].

Although various pharmaco-therapeutic alternatives including chloroquine/hydroxychloroquine, favipiravir, azithromycin, lopinavir-ritonavir, molnupravir, and ivermectin have been proposed for the treatment of COVID-19, few antiviral agents such as redeliver and nirmatrelvir-ritonavir have been approved by the US Food and Drug Administration to date [8]. Data on their safety are limited: studies so far have shown signifcant adverse reactions with redeliver (high serum liver enzymes and serum creatinine, respiratory failure), chloroquine (retinal toxicity), ivermectin (neurotoxicity and psychosis), and favipiravir (high serum liver enzymes) [9, 10].

ally assessed.

Post‑acute COVID‑19 syndrome 

Presence and/or persistence of symptoms, not attributable to any other disease, 8–12 weeks after the onset of COVID-19, define the post-acute COVID-19 syndrome [11]. The most common symptoms include fatigue, joint and muscle pain, fever, dyspnea, and cough; furthermore, multiple system involvement has been reported [11]. An observational study conducted on 1250 US patients showed that over 32% of them experienced persisting or new-onset symptoms; more than 15% required re-hospitalization with more than 6% of mortality [12]. Similar rates of mortality, re-hospitalization, and persistent symptoms have also been reported in some European studies [13, 14]. In a large-scale study including more than 1300 hospitalized patients, only 40% were independent in their activities within 30 days of discharge [15]. The most common cardiovascular symptoms were chest pain, myocarditis, and palpitations, while the most common neuropsychiatric symptoms included anxiety-depres,sion, sleep disturbances, and headache [16, 17]. The main pathophysiological mechanisms underlying the post-acute COVID-19 syndrome are immunological and inflammatory alterations, virus-specific pathophysiological changes, and other common post-infectious sequelae depending on the organ system involved.

Direct kidney involvement in COVID‑19

The genome of SARS-CoV-2 is a positive‐sense single-stranded RNA of less than 30 kb that encodes 14 open reading frames including envelope, spike, nucleocapsid, matrix, and accessory proteins [18]. The spike protein is involved in the attachment of the viral envelope to the angiotensin-converting enzyme 2 (ACE2) receptors via an N-terminal S1 subunit and fusion of the viral envelope to the host cell membrane via a C-terminal S2 subunit [19]. A step referred to as priming occurs after the attachment to the ACE2 receptors. Through this route, the spike protein is cleaved by endosomal proteases (19) [19]. At this route of the viral entry SARS-CoV-2 requires a transmembrane protease serine 2 (TMPRSS2), similar to the other members of the coronavirus family. The ACE receptors and the TMPRSS2 are co-localized in the kidney mostly in the epithelial cells of the proximal tubules and collecting ducts, with additional presence in the podocytes and mesangial cells, though to a lesser degree (Fig. 1) [20]. Despite not being the most common entry route for SARS-CoV-2, another potential route that depends on the receptor CD147 commonly expressed on the proximal tubular epithelial cells has been identified. These findings are supported by the inhibition of the viral entry and amplification in certain cell lines incubated with mepolizumab, an anti-CD147 antibody [21].

Although direct viral entry into the renal tissue has been shown in multiple studies and is supported by the presence of viral inclusion bodies on biopsy specimens, it is unclear whether the clinical kidney outcomes are caused by direct cytopathic effects, indirect mechanisms, or both [22, 23]. A detectable viral load has been observed by utilizing the RTPCR method in certain autopsy specimens which may indicate direct cytopathic effects; nevertheless, it is important not to overlook the possibility of those viral inclusions being remnants of renal cell endocytosis or clathrin-coated vesicles, since not all inclusions include a viral RNA: such an example is observed in cases of COVID-19-associated collapsing glomerulopathy (Fig. 1) [24–27]. Therefore, further studies are required to determine the underlying pathophysiology of kidney involvement in COVID-19.