COVID-19 and the Kidney: Medical and Ethical Concerns

The word pandemic has never been so poignant. Not simply because the Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-COV-2 [COVID-19]), responsible for the 2019 outbreak, now pandemic, has affected a large geographical area and an ever-increasingly high proportion of the population; but this close relative of SARS-COV and MERS-COV (responsible for the 2002-3 and 2010 outbreaks) is the deadliest of the coronavirus triad so far.

COVID-19 is infamous for affecting every aspect of our society, creating a deadly path through the physical, mental, social, economic and ethical landscape of the world. It is impossible, in one setting, and with a virus as dynamic as COVID-19, to do justice to its varied sequelae. Therefore, the focus of this discussion will intentionally be limited to one of the many organs, namely the kidney, ravaged by the COVID-19 virus.

Epidemiology
Covid-19 is an enveloped, single-stranded RNA beta coronavirus, approximately 30kb in size¹Â with distinct spikes giving the virions the appearance of a solar corona.²Â Unfortunately, despite its relatively small size and recognizable shape, the virus can be stealthy and deadly. The WHO weekly report from January 2021 showed 96 million cases and 2 million deaths on all continents except Antarctica.³Â 

In the United States, according to a January 2021 CDC report, there are 24,876,261 cases and more than 400,000 deaths.⁴ In addition, 60%-90% of hospitalized COVID-19 infected patients have a myriad of underlying co-morbidities such as hypertension (48%-57%), diabetes (17%-34%), cardiovascular disease (21%-22%), pulmonary disease (4%-10%) and chronic kidney disease (CKD) (3%-13%).⁵ 

Overall, hospital mortality is approximately 15%-20% and up to 40% among patients requiring ICU admissions.⁶ Complications such as acute kidney injury (AKI) complicate the course of nearly 1 in 3 patients with COVID-19⁷ and up to 40%⁸ in hospitalized and critically ill patients. Sadly, AKI is associated with a higher mortality rate (46.4%) in those not on renal replacement therapy (RRT) and as high as 79.3% in those requiring RRT.⁸

Pathophysiology
COVID-19 infection affects multiple systems and organs principally by damaging epithelial and endothelial cells leading to a cascading and sometimes unrelentless tsunami of proinflammatory and prothrombotic factors. The virus appears to have a predilection for the respiratory, cardiac, cerebral, gastrointestinal, hepatic and renal systems. The reason for this seems to be related to COVID-19’s spike protein affinity for angiotensin II receptors (ACE2R), which are widely abundant in the systems mentioned above. While the M spike protein acts as a kind of “key,” the ACE2R (and TMPRESS2) is the perfect lock that allows the virus’s spike protein (key) to attach to the human host cells, becoming the crucial step necessary for the life cycle of the virus to flourish by attaching, penetrating, maturing and, finally, releasing the mature virus systemically.⁹

The COVID-19 virus downregulates ACE2, which is responsible for converting Angiotensin II-(1-8) to Angiotensin (1-7). This is important because downregulation of ACE2 then promotes Ang II (1-8) effects of vasoconstriction, oxidative stress, cell proliferation, fibrosis and inflammation while disallowing the beneficial effects of Angiotensin (1-7) such as vasodilation, antioxidation, antiproliferation, antifibrosis and anti-inflammation.¹⁰ 

Additionally, the harmful and intricate relationship between the COVID-19 virus and the kidney is fostered by the a) abundance of the ACE2R in the proximal convoluted tubule and podocytes, and TMPRSS 2 in the distal convoluted tubule, leading to increased susceptibility for acute kidney injury heralded by tubular necrosis, hematuria, proteinuria and concentrating defects, and b) shared risk and comorbidities such as hypertension, diabetes, obesity and coronary artery disease, which incidentally have disproportionately higher prevalence in Black, Hispanic and low socio-economic communities. Notably, kidney disease is both a risk factor and a complication of COVID-19 infection with attendant poor outcome of COVID-19 associated AKI.⁸ 

Medical-Renal Concerns
For the sake of brevity and at the risk of unintentionally oversimplifying this extremely complicated infection, the renal complications of COVID-19 will be divided into categories:

1. Incubation/early stages of COVID-19 infection. Prerenal causes of AKI: (a) volume depletion from loss of appetite, nausea, vomiting, diarrhea and bleeding. (b) Vasoconstriction from Contrast, ACEI/ARB. (c) Pigment-Rhabdomyolysis from fever. 
2. Electrolyte disturbances from concentrating defects and insensible losses: hypokalemia, hypernatremia.
3. Tubular defects such as Fanconi syndrome occurs due to urinary losses of electrolytes and amino acids usually reabsorbed by the proximal tubules. It is characterized by hypokalemia, hypophosphatemia, hypoglycemia, hypoalbuminemia, hypouricemia and metabolic acidosis.
4. Covid 19-associated collapsing nephropathy. Proteinuria, hypoalbuminemia, edema resistant to diuretics, and hematuria. Importantly, the SARS-CoV-2 can trigger collapsing nephropathy (glomerular tuft collapse, podocyte foot process effacement & tubulitis on microscopy) in people of African Ancestry with 2 APOL1 risk alleles.¹¹Â 
5. Systemic inflammatory response phase. Sepsis, hypotension, shock, hepatic failure and multi-organ failure can lead to acute tubular necrosis: oliguria/anuria, hyperkalemia, rise in creatinine, metabolic acidosis and decrease in glomerular filtration rate (GFR).
6. Hypercoagulable phase and bleeding diathesis. Widespread thrombosis in small and large vessels such as the aorta, renal arteries, renal veins and renal replacement accesses as well as disseminated intravascular coagulopathies and microangiopathies can adversely affect the kidney.
7. Medications. (a) Broad spectrum antibiotics and NSAIDs used earlier on for body aches and fever can lead to interstitial nephritis and nephropathies. (b) Medication dosing issues, particularly with changing GFRs, can be a challenge and risk for overdose or contraindications such as with remdesivir (contraindicated in those with a GFR less than 35ml/min).

Ethical-Renal Concerns
One of the earliest ethical values we learn as physicians is “Do No Harm” (non maleficence). In other words, “Do Good” (Beneficence). Doing good is further described as respecting the autonomy and dignity of others, respecting privacy and confidentiality, being fair, showing justice particularly distributive justice, fidelity to the patient above other interests, and committing to ongoing care. 

Whether one sides with Bentham and Mill’s Utilitarianism (the greater good effect) or Kant’s categorical imperative (virtue ethics-right thing to do), physicians must wrestle endlessly with ethical questions and challenges and find a way to come up with the best solution for the problem. 

In the case of the COVID-19 pandemic, where the lid of normalcy has been ripped off, we are being forced to deal head-on with ethical quagmires relating to the escalating demands for life-saving renal replacement therapy (RRT). As with any challenging ethical issue, there are often more questions than answers. 

One such seemingly simple but rather perplexing question starts by asking if there is still a place and time for an ethical discourse during a pandemic such as SARS-COV 2? If so, how do we apply and satisfy all the ethical principles in a rapidly changing pandemic within the context of limited resources? How do we avoid ethical anxiety, prevent moral distress and limit the doctrine of double effect? (for e.g., withholding dialysis where the intention is not to hasten death even though death can be foreseen). 

Furthermore, ethical tensions and anxieties begin to surface when we ask questions such as:

• How do we respect the autonomy of a patient with no family who is unresponsive on a ventilator and needs urgent dialysis?
• How do we protect the privacy and confidentiality of a patient whose data is important to share for the public good? How does telemedicine affect privacy?
• How do we do no harm to our overworked healthcare staff who are constantly exposed to COVID-19?
• How do we do good when we need to ration staff, supplies and other dialysis resources?
• How do we maintain fidelity to care in situations that seem futile and in environments of limited resources? How about fidelity toward our co-workers and families?
• How do we respect human dignity when allocating the benefits and burdens of care (distributive justice)?
• How do we maintain fairness when deciding who gets RRT, what type, how often and for how long? How about the care of other kidney patients who do not have COVID-19? Are we being fair to them? How is the care for kidney transplant candidates and patients being handled fairly?
• What is the double effect (intended versus merely foreseen effect) of rationing supplies, staff and RRT choice, including conservative kidney management without dialysis? How about the unintended effects?
• What about equity in access to healthcare and dialysis options? What happens in communities that do not have the capacity for continuous RRT in critically ill patients who cannot be transferred elsewhere? This happens disproportionately in rural and minority communities as do negatively predicting social determinants of health. Is it morally valuable to ignore, pity, talk about a problem that can be solved and repeatedly do nothing about it? Some of the problems that keep getting sidelined include poor socioeconomic status; poor access to education, transportation and safe housing; lack of access to adequate and quality healthcare; increased comorbidities, and high morbidity and mortality in a subsection of our population. How then can we discuss virtue ethics and distributive justice without addressing disparities and inequities?
• Finally, are we carrying out distributive justice when we exclude a population that is at high risk of COVID-19 infection and mortality such as CKD from life-saving clinical trials and novel medications?

Indeed, it is time to rethink decision-making about kidney failure modalities¹²Â and kidney care, particularly in the light of pandemics. We should strive to be intentional about using ethical values and principles to guide our decision-making process. 

Preferably, these decision guidelines should be created in non-pandemic times to allow for collaboration between all stakeholders i.e.-patients, staff, clinicians, administrators, policy makers, caregivers etc., When the decision-making process is shared, based on values, interests and relevant clinical information, it becomes easier to deal with a public health crisis like COVID-19. 

Using egalitarian principles that emphasize justice allows for equal regard and treatment for all persons as well as fair and equitable procedures and distribution of goods even when rationing and allocation are imperative and unavoidable. Additionally, the shared decision-making framework relieves the physician of the sole decision-making burden, relieves ethical anxiety and prevents moral distress. Finally, by humbly looking through the moral lens of equity and by navigating the turbulent surges of the pandemic with an ethical compass, it is plausible that we can sail safely to shore with fewer casualties than the forecast predicts.