Impact Of The COVID-19 Pandemic On The Kidney Community: Lessons Learned And Future Directions

Abstract | The coronavirus disease 2019 (COVID-19) pandemic has disproportionately affected patients with kidney disease, causing significant challenges in disease management, kidney research, and trainee education. For patients, increased infection risk and disease severity, often complicated by acute kidney injury, have contributed to high mortality. Clinicians were faced with high clinical demands, resource shortages, and novel ethical dilemmas in providing patient care. In this review, we address the impact of COVID-19 on the entire spectrum of kidney care, including acute kidney injury, chronic kidney disease, dialysis and transplantation, trainee education, disparities in health care, changes in health care policies, moral distress, and the patient perspective. Based on current evidence, we provide a framework for the management and support of patients with kidney disease, infection mitigation strategies, resource allocation, and support systems for the nephrology workforce.

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The coronavirus disease 2019 (COVID-19) pandemic has impacted the kidney community on multiple levels. Acute kidney injury (AKI) is a common consequence of hospitalization with COVID-19 and portends high mortality1. Moreover, the rate of severe COVID-19 has been high in patients with chronic kidney disease (CKD), including dialysis patients and kidney transplant recipients1–3 . Throughout the pandemic, a number of dilemmas have occurred, contributing to poor outcomes in patients with kidney disease. These include decisions surrounding the delivery of safe clinical care, triaging provision of kidney replacement therapy (KRT), the safety of donors and recipients for kidney transplantation, managing COVID-19 in patients with kidney disease, modulating immunosuppression in immune-mediated kidney disease and transplant recipients, and the best ways to protect patients and health care providers. Despite being at high risk, however, patients with kidney disease were excluded from therapeutic clinical trials of COVID-19, largely because of a higher risk of mortality and concerns that CKD may alter the safety profile of drugs. As such, the lack of pre-specified subgroup analyses resulted in the application of novel therapies to this population with low evidence. Additional challenges in patient care faced by nephrologists have included nursing shortages and supply chain issues. Moreover, the pandemic has raised ethically challenging questions about the allocation of scant healthcare resources. Finally, there has been a significant impact on trainee education and on the emotional well-being of the nephrology workforce and patients4,5.

In this review, we discuss the challenges encountered in the care of patients across the spectrum of kidney disease during the COVID-19 pandemic. Strategies that were adopted to address these challenges, innovations in patient care delivery, and advocacy efforts are described. We further discuss the global inequities in the provision of health care and highlight how the pandemic may exacerbate pre-existing disparities in kidney disease. Although some lessons learned by the kidney community during the pandemic have been heartening and stimulated innovation, others have had profoundly devastating effects. These experiences by the kidney community shape preparedness efforts for future pandemics. From the lessons learned thus far, we provide a framework for the management of patients with kidney disease for future pandemics.

Key points • 

Acute kidney injury is common in severe coronavirus disease 2019 (COVID-19) and is associated with increased mortality. • Patients with chronic kidney disease are at a high risk of severe COVID-19 and severe outcomes and should be prioritized for therapeutics, including vaccines. • Establishment of global collaborative registries is key to assessing the severity and risk factors of infection. • Interruptions in routine care have been common and highlighted the advantages of the temporary implementation of telemedicine and home dialysis. • There have been gross inequities in access to COVID-19 testing, personal protective equipment, provision of dialysis services, COVID-19 vaccines and therapeutics rollout. • To prepare for future pandemics, it is important to stockpile emergency medical equipment, invest in resilient healthcare systems, have global cooperation in providing care, explore and advance remote care globally, address moral distress to improve the well-being of patients and care providers, build public trust in scientific recommendations and advocate for kidney patients to be included in clinical trials and global registries.

Challenges and opportunities of COVID-19 AKI incidence throughout the pandemic. 

AKI is common in patients diagnosed with COVID-19 (ref.1 ). The mechanism of COVID-19 infection-induced AKI is multifactorial, involving both direct invasion of the virus and indirect mechanisms through acute tubular necrosis, dysregulation of the immune system, hypercoagulopathy and collapsing glomerulopathy6. In the early stages of the pandemic, the reported incidence of AKI ranged from 0.5 to 42%1,7,8 , with a large percentage of patients requiring dialysis. Investigating how this incidence rate changed over time, one study found that in critically ill patients with COVID-19, although the incidence of AKI was 29.3%, the rates of AKI and KRT declined throughout the pandemic8. This reduced rate of AKI was likely attributable to multiple factors, including improved recognition and management, vaccine rollout, and transmission of less virulent strains9. However, in low- and lower-middle-income countries, challenges were present in the management of COVID-19-associated AKI10. In a study of over 1,000 patients with COVID-19 in two teaching hospitals in South Africa, AKI occurred at a rate of 33.9%, with approximately a quarter of patients with AKI requiring ICU management and 8.6% receiving KRT11.

APOL1 and risk of COVID-19-related AKI.

In April 2020, several case reports described collapsing glomerulopathy in patients with COVID-19. A subsequent study confirmed this finding, reporting that, out of 240 native kidney biopsies in patients with COVID-19, 62 (26%) had evidence of collapsing glomerulopathy12. Interestingly, a case series of six patients with collapsing glomerulopathy found that all six had variants in the APOL1 gene13. APOL1 genotyping studies have subsequently demonstrated that patients with high-risk APOL1 alleles had significantly higher odds of AKI and death than low-risk patients with 0 or 1 risk variants14. Furthermore, in African Americans who tested positive for COVID-19, APOL1 high-risk alleles were associated with greater odds of AKI and higher rates of persistent AKI and requirement for dialysis14.

Possible reasons for the higher risk of adverse kidney outcomes in individuals carrying APOL1 high-risk alleles include a heightened inflammatory response to COVID-19, leading to inflammatory kidney injury. Thus, the incidence and severity of AKI are likely increased in the presence of APOL1 variants, with an increased requirement for chronic dialysis.

COVID-19 and long-term kidney issues.

Hospitalized patients with COVID-19 have a higher incidence of AKI overall, and an increased risk of higher stages of AKI when compared with patients with influenza15. The risk of developing CKD is high in patients with COVID-19, as demonstrated by an observational study from the UK showing that 16% of AKI survivors had progressed to CKD at 90 days16. Similarly, approximately 20% of critically ill patients with COVID-19 and AKI requiring KRT had no recovery at 3 months after discharge in a multicentre study from the USA17. A veteran administration study on long COVID reported a higher risk of CKD with COVID-19 (refs.18,19). Similarly, in a Chinese cohort study, a third of COVID-19-infected patients had reduced kidney function 6 months post-hospitalization18. Interestingly, patients developing AKI during their COVID-19 disease course had no increased risk of CKD at 12 months follow-up compared with non-COVID-19 AKI cases20, indicating that kidney disease progression is similar in patients with or without COVID-19. Further studies are needed to evaluate risk factors for progression to CKD following COVID-19-associated AKI.

Chronic kidney disease. 

The incidence of COVID-19 in patients with CKD is difficult to establish owing to under-reporting, under-diagnosis of CKD, and variations in access to SARS-CoV-2 testing. A large, nationally representative cohort from the UK demonstrated a CKD incidence and prevalence ranging from 0.5% to 37% and reported that CKD is associated with a high co-morbidity burden and high 1-year mortality21. CKD, including end-stage kidney disease (ESKD), is associated with an increased risk of COVID-19 and subsequent adverse outcomes including hospitalization, respiratory failure, and mortality2,22–24, with risk proportional to kidney dysfunction22,24. There have been care delivery repercussions, including the postponement of kidney biopsies25, delays in arteriovenous fistula surgery and salvage, and disruption in the initiation of KRT26. There was a notable decline in incident ESKD in the USA early in the pandemic, because of both increased mortality in patients with advanced CKD and compromised access preparation for KRT27. Large-scale lockdowns resulted in the interruption of routine health care, including access to dialysis, leading to preventable deaths, especially in those parts of the world where access to dialysis was already compromised while highlighting the advantages of telemedicine in patients with CKD28–30.

There is a lack of guidelines related to the management of COVID-19 in patients with CKD. Dexamethasone was associated with both a reduced requirement for KRT and lower mortality in all patients with severe COVID-19, although fewer than 10% of patients in this trial had an estimated glomerular filtration rate of <30ml/min/1.73m2 (ref.31). Remdesivir, a direct-acting antiviral, remains off label in patients with an estimated glomerular filtration rate <30ml/min/1.73m2 (ref.32). Several monoclonal antibody therapies have been afforded emergency use authorization but their net benefit in patients with CKD remains untested. Tocilizumab, a recombinant anti-IL-6 receptor antibody was granted emergency use authorization in patients with moderate-to-severe COVID-19 (ref.33), and case reports demonstrate successful deployment in patients with ESKD. Unfortunately, phase III trials evaluating the benefits of vaccination against COVID-19 have placed little focus on specific subgroups such as patients with CKD34. Nonetheless, patients with CKD mounted a seroconversion rate that was comparable with the general population (Supplemental Table 1) and were prioritized for vaccination. It is noteworthy, however, that patients who did not receive a third dose of the vaccine had a significant decline in antibody titer after 3 to 6 months35. I

immune-mediated kidney disease. Managing patients with immune-mediated glomerular disease has presented unique challenges. At the start of the pandemic, the primary concerns for patients receiving immunosuppression included the assessment of the risk and severity of COVID-19, ways to mitigate infection risk, methods of clinical and laboratory surveillance, strategies to treat active disease and evaluation of the need for continued immunosuppressive therapy. After the vaccine rollout, questions were posed regarding the immunogenicity and safety of the vaccine in this patient subgroup, measurement of vaccine efficacy and need for modification of immunosuppressive therapy to improve vaccine response.

Although immunosuppressive therapy increases the risk of COVID-19 infection, there is currently no evidence to support deviation in the standard of care treatment of active kidney disease36. COVID-19 in patients with immune-mediated kidney disease conferred an increased risk of AKI and death37. Additionally, case reports of de novo immune-mediated kidney disease, including collapsing focal and segmental glomerulosclerosis, vasculitis and IgA nephropathy, have been described with COVID-19 infection. Among the immunosuppressive medications commonly used in this cohort, rituxi mab and prednisone dose ≥10mg were associated with increased severity of COVID-19 (ref.38); information on other therapies such as cyclophosphamide has remained scarce.

Although patients with immune-mediated kidney disease were prioritized for vaccines, understanding of the safety and immunogenicity of vaccines in this cohort was based only on observational studies. Studies in patients with rheumatic diseases on immunosuppressive therapy have consistently shown impaired humoral response with largely preserved cellular response following vaccination (Supplemental Table 1). Additionally, these studies have shown that prednisone (dose ≥10 mg), mycophenolate mofetil and rituximab were associated with impaired humoral response and that the response in rituximab-treated patients was improved when B cells were reconstituted or when time elapsed since the last rituximab administration was longer39. Temporary cessation of mycophenolate mofetil augmented humoral response following vaccination in patients with rheumatic disease40. In non-responders, the administration of a booster vaccine dose was shown to increase the response rate. De novo or relapsing autoimmunity triggered by COVID-19 vaccines remains a concern, with isolated reports of de novo and relapsing minimal change disease, membranous nephropathy, IgA nephropathy and ANCA vasculitis having been described41. However, large cohorts with increased inflammatory disease incidences have not been described following COVID-19 vaccination

In the absence of guidelines, caring during a pandemic requires personalizing immunosuppressive therapy to balance the risk of infection and disease control, and recognizing that treatment of active disease cannot be delayed. An important lesson learned is that the early establishment of global collaborative registries is critical to assessing the severity and risk factors of infection and guiding the modulation of immunosuppressive therapy in this population.

Patients on chronic dialysis. 

Early data from Wuhan foreshadowed the major challenges that other regions would have to tackle in caring for patients on dialysis during the COVID-19 pandemic. Patients on dialysis were amongst those at the highest risk of death, not just because of the propensity for serious illness but also because of missed treatments. These data generated a mandate for dialysis facilities to intensify infection prevention protocols to reassure patients and staff, to ultimately prevent missed sessions and loss of workforce. There was a strong recommendation for transition to home modalities42

However, without additional resources to match the new guidance, there was a constant shortage of personal protective equipment (PPE)43 and SARS-CoV-2 tests. Data from the universal screening of a single dialysis unit in the UK showed that patients experienced a spike in infection following a spike in infection of healthcare workers, implying potential transmission from healthcare worker to patient44. Nonetheless, widespread in-facility transmission was not reported. Lack of transportation, staff shortages and possibly personal fear or symptoms may have contributed to missed treatments in up to half of the surveyed facilities in Africa, Latin America, the Middle East, South East Asia and South Asia43. Mortality among infected and hospitalized patients receiving dialysis exceeded 50% in most regions of the world45. The pivot to home modalities was not feasible in many environments that were already strained. Thus, despite early and sensible guidance on infection prevention and management — a majority of which still holds relevance in face of the changing nature of the pandemic — there was a stark loss of life among patients receiving dialysis46. With improvement in testing capacity and identification of patients with no or minimal symptoms, there has been improvement in crude mortality rates between the first and second waves of COVID-19 (ref.47).

The success of vaccines has been accompanied by challenges. Among countries that procured vaccine supply in late 2020 or early 2021, only European countries prioritized vaccination for patients receiving dialysis. In the USA, there was no specific prioritization until March 2021, at which point policymakers acknowledged that patients receiving dialysis were disproportionately from underserved populations and at a high risk of complications from COVID-19 illness. This led to a federal effort to offer vaccination in dialysis clinics, which improved vaccine access, especially for Hispanic and Black patients48. Despite this effort, however, some patients on dialysis expressed vaccine hesitancy, albeit to a lower extent than in the general population. Capitalizing on central record keeping, the US Centers for Disease Control and Prevention has created a real-time dashboard tracking vaccination in dialysis facilities, which indicates that more than 75% of patients on dialysis have had at least two doses of the COVID-19 vaccine.

Several lines of evidence suggest that the immunogenicity of vaccination is lower among patients on dialysis than in the general population (Supplemental Table 1). Although the majority of patients ‘seroconverted’ post-vaccination, the strength of the early antibody response to vaccination was suboptimal. Furthermore, 20% lost a detectable antibody response within 6 months. Consistent with data from hepatitis B vaccination, low circulating antibody titers were associated with a 10-fold higher risk of infection among patients who had completed the initial vaccination series45. Data from a large not-for-profit dialysis center indicated efficacy against hospitalization or death of 81%, only slightly lower than contemporaneous data for the general population, noting vaccine effectiveness of around 86–87%49. Vaccine immunogenicity by vaccine type has been studied closely, and concerns have been raised regarding the lack of immunogenicity of Ad26.COV2.S, although the clinical effectiveness of this vaccine may be similar to the mRNA platform vaccines50. Furthermore, there was no difference in vaccine response by vaccine type among home dialysis versus in-center patients51.

Boosters (third doses for persons with mRNA platform vaccines) have seen a lower uptake among patients on dialysis in the USA, with roughly 50% of patients reporting an additional dose to date. Again, there was a heterogenous policy implementation, with countries in Europe implementing earlier offers of third doses among patients on dialysis. Data from France and the USA on immunogenicity are encouraging, with strong responses reported even among older patient groups.

In this landscape, given the uncertainty around persistent immunogenicity to COVID-19 vaccines and substantial risk of ‘breakthrough’ infection — a majority of which will have some clinical consequences for patients receiving dialysis, and at the very least a need for isolation during in-center dialysis — it will be critical to continue to develop future protocols for prevention, detection and early treatment of COVID-19.

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