Global Insights: How Fresenius Medical Care Increased the Understanding of COVID-19

Peter Kotanko, MD, FASN • Caitlin Monaghan, PhD

During the early days of the COVID-19 pandemic, Fresenius Medical Care responded quickly. As the world’s largest provider of care for people with end stage kidney disease, the company took the lead in developing effective strategies to protect patients, families, caregivers, and clinical staff. It also focused its scientific and research expertise on increasing the global body of knowledge about COVID-19. The depth and breadth of peer-reviewed papers, research grants, and awards attest to the contributions of Fresenius Medical Care researchers and their associates.

The COVID-19 pandemic sparked an unprecedented surge in biomedical research and demonstrated what can be achieved when working toward a joint goal. As the world’s largest provider of care for individuals with end stage kidney disease (ESKD), Fresenius Medical Care swiftly pivoted resources to address pandemic-related knowledge gaps for individuals with kidney disease, contributing to the global body of knowledge (Figure 1). The goal of these activities was to provide insights to improve care for individuals with ESKD receiving dialysis and further understand potential innovative diagnostic strategies. The following is a summary of peer-reviewed publications that associates of and scientists within Fresenius Medical Care contributed to, along with federal funding awards.

FIGURE 1  |  Fresenius Medical Care publications by month

Early on during the crisis, it became apparent that individuals with COVID-19 were at significantly higher risk of developing acute kidney injury (AKI), leading to the need for dialysis, mechanical ventilation, vasopressor use, and other critical care interventions, summarized in a review by Goel et al.1 The pandemic created a surge in hospitalized patients requiring dialysis and resulted in a shortage of continuous renal replacement therapy (CRRT) machines across the United States. Anger et al. detailed the many steps Fresenius Medical Care North America (FMCNA) took to ensure the care of individuals with AKI.2

THE CHALLENGE OF DIAGNOSING COVID-19

At the beginning of the pandemic, testing resources for SARS-CoV-2 were limited. To address this pressing problem, a test strategy called “pool testing” was proposed by Cherif et al.3 Pool testing strategies combine samples from multiple people and test them as a group. This approach can shorten the screening time and increase the test rate and reporting speed. The authors put pool testing on a sound mathematical basis. The paper was widely referenced, and in July 2020, shortly after its publication, pool testing for COVID-19 received emergency use authorization from the U.S. Food and Drug Administration (FDA). In their extensive narrative review, Grobe et al. described practical aspects and current experience with pool testing.4 In April 2021, the FDA announced a streamlined approach to include pooled serial screening in testing protocols. Additionally, several communities — such as universities, hospitals, and long-term care homes in Asia, Europe, South America, and Africa — implemented pool testing strategies. 

Fresenius Medical Care explored how innovative devices and artificial intelligence may potentially improve identification of individuals with COVID-19. Using Fresenius Medical Care’s Crit-Line® device, Preciado et al. explored arterial blood oxygen saturation (SaO2) levels before the diagnosis of COVID-19 and discovered that SaO2 declined sharply during the incubation period in patients who were later either hospitalized or passed away.5 Monaghan et al. built a machine learning model to identify COVID-19 infections days before symptoms occurred.6 Their predictive model identified subtle patterns in changes in treatment and laboratory measurements indicating an active infection. The authors proposed using this model to augment screening currently in place to identify pre-symptomatic and potentially asymptomatic individuals receiving hemodialysis (HD). In their research, Chaudhuri et al. identified trajectories of clinical and laboratory characteristics associated with COVID-19 in hemodialysis patients.7

PERITONEAL DIALYSIS

There were early concerns in 2020 that SARS-CoV-2 may infect peritoneal fluid, rendering spent peritoneal dialysate potentially infectious. Collaborating with the FMCNA Medical Office, Wang et al. collected 26 spent peritoneal dialysis (PD) dialysate samples from 11 patients at 10 Fresenius Kidney Care (FKC) and Renal Research Institute (RRI) dialysis centers.8 The research indicated the absence of SARS-CoV-2 in spent peritoneal dialysate collected 10 or more days after the onset of COVID-19 symptoms; however, SARS-CoV-2 in spent dialysate in the early stage of COVID-19 could not be ruled out. Subsequently, Wang et al. pioneered the identification of SARS-CoV-2 antibodies in spent peritoneal dialysate.9 This is important, as PD effluent antibody testing could complement serum serology testing. Whether post-COVID-19 or vaccinal antibodies in PD effluent indicate immunity is a topic of ongoing research. As the world is accelerating vaccination efforts, a point-of-care test (e.g., lateral flow assay) will allow individuals on PD to quickly and frequently check for SARS-CoV-2 antibodies in spent dialysate and monitor the antibody response between clinic visits.

HEMODIALYSIS

Fresenius Medical Care clinics reacted swiftly to the pandemic by implementing strict protective measures for patients and clinic staff, such as universal masking and entrance controls. It is of great interest to understand if, and to what extent, these efforts have translated into lower infection rates in individuals receiving dialysis. Cherif et al. analyzed aggregated daily counts of confirmed COVID-19 cases from March 1 to July 29, 2020, in the general U.S. population and Fresenius Kidney Care, and then computed the time-varying reproduction number Rt, which represents the expected number of secondary cases arising from each new infectious individual.10 They demonstrated that for most U.S. states, the lifestyle of in-center hemodialysis patients and interventions to prevent SARS-CoV-2 spread were effective in reducing risk. These results were directionally corroborated by Thwin et al., who conducted a seroprevalence study in New York and compared the prevalence of SARS-CoV-2 antibodies in dialysis clinic staff  and in-center patients with publicly available seroprevalence data.11

An early report by Tortonese et al. highlighted the severity of COVID-19 infections in 44 individuals on maintenance dialysis who were referred to an in-patient hospital dialysis center in the Paris, France, region from March 11 to April 11, 2020.12 In comparison to non-dialyzed patients admitted to the hospital, the mortality rate of individuals receiving dialysis was over twice as high and in-ICU mortality was almost three times higher. Additionally, they found that cough, thrombopenia, higher LDH concentrations, and higher blood CRP concentrations were independently associated with higher mortality in individuals receiving dialysis.

Chawki et al. reported on associations between elements within medical treatment histories and mortality risk in almost 250 individuals affected by COVID-19 and receiving HD.13 Along with widely reported risk factors such as age, facility living, and dyspnea, they also found that previous immunosuppressive treatment was associated with increased mortality. However, previous treatment with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers was associated with decreased mortality. Rincón et al. reported retrospective analyses after a COVID-19 outbreak in a HD clinic prompted clinic-wide COVID-19 testing.14 After testing the entire clinic for COVID-19 infection, the authors discovered that asymptomatic cases accounted for almost 40 percent of all infections. Key risk factors included living in a nursing home or being homeless, hospital admission in the previous two weeks, and sharing healthcare transportation with a future positive patient — none of which differed significantly between those who were symptomatic and asymptomatic. 

Early in the pandemic, elective surgeries were postponed in many countries worldwide. Initially this included vascular access procedures as well. After an outcry from the nephrology community at large and, for example, from Franco et al. in Brazil, it was ultimately clarified that vascular access procedures should not be considered elective.15 Zebrowski et al. argued that infection control measures necessary to contain and prevent outbreaks should drive adoption of home therapy in healthcare systems, especially in countries such as Poland where home therapy rates are very low.16

Using activity trackers worn by 42 individuals receiving in-center HD, Han et al. were the first to report the impact of lockdown on physical activities.18 After a national emergency was declared in the U.S., the average number of daily steps in this small cohort decreased sharply. Most interesting, compared to those who were COVID-19 negative, five out of six individuals who tested positive exhibited significantly higher physical activity in the two weeks prior to developing COVID-19 symptoms. 

The pandemic took a toll on individuals in ways unrelated to infections, as reported by Sousa et al.17 A quantitative and qualitative analysis of changes in patient characteristics from pre-outbreak (February 2020) to lockdown (April 2020) in Portugal revealed that both dialysis adequacy and serum albumin levels decreased significantly, while phosphorus levels increased. While no changes to dialysis prescriptions were reported during this time, treatments were significantly shorter during the lockdown, which could contribute to this finding. The authors also proposed an additional explanation based on associations with qualitative findings from semi-structured interviews with individuals receiving dialysis who reported decreased physical activity and increased difficulties with managing dietary and fluid restrictions.

It is important to keep in mind the pandemic’s impact not only on patients and clinicians, but family caregivers as well. Sousa et al. performed a qualitative study interviewing family caregivers and identified four major themes surrounding additional caregiver burdens: emotional distress, changes in caregiving responsibilities, educational and supportive needs, and coping strategies to deal with the outbreak and lockdown.19

VACCINATION AGAINST SARS-COV-2: A SILVER LINING 

It is undisputed that comprehensive vaccination is key to overcoming the pandemic. Pamplona et al. were the first to report on vaccination acceptance and hesitancy in staff from four RRI dialysis clinics located in New York City.20 Out of 157 staff members, 42 (26.8 percent) were not vaccinated for various reasons, such as leave of absence (4; 2.6 percent), pregnancy or breastfeeding (8; 5.1 percent), past COVID-19 (24; 15.3 percent), and explicitly expressed vaccination hesitancy (6; 3.8 percent). In the authors’ opinion, the low rate of vaccination hesitancy was due to transparent information and unanimous support of vaccination by all levels of leadership, among other factors. Mulhern et al. compared antibody response of mRNA-based vaccine with an adenovirus vector-based vaccine (Ad26.COV2.S) in dialysis patients. The authors found that markedly fewer dialysis patients vaccinated with Ad26.COV2.S had an adequate antibody response to SARS-COV2 when compared to patients vaccinated with mRNA vaccines.21

RESEARCH GRANTS AND AWARDS

Funding agencies around the world swiftly issued requests for research proposals in response to the pandemic. A research network composed of the FMCNA Medical Office, RRI, the University of California Santa Barbara, and the University of Pennsylvania was awarded a three-year research grant by the U.S. National Institutes of Health for the project “Early Detection, Containment, and Management of COVID-19 in Dialysis Facilities Using Multi-Modal Data Sources.” The goal of this project is to predict COVID-19 by using advanced statistical methods on routinely collected data.

The U.S. Department of Health and Human Services and the American Society of Nephrology joined forces to establish the KidneyX COVID-19 Kidney Care Challenge. This effort seeks solutions to reduce the transmission of SARS-CoV-2 among people with kidney diseases and/or reduce the risk of kidney damage among people who contract the virus. Grobe et al. from RRI were awarded a grant to support their innovative proposal, “Pool Testing of Used Masks for Timely Diagnosis of SARS-CoV-2.” Because face masks must be worn by all in-center patients and staff, testing of spent face masks may be a novel method to diagnose SARS-CoV-2 by reverse transcription polymerase chain reaction (RT-PCR). In a proof-of-concept research study, Wang et al. have implemented face mask testing in RRI clinics located in New York City. The researchers were able to detect SARS-CoV-2 RNA on worn face masks and identified a hitherto undiagnosed patient with COVID-19.22

Mask testing may lend itself to pool testing, a strategy that is particularly efficient in settings with a low disease prevalence.23,24 This approach will require the development of setting-specific workflows to optimize mask collection and processing.

CONCLUSION

While social distancing required during the COVID-19 pandemic has kept many apart, it could not contain the flourishing of ideas, analytics, or drive to keep individuals with kidney failure and their providers safe. This is apparent in the number of peer-reviewed publications from and awards received by Fresenius Medical Care and associates. Through a strong commitment to providing the best care and collaboration, Fresenius Medical Care has advanced knowledge across a wide spectrum of topics surrounding COVID-19 across the globe.

Meet The Experts

References

1. Goel N, Deepika J, Haddad DB. COVID-19 and the kidneys, implications and outcomes. Iran J Kidney Dis 2021 Jan;1(1):1-9. https://pubmed.ncbi.nlm.nih.gov/33492298/.
2. Anger MS, Mullon C, Ficociello LH, et al. Meeting the demand for renal replacement therapy during the COVID-19 pandemic: a manufacturer’s perspective. Kidney360 2021 Feb;2(2):350-54. doi.org/10.34067/KID.0006192020.
3. Cherif A, Grobe N; Wang X, et al. Simulation of pool testing to identify patients with coronavirus disease 2019 under conditions of limited test availability. JAMA Netw Open 2020;3(6):e2013075. doi: 10.1001/jamanetworkopen.2020.13075.
4. Grobe N, Cherif A, Wang X, et al. Sample pooling: burden or solution? Clin Microbiol Infect 2021 Apr 18;S1198-743X(21)00190-7. doi: 10.1016/j.cmi.2021.04.007.
5. Preciado P, Tapia Silva LM, Ye X, et al. Arterial oxygen saturation and hypoxemia in hemodialysis patients with COVID-19. Clin Kidney J 2021 Apr;14(4):1222-28. doi. org/10.1093/ckj/sfab019.
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7. Chaudhuri S, Lasky R, Jiao Y, et al. Trajectories of clinical and laboratory characteristics associated with COVID-19 in hemodialysis patients by survival. Hemodialysis International 2021:1-14. https://doi.org/10.1111/hdi.12977.
8. Wang X, Patel A, Tisdale L, et al. SARS-CoV-2 in spent dialysate from chronic peritoneal dialysis patients with COVID-19. Kidney360 2021 Jan;2(1):86-89. https://doi.org/10.34067/KID.0006102020.
9. Wang X, Grobe N, Patel A, et al. Presence of SARS-CoV-2 antibodies in spent peritoneal dialysate. J Am Soc Nephrol, July 2021. https://doi.org/10.1681/ASN.2021020161.
10. Cherif A, Willetts JL, Usvyat L, et al. Comparative analysis of SARS-CoV-2 reproduction rates in the dialysis and general populations. J Am Soc Nephrol 2021 Mar 8;32(4):791-94. doi: 10.1681/ASN.2020121691.
11. Thwin O, Grobe N, Tapia Silva LM, et al. SARS-CoV-2 seropositivity rates in patients and clinical staff in New York City dialysis facilities: association with the general population. Kidney Med 2021 Apr 20. doi: 10.1016/j.xkme.2021.02.010. 
12. Tortonese S, Scriabine I, Anjou L, et al. COVID-19 in patients on maintenance dialysis in the Paris region. Kidney Int Rep 2020;5(9):1535-44. doi:10.1016/j.ekir.2020.07.016.
13. Chawki S, Buchard A, Sakhi H, et al. Treatment impact on COVID-19 evolution in hemodialysis patients. Kidney Int 2020;98(4):1053-54. doi:10.1016/j. kint.2020.07.010.
14. Rincón A, Moreso F, López-Herradón A, et al. The keys to control a COVID-19 outbreak in a haemodialysis unit. Clin Kidney J 2020 Aug;13(4):542-49. doi.org/10.1093/ckj/sfaa119.
15. Franco RP, Costa CBS, Sousa CS, et al. Hemodialysis vascular access maintenance in the Covid-19 pandemic: positioning paper from the Interventional Nephrology Committee of the Brazilian Society of Nephrology. J Bras Nefrol 2020 Aug 26;42(2 suppl 1):41-43. doi:10.1590/2175-8239-JBN-2020-S110.
16. Żebrowski P, Zawierucha J, Marcinkowski W, et al. Home dialysis during COVID-19 outbreak—it is worth to consider. Wiad Lek 2020;73(10):2316-18. https://pubmed.ncbi.nlm.nih.gov/33310971/.
17. Han M, Preciado P, Thwin O, et al. Effect of statewide lockdown in response to COVID-19 pandemic on physical activity levels of hemodialysis patients. Blood Purif 2021 Mar 31;1-8. doi:10.1159/000514935.
18. Sousa H, Ribeiro O, Costa E, et al. Being on hemodialysis during the COVID-19 outbreak: a mixed-methods’ study exploring the impacts on dialysis adequacy, analytical data, and patients’ experiences. Semin Dial 2021 Jan;34(1):66-76. doi:10.1111/sdi.12914.
19. Sousa H, Frontini R, Ribeiro O, et al. Caring for patients with end-stage renal disease during COVID-19 lockdown: what (additional) challenges to family caregivers? Scandinav J Caring Sci, March 28, 2021. https://doi.org/10.1111/scs.12980.
20. Pamplona GM, Sullivan T, Kotanko P. COVID-19 vaccination acceptance and hesitancy in dialysis staff: first results from New York City. Kidney Int Rep 2021 Apr;6(4):1192-93. doi:10.1016/j.ekir.2021.02.001.
21. Mulhern J, Fadia A, Patel R, et al. Humoral response to mRNA versus an adenovirus vector-based SARS-COV2 (Ad26.COV2.S) vaccine in dialysis patients. CJASN 2021 July;CJN.06450521. https://doi.org/10.2215/CJN.06450521.
22. Wang X, Grobe N, Haq Z, Thwin O, Fuentes LR, Maddux D, Kotanko P. Testing of worn face masks for timely diagnosis of SARS-CoV-2 in hemodialysis patients. (J Am Soc Nephrol, accepted for publication, 2021.)
23. Cherif, Grobe, Wang, et al. Simulation of pool testing to identify patients with coronavirus disease 2019. 
24. Grobe et al. Sample pooling: burden or solution?