key: cord-306214-2wjv6aeb
authors: Medjeral-Thomas, Nicholas R.; Thomson, Tina; Ashby, Damien; Muthusamy, Anand; Nevin, Margaret; Duncan, Neill; Loucaidou, Marina
title: Cohort study of outpatient hemodialysis management strategies for COVID-19 in North-West London
date: 2020-08-25
journal: Kidney Int Rep
DOI: 10.1016/j.ekir.2020.08.022
sha: 
doc_id: 306214
cord_uid: 2wjv6aeb

BACKGROUND: Dialysis patients are at risk of severe COVID-19. We managed COVID-19 haemodialysis outpatients in dedicated satellite dialysis units. This provided rare opportunity to study early disease progress in community-based patients. We aimed to (1) understand COVID-19 progression, (2) identify markers of future clinical severity and (3) assess associations between dialysis management strategies and COVID-19 clinical outcomes. METHODS: We conducted a cohort study of all outpatients managed at a COVID-19 haemodialysis unit. We analysed data recorded as part of providing COVID-19 clinical care. We analysed associations between features at diagnosis and the first 3 consecutive haemodialysis sessions in patients who required future hospital admission, and those who had died at 28 days. RESULTS: Isolated outpatient haemodialysis was provided to 106 patients over 8 weeks. No patients received antiviral medication or hydroxychloroquine. 21 patients (20%) were admitted at COVID-19 diagnosis. 29 of 85 patients (34%) were admitted after initial outpatient management. 16 patients (15%) died. By multivariate analysis, non-active transplant list status, use of institutional transport, and increased white cell count associated with future hospitalisation and increased age associated with death. Oxygen saturations progressively decreased over the first 3 dialysis sessions in the cohorts who progressed to future hospital admission or death. Mean ultrafiltration volume of the first three haemodialysis sessions was reduced in the same cohorts. CONCLUSIONS: Outpatient haemodialysis in patients with COVID-19 is safe for patients and staff. Features at the first 3 dialysis sessions can identify individuals at risk of future hospitalisation and death from COVID-19.

Features at the first 3 dialysis sessions can identify individuals at risk of future hospitalisation and death from COVID-19 3 . The high prevalence of comorbidities 4 associated with COVID-19 severity, such as diabetes, age and Black, Asian or Minority ethnicity (BAME) [5] [6] [7] [8] [9] [10] , may contribute to both poor prognosis and limited access to inpatient intensive care for haemodialysis patients during the COVID-19 pandemic. However, the contributors to COVID-19 severity, J o u r n a l P r e -p r o o f

This was a cohort study of all COVID-19 haemodialysis patients managed on IsolHD. Data were recorded as part of routine clinical care in electronic healthy records and clinical results systems. Analysed characteristics are listed in Table 1 and Table 3 , when a second unit was opened 11 . After

March 30 th , case allocation was based on haemodialysis availability.

Compared to our total dialysis population, the IsolHD cohort was of similar age (median 65 years (interquartile range (IQR) 54-74 years) for IsolHD vs 66 years (IQR 55-75) for total population), sex ratio (38% female for IsolHD vs 42% female for total population, P=0.5) and proportion of patents with diabetes (53% for IsolHD vs 45% for total population, P=0.2). The proportion of BAME patients was higher in the IsolHD cohort than the total population (84% vs 69%, P=0.001).

Fever and cough were the two most common symptoms at HD1 ( Figure 2 , Table 1 ). In general, symptom burden improved at consecutive IsolHD sessions ( Figure 2 ). However, relative to other symptoms, cough, breathlessness, and diarrhoea were described more frequently from haemodialysis sessions 3 to 5 post COVID-19 diagnosis ( Figure 2 ). In addition, diarrhoea was both a presenting symptom and a symptom that developed later on in the course of the illness.

The flow of patients through the unit is shown in Figure 1 . Of the 85 patients who received outpatient haemodialysis on IsolHD immediately following COVID-19 diagnosis (IsolHD-first cohort, Figure 1 ), 29 patients (34%) were admitted after median 3 dialysis sessions (IQR 2-4) over 9 days (IQR 5-12 days). 21 of 106 patients (20%) were admitted at the time of diagnosis for median 10 days (IQR 8-13 days) and attended IsolHD following discharge. There were 16 deaths (15% of the total cohort) all of which occurred during inpatient admission.

Characteristics at the first haemodialysis session following COVID-19 diagnosis (HD1) were associated with hospital admission and death at 28 days (Table 1 ). The cohort who did not require hospital admission Table 1) .

Use of institutional transport (P=0.005), diabetes as cause of ESKD (P=0.03) and symptomatic breathlessness at HD1 (P=0.01) were more common in the cohort requiring admission (Table 1) .

Death within 28 days associated with older age (P=0.008) and diabetes as cause of ESKD (P=0.01). Angiotensinconverting enzyme inhibitor (ACEi) or angiotensin 2 receptor blocker (ARB) use were more common in the cohort who survived, although the association did not reach statistical significance (P=0.05). None of the 20 patients with diarrhoea at HD1 had died at 28 days (P=0.04). We did not detect differences between patients with and without diarrhoea in demographic characteristics, antibiotic use, pre-dialysis blood pressure or post-J o u r n a l P r e -p r o o f dialysis weight loss (Supplementary table S1 ). Survival also associated with lower WCC (P=0.02), CRP (P=0.001), LDH (P=0.02) and troponin (P=0.006) at HD1 (Table 1) . Neither BAME ethnicity nor diabetes was associated with admission or death.

Multivariate analysis demonstrated non-active transplant waiting list status (P=0.04), use of institutional transport (P=0.03), and high WCC (P=0.03) were associated with increased risk of hospital admission (Table 2 ).

By multivariate analysis increased age (P=0.01) was the only feature associated with risk of death at 28 days from COVID-19 diagnosis ( Table 2) .

We next questioned whether clinical parameters at consecutive outpatient haemodialysis following COVID-19 diagnosis were associated with clinical outcomes. We analysed the IsolHD-first cohort only (n=85, Figure1) . The IsolHD-first cohort was similar to the total cohort (Supplementary table S2) with the exceptions that older age and higher D-dimer at HD1 were associated with both future admission (P=0.04 for age; P=0.008 for D-dimer) and death (P=0.02 for age. P=0.01 for D-dimer), and lower pre dialysis SaO2 and less diarrhoea at HD1 were associated with admission (P=0.01 for SaO 2 ; P=0.002 for diarrhoea) but not death (Supplementryl table S2 ).

Unlike other clinical observations, pre and post dialysis SaO 2 decreased over the first 3 dialysis sessions in the future hospital admission and death by 28 days cohorts (Table 3) . Consequently, the differences in SaO2 between clinical outcome cohorts was greatest at the third haemodialysis session (HD3) post COVID-19 diagnosis; SaO 2 were 5% and 6% lower in the 'future admission' and 'death by 28 days' cohorts respectively ( Figure 3 ). Also, the proportion of patients with hypoxia was greater in the cohorts who would progress to hospitalisation and death ( Figure 3E and 3F). These data are potentially confounded by progressive cohort size reduction at consecutive haemodialysis sessions. Due to clinical deterioration and requirement for inpatient care, patient removal was more common in the future hospital admission and death by 28 days cohorts. The inclusion of these severe COVID-19 cases would have exaggerated differences in hypoxia and SaO 2 between outcome cohorts , and therefore their loss is unlikely to explain the differences we detected. We did not detect significant differences in blood pressure or pre dialysis weights between outcome cohorts (Table 3 ). There were no significant correlations between blood pressure and SaO 2 (data not shown).

We next interrogated fluid balance management. The mean ultrafiltration volume for HD3 was significantly less than HD1 in cohorts subsequently requiring hospital admission (P=0.03) and the reduction seemed to be progressive from HD1 to HD2 to HD3 (Table 3 and Figure 4A ). We saw a similar pattern when the volume was expressed as a percentage of pre-dialysis weight (P=0.07) (Supplementary Figure S1 ). Similar associations were identified in the cohort who died (Supplementary Figure S2) . We did not identify associations between ultrafiltration volume and age or blood pressure (data not shown).

There was significant overlap in ultrafiltration volumes between the outcome cohorts ( Figure 4A and

Supplementary Figures S1 and S2) and some required admission despite significant net ultrafiltration. We therefore questioned whether CRP and D-dimer, as surrogates of COVID-19 severity, were raised in these individuals. D-dimer was significantly higher in patients requiring admission despite net ultrafiltration of 2% J o u r n a l P r e -p r o o f pre-dialysis weight (P=0.004) ( Figure 4B ). We did not detect similar associations for CRP (Supplementary Figure   S3 ). Mean UF did not correlate significantly with D-dimer in the total IsolHD population (data not shown).

None of our patients received antiviral medication, hydroxychloroquine or corticosteroids. Antibiotics were administered to 19 of 85 (22%) IsolHD-first patients. Antibiotic use was more common in the future hospital admission cohort (11 of 29 (58%) patients) than the outpatient only cohort (8 of 56 (14%) patients, P=0.03. OR 3.7; 95% CI 1.3-10.2). There was no association between antibiotic administration and death at 28 days. In addition to routine anticoagulation administered on dialysis, 5 patients took oral coumarin for pre-existing clinical conditions. One patient admitted at COVID-19 diagnosis had pulmonary embolus. No venous thromboemboli were detected in the IsolHD-first cohort. Acetominophen was administered to 25% of the cohort at HD1 and 26% of the cohort at HD2. Acetominophen use decreased over subsequent IsolHD sessions.

We asked patients about their haemodialysis experience at IsolHD. Despite 50% of the 78 patient survey responders feeling scared or sad when first moved to IsolHD unit, 91% were happy or very happy with their overall treatment. Physician allocation to the unit increased from 1 doctor for 1 day weekly to 3 doctors for 6 days weekly. None of the nursing or medical staff at IsolHD developed symptoms of COVID-19.

J o u r n a l P r e -p r o o f

The risk factors associated with hospital admission and death from COVID-19 have not been established in dialysis patients 1 . Importantly, safe and effective management protocols for COVID-19 haemodialysis patients have not been identified. Our study provides essential insight into early markers of clinical severity and effective management strategies for COVID-19 in an urban, outpatient haemodialysis cohort.

Similar to non-ESKD populations, age and frailty, as represented by non-active transplant waiting list status and dependence on institutional transport, associated with worse clinical outcomes. Given that transplant waiting list status and use of hospital-organised transport are generally easily accessible and clearly documented in patient records, we were interested whether these surrogate markers of frailty would associate with COVID-19 severity. This information may allow rapid identification of patients particularly at risk of disease severity. BAME individuals were over-represented in the COVID-19 cohort and all the patients who died were of BAME ethnicity. This supports growing evidence that BAME ethnicity independently associates with COVID-19 disease severity and demands urgent research investment 10, 12 .

We identified novel associations with COVID-19 severity that may be specific to haemodialysis patients and our urban, multi-ethnic patient population. Our data suggest diabetes does not significantly influence risk of death from COVID-19 and therefore should not influence access to intensive care resources. We detected a trend towards ACEi or ARB use and survival. This contradicts concerns that ACEi use may contribute to COVID-19

severity. The association of diarrhoea early in COVID-19 disease with survival was not seen in a similar dialysis population from Italy 1 and may be anomalous to population size. However, if seen in other populations, the possibility it represents differences in, for example, immune responses or dietary intake should be considered.

Oxygen saturations decreased progressively at consecutive dialysis sessions in cohorts who would progress to hospitalisation and death. Whether this is a modifiable observation or marker of established severe pneumonitis is unclear. Progressive decreases in ultrafiltration volume at consecutive dialysis sessions corresponded with SaO 2 patterns. Fluid balance management of COVID-19 patients has attracted debate 13, 14 .

Although causality cannot be inferred, our data indicate maintained ultrafiltration volumes associate with better clinical outcomes in COVID-19 dialysis patients.

We administered standard haemodialysis anticoagulation only to 94% of patients. Despite detecting raised Ddimer in 90% patients, no VTE were detected in the IsolHD-first population. Furthermore, we observed significant overlap in D-dimer levels between outcome cohorts ( Figure 4B ). Our findings suggest D-dimer based anticoagulation regimens for COVID-19 should not be prescribed to dialysis patients. Raised D-dimer could indicate pulmonary endothelial dysfunction and thrombosis in a subset of patients with deteriorating COVID-19 unresponsive to fluid balance management 15 .

The majority of our patients recovered from COVID-19 with outpatient haemodialysis management alone (Supplementary Figure S4) . Excluding SaO2, clinical observations remained stable at consecutive dialysis sessions ( . A kidney centre that provides care to 670 haemodialysis patients in South London reported a smaller proportion of patients (11.3%) who tested positive for COVID-19 and similar rates of admission (40.8%) and death (9.2%) 16 . Similar to our cohort, CXOVID-19 was more common in patients who attended haemodialysis using hospital-organised patient transport 16 . Determining whether features specific to our IsolHD regimen, that involved physician review at every dialysis session and liberal use of intradialytic acetaminophen and supplemental oxygen, contributed to our relatively high survival rate requires further research.

Unlike other clinical areas for dialysis patients with COVID-19 at our hospital trust 11 , no IsolHD staff developed COVID-19 symptoms. National UK PPE guidelines were not followed on IsolHD; staff on IsolHD used PPE normally reserved for clinical areas with aerosol generating procedures, such as intensive care units. Our data suggests the provision of comprehensive PPE, including FFP3 masks, eye shields and full body gowns, is essential for protecting healthcare staff in clinical areas with known cases from COVID-19 transmission.

Our data are limited by the cohort nature of the study and the significant patient loss at consecutive dialysis sessions. However, our study provides a rare opportunity to analyse comprehensive, thrice weekly assessments of COVID-19 patients who, without the unavoidable need for outpatient haemodialysis, would not have interacted with clinical services, but of whom 34% progressed to hospitalisation or death (Supplementary table S2 ).

In conclusion, we have identified novel features at diagnosis and consecutive dialysis sessions that associate with future hospitalisation and death from COVID-19. We have demonstrated outpatient haemodialysis is safe for patients with COVID-19 and highlighted strategies that will improve patient outcomes and staff safety.

These results are important for the management of dialysis patients during the COVID-19 and will inform practice in the event of subsequent waves of the disease.

We acknowledge the contributions of a large number of senior clinicians at the Imperial College Healthcare NHS Trust Renal and Transplant Centre caring for these patients. We also acknowledge the participation of the patients involved.

None. J o u r n a l P r e -p r o o f 4A: Net dialysis ultrafiltration (UF) at the first three consecutive isolated haemodialysis sessions (HD1, HD2, HD3) and the mean volume of HD1-HD3 in patients who required future hospital admission with COVID-19. UF was not available from HD1 for one patient who required future admission.

4B: D-dimer at first dialysis post COVID-19 diagnosis and future hospital admission despite mean UF volume (Mean UF/weight) from HD1-HD3 of more than 2% pre-dialysis weight. All patients with available D-dimer

A report from the Brescia Renal COVID Task Force on the clinical characteristics and short-term outcome of hemodialysis patients with SARS-CoV-2 infection

Chronic kidney disease is associated with severe coronavirus disease 2019 (COVID-19) infection

The Renal Association BU. UK Renal Registry (2020) COVID-19 surveillance report for renal centres in the UK: All regions and centres

Comorbidity and other factors associated with modality selection in incident dialysis patients: the CHOICE Study. Choices for Healthy Outcomes in Caring for End-Stage Renal Disease

Characteristics of and Important Lessons From the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72314 Cases From the Chinese Center for Disease Control and Prevention

Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China

Clinical Characteristics of Coronavirus Disease 2019 in China

Clinical characteristics of 140 patients infected with SARS-CoV-2 in Wuhan

Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study

Is ethnicity linked to incidence or outcomes of covid-19?

Epidemiology of COVID-19 in an Urban Dialysis Center

Ethnicity and COVID-19: an urgent public health research priority

Need for Objective Assessment of Volume Status in Critically Ill Patients with COVID-19: The Tri-POCUS Approach

Intensive care management of coronavirus disease 2019 (COVID-19): challenges and recommendations

COVID-19 and Thrombotic or Thromboembolic Disease: Implications for Prevention, Antithrombotic Therapy, and Follow-up

Delivering Dialysis During the COVID-19 Outbreak: Strategies and Outcomes