High dependency renal unit for the management of COVID-19 in patients with severe acute or chronic kidney disease

Coronavirus disease 2019 (COVID-19) in patients with severe impairment of kidney function is associated with high mortality. We evaluated the effect of high dependency renal unit (HDRU), with nephrologists as primary care physicians, as a quality improvement initiative for the management of these patients. This was a quasi-experimental observational study conducted at a tertiary care hospital in western India. Patients hospitalized for COVID-19 with pre-existing end-stage-renal-disease and those with severe AKI requiring dialysis (AKI-D) were included. For the first 2 months, these patients were cared for in medical wards designated for COVID-19, after which HDRU was set up for their management. With nephrologists as primary care providers, the 4 key components of care in HDRU included: care bundles focusing on key nephrology and COVID-19 related issues, checklist-based clinical monitoring, integration of multi-specialty care, and training of nurses and doctors. Primary outcome of the study was in-hospital mortality before and after institution of the HDRU care. Secondary outcomes were dialysis dependence in AKI-D and predictors of death. A total of 238 out of 4254 (5.59%) patients with COVID-19, admitted from 28th March to 30th September 2020, had severe renal impairment (116 AKI-D and 122 end-stage-renal-disease). 145 (62%) had severe COVID-19. From 28th May to 31st August 2020, these patients were managed in HDRU. Kaplan–Meier analysis showed significant improvement in survival during HDRU care [19 of 52 (36.5%) in pre-HDRU versus 35 of 160 (21.9%) in HDRU died, P ≤ .01]. 44 (67.7%) AKI-D survivors were dialysis dependent at discharge. Breathlessness and altered mental status at presentation, development of shock during hospital stay, and leukocytosis predicted mortality. HDRU managed by nephrologists is a feasible and potentially effective approach to improve the outcomes of patients with COVID-19 and severe renal impairment.

vulnerable subsets of the hospitalized COVID-19 patients; strategies to improve outcomes in these patients are urgently needed. We present here our experience of a high dependency renal unit (HDRU), primarily managed by nephrology team, which was commissioned to optimize the management of COVID-19 in patients receiving hemodialysis for acute or chronic kidney disease.

Methods
Our hospital is an 1800 bedded tertiary care public hospital in western India and is one of the largest public hospital designated for hospitalization of patients with COVID-19. We started admitting patients with COVID-19 and kidney diseases from 28 th March 2020. Consecutive patients with ESRD with COVID-19 and COVID-19 associated AKI-D were included for the study. The study was approved by the Institutional Ethics Committee (IEC) of KEM hospital, Mumbai. Waiver of consent was obtained from the IEC (EC/OA/96/2020) and study was registered at Clinical Trial Registry of India (CTRI) (REF/2020/05/033696), date of registration-26/06/2020. Patients were evaluated by nephrology services within two hours of the hospitalization, and following data was obtained: demographic details, co-morbid conditions, vitals parameters -temperature, heart rate, respiratory rate, blood pressure in supine and sitting /standing position, assessment of hydration, and review of systems. Oxygen saturation on room air, arterial blood gas and chest x-ray was obtained at admission in all the patients. Severe COVID-19 illness was de ned as oxygen saturation less than< 94% or any need of oxygen therapy. Acute Kidney Injury was de ned by KDIGO criteria. Laboratory evaluation included complete blood count, renal and liver chemistries, C reactive protein, lactose dehydrogenase in all and D-Dimer, interleukin 6, ferritin, in selected cases. High resolution computed tomography (HRCT) of chest was done in patients with severe disease or when felt necessary by treating physician. From the rst two months i.e. 28 th March 2020 to 28 th May 2020, patients were admitted in a dedicated COVID-19 ward or intensive care unit (depending upon the severity of the illness) managed by primary care physicians. Staff and fellow nephrologists attended these patients once daily and decided about the need of dialysis initiation, dialysis discontinuation, and made suggestions about uid therapy, diuretics, and drug dosing.
After auditing the outcomes of the patients and discussion with hospital administration, a dedicated 45 bedded COVID-19 High Dependency Renal Unit (HDRU), to be primarily managed by nephrology team, was commissioned on 28 th May 2020. HDRU was staffed with 4 staff nephrologists, 3 nephrology fellows, and 10 fellows from other specialties, 14 nurses which included 4 dialysis nurses, 14 patient care assistants, and 8 dialysis technicians. 13 bedded hemodialysis unit was located next to the HDRU. A 6bedded dialysis unit for all other non-COVID-19 patients was created in another area in the hospital. Fellows from other specialties received training sessions conducted by staff nephrologists (repeated every two weeks) which included overview of the management of patients with severe renal impairment, dialysis access care, acute dialysis procedure, monitoring during hemodialysis and acute complications related to dialysis. Staff and fellows from non-clinical specialties were included for managing logistics of the unit-provision of essential medical supplies and drugs, management of manpower, fellow's duty schedules, managing daily log and reporting of new cases, deaths, discharges, facilitating transfers in and out of the unit and communication with patient's relatives by a daily telephonic call (Figure 3 and 4 ) Upon admission to HDRU, patients were evaluated every six hourly: subjective assessment, focused clinical evaluation, vital parameters, oxygen saturation, blood glucose and arterial blood gas if needed. 3 staff nephrologists evaluated patients three times daily focusing on vital parameters, volume status, need of uids or diuretics, and decision to start or stop dialysis and the change in the severity of COVID-19.
Staff nephrologists evaluating these patients made decisions about the conservative management of AKI, need of starting or stopping dialysis, initiation of steroids, antivirals, other anti-in ammatory agents, prophylactic antibiotics and anticoagulant management. Depending upon the severity of hypoxia, patients received oxygen by nasal canula, venturi mask, non-rebreathing mask, high ow nasal cannula or non-invasive ventilation (NIV).
Checklist of the key clinical parameters to be monitored every six hourly was followed by staff nurses and duty doctors for patient monitoring . Staff nephrologists ensured that the crucial clinical issues (related and unrelated to COVID-19) were addressed as soon as possible after admission by completing the care bundle ( Table 4). The six hourly HDRU duty rotations included fellows from different subspecialties like radiology, general surgery, psychiatry, dermatology, ophthalmology. The unit got priority consultation visits from cardiology, chest medicine, urology for cross specialty referral care (like bedside ultrasound of the urinary tract, IVC diameter, surgical debridement and dressings, patient counseling, 2Dechocardiography, urological evaluations). In charge nephrologists, who made the nal decisions on the treatment ensured close coordination among various specialties.
Patients with worsening hypoxemia, hemodynamic instability, worsening AKI and severe organ dysfunction were triaged for more intensive monitoring, which included continuous monitoring of oxygen saturation, heart rate, rhythm, respiratory rate and blood pressure. Triaged patients were discussed daily on a telephonic conference call which followed the staff nephrologists' morning clinical rounds. This was attended by all staff nephrologists and fellows to facilitate smooth communication across the duty shifts. Management decisions like initiation of anti-in ammatory and antiviral treatments (steroids, tocilizumab, and remdesivir) were also made during this call conference. In addition, all the patients with severe COVID-19 or with clinical worsening were discussed in an interdisciplinary critical care team meeting. Critical care committee consisted of a senior pulmonologist, anesthesiologist, cardiologist, diabetologist and intensivist, who met daily to discuss such patients where various therapy decisions were discussed and nalized. Patients needing intubation or invasive mechanical ventilation were transferred to intensive care units.

COVID-19 Hemodialysis Unit
A dedicated 13-bedded hemodialysis unit for dialysis of these patients was created adjacent to the HDRU. This was staffed with a nephrology fellow, one resident doctor from other clinical specialty, dialysis nurse, and dialysis technician round the clock. Intermittent hemodialysis (IHD) was continued for patients on maintenance hemodialysis and Slow Low E ciency Dialysis (SLED) (QB 200, QD 300, duration 6 to 8 hours) was given for patients with hemodynamic instability. In patients with acute kidney injury, we followed the strategy of delayed initiation of dialysis-initiation only when clinically indicated for any of the following: refractory uid overload, hyperkalemia, severe metabolic acidosis, alteration of the mental status attributable to uremia, or need of blood transfusion in the setting of oligo-anuria. Alternate daily dialysis was continued until recovery or discharge from the hospital. Patients during hemodialysis were monitored for vital parameters, continuous cardiac monitoring and pulse oximetry. Hemodialysis unit was equipped with facilities to provide high ow nasal oxygen, non-invasive and invasive ventilation in case of the deterioration in the oxygen saturation during dialysis treatment. Patients were considered for discharge after being asymptomatic for over 5 days, room air oxygen saturation above 94% and no subjective sense of breathlessness.
Statistical analysis was done using IBMâ SPSSâ Statistics software version 26. Quantitative variables were expressed as mean standard deviation (SD). Qualitative variables were expressed as numbers with percentage. Chi square or Fischer's exact test was used for categorical data. Independent samples t test was used for continuous data. Comparison of baseline, clinical and laboratory parameters between survivors and non-survivors was rst done independently for AKI-D and ESRD groups, then for the combined group of all dialysis requiring patients. Comparison of these parameters was done for patients before and after implementation of HDRU. Primary outcome of the study was in-hospital mortality which was compared between pre and post HDRU cohorts. Causes of death were adjudicated by nephrologists treating the patients. Predictors of renal outcome (need of dialysis at discharge from hospital) in AKI-D group were analyzed. Depending on the nature of the variable, one or two-sided p value <0.05 was taken for statistical signi cance in univariate and multivariate analyses. Kaplan-Meier survival curves were generated for comparing pre and post HDRU survival, and comparison was done using log-rank test. A proportional monthly mortality rate was calculated by entering numerator as number of deaths in a given month and denominator as total number of patients cared for.
In stepwise forward conditional regression analysis for the entire cohort (Supplementary Table 2), male sex, breathlessness and altered mental status at presentation, shock during hospital stay and leukocytosis were independent predictors of death. For AKI-D cohort, presence of shock at presentation or developing during stay and leukocytosis were the only features predicting mortality. In patients with ESRD, shock at presentation or developing during stay, altered mental status, severe COVID-19 and need of packed cell transfusions predicted mortality.
Non-COVID-19 issues at admission and cause speci c mortality 49 of 238 patients (20.6%) had signi cant medical issues apart from COVID-19 at the time of admission, which included tropical infections and sepsis (urinary or dialysis access related) in 28 patients and issues due to underlying medical condition in 21 patients. In ESRD cohort, 35 of 118 (29.6%) had an inter-dialytic interval of >3 days due to missed dialysis session prior to admission. 14 (11.9%) had complications related to hemodialysis access at admission. In 25 of 76 (32.9%) patients who died, cause of death was not directly related to COVID-19 acute respiratory distress syndrome (ARDS). Causes of death in these patients were sepsis-10, cardiac -7, intra-cerebral bleeding-6, malignancy-1 and complications of uremia-1.

Discussion
Our data suggests that COVID-19 in patients with severe acute or chronic kidney disease needing dialysis (AKI-D and ESRD) is associated with signi cant mortality and morbidity. It is feasible for a dedicated nephrology team to deliver high dependency care, implementation of which led to signi cant improvement in the survival. Male sex, presence of leukocytosis, breathlessness, altered mental status at presentation and development of shock during hospital stay were independent predictors of death. In patients with AKI, survivors had a high risk of dialysis dependence which was signi cantly associated with presence of CKD and hypertension at baseline.
To our knowledge, this is the rst report of the nephrologists as primary care physician for the management of COVID-19 and care in HDRU set-up lead to improvement in survival. Key components of HDRU i.e. checklist based close clinical monitoring, care bundle approach focusing on key clinical issues and integration of multispecialty care by primary care physician-nephrologists-most likely underlie the observed bene ts of HDRU. Sudden and unexpected clinical deterioration is not uncommon in patients with COVID-19 8 . In a report from Italy, patient with ESRD and COVID-19 assigned to outpatient management based upon initial evaluation, experienced late clinical deterioration and associated mortality. 9 31 of 234 (13.2%) patients in our cohort were not hypoxic at admission and developed the need of respiratory support during hospitalization; highlighting the need of close monitoring. Checklist of the key clinical parameters enabled us to quickly identify such patients and triage them for closer monitoring. Use of checklists for the management of critically ill patients can reduce the errors of omission and potentially improve the outcomes 10 and their use by fellows and nurses working in six hourly rotations simpli ed the relatively complex process of caring for hospitalized patients on dialysis. Bundle care approach which focused on prompt optimization of hemodynamics, dialysis adequacy, dialysis access issues and therapies of COVID-19 ensured that key clinical needs are addressed as soon as possible after admission. 20.6% of the patients had major medical issues apart from COVID-19 at admission and 32.9% the deaths were not directly related to COVID-19 ARDS. This makes strong case for involvement of nephrologists as the primary care physician for the management of these patients. For instance, relative hypotension, which in critically ill patients is associated with Major Adverse Kidney Events (MAKE) 11 , was observed more often in patients who died. Staff nephrologists ensured that this was promptly identi ed, and such patients were monitored closely for further deterioration.
Our cohort of AKI-D patients had a high rate of dialysis dependence at discharge, which could possibly be due to high prevalence of CKD at baseline; however, this could also be due to higher survival and discharge rates in our cohort as compared to the reported literature. Large number of patients needed transfer to chronic dialysis, and this process-involving counseling of patients and families, chronic dialysis access and plan of follow up care was facilitated in the presence of nephrologists as primary care physicians. High mortality (54.5%) in the rst year (22.5% in the rst month) early after dialysis initiation has been reported in elderly patients with morbidities 12 , highlighting the importance of period of 'transition' in the care where nephrologists can play crucial role.
Hospitalized patients with both CKD and COVID-19 typically have multiple co-morbidities 13,14 which potentially lead to fragmentation of the care and can contribute to adverse clinical outcomes. Coordination among multiple specialties can be challenging especially during the pandemic time but is vital for the management of the patients with multi morbidities. Daily conference and critical care committee meeting facilitated direct communication within the team and across the specialties, thus preventing fragmentation of care.
Association of male sex with mortality in our cohort is consistent with the reported higher risk of death in men with COVID-19 in general population. 14,15 Shock during the hospital stay was probably related to severe systemic in ammation at presentation and development of sepsis, which contributed to mortality. This nding is further supported by association of leukocytosis with mortality. While bacterial sepsis in not a common feature of COVID-19, reported as 3.8% in a series 16 , 21 (9%) of our patients had sepsis at presentation. Patients with CKD and ESRD are 100-300 times prone to sepsis associated mortality 17 . Altered mental status at presentation was associated with mortality, indicating multisystem involvement in severe COVID-19, severe uremia due to missed regular dialysis sessions or sepsis itself. 35 (28.5%) patients missed their scheduled dialysis sessions after diagnosis of COVID-19 as indicated by long interval of >3 days from their last dialysis session. This highlights the importance of rapid evaluation and management of sepsis (with antimicrobials or access removal) and optimization of dialysis dose in these patients.
Our study has limitations. Being an observational study, de nite conclusions about survival bene ts of HDRU can't be made. Imbalances in the baseline characteristics of the patients were noted in the pre and post HDRU cohorts: post HDRU cohort patients were older, more likely to be diabetic, present with symptoms, need oxygen for longer duration, were less likely to receive HCQS and more likely to receive remdesivir. Therapy of COVID-19 is evolving and learning curve issues in the management of disease early in the course might underlie the observed higher mortality in pre-HDRU cohort. Treatment protocols were modi ed with time as per the available evidence (fewer patients receiving HCQS, more patients getting remdesivir in HDRU). However, these imbalances are unlikely to explain the marked decrease in the mortality after HDRU as no single therapy has shown to decrease mortality so far. Patients receiving HCQS were monitored regularly for QT interval and arrhythmias, and sudden cardiac deaths were not observed in these patients. Pre HDRU cohort in our study was small, however, our post-HDRU cohort had far lower mortality rate in AKI-D than reported in a large study (43.9% vs 64%). 18 Similarly, post-HDRU ESRD cohort mortality rate is lower than those reported in India 19 (37%) and elsewhere (31% 4 , 27.3% 20 ). These observations support the bene cial effect of HDRU on outcomes.
In conclusion, it is a feasible for nephrologists to deliver high dependency renal care as primary care physicians, and this approach can potentially improve the survival of patients with COVID-19 and severe kidney disease. Further evaluation of this approach is needed.

Declarations
Ethics approval and consent to participate: Study was approved by Institutional Ethics Committee (EC/OA/96/2020). All study procedures were conducted in accordance with the guidelines of IEC and declarations of Helsinki.

Consent for publication: yes
Availability of data and materials: Raw data is available with the authors for any further evaluations      Structure of High Dependency Renal Unit