www.kidney-international.org editorial

The Novel 2019 epidemic and kidneys OPEN Kidney International (2020) -, -–-; https://doi.org/10.1016/j.kint.2020.03.001 KEYWORDS: acute kidney injury; hemodialysis Copyright ª 2020, International Society of Nephrology. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

ovel Coronavirus disease (COVID-19) is examination of the chest (bilateral lobular and a newly discovered contagious disease subsegmental areas of consolidation), and 32% N caused by severe acute respiratory syn- required care from the intensive care unit. Higher drome (SARS)–coronavirus (CoV)-2 virus, plasma cytokine levels (interleukin [IL]-2, IL-7, primarily manifesting as an acute respiratory IL-10, granulocyte-colony stimulating factor, illness with interstitial and alveolar , interferon-inducing protein-10, monocyte che- but it can affect multiple organs such as the moattractant protein 1, macrophage inflamma- kidney, heart, digestive tract, blood, and nervous tory protein-1a, tumor necrosis factor a)were system.1 The rapidly spreading outbreak, which present in patients requiring intensive care unit first emerged in , Province, , admission. Limited reports suggest that severe in December 2019, has since been declared a complications are uncommon in children.7 Saraladevi Naicker1, global pandemic. As of March 16, 2020, 167,511 Chih-Wei Yang2, cases of COVID-19 have been reported world- Diagnosis Shang-Jyh Hwang3, wide in 151 countries (and a cruise ship), with The diagnosis is mainly based on epidemio- 4 Bi-Cheng Liu , 6606 deaths.2 In recent days, the number of cases logical factors (history of contact), clinical 5 Jiang-Hua Chen and has risen rapidly in South Korea, Japan, Europe, manifestations, and laboratory examination Vivekanand Jha6,7 1 and the United States. (hemogram, chest computed tomography, and Department of Internal fi 8 Medicine, School of Clinical SARS-CoV-2 has been identi ed as a bat- virological examination). Of note, there are Medicine, Faculty of Health origin CoV. The full-length genome sequence recent cases without any travel history or Sciences, University of the of the COVID-19 virus shows a close rela- apparent contact with infected individuals. Witwatersrand, Johannesburg, tionship with the bat SARS-like coronavirus Several COVID-19 nucleic acid detection assays 2 South Africa; Department of strain BatCov RaTG13 belonging to the Beta- have been developed, both in-house and com- Nephrology, Chang Gung coronavirus 3 fl Memorial Hospital, College of genus. mercial. They use uorescence polymerase Medicine, Chang Gung Previous coronavirus infections, SARS-CoV chain reaction and probe anchoring polymeri- University, Taoyuan, Taiwan; and Middle East respiratory syndrome coro- zation techniques. Gene sequencing has also 3Division of Nephrology, navirus (MERS-Co-V), have infected more been used. The World Health Organization has Department of Internal than 10,000 people in the past 2 decades, with appointed referral laboratories in different Medicine, Kaohsiung Medical 4,5 9 University Hospital, Kaohsiung mortality rates of 10% and 37%, respectively. countries. A serological test has been devel- Medical University, Kaohsiung, COVID-19 is more contagious than these ill- oped and allowed detection of a cluster of cases 10 Taiwan; 4Institute of nesses, spreads by human-to-human trans- in Singapore. More sensitive and convenient Nephrology, Da mission via droplets, fecal, or direct contact, detection methods continue to be developed. Hospital, Southeast University and has an incubation period estimated at 1 to School of Medicine, , China; 5Kidney Disease Center, 14 days (usually 3 to 7 days). Kidney involvement in COVID-19 infection The First Affiliated Hospital, Infection has been reported in all ages, In previous reports of SARS and MERS-CoV College of Medicine, Zhejiang including children. The majority of infections are infections, acute kidney injury (AKI) devel- University, Hangzhou, China; fl 6 mild, presenting with a u-like illness. The com- oped in 5% to 15% cases and carried a high George Institute for Global mon clinical presentations of COVID-19 are fever – Health India, UNSW, New Delhi, (60% 90%) mortality rate. Early reports sug- 7 – India; and Manipal Academy (98%), cough (76%), and myalgia and fatigue gested a lower incidence (3% 9%) of AKI in 6 1,11–13 of Higher Education, Manipal, (18% each), with accompanying leucopenia those with COVID-19 infection. Recent India (25%) and lymphopenia (63%). Symptoms of reports, however, have shown higher frequency Correspondence: Vivekanand upper respiratory infection with rhinorrhea and of renal abnormalities. A study of 59 patients Jha, The George Institute for productive cough are uncommon, except in chil- with COVID-19 found that 34% of patients Global Health, 310-11 Elegance dren. About 16% to 20% cases have been classified developed massive albuminuria on the first day Tower, Jasola District Centre, severe critical New Delhi 110025, India. as or . Of the 41 patients described by of admission, and 63% developed proteinuria 6 14 E-mail: vjha@georgeinstitute. Huang et al., all had pneumonia with abnor- during their stay in hospital. Blood urea org.in malities on computerized tomographic nitrogen was elevated in 27% overall and in

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two-thirds of patients who died. Computed to- reported in a patient with COVID-19; a clinical mography scan of the kidneys showed reduced trial on the efficacy of remdesivir in patients density, suggestive of inflammation and edema. with COVID-19 is currently underway in China Cheng et al.13 recently reported that amongst (NCT0425266; NCT04257656) and is expected 710 consecutive hospitalized patients with to be completed in April 2020. Chloroquine COVID-19, 44% had proteinuria and hematuria phosphate has been shown to have some efficacy and 26.7% had hematuria on admission. The against COVID-19–associated pneumonia in prevalence of elevated serum creatinine and multicenter clinical trials conducted in China.21 blood urea nitrogen was 15.5% and 14.1%, Extracorporeal treatments. Continuous respectively. AKI was an independent risk factor renal replacement therapy (CRRT) has been for patients’ in-hospital mortality.13,14 successfully applied in the treatment of SARS, MERS, and sepsis.22,23 High-volume hemofil- Pathogenesis of kidney injury tration in a dose of 6 l/h removed inflammatory The exact mechanism of kidney involvement is cytokines (IL-6) and improved the Sequential unclear: postulated mechanisms include sepsis Organ Failure Assessment scores at day 7 in leading to cytokine storm syndrome or direct patients with sepsis.24 Therefore, CRRT may cellular injury due to the virus. Angiotensin- play a role in patients with COVID-19 and converting enzyme and dipeptidyl peptidase-4, sepsis syndrome. The potential role of extra- both expressed on renal tubular cells, were corporeal therapy techniques needs to be identified as binding partners for SARS-CoV evaluated, however. and MERS-CoV, respectively.15,16 Viral RNA Glucocorticoids. In a retrospective study of has been identified in kidney tissue and urine in patients with SARS-CoV and sepsis, steroids, at both infections.17,18 Recently, Zhong’s lab in a mean daily dose of 105.3 Æ 86.1 mg in 147 of Guangzhou successfully isolated SARS-CoV-2 249 noncritical patients (59.0%), reduced from the urine sample of an infected patient, mortality rate and shortened duration of hos- suggesting the kidney as the target of this novel pitalization, whereas 121 of 152 critical patients coronavirus.19 (79.6%) received corticosteroids at a mean daily dose of 133.5 Æ 102.3 mg, and 25 died.25 Treatment A subsequent retrospective, observational study The current treatment of COVID-19 with AKI of 309 patients with MERS showed that those includes general and supportive management who received high-dose steroids were more and kidney replacement therapy. There is no likely to require , vaso- effective antiviral therapy available at present. pressors, and renal replacement therapy General management. All patients with (RRT).26 In a meta-analysis of corticosteroid confirmed COVID-19 need to be quarantined. use in patients with SARS, 4 studies provided An N95 fit-tested respirator and protective conclusive evidence of harm (psychosis, dia- clothes and equipment are essential. Early betes, avascular necrosis, and delayed viral admission to intensive care units in designated clearance).27 Therefore, the use of steroids is hospitals is recommended for severely ill patients. controversial and not recommended by the Supportive care, namely bed rest, nutritional World Health Organization because of poten- and fluid support, and maintenance of blood tial inhibition of viral clearance and prolonga- pressure and oxygenation are important mea- tion of the duration of viremia.28 sures, as for all critically ill patients. Other Convalescent plasma. Preliminary clinical measures include prevention and treatment of studies in China have shown that early appli- complications by providing organ support, cation of convalescent plasma in patients with maintaining hemodynamic stability, and pre- COVID-19 could accelerate clinical recovery.6 venting secondary infection. Currently 2 trials, an open-label, non- Antiviral therapy. There is no specific randomized clinical trial (NCT04264858) and a effective antiviral drug for COVID-19 at present. multicenter, randomized, and parallel- The guidelines of the Chinese National Health controlled trial (ChiCTR2000029757) on the Commission recommend aerosolized inhalation efficacy of convalescent plasma in patients with of interferon a and lopinavir/ritonavir. The COVID-19, are underway in China. specific therapeutic value and safety of lopina- . Monoclonal anti- vir/ritonavir in patients with COVID-19 are body directed against the Ras-binding domain under investigation (ChiCTR2000029308).20 of the S protein of MERS-CoV has been found Successful treatment with remdesivir has been to have neutralizing activities in plaque assays

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in vitro.29 A monoclonal antibody against prevention tools, and guidelines from the COVID-19 has not yet been developed. Tocili- government, academic society, and hospital zumab, a monoclonal antibody against the IL-6 authority. The list of staff should be recor- receptor, has achieved encouraging preliminary ded and retained by dialysis hospitals. clinical results. The safety and efficacy of toci- 2. Information on travel, occupation, con- lizumab in COVID-19 infection are undergoing tacts, and cluster (TOCC) history of each evaluation by a multicenter randomized medical staff, dialysis patient, their family controlled trial (ChiCTR2000029765). members, residents of the same institution, and colleagues at work should be collected COVID-19 in patients with kidney disease and updated regularly. Pregnant women, newborns, the elderly, and 3. Latest care recommendations and epidemic patients with comorbidities like diabetes mel- information should be updated and deliv- litus, hypertension, and cardiovascular disease ered to all medical care personnel as are susceptible to COVID-19 infection and are needed. Training can be done peer-to-peer likely to have more severe illness often or online. requiring care from an intensive care unit. The 4. Group activities, including group rounds, impact of COVID-19 on chronic kidney disease group studies, and case discussions, should has not been reported.30 be minimized. COVID-19 infection presents a special 5. It is recommended that staff members have threat to patients on dialysis. There are 7184 meals at different times to avoid dining patients on hemodialysis (HD) in 61 treatment together. Goggles, masks, and hats should centers in Wuhan City. At a single HD center in be removed before meals, and hands Renmin Hospital, Wuhan University, 37 out of washed with flowing water. Talking during 230 patients on HD and 4 of 33 staff members meals should be minimized to reduce the developed COVID-19 infection between spread of droplets. January 14 and February 17, 2020.30 A total of 7 6. Staff should self-monitor their symptoms patients on HD died, of whom 6 had COVID- and should inform the team leader in case 19 infection. However, the deaths were deemed they or their family members develop symp- to be due to cardiovascular causes and not tom(s) suggestive of COVID-19 infection. directly to the COVID-19 infection. Patients on 7. Entrance control, identification and HD with COVID-19 had less lymphopenia, shunting of people at risk of infection, body lower serum levels of inflammatory cytokines, temperature measurement, hand washing, and milder clinical disease than other patients wearing of proper (surgical or N95) masks with COVID-19 infection. throughout the process, machine disinfec- tion, environmental cleanliness, good air Management of patients on dialysis conditioning, and ventilation conditions COVID-19 infection presents particular chal- should be instituted. lenges for patients on dialysis, in particular, 8. Patients and accompanying persons should those in in-center HD. Patients with uremia are be given motion-activated hand sanitizer particularly vulnerable to infection and may while entering the dialysis room. Patients exhibit greater variations in clinical symptoms should wear medical masks and avoid and infectivity. In-center HD significantly in- meals during dialysis. They can bring con- creases the risk of transmission of infection, venience food such as candy to prevent including to medical staff and facility workers, hypoglycemia. patients themselves, family members, and all 9. Patients with suspected or confirmed others. COVID-19 infection should be admitted to The Chinese Society of Nephrology31 and a negative-pressure isolation ward of spec- the Taiwan Society of Nephrology32 have ified hospitals. If the capacity of the isola- recently developed guidelines for dialysis units tion facility is overloaded, the Fixed Dialysis during the COVID-19 outbreak. A summary of Care Model detailed below is recommended these guidelines is provided below. for dialysis patients under the 14-day 1. A working team consisting of dialysis phy- period of quarantine for possible contact sicians, nursing staff, and technologists with COVID-19. should receive training in updated clinical a. Place of dialysis treatment: patients knowledge of epidemic COVID-19, notifi- should continue HD at the original HD cation of infection at risk, epidemic center and not change to another center.

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b. Dialysis shift and personnel: do not 11. The medical waste from confirmed or sus- change dialysis shifts and caregiver staff pected patients with novel coronavirus to avoid cross-contamination and infec- infection should be considered as infectious tion. Minimize the relevant contacts. medical waste and disposed accordingly. c. Patients who need vascular access sur- gery should be screened for novel Operational strategies for family member and coronavirus before the surgery. Opera- caregivers tions on patients with confirmed or (i) All family members living with patients on suspected novel coronavirus infection dialysis must follow all the precautions and should be carried out in a designated regulations given to patients to prevent room with necessary protection for person-to-person and within-family medical staff. transmission of COVID-19, which d. Transportation: public transport should include body temperature measurement, not be used. Patients should arrange good personal hygiene, handwashing, and personal transportation and take fixed prompt reporting of potentially sick transportation routes. Transport people. personnel and escorts should wear (ii) Patients on dialysis who have a family surgical-grade or N95 masks member or caregiver subject to basic throughout. quarantine can have dialysis as usual in e. All patients who have fever should be accordance during the 14-day period. screened for novel coronavirus infection (iii) Once the family members or caregiver of a and should be given dialysis in the last patient on dialysis have been converted to shift of the day until infection is aconfirmed case, the patient’s identity excluded. should be upgraded and treated in accor- f. Pass route for entering hospital and dance with the above-mentioned dialysis unit: the pick-up and drop-off conditions. points should not be shared with other In summary, COVID-19, a pandemic dialysis patients. Entering and exiting caused by a novel coronavirus, is a major with other patients at the same time global human threat. Kidney involvement should be avoided. The route, mode, and seems to be frequent in this infection, and AKI time of transport of dialysis personnel is an independent predictor of mortality. The should be fixed. impact of this infection in those with chronic g. Precautions in dialysis unit: patients kidney disease has not been studied. Manage- should not be in close proximity; treat- ment of patients on dialysis who have been ment and waiting areas should have suspected to have been in contact with good air conditioning and ventilation to COVID-19 should be carried out according to remove droplet particles from the air. strict protocols to minimize risk to other pa- h. Designated care personnel: all personnel tients and healthcare personnel taking care of involved in direct patient care should these patients. undertake full protection, including long-sleeved, waterproof isolation clothing; hair caps; goggles; gloves; and DISCLOSURE VJ reports grants from Baxter Healthcare, GSK, medical masks (surgical mask grade or NephroPlus, Biocon, and Zydus Cadilla. All the other above). Hand hygiene should be strictly authors declared no competing interests. implemented. i. Dialysis machine: equipment that may REFERENCES come into contact with patients or 1. Wang D, Hu B, Hu C, et al. Clinical characteristics of potentially contaminated material 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. should be disinfected according to stan- JAMA. https://doi.org/10.1001/jama.2020.1585. dard protocols. Accessed March 2, 2020. 10. If a newly confirmed or highly suspected 2. World Health Organization. Coronavirus disease (COVID-2019) situation reports. Available at: https:// case of novel coronavirus infection in www.who.int/emergencies/diseases/novel- dialysis centers is identified, disinfection coronavirus-2019/situation-reports. Accessed March should be carried out immediately. Areas in 16, 2020. 3. World Health Organization. Report of the WHO-China close contact with these patients should not Joint Mission on Coronavirus Disease 2019 (COVID-19). be used for other patients until cleared. Available at: https://www.who.int/docs/default-

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