SARS-CoV-2 Infection in Hospitalized Patients With Kidney Disease

Abstract

Since the outbreak of coronavirus disease 2019 (COVID-19) in December 2019, the disease has spread rapidly across the globe. Up to April 1, 2020, there have been 823,626 confirmed cases and 40,598 deaths.1Situation Report–72.https://www.who.int/docs/default-source/coronaviruse/situation-reports/20200401-sitrep-72-covid-19.pdf?sfvrsn=3dd8971b_2Date accessed: April 1, 2020Google Scholar Actual case fatality ratio is still unknown, but some studies have reported ranges between 1.4% and 3.8%.2Ruan S. Comment. Likelihood of survival of coronavirus disease 2019.Lancet Infect Dis. 2020; 3099: 2019-2020Google Scholar Clinical features and outcomes of patients with COVID-19 have been published in previous studies,3Wang D. Hu B. Hu C. et al.Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China.JAMA. 2020; 323: 1061-1069Crossref PubMed Scopus (16387) Google Scholar,4Zhou F. Yu T. Du R. et al.Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study.Lancet. 2020; 6736: 1-9Google Scholar yet, scarce information is available regarding patients with end-stage renal disease and kidney transplantation. Small series and case reports suggest that clinical presentation is mostly mild and unlikely to progress to severe disease possibly as a consequence of impaired T-cell immune response and less capability of developing a cytokine storm.5Ma Y. Diao B. Lv X. et al.2019 novel coronavirus disease in hemodialysis (HD) patients: report from one HD center in Wuhan, China.medRxiv. 2020; (02.24.20027201): 2020Google Scholar, 6Wang R, Liao C, He H, et al. COVID-19 in hemodialysis patients: a report of 5 cases [e-pub ahead of print]. Am J Kidney Dis. https://doi.org/10.1053/j.ajkd.2020.03.009. Accessed April 20, 2020.Google Scholar, 7Guillen E, Pineiro GJ, Revuelta I, et al. Case report of COVID-19 in a kidney transplant recipient: does immunosuppression alter the clinical presentation [e-pub ahed of print]? Am J Transplant. https://doi.org/10.1111/ajt.15874. Accessed April 20, 2020.Google Scholar, 8Gandolfini I, Delsante M, Fiaccadori E, et al. COVID-19 in kidney transplant recipients [e-pub ahead of print]. Am J Transplant. https://doi.org/10.1111/ajt.15891. Accessed April 20, 2020.Google Scholar, 9Zhu L, Xu X, Ma K, et al. Successful recovery of COVID-19 pneumonia in a renal transplant recipient with long-term immunosuppression [e-pub ahead of print]. Am J Transplant. https://doi.org/10.1111/ajt.15869. Accessed April 20, 2020.Google Scholar In this report, we describe our experience with 51 patients with end-stage renal disease on dialysis (n = 25) and renal transplantation (n = 26) who developed COVID-19 and required hospital admission. The study group consisted of 51 patients with a mean age of 64 ± 15 years, 57% men. Twenty-three cases (46%) were on hemodialysis, 2 cases (4%) on peritoneal dialysis, and 26 patients (51%) were kidney transplant (KT) recipients. Demographics and baseline clinical characteristics of the study population are detailed in Table 1. As expected, the group of patients on dialysis had higher Charlson comorbidity index scores together with a higher proportion of diabetes mellitus (48%) and ischemic heart disease (32%). Maintenance immunosuppression in the KT group included low-dose steroids in 22 (84%), tacrolimus in 24 (92%), mycophenolate mofetil in 14 (54%), and mammalian target of rapamycin inhibitors in 7 (27%).Table 1Baseline characteristics of the study populationTotal (n = 51)Dialysis (n = 25)Kidney transplantation (n = 26)Baseline Age, yr64 ± 1566 ± 1561 ± 14 Sex, male (%)29 (57)17 (68)12 (46) Charlson comorbidity index7 [4–8]8 [6–9]4 [3–7] Current smokers, n (%)2 (4)2 (8)0 (0) Hypertension, n (%)46 (90)22 (88)24 (92) Diabetes mellitus, n (%)18 (35)12 (48)6 (23) Ischemic heart disease, n (%)8 (16)8 (32)0 (0) COPD, n (%)4 (8)2 (8)2 (8)Clinical presentation Diagnosis from the onset of symptoms, d1 [1–4]1 [1–3]3 [1–7] Systolic BP, mm Hg126 ± 27122 ± 30129 ± 23 Diastolic BP, mm Hg68 ± 1660 ± 1174 ± 18 Oxygen saturation ≤90%, n (%)8 (16)4 (16)4 (15) Temperature, ° C37.7 ± 0.937.8 ± 0.937.6 ± 1 Fever, n (%)28 (55)16 (64)12 (46) Asthenia/myalgia10 (19)6 (24)4 (15) Nonproductive cough, n (%)33 (64)16 (64)17 (65) Productive cough, n (%)9 (18)3 (12)6 (24) Dyspnea, n (%)25 (49)10 (40)15 (58) GI symptoms, n (%)15 (29)5 (20)10 (38)Pneumonia severity scores CURB-652 ± 1.12.1 ± 1.21.9 ± 1 SOAR1.4 ± 1.21.4 ± 1.21.3 ± 1Laboratory Serum creatinine, mg/dl2.3 [1.6–4.1]5 [2.8–7.6]1.9 [1.5–2.4] Serum albumin, g/dl3.7 ± 0.53.6 ± 0.63.7 ± 0.4 Lactate dehydrogenase, IU/l313 ± 100310 ± 101312 ± 97 C-reactive protein, mg/dl11 [4–21]8 [2–20]13 [6–23] Hemoglobin, g/dl11.5 ± 211.1 ± 212 ± 2 Lymphocytes, per 1000/mm30.6 [0.4–0.9]0.5 [0.3–0.8]0.7 [0.4–1.1] D-dimer, ng/ml1078 [588–1282]1106 [635–1644]822 [506–1180]Chest radiology, n (%) Ground glass opacities31 (61)15 (60)16 (62) Alveolar consolidations22 (43)8 (32)14 (54) Bilateral involvement33 (65)16 (64)17 (65) Pleural effusion3 (6)0 (0)3 (12)Treatment regimens and outcomes, n (%) Hydroxychloroquine47 (92)24 (96)23 (86) Lopinavir/ritonavir19 (37)12 (48)7 (27) AntibioticsAmoxycillin/clavulanic acid1 (2)1 (4)0 (0)Cephalosporins31 (61)17 (68)14 (54)Carbapenem20 (39)9 (33)11 (42)Macrolides30 (58)15 (60)15 (58)Linezolid6 (12)4 (16)2 (8) Steroids22 (43)10 (40)12 (46) Interferon beta 1b3 (6)3 (11)0 (0) Tocilizumab6 (11)1 (4)5 (19) i.v. Ig6 (11)0 (0)6 (23) Prophylactic anticoagulation33 (65)17 (68)16 (62)Follow-up time, d13 ± 712 ± 614 ± 7 ARDS, n (%)20 (39)10 (40)10 (39) Death, n (%)13 (26)7 (28)6 (23)ARDS, acute respiratory distress syndrome; BP, blood pressure; COPD, chronic obstructive pulmonary disease; GI, gastrointestinal.Data are presented as mean ±SD, or median [interquartile range]. Open table in a new tab ARDS, acute respiratory distress syndrome; BP, blood pressure; COPD, chronic obstructive pulmonary disease; GI, gastrointestinal. Data are presented as mean ±SD, or median [interquartile range]. Clinical presentation of COVID-19 was similar in both groups, and was characterized by fever (55%), nonproductive cough (64%), dyspnea (49%), gastrointestinal symptoms (28%), and asthenia/myalgias (19%). Median time (interquartile range) to diagnosis from the onset of symptoms was 1 day (1–3) in the dialysis group and 3 days (1–7) in KT recipients. The most frequent biochemical findings (in both groups) included mild to moderate lactate dehydrogenase elevation, high C-reactive protein, D-dimer elevation, and a moderate decrease in the lymphocyte count. Sixty-nine percent of patients with KT had acute kidney injury on admission. According to the AKIN classification, 14 of 18 (78%) were AKIN 1 and 4 of 18 (22%) were AKIN 2. None of the cases required renal replacement therapy during the observation period. Pneumonia CURB-65 and SOAR scores were similar in both groups. Chest X-ray showed ground glass opacities in 61% of the cases, alveolar consolidations in 43%, and bilateral pulmonary involvement in 65%. Most patients were treated with hydroxychloroquine (92%). In 4 cases (8%), hydroxychloroquine was not prescribed at the physician’s discretion because of prolonged QT interval on the initial electrocardiogram. Other therapeutic regimens were added according to clinical course and severity: 37% received lopinavir/ritonavir, 43% received a 3-day course of i.v. steroids (methylprednisolone 0.5mg/kg once or twice daily), 6% received interferon beta 1b, 11% tocilizumab, and 11% i.v. Ig. All patients received antibiotics, mainly cephalosporins (61%) and azithromycin (58%). Thirty-three patients (65%) received prophylactic anticoagulation with low-molecular-weight heparin. No thrombotic or hemorrhagic events were observed. Among the KT group, reduction of immunosuppression was performed in most cases: mycophenolate mofetil was stopped in 13 cases (50%), tacrolimus in 4 (15%), and mammalian target of rapamycin inhibitors in 2 (8%). Although only 8 cases had oxygen saturation ≤90% at presentation, 45 of 51 (88%) required some kind of oxygen therapy in the course of the observation period. During a mean follow-up of 13 ± 7 days of in-hospital stay, 10 patients (40%) in the dialysis group and 10 patients (39%) in the KT group developed acute respiratory distress syndrome (ARDS) and 13 patients (7 on dialysis and 6 KT recipients) eventually died. Patients who developed ARDS presented significant radiologic deterioration within a median time (interquartile range) from admission of 5 days (3–7). Factors associated with death included age, higher Charlson comorbidity index, low systolic blood pressure, higher pneumonia severity scores, higher level of C-reactive protein, steroid therapy, and development of ARDS in the dialysis group (Table 2); and oxygen saturation ≤90%, dyspnea on admission, a higher SOAR pneumonia severity score, and development of ARDS in KT recipients (Table 3). By Cox regression analysis, the main determinants of death in the whole study group are shown in Table 4.Table 2Clinical characteristics of dialysis patients according to outcomeDialysis patients who died (n = 7)Dialysis patients who survived (n = 18)PBaseline Age, yr77 ± 1262 ± 140.023 Sex, male (%)6 (86)11 (61)0.246 Race/ethnicity, n (%)0.785Caucasian5 (71)15 (83)Hispanic2 (29)2 (11)Asian0 (0)1 (6) Charlson comorbidity index9 [7–10]8 [4–8]0.029 Current smokers, n (%)2 (29)0 (0)0.070 Hypertension, n (%)6 (86)16 (89)0.645 Diabetes mellitus, n (%)4 (57)8 (44)0.450 Ischemic heart disease, n (%)4 (57)4 (22)0.116 Liver disease, n (%)2 (29)1 (6)0.180 COPD, n (%)1 (14)1 (6)0.490 Hypothyroidism, n (%)1 (14)2 (11)0.645 Dialysis vintage, yr2 (2–5)5 (3–6)0.258Clinical presentation Diagnosis delay from the onset of symptoms, d2 [1–3]1 [1–2]0.329 Systolic BP, mm Hg102 ± 21131 ± 300.023 Diastolic BP, mm Hg54 ± 764 ± 120.071 Oxygen saturation ≤90%, n (%)2 (29)2 (11)0.307 Fever, n (%)4 (57)12 (67)0.499 Asthenia/myalgia1 (14)5 (28)0.443 Nonproductive cough, n (%)5 (71)11 (61)0.501 Productive cough, n (%)2 (29)1 (6)0.112 Dyspnea, n (%)4 (57)6 (33)0.261 GI symptoms, n (%)0 (0)5 (27)0.155Pneumonia severity scores CURB-653.3 ± 1.31.7 ± 0.80.001 SOAR3.3 ± 0.80.7 ± 0.80.001Laboratory Serum creatinine, mg/dl6.8 [2.3–7.7]4.2 [2.9–8.3]0.893 Serum albumin, g/dl3.3 ± 0.73.7 ± 0.60.096 Lactate dehydrogenase, IU/l341 ± 65302 ± 1160.412 C-reactive protein, mg/dl23 [11–32]4 [1–12]0.002 Hemoglobin, g/dl11.1 ± 111.1 ± 20.973 Lymphocytes, per 1000/mm30.4 [0.3–0.6]0.7 [0.4–0.9]0.085 D-dimer, ng/ml1231 [594–1558]1078 [624–1614]0.940Chest radiology, n (%) Ground glass opacities6 (86)9 (50)0.118 Alveolar consolidations2 (29)6 (35)0.572 Bilateral involvement6 (86)10 (56)0.174Treatment regimens and outcomes, n (%) Hydroxychloroquine6 (86)18 (100)0.109 Lopinavir/Ritonavir4 (57)8 (44)0.568 AntibioticsAmoxycillin/clavulanic acid0 (0)1 (6)0.720Cephalosporins3 (43)14 (78)0.116Carbapenem3 (43)6 (33)0.499Macrolides4 (57)11 (61)0.601Linezolid0 (0)4 (22)0.242 Steroids6 (86)4 (22)0.004 Interferon beta 1b1 (14)2 (11)0.826 Tocilizumab0 (0)1 (6)0.524 Prophylactic anticoagulation5 (71)12 (66)0.278ARDS, n (%)6 (86)4 (22)0.004ARDS, acute respiratory distress syndrome; BP, blood pressure; COPD, chronic obstructive pulmonary disease; GI, gastrointestinal. Open table in a new tab Table 3Clinical characteristics of kidney transplant patients according to outcomeKidney transplant patients who died (n = 6)Kidney transplant patients who survived (n = 20)PBaselineAge, yr70±1358±130.070Sex, male (%)2 (33)10 (50)0.473Race/ethnicity, n (%)0.234 Caucasian6 (100)16 (80) Hispanic0 (0)4 (20) Asian0 (0)0 (0)Charlson comorbidity index7 [4–8]4 [2–7]0.139Hypertension, n (%)6 (100)18 (100)0.420Diabetes mellitus, n (%)0 (0)6 (30)0.134Liver disease, n (%)0 (0)2 (10)0.585COPD, n (%)1 (17)1 (5)0.347Hypothyroidism, n (%)3 (50)4 (20)0.146Time from transplant, yr9 (6–15)7 (4–15)0.744Clinical presentationDiagnosis delay from the onset of symptoms, d2 [1–8]4 [1–7]0.519Systolic BP, mm Hg118±22133±230.176Diastolic BP, mm Hg70±2076±170.549Oxygen saturation ≤90%, n (%)3 (50)1 (5)0.007Fever, n (%)2 (33)10 (50)0.473Asthenia/myalgia0 (0)4 (20)0.234Nonproductive cough, n (%)3 (50)14 (70)0.366Productive cough, n (%)1 (17)5 (20)0.657Dyspnea, n (%)6 (100)9 (45)0.017GI symptoms, n (%)2 (33)8 (40)0.664Pneumonia severity scoresCURB-652.5±1.51.7±0.80.110SOAR2.8±0.70.8±0.60.001LaboratorySerum creatinine, mg/dl1.9 [1.4–3.1]1.9 [1.5–2.3]0.929Serum albumin, g/dl3.5±0.63.8±0.30.420Lactate dehydrogenase, IU/l372±74295±980.089C-reactive protein, mg/dl14 [13–28]10 [3.8–22]0.196Hemoglobin, g/dl11.3±2.812.3±1.80.429Lymphocytes, per 1000/mm30.8 [0.5–3.6]0.7 [0.4–1.1]0.533D-dimer, ng/ml1282 [468–1782]947 [564–1282]0.573Chest radiologyGround glass opacities, n (%)5 (83)11 (55)0.211Alveolar consolidations, n (%)2 (33)12 (60)0.250Bilateral involvement, n (%)4 (67)13 (65)0.940Pleural effusion, n (%)1 (17)2 (10)0.654Treatment regimens and outcomesHydroxychloroquine, n (%)4 (67)19 (95)0.057Lopinavir/Ritonavir, n (%)2 (33)5 (25)0.686Antibiotics, n (%) Cephalosporins0 (0)14 (70)0.003 Carbapenem2 (33)9 (45)0.612 Macrolides0 (0)15 (75)0.002 Linezolid0 (0)2 (10)0.420Steroids, n (%)3 (50)9 (45)0.829i.v. Ig, n (%)2 (33)4 (20)0.428Tocilizumab, n (%)2 (33)3 (15)0.322Prophylactic anticoagulation, n (%)1 (17)15 (75)0.015ARDS, n (%)5 (83)5 (25)0.010ARDS, acute respiratory distress syndrome; BP, blood pressure; COPD, chronic obstructive pulmonary disease; GI, gastrointestinal. Open table in a new tab Table 4Cox proportional hazards regression analysis for the main determinants of deathaNumber of events: 13.VariableUnivariableMultivariableHazard ratio (95% CI)PHazard ratio (95% CI)PGender (female vs. male)0.745 (0.081–6.832)0.795Age (<65 vs. ≥65 yr)0.286 (0.010–7.869)0.459Charlson comorbidity index (<7 vs. ≥7)0.736 (0.065–8.293)0.804Systolic BP (<120 vs. ≥120 mm Hg)0.350 (0.035–3.483)0.371Diastolic BP (<60 vs. ≥60 mm Hg)0.467 (0.070–3.108)0.431Oxygen saturation (<90% vs. ≥90%)1.217 (1.069–1.479)0.030CRP (<12 vs. ≥12 mg/dl)1.518 (0.252–9.150)0.649Lymphocyte count (<0.6 vs. ≥0.6 per 1000/mm3)0.812 (0.138–4.790)0.818D-dimer (<1000 vs. ≥1000 ng/ml)0.139 (0.014–1.425)0.096LDH (<240 vs. ≥240 IU/l)1.012 (0.998–1.026)0.104Bilateral CXR involvement (no vs. yes)2.322 (0.229–3.576)0.476ARDS (no vs. yes)4.317 (1.004–8.095)0.0456.801 (2.169–13.46)0.007ARDS, acute respiratory distress syndrome; BP, blood pressure; CI, confidence interval; CRP, C-reactive protein; CXR, chest X-ray; LDH, lactate dehydrogenase.a Number of events: 13. Open table in a new tab ARDS, acute respiratory distress syndrome; BP, blood pressure; COPD, chronic obstructive pulmonary disease; GI, gastrointestinal. ARDS, acute respiratory distress syndrome; BP, blood pressure; COPD, chronic obstructive pulmonary disease; GI, gastrointestinal. ARDS, acute respiratory distress syndrome; BP, blood pressure; CI, confidence interval; CRP, C-reactive protein; CXR, chest X-ray; LDH, lactate dehydrogenase. All cases were admitted to the floor from the emergency department. Although some cases met criteria for intensive care unit admission, none of the patients was accepted because of capacity constraints. At the end of the observation period, 14 patients (7 dialysis patients and 7 KT recipients) were discharged from hospital. In this study, we present early clinical course and outcomes of patients with end-stage renal disease on dialysis and kidney transplantation who developed severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection and required in-hospital management. Although clinical presentation was similar compared with the general population,3Wang D. Hu B. Hu C. et al.Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China.JAMA. 2020; 323: 1061-1069Crossref PubMed Scopus (16387) Google Scholar,4Zhou F. Yu T. Du R. et al.Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study.Lancet. 2020; 6736: 1-9Google Scholar KT recipients seem to present with less fever and more gastrointestinal symptoms (Table 1). In addition, compared with previous reports in which most patients on dialysis reported no obvious symptoms,5Ma Y. Diao B. Lv X. et al.2019 novel coronavirus disease in hemodialysis (HD) patients: report from one HD center in Wuhan, China.medRxiv. 2020; (02.24.20027201): 2020Google Scholar fever and respiratory symptoms were common in our dialysis group. On the other hand, COVID-19 distinctive biochemical alterations described in early reports from China4Zhou F. Yu T. Du R. et al.Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study.Lancet. 2020; 6736: 1-9Google Scholar were comparable to our findings. Elevation of C-reactive protein, lactate dehydrogenase, D-dimer, and lymphopenia were all frequently observed in our study population. Regarding imaging studies, alveolar consolidations were more commonly observed in KT recipients. Previous reports suggested that patients on maintenance hemodialysis with SARS-CoV-2 infection presented with mild disease and a favorable outcome,5Ma Y. Diao B. Lv X. et al.2019 novel coronavirus disease in hemodialysis (HD) patients: report from one HD center in Wuhan, China.medRxiv. 2020; (02.24.20027201): 2020Google Scholar,6Wang R, Liao C, He H, et al. COVID-19 in hemodialysis patients: a report of 5 cases [e-pub ahead of print]. Am J Kidney Dis. https://doi.org/10.1053/j.ajkd.2020.03.009. Accessed April 20, 2020.Google Scholar possibly due to a compromised immune system that would hypothetically limit a striking cytokine release.5Ma Y. Diao B. Lv X. et al.2019 novel coronavirus disease in hemodialysis (HD) patients: report from one HD center in Wuhan, China.medRxiv. 2020; (02.24.20027201): 2020Google Scholar In our experience, this was not the case. Our institution has 208 active hemodialysis patients and 39 peritoneal dialysis patients, of whom 25 (10.1%) required hospital admission and 7 (28%) died from direct complications of COVID-19. This mortality was similar to that of a recently published Italian series.S1 We speculate that older age and a high comorbidity burden, well-known risk factors for worse outcomes in COVID-19, might explain the higher mortality observed in our patients. Although steroid therapy was associated with risk of death, this may be because of a selection bias, as patients with more severe disease were more likely to receive them. Of note, we have frequently observed poor hemodynamic tolerance during intermittent hemodialysis sessions. In the case of renal transplantation, data regarding is as only case reports and series have been published to E, Pineiro GJ, Revuelta I, et al. Case report of COVID-19 in a kidney transplant recipient: does immunosuppression alter the clinical presentation [e-pub ahed of print]? Am J Transplant. https://doi.org/10.1111/ajt.15874. Accessed April 20, 2020.Google Scholar, 8Gandolfini I, Delsante M, Fiaccadori E, et al. COVID-19 in kidney transplant recipients [e-pub ahead of print]. Am J Transplant. https://doi.org/10.1111/ajt.15891. Accessed April 20, 2020.Google Scholar, 9Zhu L, Xu X, Ma K, et al. Successful recovery of COVID-19 pneumonia in a renal transplant recipient with long-term immunosuppression [e-pub ahead of print]. Am J Transplant. https://doi.org/10.1111/ajt.15869. Accessed April 20, 2020.Google Our transplant has KT patients in active follow-up and required hospital admission the study period. Of 6 of 26 died of direct complications of COVID-19. Although KT patients who died were is chronic immunosuppression therapy the presentation and course of SARS-CoV-2 Our included reduction of immunosuppression on of mammalian target of rapamycin tacrolimus and low-dose no or development of were observed. development of ARDS was a common risk for death in both groups. None of the patients was admitted to the intensive care is to speculate that the to intensive care have the of some patients who eventually died. a series reported outcomes in KT patients with COVID-19 who required is to that of our analysis be with because of the Of note, with hydroxychloroquine and prophylactic anticoagulation were more commonly in KT a in this group (Table 3). because of the retrospective of our and the of our study no be In this is one of the series to report initial clinical presentation and outcomes of COVID-19 in patients with end-stage renal disease and kidney transplantation who required admission. mortality in dialysis and KT patients with SARS-CoV-2 infection was higher of ARDS was a risk for mortality in both groups. All the no The the of the of and with

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