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

Abstract

INTRODUCTION 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 [1]. Actual case fatality ratio is still unknown but some studies have reported ranges between 1.4%—3.8% [2]. Clinical features and outcomes of patients with COVID-19 have been published in previous studies [3,4], 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 [[5], [6], [7], [8], [9]]. In this report, we describe our experience with 51 patients with end-stage renal disease on dialysis (n = 25) and renal transplantation (n = 26) that developed COVID-19 and required hospital admission. RESULTS The study group consisted of 51 patients with a mean age of 64±15 years, 57% males. 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 (MMF) in 14 (54%) and mammalian target of rapamycin inhibitors (mTORi) in 7 (27%). Table 1 Baseline characteristics of the study population. Total (n=51) Dialysis (n=25) Kidney transplantation (n=26) Baseline Age, years 64±15 66±15 61±14 Sex, male (%) 29 (57) 17 (68) 12 (46) Charlson comorbidity index 7 [[4], [5], [6], [7], [8]] 8 [[6], [7], [8], [9]] 4 [[3], [4], [5], [6], [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, days 1 [[1], [2], [3], [4]] 1 [[1], [2], [3]] 3 [[1], [2], [3], [4], [5], [6], [7]] Systolic BP, mmHg 126±27 122±30 129±23 Diastolic BP, mmHg 68±16 60±11 74±18 Oxygen saturation ≤90%, N (%) 8 (16) 4 (16) 4 (15) Temperature, º C 37.7±0.9 37.8±0.9 37.6±1 Fever, N (%) 28 (55) 16 (64) 12 (46) Asthenia/myalgia 10 (19) 6 (24) 4 (15) Non-productive 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-65 2±1.1 2.1±1.2 1.9±1 SOAR 1.4±1.2 1.4±1.2 1.3±1 Laboratory Serum creatinine, mg/dl 2.3 [1.6–4.1] 5 [2.8–7.6] 1.9 [1.5–2.4] Serum albumin, g/dl 3.7±0.5 3.6±0.6 3.7±0.4 Lactate dehydrogenase, IU/l 313±100 310±101 312±97 C-reactive protein, mg/dl 11 [4–21] 8 [2–20] 13 [6–23] Hemoglobin, g/dl 11.5±2 11.1±2 12±2 Lymphocytes, per 1000/mm3 0.6 [0.4–0.9] 0.5 [0.3–0.8] 0.7 [0.4-1.1] D-dimer, ng/ml 1078 [588-1282] 1106 [635-1644] 822 [506-1180] Chest radiology Ground glass opacities, N (%) 31 (61) 15 (60) 16 (62) Alveolar consolidations, N (%) 22 (43) 8 (32) 14 (54) Bilateral involvement, N (%) 33 (65) 16 (64) 17 (65) Pleural effusion, N (%) 3 (6) 0 (0) 3 (12) Treatment regimens and Outcomes Hydroxychloroquine, N (%) 47 (92) 24 (96) 23 (86) Lopinavir/Ritonavir, N (%) 19 (37) 12 (48) 7 (27) Antibiotics, N (%)Amoxycillin/clavulanic acidCephalosporinesCarbapenemMacrolidesLinezolid 1 (2)31 (61)20 (39)30 (58)6 (12) 1 (4)17 (68)9 (33)15 (60)4 (16) 0 (0)14 (54)11 (42)15 (58)2 (8) Steroids, N (%) 22 (43) 10 (40) 12 (46) Interferon beta 1b, N (%) 3 (6) 3 (11) 0 (0) Tocilizumab, N (%) 6 (11) 1 (4) 5 (19) IVIG, N (%) 6 (11) 0 (0) 6 (23) Prophylactic anticoagulation, N (%) 33 (65) 17 (68) 16 (62) Follow-up time, days 13±7 12±6 14±7 ARDS, N (%) 20 (39) 10 (40) 10 (39) Death, N (%) 13 (26) 7 (28) 6 (23) Data is presented as mean±SD, or median (IQR). Abbreviations: ARDS: acute respiratory distress syndrome; BP: blood pressure; COPD: Chronic obstructive pulmonary disease; GI: gastrointestinal; IVIG: intravenous immunoglobulin; Clinical presentation of COVID-19 was similar in both groups, and was characterized by fever (55%), non-productive cough (64%), dyspnea (49%), gastrointestinal symptoms (28%) and asthenia/myalgias (19%). Median time (IQR) 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 (LDH) elevation, high C-reactive protein (CRP), D-dimer elevation, and a moderate decrease in the lymphocyte count. Sixty-nine percent of KT patients had acute kidney injury on admission. According to AKIN classification, 14/18 (78%) were AKIN 1 and 4/18 (22%) 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 (CXR) 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 due to 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 intravenous steroids (methylprednisolone 0.5mg/kg once or twice daily), 6% received interferon beta 1b, 11% tocilizumab and 11% intravenous immunoglobulin (IVIG). All patients received antibiotics, mainly cephalosporines (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 the majority of cases: MMF was stopped in 13 cases (50%), tacrolimus in 4 (15%) and mTORi in 2 (8%). Although only 8 cases had oxygen saturation ≤90% at presentation, 45/51 (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 (IQR) 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 CRP, 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 2 Clinical characteristics of dialysis patients according to outcome. Dialysis patients who died (n=7) Dialysis patients who survived (n=18) p Baseline Age, years 77±12 62±14 0.023 Sex, male (%) 6 (86) 11 (61) 0.246 Race/ethnicity, N (%)CaucasianHispanicAsian 5 (71)2 (29)0 (0) 15 (83)2 (11)1 (6) 0.785 Charlson comorbidity index 9 [[7], [8], [9], [10]] 8 [[4], [5], [6], [7], [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, years 2 (2–5) 5 (3–6) 0.258 Clinical presentation Diagnosis delay from the onset of symptoms, days 2 [[1], [2], [3]] 1 [[1], [2]] 0.329 Systolic BP, mmHg 102±21 131±30 0.023 Diastolic BP, mmHg 54±7 64±12 0.071 Oxygen saturation ≤90%, N (%) 2 (29) 2 (11) 0.307 Fever, N (%) 4 (57) 12 (67) 0.499 Asthenia/myalgia 1 (14) 5 (28) 0.443 Non-productive 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) 0.155 Pneumonia severity scores CURB-65 3.3±1.3 1.7±0.8 0.001 SOAR 3.3±0.8 0.7±0.8 0.001 Laboratory Serum creatinine, mg/dl 6.8 [2.3–7.7] 4.2 [2.9–8.3] 0.893 Serum albumin, g/dl 3.3±0.7 3.7±0.6 0.096 Lactate dehydrogenase, IU/l 341±65 302±116 0.412 C-reactive protein, mg/dl 23 [11–32] 4 [1–12] 0.002 Hemoglobin, g/dl 11.1±1 11.1±2 0.973 Lymphocytes, per 1000/mm3 0.4 [0.3–0.6] 0.7 [0.4–0.9] 0.085 D-dimer, ng/ml 1231 [594-1558] 1078 [624–1614] 0.940 Chest radiology Ground glass opacities, N (%) 6 (86) 9 (50) 0.118 Alveolar consolidations, N (%) 2 (29) 6 (35) 0.572 Bilateral involvement, N (%) 6 (86) 10 (56) 0.174 Treatment regimens and Outcomes Hydroxychloroquine, N (%) 6 (86) 18 (100) 0.109 Lopinavir/Ritonavir, N (%) 4 (57) 8 (44) 0.568 Antibiotics, N (%)Amoxycillin/clavulanic acidCephalosporinesCarbapenemMacrolidesLinezolid 0 (0)3 (43)3 (43)4 (57)0 (0) 1 (6)14 (78)6 (33)11 (61)4 (22) 0.7200.1160.4990.6010.242 Steroids, N (%) 6 (86) 4 (22) 0.004 Interferon beta 1b, N (%) 1 (14) 2 (11) 0.826 Tocilizumab, N (%) 0 (0) 1 (6) 0.524 Prophylactic anticoagulation, N (%) 5 (71) 12 (66) 0.278 ARDS, N (%) 6 (86) 4 (22) 0.004 Abbreviations: ARDS: acute respiratory distress syndrome; BP: blood pressure; COPD: Chronic obstructive pulmonary disease; GI: gastrointestinal; Table 3 Clinical characteristics of kidney transplant patients according to outcome. Kidney transplant patients who died (n=6) Kidney transplant patients who survived (n=20) p Baseline Age, years 70±13 58±13 0.070 Sex, male (%) 2 (33) 10 (50) 0.473 Race/ethnicity, N (%)CaucasianHispanicAsian 6 (100)0 (0)0 (0) 16 (80)4 (20)0 (0) 0.234 Charlson comorbidity index 7 [[4], [5], [6], [7], [8]] 4 [[2], [3], [4], [5], [6], [7]] 0.139 Hypertension, N (%) 6 (100) 18 (100) 0.420 Diabetes mellitus, N (%) 0 (0) 6 (30) 0.134 Liver disease, N (%) 0 (0) 2 (10) 0.585 COPD, N (%) 1 (17) 1 (5) 0.347 Hypothyroidism, N (%) 3 (50) 4 (20) 0.146 Time from transplant, years 9 (6–15) 7 (4–15) 0.744 Clinical presentation Diagnosis delay from the onset of symptoms, days 2 [[1], [2], [3], [4], [5], [6], [7], [8]] 4 [1], [2], [3], [4], [5], [6], [7] 0.519 Systolic BP, mmHg 118±22 133±23 0.176 Diastolic BP, mmHg 70±20 76±17 0.549 Oxygen saturation ≤90%, N (%) 3 (50) 1 (5) 0.007 Fever, N (%) 2 (33) 10 (50) 0.473 Asthenia/myalgia 0 (0) 4 (20) 0.234 Non-productive cough, N (%) 3 (50) 14 (70) 0.366 Productive cough, N (%) 1 (17) 5 (20) 0.657 Dyspnea, N (%) 6 (100) 9 (45) 0.017 GI symptoms, N (%) 2 (33) 8 (40) 0.664 Pneumonia severity scores CURB-65 2.5±1.5 1.7±0.8 0.110 SOAR 2.8±0.7 0.8±0.6 0.001 Laboratory Serum creatinine, mg/dl 1.9 [1.4–3.1] 1.9 [1.5–2.3] 0.929 Serum albumin, g/dl 3.5±0.6 3.8±0.3 0.420 Lactate dehydrogenase, IU/l 372±74 295±98 0.089 C-reactive protein, mg/dl 14 [13–28] 10 [3.8–22] 0.196 Hemoglobin, g/dl 11.3±2.8 12.3±1.8 0.429 Lymphocytes, per 1000/mm3 0.8 [0.5–3.6] 0.7 [0.4–1.1] 0.533 D-dimer, ng/ml 1282 [468-1782] 947 [564-1282] 0.573 Chest radiology Ground glass opacities, N (%) 5 (83) 11 (55) 0.211 Alveolar consolidations, N (%) 2 (33) 12 (60) 0.250 Bilateral involvement, N (%) 4 (67) 13 (65) 0.940 Pleural effusion, N (%) 1 (17) 2 (10) 0.654 Treatment regimens and Outcomes Hydroxychloroquine, N (%) 4 (67) 19 (95) 0.057 Lopinavir/Ritonavir, N (%) 2 (33) 5 (25) 0.686 Antibiotics, N (%)CephalosporinesCarbapenemMacrolidesLinezolid 0 (0)2 (33)0 (0)0 (0) 14 (70)9 (45)15 (75)2 (10) 0.0030.6120.0020.420 Steroids, N (%) 3 (50) 9 (45) 0.829 IVIG, N (%) 2 (33) 4 (20) 0.428 Tocilizumab, N (%) 2 (33) 3 (15) 0.322 Prophylactic anticoagulation, N (%) 1 (17) 15 (75) 0.015 ARDS, N (%) 5 (83) 5 (25) 0.010 Abbreviations: ARDS: acute respiratory distress syndrome; BP: blood pressure; COPD: chronic obstructive pulmonary disease; GI: gastrointestinal; IVIG: intravenous immunoglobulin; Table 4 Cox proportional hazards regression analysis for the main determinants of death*. Univariable Multivariable Variable Hazard ratio (95% CI) P Hazard ratio (95% CI) P Gender (female vs male) 0.745 (0.081-6.832) 0.795 Age (<65 vs ≥65 years) 0.286 (0.010-7.869) 0.459 Charlson comorbidity index (<7 vs ≥7) 0.736 (0.065-8.293) 0.804 Systolic BP (<120 vs ≥120 mmHg) 0.350 (0.035-3.483) 0.371 Diastolic BP (<60 vs ≥60 mmHg) 0.467 (0.070-3.108) 0.431 Oxygen saturation (<90 vs ≥90%) 1.217 (1.069-1.479) 0.030 CRP (<12 vs ≥12 mg/dl) 1.518 (0.252-9.150) 0.649 Lymphocyte count (<0.6 vs ≥0.6 per 1000/mm3) 0.812 (0.138-4.790) 0.818 D-dimer (<1000 vs ≥1000 ng/ml) 0.139 (0.014-1.425) 0.096 LDH (<240 vs ≥240 IU/l) 1.012 (0.998-1.026) 0.104 Bilateral CXR involvement (no vs yes) 2.322 (0.229-3.576) 0.476 ARDS (no vs yes) 4.317 (1.004-8.095) 0.045 6.801 (2.169-13.46) 0.007 * Number of events: 13 Abbreviations: ARDS: acute respiratory distress syndrome; BP: blood pressure; CRP: C-reactive protein; CXR: chest X-ray; LDH: lactate dehydrogenase; vs: versus; All cases were admitted to the floor from the emergency department. Although some cases met criteria for ICU admission, none of the patients was accepted due to capacity constraints. At the end of the observation period, 14 patients (7 dialysis patients and 7 KT recipients) were discharged from hospital. DISCUSSION 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 to the general population [3,4], KT patients seem to present with less fever and more gastrointestinal symptoms ( Table 1 ). Additionally, compared to previous reports where the majority of patients on dialysis reported no obvious symptoms [5], fever and respiratory symptoms were common in our dialysis group. On the other hand, COVID-19 distinctive biochemical alterations described in early reports from China [4] were comparable to our findings. Elevation of CRP, LDH, D-dimer and lymphopenia were all frequently observed in our study population. Regarding imaging studies, alveolar consolidations were more commonly observed in KT patients. Previous reports suggested that patients on maintenance hemodialysis with SARS-CoV-2 infection presented with mild disease and a favorable outcome [5,6], possibly due to a compromised immune system that would hypothetically limit a striking cytokine release [5]. 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 [10]. 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 due to 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 SARS-CoV-2 associated lethality is very limited as only case reports and small series have been published to date [[7], [8], [9], [10]]. Our transplant clinic has approximately 2,500 KT patients in active follow-up and less than 1% required hospital admission throughout the study period. Of those, 6/23 (23%) died from direct complications of COVID-19. Although non-significant, KT patients who died were numerically older. It is unknown if chronic immunosuppression therapy modifies the presentation and course of SARS-CoV-2 infection. Our local protocol included partial reduction of immunosuppression based on interruption of antimetabolites (mycophenolate mofetil/azathioprine) and/or mTORi, reducing tacrolimus dose (25-50%, trough levels 5-6ng/mL) and continue low-dose prednisone (2.5-5mg/day). Notably, no rejection episodes or development of donor specific antibodies were observed. Not surprisingly, development of ARDS was a common risk factor for death in both groups. None of the patients was admitted to ICU, therefore; we tempt to speculate that the inability to attain advanced intensive care support could have influence the outcome of some patients who eventually died. However, a recent small series reported variable outcomes in KT patients with COVID-19 that required mechanical ventilation [11]. It is important to point out that results of our multivariate analysis should be interpreted with caution due to the small sample size. Of note, treatment with hydroxychloroquine and prophylactic anticoagulation were more commonly administered in kidney transplant survivors, suggesting a hypothetical protective role in this group ( Table 3 ). However, due to the retrospective nature of our work and the size of our study population, no causal relationships can be established. In conclusion, this is one of the largest series to report initial clinical presentation and outcomes of COVID-19 in patients with end-stage renal disease and kidney transplantation that required admission. In-hospital mortality in dialysis and kidney transplant patients with SARS-CoV-2 infection was higher than previously reported. Development of ARDS was a risk factor for mortality in both groups. CONFLICT OF INTEREST None declared.