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.