Introduction
The disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; coronavirus disease 2019 [COVID-19 ]), in addition to the known tropism to the respiratory epithelium, can also affect the kidneys, heart, and the digestive tract, among others (1 2 3 4 5–6 7
Several abnormalities have been identified in the kidney tissue of deceased patients with AKI and COVID-19 , mostly diffuse acute tubular injury (ATI) with cytoplasmic vacuoles (8 9 9 10 9 9 11 11
The objective of this study was to identify the histopathologic characteristics of patients who died from COVID-19 and evaluate the association with clinical variables, including AKI severity.
Materials and Methods
Study Design
This is a multicenter, observational cohort study. We prospectively included adult critically ill patients with diagnosis of COVID-19 by positive PCR for SARS-CoV-2 or with high clinical suspicion, including COVID-19 Reporting and Data System 5 (predominant basal and peripheral multifocal ground glass opacities with or without consolidations) by computed tomography, who died between March and June 2020 in three hospitals in Mexico City. Clinical characteristics were retrospectively obtained from medical records. AKI was defined according to Kidney Disease Improving Global Outcomes guidelines only on the basis of serum creatinine, and AKI stages 2 and 3 were considered as severe AKI. Kidney function recovery prior to death was clinically defined as returning to baseline creatinine or minimum serum creatinine, having lower than half of peak serum creatinine, and being free from KRT, all of them at the end of follow-up prior to their fatal outcome. The research was approved by the ethics committee of each institution (DI/20/105 B/03/60). Informed consent was obtained from the responsible guardians for all patients.
Biopsy Procedure
Biopsies were performed in the autopsy room in one institution within the facilities of the pathology department, with a median time from death to biopsy of 4 (4–8) hours, and inside the intensive care unit in the other two centers, having a median time from death to biopsy of 1 (1–2) hour. In all cases, they were performed by a trained nephrologist by ultrasound scanning and a BARD MONOPTY Disposable Core Biopsy Instrument 16 gauge × 22 cm, placing the specimen in a sterile bottle with 4% formaldehyde. The use of personal protective equipment was carried out by World Health Organization recommendations and supervised by the institution.
Histopathologic Analyses
Kidney specimens were processed for paraffin block fixation; findings were described by direct light microscopy. Four techniques were used (hematoxylin and eosin, Masson trichrome, periodic acid–Schiff, and silver methenamine) using the Olympus BX51 Microscope and the VF Evolution C camera (Media-Cybernetics). Analysis was also carried out by EM. The nephropathologist was blinded to the clinical characteristics of the patients (Supplemental Material
Statistical Analyses
The data were captured in Microsoft Office Excel, maintaining the confidentiality of the participants by assigning an internal code for each institution. Variables were expressed as numbers and proportions for categorical data and as medians with 25th to 75th percentiles for continuous variables. Patients with inadequate tissue or without serum creatinine were excluded. Other data on continuous variables for clinical characteristics were imputed by their median value if <20% were missing; otherwise, these variables were not considered. Categorical missing values were not imputed. Serum albumin, d -dimer, creatin kinase, and C-reactive protein had <20% of missing values, whereas IL-6 had >50%; therefore, it was excluded. Analyses by groups (severe AKI) were obtained through chi-squared and t tests or the Mann–Whitney U test according to their distribution. Receiver operating characteristic curves were constructed to analyze cutoff points for continuous variables. Unadjusted and multivariable logistic regression analyses were performed. Forest plots were constructed for displaying odd ratios between clinical and histopathologic characteristics. No sample size was calculated; we analyzed the full available population with these criteria in the period. The SPSS program version 23.0 was used.
Results
Six hundred and twenty-three patients with confirmed or suspected COVID-19 died in all three hospitals in the time interval of the study. Limited information from the mortality registries available showed a median age of 58 (49–65) years, that 76% were men, and that 28% had diabetes. Eighty-nine patients were included in the study and underwent kidney biopsy; three patients were excluded due to their degree of autolysis, and one was excluded due to missing data.
Clinical Characteristics
A total of 85 patients were analyzed. Clinical data are provided in Supplemental Table 1 2 , 43 (51%) had diabetes, and 39 (46%) had chronic hypertension. All patients required invasive mechanical ventilation, 70 (82%) received vasopressors, 83 (98%) were treated with anticoagulants (43% prophylactic and 53% therapeutic dose), 56 (66%) were treated with steroids, and 30 (35%) received at least one potential nephrotoxic medication. In-hospital superimposed bacterial infections were present in 45 (53%) patients, and 40 (47%) patients fulfilled septic shock criteria. Main final diagnosis was acute respiratory distress syndrome due to COVID-19 , and median hospital length of stay was 11 (7–17) days.
AKI was present in 85% of patients, whereas 54% had severe AKI and 31% had AKI stage 1. A total of 18% required KRT. Among patients with severe AKI, 83% had no kidney function recovery, whereas 9% showed partial recovery and 9% showed complete recovery at their last evaluation.
Histopathologic Characteristics
Biopsy findings are summarized in Tables 1 and 2 . A median of 26 (13–51) glomeruli were observed per patient, and 6% (0–11) had global sclerosis. Pathology descriptions included 25 (29%) with FSGS, 17 of them (68%) having the perihilar variant (with no cases of collapsing glomerulopathy); 23 (27%) with diabetic nephropathy; 24 (28%) with glomerulomegaly; and 69 (81%) with arteriosclerosis. Additionally, eleven (13%) had interstitial fibrosis/tubular atrophy grades 2–3, five (6%) showed amyloid deposits, one (1%) had IgA nephropathy, and one (1%) had neoplastic infiltration from leukemia.
Table 1. -
Tubulointerstitial light microscopy
Tubulointerstitium
Total, n =85
Severe AKI, n =46
No Severe AKI, n =39
Acute tubular injury
Mild
36 (42)
17 (37)
19 (49)
Moderate
27 (32)
13 (28)
14 (36)
Severe
15 (18)
11 (24)
4 (10)
Bacterial foci
4 (5)
3 (6)
1 (3)
Protein casts
52 (61)
27 (59)
25 (64)
Molding casts
21 (25)
12 (26)
9 (23)
Pigment casts
46 (54)
24 (52)
22 (56)
Cytoplasmatic pigments
50 (59)
25 (54)
25 (64)
Syncytium
24 (28)
15 (33)
9 (23)
Regeneration
Mild
48 (56)
25 (54)
23 (59)
Moderate
28 (33)
14 (30)
14 (36)
Severe
6 (7)
4 (9)
2 (5)
Isometric vacuolation
66 (78)
38 (83)
28 (72)
Microthrombosis
2 (2)
1 (2)
1 (3)
TA/IF
0
32 (38)
19 (41)
13 (33)
1
38 (45)
17 (37)
21 (54)
2
9 (11)
7 (15)
2 (5)
3
2 (2)
0 (0)
2 (5)
Tubulointerstitial nephritis
6 (7)
4 (9)
2 (5)
Data are expressed as n (%). TA/IF, tubular atrophy/interstitial fibrosis.
Table 2. -
Glomerular light microscopy and electron microscopy
Histopathological Findings
Total, n =85
Severe AKI, n =46
No Severe AKI, n =39
Glomeruli
No. of glomeruli
26 (13–51)
20 (13–41)
32 (13–60)
Global sclerosis (%)
6 (0–10)
6 (0–13)
4 (2–8)
Segmental sclerosis (%)
0 (0–7)
0 (0–0)
0 (0–13)
Focal segmental sclerosis variant
Perihilar
17 (20)
9 (20)
8 (20)
Tip lesion
4 (5)
0 (0)
4 (10)
Not otherwise specified
4 (5)
1 (2)
3 (8)
Hypoperfusion
46 (54)
21 (46)
25 (64)
Diabetic nephropathy
DGP class IIA
5 (6)
1 (2)
4 (10)
DGP class IIB
11 (13)
7 (15)
4 (10)
DGP class III
7 (8)
3 (6)
4 (10)
Glomerulomegaly
24 (28)
11 (24)
13 (33)
Thrombotic microangiopathy
6 (7)
2 (4)
4 (10)
Arteriosclerosis
69 (81)
38 (83)
31 (79)
Electron microscopy
Loss of tubular epithelium
50 (59)
25 (54)
25 (64)
Mitochondrial edema
63 (74)
37 (80)
26 (67)
Multivesicular bodies
37 (43)
18 (39)
19 (49)
Clathrin-coated structures
28 (33)
11 (24)
17 (44)
Podocyte foot processes edema
13 (15)
7 (15)
6 (15)
Endothelial edema
15 (18)
8 (17)
7 (18)
GBM thickening
20 (23)
9 (20)
11 (28)
Mesangial sclerosis
17 (20)
9 (20)
8 (20)
Data are expressed as median (25th to 75th) or as n (%). DGP, diabetic glomerulopathy; GBM, glomerular basement membrane.
On light microscopy (Figure 1 ), ATI grades 2–3 were observed in 42 (49%), casts were found in 65 (77%), cytoplasmic pigments were found in 50 (59%), isometric vacuolation was found in 66 (78%), and glomerular hypoperfusion was found in 46 (54%). Acute tubulointerstitial nephritis (AIN) was seen in six (7%), interstitial microthrombosis was seen in two (2%), and thrombotic microangiopathy (TMA) was seen in six (7%) patients.
Figure 1.: Acute tubular injury in kidney biopsies of patients with COVID-19 . (A) Acute tubular injury with retraction of glomerular capillaries, tubular lumen with proteinaceous cylinders, and regenerative changes in the tubular epithelium and syncitial cells (periodic acid–Schiff, ×10). (B and C) Tubular lumen with pigmented casts and loss of brush borders (hematoxylin and eosin, ×40 and Masson trichrome, ×40). (D) Tubular isometric vacuolization with debris in tubular lumen (Masson trichrome, ×40).
On EM (Figure 2 ), the most frequent findings were loss of tubular epithelium (59%), mitochondrial edema (74%), and multivesicular bodies (44%); also, 33% had clathrin-coated structures.
Figure 2.: Ultraestructural features on electron microscopy in kidney biopsies of patients with COVID-19 . Multivesicular bodies and clathrin-coated vesicles into endothelial cells of the kidney (transmission electron microscopy: magnification, (A) ×5000 and (B) ×20,000).
Clinical and Histopathologic Characteristics Associated with Severe AKI
Medications, such as steroids, vancomycin, and vasopressors, and superimposed bacterial infections were associated with severe AKI (P =0.05) (Supplemental Table 1 Tables 1 and 2 show the association with biopsy findings, where only the percentage of segmental sclerosis was related to severe AKI. In multivariable models, only superimposed bacterial infections (odds ratio [OR], 2.48; 95% confidence interval [95% CI], 0.94 to 6.57), vancomycin (OR, 3.56; 95% CI, 0.86 to 14.78), and vasopressors (OR, 3.58; 95% CI, 0.94 to 13.62) showed a trend for risk of severe AKI. In the multivariable analysis for kidney function recovery before death, pigment casts were associated with a significantly lower probability of kidney recovery (OR, 0.07; 95% CI, 0.01 to 0.77).
Clinical Characteristics Associated with Histopathologic Findings
Figure 3 shows the forest plots for relevant ORs. The use of amikacin, gentamycin, or colistin showed a trend toward increasing the presence of molding casts, pigment casts, and ATI on light microscopy and loss of tubular epithelium on EM. High levels of C-reactive protein and low serum albumin were associated with ATI, glomerular hypoperfusion, and clathrin-coated structures on EM. Previous use of angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers was associated with loss of tubular epithelium on EM, and full dose of anticoagulants showed a reduction in ATI on light microscopy and a reduction in clathrin-coated structures on EM.
Figure 3.: Forest plots for add ratios between clinical variables and biopsy findings. (A) Molding casts; (B) pigment casts; (C) Clathrin-coated structures; (D) glomerular hypoperfusion; (E) acute tubular injury; (F) loss of tubular epitelium. AMK, amikacin; CLS, colistin; EM, electron microscopy; GNT, gentamicin.
Finally, all cases with AIN were present in subjects receiving antiviral medication (either lopinavir/ritonavir or oseltamivir), and all patients who were treated with nonsteroid anti-inflammatory drugs showed glomerular hypoperfusion (data not shown).
Discussion
We present the largest postmortem kidney biopsy series to date (Table 3 ). Santoriello et al. (11 COVID-19 (4 12 13 et al. (14 et al. (11 et al. (9 et al. (15
Table 3. -
Published studies on kidney histopathology analysis in coronavirus disease 2019
Histopathological Findings
Study
Akilesh et al. (19 )
Bradley et al. (15 )
Bryce et al. (unpublished observations)
Golmai et al. (8 )
Hanley et al. (24 )
Kudose et al. (21 )
Nasr et al. (20 )
Remmelink et al. (14 )
Santoriello et al. (11 )
Sharma et al. (22 )
Su et al. (9 )
Country
USA
USA
USA
USA
UK
USA
USA
Belgium
USA
USA
China
Sample
Biopsies
Autopsies
Autopsies
Biopsies
Autopsies
Biopsies
Biopsies
Autopsies
Autopsies
Biopsies
Autopsies
N
17
14
25
12
9
17
13
17
42
10
26
Age, yr
54 (34–77)
73 (67–77)
69 (34–94)
75 (57–77)
73 (52–79)
54 (22–72)
52
72 (62–77)
71 (38–97)
66 (60–69)
69 (39–87)
Hypertension, %
82
71
63
75
40
65
85
59
73
70
55
Diabetes, %
29
36
40
33
20
18
46
53
42
30
15
CKD, %
NA
57
27
8
10
NA
44
NA
29
0
10
AKI, %
88
43
NA
100
NA
88
100
82
94
100
35
FSGS, %
65
7
0
NA
0
35
62
NA
3
10
8
Diabetic nephropathy, %
12
21
8
8
0
NA
23
NA
17
10
8
Arteriosclerosis, %
NA
79
NA
83
83
50
77
NA
85
80
69
ATI, %
82
79
24
100
100
71
100
NA
62
100
100
GN, %
18
NA
0
0
0
71
31
NA
NA
10
0
TMA, %
35
NA
0
0
17
NA
0
0
14
20
12
USA, United States; UK, United Kingdom; N , number; NA, not available; ATI, acute tubular injury; TMA, thrombotic microangiopathy.
Our findings revealed no evidence of collapsing or postinfectious glomerulopathies. Series of case reports from one to six patients have described collapsing glomerulopathy in COVID-19 ; however, most of them linked to the Black population with a high-risk allele genotype for apoL1 or in the context of transplant recipients, which may explain why these findings were not prevalent in other reports, including our Hispanic patients (16 17–18 et al. (19 COVID-19 , 88% had AKI and 65% with heavy proteinuria as criteria for biopsy, seven patients (41%) had collapsing glomerulopathy, six of them with Black race and one of them had this diagnosis 3 years before. Nasr et al. (20 COVID-19 (only one required intubation) who underwent biopsy due to AKI (92% severe) and nephrotic-range proteinuria (85%); eight (61%) had collapsing glomerulopathy, and all of them were Black patients. Although direct immunofluorescence analysis was not performed, the EM allowed us to confirm an absence of immune complexes. Kudose et al. (21 COVID-19 , and there were other indications for biopsy, including 52.9% had nephrotic-range proteinuria and 17.6% had kidney transplantation. Additionally, Sharma et al. (22 COVID-19 only in case of a clinical glomerular syndrome (nephrotic, nephritic, or rapid progressive GN) or a suggestive urine sediment, as usual.
The presence of TMA in diverse organs, including kidneys, has been reported (23 8 9 11 14 et al. (19 COVID-19 , with a sampling range from 3 days up to 7 weeks from COVID-19 diagnosis; however, patients had severe hypertension, and four of six had clinically overt TMA, which was part of the criteria for kidney biopsy. Finally, 75% of the latter had additional conditions that may have contributed to TMA (cytotoxic or illicit drugs) as stated by the authors (19
We believe the presence of FSGS in our population could be associated with comorbidities and not necessarily with the virus. In a subanalysis, we explored the association between FSGS excluding tip variant and the rest of histopathologic and clinical characteristics. Although diabetes, diabetic glomerulopathy, arteriosclerosis, and glomerular basement membrane thickening seemed more prevalent in the FSGS group, they did not reach statistical significance; however, glomerulomegaly was present in 52% with FSGS versus 20% (P =0.005), and the interstitial fibrosis/tubular atrophy score was also higher in the FSGS group (P =0.05) (Supplemental Table 2 et al. (21 et al. (19 et al. (20 19 20–21 et al. [24 COVID-19 (7 25 26
In the EM, mitochondrial edema and loss of the tubular epithelium were observed in the vast majority, similar to other series (9 11 22 27 et al. (15 et al. (9 in situ hybridization, Kudose et al. (21 et al. (14 et al. (24 et al. (15
Until now, studies have focused on the histopathologic description (9 22 28 COVID-19 critically ill patients, so this information might be useful in the context of other forms of AKI, including septic AKI. Other well-known contributors for AKI as invasive mechanical ventilation and hemodynamic instability could not be evaluated as they were common denominators in our population (7 29 30–31 COVID-19 studies with 70.6%–100%; contrary to this, in patients who are septic, some reports account for 20%–30% of ATI (32 33
Our study has some other limitations. First, our patients were all critically ill and required mechanical ventilation; therefore, our findings may not be generalizable to other cohorts with COVID-19 . Second, we did not have any other valuable method for identification of the virus in kidney tissue, such as antibodies against SARS-CoV-2. Finally, we do not have measurements of proinflammatory cytokines and viral load in most of the cases. Our main strength relies on our sample size and having EM in all cases.
In conclusion, kidney biopsies in deceased patients with COVID-19 in the Mexican population showed a higher than expected prevalence of chronic histopathologic disease, and inflammatory markers and medications might be associated with some acute biopsy findings.
Disclosures
M. Madero reports employment with Instituto Nacional de Cardiologia Ignacio Chavez; receiving research funding from Abbvie, AstraZeneca, Bayer, and Boehringer; receiving honoraria from AstraZeneca, Bayer, and Fresenius Medical Center; serving as a scientific advisor or member of American Journal of Kidney Disease , the International Society of Nephrology, and the Kidney Disease Improving Global Outcomes Executive Committee; and serving on advisory boards of Abbvie, AstraZeneca, and Bayer. G. Rojas reports employment with Instituto Nacional de Cardiología Ignacio Chávez; consultancy agreements with Boehringer Ingelheim and Eli Lilly; research funding from Eli Lilly; honoraria from Boehringer Ingelheim; and speakers bureau for Boehringer Ingelheim and Eli Lilly. R. Valdez-Ortiz reports employment with Hospital General de Mexico Dr. Eduardo Liceaga; consultancy agreements with Alexion, Amgen, AstraZeneca, Bayer, and Novartis; receiving research funding from Alexion, AstraZeneca, and Bayer; speakers bureau for Alexion, AstraZeneca, and Bayer; and other interests/relationships with the Colegio Mexicano de Nefrología, Instituto Mexicano de Investigaciones Nefrológicas, and the International Society of Nephrology. A. Vazquez-Rangel reports consultancy agreements with Baxter, BBraun, and Medtronic; honoraria from Baxter, BBraun, and Medtronic; and speakers bureau for Baxter, BBraun, and Medtronic. C. Zabal reports serving as a consultant to Abbott. All remaining authors have nothing to disclose.
Funding
Publication fee was funded by the Instituto Nacional de Cardiología-Ignacio Chávez.
Acknowledgments
The authors appreciate all of the hospital staff members for their efforts in recruiting and treating patients and thank all patients involved in this study.
Supplemental Material
This article contains the following supplemental material online at http://cjasn.asnjournals.org/lookup/suppl/doi:10.2215/CJN.16281020/-/DCSupplemental
Supplemental Table 1
Supplemental Table 2
Supplemental Material
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