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Kidney Transplantation in Patients With SARS-CoV-2 Infection: A Case Series Report

Viana, Laila A. MD1; Cristelli, Marina P. MD1; Ficher, Klaus N. MD1; Rezende, Juliana T. MD1; Villanueva, Lucía A.A. MD1; Santos, Daniel W.C.L. MD1; Fernandes, Ruan MD1; Foresto, Renato D. MD1; Tedesco-Silva, Helio PhD1; Medina-Pestana, José PhD11

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doi: 10.1097/TP.0000000000003521
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To the Editor:

The first confirmed case of coronavirus disease 2019 (COVID-19) in Brazil was reported on February 26. Since then, transplant centers have been implementing recommendations to maintain organ procurement and transplantation.1,2 While postponing living-donor kidney transplant (KT) was an obvious strategy, recommendations for deceased donors and potential recipients were more challenging due to the heterogeneities and rapidly changing local epidemiology, access to polymerase chain reaction (PCR) severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) test and fast laboratory turnaround time.1,3

From February 26 to April 6, when the number of patients with COVID-19 in the city of Sao Paulo was still incipient, we performed 111 KTs. At that time, we considered safe to perform transplants in asymptomatic patients with no epidemiology for COVID-19 plus and with a high-resolution chest computer tomography (CT) excluding pulmonary lesions associated with the disease. Since April 6, as the number of patients with COVID-19 increased, we started screening potential deceased donors before organ recovery using a validated real-time PCR (RT-PCR) test with nasopharyngeal samples. From April 6 to April 19, 36 KTs were performed under these conditions. Subsequently, from April 20 we started testing all potential recipients using the same technique, although results would be known only after the transplant surgery due to logistical reasons. At that time, this approach was justified based on the low RT-PCR positive pretest probability in asymptomatic individuals, with no epidemiology and a normal chest CT. Furthermore, the benefits of the transplant could outweigh the risks especially when we consider the risk of community acquisition of SARS-CoV-2 infection among patients undergoing 3-times-a-week hemodialysis sessions. From April 20 to June 12, we performed 118 transplants without knowing the result of the pretransplant PCR SARS-CoV-2 test and 3 of them were positive (May 9, June 6, and June 8). Since June 12, we were able to improve the logistics to obtain the test result before the KT. Yet, another patient underwent KT without the test result due to a 36-hours cold-ischemia-time and was confirmed positive (June 25).

Altogether, from February 26 to June 25, 14 deceased donors (9%) were positive and their organs were not recovered. Four potential recipients tested positive and were not transplanted. Of 275 KTs performed during this period, 111 recipients were not tested, 160 tested negative, and 4 tested positive for SARS-CoV-2. This clinical situation has been described previously only in a lung transplant recipient.4

The demographic characteristics and outcomes of these 4 patients are shown in Table 1. With 1 exception, patients were young and with few comorbidities. In retrospect, patient #3 recalled a mild headache in the week before. All patients received methylprednisolone and antithymocyte globulin (rATG) followed by tacrolimus, prednisone, and either azathioprine or mycophenolate. The RT-PCR cycle threshold values obtained in the pretransplant nasal swab sample were 27, 28, 17, and 27, respectively, suggesting a recent infection rather than a previous and largely resolved event. Two patients presented mild headache after the transplant surgery. All patients received prophylactic unfractionated subcutaneous heparin. No specific treatment, including oxygen therapy, was needed. The antimetabolite dose was reduced by 50% in the first 3 patients immediately after receiving the positive SARS-CoV-2 RT-PCR test. The uncertainty regarding the clinical course and the recommendations at that time was the basis for this rather empirical decision. As the knowledge regarding the disease and the number of infected patients with favorable outcomes increased, we became less reactive and decided to maintain the doses of the immunosuppressive drugs with close monitoring, as in patient #4.

TABLE 1. - Characteristics and outcomes of the 4 patients with SARS-CoV-2
Patient #1 Patient #2 Patient #3 Patient #4
Age (y), gender 34, male 27, male 41, male 65, female
Time on dialysis (mo) 26 96 18 15
Comorbidities Sickle cell anemia Hypertension Hypertension, smoking Hypertension
BMI (kg/m2) 20 20 21 23
CIT (h) 21 19 23 36
Maintenance immunosuppression TAC-PRED-MPS TAC-PRED-AZA TAC-PRED-MPS TAC-PRED-MPS
Pretransplant RT-PCR cycle threshold values 27 28 17 27
COVID-19 symptoms after transplantation Headache Headache None None
Severity of SARS-CoV-2 infection Mild Mild Asymptomatic Asymptomatic
Chest CT scan Normal Normal Normal Normal
Pretransplant peripheral capillary oxygen saturation 97% 96% 100% 100%
Peak disease associated markers (PO)
Ferritin, 22–275 ng/mLa 15 583 (6) 193 (5) 902 (3) 2140 (2)
LDH, 140–271 U/mLa 732 (3) 281 (4) 1162 (3) 360 (2)
D-dimer, <500 ng/mLa 16 580 (6) 850 (5) 17 900 (3) 5560 (2)
Lymphocytes, 900–2900 N/mm3 1170 (5) 441 (4) 154 (14) 248 (3)
Antimetabolite reduction ↓ 50% MPS ↓ 50% AZA ↓ 50% MPS No
Kidney allograft biopsy (PO)b Borderline changes (30) No Banff IIB6 (11) No
Banff IIA6 (18)
No rejection (30)
RT-PCR SARS-CoV-2 (PO)b + (3), + (17), − (22) + (1), Indeterminate (3), + (6), − (2) + (2), + (14), + (21), + (28), + (35), + (42), + (54), + (90) − (1), − (7)
SARS-CoV-2 IgG serology (pretransplant) ND Positive ND Positive
SARS-CoV-2 IgG serology (PO 28) Positive Positive Positive Positive
eGFR, mL/min/1.73 m2 (PO 30) 28 80 7 28
aLaboratory results obtained after the information regarding the diagnosis of SARS-CoV-2, but using the pretransplant stored blood sample.
bNumbers in parenthesis represent the postoperative transplant day.
AZA: azathioprine; BMI, body mass index (kg/m2); CIT, cold ischemia time; CT, computadorized tomography; eGFR, estimated glomerular filtration rate by CKD-EPI equation; LDH, lactate dehydrogenase; MPS, mycophenolate sodium; PO, postoperative day; PRED, prednisone; TAC, tacrolimus.

The inflammatory markers were obtained after the SARS-CoV-2 RT-PCR positive test using stored pretransplant blood samples and were monitored weekly afterward. Follow-up PCR SARS-CoV-2 test remained positive in all but 1 patient. Indeed, patient #4 had positive PCR even 75 days after transplantation. However, viral culture using this nasopharyngeal sample was negative. All patients presented SARS-CoV-2 IgG at day 28 after transplantation.

Two patients were treated for biopsy-proven acute rejection, 1 with 1.5 g of methylprednisolone at day 30 after transplantation, and the other with 8.3 mg/kg of rATG on day 11. The reasons for these unexpected rejection episodes are unclear and might be multifactorial. Biopsy studies in native kidneys in individuals who presented COVID-19 mainly showed the presence of acute tubular necrosis and thrombotic microangiopathy.5 Therefore, viral-induced increase in the expression of HLA antigens on endothelial and epithelial cells may have triggered an alloimmune-mediated injury. While we are not able to rule out the influence of the reduction in the antimetabolite, the clinical evidence is limited. Our allocation system is designed to perform low-immunological risk transplants. Ultimately, only patients without preformed donor-specific antibodies and a negative flow crossmatch receive a KT and about 85% have zero mismatches in DR loci. Furthermore, all patients receive a single 3 mg/kg dose of rATG induction, tacrolimus, prednisone, and either azathioprine or mycophenolate. This strategy has been associated with 7% incidence of treated acute rejection during the first year. On the other hand, the incidence of delayed graft function in our center is around 70% among deceased donor KT recipients and a significant proportion of patients eventually require mycophenolate dose reduction due to gastrointestinal and hematologic adverse events. By day 30 after transplantation, all patients were asymptomatic and in use of the maintenance immunosuppression. Renal function recovered as expected in those 2 patients without acute rejection and was still reduced in those who were treated for acute rejection.

This report highlights the challenges and uncertainties associated with transplantation during the COVID-19 pandemic, providing data to assist during decision making and patient management, taking into account the heterogeneity of the local epidemiology of the pandemic. Despite favorable outcomes, the data reported here should not support transplantation in the absence of donor and recipient screening for SARS-CoV-2 infection.

REFERENCES

1. Galvan NTN, Moreno NF, Garza JE, et al. Donor and transplant candidate selection for solid organ transplantation during the COVID-19 pandemic. Am J Transplant. 2020;20:3113–3122.
2. Martino F, Plebani M, Ronco C. Kidney transplant programmes during the COVID-19 pandemic. Lancet Respir Med. 2020;8:e39
3. López V, Vázquez T, Alonso-Titos J, et al.; Grupo de Estudio GREAT (Grupo Español de Actualizaciones en Trasplante). Recommendations on management of the SARS-CoV-2 coronavirus pandemic (Covid-19) in kidney transplant patients. Nefrologia. 2020;40:265–271.
4. Lang C, Jaksch P, Hoda MA, et al. Lung transplantation for COVID-19-associated acute respiratory distress syndrome in a PCR-positive patient. Lancet Respir Med. 2020;8:1057–1060.
5. Kudose S, Batal I, Santoriello D, et al. Kidney Biopsy Findings in Patients with COVID-19. J Am Soc Nephrol. 2020;31:1959–1968.
6. Loupy A, Haas M, Solez K, et al. The Banff 2015 Kidney Meeting Report: Current Challenges in Rejection Classification and Prospects for Adopting Molecular Pathology. Am J Transplant. 2017;17:28–41.
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