Presentation of COVID-19 in renal transplant recipients is similar to that shown in the nonimmunocompromised population; almost all recipients who have this disease present with symptoms of the respiratory system. Acute kidney injury has been found prevalent in transplant recipients with COVID-19. In those with severe COVID-19 disease who transfer to an intensive care unit prevalence of acute kidney injury is more than 50%. The pathophysiological mechanisms of kidney involvement and the type of involvement are unclear. Here, we present a 71-year-old kidney transplant recipient who was admitted to our hospital with pulmonary and renal involvement. A kidney allograft biopsy demonstrated diffuse intrarenal hemorrhage, capillary congestion, and severe acute tubular injury. COVID-19 RNA was detected by real-time polymerase chain reaction from lysed allograft tissues, but no findings of acute or chronic cellular or antibody-mediated rejection were detected. This case indicates that COVID-19 may involve the allograft by causing hemorrhage within the renal parenchymal via direct or indirect pathways.
Key words : Coronavirus disease 2019, COVID-19 renal pathology, Renal transplantation, Severe acute respiratory syndrome coronavirus 2
COVID-19 is an ongoing pandemic that has affected over 148 million people worldwide and has resulted in more than 3 million deaths as of April 2021. At the beginning of the pandemic, it was thought that renal involvement was rare. However, updated reports have suggested that the disease causes acute kidney injury (AKI) in >20% of hospitalized patients and >50% of patients in the intensive care unit (ICU).1-3
COVID-19-associated adverse events in the kidney may occur via cytopathic effects on the renal tubular epithelium and podocytes, accompanied by systemic inflammation, coagulopathy, and/or hypoxia from severe respiratory or circulatory complications. The clinical aspects of renal involvement include hematuria, proteinuria, and AKI.4,5 Although those complications recover within 3 weeks after the onset of symptom, AKI has strict relation with mortality, and its long-term implications are unknown.5
Presentation of COVID-19 in transplant recipients is similar to the nonimmunocompromised population.6 In a recent study, Ozturk and colleagues demonstrated that patients with stages 3 to 5 chronic kidney disease, hemodialysis, and kidney transplant recipients have higher mortality rates than patients without kidney disease.7 COVID-19 disease has been linked more commonly to moderate to severe pneumonia in kidney transplant recipients.8 Whether the type of renal involvement differs from nontransplant patients is unknown. Despite the different treatment strategies among transplant centers, the general treatment modality is based on lowering overall immunosuppression during active severe disease.6
Here, we report a patient who received a deceased-donor allograft 7 years ago and was admitted with pneumonia and AKI. His renal allograft biopsy findings demonstrated diffuse intrarenal hemorrhage, vascular congestion, and acute tubular necrosis, with COVID-19 RNA isolated from kidney allograft tissue with the use of a real-time polymerase chain reaction (RT-PCR) kit.
The 71-year-old male patient was referred to our transplant center with dyspnea, fever, and weakness. In 2013, he had received a kidney allograft from a deceased donor in our center. The cause of end-stage kidney disease was long-standing hypertension. His medical history showed that he had received maintenance hemodialysis treatment and experienced pulmonary mycobacterium tuberculosis infection. The patient received 300 mg rabbit antithymocyte globulin for induction therapy and a combination of tacrolimus plus mycophenolate mofetil plus prednisolone therapy for maintenance therapy. He had no history of acute rejection and was being followed up with a good functioning kidney. In another hospital, the patient had also received 1 session of hemodialysis treatment with a prediagnosis of uremic lung disease, due to poor renal function and dyspnea. After this treatment, the patient was referred to our center.
At physical examination, the patient showed signs of hypervolemia, with crackles in the lungs and decreased respiratory sounds, and right upper quadrant tenderness at palpation. Chest computed tomography (CT) revealed a right apical focal infiltration area and sequela of past tuberculosis infection (Figure 1). Laboratory tests showed severely impaired renal functions. C-reactive protein and lactate dehydrogenase levels were high (Table 1). The patient was admitted to the hospital.
Blood, sputum, and urine samples were collected, and dialysis catheter culture and microscopic analyses were performed. Influenza A and B antigen screening was also performed. An oropharyngeal swab sample for COVID-19 RNA isolation was also collected. Acid-resistant bacilli staining results for tuberculosis, performed in morning sputum samples for 3 consecutive days, were negative. Cytomegalovirus and polyoma BK virus RT-PCR tests were also negative.
The patient received hydroxychloroquine, high-dose vitamin C, and azithromycin treatment, which were first-line therapy in our country at the onset of the pandemic. Mycophenolate mofetil was stopped, and prednisolone dose was increased to 20 mg/day, whereas tacrolimus doses were not changed (target range, 6-8 µg/L). Abdominal ultrasonography and CT imaging revealed pericholecystic fluid and apparent gallbladder congestion, perhaps indicating companying cholecystitis (Figure 2). A broad-spectrum antibiotherapy consisting of ciprofloxacin plus clindamycin was started empirically.
During follow-up, culture test results were negative and C-reactive protein level decreased to <25 mg/L; right upper quadrant pain had also subsided. All antibiotics were withdrawn. The patient also had a negative COVID-19 RT-PCR test from an oropharyngeal swab. Mycophenolate mofetil was added to therapy to prevent or reverse a probable acute rejection episode. Hemodialysis treatment was continued according to clinical requirement.
On day 10 of hospitalization, the patient felt well, with no dyspnea and fever. A kidney biopsy was planned to identify the cause of AKI. On day 12 of hospitalization and the day before kidney allograft biopsy, he developed cough and dyspnea without fever, and repeat thorax CT revealed bilateral diffuse parenchymal infiltration (Figure 3). Multiple samples for microbiological culture assessment and oropharyngeal swab samples for COVID-19 PCR were again obtained; however, results were again negative, except a urinary finding of 20 000 colony-forming units/mL Enterococcus faecalis. Procalcitonin, C-reactive protein, and lactate dehydrogenase levels were moderately elevated, and a broad spectrum of antibiotics was started for 10 days. Meanwhile, the patient still needed hemodialysis. Three days after the relapse of symptoms, the patient felt well, and the symptoms had resolved.
An allograft biopsy was performed. Two days after allograft biopsy, the patient became hypoxic and tachypneic; despite intensive oxygen support, his oxygen saturation level was less than 88%. Tacrolimus and mycophenolate mofetil were held, and prednisolone was increased to 20 mg/day. He was transported to the ICU. He was diagnosed with severe acute respiratory distress syndrome. An empirical treatment approach was conducted given the patient’s serious clinical aspect, with administration of tocilizumab at 2 repeated doses of 600 mg, trimethoprim/sulfamethoxazole for Pneumocystis carinii pneumonia (PCP) prophylaxis (subsequent deep tracheal fluid testing for PCP was found to be negative), teicoplanin, moxifloxacin, convalescent plasma therapy, favipiravir, and a second course of hydroxychloroquine. In addition, anticoagulation treatment was started with low-molecular-weight heparin/fondaparinux. He died on day 15 of the ICU stay.
Results of the allograft biopsy were obtained the day after the patient had been transferred to the ICU. The Tru-Cut biopsy consisted of 75% renal medulla. Medulla was apparently hemorrhagic and had diffuse vascular congestion (Figure 4). The cortical tissue contained several glomeruli with slight congestion. Capillary basal membranes and cellularity of the glomeruli were normal. There were acute tubular injury findings and necrotic cellular debris in the renal tubules (Figure 5). However, no signs of acute cellular or antibody-mediated rejection were identified. An SV40 stain for polyoma BK virus infection was negative, and C4d staining of peritubular capillaries was also negative. In addition, light microscopy showed no findings of any other viral inclusion in renal tubular cells and podocytes. Glomerular capillaries were also congestive, and endothelial cells were swollen; however, endocapillary fibrin thrombosis and clinical thrombocytopenia were absent. An immunohistochemical assessment could not be performed to detect whether erythrocyte or platelet components existed in the fibrin plaques in the capillary lumen.
Two renal tissue samples were lysed with a Roche “high pure viral nucleic acid extraction” buffer kit. The buffer solutions subsequently were processed with a SARS-CoV-2 quantitative PCR detection kit (bioSpeedy) and analyzed with a CFX Systems RT-PCR analyzer. Positivity for SARS-CoV-2 RNA was found in the 2 tissue samples.
This case demonstrates that COVID-19 can affect various organs and that renal involvement may accompany atypical pathological features.
COVID-19 has resulted in high morbidity and mortality rates in certain risk groups. The disease can progress to include involvement of various organs, presenting primarily as severe pulmonary disease. Acute kidney injury may occur during the course of COVID-19 infection; however, the incidence, pathophysiological mechanisms of the renal involvement, and the relationship of renal involvement with the course of the disease and prognosis are unknown.
SARS-CoV-2 (COVID-19) was first described as a human infection in December 2019 in Wuhan, China. After a high spread rate all over the world, the World Health Organization declared COVID-19 as a new pandemic in March 2020. The disease characteristics have been better understood over time. However, pathophysiological mechanisms leading to extrapulmonary organ involvement need to be clarified.
Renal involvement in the course of COVID-19 infection is a common entity, and it has been postulated that AKI is an independent predictor of worse prognosis in COVID-19 disease.4 A recent study demonstrated that, in low-income minority populations, the mortality rate was as high as 71% in hospitalized COVID-19 patients with AKI.9
COVID-19 causes organ damage via various pathophysiological mechanisms. Clotting abnormalities, disseminated intravascular coagulopathy, and a cytokine storm (because SARS-CoV-2 targets lymphocytes as they express angiotensin-converting enzyme receptors) are common pathways in the disease course. SARS-CoV-2 binds to angiotensin-converting enzyme 2 (ACE2) receptors in a variety of human organs and tissues via its spike proteins and enters host cells.10 The ACE2 receptor is highly expressed on myocardial cells, proximal tubule cells of the kidney, enterocytes of the small intestine, and type 2 alveolar epithelial cells. The kidney is a highly vulnerable organ to COVID-19 infection, and AKI may emerge even in patients who do not exhibit respiratory symptoms. Furthermore, it has been demonstrated that ACE2 receptor intensity on renal epithelial cells is more than the intensity shown on lung tissue. Although it is present at lower levels on glomeruli (on podocytes and mesangial cells), ACE2 is strongly expressed on the apical surface of the proximal tubules. However, glomerular endothelial cells do not have ACE2 activity on their surfaces. On the other hand, ACE2 receptor binding is not solely enough for COVID-19 infectivity. Transmembrane proteases on the cell surface play crucial roles in the emergence of the fusion complex, which consists of cell membranes and SARS-CoV-2 spike proteins. The pathways in the formation of the fusion complex need further investigations.11
Postmortem autopsies of kidneys have demonstrated the presence of virus-like particles in podocytes and renal tubular cells by electron microscopy. The lengths of these particles were similar to those detected in kidneys from patients with severe acute respiratory syndrome and Middle East respiratory syndrome.12 In another study of postmortem renal pathological assessment, Bo and associates demonstrated SARS-CoV-2 nucleocapsid protein in renal tubule cells in the kidneys of 6 patients.13
In a more recent study, definitive viral particles in kidney cells of SARS-CoV-2 patients were not demonstrated, despite the use of 5 distinct methodologies (immunostains for viral spike and nucleocapsid proteins, in situ hybridization for viral RNA [by automated platform and manual RNAScope], and ultrastructural examination).16 However, the authors suggested that their techniques may have lacked sufficient sensitivity for definitive viral detection. In contrast, Puelles and associates15 reported that they were able to detect SARS-CoV-2 RNA in kidneys, but at a lower level compared with lung tissues, in an autopsy series of 22 patients who had died from COVID-19.
Renal histopathological analysis of postmortem findings of COVID-19 patients has demonstrated peritubular red blood cell aggregates and acute tubular injury in light microscopy examination.11 In our case, with a similar light microscopic examination, the major appearance was “intraparenchymal hemorrhages,” which we believe may have been due to the disease severity rather than the red blood cell aggregates. Severe acute tubular necrosis was present, and this may have been the consequence of the direct tubulotoxic effect of SARS-CoV-2. There was no finding of acute cortical necrosis, interstitial inflammation, or vasculitis. Prominent capillary congestion may be due to the consequence of the systemic cytokine storm rather than direct viral cytopathic effect. In addition, in glomerular capillaries, congestion and fibrinoid formation were mild compared with that shown in peritubular capillaries. We were not able to define immunochemically the fibrin components, and light microscopy did not indicate any cellular fragmentation in capillary congestive fields other than fibrin appearance.
To our knowledge, this is the first kidney biopsy from a living patient versus reports from postmortem studies. We believe that renal injury and renal pathological aspects are highly dependent on disease severity, and pathological findings may be related to both the direct cytopathic effect of the SARS-CoV-2 and systemic inflammation.
DOI : 10.6002/ect.2020.0529
From the 1Yeni Yuzyil University School of Medicine, Nephrology and Organ Transplantation; the 2Mehmet Ali Aydinlar Acibadem International Hospital, Clinical Microbiology; the 3Yeni Yuzyil University School of Medicine, General Surgery and Organ Transplantation; and the 4Yeni Yuzyil University School of Medicine, Pathology, Istanbul, Turkey
Acknowledgements: The authors have not received any funding or grants in support of the presented research or for the preparation of this work and have no declarations of potential conflicts of interest.
Corresponding author: Mehmet Emin Demir, Yeni Yuzyil University School of Medicine. Nephrology and Organ Transplantation, Cukurcesme Street, No: 51, Gaziosmanpasa, Istanbul, Turkey
Phone: +90 531 997 38 09
Table 1.Laboratory Results of the Patient at Hospital Admission
Figure 1.Chest Computed Tomography Showing Right Apical Focal Infiltration Area
Figure 2.Image Showing Pericholecystic Fluid and Apparent Gallbladder Congestion
Figure 3.Repeat Thorax Computed Tomography Showing Bilateral Diffuse Parenchymal Infiltration
Figure 4.Allograft Biopsy Results Showing Apparently Hemorrhagic Medulla With Diffuse Vascular Congestion
Figure 5.Allograft Biopsy Results Showing Acute Tubular Injury Findings and Necrotic Cellular Debris in Renal Tubules