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Thrombotic Microangiopathy in a Kidney Transplant Patient With COVID-19

Open AccessPublished:December 09, 2020DOI:https://doi.org/10.1016/j.xkme.2020.09.014
      Kidney transplant recipients are at increased risk for infection, including coronavirus disease 2019 (COVID-19), given ongoing immunosuppression. In individuals with COVID-19, complications including thrombosis and endothelial dysfunction portend worse outcomes. In this report, we describe a kidney transplant recipient who developed severe thrombotic microangiopathy with a low platelet count (12 ×109/L), anemia (hemoglobin, 7.5 g/dL with 7% schistocytes on peripheral-blood smear), and severe acute kidney injury concurrent with COVID-19. The clinical course improved after plasma exchange. Given this presentation, we hypothesize that COVID-19 triggered thrombotic microangiopathy.

      Index Words

      Many systemic complications associated with coronavirus disease 2019 (COVID-19) have been described.
      • Huang C.
      • Wang Y.
      • Li X.
      • et al.
      Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.
      • Zhou P.
      • Yang X.-L.
      • Wang X.-G.
      • et al.
      A pneumonia outbreak associated with a new coronavirus of probable bat origin.
      • Zhu N.
      • Zhang D.
      • Wang W.
      • et al.
      A novel coronavirus from patients with pneumonia in China, 2019.
      • Rothe C.
      • Schunk M.
      • Sothmann P.
      • et al.
      Transmission of 2019-nCoV infection from an asymptomatic contact in Germany.
      There is a complex relationship between COVID-19 and pathologic activation of immune cells, with not only inflammatory pathway activation and the presence of cytokine storm but also endothelial injury, dysfunction, and microthrombotic pathway activation.
      • Holshue M.L.
      • DeBolt C.
      • Lindquist S.
      • et al.
      First case of 2019 novel coronavirus in the United States.
      • Onder G.
      • Rezza G.
      • Brusaferro S.
      Case-fatality rate and characteristics of patients dying in relation to COVID-19 in Italy.
      • Zhou F.
      • Yu T.
      • Du R.
      • et al.
      Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study.
      • Wang D.
      • Hu B.
      • Hu Ch
      • et al.
      Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China.
      We describe a kidney transplant recipient with COVID-19 who developed severe thrombotic microangiopathy (TMA) in the setting of acute infection.

      Case report

      The patient is a man in his 40s who is 9 years status post cadaveric donor kidney transplantation; kidney failure was secondary to Liddle syndrome with mutation of gene SCNN1B. The patient was maintained on an immunosuppression regimen of tacrolimus, everolimus, and prednisone. There was no history of rejection, and he had no history of donor-specific antibodies. At his most recent follow-up assessment 1 month before admission, serum creatinine level was 1.75 mg/dL, estimated glomerular filtration rate was 42 mL/min, serum tacrolimus level was 5.3 ng/mL, and everolimus level was 3.6 ng/mL, with normal urinalysis results.
      The patient presented with fever (maximum noted of 38 ºC at home), dyspnea, diarrhea, and abdominal pain for 1 week. On initial examination, temperature was 37 ºC, blood pressure was 122/60 mm Hg, pulse rate was 90 beats/min, and oxygen saturation was 93% (while breathing ambient air); he had bibasilar crackles and appeared volume depleted. Laboratory results are summarized in Table 1. The main findings were lymphopenia, thrombocytopenia, high serum C-reactive protein and D-dimer levels, acute kidney injury with metabolic acidosis, and the presence of epithelial and granular casts on urinalysis. Anemia was not present. Thoracic radiography showed an interstitial pulmonary infiltrate on the basal right lung. A nasopharyngeal swab followed by reverse-transcription polymerase chain reaction assessment confirmed the diagnosis of COVID-19.
      Table 1Baseline and Follow-up Serum Parameters
      MeasureReference RangeBaselineD1D3D6D8D11D13D17D19D22D23D36
      Hemoglobin, g/dL13-17.514.213.111.611.210.77.67.07.88.09.39.611.6
      White blood cell count, ×109/L4.00-10.006.809.7011.906.7010.208.8010.3011.6510.309.96.06.0
      Total neutrophils1.8-7.54.58.910.94.98.26.58.09.47.97.64.04.0
      Total lymphocytes1.3-3.51.60.60.7110.90.91.21.01.11.41.5
      Total monocytes0.2-1.00.50.30.30.70.91.31.31.01.31.11.01.0
      Platelet count, ×109/L)140-400144858454291260151163155135160
      Prothrombin time, s10.5-13.511.813.213.012.712.513.412.412.913.414.112.112.0
      Activated partial thromboplastin time, s27-380.9521.827.830.12524.227.827.627.830.230.029.3
      Fibrinogen, mg/dL150-450409720692793712733297332452684431469
      D-Dimer, ng/mL0-25030417751548852646558045552856795
      Haptoglobin, mg/dL27-129<6<6<63241
      Albumin, g/L3.4-4.84.23.72.82.93.12.62.93.23.23.23.63.6
      Alanine aminotransferase, U/L5-412425404629213537372630
      Lactate dehydrogenase, U/L39-308519672894
      Hemolysis interference.
      Hemolysis interference.
      564324
      Hemolysis interference.
      276175129
      Creatinine kinase, U/L39-308118437376533402824333181931
      Creatinine, mg/dL0.70-1.201.753.693.754.567.368.796.063.052.682.681.91.9
      eGFR, mL/min/1.73 m2≥60421817<15<15<15247<1526273939
      Urea, mg/dL15-4581139167179257311<151221101216943
      High-sensitivity cardiac troponin I, pg/mL1618.5830131.728.24.8352707.3
      Serum ferritin, μg/L22-27410,0317,1888,5541,650190
      Procalcitonin, ng/mL0.00-0.500.330.480.390.430.760.601.90.150.080.08
      C-Reactive protein, mg/dL0.-0.51315.623.116.120.64.40.123.28.15.20.6
      Interleukin 6, pg/mL<4.3105.9216.787.0
      Tacrolimus, ng/mL4.0-10.05.4>30>302.90.64.2
      Everolimus, ng/mL3.0-8.03.612.76.1<0.43.0
      Note: Conversion factors for units: creatinine in mg/dL to μmol/L, ×88.4.
      Abbreviations: D, day; eGFR, estimated glomerular filtration rate.
      a Hemolysis interference.
      The course of the patient’s symptoms and treatments are summarized in Figure 1. We initiated supportive treatment with oxygen therapy and volume repletion and started empiric treatment with hydroxychloroquine and azithromycin. We initially reduced the tacrolimus dose and discontinued everolimus treatment. Two days later, tacrolimus level remained elevated and we discontinued all immunosuppression. On the third hospital day, the patient had high levels of pancreatic enzymes without abdominal pain, diarrhea, or other gastrointestinal symptoms, with subsequent normalization on the following days. On hospital day 9, he had an elevated high-sensitivity cardiac troponin I level without chest pain and with a normal electrocardiogram and normal biventricular function on the echocardiogram. Myocarditis related to COVID-19 was presumptively diagnosed. His respiratory status subsequently worsened and a chest radiograph revealed new bilateral pulmonary infiltrations. He started a methylprednisolone bolus (2 mg/kg per day) for 7 days and oxygen supplementation was increased.
      Figure thumbnail gr1
      Figure 1Baseline and follow-up clinical symptoms and treatments. Abbreviations: NC, nasal cannula; RB, reservoir bag; RT-PCR, reverse transcriptase polymerase chain reaction; SARS-CoV2, severe acute respiratory syndrome coronavirus 2.
      On hospital day 11, a diagnosis of TMA was made based on the following findings: anemia with hemoglobin level of 7.5 g/dL, thrombocytopenia with platelet count of 12 ×109 /L, reticulocytosis, elevated lactate dehydrogenase level, 7% schistocytes on peripheral-blood smear, negative direct and indirect Coombs test, undetectable haptoglobin, and acute kidney injury with serum creatinine level peaking at 8.79 mg/dL. ADAMTS 13 (von Willebrand factor protease) activity of 68% excluded thrombotic thrombocytopenic purpura. There was no presence of bacteria pathogens on stool culture or urinary antigen Streptococcus pneumoniae. Serologic tests for HIV, hepatitis C virus, and parvovirus B19 were negative. Cytomegalovirus and Epstein-Barr virus serologic test results were negative. Immunologic study results, including antinuclear antibody, anti–double strand DNA, antiphospholipid antibody, complement, and immunoglobulin, were normal.
      To treat TMA, the patient received 5 sessions of plasma exchange with fresh frozen plasma replacement, and 2 hemodialysis sessions were necessary. Subsequently, serum creatinine level decreased to 2.5 mg/dL and there was no evidence of further hemolysis. Immunosuppressive treatment was reintroduced. On hospital day 23, the patient developed chest pain accompanied by elevated high-sensitivity cardiac troponin I level. Acute myocardial infarction was diagnosed and he was successfully treated with angioplasty of the right coronary artery. He was discharged on hospital day 36 with recovery of kidney function and normalized platelet count.

      Discussion

      Multiple complications related to COVID-19 have been described, including respiratory failure, myocarditis, and thrombosis.
      • Shi S.
      • Qin M.
      • Shen B.
      • et al.
      Association of cardiac injury with mortality in hospitalized patients with COVID-19 in Wuhan, China.
      To our knowledge, this is one of the only reports of COVID-19–associated TMA.
      Kidney transplant recipients have risk factors for TMA, specifically use of calcineurin inhibitors such as tacrolimus. Our patient had been receiving tacrolimus for the last 9 years without side effects. Although markedly elevated serum tacrolimus levels could play a role in the development of TMA, many viruses may provoke TMA.
      • Kumar D.
      • Michaels M.G.
      • Morris M.I.
      • et al.
      Outcomes from pandemic influenza A H1N1 infection in recipients of solid-organ transplants: a multicentre cohort study.
      • Wux C.
      • Chen X.
      • Cai Y.
      • et al.
      Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China.
      • Danzi G.B.
      • Loffi M.
      • Galeazzi G.
      • Gherbesi E.
      Acute pulmonary embolism and COVID-19 pneumonia: a random association?.
      • Murer L.
      • Zacchello G.
      • Bianchi D.
      • et al.
      Thrombotic microangiopathy associated with parvovirus B 19 infection after renal transplantation.
      • Java A.
      • Edwards A.
      • Rossi A.
      • et al.
      Cytomegalovirus-induced thrombotic microangiopathy after renal transplant successfully treated with eculizumab: case report and review of the literature.
      • Pham P.T.
      • Peng A.
      • Wilkinson A.H.
      • et al.
      Cyclosporine and tacrolimus-associated thrombotic microangiopathy.
      In this case, although it is possible that both factors were complicit in TMA, previous studies published about COVID-19 in kidney transplant recipients suggest that high serum tacrolimus levels and acute kidney injury are frequent; however, TMA has not been reported.
      Multiple reports indicate that systemic effects on the vasculature are common in COVID-19, including a procoagulant milieu.
      • Shi S.
      • Qin M.
      • Shen B.
      • et al.
      Association of cardiac injury with mortality in hospitalized patients with COVID-19 in Wuhan, China.
      ,
      • Wux C.
      • Chen X.
      • Cai Y.
      • et al.
      Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China.
      ,
      • Danzi G.B.
      • Loffi M.
      • Galeazzi G.
      • Gherbesi E.
      Acute pulmonary embolism and COVID-19 pneumonia: a random association?.
      There is pathologic activation of immune cells with destructive mechanisms through the endothelial system, with subsequent endothelial dysfunction, microthrombotic pathway activation, and complement activation.
      • Zhu L.
      • Xu X.
      • Ma K.
      • et al.
      Successful recovery of COVID-19 pneumonia in a renal transplant recipient with long-term immunosuppression.
      • Su H.
      • Yang M.
      • Wan C.
      • et al.
      Renal histopathological analysis for 26 postmortem findings of patients with COVID-19 in China.
      • Valga F.
      • Vega N.
      • Macia M.
      • et al.
      Targeting complement in severe coronavirus disease 2019 to address microthrombosis.
      • Ackermann M.
      • Verleden S.E.
      • Kuehnel M.
      • et al.
      Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in Covid-19.
      • Hirsch J.S.
      • Ng J.H.
      • Ross D.W.
      • et al.
      Acute kidney injury in patients hospitalized with COVID-19.
      In the current case, we ruled out many additional causes for TMA given negative serologic test results and negative blood, urine, and stool cultures. The patient received low doses of enoxaparin as prophylaxis during the first 5 days, but we stopped the treatment when platelet counts decreased, and we did not appreciate any platelet recovery, making heparin-induced thrombocytopenia unlikely.
      COVID-19 may have direct and indirect effects on the kidney, with studies suggesting that 7% of patients with COVID-19 develop acute kidney injury, with as many as 37% of hospitalized patients developing acute kidney injury.
      • Hirsch J.S.
      • Ng J.H.
      • Ross D.W.
      • et al.
      Acute kidney injury in patients hospitalized with COVID-19.
      Whether this is a direct effect of the virus on the kidney or indirect effects in the setting of systemic illness or a combination of these factors remains uncertain. In our case, the clinical presentation was most consistent with acute kidney injury in the setting of TMA.

      Article Information

      Authors’ Full Names and Academic Degrees

      Arturo Bascuñana, MD, Antonia Mijaylova, MD, Almudena Vega, PhD, Nicolás Macías, PhD, Eduardo Verde, PhD, Maria Luisa Rodríguez-Ferrero, MD, Andrés Delgado, MD, Javier Carbayo, MD, and Marian Goicoechea, PhD.

      Support

      None.

      Financial Disclosure

      The authors declare that they have no relevant financial interests

      Patient Consent

      The authors declare that they have obtained consent from the patient discussed in the report.

      Peer Review

      Received April 21, 2020. Evaluated by 1 external peer reviewer, with direct editorial input from an Associate Editor and the Editor-in-Chief. Accepted in revised form September 27, 2020.

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