PMC8148337_01
Timeline of hospitalization. CRRT, continuous renal replacement therapy; EVE, everolimus; ER, emergency room; HD, hemodialysis; ICU, intensive care unit; IVIG, intravenous immunoglobulin; MV, mechanical ventilation; oral P, oral prednisone; TAC, tacrolimus; W/D, withdrawal; 6MP, 6-methylprednisolone.
fimmu-12-671013-g001.jpg
PMC8148337_01_fimmu-12-671013-g001.jpg
f1
During the course of the first wave of the pandemic, a 54-year-old man with end-stage renal disease of unknown etiology, recipient of a renal allograft in 2015 under combined maintenance immunosuppression with prednisone, tacrolimus (TAC) and everolimus (EVE), baseline serum creatinine of 1.2 mg/dL and estimated glomerular filtration rate of 67 mL/min, was admitted to Emergency Room on 19th March with a 5-day history of fever and dyspnea unresponsive to paracetamol and levofloxacin intake ( Figure 1 ). IL-6 234.7 pg/mL;  Figures 2 ,  3 ) became highly suggestive of an unbalanced systemic inflammatory response in the context of a cytokine-storm. In this setting, a three-day consecutive course of high-dose intravenous immunoglobulin (IVIG) 65 g/day (an accumulated 2.2 g/kg) and 125 mg/day of 6MP were administered (days +9, +10 and +11 since admission;  Figure 1 ). The patient was discharged after 49 hospital days ( Figure 1 ) with a serum creatinine of 2.3 mg/dL, 1200 mg/L proteinuria and resumed regular outpatient clinic reviews.
Acute-phase reactants levels, including ferritin (A), D-dimer (B), lactate dehydrogenase (LDH, C) and C-reactive protein (CRP, D), analyzed in serum samples of the patient on attendance to hospital date, on admission to Intensive Care Unit (ICU) date, on the day of the intravenous immunoglobulin (IVIG) plus 6-methylprednisolone (6MP) infusion, early (3 days) after the IVIG plus 6MP infusion and on mechanical ventilation removal. Normal range laboratory values are displayed in broken lines. The treatment administration is indicated in a grey box. Ferritin was assessed from serum samples by sandwich immunoassay using direct chemiluminescence technology (Atellica IM Ferritin -Fer-, ref. 10995568) on an Atellica  IM Analyzer (Siemens Healthineers Diagnostics Inc.). D-dimer was determined from citrated plasma by automated latex enhanced immunoassay (ref. 0020008500, Instrumentation Laboratory, Werfen) on an ACL TOP 700 LAS (Werfen). LDH was quantified from serum samples according to the proportional increase in the absorbance at 340/310 nm of NADH (Atellica CH Lactate Dehydrogenase L-P -LDPL-, ref. 11097594) on an Atellica  CH Analyzer (Siemens Healthineers Diagnostics Inc.). CRP was measured from serum samples by latex enhanced immunoturbidimetry assay (Atellica CH Wide Range C-Reactive Protein -wrCRP-, ref. 11097645) on an Atellica  CH Analyzer (Siemens Healthineers Diagnostics Inc.). All the automatic assays were performed according to manufacturer instructions.
fimmu-12-671013-g002.jpg
PMC8148337_01_fimmu-12-671013-g002.jpg
f2
IL-6 234.7 pg/mL;  Figures 2 ,  3 ) became highly suggestive of an unbalanced systemic inflammatory response in the context of a cytokine-storm. In this setting, a three-day consecutive course of high-dose intravenous immunoglobulin (IVIG) 65 g/day (an accumulated 2.2 g/kg) and 125 mg/day of 6MP were administered (days +9, +10 and +11 since admission;  Figure 1 ). This cycle was followed by a rapid and significant improvement in the pro-inflammatory profile (ferritin 1949.1 ng/mL; D-dimer 1597 ng/mL; c-reactive protein 29.9 mg/L; lactate dehydrogenase 525 U/L; IL-6 4.1 pg/mL;  Figures 2 ,  3 ) with hemodynamic stabilization and discontinuation of CRRT six days after IVIG plus corticosteroid pulses completion (having received a total course of 9 days of CRRT).
Cytokine levels (pg/mL) including IL-1alpha, IL-1beta, IL-6, IL-8, IL-10, IL-12(p70), IL-18, INF-gamma, MCP-1, MIP-1alpha, MIP-1beta, TNF-alpha, MIF and PAI-1 (A-N), analyzed in serum samples of the patient obtained on attendance to hospital date, on admission to Intensive Care Unit (ICU) date, on the day of the intravenous immunoglobulin (IVIG) plus 6-methylprednisolone (6MP) infusion, early (3 days) after the IVIG plus 6MP infusion and on mechanical ventilation removal. Cytokine measurements were retrospectively performed on -80  C preserved samples, except for IL-6 (prospectively analyzed), using customized Milliplex  MAP kits (Panel A: IL-1alpha, IL-1beta, IL-6, IL-8, IL-10, IL-12(p70), IL-18, INF-gamma, MCP-1, MIP-1alpha, MIP-1beta and TNF-alpha, ref. HCYTA-60K; Panel B: MIF and PAI-1, ref. HSP1MAG-63K; Merk-Millipore) according to manufacturer instructions on a Luminex platform with xPONENT vs. 4.2 as acquisition and analysis software.
fimmu-12-671013-g003.jpg
PMC8148337_01_fimmu-12-671013-g003.jpg
f3
IL-6 234.7 pg/mL;  Figures 2 ,  3 ) became highly suggestive of an unbalanced systemic inflammatory response in the context of a cytokine-storm. In this setting, a three-day consecutive course of high-dose intravenous immunoglobulin (IVIG) 65 g/day (an accumulated 2.2 g/kg) and 125 mg/day of 6MP were administered (days +9, +10 and +11 since admission;  Figure 1 ). This cycle was followed by a rapid and significant improvement in the pro-inflammatory profile (ferritin 1949.1 ng/mL; D-dimer 1597 ng/mL; c-reactive protein 29.9 mg/L; lactate dehydrogenase 525 U/L; IL-6 4.1 pg/mL;  Figures 2 ,  3 ) with hemodynamic stabilization and discontinuation of CRRT six days after IVIG plus corticosteroid pulses completion (having received a total course of 9 days of CRRT).