Complement Activation is More Pronounced in the Kidneys of Critically Ill Patients With COVID-19 Than in Those With Bacterial Sepsis

Abstract

Introduction: Previous studies have shown that the complement system plays an important role in COVID-19 acute kidney injury (AKI). However, studies evaluating the activation pathways in vivo are scarce and have shown contradictory findings. It has also been suggested that COVID-19 AKI has a pathophysiology similar to that of bacterial sepsis AKI. Nonetheless, no study has compared the complement activation between these 2 types of AKI.

Methods: This study used postmortem kidney tissue from 22 patients with COVID-19 and 22 patients with bacterial sepsis. Control kidney tissues were obtained from 12 patients who underwent total nephrectomy. Immunohistochemical staining was performed for complement factor properdin and complement activation products C4d, C3d, and C5b-9. Glomerular and tubulointerstitial complement deposition was quantitatively analyzed using ImageScope.

Results: Peritubular capillary thrombi were found in 82% of the biopsies in the COVID-19 group but were absent in the bacterial sepsis group. Both C3d and properdin positivity in the tubulointerstitial area were significantly higher in COVID-19 than in bacterial sepsis (P = 0.034 and P = 0.001, respectively) and in the control group (P = 0.034 and P < 0.001, respectively) and were predominantly found in the peritubular capillaries. In contrast, no difference was found in tubulointerstitial C4d and C5b-9 positivity between the COVID-19 and the bacterial sepsis groups.

Conclusions: There was marked tubulointerstitial complement deposition in the kidneys of patients with COVID-19, particularly in the peritubular capillaries, with activation via the alternative pathway. Thus, alternative complement pathway inhibition might be a possible treatment option for patients with COVID-19 AKI.

Keywords: COVID-19; acute kidney injury; complement; kidney; sepsis.

Graphical abstract

Figure 1

Comparison of the complement factors positivity between controls, patients with bacterial sepsis, and patients with COVID-19. (a) In the tubulointerstitial area. (b) In the glomeruli. Mann-Whitney U test was used to test for differences between groups, and the P-value was corrected for multiple comparisons using the false discovery rate method. The correction was performed separately for each complement staining. P < 0.05 was considered significant.

Figure 2

Representative figures of immunohistochemical staining for complement factors in the kidney biopsy in controls, patients with bacterial sepsis, and patients with COVID-19.