A link between circulating immune complexes and acute kidney injury in human visceral leishmaniasis

Abstract

Visceral leishmaniasis (VL) is an infectious disease caused by Leishmania infantum. Clinically, VL evolves with systemic impairment, immunosuppression and hyperactivation with hypergammaglobulinemia. Although renal involvement has been recognized, a dearth of understanding about the underlying mechanisms driving acute kidney injury (AKI) in VL remains. We aimed to evaluate the involvement of immunoglobulins (Igs) and immune complexes (CIC) in the occurrence of AKI in VL patients. Fourteen VL patients were evaluated between early treatment and 12 months post-treatment (mpt). Anti-Leishmania Igs, CIC, cystatin C, C3a and C5a were assessed and correlated with AKI markers. Interestingly, high levels of CIC were observed in VL patients up to 6 mpt. Concomitantly, twelve patients met the criteria for AKI, while high levels of cystatin C were observed up to 6 mpt. Plasmatic cystatin C was positively correlated with CIC and Igs. Moreover, C5a was correlated with cystatin C, CIC and Igs. We did not identify any correlation between amphotericin B use and kidney function markers in VL patients, although this association needs to be further explored in subsequent studies. Our data reinforce the presence of an important renal function impairment during VL, suggesting the involvement of Igs, CIC, and C5a in this clinical condition.

Figure 1

CIC levels in patients with VL throughout the clinical follow-up. IgG- (a), IgG1- (b), and IgG3- (c) containing immune complexes. Each symbol represents a patient with VL. Each color represents the same patient in different phases of clinical follow-up. The horizontal bars represent the median values of each group. The dashed line represents the median value of healthy individuals. CIC, circulating immune complexes. Mpt, months post-treatment. OD, optical density. Asterisks denote significant differences between the phases of clinical follow-up: *p < 0.05. **p < 0.01.

Figure 2

Correlation between CIC levels and anti-Leishmania Igs levels throughout the clinical follow-up. Positive correlation of IgG (a, Spearman correlation, r = 0.815, p < 0.001), IgG1 (b, Spearman correlation, r = 0.716, p < 0.001), and IgG3 (c, Spearman correlation, r = 0.738, p < 0.001). CIC: circulating immune complexes. EI: ELISA index. Mpt: months post-treatment. OD: optical density.

Figure 3

Markers of renal function in patients with VL throughout the clinical follow-up. sCr (a) and eGFR rate by CKD-EPI equation (b) during hospitalization. Peak demonstrates the highest value of sCr recorded during the hospitalization period. The temporal distribution of this point regarding anti-Leishmania treatment is demonstrated in Supplementary Fig. S2. Cystatin C plasmatic levels (c) during the prospective follow-up. Each symbol represents a patient with VL. Each color represents the same patient in the different phases of clinical follow-up. The horizontal bars represent the median values of each group. The dashed line represents the median value of healthy individuals. eGFR, estimated glomerular filtration rate. Mpt, months post-treatment. sCr, serum creatinine. Asterisks denote significant differences between the phases of clinical follow-up: *p < 0.05. **p < 0.01. ***p < 0.001.

Figure 4

Correlation between cystatin C and CIC or anti-Leishmania Igs throughout the clinical follow-up. Positive correlation between cystatin C and IgG- (a, Spearman correlation, r = 0.540, p < 0.001), IgG1- (b, Spearman correlation, r = 0.482, p < 0.001) and IgG3- (c, Spearman correlation, r = 0.610, p < 0.001) CIC. Positive correlation between cystatin C and levels of anti-Leishmania IgG (d, Spearman correlation, r = 0.554, p < 0.001), IgG1 (e, Spearman correlation, r = 0.362, p < 0.016) and IgG3 (f, Spearman correlation, r = 0.507, p < 0.001). CIC, circulating immune complexes.

Figure 5

Levels of complement anaphylatoxins C3a and C5a in patients with VL throughout the clinical follow-up. C3a (a) and C5a (b). Each symbol represents a patient with VL. Each color represents the same patient in the different phases of clinical follow-up. The horizontal bars represent the median values of each group. The dashed line represents the median value of healthy individuals. Mpt, months post-treatment. Asterisks denote significant differences between the phases of clinical follow-up: *p < 0.05. Positive correlation between cystatin C and C5a throughout clinical follow-up (c, Spearman correlation, r = 0.353, p = 0.021).

Figure 6

Markers of renal function in patients with VL throughout the anti-Leishmania treatment. sCr (a–c), eGFR (d–f), and cystatin C (g–i) levels according to the cumulative amphotericin B dose, daily amphotericin B dose, or treatment days, respectively. Each symbol represents a patient with VL. Each color represents the same patient in the different phases of anti-Leishmania treatment. The horizontal bars represent the median values of each group. Amph. B, Amphotericin B. sCr, serum creatinine. eGFR, estimated glomerular filtration rate.