Kevin J. Esch, Robert G. Schaut, Ian M. Lamb, Gwendolyn Clay, Ádila L. Morais Lima, Paulo R.P. do Nascimento, Elizabeth M. Whitley, Selma M.B. Jeronimo, Fayyaz S. Sutterwala, Joseph S. Haynes, Christine A. Petersen

Chronic kidney disease is a major health burden and major contributor to human and companion animal morbidity and mortality. Renal complications are a sequelae of canine (>96% of cases) and human visceral leishmaniasis (VL; 25% to 30% of cases). Despite the high incidence of infection-mediated glomerulonephritis, little is known about pathogenesis and mechanisms of VL-associated renal disease. Leishmania infantum-infected dogs serve as a naturally occurring model of VL and VL-associated glomerulonephritis. Membranoproliferative glomerulonephritis type I [24 of 25 (96%)], with interstitial lymphoplasmacytic nephritis [23 of 25 (92%)], and glomerular and interstitial fibrosis [12 of 25 (48%)] were predominant histopathological lesions. An ultrastructural evaluation of glomeruli from animals with VL identified mesangial cell proliferation and interposition. Immunohistochemistry demonstrated significant Leishmania antigen, IgG, and C3b deposition in VL dog glomeruli. Asymptomatic and symptomatic dogs had increased glomerular NLR family, pyrin domain containing 3 and autophagosome-associated microtubule-associated protein 1 light chain 3 associated with glomerular lesion severity. Transcriptional analyses from symptomatic dogs confirmed induction of autophagy and inflammasome genes within glomeruli and tubules. On the basis of temporal VL staging, glomerulonephritis was initiated by glomerular antibody complex and complement deposition. This deposition preceded presence of NLR family, pyrin domain containing 3-associated inflammasomes, increased light chain 3 puncta, and autophagosomes in glomeruli from dogs with clinical VL and renal failure. These findings indicate potential roles for inflammasome complexes in glomerular damage during VL and autophagy in ensuing cellular responses.