Although the role of bacterial infection as the major determinant in the development of acute pyelonephritis has been well documented for years, the nature of the renal scarring typical of chronic "atrophic" pyelonephritis has been a matter of controversy for at least three decades. In the past, recurrent bacterial infection of the kidney was thought to be responsible for the pathologic entity of "chronic pyelonephritis." However, more recent studies suggest that recurrent bacteriuria, in the absence of some form of obstructive uropathy, rarely produces chronic pyelonephritis. The close association between vesicoureteral reflex and chronic pyelonephritis has also been firmly established and has been observed to occur frequently in the absence of urinary tract infection. However, the mechanism by which vesicoureteral reflux injures the kidney has not been firmly established. A number of observations have suggested that some normal component of urine, particularly Tamm-Horsfall protein, might serve as an antigenic determinant involved in the immunopathogenesis of renal scarring in vesicoureteral reflux. The present studies were designed to investigate the immunopathogenic role of Tamm-Horsfall protein in a rabbit model of tubulointerstitial nephritis, and in a swine model of reflux nephropathy. The immune responses to Tamm-Horsfall protein in patients with recurrent nephrolithiasis were also examined, as were the antigenic similarities between Tamm-Horsfall protein and protein-containing components of uropathic bacteria. The results of these studies indicate that autoimmune responses to Tamm-Horsfall protein may occur after exposure to Tamm-Horsfall protein by intravenous challenge in rabbits, and by urinary reflux in pigs, as well as in recurrent nephrolithiasis in man.(ABSTRACT TRUNCATED AT 250 WORDS)