BACKGROUND: To study loin pain-hematuria syndrome (LPHS) pathogenesis, we evaluated 43 consecutive patients for whom urological evaluation failed to disclose the cause of their recurrent flank pain and hematuria. Each underwent percutaneous kidney biopsy. In 9 patients, the biopsy specimen showed immunoglobulin A nephritis, an established cause of LPHS. We suggest these cases be designated secondary LPHS. They are not included in this analysis. The remaining patients (N = 34) are designated idiopathic (primary) LPHS. They are the basis of this report. METHODS: Demographics of patients with primary LPHS are mean age of 30.8 +/- 10.3 years; 74% women; 94% white; and history of kidney stones, 47%, although none was obstructing. RESULTS: Primary LPHS kidney biopsy specimens showed red blood cells (RBCs) in multiple tubules, consistent with glomerular hematuria. Glomeruli were normal by means of light and immunofluorescent microscopy; however, more than 50% of biopsy specimens showed unusually thin or thick glomerular basement membranes. To assess whether the biopsy itself caused RBCs in tubules, we compared RBCs in renal tubular cross-sections from primary LPHS biopsies with those of normal kidneys (donors, n = 10). The mean percentage of tubular cross-sections containing RBCs was greater in primary LPHS than normal specimens (7.2% +/- 6.5% versus 1.6% +/- 1.0% [SD]; P < 0.0001), confirming glomerular hematuria in patients with primary LPHS. CONCLUSION: Primary LPHS pathogenesis includes glomerular hematuria, apparently from structurally abnormal glomerular basement membrane. Primary LPHS pain may be initiated by obstructing RBC casts and perhaps microcrystals in those with a history of urolithiasis. Nevertheless, other factors are needed to explain the severe pain in patients with primary LPHS.