BACKGROUND: Recovery of renal function following acute tubular necrosis (ATN) is dependent on the replacement of necrotic tubular cells with functional tubular epithelium. The source of these new tubular cells is thought to be resident renal tubular cells. The discovery of pluripotent bone marrow-derived stem cells has led to a reexamination of the cellular source and processes involved in the recovery from organ injury. METHODS: To test the hypothesis in humans that extrarenal cells participate in the recovery following ATN, we examined the origin of tubular cells in male patients with resolving ATN who had received a kidney transplant from a female donor. Immunohistochmistry of kidney biopsies was performed to identify renal tubular epithelial cells (cytokeratin positive) and leukocytes (CD45 positive). Fluorescent in-situ hybridization was used to detect Y chromosome containing cells with DAPI serving as a nuclear stain. All staining was performed on the same section. RESULTS: The Y chromosome was detected in approximately 40% of tubular cell nuclei in male kidneys (positive control) and in no nuclei of female kidneys (negative control). In male recipients of female kidneys who developed ATN, 1% of tubules contained Y chromosome cells defined by their morphology, positive staining for cytokeratin, and negative staining for CD45. When present, multiple cells in a positive tubule stained for the Y chromosome. No Y chromosome containing tubular cells were seen in similar sex mismatched transplants in male recipients who did not develop ATN, suggesting that recipient derived cells do not routinely repopulate the transplanted kidney. CONCLUSIONS: This proof-of-principle clinical observation demonstrates that extrarenal cells can participate in the regenerative response following ATN. These findings provide rationale for the cellular therapy of acute renal failure.