Diabetic nephropathy, the most common cause of progressive chronic renal failure and end-stage renal disease, has now reached global proportions. The only means to rescue diabetic patients on dialysis is renal transplantation, a very effective therapy, but severely limited by availability of donor kidneys. Hence, we tested the role of intravenous renal cell transplantation (IRCT) on obese/diabetic ZS female rats with severe ischemic and diabetic nephropathy. Renal ischemia was produced by bilateral renal clamping of the renal arteries at 10 weeks of age, and IRCT with genetically modified normal ZS male tubular cells was given intravenously at 15 and 20 weeks of age. The rats were terminated at 34 weeks of age. IRCT with cells expressing serum amyloid A (SAA) had strong and long-lasting beneficial effects on renal function and structure, including tubules and glomeruli. However, donor cells were found engrafted only in renal tubules 14 weeks after the second infusion. The results indicate that IRCT with SAA+ cells is effective in preventing CKD progression in rats with diabetic and ischemic nephropathy.