Interleukin 6 (IL-6) is produced by human mesangial and tubular cells, and its urinary levels has been proposed as a marker of mesangial proliferation and tubulointerstitial damage. Epidermal growth factor (EGF) is expressed within the Henle's loop and the distal tubule and has been shown to accelerate recovery from renal injury. In the present study we have defined renal gene and protein expression of IL-6 and EGF in 10 normal, 10 nonproliferative glomerulonephritis (NPGN) and 30 IgA nephropathy (IgAN) human kidneys by RT-PCR, in situ hybridization and immunohistochemical techniques. Moreover, urinary IL-6 and EGF levels were measured in 41 patients with IgAN and in 20 normal subjects (N). In normal kidneys, EGF was localized in Henle's loop and distal convoluted tubule whereas IL-6 was mainly located in the proximal tubule and, less, within the glomerulus. In IgAN patients, EGF was decreased whereas IL-6 expression was upregulated. These modifications paralleled the degree of tubulointerstitial damage. Moreover, IgAN patients as a whole exhibited a reduction of EGF and an increase of IL-6 urinary concentration (EGF values: N, 12.96 +/- 1.15; IgAN Grades 1-2, 20.05 +/- 2.64; Grades 3-4 7.60 +/- 1.70: Grade 5, 3.14 +/- 0.71, ng/mg urinary creatinine. IL-6 values: N, 2.04 +/- 0.51; IgAN Grades 1-2, 3.26 +/- 0.38; Grades 3-4, 5.67 +/- 0.92; Grade 5, 27.20 +/- 9.70 pg/mg urinary creatinine), that correlated with the degree of histological lesions, the presence of hypertension and serum creatinine level. Interestingly, patients with the highest urinary IL-6/EGF ratio showed a worse evolution in a three year follow-up. In conclusion, our data show that: (1) renal IL-6 and EGF expression are strictly correlated to the degree of tubulointerstitial damage; and (2) urinary IL-6/EGF ratio might be a valuable prognostic marker for the progression of the renal damage in IgAN.